Pamela Russell

Protein expression alterations in a unique gleason prostate cancer progression cohort

Publisher: Wiley

Date: 18-07-2013

DOI: 10.1111/BJU.12293

Growth and metastasis of human bladder cancer xenografts in the bladder of nude rats

Publisher: Springer Science and Business Media LLC

Date: 07-1991

DOI: 10.1007/BF00305296

An inverse relationship between KAI1 expression, invasive ability, and MMP-2 expression and activity in bladder cancer cell lines

Publisher: Elsevier BV

Date: 07-2012

DOI: 10.1016/J.UROLONC.2010.02.013

Abstract: To investigate the relationship between the expression of the cancer metastasis suppressor gene KAI1 and MMP-2 and MMP-9 in human bladder cancer cell lines that express variable levels of KAI1. Five bladder cancer cell lines (BL-28/0, BL-13/0, BL-17/0/×1, B10, and D2) were grown in standard culture conditions. Gelatinase activities in serum-free conditioned medium were assessed using gelatin zymography. Whole cell lysates were prepared and Western blotting used to detect the protein expression of MMP-9, MMP-2, TIMP-1, TIMP-2, and KAI1. Semiquantitative RT-PCR was performed to analyze the mRNA expression level of MMP-2, MMP-9, TIMP-1, TIMP-2, and KAI1. Western blotting analysis confirmed that KAI1 was expressed in BL-28/0 and Bl-13/0 but not in D2, B10 and BL-17/0/×1 cell lines. This was consistent with in vitro invasion assays reported previously which showed that cell lines lacking KAI1 expression were 2× to 10× more invasive than cell lines that expressed KAI1. MMP-2 protein was detected in BL-28/0, BL-13/0. and BL-17/0/×1 only. Very low levels of MMP-9 were present in BL-28/0, BL-13/0, B10, and BL-17/0/×1 but not D2, whilst very low levels of TIMP-1 were present in all cell lines. No TIMP-2 was detected. Gelatin zymography showed detectable MMP-2 expression in conditioned medium from BL-28/0 and BL-13/0. Very weak MMP-9 was detected in BL-28/0 conditioned medium only. mRNA expression of MMP-2 was only detectable in BL-28/0 and BL-13/0 cell lines. MMP-9 mRNA levels were extremely low in all lines and not detectable in D2 cells. TIMP-1 and TIMP-2 mRNA were detected in all lines. We found that KAI1 expression in bladder cancer cell lines is related to a poor invasive potential and expression of latent MMP-2 but not MMP-9. These results are unexpected given other studies showing high levels of MMP-2 and MMP-9 protein expression in patients with invasive bladder cancer. This may reflect differences in the regulation and secretion of MMP-2 and MMP-9 in vitro compared with the in vivo situation, where tumor cells interact with the surrounding environment.

Karyotypic analysis of a heterogeneous human transitional cell carcinoma of the bladder

Publisher: Elsevier BV

Date: 02-1994

DOI: 10.1016/0165-4608(94)90126-0

Abstract: The UCRU-BL-17 (BL-17) series of xenografts, tissue culture sublines, and cloned cell lines (Fig. 1) shows a range of heterogeneous growth characteristics both in vitro and in vivo (Table 1) and represents a model of human bladder cancer heterogeneity. Cytogenetic analysis was undertaken to determine if specific chromosome changes correlated with particular aspects of the heterogeneous phenotypes. The BL-17 sublines and cloned cell lines shared many common chromosome abnormalities. Indeed, the cloned cell lines showed nearly identical karyotypes despite their marked differences in growth characteristics. Karyotypic evolution with passage through the nude mice was apparent, however. This evolution occurred at the specific chromosome regions of 1p12, 3cen-3p21, and 6cen-6q21. Whether the heterogeneity of karyotype between the BL-17 cell lines resulted from the existence of multiple clones in the original patient tumor or from karyotypic instability through passage in nude mice is uncertain, but in either case the specificity of karyotypic evolution observed suggests that 1p12, 3cen-3p21, and 6cen-6q21 are hotspots for rearrangement in the BL-17 tumor. No specific correlations between chromosome abnormalities and biologic characteristics could be made, but several unique karyotypic features arose in the progression to two of the sublines, BL-17/23 alpha and BL-17/0/X2A, coinciding with a loss of anchorage-independent growth by BL-17/23 alpha and a change in growth in vivo from a solid tumor to a fluid-filled tumor by BL-17/0/X2A.

Second primary tumours of the head and neck are not associated with adverse overall survival in oral sccs

Publisher: OMICS Publishing Group

Date: 2011

DOI: 10.4172/1948-5956.1000053

Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Publisher: Springer Science and Business Media LLC

Date: 24-08-2011

DOI: 10.1186/1471-2407-11-368

Abstract: Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered in idual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or in idual treatments with potential for 10-50 fold dose reduction compared to that required for in idual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life.

Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression.

Publisher: Springer Science and Business Media LLC

Date: 06-2003

DOI: 10.1038/SJ.PCAN.4500634

Tissue engineered humanized bone supports human hematopoiesis in vivo

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1016/J.BIOMATERIALS.2015.04.057

Abstract: Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to-mouse transplantation assay was used to prove the functionality of the tissue-engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches.

Erratum

Publisher: Informa UK Limited

Date: 1997

DOI: 10.1080/095530097142933

Active and pro-plasminogen activator on the surface of human bladder cancer cells derived from a high grade invasive tumour

Publisher: Elsevier BV

Date: 10-1990

DOI: 10.1016/0006-291X(90)90756-D

Abstract: Intact UCRU-BL28 cells derived from a high grade invasive human bladder cancer produced both active and pro-plasminogen activator. Following culture of cells in the presence of plasminogen, all of the pro-plasminogen activator was converted to an active form. Cell-surface extracts showed plasminogen activator activity with a molecular mass of 55,000, similar to that of human urokinase. Extracts also contained gelatinase activities with molecular masses of 101,000 80,000 74,000 and 70,000 in polyacrylamide gel electrophoresis. These tumour cell-surface proteinases may be involved in invasion and metastasis in human bladder cancer.

Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 15-12-2008

DOI: 10.1158/1078-0432.CCR-08-0566

Abstract: Purpose: Cytosolic phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer cell lines and tissue and the effect of targeting cPLA2-α in vitro and in vivo. Experimental Design: The expression of cPLA2-α was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-α activity were determined after inhibition with cPLA2-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA2-α is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-α is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA2-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.

Gene‐directed enzyme prodrug therapy for prostate cancer in a mouse model that imitates the development of human disease

Publisher: Wiley

Date: 2004

DOI: 10.1002/JGM.474

Abstract: Gene-directed enzyme prodrug therapy (GDEPT) based on the E. coli enzyme purine nucleoside phosphorylase (PNP) represents a new approach for treating slow growing tumours like prostate cancer (PCa). Expressed enzyme converts a systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine. Infected and neighbouring cells are killed by a bystander effect that results from the inhibition of DNA and RNA synthesis. These studies were carried out using the transgenic adenocarcinoma of the prostate (TRAMP) model that mimics human PCa development and progression. Control TRAMP mice were injected intraprostatically with vector vehicle and thereafter intraperitoneally with saline or fludarabine phosphate ( approximately 600 mg/m(2)/day) once daily for 5 consecutive days. Treated mice received a single intraprostatic injection containing 10(10) particles of OAdV220, an ovine atadenovirus which expresses the E. coli PNP gene under the control of the Rous sarcoma virus promoter, followed by systemic fludarabine treatment. The weight of the genitourinary tract, seminal vesicles and the prostate as well as animal survival were monitored. Tumours were also analysed histologically. Preliminary studies showed that fludarabine alone caused no significant change in genitourinary (GU) tract weight in TRAMP mice. Animals injected with vector and prodrug showed a significant reduction (36-47%) in GU tract weight (ANOVA p = 0.0002) and a 35-50% reduction in seminal vesicle weight (ANOVA p = 0.0007). In particular, the target organ showed a significant 57% reduction in prostate weight (ANOVA p = 0.0007). PNP-GDEPT mice also showed a survival advantage over control mice. Histological analysis suggested that the cancer progression was slowed in GDEPT-treated animals. A single course of GDEPT based on OAdV-delivered PNP and fludarabine produced highly significant suppression of PCa progression in immune-competent TRAMP mice.

Regulation of epidermal growth factor receptor in human colon cancer cell lines by interferon α

Publisher: BMJ

Date: 2004

DOI: 10.1136/GUT.53.1.123

Abstract: The biology of growth factor receptor expression has implications for receptor specific cancer therapy. In this study, we examined: (a) regulation of epidermal growth factor receptor (EGFR) expression in a panel of 10 human colon cancer cell lines using interferon alpha (IFN-alpha) (b) ability of IFN-alpha to inhibit cell proliferation and (c) sensitivity of IFN-alpha pretreated cells to EGF. Cell proliferation was measured both by crystal violet colorimetric and clonogenic assays. Cell surface, intracellular, and/or total cell protein expression of EGFR was assessed by indirect immunofluorescence flow cytometry and/or fluorescein isothiocyanate (FITC)-EGF binding and internalisation flow cytometric assay. IFN-alpha treatment upregulated expression of cell surface EGFR in seven of 10 colon cancer cell lines within 16 hours, reaching a peak within 48-96 hours this was accompanied by transient elevation of intracellular EGFR and marked growth inhibition. IFN-alpha treated cancer cells were still sensitive to EGF proliferative stimulation. Our results indicate that cytostatic concentrations of IFN-alpha can enhance cell surface and intracellular EGFR expression in a proportion of human colon cancer cells. The antiproliferative action of IFN-alpha could not block the signal transduction of the EGF-EGFR pathway. This may have clinical implications for improving treatment based on targeting of EGFR.

THE SEPARATION OF DIFFERENT CELL CLASSES FROM LYMPHOID ORGANS

Publisher: Rockefeller University Press

Date: 03-1971

DOI: 10.1083/JCB.48.3.566

Abstract: Four separate effects can be demonstrated when lymphoid cell suspensions are passed through columns of siliconed glass beads. (a) A temperature-dependent "active adherence" of phagocytic cells, such as macrophages and polymorphs. (b) A temperature-independent and selective trapping by "physical adherence" of particular classes of lymphoid cells, including certain antibody-forming cells. (c) A "size-filtration" effect that traps larger cells, but only becomes significant with beads below 100 µ in diameter. (d) A selective retention of damaged cells, which occurs with all columns under all conditions tested. An active adherence column technique has been developed to separate phagocytes from lymphocytes while minimizing selection within the lymphocyte population by physical adherence or size filtration. In less than 10 min at 37°C it reproducibly produces a preparation of mouse spleen lymphocytes & -fold depleted of active macrophages, and approximately 50-fold depleted of active polymorphs, with good over-all cell recoveries and cell viability. The lymphocyte fraction appears fully active in its ability to initiate immune responses to at least two different antigens, but is changed in over-all composition and selectively depleted in certain classes of antibody-forming cells.

Expression of insulin-like growth factor mitogenic signals in adult soft-tissue sarcomas: Significant correlation with malignant potential

Publisher: Springer Science and Business Media LLC

Date: 02-2004

DOI: 10.1007/S00428-003-0931-Y

Abstract: The insulin-like growth factor (IGF) signal transduction system involves receptors, ligands and binding proteins (IGFBPs) that have been shown to have mitogenic and distinct anti-apoptotic effects on malignant cell lines of both epithelial and mesenchymal origin. Expression of the IGF signal system might be a mechanism by which human soft-tissue sarcomas (STS) obtain a proliferative advantage over normal adjacent tissues. IGFBP2, one of at least six different binding proteins identified to date, is secreted by most sarcoma cell lines and appears to be involved in cell proliferation and transformation. Circulating levels of this protein are markedly increased in malignancy. We have assessed 46 adult STS specimens of low, intermediate and high pathological grade of malignancy for the immunohistochemical expression of IGFBP2, IGF1, IGF2, IGF1 receptor-alpha and -beta (IGF1Ralpha/beta). The protein expression was measured by quantitative color video image analysis and semi-quantitative evaluation, and the measurements correlated well (Spearman, P<0.001). Using both methods, significant differences in expression of IGFBP2 among each of the three grades, expression of IGF2 between intermediate and high grade, and expression of IGF1Rbeta between low-intermediate and low-high grade were observed (Dunnett test, P<0.05). Multiple regression analysis for both quantitative and semi-quantitative data confirmed the significance of the relationship and independence of the proteins, except IGF2. We concluded that IGFBP2 and IGF1Rbeta are independent predictors of the malignant potential of adult STS.

Paclitaxel suppresses the growth of primary prostate tumours (RM-1) and metastases in the lung in C57BL/6 mice

Publisher: Elsevier BV

Date: 02-2006

DOI: 10.1016/J.CANLET.2005.03.051

Abstract: Paclitaxel has potent anti-cancer effects through its ability to block metaphase/anaphase transition during cell mitosis. This study shows that paclitaxel can significantly suppress both primary orthotopic murine (RM-1) prostate tumour growth (up to 60%) and the formation of pseudometastatic tumour colony formation in the lungs (by up to 46%) in C57BL/6 mice in vivo. Tumour growth suppression was associated with increased RM-1 cell apoptosis in the primary prostate tumours. In vitro studies found that the duration of exposure time to Paclitaxel was correlated with its ability to suppress cell proliferation and induce G2/M arrest.

Derivation of MPR and TRAMP models of prostate cancer and prostate cancer metastasis for evaluation of therapeutic strategies

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S1078-1439(01)00180-6

Abstract: Pre-clinical models of primary and metastatic prostate cancer are increasingly needed to evaluate efficacy of the new therapeutic strategies currently under investigation. The androgen-independent RM1 and androgen-dependent TR cell lines derived from transgenic mouse models of prostate cancer were examined in this regard. Following implantation in immune competent mice, the RM1 cell line was able to generate extremely fast growing s.c. and iprost tumors and metastatic lung lesions providing a time period of approximately 14-17 days from the time of tumor establishment to animal sacrifice to assess therapies. Implantation of TR cell lines resulted in more slowly growing s.c. and iprost tumors and metastatic lung lesions that exhibited highly variable incidence and growth. These models represent the best available means to evaluate therapeutics in primary and metastatic prostate cancer variants in an intact immune system.

Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression

Publisher: Springer Science and Business Media LLC

Date: 24-08-2010

DOI: 10.1038/SJ.BJC.6605839

Active protease mapping in 2DE gels.

Publisher: Humana Press

Date: 2009

DOI: 10.1007/978-1-59745-281-6_28

Abstract: Proteases act as the molecular mediators of many vital biological processes. To understand the function of each protease, it needs to be separated from other proteins and characterized in its natural, biologically active form. In the method described in this chapter, proteases in a biological s le are separated under nonreducing conditions in 2DE gels. A specific small protease substrate, tagged with a fluorescent dye, is copolymerized into the SDS gel in the second dimension. After electrophoresis, the proteins are renatured by washing the gel with Triton X-100 solution or Milli Q water to remove SDS. The gel is then incubated in a protease assay buffer. The hydrolysis of the tagged specific substrate by the renatured protease releases the free fluorescent dye, which fluoresces in situ. The fluorescent spots indicate the location of the specific proteases in the gel and the specificity of the proteases.

Multifunctional core-shell magnetic cisplatin nanocarriers

Publisher: Royal Society of Chemistry (RSC)

Date: 2009

DOI: 10.1039/B911703B

Abstract: Towards an integrated multifunctional nanocarrier, core-shell nanostructures have been developed using the electrostatic self-assembly of an organic shell onto magnetic nanoparticles.

Paclitaxel enhanced radiation sensitization for the suppression of human prostate cancer tumor growth via a p53 independent pathway

Publisher: Wiley

Date: 06-09-2007

DOI: 10.1002/PROS.20638

Abstract: This study investigated the influence of p53 status on treatment using combined paclitaxel and irradiation for human prostate cancer (PC) in vitro and in vivo. Enhancement of the radiation response by paclitaxel was determined by MTT and clonogenic assays in four sublines of the human PC cell line, LNCaP, stably transfected to express different p53 mutations found in PC patients. Suppression of xenograft growth by combined paclitaxel and radiation was assessed in NOD.SCID mice in vivo. Expression of p53 and downstream functional proteins, p21 and Bax, was assessed by Western blotting. Paclitaxel (8-10 nM) suppressed cell proliferation by 50% by inducing G2M mitotic arrest in LNCaP cell lines transfected to overexpress wild-type or mutant p53. Exposure to 20 nM paclitaxel before radiation therapy enhanced cytotoxicity in clonogenic assays. The dose and duration of paclitaxel exposure were important in inducing both G2M arrest and cell growth suppression and were critical factors in paclitaxel/irradiation combination therapy. Western blotting indicated that combination therapy increased p21 protein expression to varying degrees in all cell lines. In vivo studies indicated that paclitaxel pre-treatment followed by irradiation significantly suppressed tumor growth compared with either treatment alone. Pre-treatment with paclitaxel enhances radiation efficacy on cell killing and suppression of growth of human PC cell lines in vitro and in vivo via p53 independent pathways. Paclitaxel has potential for use as a radiosensitizer in the treatment of patients with PC with either wild-type or mutant p53 genetic status.

Paradoxical roles of tumour necrosis factor-alpha in prostate cancer biology.

Publisher: Hindawi Limited

Date: 2012

DOI: 10.1155/2012/128965

Abstract: Tumour necrosis factor (TNF) is a pleiotropic cytokine with dual roles in cancer biology including prostate cancer (PCa). On the one hand, there is evidence that it stimulates tumour angiogenesis, is involved in the initiation of PCa from an androgen-dependent to a castrate resistant state, plays a role in epithelial to mesenchymal plasticity, and may contribute to the aberrant regulation of eicosanoid pathways. On the other hand, TNF has also been reported to inhibit neovascularisation, induce apoptosis of PCa cells, and stimulate antitumour immunity. Much of the confusion surrounding its seemingly paradoxical roles in cancer biology stems from the dependence of its effects on the biological model within which TNF is investigated. This paper will address some of these issues and also discuss the therapeutic implications.

Androgen decreases osteoprotegerin expression in prostate cancer cells.

Publisher: Springer Science and Business Media LLC

Date: 26-12-2007

DOI: 10.1038/SJ.PCAN.4500927

Abstract: Osteoprotegerin (OPG), a key regulator of bone resorption, is hypothesized to have a role in prostate cancer (CaP) bone metastasis. As advanced CaP is treated by androgen ablation, we examined if androgen modulates OPG expression by CaP cell lines in vitro. Basal levels of secreted OPG protein were significantly greater in androgen-independent PC-3 cells compared with androgen-responsive LNCaP-FGC cells (P<0.001) OPG was not detected in the androgen-responsive CaP cell lines LAPC-4 or DuCaP. Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) significantly decreased OPG protein levels in both PC-3 and LNCaP-FGC, with maximal suppression using 10(-9)-10(-7) M 5alpha-DHT in PC-3 (P<0.01 day 3), and using 10(-10)-10(-9) M 5alpha-DHT in LNCaP-FGC cells (P<0.01 day 6). OPG messenger RNA levels were not significantly altered by this 5alpha-DHT treatment. Co-treatment with 10(-6) M flutamide blocked 5alpha-DHT inhibition of OPG protein expression in LNCaP-FGC cells. These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism.

Detection of a rare point mutation in Ki-ras of a human bladder cancer xenograft by polymerase chain reaction and direct sequencing

Publisher: Springer Science and Business Media LLC

Date: 02-1992

DOI: 10.1007/BF00296523

Tryptic digestion of in-gel proteins for mass spectrometry analysis.

Publisher: Humana Press

Date: 2009

DOI: 10.1007/978-1-59745-281-6_34

Abstract: Identification and characterization of proteins are ultimately the goal in proteomic analysis. In order to identify a protein trypsin is commonly used to digest protein into peptides which can be analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). This chapter describes a tryptic digestion method for digestion of proteins in one-dimensional (1DE) or two-dimensional (2DE) polyacrylamide gels. The method involves cutting target protein bands or spots, removal of protein stain, reduction and alkylation of native protein, digestion and finally extraction of peptides for mass spectrometry analysis. The method is simple and reasonably sensitive that many in-gel proteins that are barely visible with Coomassie blue stain have been successfully identified.

Flow cytometric and karyotypic analysis of a primary small cell carcinoma of the prostate: A xenografted cell line

Publisher: Elsevier BV

Date: 05-1987

DOI: 10.1016/0165-4608(87)90143-9

Abstract: A human small cell undifferentiated carcinoma of the prostate, xenografted in nude mice, was analyzed both cytogenetically and by DNA flow cytometry. The DNA content of the line indicated its stability on serial passage, and was consistent with the cytogenetic findings. The banded karyotype was hypodiploid with nonrandom losses of chromosomes #6, #7, #10, and #13. Structural rearrangements involved chromosomes #1 and #2, and there were three unidentified markers. The findings were compared with those described in other types of prostatic carcinoma.

Trypsin activity assay in substrate-specific one- and two-dimensional gels: a powerful method to separate and characterize novel proteases in active form in biological samples.

Publisher: Wiley

Date: 09-2003

DOI: 10.1002/ELPS.200305531

Abstract: To separate and identify the proteases, a substrate-specific, sensitive assay in sodium dodecyl sulfate (SDS)-polyacrylamide gels after two-dimensional (2-D) electrophoresis has been developed. This method allows simultaneous determination of protease cleavage specificity, molecular weight, isoelectric point, and if necessary, amino acid sequencing. After isoelectric focusing in immobilized pH gradient (IPG) strips (pH 6-11) (first dimension), trypsin was electrophoresed in 12% SDS polyacrylamide gels (second dimension) copolymerized with Boc-Gln-Ala-Arg-MCA (4-methyl-coumaryl-7-amide). The gels were washed in cold 2.5% Triton X-100 and water, and incubated in assay buffer (6.3 mM Bicine, 100 mM NaCl). Trypsin cleavage of the peptide-MCA generated fluorescent 7-amino-4-methyl-coumarin. In 1-D gels, as low as 500 pg trypsin could be detected and trypsin band volumes correlated linearly with the amounts of trypsin (R(2) = 0.999). In 2-D gels, the lowest amount of trypsin detected was 1 ng. The linear regression of spot volume and loading amount was still good (R(2) = 0.974). To optimize renaturation conditions, 5x5 min washes with 2.5% Triton X-100 and water, respectively, gave the strongest band volume. For fluorescence development, an assay buffer at pH 9 was the best incubation at 37 degrees C for 30 min was sufficient. The method has application for identifying novel proteases as it does not rely on antibodies.

Clinical pharmacology of isoflavones and its relevance for potential prevention of prostate cancer

Publisher: Oxford University Press (OUP)

Date: 26-08-2010

DOI: 10.1111/J.1753-4887.2010.00314.X

Abstract: Isoflavones are phytoestrogens that have pleiotropic effects in a wide variety of cancer cell lines. Many of these biological effects involve key components of signal transduction pathways within cancer cells, including prostate cancer cells. Epidemiological studies have raised the hypothesis that isoflavones may play an important role in the prevention and modulation of prostate cancer growth. Since randomized phase III trials of isoflavones in prostate cancer prevention are currently lacking, the best evidence for this concept is presently provided by case control studies. However, in vitro data are much more convincing in regard to the activity of a number of isoflavones, and have led to the development of genistein and phenoxodiol in the clinic as potential treatments for cancer. In addition, the potential activity of isoflavones in combination with cytotoxics or radiotherapy warrants further investigation. This review focuses on the clinical pharmacology of isoflavones and its relevance to their development for use in the prevention of prostate cancer, and it evaluates some of the conflicting data in the literature.

The role of extracellular matrix metalloproteinase inducer protein in prostate cancer progression

Publisher: Springer Science and Business Media LLC

Date: 14-02-2008

DOI: 10.1007/S00262-008-0473-X

Abstract: Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is a multifunctional membrane glycoprotein overexpressed in many solid tumors, and involved in tumor invasion and angiogenesis. We investigated EMMPRIN expression in human prostate cancer (CaP) tissues and cells, and evaluated whether EMMPRIN expression is related to tumor progression and matrix metalloproteinase (MMPs) expression in human CaP. An immunohistochemical study using tissue microarrays of 120 primary CaPs of different grades and 20 matched lymph node metastases from untreated patients was performed. The association of EMMPRIN expression with clinicopathological parameters was evaluated. Co-immunolocalization for EMMPRIN and MMP-1, MMP-2 or MMP-9 in primary tumors was examined using confocal microscopy. Flow cytometry and immunoblotting were used to examine EMMPRIN expression in 11 metastatic CaP cell lines. Heterogeneous expression of EMMPRIN was found in 78/120 (65%) CaPs, correlated significantly with progression parameters including pre-treatment PSA level (P < 0.05) and increased with progression of CaP (Gleason score, P < 0.05 pathological stage, P < 0.01 nodal involvement, P < 0.05 and surgical margin, P 3 + 4. Metastatic CaP cell lines, except DuCaP, expressed abundant EMMPRIN protein, indicating highly ( approximately 45 to approximately 65 kDa) and less ( approximately 30 kDa) glycosylated forms, although with no relationship to cells being either androgen responsive or nonresponsive. Our results suggest that EMMPRIN may regulate MMPs and be involved in CaP progression, and as such, could provide a target for treating metastatic CaP disease.

Protein expression of epidermal growth factor receptor in laryngeal squamous cell carcinoma index tumors correlates with diagnosis of second primary tumors of the upper aero-digestive tract

Publisher: Springer Science and Business Media LLC

Date: 11-08-2009

DOI: 10.1245/S10434-009-0649-4

Abstract: Field cancerization is a feature of HNSCCs. No biological marker in the index tumor has correlated with second primary tumor (SPTs) development. Changes in MDM-2 and epidermal growth factor receptor (EGFR) expression are known to be early neoplastic changes in HNSCC. EGFR expression is correlated with clinical outcomes. This study has assessed the predictive correlation of MDM-2 and EGFR protein expression with clinicopathological parameters and occurrence of SPTs in HNSCC. Using immunohistochemistry, 106 patients who were treated for primary laryngeal squamous cell carcinoma were investigated for expression of MDM-2 and EGFR. Positive expression of MDM-2 and EGFR was found in 51 of 106 (48.1%) and 82 of 106 (77.4%) cases, respectively. EGFR expression was found to correlate with diagnosis of new primary tumors (P = 0.003), disease-free survival (P = 0.008), as well as overall survival (P = 0.003). MDM-2 expression correlated with nodal relapse (P = 0.03). SPTs relate to poor prognosis in HNSCC, indicating that closer clinical surveillance of this patient group would be beneficial. Examination of the expression of EGFR by the primary tumor could have potential clinical benefits because this study suggests that it may become a vital biomarker for patients who are most at risk of developing SPTs.

Correction: 3D cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared to cells cultured in monolayer

Publisher: Public Library of Science (PLoS)

Date: 22-04-2015

DOI: 10.1371/JOURNAL.PONE.0125641

Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets

Publisher: Wiley

Date: 2000

DOI: 10.1002/1097-0215(20000920)89:5<431::AID-IJC6>3.0.CO;2-V

Abstract: Urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) have been observed in many cancers and may contribute to progression and metastasis. In our study, we examined the expression of the 5 proteins by immunohistochemistry in 59 consecutive primary colorectal cancers (CRC) and correlated the protein expression with patient outcome. In addition, we determined the effect of down-regulation of uPAR on the invasive/metastatic capability of CRC cells, by measuring antisense-uPAR transfected HCT116 and control cell lines, in terms of uPAR expression, uPA-binding activity, invasiveness through Matrigel in vitro and metastasis after cecal orthotopic implantation in nude mice in vivo. We found that higher expression of uPA or uPAR in primary tumor tissues was positively correlated with distant metastasis of CRC (Mann-Whitney, p < 0.02) and negatively correlated with both patient overall survival (OS) and cancer-specific survival (CSS Cox model, p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was independent of other variables (multivariate Cox model, p < 0. 007). Antisense-uPAR transfected HCT116 cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA-binding activity compared with either wild-type or cells transfected with vector alone (Bonferroni, p < 0.05/3), consistently showed decreased invasiveness through Matrigel (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05). Our data suggest that uPAR and uPA are independent prognostic factors in CRC anti-uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease.

Control of prostate cancer spheroid growth using ²¹³ Bi-labeled multiple targeted α radioimmunoconjugates

Publisher: Wiley

Date: 05-09-2006

DOI: 10.1002/PROS.20502

Abstract: Micrometastasis is a major problem for prostate cancer (CaP) patients. Our study investigated the therapeutic potential of multiple targeted alpha-therapy (MTAT) in the treatment of CaP micrometastases (spheroids) using (213)Bi-labeled multiple targeted alpha-radioimmunoconjugates. The expression of multiple tumor-associated antigens (TAAs) on frozen sections of human fresh CaP tissues and spheroids cultured from DU 145 and LNCaP-LN3 CaP cell lines was detected by immunohistochemistry and flow cytometry. Targeting vectors were two monoclonal antibodies (MAbs), and plasminogen activator inhibitor type 2 (PAI2) that binds to cell surface urokinase plasminogen activator (uPA). These vectors were labeled with (213)Bi using standard methodology. DU 145 and LNCaP-LN3 spheroids were incubated with different activities of test and control alpha-conjugates (ACs), and spheroid growth was measured for volume change and growth delay over a 50-day period using light microscopy. TAAs were expressed heterogeneously on frozen sections from human CaP tissues and CaP spheroids. MTAT combining three ACs (one-third dose of each) with an activity of 6.4 MBq/ml completely targeted small DU 145 and LNCaP-LN3 spheroids (diameter <100 microm) and slightly regressed the growth of medium spheroids (180-200 microm) MTAT with 2.2 or 4.8 MBq/ml activities delayed the growth of tumor spheroids. Our results suggest that the cytotoxicity of MTAT to CaP spheroids is highly dependent on antigenic expression, concentration of radioactivity and spheroid size. MTAT may be a potent therapeutic agent for micrometastases, effectively targeting small CaP cell clusters, and overcoming the heterogeneous expression of targeted antigens.

Physiotherapy exercises for low back pain: Process and clinical outcome

Publisher: Informa UK Limited

Date: 1986

DOI: 10.3109/03790798609166509

Abstract: This study was designed to assess whether physiotherapy exercises administered for low back pain have the physiological effects that they purport to have (increase spinal mobility and muscle strength) and whether these effects are of clinical relevance (related to changes in pain and function). Thirty-six patients were allocated to three treatment conditions, mobilizing exercises, isometric exercises or an attention-placebo control procedure. The results did not support the hypotheses concerning the effects of physiotherapy exercises, and hence challenge widely held views concerning the mechanism by which some patients suffering from low back pain improve whilst undergoing physiotherapy exercises.

Characterisation of the anti-bladder-cancer monoclonal antibody BLCA-8: Identification of its antigen as a neutral glycolipid

Publisher: Springer Science and Business Media LLC

Date: 11-1995

DOI: 10.1007/BF01526554

Abstract: Akin to their mammalian counterparts, teleost fish possess a complex assortment of highly specialized immune cells that are capable of unleashing potent innate immune responses to eradicate or mitigate incoming pathogens, and also differentiate into memory lymphocytes to provide long-term protection. Investigations into specific roles and functions of fish immune cells depend on the precise separation of each cell type. Commonly used techniques, for ex le, density gradient centrifugation, rely on immune cells to have differing sizes or densities and thus fail to separate between similar cell types (e.g. T and B lymphocytes). Furthermore, a continuously growing database of teleost genomic information has revealed an inventory of cellular markers, indicating the possible presence of immune cell subsets in teleost fish. This further complicates the interpretation of results if subsets of immune cells are not properly separated. Consequently, monoclonal antibodies (mAbs) against specific cellular markers are required to precisely identify and separate novel subsets of immune cells in fish. In the field of fish immunology, mAbs are largely generated using the hybridoma technology, resulting in the development of mAbs against specific cellular markers in different fish species. Nevertheless, this technology suffers from being labour-intensive, time-consuming and most importantly, the inevitable loss of ersities of antibodies during the fusion of antibody-expressing B lymphocytes and myeloma cells. In light of this, the focus of this review is to discuss the potential applications of fluorescence-activated cell sorting and droplet-based microfluidics, two emerging technologies capable of screening and identifying antigen-specific B lymphocytes in a high-throughput manner, in promoting the development of valuable reagents for fish immunology studies. Our main goal is to encourage the incorporation of alternative technologies into the field of fish immunology to promote the production of specific antibodies in a high-throughput and cost-effective way, which could better allow for the precise separation of fish immune cells and also facilitate the identification of novel immune cell subsets in teleost fish.

Humanised xenograft models of bone metastasis revisited: Novel insights into species-specific mechanisms of cancer cell osteotropism

Publisher: Springer Science and Business Media LLC

Date: 09-05-2013

DOI: 10.1007/S10555-013-9437-5

Abstract: The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis.

Monoclonal antibodies for intravesical radioimmunotherapy of human bladder cancer

Publisher: Springer Science and Business Media LLC

Date: 1993

DOI: 10.1007/BF03033865

Abstract: Infectious disease surveillance is often case-based, focused on people diagnosed and their contacts in a predefined time window, and treated as independent across infections. Network analysis of partners and contacts joining multiple investigations and infections can reveal social or temporal trends, providing opportunities for epidemic control within broader networks. We constructed a sociosexual network of all HIV and early syphilis cases and contacts investigated among residents of 11 contiguous counties in North Carolina over a two-year period (2012-2013). We anchored the analysis on new HIV diagnoses ("indexes"), but also included nodes and edges from syphilis investigations that were within the same network component as any new HIV index. After adding syphilis investigations and deduplicating people included in multiple investigations (entity resolution), the final network comprised 1470 people: 569 HIV indexes, 700 contacts to HIV indexes who were not also new cases themselves, and 201 people who were either indexes or contacts in eligible syphilis investigations. Among HIV indexes, nearly half (48% n = 273) had no located contacts during single-investigation contact tracing, though 25 (9%) of these were identified by other network members and thus not isolated in the final multiple investigation network. Constructing a sociosexual network from cases and contacts across multiple investigations mitigated some effects of unobserved partnerships underlying the HIV epidemic and demonstrated the HIV and syphilis overlap in these networks.

Detection of tumor-associated membrane proteins in prostate and bladder carcinomas by means of protein blotting

Publisher: Springer Science and Business Media LLC

Date: 09-1989

DOI: 10.1007/BF00262988

Abstract: Electronic medical records (EMRs) hold the promise of making routine comprehensive measurement of care quality a reality. However, there are many informatics challenges that stand in the way of this goal. Guidelines are rarely stated in precise enough language for automated measurement of clinical practices and the data necessary for that measurement often reside in the text notes of EMRs. We designed a technology platform for scalable and routine measurement of care quality using comprehensive EMR data, including providers' freetext notes documenting clinical encounters. We are in the process of implementing this system to assess the quality of ambulatory asthma care in two erse healthcare systems: a mid-size HMO and a consortium of Federally Qualified Healthcare Center (FQHC) clinics on the west coast of the United States.

A NEW METHOD OF MEASURING BLOOD-PRESSURE IN MICE

Publisher: Elsevier BV

Date: 11-1965

DOI: 10.1016/S0140-6736(65)92904-1

Abstract: Although Treg-cell-mediated suppression during infection or autoimmunity has been described, functions of Treg cells during highly pathogenic avian influenza virus infection remain poorly characterized. Here we found that in Foxp3-GFP transgenic mice, CD8(+) Foxp3(+) Treg cells, but not CD4(+) Foxp3(+) Treg cells, were remarkably induced during H5N1 infection. In addition to expressing CD25, the CD8(+) Foxp3(+) Treg cells showed a high level of GITR and produced IL-10. In an adoptive transfer model, CD8(+) Treg cells suppressed CD8(+) T-cell responses and promoted H5N1 virus infection, resulting in enhanced mortality and increased virus load in the lung. Furthermore, in vitro neutralization of IL-10 and studies with IL-10R-deficient mice in vitro and in vivo demonstrated an important role for IL-10 production in the capacity of CD8(+) Treg cells to inhibit CD8(+) T-cell responses. Our findings identify a previously unrecognized role of CD8(+) Treg cells in the negative regulation of CD8(+) T-cell responses and suggest that modulation of CD8(+) Treg cells may be a therapeutic strategy to control H5N1 viral infection.

Evidence for post-transcriptional down-regulation of the apoptosis-related genebcl-2 in human colorectal cancer

Publisher: Wiley

Date: 05-2000

DOI: 10.1002/(SICI)1096-9896(200005)191:1<15::AID-PATH566>3.0.CO;2-E

A Tissue-Specific Enhancer of the Prostate-Specific Membrane Antigen Gene, FOLH1

Publisher: Elsevier BV

Date: 05-2001

DOI: 10.1006/GENO.2000.6446

Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis

Publisher: Wiley

Date: 24-10-2003

DOI: 10.1002/MC.10154

Abstract: The underlying basis for rising levels of prostate-specific antigen (PSA) in prostate cancer is not fully understood, but attention has turned to the possibility that loss of normal p53 function might be directly involved. We have investigated the relationship between p53 function and PSA expression using in vitro and in vivo approaches. Three prostate cancer-derived p53 mutants (F134L, M237L, R273H) were introduced into LNCaP prostate cancer cells and stable transfectants established. Expression of mutant p53 was demonstrated by Western blot analysis, inactivation of wtp53 function, and a loss of p53-dependent responses to DNA damage induced by UV-irradiation and cisplatin. Levels of PSA mRNA and secreted protein were determined by RT-PCR and Western blotting, respectively. Serine protease activity was assessed using an esterase assay. In vivo effects of mutant p53 expression were examined after orthotopic implantation into prostates of nude mice. Expression of all p53 mutants was associated with elevated PSA mRNA and secreted PSA protein. In a representative line, mutant p53 was also associated with increased PSA protease-like activity compared with a control line expressing wildtype p53. Overall PSA levels, and PSA levels in serum from mice bearing tumors derived from cells expressing mutant p53, were increased compared with levels in mice bearing tumors derived from control cells. In addition, the tumors derived from cells with mutant p53 had increased vascularization and induced lymph node metastases. These data provide in vitro and in vivo support for the notion that p53 mutations directly contribute to increased levels of serum PSA, and are associated with more aggressive tumors.

Protein markers in colorectal cancer: Predictors of liver metastasis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-1999

DOI: 10.1097/00000658-199908000-00007

Abstract: To assess the significance of the expression of five protein markers (nm23, p53, c-erbB-2, u-PA, and VEGF) to the development of metastasis in colorectal cancer. The metastatic cascade is a complex multistep process involving several genetic alterations, angiogenesis activation, and tissue proteolysis. Although the prognosis of colorectal cancer depends on the stage of the tumor, the development of metastasis is difficult to predict. Paraffin-embedded specimens of 58 patients who underwent surgery for colorectal cancer were retrospectively analyzed by immunohistochemistry, and the coexpression of these protein markers was related to patient outcome. The risk of developing liver secondaries was correlated with the expression of nm23 protein (p < 0.0001) this was also the case in those patients with Dukes' stage B showing positive nm23 immunostaining (p = 0.006). The determination of the number of positive markers or the cumulative intensity score did not improve the predictive value over and above that of nm23 protein alone. Expression of nm23 protein is correlated with the risk of developing liver metastasis. Its evaluation alone may help to determine which patients who have undergone apparently curative resection of a colorectal cancer have an increased risk of liver recurrence, especially those with Dukes' stage B tumors who might be considered for adjuvant chemotherapy.

Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model

Publisher: Public Library of Science (PLoS)

Date: 16-05-2011

DOI: 10.1371/JOURNAL.PONE.0019389

Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency

Publisher: American Chemical Society (ACS)

Date: 03-09-2015

DOI: 10.1021/ACS.BIOMAC.5B00913

Abstract: Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Measurement of Serum Levels of Macrophage Inhibitory Cytokine 1 Combined with Prostate-Specific Antigen Improves Prostate Cancer Diagnosis

Publisher: American Association for Cancer Research (AACR)

Date: 2006

DOI: 10.1158/1078-0432.CCR-05-1331

Abstract: Purpose: Current serum testing for the detection of prostate cancer (PCa) lacks specificity. On diagnosis, the optimal therapeutic pathway is not clear and tools for adequate risk assessment of localized PCa progression are not available. This leads to a significant number of men having unnecessary diagnostic biopsies and surgery. A search for novel tumor markers identified macrophage inhibitory cytokine 1 (MIC-1) as a potentially useful marker. Follow-up studies revealed MIC-1 overexpression in local and metastatic PCa whereas peritumoral interstitial staining for MIC-1 identified lower-grade tumors destined for recurrence. Consequently, we sought to assess serum MIC-1 measurement as a diagnostic tool. Experimental Design: Using immunoassay determination of serum MIC-1 concentration in 1,000 men, 538 of whom had PCa, we defined the relationship of MIC-1 to disease variables. A diagnostic algorithm (MIC-PSA score) based on serum levels of MIC-1, total serum prostate-specific antigen, and percentage of free prostate-specific antigen was developed. Results: Serum MIC-1 was found to be an independent predictor of the presence of PCa and tumors with a Gleason sum ≥7. We validated the MIC-PSA score in a separate population and showed an improved specificity for diagnostic blood testing for PCa over percentage of free prostate-specific antigen, potentially reducing unnecessary biopsies by 27%. Conclusions: Serum MIC-1 is an independent marker of the presence of PCa and tumors with a Gleason sum of ≥7. The use of serum MIC-1 significantly increases diagnostic specificity and may be a future tool in the management of PCa.

Innovative biomarkers for prostate cancer early diagnosis and progression

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.CRITREVONC.2009.02.007

Abstract: The marker currently used for prostate cancer (CaP) detection is an increase in serum prostate-specific antigen (PSA). However, the PSA test which may give false positive or negative information, is not reliable and does not allow the differentiation of benign prostate hyperplasia (BPH), non-aggressive CaP and aggressive CaP. There is thus an urgent need to search for novel CaP biomarkers to improve the early detection and accuracy of diagnosis, determine the aggressiveness of CaP and to monitor the efficacy of treatment. Proteomic techniques allow for a high-throughput analysis of bio-fluids with the visualization and quantification of thousands of potential protein markers and represent very promising tools in the search for new, improved molecular markers of CaP. In this review, we will summarize conventional CaP biomarkers and focus on novel identified biomarkers for CaP early diagnosis and progression that might be used in the future.

Features of squamous and adenocarcinoma in the same cell in a xenografted human transitional cell carcinoma: Evidence of a common histogenesis?

Publisher: Springer Science and Business Media LLC

Date: 03-1988

DOI: 10.1007/BF00261960

Abstract: In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically erse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA. The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors.

Radiotherapy is not associated with an increased rate of Second Primary Tumours in Oral Squamous Carcinoma: A study of 370 patients

Publisher: Elsevier BV

Date: 11-2009

DOI: 10.1016/J.ORALONCOLOGY.2009.05.634

Abstract: Oral Squamous Cell Carcinoma (OSCC) remains a public health scourge. Radiotherapy (RT) is a major treatment modality and has been implicated in possible formation of Second Primary Tumours (SPT). In a single centre retrospective study of 370 patients with OSCCs (1967-2004) associations between RT, diagnosis of SPTs, median SPT diagnostic time lag, Disease Free Survival (DFS) and overall survival (OS) were analysed. Sixty-eight (18.4%) patients developed metachronous SPTs. Two hundred and twenty patients (59.3%) underwent some form of RT whilst 151 (40.7%) patients were not exposed to RT. No significant increased incidence of SPTs was demonstrated in the RT group. No significant difference in SPT diagnostic time lag was noted amongst the groups. This study suggests that RT is neither a risk for SPT induction nor increases the relative diagnostic time delay of upper aero-digestive tract SPTs.

Heterogeneity of in vitro radiosensitivity in human bladder cancer cells

Publisher: Wiley

Date: 1999

DOI: 10.1002/(SICI)1520-6823(1999)7:2<66::AID-ROI2>3.0.CO;2-T

An investigation of fludarabine as a potential radiation sensitizer of human prostate cancer cells in vitro

Publisher: Wiley

Date: 03-2008

DOI: 10.1111/J.1743-7563.2008.00149.X

Overexpression of nm23 protein assessed by color video image analysis in metastatic colorectal cancer: Correlation with reduced patient survival

Publisher: Springer Science and Business Media LLC

Date: 05-1998

DOI: 10.1007/S002689900421

Abstract: The function and prognostic significance of the nm23 gene is controversial in colorectal cancer (CRC). The aim of this study was to determine if nm23 protein expression correlated with the subsequent development of liver metastasis. Paraffin-embedded sections of 30 metastasizing CRC primaries and their subsequently resected liver secondaries were compared with those of 28 nonmetastasizing CRCs, 20 adenomas, and 20 cases of normal colonic mucosa. Expression of nm23 protein, assayed by immunohistochemistry, was measured using a standard semiquantitative scaling system and compared with a microcomputerbased color video image analysis (VIA). There was good correlation between color VIA and semiquantitative evaluation of nm23 immunoreactivity, confirming the validity of quantitative analysis (Pearson's r = 0.88 p < 0.001). Metastasizing CRC primaries and secondaries overexpressed nm23 protein when compared with the other clinical groups, particularly nonmetastasizing CRC (Student's t-test, p < 0.001). Furthermore, more nm23 immunoreactivity was associated with a higher risk of death from CRC (log-rank test, p = 0.002). These results suggest that overexpression of nm23 is highly associated with liver metastases from CRC and reduced survival.

VARIATION IN LUMBAR SPINE MOBILITY MEASURED OVER A 24-HOUR PERIOD

Publisher: Oxford University Press (OUP)

Date: 1992

DOI: 10.1093/RHEUMATOLOGY/31.5.329

Abstract: An electronic device for the measurement of three-dimensional movements, the Polhemus Navigation Sciences 3Space Isotrak system, was used to measure the range of movement in the lumbar spine of: (1) 10 young adults pre- and post-normal night-time sleep (2) 10 young adults tested every 2 h over a 24-h period. The results obtained for the 10 subjects tested pre- ost-sleep showed there to be significant decreases in flexion, extension and lateral bend post-sleep. Axial rotation was not seen to alter significantly. The results obtained for the 10 subjects tested over a 24-h period showed movement during the day to be significantly more than at night. A decrease in the range of all movements except extension was observed when testing subjects in the early hours of the morning (after they had been supine for a minimum of 4 h) relative to the range observed from mid-afternoon to early evening.

Radiotherapy in Larynx Squamous Cell Carcinoma is not Associated with an Increased Diagnosis of Second Primary Tumours

Publisher: Elsevier BV

Date: 05-2009

DOI: 10.1016/J.CLON.2009.01.008

Abstract: Larynx cancer is the most common form of head and neck squamous cell carcinoma (HNSCC). Radiotherapy is a major treatment modality and is implicated in the possible formation of second primary tumours (SPT). The aims of this retrospective study were to establish the incidence of SPTs and their correlation with previous radiotherapy and to establish overall survival and the SPT diagnostic time lag from the index tumour according to subtype as well as radiotherapy status. In a retrospective study of 987 patients with larynx SCCs (1967-2004) associations between radiotherapy, diagnosis of SPTs, median SPT diagnostic time lag, disease-free survival and overall survival were analysed. In total, 184 (18.6%) patients developed metachronous SPTs with an overall survival of 93.0 (standard error 6.8 months). One hundred and seventy (92.4%) underwent radiotherapy, whereas 14 (7.6%) patients were not exposed to radiotherapy. No significant increased incidence of SPT was shown in the radiotherapy group. A statistically non-significant increase in SPT diagnostic time lag trend was noted for both HNSCC SPTs (radiotherapy vs non-radiotherapy 76.0 [standard error 6.7] vs 50.0 [standard error 23.0]) and lung SPTs (45.0 [standard error 12.1] vs 24.0 [standard error 4.9]) months. This study suggests that radiotherapy is not a risk for SPT induction it may, however, neutralise a proportion of cancerised fields in the lung and head and neck areas without any significant benefit on overall survival.

Mutant p53 and cyclin A1 protein expression in primary laryngeal squamous cell carcinomas do not correlate to second primary tumours of the head and neck.

Publisher: Wiley

Date: 2009

DOI: 10.1111/J.1445-2197.2008.04799.X

Abstract: Background: Field cancerization is a feature of head and neck squamous cell carcinoma. No biological marker in the index tumour has been correlated to the development of second primary tumours (SPT). Cyclin A1 is a cell cycle regulator and a downstream target of p53. This study assessed predictive correlation of cyclin A1 and mut‐p53 with clinicopathological parameters and occurrence of (SPT) 7in the head and neck. Methods: Using immunohistochemistry 106 patients treated for primary laryngeal squamous cell carcinoma were investigated for expression of cyclin A1 and mut‐p53. Results: Expression of cyclin A1 and mut‐p53 were noted in 83 of 106 (78.3%) and 25 of 106 (23.6%) patients. There was a weak but significant correlation between mut‐p53 and cyclin A1 ( r = 0.301, P = 0.002) expression. During the follow‐up period (median 41.0 months (range 1–205 months)), 21 of 106 (19.8%) patients developed an SPT. There was no statistically significant correlation between the markers investigated and disease recurrence, SPT diagnosis or clinicopathological parameters. Conclusion: Second primary tumours are an intriguing problem in treatment of HNSCC and a predictive marker identifying those greatest at risk would be a leap forward.

Modeling prostate cancer: a perspective on transgenic mouse models

Publisher: Springer Science and Business Media LLC

Date: 10-02-2010

DOI: 10.1007/S10555-010-9212-9

Abstract: Despite considerable success in treatment of early stage localized prostate cancer (PC), acute inadequacy of late stage PC treatment and its inherent heterogeneity poses a formidable challenge. Clearly, an improved understanding of PC genesis and progression along with the development of new targeted therapies are warranted. Animal models, especially, transgenic immunocompetent mouse models, have proven to be the best ally in this respect. A series of models have been developed by modulation of expression of genes implicated in cancer-genesis and progression mainly, modulation of expression of oncogenes, steroid hormone receptors, growth factors and their receptors, cell cycle and apoptosis regulators, and tumor suppressor genes have been used. Such models have contributed significantly to our understanding of the molecular and pathological aspects of PC initiation and progression. In particular, the transgenic mouse models based on multiple genetic alterations can more accurately address the inherent complexity of PC, not only in revealing the mechanisms of tumorigenesis and progression but also for clinically relevant evaluation of new therapies. Further, with advances in conditional knockout technologies, otherwise embryonically lethal gene changes can be incorporated leading to the development of new generation transgenics, thus adding significantly to our existing knowledge base. Different models and their relevance to PC research are discussed.

Molecular profiling of bladder cancer: Involvement of the TGF-β pathway in bladder cancer progression

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.CANLET.2008.02.034

Abstract: A human bladder cancer model of nine cell sublines derived from the BL17/2 cell line was used to evaluate genes related to disease progression. Molecular profiling of sublines that were non-tumorigenic and invasive in nude mice was performed and identified 1367 differentially-expressed genes. Quantitative real-time PCR analysis of six transforming growth factor-beta (TGF-beta) pathway genes using the entire panel of nine cell lines was performed. Bone morphogenetic protein-2 expression was significantly associated with in vivo tumorigenicity of the cell lines (p=0.0228, Mann-Whitney) inhibin-betaB was related to their invasiveness (p=0.0468, Mann-Whitney). Analysis of conditioned medium showed TGF-beta1 production to be significantly associated with the phenotype of the cell line. The study shows the possible involvement of the TGF-beta pathway in bladder cancer progression.

Elastase activities of human bladder cancer cell lines derived from high grade invasive tumours

Publisher: Elsevier BV

Date: 07-1989

DOI: 10.1016/0006-291X(89)91997-9

Abstract: Elastase activities in intact human bladder cancer cell lines, established from three patients, were measured using a fluorogenic substrate highly specific for elastase, under conditions of physiological pH and ionic strength. This method allowed separation of cell-associated from secreted enzyme activity. As secreted elastase accounted for only 8% of the total, we concluded that the elastases were present at the cell surface. Inhibition studies using extracts of cell-surface elastases showed them to be serine proteinases which were also inhibited by alpha 1-antitrypsin. Partially purified fractions showing the highest specific activity towards the fluorogenic substrate hydrolysed insoluble elastin thus confirming the presence of elastases. This is the first time that elastase activity has been demonstrated in human bladder cancer cells and may represent a mechanism involved in tumour invasion.

Active protease mapping in 2DE gels

Publisher: No publisher found

Date: 2009

DOI: 10.1007/978-1-59745-281-6\_28

Synthesis and study of nanocrystalline Ni-Cu-Zn ferrites prepared by oxalate based precursor method

Publisher: Elsevier BV

Date: 06-2011

DOI: 10.1016/J.JALLCOM.2011.03.127

Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene

Publisher: Elsevier BV

Date: 11-1998

DOI: 10.1016/S0167-4781(98)00200-0

Abstract: Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane protein with folate hydrolase and NAALAdase activity. PSMA is highly expressed in prostate cancer and the vasculature of most solid tumors, and is currently the target of a number of diagnostic and therapeutic strategies. PSMA is also expressed in the brain, and is involved in conversion of the major neurotransmitter NAAG (N-acetyl-aspartyl glutamate) to NAA and free glutamate, the levels of which are disrupted in several neurological disorders including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and schizophrenia. To facilitate analysis of the role of PSMA in carcinoma we have determined the structural organization of the gene. The gene consists of 19 exons spanning approximately 60 kb of genomic DNA. A 1244 nt portion of the 5' region of the PSMA gene was able to drive the firefly luciferase reporter gene in prostate but not breast-derived cell lines. We have mapped the gene encoding PSMA to 11p11-p12, however a gene homologous, but not identical, to PSMA exists on chromosome 11q14. Analysis of sequence differences between non-coding regions of the two genes suggests duplication and ergence occurred 22 million years ago.

The prognostic significance of tumor-associated markers p53, HER-2/neu, c-myc, v-H-ras, PCNA and EGFr of local and distant recurrence in localized human prostatic adenocarcinoma

Publisher: Elsevier BV

Date: 07-1995

DOI: 10.1016/1078-1439(95)00059-3

Abstract: The intracellular expression of the gene products of tumor-associated markers p53, proliferative cell nuclear antigen (PCNA), HER-2/neu, c-myc, H-ras, and epidermal growth factor receptor (EGFr) in 86 cases of localized prostatic adenocarcinoma was investigated immunohistochemically in formalin-fixed paraffin-embedded tissue sections after pretreatment with a novel antigen retrieval buffer. A scoring system was devised to assess strength, pattern, and combined strength attern of immunostainings in the nucleus and cytoplasm for each immunomarker. The results were evaluated to determine whether overexpression of the gene products in the nucleus and cytoplasm was predictive of local and/or distant tumor recurrence and whether their expression was associated with known clinical prognostic factors. There was no significant relation between p53, PCNA, HER-2/neu, c-myc, and H-ras protein expression with risk of recurrence. EGFr expression showed a trend of increasing risk of tumor recurrence with higher composite score. Analysis of the association with other known prognostic factors in prostatic adenocarcinoma showed that PCNA was significantly correlated with tumor stage while H-ras and HER-2/neu were marginally correlated with prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) pretreatment serum levels, respectively. Together our findings suggest that overexpression of these intracellular oncoproteins in the tumor cells may not play an important role in determining whether prostatic tumors are likely to recur in localized prostatic adenocarcinoma.

Inhibition of micrometastatic prostate cancer cell spread in animal models by²¹³bilabeled multipletargeted α radioimmunoconjugates

Publisher: American Association for Cancer Research (AACR)

Date: 02-2009

DOI: 10.1158/1078-0432.CCR-08-1203

Abstract: Purpose: To investigate the therapeutic potential of 213Bilabeled multiple targeted α-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models. Experimental Design: PC-3 CaP cells were implanted s.c., in the prostate, and intratibially in NODSCID mice. The expression of multiple tumor–associated antigens on tumor xenografts and micrometastases was detected by immunohistochemistry. Targeting vectors were two monoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeled with 213Bi using standard methodology. In vivo efficacy of multiple α conjugates (MTAT) at different activities was evaluated in these mouse models. Tumor growth was monitored during observations and local regional lymph node metastases were assessed at the end of experiments. Results: The take rate of PC-3 cells was 100% for each route of injection. The tumor-associated antigens (MUC1, urokinase plasminogen activator, and BLCA-38) were heterogeneously expressed on primary tumors and metastatic cancer clusters at transit. A single i.p. injection of MTAT (test) at high and low doses caused regression of the growth of primary tumors and prevented local lymph node metastases in a concentration-dependent fashion it also caused cancer cells to undergo necrosis and apoptosis. Conclusions: Our results suggest that MTAT can impede primary PC-3 CaP growth at three different sites in vivo through induction of apoptosis, and can prevent the spread of cancer cells and target lymph node micrometastases in a concentration-dependent manner. MTAT, by targeting multiple antigens, can overcome heterogeneous antigen expression to kill small CaP cell clusters, thus providing a potent therapy for micrometastases.

Expression of steroid hormone receptors in BRCA1-associated ovarian carcinomas

Publisher: Elsevier BV

Date: 04-2005

DOI: 10.1016/J.YGYNO.2004.12.030

Abstract: BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERalpha and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERalpha and other hormone receptors in BRCA1-associated ovarian cancer was unknown. Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. ERalpha expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERalpha and ERbeta were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.

Use of targeted magnetic nanoparticles for imaging in prostate cancer

Publisher: American Association for Cancer Research (AACR)

Date: 06-02-2013

DOI: 10.1158/1538-7445.PRCA2012-C30

Abstract: Objective: Imaging techniques better than those conventionally used are needed to improve prostate cancer (PC) staging and read out of therapeutic effects in real time in treated patients. We aimed to perform preclinical evaluation of newly developed well-characterized, biocompatible, PC-targeted magnetic nanoparticles (MNPs) targeted to prostate cancer by conjugation with J591 (from N. Bander, Cornell, USA), an antibody which binds specifically to prostate specific membrane antigen (PSMA) which is expressed on the surface of ∼90% of PCs including castrate resistant prostate cancers this binding results in internalization. The use of targeted MNPs should enhance the specificity and sensitivity of magnetic resonance imaging (MRI) to enable better staging of patients with PC and future targeted delivery of therapy. Methods: MNPs were prepared, engineered to the appropriate size and conjugated with J591. There was no compromise in J591 cell binding or specificity for PSMA positive cells due to the conjugation, and Inductively Coupled Plasma Optical Emission Spectrometry and Prussian blue staining for iron indicated increased uptake of MNPs that were conjugated with the antibody. In vivo studies were performed in immunodepressed nude mice with subcutaneous LNCaP-LN3 (PSMA-positive) xenografts (post euthanasia using an 11.7T NMR system) or on live mice with orthotopic LNCaP xenografts, using a 16.4T MRI imaging system following intravenous injection of MNPs. Results: Similar enhancement of MRI was obtained by NMR after injection of MNP or J591-MNP conjugates. Live imaging of mice given systemic J591-MNPs showed uptake into the prostate tumors. Conclusions: The data indicate the promise of this technique in enabling imaging of small clusters of human prostate cancer cells. This should enable the effects of therapy to be determined by imaging in real time, improving patient management. Citation Format: Pamela J. Russell, C Soekmadji, B Thierry, G Cowin, T Strait-Gardner, N Verma, Wang Xiaochun, A Khatri. Use of targeted magnetic nanoparticles for imaging in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research 2012 Feb 6-9 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2012 (4 Suppl):Abstract nr C30.

Is a Klebsiella plasmid involved in the aetiology of ankylosing spondylitis in HLA-b27-positive individuals?

Publisher: Elsevier BV

Date: 05-1983

DOI: 10.1016/0161-5890(83)90095-0

Abstract: The possibility that plasmid genes, carried by enteric organisms previously indirectly implicated as disease agents, play a role in the pathogenesis of Ankylosing Spondylitis (AS) was explored. A particular Klebsiella isolate (K21) previously found to cross-react with cells from HLA-B27 positive (B27+) patients with AS, but not with cells from normal in iduals, was found to contain a plasmid(s). This coded for the organism's ability to produce a factor which could modify B27+ normal cells (AS-) rendering them lysable by the anti-Klebsiella serum. Curing of this isolate resulted in the loss of the plasmid concerned and a loss of ability of its culture filtrate to modify B27+ lymphocytes of clinically healthy subjects. When plasmids from K21 were transferred to a plasmid free laboratory strain, E. coli JP995, the recipient strain acquired the ability to elaborate modifying factor. These data suggest that plasmids, harboured by some enteric bacteria, and their products, may be implicated in modifying cells bearing certain Major Histocompatibility Complex genes, and that such modification may be an important factor in the pathogenesis of a number of diseases including the seronegative arthropathies.

Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo

Publisher: Elsevier BV

Date: 07-2006

DOI: 10.1016/J.BBRC.2006.05.020

Abstract: This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous "take rate" in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.

In vitro assessment of migratory behavior of two cell populations in a simple multichannel microdevice

Publisher: MDPI AG

Date: 18-12-2013

DOI: 10.3390/PR1030349

Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

Publisher: Springer Science and Business Media LLC

Date: 06-2002

DOI: 10.1038/SJ.GT.3301698

Abstract: A gene-directed enzyme pro-drug therapy (GDEPT) based on purine nucleoside phosphorylase (PNP), that converts the prodrug, fludarabine to 2-fluoroadenine, has been described, but studies are limited compared with other GDEPTs. We investigated the in vitro and in vivo efficacies of PNP-GDEPT for treating androgen-independent (AI) prostate cancer. The PNP gene controlled by Rous sarcoma virus (RSV) constitutive promoter was delivered using a recombinant ovine adenovirus vector (OAdV220) that uses a different receptor from human adenovirus type 5. In vitro, OAdV220 provided increased transgene expression over a comparable human Ad5 vector in infected AI, murine RM1 prostate cancer cells. Subsequent in vivo testing was therefore confined to OAdV220. Transduction of RM1 cells with OAdV220 before implantation in immunocompetent mice dramatically inhibited subcutaneous (s.c.) tumor growth when fludarabine phosphate was administered systemically and increased mouse survival in a dose-dependent manner. In tumor-bearing C57BL/6 mice, a single intratumoral injection of OAdV220 produced detectable PNP activity for at least 6 days and with prodrug, retarded the growth of aggressive RM1 s.c. tumors by 35% at day 14. There was a consistent trend to reduction of pre-established intraprostatic RM1 tumors. A similar regimen induced significant therapeutic efficacy in human PC3 xenografts. Thus, ovine adenovirus-mediated GDEPT using the PNP system was effective in vivo against AI prostate cancers, the aggressive murine RM1, and the human PC3 lines. Methods that improve viral dissemination and stimulate the immune system in vivo may further improve efficacy.

Molecular chemotherapy and chemotherapy: A new front against late-stage hormone-refractory prostate cancer

Publisher: American Association for Cancer Research (AACR)

Date: 15-06-2011

DOI: 10.1158/1078-0432.CCR-11-0248

Abstract: Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with in idual treatments. Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the in idual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res 17(12) 4006–18. ©2011 AACR.

Tryptic digestion of in-gel proteins for mass spectrometry analysis

Publisher: No publisher found

Date: 2009

DOI: 10.1007/978-1-59745-281-6\_34

Alterations to the protein profile of bladder carcinoma cell lines induced by plant extract MINA-05 in vitro

Publisher: Wiley

Date: 30-03-2009

DOI: 10.1002/PMIC.200700839

Abstract: Bladder cancer (BLCa) is a severe urological cancer of both men and women that commonly recurs and once invasive, is difficult to treat. MINA-05 (CK Life Sciences Int'l, Hong Kong) is a derivative of complex botanical extracts, shown to reduce cellular proliferation of bladder and prostate carcinomas. We tested the effects of MINA-05 against human BLCa cell sublines, B8, B8-RSP-GCK, B8-RSP-LN and C3, from a transitional cell carcinoma, grade IV, to determine the molecular targets of treatment by observing the cellular protein profile. Cells were acclimatised for 48 h then treated for 72 h with concentrations of MINA-05 reflecting 1/2 IC(50), IC(50) and 2 x IC(50) (n = 3) or with vehicle, (0.5% DMSO). Dose-dependant changes in protein abundance were detected and characterised using 2-dimensional electrophoresis and MS. We identified 10 proteins that underwent changes in abundance, pI and/or molecular mass in response to treatment. MINA-05 was shown to influence proteins across numerous functional classes including cytoskeletal proteins, energy metabolism proteins, protein degradation proteins and tumour suppressors, suggesting a global impact on these cell lines. This study implies that the ability of MINA-05 to retard cellular proliferation is attributed to its ability to alter cell cycling, metabolism, protein degradation and the cancer cell environment.

Oncogenic action of phospholipase A2 in prostate cancer

Publisher: Elsevier BV

Date: 08-2006

DOI: 10.1016/J.CANLET.2005.08.012

Abstract: Mortality from prostate cancer is a result of progression of cancer cells to become androgen-refractory and metastatic. Eicosanoid products of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumour vascularisation and metastasis in animal models. Pharmacological agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Recently, phospholipase A(2) (PLA(2)) enzymes, which regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, are found to also regulate the growth of prostate cancer cells and tumours, with one enzyme, secreted PLA(2)-IIA, being increased in prostate cancer tissues. Annexin A1 and A2, known inhibitors of cytosolic phospholipase A(2)-alpha activity, are absent in prostate cancer tissues. We propose that PLA(2) enzyme function is dysregulated by aberrant up regulation of secreted enzymes and downregulation of endogenous inhibitors of cytosolic phospholipase A(2) activity in prostate cancer and that this dysregulation contributes to the pathogenesis of prostate cancer. Thus, in addition to COX and LOX enzymes, PLA(2) enzymes represent important targets for the treatment of prostate cancer.

No differences in p53 mutation frequencies between BRCA1-associated and sporadic ovarian cancers

Publisher: Elsevier BV

Date: 12-2004

DOI: 10.1016/J.YGYNO.2004.08.035

Abstract: Mutation of the BRCA1 gene, which has incomplete penetrance, is involved in ovarian cancer development. Cell cycle check point inactivation via acquired somatic mutations in the check point regulatory genes, particularly p53, may be required for BRCA1-linked ovarian tumorigenesis. In the few studies directly comparing p53 mutations in BRCA1-linked and sporadic ovarian cancers, data have been contradictory. This study aimed to clarify the role of p53 mutation in BRCA1-associated and sporadic ovarian cancer by comparing two, large, matched cohorts from two different populations who developed BRCA1-linked or sporadic ovarian cancers. Forty-eight BRCA1-associated ovarian tumor s les (22 from Australia and 26 from Norway) were collected and matched with 48 sporadic ovarian cancers for tumor stage, grade, histological subtype, and patient age. Expression of p53 protein was measured by immunohistochemistry (IHC). Consistent with the presence of a mutated p53 protein, the majority of BRCA1-associated (79%) and sporadic (73%) ovarian carcinomas from Australia and Norway overexpressed p53 protein. There was no significant difference between BRCA1-linked ovarian cancers and their sporadic counterparts with regard to p53 protein expression (P = 0.5). Our results suggest that p53 inactivation is associated with both BRCA1-associated and sporadic ovarian tumorigenesis, and that BRCA1-linked and sporadic ovarian cancers may develop through a similar carcinogenic pathway.

Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.BIOMATERIALS.2014.01.062

Abstract: The development of effective therapeutic strategies against prostate cancer bone metastases has been impeded by the lack of adequate animal models that are able to recapitulate the biology of the disease in humans. Bioengineered approaches allow researchers to create sophisticated experimentally and physiologically relevant in vivo models to study interactions between cancer cells and their microenvironment under reproducible conditions. The aim of this study was to engineer a morphologically and functionally intact humanized organ bone which can serve as a homing site for human prostate cancer cells. Transplantation of biodegradable tubular composite scaffolds seeded with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone construct including a large number of human mesenchymal cells which were shown to be metabolically active and capable of producing extracellular matrix components. Micro-CT analysis demonstrated that the newly formed ossicle recapitulated the morphological features of a physiological organ bone with a trabecular network surrounded by a cortex-like outer structure. This microenvironment was supportive of the lodgement and maintenance of murine haematopoietic cell clusters, thus mimicking a functional organ bone. Bioluminescence imaging demonstrated that luciferase-transduced human PC3 cells reproducibly homed to the humanized tissue engineered bone constructs, proliferated, and developed macro-metastases. This model allows the analysis of interactions between human prostate cancer cells and a functional humanized bone organ within an immuno-incompetent murine host. The system can serve as a reproducible platform to study effects of therapeutics against prostate cancer bone metastases within a humanized microenvironment.

Oncogenic Action of Secreted Phospholipase A2 in Prostate Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 10-2004

DOI: 10.1158/0008-5472.CAN-03-3018

Abstract: Mortality from prostate cancer is associated with progression of tumors to androgen-independent growth and metastasis. Eicosanoid products of both the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumor vascularization and metastasis in animal models. Pharmacologic agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Phospholipase A2 (PLA2) enzymes regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, and a secreted form of the enzyme (sPLA2-IIA) is elevated in prostate cancer tissues. Here, we show by immunohistochemistry, in patients receiving androgen ablation therapy, that sPLA2-IIA remains elevated in remaining cancer cells relative to benign glands after treatment. Furthermore, sPLA2-IIA expression seen in benign glands is substantially decreased after androgen depletion, whereas cytosolic PLA2-α (cPLA2-α) levels are unchanged. sPLA2-IIA mRNA expression is detectable and inducible by androgen (0.01–10 nmol/L) in the androgen-sensitive cell line LNCaP, and exogenous addition of sPLA2-IIA (1–100 nmol/L), but not an inactive sPLA2-IIA mutant (H48Q), results in a dose-dependent increase in cell numbers or the fraction of cells in G2-M phase, which is inhibited by sPLA2-IIA-selective inhibitors. The effect of exogenous sPLA2-IIA can also be blocked by inhibition of cPLA2-α, suggesting a role for cPLA2-α in mediating sPLA2-IIΑ action. sPLA2-IIA inhibitors suppressed basal proliferation in LNCaP cells and in the androgen-independent, sPLA2-positive cell line PC3 but not in the sPLA2-IIA-negative androgen-independent cell line DU145. Established PC3 xenograft tumors grew more slowly in mice treated with sPLA2-IIA inhibitors than those treated with saline only. The PLA2 enzymes, and sPLA2-IIA in particular, thus represent important targets for the treatment of sPLA2-IIA-positive androgen-independent prostate cancer.

Establishing prostate cancer patient derived xenografts: Lessons learned from older studies

Publisher: Wiley

Date: 05-01-2015

DOI: 10.1002/PROS.22946

Studies of peritoneal macrophage function in mice with systemic lupus erythematosus: Depressed phagocytosis of opsonized sheep erythrocytes in vitro

Publisher: Elsevier BV

Date: 06-1983

DOI: 10.1016/0090-1229(83)90091-0

Abstract: Resident peritoneal macrophages from systemic lupus erythematosus (SLE)-prone strains, NZB, (NZB X NZW)F1 and MRL/MpJ-lpr/lpr mice, exhibited very low binding and phagocytosis of opsonized 51Cr-labeled sheep erythrocytes (EA) compared with cells from normal mice. Male BXSB mice, which also develop SLE, were not clearly defective in phagocytosis and binding of EA compared with C57B1/6J, the lowest of the "normal" mice tested, but were less effective than their normal female BXSB counterparts. The extent of the defect depended on the age of the animals tested. Young NZB/N mice showed hyperactive binding and phagocytosis and became defective about the time of disease onset. Even young (NZB X NZW)F1 and MRL/MpJ-lpr/lpr mice were defective and worsened with age. Increasing numbers of resident peritoneal macrophages were recovered from the autoimmune mice as they aged. Near normal binding and phagocytosis of EA could be effected by stimulation in vivo by injection of killed Corynebacterium parvum. Resident peritoneal macrophages from congeneic xid (X-linked immune deficiency gene) bearing NZB and (NZB X NZW)F1 mice showed normal reactivity. Binding and phagocytosis of EA was Fc mediated and was inhibited by pretreatment with large doses of heat-aggregated human gamma-globulin. Defective macrophage Fc receptor binding or turnover may play an important role in the observed manifestations of autoimmune disease in murine SLE.

Interferon-α promotes the anti-proliferative effect of gefitinib (ZD1839) on human colon cancer cell lines

Publisher: S. Karger AG

Date: 2005

DOI: 10.1159/000088070

Abstract: i Objective: /i Interferon-α (IFNα) treatment is associated with up-regulation of epidermal growth factor receptor (HER1/EGFR) expression and marked growth inhibition of colon cancer cell lines in vitro.We aimed to determine the effect of combining IFNα and gefitinib on colon cancer cell line growth. i Methods: /i A panel of nine colon cancer cell lines were characterised for expression of HER1/EGFR and then treated with gefitinib alone, or IFNα alone, or IFNα plus gefitinib, following a pre-treatment using vehicle or IFNα. Crystal violet staining and flow cytometry were used to assess cell proliferation and expression of HER1/EGFR. The indexes and statistical assays were used to evaluate significant differences between treatment groups against vehicle control. i Results: /i All cell lines except SW620 were HER1/EGFR positive. IFNα treatment was associated with significant up-regulation of cell surface HER1/EGFR expression in all HER1/EGFR-positive cell lines except KM12SM. Concurrent treatment with IFNα and gefitinib, or IFNα pre-treatment followed by gefitinib, or IFNα pre-treatment followed by a combination of IFNα plus gefitinib, additively or supra-additively/synergistically enhanced the sensitivity of the seven HER1/EGFR-up-regulated cell lines. i Conclusion: /i IFNα improves the anti-proliferative effect of EGFR inhibition in colorectal cancer cell lines. This approach may have clinical implications for improving treatment based on targeting of HER1/EGFR.

Erlotinib (OSI-774)-induced inhibition of transitional cell carcinoma of bladder cell line growth is enhanced by interferon-α

Publisher: Wiley

Date: 06-03-2007

DOI: 10.1111/J.1464-410X.2007.06778.X

From Bench to Bedside: Immunotherapy for Prostate Cancer

Publisher: Hindawi Limited

Date: 2014

DOI: 10.1155/2014/981434

Abstract: The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.

Interferon-alpha promotes the anti-proliferative effect of Erlotinib (OSI-774) on human colon cancer cell lines

Publisher: Elsevier BV

Date: 08-07-2005

DOI: 10.1016/J.CANLET.2004.11.041

Abstract: Interferon-alpha (IFNalpha) treatment is associated with up-regulation of epidermal growth factor receptor (HER1/EGFR) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor (Gut 2004 :123). We aimed to determine the effect of combining IFNalpha and Erlotinib (an HER1/EGFR inhibitor) on colon cancer cell line growth. Crystal-violet staining and flow cytometry were used to assess cell proliferation and expression of HER1/EGFR. IFNalpha pre-treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7/9 of colon cancer cell lines by 7-43%. This approach may have clinical implications for improving treatment based on targeting of HER1/EGFR.

Failure Ofklebsiella pneumoniae antibodies to cross-react with peripheral blood mononuclear cells from patients with ankylosing spondylitis

Publisher: Wiley

Date: 03-1987

DOI: 10.1002/ART.1780300309

Abstract: Cross-reactivity between antibodies to 2 strains of Klebsiella pneumoniae (K43 and F77) and the peripheral blood lymphocytes of patients with ankylosing spondylitis (AS) was examined in 3 separate antibody binding and cytotoxicity assays. Using K pneumoniae antisera in a chromium release cytotoxicity assay, we found no difference in the reactions of cells from AS patients and those from control subjects. This result contrasts with the results of previous studies. Similarly, using an enzyme-linked immunosorbent assay, we detected no significant increase in antibody binding to peripheral blood mononuclear cells (PBMC) in HLA-B27 positive patients with AS. Low levels of antibody binding were detected by a fluoresceinated antibody binding assay however, normal rabbit serum, which was used as a control, was shown to have a binding affinity for PBMC that was significantly greater than that of specific K pneumoniae antisera. The results of our present study do not support the concept of a specific cross-reactivity between antibodies to K pneumoniae and the PBMC of patients with AS who are HLA-B27 positive.

Mutations within the tumour suppressor gene p53 are not confined to a late event in prostate cancer progression

Publisher: Elsevier BV

Date: 05-2001

DOI: 10.1016/S1078-1439(00)00119-8

Abstract: Mutations in the p53 tumour suppressor gene are generally believed to be a late event in the progression of prostate cancer, and are associated with androgen independence, metastasis, and a worse prognosis. In this review, we examine the current literature available on p53 mutations and focus on stages A (T1) and B (T2) of prostate cancer. We report here that p53 mutations can be found in approximately one third of prostate cancers that are clinically localized to the prostate. In addition, high levels of p53 mutation are found in normal prostate tissue of prostate cancer patients, prostatic intraepithelial neoplasia, and benign prostatic hyperplasia. The limitations of techniques used to determine p53 mutations are discussed, as well as other modes of p53 loss in early stage prostate cancer.

Relationship between expression of the KAI1 metastasis suppressor and other markers of advanced bladder cancer

Publisher: Wiley

Date: 05-2000

DOI: 10.1002/(SICI)1096-9896(200005)191:1<39::AID-PATH580>3.0.CO;2-K

Diagnosis of second head and neck tumors in primary laryngeal SCC is an indicator of overall survival and not associated with poorer overall survival: A single centre study in 987 patients

Publisher: Wiley

Date: 10-2009

DOI: 10.1002/JSO.21413

Abstract: Second primary tumors (SPTs) have been implicated in poor overall survival (OS) of head and neck squamous cell carcinomas (HNSCCs). Confusion remains regarding their actual incidence and prognostic impact. This study assessed the incidence of SPTs the SPT diagnostic time lag the impact on OS and the mean annual risk. Nine hundred eighty seven consecutive patients treated for primary larynx SCC (1967-2004) were analyzed in this study. 96.3% and 91.4% of patients reached a minimum follow-up period of 3 and 5 years. Two hundred eight (21.1%) patients were diagnosed with SPTs. One hundred forty three (14.5%) patients developed upper aero-digestive tract (UAD)-SPTs, 83 (8.4%) were HNSCCs, 56 (5.7%) were lung, and 4 (0.41%) were esophageal-SPTs. Survival analysis demonstrated clear superior OS rates for the UAD-SPT (P < 0.008) and HNSCC-SPT (P < 0.001) groups. A comparison of survival of subgroups showed lung/esophagus to have a poorer survival when compared to all other subgroups. OS after diagnosis of an SPT was poorer when compared with no-SPT group (P < 0.001). The mean annual risk of developing UAD-SPTs was 2.4%. These results suggest that HNSCC-SPT should not be viewed as an adverse prognostic factor. Reclassifications of UAD-SPTs into HNSCC-SPT and non-HNSCC-SPT better reflects their clinical behavior and prognosis.

Emerging roles for phospholipase A2 enzymes in cancer

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.BIOCHI.2010.03.019

Abstract: Phospholipase A(2) (PLA(2)) enzymes (EC3.1.4.4) regulate the release of biologically active fatty acids and lysophospholipids from membrane phospholipid pools. These lipids are also substrates for intracellular biochemical pathways that generate potent autocrine and paracrine lipid mediators such as the eicosanoids and platelet activating factor. These factors, in turn, regulate cell proliferation, survival, differentiation, motility, tissue vascularisation, and immune surveillance in virtually all tissues, functions that are subverted by cancer cells for tumour growth and metastasis. Thus the relevance of PLA(2)-dependent pathways to the genesis and progression of cancer has been of interest since their discovery and with recent technological advances, their role in tumourigenesis has become more tractable experimentally. Limited human genetic studies have not yet identified PLA(2) enzymes as classical mutated oncogenes or tumour suppressor genes. However, there is strong evidence that of the 22 identified human PLA(2) enzymes, ten of which have been studied in cancer to date, most are aberrantly expressed in a proportion of tumours derived from erse organs. Correlative and functional studies implicate the expression of some secreted enzymes (sPLA(2)s), particularly the best studied enzyme Group IIA sPLA(2) in either tumour promotion or inhibition, depending on the organ involved and the biochemical microenvironment of tumours. As in immune-mediated inflammatory pathologies, genetic deletion studies in mice, supported by limited studies with human cells and tissues, have identified an important role for Group IVA PLA(2) in regulating certain cancers. Pharmacological intervention studies in prostate cancer suggest that hGIIA-dependent tumour growth is dependent on indirect regulation of Group IVA PLA(2). Group VI calcium-independent PLA(2) enzymes have also been recently implicated in tumourigenesis with in vitro studies suggesting multiple possible roles for these enzymes. Though apparently complex, further characterization of the regulatory relationships amongst PLA(2) enzymes, lipid mediator biosynthetic enzymes and the lipid mediators they produce during tumour progression is required to define the biochemical context in which the enzymes modulate cancer growth and development.

Genetic markers of survival and liver recurrence after resection of liver metastases from colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 09-07-2001

DOI: 10.1007/S00268-001-0069-5

Abstract: A significant number of patients with liver metastases from colorectal cancer (CRC) achieve 5-year survival after liver resection. Increased expression of genetic markers in the primary tumor are known to predict outcome after colonic resection, but the predictive value of such markers after resection of hepatic metastases is unknown. The objective of this study was to evaluate whether DNA content and multiple genetic markers, separately or expressed together, can predict patient outcome (liver recurrence and survival) after resection of hepatic metastases. We studied the paraffin-embedded liver tissue of 71 consecutive patients who had undergone a potentially curative resection of hepatic metastases from CRC. Using DNA flow cytometry and immunohistochemical staining techniques we determined the DNA content and the level of co-expression of seven tumor-associated proteins: proliferating cellular nuclear antigen (PCNA), epidermal growth factor receptor (EGFr), p53, c-erbB-2, H-ras, c-myc, and nm23. Three endpoints (liver recurrence, cancer specific, overall survival) were correlated with these tumor markers. The 5-year overall survival of the group was 31.2%. There was no correlation detected between the DNA aneuploidy and overall or cancer-specific survival. Similarly, expression of the in idual tumor-associated proteins did not predict survival. Patients whose tumors co-expressed multiple markers had survivals similar to those whose tumors expressed fewer markers. However, a significant difference in hepatic recurrence was found between the p53-positive and p53-negative patients (p = 0.007), with marker-negative tumors having decreased recurrence. In conclusion, this study demonstrates that the DNA content and genetic markers c-myc, c-erbB-2, EGFr, H-ras, p53, PCNA, and nm23 do not predict survival after potentially curative resection of hepatic metastases from CRC. However, the immunoreactivity of p53 may be an important marker of local recurrence in the liver, which may be useful if re-resection of metastatic liver tumors is considered a viable management option in this disease.

Preparation, Characterization, DNA Binding, and in Vitro Cytotoxicity of the Enantiomers of the Platinum(II) Complexes N-Methyl-, N-Ethyl- and N,N-Dimethyl-(R

Publisher: American Chemical Society (ACS)

Date: 10-1997

DOI: 10.1021/JM960854N

Search for gravitational waves associated with the gamma ray burst GRB030329 using the LIGO detectors

Publisher: American Physical Society (APS)

Date: 12-08-2005

DOI: 10.1103/PHYSREVD.72.042002

Murine CTLL-2 cells respond to mIL12: Prospects for developing an alternative bioassay for measurement of murine cytokines IL12 and IL18

Publisher: Elsevier BV

Date: 09-2007

DOI: 10.1016/J.JIM.2007.07.002

Abstract: Cell line-based bioassays are becoming increasingly popular for assessment of biological activities of cytokines primarily because these are easy to perform and are not subject to donor variation. A well characterised cell line with world wide availability would further minimise the inter-assay variations. C57BL/6 mice derived T cell line CTLL-2 fits this criterion. We explored the potential of CTLL-2 cells to develop a bioassay to detection of murine (m) IL12 and mIL18. Both cytokines have shown significant activity against a number of cancers and importantly, act synergistically via mutual upregulation of each other's receptors. The preliminary flow cytometric analyses of immunostained CTLL-2 cells showed that approximately 65% expressed mIL12 and approximately 5% expressed mIL18 receptors suggesting that these may respond to mIL12. As predicted, cells incubated with different doses of mIL12 or mIL18 for 72 h were responsive to mIL12 and not to mIL18. However, when pre-treated with mIL12 for 24 h prior to incubation with mIL18, there was a significant enhancement in response. The sensitivity of the response was comparable to that obtained using the conventional splenocyte-based IFNgamma release assay. The cytokine specificity of the response was proven unequivocally when significant reduction in CTLL-2 response was observed in the presence of the relevant neutralising antibodies. Finally, we could successfully detect lowest doses of approximately 0.1 pg/microL mIL12 or 40 pg/mL of mIL18 in cell supernatants in a cytokine specific manner, which is lower than the resting levels of these cytokines in mouse sera. Again the sensitivity was comparable to that observed in the conventional IFNgamma release assay. Hence, we have demonstrated the potential of CTLL-2-based bioassay to detect biologically active mIL12 and mIL18 in biological s les accurately and reproducibly.

Molecular and traditional chemotherapy: A united front against prostate cancer

Publisher: Elsevier BV

Date: 07-2010

DOI: 10.1016/J.CANLET.2009.11.019

Abstract: Castrate resistant prostate cancer (CRPC) is essentially incurable. Recently though, chemotherapy demonstrated a survival benefit ( approximately 2months) in the treatment of CRPC. While this was a landmark finding, suboptimal efficacy and systemic toxicities at the therapeutic doses warranted further development. Smart combination therapies, acting through multiple mechanisms to target the heterogeneous cell populations of PC and with potential for reduction in in idual dosing, need to be developed. In that, targeted molecular chemotherapy has generated significant interest with the potential for localized treatment to generate systemic efficacy. This can be further enhanced through the use of oncolytic conditionally replicative adenoviruses (CRAds) to deliver molecular chemotherapy. The prospects of chemotherapy and molecular-chemotherapy as single and as components of combination therapies are discussed.

Stability of lectin binding properties expressed by human bladder carcinoma cell lines passaged in vitro or in nude mice

Publisher: Springer Science and Business Media LLC

Date: 11-1988

DOI: 10.1007/BF00280020

Abstract: Insulin action has been reported to be normal in type 1 diabetic patients. However, some studies have reported an insulin resistance state in these patients. The aim of this study was to investigate insulin resistance in a group of type 1 diabetic patients. We studied the insulin action in adipose tissue and analyzed the effects of duration of disease, body mass index (BMI), and glycosylated hemoglobin on insulin action at the receptor and postreceptor levels in adipocytes. Nine female type 1 diabetic patients with different durations of disease and eight nondiabetic female patients of comparable age and BMI were studied. (125)I-insulin binding and U-[(14)C]-D-glucose transport was measured in a s le of subcutaneous gluteus adipose tissue obtained by open surgical biopsy from each subject. The duration of disease was negatively correlated with both (125)I-insulin binding capacity (r = -0.70, P < 0.05) and basal and maximum insulin-stimulated glucose transport (r = -0.87, P < 0.01, and r = -0.88, P < 0.01, respectively). Maximum specific (125)I-insulin binding to the receptors in adipocytes was higher in the group of patients with a shorter duration of disease (P < 0.01). Basal and maximum insulin-stimulated glucose transport was significantly higher in the group with less than 5 years of disease (P < 0.01). No correlation was found between BMI and insulin action. Female type 1 diabetic patients have normal insulin action. There is a high glucose uptake in the early phase of the disease, although a longer duration of disease appears to be a contributing factor to a decrease in insulin action in these patients, and involving both receptor and postreceptor mechanisms.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice

Publisher: Public Library of Science (PLoS)

Date: 27-08-2012

DOI: 10.1371/JOURNAL.PONE.0043833

Higher expression of oncoproteins c-myc, c-erbB-2/neu, PCNA, and p53 in metastasizing colorectal cancer than in nonmetastasizing tumors

Publisher: Springer Science and Business Media LLC

Date: 11-1996

DOI: 10.1007/BF02306092

Preclinical studies of monoclonal antibodies for intravesical radioimmunotherapy of human bladder cancer

Publisher: Springer Science and Business Media LLC

Date: 1994

DOI: 10.1007/BF02789226

Abstract: Amyotrophic lateral sclerosis (ALS) is a rare yet devastating neurodegenerative condition. The mechanisms leading to ALS are most certainly complex and likely involve a joint contribution of several factors with possible synergistic or antagonistic interactions. To provide a better understanding of the association between non-genetic factors and ALS, we evaluated the joint exposure to multiple health and environmental factors linked with ALS in our previous studies, also screening for high-dimensional interactions. We used data from a nested case-control study within the Danish population, with 1086 ALS cases from 1982 to 2009, jointly investigating 4 hospital-based diagnoses - diabetes, obesity, physical/stress trauma, cardiovascular disease (CVD) during 1977-2009 and 4 environmental exposures - lead, formaldehyde, diesel exhaust, and solvents, assessed from in idual occupational history. All covariates were evaluated as ever/never exposed, and we used targeted machine learning techniques to screen for important joint predictors and interactions. These were then evaluated in a final logistic regression model adjusting for potential confounders (age, SES, geography). All analyses were stratified by sex. Among men, trauma and solvents were associated with higher odds of ALS (OR = 1.55, 95% CI: 1.08-2.23 OR = 1.49, 95% CI: 1.17-1.89, respectively), and presented a negative interaction (OR = 0.49, 95% CI: 0.30-0.80). A positive diesel/CVD interaction was observed (OR = 1.56, 95% CI: 0.94-2.60). Among women, solvents, trauma, lead, and CVD were associated with higher odds of ALS, and a negative lead/solvents interaction was documented (OR = 0.52, 95% CI: 0.42-0.63). This study is one of the first attempts to evaluate joint and interactive effects of multiple risk factors on ALS, identifying potential synergistic and antagonistic mechanisms.

KAI1 tetraspanin and metastasis suppressor

Publisher: Elsevier BV

Date: 03-2005

DOI: 10.1016/J.BIOCEL.2004.08.009

Abstract: KAI1 is a widely expressed transmembrane glycoprotein of the tetraspanin family. Substantial experimental evidence suggests that KAI1 is an important regulator of cell behaviour. A loss of KAI1 expression is also associated with the advanced stages of many human malignancies and results in the acquisition of invasive and metastatic capabilities by tumour cells, yet the underlying mechanisms responsible for this down-regulation of KAI1 expression remain to be resolved. The recent identification of signalling pathways downstream of KAI1, and proteins that specifically interact with KAI1, are beginning to elucidate the biological pathways involving KAI1.

Genomic alterations (LOH, MI) on chromosome 17q21-23 and prognosis of sporadic colorectal cancer

Publisher: Wiley

Date: 20-01-2000

DOI: 10.1002/(SICI)1097-0215(20000120)89:1<1::AID-IJC1>3.0.CO;2-7

Abstract: Genomic alterations at the long arm of chromosome 17, and in particular at the nm23 locus, are still controversial in colorectal cancer (CRC). Our aim was to investigate the possible relationship of loss of heterozygosity (LOH) and microsatellite instability (MI), at 4 microsatellite loci spanning the 17q21-23 region, to the risk of liver metastasis and nm23 protein expression. Genomic DNA extracted from 58 primary and 54 liver secondary formalin-fixed and paraffin-embedded CRCs was obtained from 82 patients. A fluorescent PCR coupled with an automated DNA sequencer was applied. Increasing fraction of loci showing LOH was positively associated with risk of liver metastases (logrank test for trend, p = 0.005) this remained independent after adjusting to T-stage (Cox regression, p = 0.022), N-stage (p = 0.007), or Dukes' stage (p = 0.012). Conversely, increasing frequency of MI was associated with a reduced risk of liver metastases in Dukes' B tumours (logrank test for trend, p = 0.032). When comparing 30 primary and matched liver secondary lesions, we found concordant genomic alteration in 72% (NME1) to 43% (D17S579). Finally, we observed a trend in association between the proportion of loci with LOH and nm23 positivity (chi2 test for trend, p = 0.024). Our findings suggest that genomic alterations in the 17q21-23 region may affect prognosis of CRC as well as regulation of the nm23 protein expression via an unknown underlying mechanism.

Broadening of transgenic adenocarcinoma of the mouse prostate (TRAMP) model to represent late stage androgen depletion independent cancer

Publisher: Wiley

Date: 04-02-2008

DOI: 10.1002/PROS.20714

Abstract: The transgenic adenocarcinoma of the mouse prostate (TRAMP) model closely mimics PC-progression as it occurs in humans. However, the timing of disease incidence and progression (especially late stage) makes it logistically difficult to conduct experiments synchronously and economically. The development and characterization of androgen depletion independent (ADI) TRAMP sublines are reported. Sublines were derived from androgen-sensitive TRAMP-C1 and TRAMP-C2 cell lines by androgen deprivation in vitro and in vivo. Epithelial origin (cytokeratin) and expression of late stage biomarkers (E-cadherin and KAI-1) were evaluated using immunohistochemistry. Androgen receptor (AR) status was assessed through quantitative real time PCR, Western blotting, and immunohistochemistry. Coexpression of AR and E-cadherin was also evaluated. Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays. Proliferation/survival of sublines in response to androgen was assessed by WST-1 assay. In vivo growth of subcutaneous tumors was assessed in castrated and sham-castrated C57BL/6 mice. The sublines were epithelial and displayed ADI in vitro and in vivo. Compared to the parental lines, these showed (1) significantly faster growth rates in vitro and in vivo independent of androgen depletion, (2) greater tumorigenic, and invasive potential in vitro. All showed substantial downregulation in expression levels of tumor suppressor, E-cadherin, and metastatis suppressor, KAI-1. Interestingly, the percentage of cells expressing AR with downregulated E-cadherin was higher in ADI cells, suggesting a possible interaction between the two pathways. The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness.

THE EFFECT OF EXERCISE ON ANKYLOSING SPONDYLITIS — A PRELIMINARY STUDY

Publisher: Oxford University Press (OUP)

Date: 1993

DOI: 10.1093/RHEUMATOLOGY/32.6.498

Abstract: The Polhemus Navigation Sciences 3Space Isotrak system was used to measure the range of lumbar spinal motion of 57 patients with ankylosing spondylitis. Forty-three of these attended voluntary exercise sessions for an average of one and a half hours per week while 14 did not participate in any formal exercise groups. Exercising patients fell into two groups: those attending moderate and those attending vigorous exercise sessions. Results for exercising patients obtained immediately pre- and post- a single exercise session showed a small but significant increase in extension for the vigorous exercise group but no significant changes in any other movement for either of the groups. In a group of 44 patients (33 exercising, 11 non-exercising) who were followed-up over a 2 to 6 month period, slight loss of flexion (5.5 degrees) and lateral bend (3 degrees) was observed but there was no change in range of extension.

Characterization of Mutations in NOT2 Indicates that it Plays an Important Role in Maintaining the Integrity of the CCR4–NOT Complex

Publisher: Elsevier BV

Date: 09-2002

DOI: 10.1016/S0022-2836(02)00707-6

Abstract: The NOT2 protein is a component of the CCR4-NOT complex that plays multiple roles in the regulation of mRNA production in the yeast Saccharomyces cerevisiae. We have identified four novel not2 mutations and have characterized these and two previously described alleles as to the means by which they affect CCR4-NOT function. While two of the not2 alleles, not2-4 (carrying a G31R alteration) and not2::L9P, resulted in severe growth defects and caused a not phenotype at the HIS3 locus, these phenotypes appear to arise from partially different effects. The not2::L9P mutation resulted in complete loss of the 1.9x10(6)Da (1.9MDa) CCR4-NOT complex, and the not2::L9P protein displayed increased ability to associate with the NOT5 protein. In contrast, the not2-4 allele destabilized the CCR4-NOT complex to a lesser extent and had no effect on NOT5 association with NOT2. Instead, as previously reported, it displayed defective interactions with ADA2, a component of the SAGA complex. The not2::R165G also abrogated NOT2 ability to interact with ADA2 but had little effect on the integrity of the CCR4-NOT complex. Alterations in NOT2 contacts to ADA2, therefore, do not necessarily result in effects on the CCR4-NOT complex nor result in severe growth defects. We also observed that the four NOT2 N-terminal mutations affected NOT5 association with the CCR4-NOT complexes, suggesting that it is the N terminus of NOT2 that contacts and stabilizes NOT5 interactions. These results indicate that it is the loss of the integrity of the CCR4-NOT complex which leads to severe not2 phenotypes and that the NOT2 contacts to ADA2 play a lesser role in NOT2 function.

Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines

Publisher: Springer Science and Business Media LLC

Date: 03-2003

DOI: 10.1038/SJ.PCAN.4500609

Engineered silk fibroin protein 3D matrices for in vitro tumor model

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1016/J.BIOMATERIALS.2010.11.052

Abstract: 3D in vitro model systems that are able to mimic the in vivo microenvironment are now highly sought after in cancer research. Antheraea mylitta silk fibroin protein matrices were investigated as potential biomaterial for in vitro tumor modeling. We compared the characteristics of MDA-MB-231 cells on A. mylitta, Bombyx mori silk matrices, Matrigel, and tissue culture plates. The attachment and morphology of the MDA-MB-231 cell line on A. mylitta silk matrices was found to be better than on B. mori matrices and comparable to Matrigel and tissue culture plates. The cells grown in all 3D cultures showed more MMP-9 activity, indicating a more invasive potential. In comparison to B. mori fibroin, A. mylitta fibroin not only provided better cell adhesion, but also improved cell viability and proliferation. Yield coefficient of glucose consumed to lactate produced by cells on 3D A. mylitta fibroin was found to be similar to that of cancer cells in vivo. LNCaP prostate cancer cells were also cultured on 3D A. mylitta fibroin and they grew as clumps in long term culture. The results indicate that A. mylitta fibroin scaffold can provide an easily manipulated microenvironment system to investigate in idual factors such as growth factors and signaling peptides, as well as evaluation of anticancer drugs.

Label-free isolation of a prostate cancer cell among blood cells and the single-cell measurement of drug accumulation using an integrated microfluidic chip

Publisher: AIP Publishing

Date: 11-2015

DOI: 10.1063/1.4934715

Abstract: Circulating tumor cells (CTCs) are found in the blood of patients with cancer. Although these cells are rare, they can provide useful information for chemotherapy. However, isolation of these rare cells from blood is technically challenging because they are small in numbers. An integrated microfluidic chip, dubbed CTC chip, was designed and fabricated for conducting tumor cell isolation. As CTCs usually show multidrug resistance (MDR), the effect of MDR inhibitors on chemotherapeutic drug accumulation in the isolated single tumor cell is measured. As a model of CTC isolation, human prostate cancer cells were mixed with mouse blood cells and the label-free isolation of the tumor cells was conducted based on cell size difference. The major advantages of the CTC chip are the ability for fast cell isolation, followed by multiple rounds of single-cell measurements, suggesting a potential assay for detecting the drug responses based on the liquid biopsy of cancer patients.

PSMA-targeting iron oxide magnetic nanoparticles enhance MRI of preclinical prostate cancer

Publisher: Future Medicine Ltd

Date: 02-2015

DOI: 10.2217/NNM.14.122

Abstract: Aim: To evaluate the potential of newly-developed, biocompatible iron oxide magnetic nanoparticles (MNPs) conjugated with J591, an antibody to an extracellular epitope of PSMA, to enhance MRI of prostate cancer. Materials & methods: Specific binding to PSMA by J591-MNP was investigated in vitro. MRI studies were performed on orthotopic tumor-bearing NOD.SCID mice 2 h and 24 h after intravenous injection of J591-MNPs, or non-targeting MNPs. Results & conclusion: In vitro, MNPs did not affect prostate cancer cell viability, and conjugation to J591 did not compromise antibody specificity and enhanced cellular iron uptake. Magnetic resonance contrast of tumors was increased in vivo using PSMA-targeting MNPs, but not by non-targeting MNPs. This provides proof-of-concept that PSMA-targeting MNPs have potential to enhance magnetic resonance detection/localization of prostate cancer.

Cytosine deaminase-uracil phosphoribosyltransferase and interleukin (IL)-12 and IL-18:A multimodal anticancer interface marked by specific modulation in serum cytokines

Publisher: American Association for Cancer Research (AACR)

Date: 04-2009

DOI: 10.1158/1078-0432.CCR-08-2039

Abstract: Purpose: To test the effects of a new combination, cytosine deaminase (CD) + uracil phosphoribosyltransferase (UPRT)–mediated gene-directed enzyme prodrug therapy (GDEPT) with interleukin (IL)-12 and IL-18, on (a) growth of murine prostate and remote tumor deposits, (b) mouse survival, and (c) T helper (Th) 1/Th2 serum cytokine balance with a special focus to assess correlation with tumor burden/survival. Experimental Design: Efficacy of intraprostatic administration of adenovirally delivered murine IL-12 and IL-18 against orthotopic RM1 tumors and lung pseudometastases was assessed in C57BL/6 mice. At necropsy, tumor growth, lung colony counts, effects on immune cell infiltration, vasculature, apoptosis, and proliferation were estimated. Next, CDUPRT-GDEPT + cytokines were tested at suboptimal doses in mice with RM1CDUPRT prostate tumors/RM1 lung deposits and analyzed as above. Effects on mouse survival were also assessed. Host immune responses to different treatments were assessed by monitoring 11 serum cytokines using Luminex technology. Results: Our data show that IL-12 and IL-18, when combined with CDUPRT-GDEPT, caused significant reduction in local RM1 tumors and lung colonies with enhanced long-term survival versus in idual treatments. A dramatic enhancement of tumor infiltration by a wider repertoire of immune cells and disruption of vasculature implied the combination to be more immunostimulatory and antiangiogenic. Remarkably, lowering of serum IL-4 and monocyte chemoattractant protein-1 (MCP-1) was consistently associated with lower tumor burden (local and systemic), and this, rather than an increase in Th1 cytokines, better predicted treatment efficacy. In addition, mouse survival correlated with substantially higher cytokine (Th1/Th2) levels after treatment. Conclusion: Locoregional application of CDUPRT-GDEPT and IL-12/IL-18 was effective against local and systemic prostate cancer and improved survival. Monitoring serum levels of IL-4 and MCP-1 may accurately reflect tumor burden and, hence, host response to therapy.

MEASUREMENT OF THE RANGE AND COUPLED MOVEMENTS OBSERVED IN THE LUMBAR SPINE

Publisher: Oxford University Press (OUP)

Date: 1993

DOI: 10.1093/RHEUMATOLOGY/32.6.490

Abstract: The aim of this study was to set up a data base, using the Polhemus Navigation Sciences 3Space Isotrak system, of the range and coupled movements expected to be seen in the lumbar spine of people not experiencing spinal problems. Measurements were taken from groups of volunteers who had not previously experienced any form of serious back pain and who were not suffering from any pathology known to affect the spine. The 'normal' group was split into sections determined by age an dsex. Age was split into five categories, those aged 20-29 years, 30-39 years, 40-49 years, 50-59 years and 60-69 years. Range of motion was seen to be affected by both the age and sex of subjects. Lateral bend and axial rotation, flexion and lateral bend and flexion and axial rotation were all strongly coupled. The younger age groups tested exhibited a greater degree of coupled movement than the older groups.

Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: in vitro and in vivo studies

Publisher: Springer Science and Business Media LLC

Date: 05-2004

DOI: 10.1007/S00262-003-0457-9

Abstract: Monoclonal antibodies (MAbs) can target therapy to tumours while minimising normal tissue exposure. Efficacy of immunoconjugates containing peptide 101, designed around the first 22 amino acids of bee venom, melittin, to maintain the hipathic helix, to enhance water solubility, and to increase hemolytic activity, was assessed in nude mice bearing subcutaneous human prostate cancer xenografts. Mouse MAbs, J591 and BLCA-38, which recognise human prostate cancer cells, were cross-linked to peptide 101 using SPDP. Tumour-bearing mice were used to compare biodistributions of radiolabeled immunoconjugates and MAb, or received multiple sequential injections of immunoconjugates. Therapeutic efficacy was assessed by delay in tumour growth and increased mouse survival. Radiolabeled immunoconjugates and antibodies showed similar xenograft tropism. Systemic or intratumoural injection of immunoconjugates inhibited tumour growth in mice relative to carrier alone, unconjugated antibody and nonspecific antibody-peptide conjugates and improved survival for treated mice. Immunoconjugates deliver beneficial effects further peptide modifications may increase cytotoxicity.

Antiproliferative effects of bacillus Calmette-Gu�rin and interferon ?2b on human bladder cancer cells in vitro

Publisher: Springer Science and Business Media LLC

Date: 09-1995

DOI: 10.1007/BF01517219

Evaluation of urokinase plasminogen activator and its receptor in different grades of human prostate cancer☆

Publisher: Elsevier BV

Date: 11-2006

DOI: 10.1016/J.HUMPATH.2006.05.002

Abstract: Increased expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) has been reported in various malignancies including prostate cancer (CaP). However, their expression in the different grades of CaP remains poorly understood. Here, we use tissue microarrays to examine the expression of uPA and uPAR in different grades of human CaP and to establish the potential of these tumor-associated antigens as candidates for targeted therapy. One hundred twenty paraffin-embedded specimens were selected from patients who underwent radical retropubic prostatectomy or transurethral resection of the prostate for primary untreated CaP and 10 matched lymph node metastases. Monoclonal antibodies #394 and #3936 were used on tissue microarrays with standard immunohistochemistry to examine uPA and uPAR expression, respectively. Overexpression of uPA and uPAR was detected in 53% and 64% of primary CaP tissues, respectively, and in more than 90% of lymph node metastases, but not in normal prostates or benign tissues. Of the uPA and uPAR positive tumors, 76% and 68% were Gleason score 7 or higher, respectively, and most of these tumors also showed stromal staining. The overexpression of uPA and uPAR was highly related to tumor differentiation in patients with CaP. Both uPA and uPAR proteins are candidate therapeutic targets for cancer therapy to control micrometastases and hormone refractory disease in CaP.

Down-regulation of KAI1/CD82 protein expression in oral cancer correlates with reduced disease free survival and overall patient survival

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1016/J.CANLET.2004.03.004

Exosomes in prostate cancer: Putting together the pieces of a puzzle

Publisher: MDPI AG

Date: 11-11-2013

DOI: 10.3390/CANCERS5041522

Electron microscopy of renal glomerular basement membrane changes in healthy mice and in spontaneous and nephrotoxic murine nephritis

Publisher: Elsevier BV

Date: 1969

DOI: 10.3109/00313026909071293

Abstract: Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning.

Experimental models of histogenesis and tumor cell heterogeneity in bladder cancer

Publisher: Wiley

Date: 09-1992

DOI: 10.1002/SSU.2980080506

Abstract: The histogenetic relationships between the subtypes of bladder cancer are not known. Each common pattern (transitional cell carcinoma, adenocarcinoma, and squamous carcinoma) can exist independently, although they may coexist in primary or metastatic bladder cancers, and tumors that are predominantly composed of transitional cell carcinoma may have regions of squamous or glandular differentiation. Morphologically identical tumors exhibit marked variation in their natural history and response to treatment. To study these aspects of the biology of human bladder cancer, a series of cell lines have been established and characterized as xenografts and in tissue culture. These studies have shown a likely common origin for transitional cell carcinoma, adenocarcinoma, and squamous carcinoma of the bladder. Morphologically similar xenografts and cell lines in vitro have shown a broad range of functional heterogeneity, including ultrastructure, tumor marker production, ploidy, cell surface characteristics, and response to chemotherapy. These are useful models of heterogeneity of response to treatment with established and new cytotoxic agents.

Biodistributions of intact monoclonal antibodies and fragments of BLCA-38, a new prostate cancer directed antibody

Publisher: Springer Science and Business Media LLC

Date: 06-2004

DOI: 10.1007/S00262-003-0460-1

Abstract: Monoclonal antibodies (MAbs) are used for targeting agents to tumours while minimizing normal tissue exposure. A new anti-prostate cancer MAb, BLCA-38, was radioiodinated (I125) and assessed for its ability to target subcutaneous human prostate cancer (DU-145) xenografts after systemic intraperitoneal administration. For comparison, the profile of J591 MAb (now in clinical trial) against LNCaP-LN3 tumours was examined. Biodistribution profiles were obtained at various times, by assessing injected dose/gram (%ID/g) and xenograft to blood (X/B) ratios. Microautoradiography of xenografts was performed. After conjugation with a melittin peptide toxin, the profiles of BLCA-38 and J591 were compared with that of an irrelevant antibody, DS-1. Xenograft localization by 125I-labeled BLCA-38 and J591 MAbs to their relevant antigen-positive tumors was comparable, and there was no unusual localization in nontumour tissues. F(ab')2 and Fab fragments gave improved X/B ratios, but the %ID/g xenograft was decreased and they accumulated in kidneys, bladder and stomach. In contrast, the conjugates of irrelevant antibody showed no tumour targeting. Microautoradiography showed more tumour accumulation of MAbs than F(ab')2s or Fabs. BLCA-38 can target prostate cancer in vivo almost as effectively as J591. Given that J591 is used clinically, BLCA-38, which targets a different antigen, has potential for radioimmunoscintigraphy and for therapeutic targeting of prostate cancer.

PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer

Publisher: Springer Science and Business Media LLC

Date: 12-08-2013

DOI: 10.1038/ONC.2013.315

Abstract: Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.

Relationship between expression of KAI1 metastasis suppressor gene, mRNA levels and p53 in human bladder and prostate cancer cell lines

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S1078-1439(01)00175-2

Abstract: The molecular basis for the loss of KAI1 expression in invasive and metastatic tumors and tumor cell lines is not understood. Recently, identification of a sequence with homology to the consensus p53-binding motif in the promoter of the KAI1 metastasis suppressor gene, has led to a proposal that transcriptional regulation by p53 controls expression of KAI1, and that a dramatic down-regulation of KAI1 mRNA levels in invasive tumors and many tumor cell lines, is directly due to loss of p53 function. We have tested this hypothesis by assessing KAI1 mRNA levels in a series of 22 cell lines derived from bladder and prostate cancers, in which we confirmed the p53 gene sequence and characterized the functional status of the endogenous p53 protein. We anticipated that cell lines expressing p53 capable of transactivation should express high levels of KAI1 mRNA compared with cell lines expressing defective p53, or which were p53-null. KAI1 mRNA levels were determined by northern analysis using a full-length KAI1 cDNA probe, and varied widely between cell lines examined. However, there was no association between these levels and p53 status. Furthermore, transfection of representative cell lines with wild-type p53, or exposure to DNA damaging agents, had no effect on KAI1 mRNA levels. Our data suggest that p53 is not a major factor regulating levels of KAI1 mRNA in bladder and prostate cancer cell lines.

Ectopic hormone production by a prostatic small cell carcinoma xenograft line

Publisher: Elsevier BV

Date: 02-1988

DOI: 10.1016/0303-7207(88)90131-1

Abstract: The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, beta-endorphin and somatostatin in vivo and ACTH and beta-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.

Changes in epidermal growth factor receptor expression in human bladder cancer cell lines following interferon-α treatment

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2004

DOI: 10.1097/01.JU.0000130751.83953.55

Abstract: We examined the regulation of epidermal growth factor (EGF) receptor (EGFR) expression in human bladder cancer cell lines by interferon-alpha (IFN-alpha), the ability of IFN-alpha to inhibit cell proliferation and the sensitivity of IFN-alpha pretreated cells to EGF. Cell proliferation was determined using crystal violet colorimetric and clonogenic assays. EGFR expression was measured by flow cytometry using specific antibody or ligand binding approaches. After IFN-alpha (100 IU/ml) treatment cell surface EGFR expression was upregulated in 6 of 11 and down-regulated in 2 of 11 bladder cancer cell lines. The over expression of cell surface EGFR peaked within 48 to 96 hours and increased by 35% to 241% in in idual cell lines. High level cell surface EGFR correlated with intracellular EGFR expression. Cell growth inhibition by IFN-alpha coexisted with EGFR over expression in the 6 lines. IFN-alpha treated cells remained sensitive to EGF treatment. IFN-alpha transiently up-regulates EGFR expression and inhibits in vitro growth in some human bladder cancer cells. IFN-alpha does not prevent EGFR from binding EGF or signal transduction via the EGF-EGFR pathway. This may have clinical implications for improving treatment based on EGFR targeting in select patients with bladder cancer.

Genome-wide synteny through highly sensitive sequence alignment: Satsuma

Publisher: Oxford University Press (OUP)

Date: 05-03-2010

DOI: 10.1093/BIOINFORMATICS/BTQ102

Abstract: Motivation: Comparative genomics heavily relies on alignments of large and often complex DNA sequences. From an engineering perspective, the problem here is to provide maximum sensitivity (to find all there is to find), specificity (to only find real homology) and speed (to accommodate the billions of base pairs of vertebrate genomes). Results: Satsuma addresses all three issues through novel strategies: (i) cross-correlation, implemented via fast Fourier transform (ii) a match scoring scheme that eliminates almost all false hits and (iii) an asynchronous ‘battleship’-like search that allows for aligning two entire fish genomes (470 and 217 Mb) in 120 CPU hours using 15 processors on a single machine. Availability: Satsuma is part of the Spines software package, implemented in C++ on Linux. The latest version of Spines can be freely downloaded under the LGPL license from cience rograms/genome-biology/spines/ Contact: grabherr@broadinstitute.org

CYCLOPHOSPHAMIDE TREATMENT OF RENAL DISEASE IN (NZB &times; NZW) F1 HYBRID MICE

Publisher: Elsevier BV

Date: 03-1968

DOI: 10.1016/S0140-6736(68)92778-5

Abstract: We hypothesized that improved acute postoperative pain relief will be achieved using general anaesthesia (GA) either in combination with continuous thoracic paravertebral block (GA-cPVB) or single shot (GA-sPVB) as compared to GA supplemented by local wound infiltration (GA-LWI) after unilateral major breast cancer surgery. A randomised controlled trial was conducted in 46 adult women in a day-care or short-stay hospital setting after major breast cancer surgery. Pain-intensity was measured using an 11-point visual analogue scale (VAS) until postoperative day 2. GA-sPVB was stopped due to slow inclusion. No significant difference in VAS score was noted between GA-LWI (VAS median 0.5 (interquartile range 0.18-2.00)) and GA-cPVB, (VAS 0.3 (0.00-1.55, p = 0.195)) 24 hours after surgery or at any point postoperatively until postoperative day 2. We conclude that both GA-LWI and GA-cPVB anaesthetic techniques are equally effective in treatment of acute postoperative pain after major oncological breast surgery. As GA-LWI is easily to perform with fewer complications and it is more cost-effective it should be preferred over GA-cPVB.

Novel gene-directed enzyme prodrug therapies against prostate cancer

Publisher: Informa Healthcare

Date: 21-07-2006

DOI: 10.1517/13543784.15.8.947

Abstract: There is no effective cure for late-stage hormone (androgen) refractory prostate cancer. Although chemotherapy offers palliation to these late-stage patients, it also leads to systemic toxicities leading to poor quality of life. Clearly, the focus is on the development and evaluation of novel biologically relevant alternatives such as cytoreductive gene-directed enzyme prodrug therapy (GDEPT). With the current limitations of effective gene delivery in vivo, the in situ lification of cytotoxicity due to bystander effects of GDEPT has special attraction for patients with prostate cancer, the prostate being dispensable. This review focuses on the development, application and potential of various GDEPTs for treating prostate cancer. The current status of research related to the issues of enhancement of in situ GDEPT delivery and prostate cancer-specific targeting of vectors (especially viral vectors) is assessed. Finally, the scope and progress of synergies between GDEPT and other treatment modalities, both traditional and alternate, are discussed.

Studies of macrophage function in murine systemic lupus erythematosus. 4. Failure to reverse the defect in Fc-mediated phagocytosis and binding by in vitro stimulants or prostaglandins.

Publisher: Elsevier BV

Date: 1986

DOI: 10.3109/00313028609090829

Abstract: Previous studies have shown that resident peritoneal macrophages from mice with systemic lupus erythematosus (SLE) show defective Fc-mediated phagocytosis and binding of opsonized sheep erythrocytes (EA) in vitro. Possible causes of this defect in (NZB X NZW)F1 (B/W) mice were investigated. These included a maturational block in peritoneal macrophage differentiation, the production by peritoneal cells of a factor which inhibits Fc receptor expression and phagocytosis, and an abnormal response by macrophages of autoimmune mice to prostaglandins. Resident peritoneal macrophages of B/W mice did not show a maturational block since incubation with either (a) differentiating agents such as 4 beta-phorbol 12 beta-myristate 13 alpha acetate or retinoic acid, or (b) lymphokine (LK), prepared by Con A stimulation of mouse spleen cells, failed to enhance Fc-mediated phagocytosis and binding by B/W cells relative to controls. However, LK from B/W and B6AF1 cells stimulated Fc-mediated phagocytosis and binding by bone-marrow (BM)-derived macrophages of CBA/H mice B/W LK also stimulated BM cells from B/W mice. Peritoneal cell supernatants did not inhibit phagocytosis of Fc receptor expression by BM-derived macrophages in vitro. Prostaglandin E treatment of peritoneal or BM-derived macrophages in vitro failed to restore decreased phagocytosis and binding of EA induced by culture in indomethacin and failed to stimulate phagocytosis by untreated cultures. The reason for the observed defect remains obscure.

Expression and regulation of MIM (Missing In Metastasis), a novel putative metastasis suppressor gene, and MIM-B, in bladder cancer cell lines

Publisher: Elsevier BV

Date: 11-2004

DOI: 10.1016/J.CANLET.2004.05.002

Abstract: It has been proposed that a 356 amino acid protein encoded by the MIM (Missing In Metastasis) gene on Chromosome 8q24.1, is a bladder cancer metastasis suppressor. Recently, Machesky and colleagues [Biochem. J. 371 (2003) 463] identified MIM-B, a 759 amino acid protein, of which the C-terminal 356 amino acids are almost identical to MIM. Importantly, PCR primers and Northern Blotting probes used in the studies of MIM in bladder cancer did not distinguish between sequences specific for MIM or MIM-B, thus the importance of either protein to bladder cancer remains unclear. We have used primer sequences specific for either MIM or MIM-B to explore the possible functional significance of MIM and MIM-B to bladder cancer cell behaviour. We have compared MIM and MIM-B mRNA levels in a non-tumourigenic, non-invasive, transformed uro-epithelial cell line versus 15 bladder cancer cell lines of differing in vitro invasive abilities, as well as in five cell lines clonally isolated from the BL17/2 bladder tumour cell line, whose in vitro and in vivo invasive abilities have been determined. MIM and MIM-B mRNA levels varied widely between cell lines. Down-regulation of MIM and MIM-B occurred in 6/15 (40%) lines but lines showing down-regulation differed between MIM and MIM-B. Reduced levels of MIM and MIM-B in BL17/2 were further reduced in 2/5 (40%) sublines (MIM and MIM-B). Importantly, there was no association between MIM or MIM-B expression and invasive behaviour in vivo or in vitro. Treatment of representative cell lines with 5-aza-2-deoxycytidine failed to induce MIM or MIM-B expression. Furthermore, there was no association between MIM or MIM-B mRNA levels and p53 functional status. Our data indicate that down-regulation of MIM and/or MIM-B expression can occur in bladder cancer cell lines but is not associated with increased invasive behaviour. Our data also suggest that in those cell lines with reduced levels of MIM and MIM-B mRNA, down-regulation is unlikely to be due to promoter hypermethylation or loss of p53 function.

Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15) Gene Deletion Promotes Cancer Growth in TRAMP Prostate Cancer Prone Mice

Publisher: Public Library of Science (PLoS)

Date: 19-02-2015

DOI: 10.1371/JOURNAL.PONE.0115189

Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum

Publisher: Proceedings of the National Academy of Sciences

Date: 06-03-2003

DOI: 10.1073/PNAS.0530278100

Abstract: Genetic alterations in tumor cells often lead to the emergence of growth-stimulatory autocrine and paracrine signals, involving overexpression of secreted peptide growth factors, cytokines, and hormones. Increased levels of these soluble proteins may be exploited for cancer diagnosis and management or as points of therapeutic intervention. Here, we combined the use of controlled vocabulary terms and sequence-based algorithms to predict genes encoding secreted proteins from among ≈12,500 sequences represented on oligonucleotide microarrays. Expression of these genes was queried in 150 carcinomas from 10 anatomic sites of origin and compared with 46 normal tissues derived from the corresponding sites of tumor origin and other body tissues and organs. Of 74 different genes identified as overexpressed in cancer tissues, several encode proteins with demonstrated clinical diagnostic application, such as α-fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or therapeutic utility, such as gastrin-releasing peptide/bombesin in lung carcinomas. We show that several of the other candidate genes encode proteins with high levels of tumor-associated expression by immunohistochemistry on tissue microarrays and further demonstrate significantly elevated levels of another novel candidate protein, macrophage inhibitory cytokine 1, a distant member of the tranforming growth factor-β superfamily, in the serum of patients with metastatic prostate, breast, and colorectal carcinomas. Our results suggest that the combination of annotation rotein sequence analysis, transcript profiling, immunohistochemistry, and immunoassay is a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to other human diseases.

Studies of autologous mixed lymphocyte reactions in patients with systemic lupus erythematosus.

Publisher: Elsevier BV

Date: 1983

DOI: 10.3109/00313028309061400

Abstract: The autologous mixed lymphocyte reaction (AMLR) measures the proliferative response of peripheral blood T cells to surface antigens of non T cells. The AMLR of SLE patients with active or inactive disease either with (13) or without (6) immunosuppressive treatment was low compared with age and sex-matched controls, confirming previous reports. Only one patient with inactive, untreated SLE and one with drug induced lupus (procainamide) showed normal AMLR. Autologous reactivity was also reduced in 2 patients without treatment who presented with clinically complex disease syndromes, including primary biliary cirrhosis, or polyarteritis nodosa, together with Sjögren's syndrome and serological evidence of lupus. The AMLR could not be increased by changing the ratio of responder to stimulator cells. Patients with decreased AMLR also showed a decreased response to phytohemagglutinin which suggested a general depression of T cells. There was no correlation between the decreased AMLR and age, clinical features or anti-DNA antibody levels of the patients. In allogeneic mixed lymphocyte reactions (MLR) it was shown that non-T cells from SLE patients were poorer stimulators of allogeneic T cells than normal cells, and T lymphocytes from SLE patients were poorer responders to allogeneic non-T cells than were normal T cells. Both effects were much more marked in patients with active disease than in those with inactive SLE. This suggests a defect in both responder and stimulating cell populations in SLE.

3D cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared to cells cultured in monolayer

Publisher: Public Library of Science (PLoS)

Date: 07-11-2014

DOI: 10.1371/JOURNAL.PONE.0111029

Methylation of a CpG island within the promoter region of the KAI1 metastasis suppressor gene is not responsible for down-regulation of KAI1 expression in invasive cancers or cancer cell lines

Publisher: Elsevier BV

Date: 09-2000

DOI: 10.1016/S0304-3835(00)00483-3

Abstract: The molecular basis for downregulation of the KAI1 metastasis suppressor gene in invasive and metastatic human cancers is unknown. We have used bisulphite methylation analysis of DNA from paraffin-embedded invasive bladder tumour s les and from bladder cancer cell lines to determine if hypermethylation of a CpG island within the KAI1 promoter is responsible for this effect. Representative invasive tumour cell lines were also exposed to 5-aza-2-deoxycytidine. We found no evidence for hypermethylation of the CpG island and suggest that mechanisms other than promoter hypermethylation are responsible for reduced KAI1 expression in invasive bladder tumours and tumour cell lines.

Drug accumulation into single drug-sensitive and drug-resistant prostate cancer cells conducted on the single cell bioanalyzer

Publisher: American Society of Mechanical Engineers

Date: 14-11-2014

DOI: 10.1115/IMECE2014-36166

Abstract: Multidrug resistance (MDR) occurs in prostate cancer, and this happens when the cancer cells resist chemotherapeutic drugs by pumping them out of the cells. MDR inhibitors such as cyclosporin A (CsA) can stop the pumping and enhance the drugs accumulated in the cells. The cellular drug accumulation is monitored using a microfluidic chip mounted on a single cell bioanalyzer. This equipment has been developed to measure accumulation of drugs such as doxorubicin (DOX) and fluorescently labeled paclitaxel (PTX) in single prostate cancer cells. The inhibition of drug efflux on the same prostate cell was examined in drug-sensitive and drug-resistant cells. Accumulation of these drug molecules was not found in the MDR cells, PC-3 RX-DT2R cells. Enhanced drug accumulation was observed only after treating the MDR cell in the presence of 5 μM of CsA as the MDR inhibitor. We envision this monitoring of the accumulation of fluorescent molecules (drug or fluorescent molecules), if conducted on single patient cancer cells, can provide information for clinical monitoring of patients undergoing chemotherapy in the future.

Relative activity and specificity of promoters from prostate-expressed genes

Publisher: Wiley

Date: 04-1998

DOI: 10.1002/(SICI)1097-0045(19980401)35:1<18::AID-PROS3>3.0.CO;2-D

Abstract: To evaluate their relative activity and specificity for prostate cells promoter and regulatory regions from three prostate-expressed genes-prostate-specific antigen (PSA), probasin, and relaxin H2-have been compared in prostate cell lines and in lines of breast, bladder, liver, kidney, lung, and ovarian origin. After transfection into different cell types, the activity of promoters was assayed using linked reporter genes and normalized against that of the Rous sarcoma virus. Activity was measured both in the presence and in the absence of co-transfected androgen receptor (AR). PSA and probasin regulatory regions showed strong responsiveness to co-transfection of the AR in most cell types. The core PSA promoter region showed low activity and specificity, but the specificity and level of expression were substantially increased by inclusion of upstream sequences, particularly the enhancer region. Probasin promoter fragments showed specificity of expression for prostate cell lines but required AR for significant levels of expression. Relaxin promoter fragments directed significant AR-inducible expression in prostate cells but showed little specificity and variable AR responsiveness in other cell types. Of regulatory regions tested, a 430-base pair probasin promoter and PSA enhancer/core promoter showed the best combination of AR-stimulated prostate cell expression with limited expression in other cell types.

Induction of Immunity and Tolerance in vitro in the Absence of Phagocytic Cells

Publisher: Springer Science and Business Media LLC

Date: 02-1970

DOI: 10.1038/225731A0

Abstract: Central venoarterial (VA) placement of extracorporeal membrane oxygenation (ECMO) is performed surgically, and in the majority of cases, the patient remains with an open sternum. Herein, a case of a 3-year-old patient who underwent insertion of a central VA ECMO for heart failure due to acute myocarditis is described. An alternative technique for ECMO placement providing sternal closure and minimizing infection risk for the safe patient transport is described.

Paraffin section storage and immunohistochemistry: Effects of time, temperature, fixation, and retrieval protocol with emphasis on p53 protein and MIB1 antigen

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2000

DOI: 10.1097/00022744-200003000-00010

Elevated expression of FGF-2 does not cause prostate cancer progression in LNCaP cells

Publisher: Wiley

Date: 15-06-1999

DOI: 10.1002/(SICI)1097-0045(19990615)40:1<1::AID-PROS1>3.0.CO;2-K

Abstract: Androgen-independent (AI) prostate cancer (CaP) resulting from progression of disease is untreatable. Such progression may relate to upregulation and autocrinicity of growth factor expression. We studied one candidate growth factor, basic fibroblast growth factor (FGF-2). LNCaP cells made autocrine for FGF-2 by stable transfection with FGF-2 were examined for cancer progression, measured by 1) altered response to androgen, 2) ability to grow more quickly when cocultured with bone cells in vitro or to form tumors when coinoculated with bone cells in vivo, or 3) increase in metastatic ability. Stably transfected lines differed in FGF-2 protein expression. LNCaP-HF (high production of FGF-2) expressed more FGF-2 than LNCaP-LF (low production of FGF-2) controls were negative. In vitro, compared with LNCaPs, LNCaP-HF cells showed a slightly increased growth rate, reduced proliferation in response to androgen but not to estrogen or progesterone, and a decreased proliferative response to epidermal growth factor (EGF) and FGF-2. Although giving a slightly faster take rate, LNCaP-HF cells without Matrigel only formed small, fast-regressing tumors in male nude mice, and with Matrigel, did not differ from LNCaPs in growth rate or tumor size. No metastases occurred. No tumors grew in females. Mixed growth of FGF-2 transfectants with human fetal osteoblasts failed to cross-stimulate in vitro, or to allow tumor formation in vivo. Although FGF-2 is overexpressed in AI CaPs, our experiments show that upregulation of FGF-2 expression is not sufficient to cause androgen independence, tumorigenicity, or metastases production (i.e., prostate cancer progression) in LNCaP cells.

Expression of HER1/EGFR protein in human soft tissue sarcomas

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.EJSO.2006.01.012

Abstract: To measure epidermal growth factor receptor (HER1/EGFR) expression in a range of soft tissue sarcoma (STS) patient s les. HER1/EGFR expression was examined by immunohistochemistry in archival tissues of 46 STS patients. HER1/EGFR was positively expressed in 36/46 of STS s les distributed among different histological types. The levels of HER1/EGFR in STS tumour tissues in positive s les were higher compared to those in nearby normal tissues. HER1/EGFR is significantly expressed in soft tissue sarcomas, which is a finding reflected in other series. The significance of this finding for targeted therapy is as yet unknown.

Relationship between radiation response and p53 status in human bladder cancer cells

Publisher: Informa UK Limited

Date: 1997

DOI: 10.1080/095530097143491

Abstract: Mutations in the p53 tumour suppressor gene are found at high frequency in bladder cancer. There is strong evidence that p53 plays an important role in controlling the cell cycle after DNA damage by ionizing radiation. However, the effect of loss of p53 function on radiosensitivity is not yet clear. Radiotherapy combined with chemotherapy is the most common treatment for patients with invasive bladder cancer. Recently three bladder cancer cell lines have been established and this paper investigates the p53 status and clonogenic survival of these cell lines following irradiation. It was found that one line expresses wt p53 (UCRU-BL-13) and two lines contain a codon 72 polymorphism (UCRU-BL-17 and UCRU-BL-28). UCRU-BL-17 cells also contain a point mutation affecting codon 280. The level of p53 expression in the cell lines is clearly different, with UCRU-BL-17 expressing a higher level of p53 compared with UCRU-BL-13 UCRU-BL-28 expressed intermediate levels. The clonogenic survival of these cell lines has been determined. It was found that the line expressing a p53 mutation was more sensitive than those with wild type p53, providing support for a model in which loss of p53 function is associated with increased radiosensitivity, possibly due to reduced p53-dependent DNA repair.

Preparation, DNA Binding, and in Vitro Cytotoxicity of a Pair of Enantiomeric Platinum(II) Complexes, [(R)- and (S)-3-Aminohexahydroazepine]dichloro- platinum(II). Crystal Structu

Publisher: American Chemical Society (ACS)

Date: 03-1997

DOI: 10.1021/JM9607966

IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms

Publisher: Public Library of Science (PLoS)

Date: 15-09-2011

DOI: 10.1371/JOURNAL.PONE.0024241

Comparison between the clonogenic, MTT, and SRB assays for determining radiosensitivity in a panel of human bladder cancer cell lines and a ureteral cell line

Publisher: Wiley

Date: 1999

DOI: 10.1002/(SICI)1520-6823(1999)7:2<77::AID-ROI3>3.0.CO;2-M

Inverse correlation between KAI1 mRNA levels and invasive behaviour in bladder cancer cell lines

Publisher: Elsevier BV

Date: 08-2000

DOI: 10.1016/S0304-3835(00)00427-4

Abstract: We have previously shown that levels of KAI1 mRNA are dramatically reduced in invasive human bladder cancers. To further investigate the role of KAI1 in bladder cancer, we have examined the relationship between KAI1 mRNA levels and cell behaviour in 18 bladder cancer cell lines and a virus-transformed uro-epithelial cell line. We found that low KAI1 mRNA levels correlated with increased in vitro invasive ability, reduced Ca(2+)-dependent and -independent cell-cell adhesion and reduced adhesion to fibronectin. These data support the idea that loss of KAI1 expression is an important factor in tumour cell invasive behaviour.

Ectopic hormone production by small cell undifferentiated carcinomas

Publisher: Elsevier BV

Date: 05-1990

DOI: 10.1016/0303-7207(90)90068-J

Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

Publisher: Wiley

Date: 26-02-2003

DOI: 10.1002/JSO.10210

Abstract: Certain pathophysiological markers may be helpful in selecting further therapies for patients with resected colorectal cancer (CRC). The aim of this study was to determine whether expression of proteins of the plasminogen activation system (PAS), which are important in tumor spread and growth, can predict outcome of human CRC. Protein expression of the PAS, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2), was determined in the colonic tissue s les of 56 patients with resected primary CRC by quantitative immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Overexpression of uPA (t-test, P < 0.001), uPAR (P < 0.001) and PAI-1 (P = 0.031) was significantly associated with liver metastatic CRC tumors. Higher uPA or uPAR expression level was significantly correlated with overall survival (OS log-rank, P = 0.001 and P < 0.0001) and cancer-specific survival (CSS P = 0.001 and P < 0.0001) after the first CRC resection. The predictive value of both uPA and uPAR in liver metastasis, OS and CSS was independent from other parameters (multivariate Cox regression: all P < 0.001). uPA and uPAR may be independent predictors of liver metastasis, patient overall survival and cancer-specific survival after resection of colorectal tumors.

Site‐specific growth of the prostate xenograft line UCRU‐PR‐2

Publisher: Wiley

Date: 1989

DOI: 10.1002/PROS.2990140209

Abstract: A xenografted small-cell, undifferentiated prostate (SCUCP) cancer line, UCRU-Pr-2, was implanted at different sites within nude mice to examine the effect of local environmental factors on tumor growth and behavior. All tumors that grew were small-cell carcinomas. Fragments implanted within muscle and under the kidney capsule were locally invasive however, tumors that grew subcutaneously or intraperitoneally showed no invasion. UCRU-Pr-2 did not grow in the spleen or the liver. No induced metastases were observed in the lung after intravenous injection. The sites of implantation did not allow the outgrowth of subpopulations as detected by the parameters used: light and electron microscopy, expression of tumor markers, levels of hormone production, and DNA flow cytometry. Electron microscopy, which showed both glandular and neuroendocrine differentiation within the same cell, does not support a dual-cell origin of SCUCP.

Targeting Aurora Kinases: A Novel Approach to Curb the Growth & Chemoresistance of Androgen Refractory Prostate Cancer

Publisher: Bentham Science Publishers Ltd.

Date: 02-2012

DOI: 10.2174/156800912799095180

Abstract: Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.

A novel model of bone-metastatic prostate cancer in immunocompetent Mice

Publisher: Wiley

Date: 07-07-2009

DOI: 10.1002/PROS.21010

Abstract: Bone metastasis is a frequent and catastrophic consequence of prostate cancer for which only palliative treatment is available. Animal models of bone metastatic prostate cancer are necessary for understanding disease mechanisms but few models exist. We have used the murine prostate carcinoma cell line RM1 to generate a bone metastatic model of prostate cancer. Repeated intracardiac injection of RM1 cells followed by isolation of cells from bone tumors has yielded a cell line with strong bone-metastatic potential, RM1 bone metastatic (BM). This cell line metastasizes to multiple bony sites in over 95% of injected C57BL/6 mice and is far less tropic to soft tissues. Bone tumors produced by the RM1(BM) cell line show no preference for particular skeletal sites as most bones are affected. Histology, and micro-computed tomography show that RM1(BM) cells form osteolytic tumors, but with evidence of osteoblastic changes. In vitro the RM1 cells express E-cadherin but not vimentin, do not form colonies in soft agar, are non-invasive but are more motile than the parent cell line. This model provides a novel means for identifying cellular and molecular mechanisms that contribute to bone metastasis and allow for preclinical testing of therapies to prevent and treat tumor metastasis to bone. Finally as the syngeneic tumor cells are injected into immunocompetent mice, this model will provide a means to study interactions between the immune system, tumors and bone, and therapies that target such interactions.

Post‐translation modification of proteins in tears

Publisher: Wiley

Date: 26-05-2010

DOI: 10.1002/ELPS.200900755

Abstract: This is the first 2-DE study using sequential dyes to analyse phospho-, glyco- and total tear protein profiles (Pro-Q Diamond for phosphoprotein, Pro-Q Emerald for glycoprotein and Sypro Ruby for total protein). This method minimised the gel-gel variations, allowing better comparisons among the three profiles and generated a whole map of PTM profiles of tear protein. A novel tear protein, dermcidin, was identified for the first time in this study. The identification of this antimicrobial protein suggests a new model of defence in tears. In addition, we are able to present the first experimental evidence of the presence of glycosylated lipocalin 1 and cystatin S. Nucleobindin 2 was only detected using phospho staining, suggesting it is only phosphorylated in tears. This study provides the groundwork for understanding the PTM of tear proteins and consequently these methods could be useful in the search for biomarkers in tears.

Tumour‐induced host stromal‐cell transformation: Induction of mouse spindle‐cell fibrosarcoma not mediated by gene transfer

Publisher: Wiley

Date: 15-08-1990

DOI: 10.1002/IJC.2910460227

Abstract: Tumour-induced host-cell transformation has been addressed by examining human tumours in situ and following xenograft to nude mice. We have found evidence for the transformation of host stromal fibroblasts both in vivo and following the introduction of the tumours to in vitro culture. The in vitro culture of one such xenograft--derived from a human prostatic adenocarcinoma--resulted in the outgrowth of a transformed aneuploid mouse cell line. This transformed line was tumourigenic both in BALB/c nu/nu (nude) mice and in heterozygous nu/+mice, with the morphology of a spindle-cell sarcoma. The cell line did not express human isozymes or human histocompatibility antigens, nor were human chromosomes present. Moreover, human DNA sequences were not detected by human Alu repeat sequence element probing in the transformed cell line grown either in vitro or in vivo. The line contained retroviral long terminal repeat sequences but there was no evidence of proviral activation. These findings indicate that tumour cells may cause transformation of neighbouring stromal cells that this transformation may proceed in the absence of DNA transfer or activation of endogenous proviruses and that the means of this observed transformation may involve humoral factors elaborated by the tumour cells.

Role of the akt pathway in prostate cancer

Publisher: Bentham Science Publishers Ltd.

Date: 03-2009

DOI: 10.2174/156800909787581006

Abstract: The Akt pathway, or more accurately, network, has assumed increasing importance with the understanding that it represents a key role in cancer cell survival and proliferation. Intense efforts to target proteins and enzymes within this pathway with highly selective compounds have led to the development of erse agents now in Phase I-III clinical trials. Moreover, the notion that exploitation of multiple "druggable" targets simultaneously or in the appropriate sequence may provide better anti-tumour effects than single drugs hold promise that chemoresistance may be overcome, at least in part. This paper reviews important aspects of the Akt network, with a particular focus on prostate cancer biology.

Development of a polymer theranostic for prostate cancer

Publisher: Royal Society of Chemistry (RSC)

Date: 04-09-2014

DOI: 10.1039/C4PY00999A

The Propeptide Mediates Formation of Stromal Stores of PROMIC-1: Role in Determining Prostate Cancer Outcome

Publisher: American Association for Cancer Research (AACR)

Date: 15-03-2005

DOI: 10.1158/0008-5472.CAN-04-3827

Abstract: The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor–β superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in ∼20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score ≤ 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.

Promising tumor-associated antigens for future prostate cancer therapy

Publisher: Wiley

Date: 18-06-2009

DOI: 10.1002/MED.20165

Abstract: Prostate cancer (CaP) is one of the most prevalent malignant diseases among men in Western countries. There is currently no cure for metastatic castrate-resistant CaP, and median survival for these patients is about 18 months the high mortality rate seen is associated with widespread metastases. Progression of CaP from primary to metastatic disease is associated with several molecular and genetic changes that can affect the expression of specific tumor-associated antigens (TAAs) or receptors on the cell surface. Targeting TAAs is emerging as an area of promise for controlling late-stage and recurrent CaP. Several reviews have summarized the progress made in targeting signaling pathways for CaP but will not be discussed here. We describe some important CaP TAAs. These include prostate stem-cell antigen, prostate-specific membrane antigen, MUC1, epidermal growth factor receptor, platelet-derived growth factor and its receptor, urokinase plasminogen activator and its receptor, and extracellular matrix metalloproteinase inducer. We summarize recent advancements in our understanding of their role in CaP metastasis, as well as potential therapeutic options for targeting CaP TAAs. We also discuss the origin, identification, and characterization of prostate cancer stem cells (CSCs) and the potential benefits of targeting prostate CSCs to overcome chemoresistance and CaP recurrence.

Scientific Program 2012 ISEV meeting Wednesday 18th April

Publisher: Wiley

Date: 2012

DOI: 10.3402/JEV.V1I0.18182

Abstracts from the Fourth International Meeting of ISEV, ISEV2015, Washington, D.C., USA, 23‐26 April 2015

Publisher: Wiley

Date: 2015

DOI: 10.3402/JEV.V4.27783

Analysis of expressed N-ras mutations in human melanoma short-term cell lines with allele specific restriction analysis induced by the polymerase chain reaction

Publisher: Elsevier BV

Date: 1992

DOI: 10.1016/0959-8049(92)90373-A

Abstract: Mutations in ras genes have been found in the DNA of numerous cancer types including melanomas, but the expression of these mutations in melanomas has not yet been addressed. We have used the polymerase chain reaction (PCR) and allele-specific restriction analysis (ASRA) to determine the frequency of expressed N-ras mutations on 25 short-term melanoma tissue culture s les. N-ras cDNA generated using reverse transcriptase from whole cells was used as the PCR template. 14 secondary melanoma cultures that varied in differentiation patterns were analysed. Only 2 were found to express N-ras mutations in both, the mutation was localised to one of the first two positions of the 61st codon of N-ras. These tumour lines, KMI-M8412a and KMI-M8412b, were established from separate tumour deposits in the same patient. Codons 12 and 13 were found to be free of mutations in all of the lines studied. 8 primary melanomas and 3 unclassified skin lesions were also analysed and found free of N-ras mutations. These results suggest that N-ras may not play such an important role in melanoma tumorigenesis as is speculated by others.

Plant-derived MINA-05 inhibits human prostate cancer proliferation in vitro and lymph node spread in vivo.

Publisher: Elsevier BV

Date: 04-2007

DOI: 10.1593/NEO.06775

Abstract: Few treatment options exist for metastatic prostate cancer (PC) that becomes hormone refractory (HRPC). In vitro, plant-derived MINA-05 caused dose-dependent decreases in cell numbers in HRPC cell lines LNCaP-C4-2B and PC-3, and in androgen-sensitive LNCaP-FGC, DuCaP, and LAPC-4, by WST-1 assay. MINA-05 pretreatment significantly decreased clonogenic survival in agar and on plastic at 1 x and 2 x IC50 for PC-3 (P < .05 and P < .001, respectively), and at 1/2 x, 1 x, and 2 x IC50 for LNCaP-FGC cells (P < .001). MINA-05 also induced G2M arrest of LNCaP-FGC and PC-3 cells (by flow cytometry) and caused some apoptosis in LNCaP-FGC (sub-G1 peak on flow, expression of activated caspase-3) but not in PC-3 cells. Western blotting indicated that these cell cycle changes were associated with decreased levels of regulatory proteins cyclin B1 and cdc25C. MINA-05 given daily by gavage for 39 days did not diminish primary orthotopic PC-3 growth in nude mice, but decreased the extent of lymph node invasion at higher doses. We conclude that MINA-05 induces G2M arrest, inhibits cell growth, reduces PC cell regrowth in vitro, and reduces lymph node invasion after orthotopic PC-3 cell implantation in vivo. It has potential as an adjuvant treatment for patients with PC.

Tie-2 regulates the stemness and metastatic properties of prostate cancer cells

Publisher: Impact Journals, LLC

Date: 29-04-2016

DOI: 10.18632/ONCOTARGET.3950

DNA-Flow cytometric analysis of bladder TCC using paraffin-embedded tissues.

Publisher: S. Karger AG

Date: 1998

DOI: 10.1159/000030256

Abstract: A retrospective study of DNA flow cytometry (FCM) in paraffin-embedded tissues of urinary bladder transitional cell carcinoma (TCC) was performed on 239 biopsy s les taken from 81 patients in the period from 1984 to 1994. 210 (87%) were analysable. Of these s les 21 patients had multiple biopsies taken from large tumours and/or bladder mucosa showing an endoscopically normal appearance. DNA-FCM results have been evaluated comparing ploidy and histopathological grade, clinical stage and different clinical status, i.e., first diagnosis, recurrence and patients who died from bladder cancer. Our results indicate that ‘diploid’ FCM correlated with a better prognosis, whilst DNA aneuploid correlated with malignancy and a poorer prognosis. There was a trend to an increasing incidence of DNA aneuploidy as the grade of the tumour rose and the proportion of biopsies with aneuploidy was significantly higher in malignant tissue s les, recurrences and in biopsies from patients who died from TCC than in other groups. In 12 patients from whom several biopsies were obtained, s les from recurrences had significantly higher DNA aneuploidy than those from the first diagnosis.

DNA flow‐cytometric analysis in colorectal cancer: A comparison of metastasizing and non‐metastasizing tumours

Publisher: Wiley

Date: 04-1996

DOI: 10.1111/J.1440-1746.1996.TB01378.X

Abstract: The most common cause of death in patients with colorectal cancer is metastatic liver disease. In order to identify patients at a high risk of developing hepatic secondaries from colorectal cancers, DNA content was measured in metastasizing colorectal primaries (Group I, n = 32) as well as in their subsequently resected liver secondaries and in sections of non-metastasizing colorectal cancers (Group II, n = 25). A modified interpretation system involving both a DNA index and percentage of cycling cells (those in S and G2 + M phases) was developed. DNA content was measured in paraffin-embedded sections by flow cytometry using internal controls (human peripheral blood mononuclear cells) and non-malignant tissue controls (19 patients with erticular disease). In Group I there were significantly more tumours with both abnormal ploidy (aneuploid or abnormal tetraploid peak) and > 15% cycling cells compared with Group II (Chi-squared P = 0.034). The combination of abnormal ploidy and > 15% cycling cells was superior to Dukes' classification for identifying metastasizing tumours (Logistic Regression P = 0.047). However, it was not possible to discriminate between the two groups using either DNA ploidy or the percentage of cycling cells alone. The metastasizing colorectal cancers exhibited similar DNA ploidy characteristics and had a similar percentage of cycling cells compared with their liver metastases. These results suggest that tumour DNA ploidy plus the percentage of cycling cells may predict the development of liver metastases and thus survival in patients with colorectal cancer.

Translational Research Institute

Location: Australia

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Royal Prince Alfred Hospital

Location: Australia

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Queensland University Of Technology

Location: Australia

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Prince Of Wales Hospital

Location: Australia

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Kolling Institute Of Medical Research

Location: Australia

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Australian National University

Location: Australia

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Walter And Eliza Hall Institute Of Medical Research

Location: Australia

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University Of Queensland

Location: Australia

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University Of New South Wales

Location: Australia

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University Of Melbourne

Location: Australia

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University Of Canberra Faculty Of Education Science Technology And Mathematics

Location: Australia

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The PSA-related Enzyme, KLK4, Is A Master Regulator Of Tumour Spread In Prostate Cancer And The Associated Bone Metastasis

Start Date: 2011

End Date: 2015

Funder: National Health and Medical Research Council

A Humanized In Vivo Model To Test Novel Therapeutic Strategies Against Prostate Cancer Bone Metastasis

Start Date: 2015

End Date: 2016

Funder: (Association for International Cancer Research

Immune Polymeric Drugs For Prostate Cancer Therapy

Start Date: 2016

End Date: 2018

Funder: National Health and Medical Research Council

Development And Validation Of Virtual Epithelial Cancer Models Using An Integrated Modelling And Experimental Three-dimensional Approach

Start Date: 2011

End Date: 2014

Funder: Australian Research Council

Numerical Modelling And Experimental Studies To Design And Engineer Nanoparticulate Systems For Bioapplications

Start Date: 2008

End Date: 2010

Funder: Australian Research Council

Comprehensive Cell Imaging Facility

Start Date: 2011

End Date: 2011

Funder: Australian Research Council

Hybrid Nanomaterials: Bispecific Antibody-targeted Polymers

Start Date: 2015

End Date: 2017

Funder: Australian Research Council

The Vevo 2100 Micro-ultrasound Plus LAZR Photoacoustic Imaging Platform

Start Date: 2015

End Date: 2015

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0774951

Start Date: 04-2007

End Date: 06-2011

Amount: $75,354.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100172

Start Date: 2011

End Date: 12-2011

Amount: $330,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP110103890

Start Date: 2011

End Date: 12-2014

Amount: $500,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP150100703

Start Date: 06-2016

End Date: 06-2019

Amount: $360,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0882720

Start Date: 03-2009

End Date: 12-2011

Amount: $371,320.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100067

Start Date: 2015

End Date: 06-2016

Amount: $390,000.00

Funder: Australian Research Council