Mel Ziman

Pax7 is expressed in the capsules surrounding adult mouse neuromuscular spindles

Publisher: Canadian Science Publishing

Date: 1999

DOI: 10.1139/BCB-77-2-153

Respiratory muscle training for respiratory deficits in neurodegenerative disorders: A systematic review

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1378/CHEST.12-1442

Abstract: Studies of the impact of respiratory muscle training (RMT) on central neurodegenerative pathologies have been aimed at improving pulmonary function. However, there is no certainty about the effectiveness of RMT in patients affected by these groups of disorders. The purpose of this review was to assess the evidence regarding the efficacy of inspiratory muscle training (IMT) and expiratory muscle training (EMT) on respiratory function in patients with neurodegenerative disorders of the CNS. A comprehensive search from 1990 to September 2012 on MEDLINE, Physiotherapy Evidence Database (PEDro), PubMed, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases was made. Studies reporting on IMT and EMT in patients with neurodegenerative diseases were included. The selected studies were abstracted using a standardized data collection instrument and were assessed by a quality checklist created and adapted from CONSORT (Consolidated Standards for Reporting Trials) and TREND (Transparent Reporting of Evaluation with Nonrandomized Designs). Twenty-four studies were identified by the search strategy. Only 19 studies met the criteria for full review. Ten studies met all the inclusion criteria and were included in the final analysis. Of the 16 parameters present in the quality assessment checklist, only six were achieved for the studies analyzed. There is some evidence that RMT improves a number of respiratory function parameters in patients with Parkinson disease and multiple sclerosis however, the number of studies and their quality are not sufficient to conclude whether IMT or EMT is effective in improving respiratory function in patients with neurodegenerative disorders of the CNS.

The effects of multidisciplinary rehabilitation in patients with early-to-middle-stage Huntington's disease: A pilot study

Publisher: Wiley

Date: 07-12-2013

DOI: 10.1111/ENE.12053

Abstract: Despite advances in the understanding of Huntington's disease (HD), treatment remains symptomatic. Multidisciplinary rehabilitation, however, appears to impact disease progression. Here we show the feasibility, safety and efficacy of a 9-month multidisciplinary rehabilitation programme in a small cohort of patients with early-to-middle-stage HD. Twenty patients with HD were assigned to two groups, equally matched for cognitive and motor scores. One group received the intervention, whilst the other served as control. The Unified-Huntington's-Disease-Rating-Scale-Total-Motor-Score was the primary outcome measure. Neurocognitive sychological tests, body composition, postural stability, strength and quality of life assessments were secondary outcome measures. The intervention reduced motor and postural stability deterioration, with minor improvements in depression, cognition and quality of life. Significant gains were observed for fat-free mass and strength. This pilot study suggests that a prolonged multidisciplinary rehabilitation programme in early-to-middle-stage HD is feasible, well-tolerated and associated with therapeutic benefit. Further explorative, larger studies are warranted.

Circulating tumor cells as biomarkers in cancer

Publisher: Springer Netherlands

Date: 2015

DOI: 10.1007/978-94-007-7681-4_21

Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1038/JID.2015.127

Genetic analysis of heterogeneous subsets of circulating tumour cells from high grade serous ovarian carcinoma patients

Publisher: Springer Science and Business Media LLC

Date: 13-02-2023

DOI: 10.1038/S41598-023-29416-Z

Abstract: Circulating tumour cells (CTCs) are heterogenous and contain genetic information from the tumour of origin. They bear specific intra- and extra-cellular protein markers aiding in their detection. However, since these markers may be shared with other rare cells in the blood, only genetic testing can confirm their malignancy. Herein, we analyse different CTC subsets using single cell whole genome DNA sequencing to validate their malignant origin. We randomly selected putative CTCs identified by immunostaining that were isolated from 4 patients with high grade serous ovarian cancer (HGSOC) and one with benign cystadenoma. We specifically targeted CTCs positive for epithelial (CK/EpCAM pos ), mesenchymal (vimentin pos ), and pseudoendothelial (CK/EpCAM pos plus CD31 pos ) markers. We isolated these cells and performed whole genome lification (WGA) and low-pass whole-genome sequencing (LP-WGS) for analysis of copy number alterations (CNA). Of the CK/EpCAM pos cells analysed from the HGSOC patients, 2 of 3 cells showed erse chromosomal CNAs. However, the 4 pseudoendothelial cells (CK/EpCAM pos plus CD31 pos ) observed in the HGSOC cases did not carry any CNA. Lastly, two of the clusters of vimentin positive cells sequenced from those found in the benign cystadenoma case had CNA. Despite the low number of cells analysed, our results underscore the importance of genetic analysis of putative CTCs to confirm their neoplastic origin. In particular, it highlights the presence of a population of CK/EpCAM pos cells that are not tumour cells in patients with HGSOC, which otherwise would be counted as CTCs.

Repurposing nano-enabled polymeric scaffolds for tumor-wound management and 3D tumor engineering

Publisher: Future Medicine Ltd

Date: 10-2020

DOI: 10.2217/RME-2020-0072

Abstract: The main challenges of cancer drugs are toxicity, effect on wound healing atient outcome and in vivo instability. Polymeric scaffolds have been used separately for tissue regeneration in wound healing and as anticancer drug releasing devices. Bringing these two together in bifunctional scaffolds can provide a tool for postoperative local tumor management by promoting healthy tissue regrowth and to deliver anticancer drugs. Another addition to the versatility of polymeric scaffold is its recently discovered ability to act as 3D cell culture models for in vitro isolation and lification of cancer cells for personalized drug screening and to recapitulate the tumor microenvironment. This review focuses on the repurposing of 3D polymeric scaffolds for local tumor-wound management and development of in vitro cell culture models.

Detection of BRAF-V600E and V600K in melanoma circulating tumour cells by droplet digital PCR

Publisher: Elsevier BV

Date: 10-2015

DOI: 10.1016/J.CLINBIOCHEM.2014.12.007

Abstract: Defining the BRAF mutation status in metastatic melanoma patients is critical to selecting patients for therapeutic treatment with targeted therapies. Circulating tumour cells (CTCs) can provide an alternative source of contemporaneous tumour genetic material. However methodologies to analyse the presence of rare mutations in a background of wild-type DNA requires a detailed assessment. Here we evaluate the sensitivity of two technologies for cancer mutation detection and the suitability of whole genome lified DNA as a template for the detection of BRAF-V600 mutations. Serial dilutions of mutant BRAF-V600E DNA in wild-type DNA were tested using both competitive allele-specific PCR (castPCR) and droplet digital PCR (ddPCR), with and without previous whole genome lification (WGA). Using immunomagnetic beads, we partially enriched CTCs from blood obtained from metastatic melanoma patients with confirmed BRAF mutation positive tumours and extracted RNA and DNA from the CTCs. We used RT-PCR of RNA to confirm the presence of melanoma cells in the CTC fraction then the DNAs of CTC positive fractions were WGA and tested for BRAF V600E or V600K mutations by ddPCRs. WGA DNA produced lower than expected fractional abundances by castPCR analysis but not by ddPCR. Moreover, ddPCR was found to be 200 times more sensitive than castPCR and in combination with WGA produced the most concordant results, with a limit of detection of 0.0005%. BRAF-V600E or V600K mutated DNA was detected in 77% and 44%, respectively, of enriched CTC fractions from metastatic melanoma patients carrying the corresponding mutations. Our results demonstrate that using ddPCR in combination with WGA DNA allows the detection with high sensitivity of cancer mutations in partially enriched CTC fractions.

Droplet Digital PCR for Mutation Detection in Formalin-Fixed, Paraffin-Embedded Melanoma Tissues

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.JMOLDX.2017.11.009

Abstract: The identification of somatic mutations is crucial for guiding therapeutic decisions about personalized melanoma treatment. However, genetic analysis of tumors is usually performed on limited and often low-quality DNA from tumors with low tumor cellularity and high tumor heterogeneity. Different mutation-detection platforms exist, with varying analytical sensitivities. Here we evaluated the detection of common mutations in BRAF, NRAS, and TERT promoter in 40 melanoma FFPE tissues using Droplet Digital (dd)PCR, and compared the results to the detection rates obtained by Sanger sequencing and pyrosequencing. The cellularity of tumors analyzed ranged from 5% to 50% (n = 28) and 50% to 90% (n = 12). Overall, droplet digital (dd)PCR was more sensitive, detecting mutations in 12.5% and 23% of tumors deemed as wild-type by pyrosequencing and Sanger sequencing, respectively. The increased sensitivity of ddPCR was more apparent among tumors with <50% tumor cellularity. Implementation of ddPCR-based assays may facilitate analysis of early-stage tumors and support research into improving outcomes in melanoma patients.

The degradation of different forms of cytochrome P-450 in vivo by fluroxene and allyl-iso-propylacetamide

Publisher: Elsevier BV

Date: 12-1978

DOI: 10.1016/0006-291X(78)90623-X

Molecular markers of circulating melanoma cells

Publisher: Wiley

Date: 20-12-2007

DOI: 10.1111/J.1600-0749.2006.00356.X

Abstract: Of all skin cancers, cutaneous malignant melanoma (CMM) is the most aggressive and the life expectancy of patients with lymphatic or systemic metastases is dramatically reduced. Understandably therefore, scientists and clinicians have focused on improving diagnostic and prognostic techniques. Of these, perhaps the most promising are multimarker real-time RT-PCR and microarray for detection of circulating CMM cells in peripheral blood. While the optimal set of markers is still to be identified that can accurately assess disease severity and progression at all clinical stages of the disease, recent progress has been dramatic. Here we provide an exhaustive review of recent studies in which a variety of markers are assessed. Moreover, the efficacy of the markers relative to clinical stage is discussed in light of experimental findings. From these studies, it is apparent that researchers are now much closer to defining a set of markers of circulating cells that can be utilized in routine diagnostic tests.

Genetic factors in metastatic progression of cutaneous melanoma: The future role of circulating melanoma cells in prognosis and management

Publisher: Springer Science and Business Media LLC

Date: 11-02-2011

DOI: 10.1007/S10585-010-9368-2

Abstract: The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any in idual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment.

Perplexing pax: From puzzle to paradigm

Publisher: Wiley

Date: 24-09-2008

DOI: 10.1002/DVDY.21711

Abstract: Pax transcription factors are critical for the development of the central nervous system (CNS) where they have a biphasic role, initially dictating CNS regionalization, while later orchestrating differentiation of specific cell subtypes. While a plethora of expression, misexpression, and mutation studies lend support for this argument and clarify the importance of Pax genes in CNS development, less well understood, and more perplexing, is the continued Pax expression in the adult CNS. In this article we explore the mechanism of action of Pax genes in general, and while being cognizant of existing developmental data, we also draw evidence from (1) adult progenitor cells involved in regeneration and tissue maintenance, (2) specific expression patterns in fully differentiated adult cells, and (3) analysis of direct target genes functioning downstream of Pax proteins. From this, we present a more encompassing theory that Pax genes are key regulators of a cell's measured response to a dynamic environment.

Prognostic Relevance of CCDC88C (Daple) Transcripts in the Peripheral Blood of Patients with Cutaneous Melanoma

Publisher: Springer Science and Business Media LLC

Date: 21-12-2018

DOI: 10.1038/S41598-018-36173-X

Abstract: A loss of balance between G protein activation and deactivation has been implicated in the initiation of melanomas, and non-canonical Wnt signaling via the Wnt5A/Frizzled (FZD) pathway has been shown to be critical for the switch to an invasive phenotype. Daple [CCDC88C], a cytosolic guanine nucleotide exchange modulator (GEM) which enhances non-canonical Wnt5A/FZD signaling via activation of trimeric G protein, Gαi, has been shown to serve opposing roles–as an inducer of EMT and invasiveness and a potent tumor suppressor–via two isoforms, V1 (full-length) and V2 (short spliced isoform), respectively. Here we report that the relative abundance of these isoforms in the peripheral circulation, presumably largely from circulating tumor cells (CTCs), is a prognostic marker of cutaneous melanomas. Expression of V1 is increased in both the early and late clinical stages ( p 0.001, p = 0.002, respectively) V2 is decreased exclusively in the late clinical stage ( p = 0.003). The two isoforms have opposing prognostic effects: high expression of V2 increases relapse-free survival (RFS p = 0.014), whereas high expression of V1 tends to decrease RFS ( p = 0.051). Furthermore, these effects are additive, in that melanoma patients with a low V2-high V1 signature carry the highest risk of metastatic disease. We conclude that detection of Daple transcripts in the peripheral blood (i.e., liquid biopsies) of patients with melanoma may serve as a prognostic marker and an effective strategy for non-invasive long-term follow-up of patients with melanoma.

Evaluation of a multi-marker immunomagnetic enrichment assay for the quantification of circulating melanoma cells

Publisher: Springer Science and Business Media LLC

Date: 15-09-2012

DOI: 10.1186/1479-5876-10-192

Abstract: Circulating melanoma cells (CMCs) are thought to be valuable in improving measures of prognosis in melanoma patients and may be a useful marker of residual disease to identify non-metastatic patients requiring adjuvant therapy. We investigated whether immunomagnetic enrichment targeting multiple markers allows more efficient enrichment of CMCs from patient peripheral blood than targeting a single marker. Furthermore, we aimed to determine whether the number of CMCs in patient blood was associated with disease stage. We captured CMCs by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271, both in idually and in combination, by immunomagnetic enrichment. CMCs were enriched and quantified from the peripheral blood of 10 non-metastatic and 13 metastatic melanoma patients. Targeting all markers in combination resulted in the enrichment of more CMCs than when any in idual marker was targeted (p 0.001-0.028). Furthermore, when a combination of markers was targeted, a greater number of CMCs were enriched in metastatic patients compared with non-metastatic patients (p = 0.007). Our results demonstrated that a combination of markers should be targeted for optimal isolation of CMCs. In addition, there are significantly more CMCs in metastatic patients compared with non-metastatic patients and therefore quantification of CMCs may prove to be a useful marker of disease progression.

Pax genes: Regulators of lineage specification and progenitor cell maintenance

Publisher: The Company of Biologists

Date: 15-02-2014

DOI: 10.1242/DEV.091785

Abstract: Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer.

The role of Pax7 in determining the cytoarchitecture of the superior colliculus

Publisher: Wiley

Date: 06-2004

DOI: 10.1111/J.1440-169X.2004.00744.X

Reaction schemes for the degradation of cytochromes P-450 by allyl-iso-propylacetamide and fluroxene

Publisher: Elsevier BV

Date: 10-1980

DOI: 10.1016/0006-2952(80)90015-5

Abstract: Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.

Multi-marker immunofluorescent staining and pd-l1 detection on circulating tumour cells from ovarian cancer patients

Publisher: MDPI AG

Date: 10-12-2021

DOI: 10.3390/CANCERS13246225

Abstract: Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1.

Δ6-Desaturase: Improved methodology and analysis of the kinetics in a multi-enzyme system

Publisher: Elsevier BV

Date: 1996

DOI: 10.1016/0167-4838(95)00174-3

Abstract: A new method of assay for the delta 6-desaturation of linoleic acid was developed. This method, which uses HPLC for separation of the fatty acid substrate and product, exhibited a lower coefficient of variation (0.3%) than the reported TLC method (3.5%), and avoided the step of methylation of the saponified fatty acid substrate and product. Using this new method of assay, the kinetics of the delta 6-desaturase in a multi-enzyme system were analysed. A number of factors that could have striking effects on desaturase kinetics were investigated, including the effect of (i) endogenous microsomal linoleic acid on total substrate concentration, and (ii) the pre-reaction catalysed by acyl-CoA synthetase and competing reactions catalysed by lysophospholipid acyltransferase and acyl-CoA hydrolase. Endogenous free linoleate in the hepatic microsomes was found to be 2.9 +/- 1.0 microM (0.5 mg microsomal protein/ml), which was comparable to added substrate concentrations (1.8 to 7.9 microM). The kinetics of the delta 6-desaturase were dissected from the kinetics of the above mentioned pre-reaction and competing reactions through a combination of experimental approaches and computer modeling. From computer modeling, a Km and Vmax of 1.5 microM and 0.63 nmol/min were calculated for the delta 6-desaturase, compared to Km and Vmax of 10.7 microM and 0.08 nmol/min calculated directly from data uncorrected for endogenous substrate. It was concluded that lysophospholipid acyltransferase, acyl-CoA synthetase and endogenous linoleic acid significantly affect the kinetic measurements of hepatic microsomal delta 6-desaturase. These results have implications for kinetic analyses of all desaturates in microsomal systems.

Pulmonary function in patients with Huntington's Disease

Publisher: Springer Science and Business Media LLC

Date: 26-05-2014

DOI: 10.1186/1471-2466-14-89

A dorso-ventral gradient of Pax6 in the developing retina suggests a role in topographic map formation

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0165-3806(02)00605-3

Abstract: Expression of the transcription factor Pax6 was assessed immunohistochemically in embryonic chick retina during retino-tectal map formation. A low dorsal to high ventral gradient was found that correlated with expression of the axonal guidance cue EphB2. Furthermore, transfection of Pax6 into undifferentiated P19 cells up-regulated EphB2. The results raise the possibility that Pax6 is upstream of EphB2 and that its graded expression defines the dorso-ventral axis of the retino-tectal projection.

Circulating Tumour DNA in Advanced Melanoma Patients Ceasing PD1 Inhibition in the Absence of Disease Progression

Publisher: MDPI AG

Date: 23-11-2020

DOI: 10.3390/CANCERS12113486

Abstract: Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2–70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher’s exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645–0.930) and 0.80 (95% CI 0.284–0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p 0.001, HR: 0.008, 95% CI: 0.001–0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.

Computerised Dynamic Posturography in Premanifest and Manifest individuals with Huntington’s Disease

Publisher: Springer Science and Business Media LLC

Date: 02-10-2018

DOI: 10.1038/S41598-018-32924-Y

Abstract: Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington’s disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy in iduals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p 0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p 0.001), maximum excursion (p ≤ 0.001), and directional control (p ≤ 0.004) values than healthy in iduals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that in iduals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials.

Melanoma biomolecules: Independently identified but functionally intertwined

Publisher: Frontiers Media SA

Date: 2013

DOI: 10.3389/FONC.2013.00252

Advances in personalized targeted treatment of metastatic melanoma and non-invasive tumor monitoring

Publisher: Frontiers Media SA

Date: 2013

DOI: 10.3389/FONC.2013.00054

Heat stress: A risk factor for skin carcinogenesis

Publisher: Elsevier BV

Date: 08-2201

DOI: 10.1016/J.CANLET.2013.05.039

Abstract: Recent evidence suggests that heat stress may also be a risk factor of skin carcinogenesis. Heat stress causes activation of heat shock proteins (HSPs), chaperone proteins which prevent cells from undergoing apoptosis and ensuring their cellular function. However, HSPs recruitment may also have deleterious effects particularly if the cells rescued from apoptosis carry oncogenic mutations. We hypothesise that exposures to both heat and UV induce skin cancer(s) by concomitant expression of HSPs and oncogenic mutant proteins. Here we review studies demonstrating that heat stress-activated heat shock proteins such as HSP72 and HSP90 can influence signalling pathways such as MAPK, JNK and p53, which are all involved in regulating cell proliferation, survival and apoptosis.

A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2015

DOI: 10.1097/MD.0000000000000411

Novel nut and bolt task quantifies motor deficits in premanifest and manifest huntington’s disease

Publisher: Public Library of Science (PLoS)

Date: 2015

DOI: 10.1371/CURRENTS.HD.DED251617AE62A1364506B0521BD3761

Pax3 transcripts in melanoblast development

Publisher: Wiley

Date: 30-11-2005

DOI: 10.1111/J.1440-169X.2005.00835.X

Purification of and kinetic studies on a cloned protoporphyrinogen oxidase from the aerobic bacterium Bacillus subtilis

Publisher: Elsevier BV

Date: 10-1998

DOI: 10.1006/ABBI.1998.0834

Abstract: The previously cloned and expressed protoporphyrinogen oxidase from Bacillus subtilis has been purified to homogeneity by Ni2+ affinity chromatography using a His6 tag and characterized. The enzyme has a molecular weight of approximately 56,000 daltons, a pI of 7.5, a pH optimum (protoporphyrinogen) of 8.7, and a noncovalently bound flavine adenine dinucleotide cofactor. The Michaelis constants (Km) for protoporphyrinogen-IX, coproporphyrinogen-III, and mesoporphyrinogen-IX are 1.0, 5.29, and 4.92 microM, respectively. Polyclonal antibody to B. subtilis protoporphyrinogen oxidase demonstrated weak cross-reactivity with both human and Myxococcus xanthus protoporphyrinogen oxidase. B. subtilis protoporphyrinogen oxidase is not inhibited by the diphenyl ether herbicide acifluorfen at 100 microM and is weakly inhibited by methylacifluorfen at the same concentration. Bilirubin, biliverdin, and hemin are all competitive inhibitors of this enzyme.

Characterization of the alternate allelic forms of human PAX7

Publisher: Springer Science and Business Media LLC

Date: 04-2000

DOI: 10.1007/S003350010061

Abstract: Six different allelic forms of the human neurogenic and myogenic developmental gene, PAX7, have been identified. They are distinguished by the number of tandem tetranucleotide, GAAG, repeats at a polymorphic site within the second intron of the paired box. Within the same intron, a second polymorphic site was found to have variable numbers of a dinucleotide TG repeat. The alleles are identified by a PCR-based method with oligo primers that span the variable regions of the intron. Several of the alleles include a duplicate copy of the entire paired box. Segregation studies demonstrate that the PAX7 alleles are inherited in a Mendelian fashion and that the duplicate copies of the PAX7 paired box region present in some of the alleles are closely linked. This initial study identified differences in the distribution of PAX7 alleles in DNA from patients with the skeletal muscle myopathy, dermatomyositis. Recognition of genetic polymorphism of PAX7 allows new approaches to understanding the role of PAX7 in myogenesis, neurogenesis, and neuromuscular disorders.

The Characterisation of Pax3 Expressant Cells in Adult Peripheral Nerve

Publisher: Public Library of Science (PLoS)

Date: 19-03-2013

DOI: 10.1371/JOURNAL.PONE.0059184

Pax7 includes two polymorphic homeoboxes which contain rearrangements associated with differences in the ability to regenerate damaged skeletal muscle in adult mice

Publisher: Elsevier BV

Date: 03-1998

DOI: 10.1016/S1357-2725(97)00108-8

Abstract: Pax7 is a paired-type homeobox gene which has previously been shown to play an important role in skeletal muscle formation. It is expressed in skeletal muscle of the limbs during embryogenesis and in adulthood. The aims of this study were firstly to determine the degree of polymorphism of Pax7 amongst inbred laboratory mice using Southern blotting and Pax7 regional specific sub-probes. Secondly, functional studies were performed on mice with each of the different structural forms of Pax7 to determine whether they were associated with differences in the ability to regenerate damaged skeletal muscle. Four different allelic forms of Pax7 have now been identified in laboratory mice indicating that the previously reported DNA sequence of Pax7 is not applicable to all laboratory mice. Hybridisation patterns of TaqI digested DNA representing each of the different Pax7 alleles with the Pax7 specific sub-probes suggested that in contrast to previous findings, Pax7 is associated with two highly polymorphic homeoboxes. The presence of two homeoboxes in BALB/c mice has been confirmed by DNA sequencing. Results of functional studies have also shown that the ability to regenerate damaged skeletal muscle in adult mice is strongly associated with the presence of a 0.15-kb TaqI fragment derived from one of the homeoboxes.

Lab-on-chip platform for circulating tumor cells isolation

Publisher: SPIE

Date: 22-12-2015

DOI: 10.1117/12.2201127

Alternate Pax7 paired box transcripts which include a trinucleotide or a hexanucleotide are generated by use of alternate 3' intronic splice sites which are not utilized in the ancestral homologue

Publisher: Elsevier BV

Date: 04-1999

DOI: 10.1016/S0378-1119(99)00049-9

Abstract: In the mouse, Pax7 plays an important role in development of the skeletal muscles of the limbs, elements of the nervous system and cranio-facial structures. It is expressed in the brain and skeletal muscles of the limbs in the mature mouse. Recently, we have identified alternate transcripts that differ by inclusion or exclusion of a trinucleotide and/or a hexanucleotide in the paired domain encoding region. Sequencing of the paired box in genomic DNA from SJL/J and BALB/c mice reveals that the trinucleotide and hexanucleotide are generated by selection of alternate splice sites at the 3' terminus of each of the two paired box introns, respectively. The proximal 3' splice site of the first intron, which includes the trinucleotide in the mature transcript, is preferentially selected in skeletal muscle and brain. By contrast, the proximal 3' splice site of the second intron, which results in inclusion of the hexanucleotide in the mature transcript, is preferentially selected only in skeletal muscle. The distal alternate 3' splice site, which results in exclusion of the hexanucleotide in the mature transcript, is preferentially selected in the brain. These findings raise the possibility that there may be tissue-specific factors that influence the specificity of the spliceosomal machinary. Reference to the structure of the proposed primordial form of Pax7 suggests that the ability to utilize the alternate splice sites that generate inclusion of the trinucleotide and the hexanucleotide in the mature transcripts may have occurred in recent evolutionary times.

Serologic autoantibodies as diagnostic cancer biomarkers - A review

Publisher: American Association for Cancer Research (AACR)

Date: 12-2013

DOI: 10.1158/1055-9965.EPI-13-0621

Abstract: Current diagnostic techniques used for the early detection of cancers are successful but subject to detection bias. A recent focus lies in the development of more accurate diagnostic tools. An increase in serologic autoantibody levels has been shown to precede the development of cancer disease symptoms. Therefore, autoantibody levels in patient blood serum have been proposed as diagnostic biomarkers for early-stage diagnosis of cancers. Their clinical application has, however, been hindered by low sensitivity, specificity, and low predictive value scores. These scores have been shown to improve when panels of multiple diagnostic autoantibody biomarkers are used. A five-marker biomarker panel has been shown to increase the sensitivity of prostate cancer diagnosis to 95% as compared with 12.2% for prostate-specific antigen alone. New potential biomarker panels were also discovered for lung, colon, and stomach cancer diagnosis with sensitivity of 76%, 65.4%, and 50.8%, respectively. Studies in breast and liver cancer, however, seem to favor single markers, namely α-2-HS-glycoprotein and des-γ-carboxyprothrombin with sensitivities of 79% and 89% for the early detection of the cancers. The aim of this review is to discuss the relevance of autoantibodies in cancer diagnosis and to outline the current methodologies used in the detection of autoantibodies. The review concludes with a discussion of the autoantibodies currently used in the diagnosis of cancers of the prostate, breast, lung, colon, stomach, and liver. A discussion of the potential future use of autoantibodies as diagnostic cancer biomarkers is also included in this review. Cancer Epidemiol Biomarkers Prev 22(12) 2161–81. ©2013 AACR.

A multiphasic role for Pax7 in tectal development

Publisher: Springer Science and Business Media LLC

Date: 21-01-2006

DOI: 10.1007/S00221-005-0335-0

Abstract: The optic tectum differentiates from the mesencephalic alar plate and matures into a characteristically laminated structure. Evidence presented here suggests a role for Pax7 in all stages of development of tectal architecture, from regionalisation to specification of neurons and tectal topography. Analysis of Pax7 expression profiles over a range of developmental stages (E2-E12) suggests a biphasic role for Pax7: initially Pax7 expressing cells in the proliferative neuroepithelial layer establish tectal polarity whereas later Pax7 is expressed in neurons of the retino-recipient precursor stratum griseum et fibrosum superficiale (sgfs) laminae where graded levels may establish tectal topography. Furthermore, co-localisation immunofluorescence confirmed that Pax7 is initially expressed in the majority of proliferative neuroepithelial cells and later in a subset of neurons of the sgfs laminae.

Mechanisms contributing to differential regulation of PAX3 downstream target genes in normal human epidermal melanocytes versus melanoma cells

Publisher: Public Library of Science (PLoS)

Date: 16-04-2015

DOI: 10.1371/JOURNAL.PONE.0124154

Alternate Pax7 transcripts are expressed specifically in skeletal muscle, brain and other organs of adult mice

Publisher: Elsevier BV

Date: 07-1997

DOI: 10.1016/S1357-2725(97)00023-X

Abstract: Pax7 is associated with formation of skeletal muscle and the neural tube in developing embryos. Interestingly, in adult mice, rearrangements of Pax7 are associated with differences in the efficiency of skeletal muscle regrowth between mouse strains. The aim of this study was to investigate the possibility that Pax7 is expressed in skeletal muscle or other tissues from adult mice. Total RNA was isolated from adult mouse tissues and the polymerase chain reaction was performed on reverse transcribed mRNA using primers specific for regions that encode the paired and homeodomain of Pax7. At least four different Pax7 transcripts were found. A full-length transcript similar in sequence to that published previously was identified in skeletal muscle, brain and spleen cells of adult mice. Further putative full-length Pax7 transcripts, including one that contains a hexanucleotide insertion in the paired box and one in which approximately 10 bp have been deleted in the homeobox, were found to be expressed in skeletal muscle and brain of adult mice, respectively. A truncated Pax7 splice product comprising the paired box only was found to be expressed in most adult tissues except liver. Results of these studies demonstrate that there are alternate transcripts of Pax7, some of which are expressed exclusively in adult skeletal muscle and brain. It is possible that one of these transcripts may specify an alternate myogenic pathway involved in regeneration of damaged skeletal muscle in adult mice.

Pax7 and superior collicular polarity: Insights from Pax6 (Sey) mutant mice

Publisher: Springer Science and Business Media LLC

Date: 08-11-2007

DOI: 10.1007/S00221-006-0735-9

Abstract: Pax genes are important modulators of CNS development. Pax7 and Pax6 polarise the neural tube and regionalise the brain. Pax7 is pivotal in specifying the superior colliculus/tectum, an important centre for integration of visuomotor responses and a target for Pax6+ retinal ganglion cell axons during retinocollicular mapping. Whilst initial Pax7-specification of the mesencephalon is well-established, a role in regulating polarity within the maturing mouse superior colliculus is yet to be defined, although already detailed for the chick tectum. We therefore quantified Pax7 cellular distribution and expression levels at three functionally distinct stages of superior collicular development, and analysed Pax7 expression in response to aberrant axonal input and altered forebrain/midbrain boundary placement in Pax6 mutant mice. Comparative expression profiles of ephrin-A2 and its co-localisation with Pax7 were determined in wildtype and Pax6 mutant mice. Results indicate that graded Pax7 expression in wildtype mice is perturbed in Pax6 mutant mice changes manifest as a shift in polarity, loss of graded expression and dramatically reduced protein levels during RGC synaptogenesis. Ephrin-A2 expression is similarly altered. These results implicate Pax7 as an important determinant of polarity within the mouse superior colliculus, and suggest a role in retinotopic mapping.

Analysis of Circulating Tumour Cells in Early-Stage Uveal Melanoma: Evaluation of Tumour Marker Expression to Increase Capture

Publisher: MDPI AG

Date: 28-11-2021

DOI: 10.3390/CANCERS13235990

Abstract: (1) Background: The stratification of uveal melanoma (UM) patients into prognostic groups is critical for patient management and for directing patients towards clinical trials. Current classification is based on clinicopathological and molecular features of the tumour. Analysis of circulating tumour cells (CTCs) has been proposed as a tool to avoid invasive biopsy of the primary tumour. However, the clinical utility of such liquid biopsy depends on the detection rate of CTCs. (2) Methods: The expression of melanoma, melanocyte, and stem cell markers was tested in a primary tissue microarray (TMA) and UM cell lines. Markers found to be highly expressed in primary UM were used to either immunomagnetically isolate or immunostain UM CTCs prior to treatment of the primary lesion. (3) Results: TMA and cell lines had heterogeneous expression of common melanoma, melanocyte, and stem cell markers. A multi-marker panel of immunomagnetic beads enabled isolation of CTCs in 37/43 (86%) patients with UM. Detection of three or more CTCs using the multi-marker panel, but not MCSP alone, was a significant predictor of shorter progression free (p = 0.040) and overall (p = 0.022) survival. (4) Conclusions: The multi-marker immunomagnetic isolation protocol enabled the detection of CTCs in most primary UM patients. Overall, our results suggest that a multi-marker approach could be a powerful tool for CTC separation for non-invasive prognostication of UM.

Pax7 expression in the adult rat superior colliculus following optic nerve injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 22-01-2007

DOI: 10.1097/WNR.0B013E328010FF29

PAX3 across the spectrum: From melanoblast to melanoma PAX3 expression in melanocyte development and melanoma S. Medic and M. Ziman

Publisher: Informa UK Limited

Date: 06-2009

DOI: 10.1080/10409230902755056

Abstract: The PAX3 transcription factor is critical for the proper development of neural crest lineages including melanocytes. These cells show continued PAX3 expression from formation to differentiation. While many expression, misexpression and mutation studies clarify the importance of PAX3 in melanocyte development, less well understood, and more perplexing, is the continued PAX3 expression in the adult skin. In this article we explore the multiple roles of PAX3 in melanocyte genesis, and draw on evidence from expression in developing melanoblasts, adult melanocytes and melanocyte stem cells. From this, we present a more encompassing theory that PAX3 is a key regulator of the myriad steps in melanocytic cell determination. These roles may be accomplished by differential association with cofactors, via alternate transcripts or posttranslational protein modification(s). In light of the plethora of information gleaned from development we then consider its roles in melanoma and provide here a comprehensive consideration of the significance of PAX3 expression in melanoma. PAX3 and Pax3 indicate human and mouse transcription factors respectively.

A conserved TN8TCCT motif in the octapeptide-encoding region of Pax genes which has the potential to direct cytosine methylation

Publisher: Elsevier BV

Date: 11-1998

DOI: 10.1016/S0378-1119(98)00162-0

Abstract: Our previous findings have shown that the developmental genes Pax7 and Pax3 are differentially methylated the gene region that encodes the paired domain is hypomethylated, whereas the region that encodes the homeodomain is hypermethylated. For this reason, the known DNA sequence between the paired and homeoboxes was analysed for the presence of a conserved DNA motif to which a modifying protein could bind in order to direct the methylation or demethylation of surrounding gene sequences. The octapeptide-encoding region was found to contain several nucleotides that were highly conserved throughout the Pax gene family from phylogenetically distant species. The most conserved nucleotides are thought to comprise a motif TN8TCCT where N8=any combination of eight nucleotides. A conserved octapeptide-like-encoding sequence containing the TN8TCCT motif was also found in non-Pax genes of higher eukaryotes and in the non-coding strand of plants. Moreover, differential methylation seems to be associated with the presence of the TN8TCCT motif in p53 and the human oestrogen receptor genes. The presence of the TN8TCCT motif within an octapeptide-like-encoding sequence in human T-cell leukaemia virus type 1 might suggest that the putative recognition motif may have been introduced into various host genomes via some form of retroviral agent.

Factors that contribute to balance and mobility impairments in individuals with Huntington's disease

Publisher: Elsevier BV

Date: 06-2014

DOI: 10.1016/J.BAGA.2014.04.002

The Prognostic Impact of Circulating Tumour DNA in Melanoma Patients Treated with Systemic Therapies—Beyond BRAF Mutant Detection

Publisher: MDPI AG

Date: 16-12-2020

DOI: 10.3390/CANCERS12123793

Abstract: In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma s les from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen’s k = 0.798, p 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.

A key role for Pax7 transcripts in determination of muscle and nerve cells

Publisher: Elsevier BV

Date: 08-2001

DOI: 10.1006/EXCR.2001.5282

PAX3 expression in normal skin Melanocytes and Melanocytic lesions (Naevi and Melanomas)

Publisher: Public Library of Science (PLoS)

Date: 22-04-2010

DOI: 10.1371/JOURNAL.PONE.0009977

Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service

Publisher: BMJ

Date: 13-05-2011

DOI: 10.1136/EMJ.2009.078717

Abstract: This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain. A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores. Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous. MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients.

Isolation and expression analysis of a Pax group III gene from the crustacean Cherax destructor

Publisher: Springer Science and Business Media LLC

Date: 17-03-2005

DOI: 10.1007/S00427-005-0478-9

Abstract: Pax genes encode transcription factors that are critical regulators of key developmental processes in evolutionarily erse animal phyla. Here we report the first isolation of a Pax gene from a crustacean: a Pax group III gene we have termed CdpaxIII that contains highly conserved DNA-binding domains, the paired domain and homeodomain. CdpaxIII is expressed in the embryo, in adult limb muscle during both quiescence and regeneration, and during the distinct process of epimorphic limb regeneration. Interestingly, CdpaxIII is expressed as two distinct alternate transcripts, one of which is novel in lacking a large portion of its paired domain.

Surface electromyograph activity of submental muscles during swallowing and expiratory muscle training tasks in Huntington's disease patients

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1016/J.JELEKIN.2013.09.009

Abstract: Huntington's disease (HD) patients have difficulty in swallowing, leading to aspiration pneumonia, which is a major cause of death. It seems possible that submental muscles that are crucial for preventing an escape of a bolus into the airway, are affected by HD, but no previous studies have investigated this. To assess surface electromyograph (sEMG) activity of submental muscles during swallowing and expiratory muscle training (EMT) tasks in HD patients in comparison to healthy volunteers. sEMG activities of submental muscles during saliva, water swallowing, EMT tasks performed at 25% and 75% of maximum expiratory pressure were recorded and normalised by the sEMG activity during an effortful swallow in 17 early to mid stage HD patients and 17 healthy volunteers. sEMG activity was greater (p<0.05) during EMT tasks than saliva and water swallowing, but was not significantly different between groups for saliva, water swallowing and EMT at 25%. HD patients had lower sEMG activity for EMT at 75% (p<0.05). Decreases in submental muscle activity were not evident in HD patients except during EMT at 75%. This suggests that relative submental muscle weakness is observed only during a high intensity task in early to mid stage HD patients.

Pax7 is requisite for maintenance of a subpopulation of superior collicular neurons and shows a diverging expression pattern to Pax3 during superior collicular development

Publisher: Springer Science and Business Media LLC

Date: 30-05-2008

DOI: 10.1186/1471-213X-8-62

Abstract: Pax7 encodes a transcription factor well-established as an important determinant of mesencephalic identity and superior collicular development. Pax7 mutant mice, however, present with no obvious morphological impairments to the superior colliculus. This finding is paradoxical and has been attributed to functional redundancy afforded by its paralogue Pax3 . Here we utilise Pax7 mutant mice to investigate the precise role of this important developmental regulator during superior collicular development and neuronal specification/differentiation. We also assess its spatiotemporal relationship with Pax3 during embryonic development. Analysis of the superior colliculus of Pax7 mutant and wildtype mice at a variety of developmental timepoints revealed that whilst correct initial specification is maintained, a subpopulation of dorsal mesencephalic neurons is lost at early postnatal stages. Moreover, a comparative analysis of embryonic Pax3 and Pax7 expression profiles indicate that Pax3 expression overlaps extensively with that of Pax7 initially, but their expression domains increasingly erge as development progresses, coinciding spatiotemporally with neuronal differentiation and maturation of the tissue. Furthermore, Pax3 expression is perturbed within the CNS of embryonic Pax7 mutant mice. In summary, these results demonstrate that during superior collicular development, Pax7 is required to maintain a subpopulation of dorsal, mesencephalic neurons and partially regulates, spatiotemporally, Pax3 expression within the CNS. The differential nature of Pax7 and Pax3 with respect to neuronal differentiation may have implications for future stem cell therapies aimed at exploiting their developmental capabilities.

Is the Blood an Alternative for Programmed Cell Death Ligand 1 Assessment in Non-Small Cell Lung Cancer?

Publisher: MDPI AG

Date: 30-06-2019

DOI: 10.3390/CANCERS11070920

Abstract: Anti-programmed cell death (PD)-1/PD-ligand 1 (L1) therapies have significantly improved the outcomes for non-small cell lung cancer (NSCLC) patients in recent years. These therapies work by reactivating the immune system and enabling it to target cancer cells once more. There is a general agreement that expression of PD-L1 on tumour cells predicts the therapeutic response to PD-1/PD-L1 inhibitors in NSCLC. Hence, immunohistochemical staining of tumour tissue biopsies from NSCLC patients with PD-L1 antibodies is the current standard used to aid selection of patients for treatment with anti-PD-1 as first line therapy. However, issues of small tissue s les, tissue heterogeneity, the emergence of new metastatic sites, and dynamic changes in the expression of PD-L1 may influence PD-L1 status during disease evolution. Re-biopsy would expose patients to the risk of complications and tardy results. Analysis of PD-L1 expression on circulating tumour cells (CTCs) may provide an accessible and non-invasive means to select patients for anti-PD-1 therapies. Additionally, CTCs could potentially provide a useful biomarker in their own right. Several published studies have assessed PD-L1 expression on CTCs from NSCLC patients. Overall, analysis of PD-L1 on CTCs is feasible and could be detected prior to and after frontline therapy. However, there is no evidence on whether PD-L1 expression on CTCs could predict the response to anti-PD-1/PD-L1 treatment. This review examines the challenges that need to be addressed to demonstrate the clinical validity of PD-L1 analysis in CTCs as a biomarker capable of predicting the response to immune checkpoint blockade.

Autoantibody Production in Cancer-The Humoral Immune Response toward Autologous Antigens in Cancer Patients

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.AUTREV.2016.01.017

Abstract: A link between autoimmune responses and cancer via autoantibodies was first described in the 1950s. Since, autoantibodies have been studied for their potential use as cancer biomarkers, however the exact causes of their production remain to be elucidated. This review summarizes current theories of the causes of autoantibody production in cancer, namely: 1) defects in tolerance and inflammation, 2) changes in protein expression levels, 3) altered protein structure, and 4) cellular death mechanisms. We also highlight the need for further research into this field to improve our understanding of autoantibodies as biomarkers for cancer development and progression.

PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation

Publisher: Springer Science and Business Media LLC

Date: 03-2012

DOI: 10.1007/S12094-012-0784-4

Abstract: Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process. We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019. This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor. Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.

Discriminant validity of the Hospital Anxiety and Depression Scale, Beck Depression Inventory (II) and Beck Anxiety Inventory to confirmed clinical diagnosis of depression and anxiety in patients with chronic obstructive pulmonary disease

Publisher: SAGE Publications

Date: 23-06-2016

DOI: 10.1177/1479972316634604

Abstract: The objective of this study was to investigate the discriminant validity of commonly used depression and anxiety screening tools in order to determine the most suitable tool for patients with chronic obstructive pulmonary disease (COPD). COPD patients ( n = 56) completed the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). These scores were compared to confirmed clinical diagnoses of depression and anxiety using the Mini Neuropsychiatric Interview. HADS depression subscale (HADS-D) sensitivity/specificity was 78/81% BDI-II 89/77% HADS anxiety subscale (HADS-A) 71/81% and BAI 89/62%. HADS-D sensitivity/specificity was improved (100/83%) with the removal of Q4 ‘I feel as if I am slowed down’ and adjusted cut-off (≥5). Removal of BDI-II Q21 ‘Loss of interest in sex’ with adjusted cut-off ≥12 resulted in similar improvement (100/79%). No problematic items were identified for HADS-A or BAI. Previously reported low sensitivity/specificity of the HADS for COPD patients was not replicated. Furthermore, simple modifications of the HADS-D markedly improved sensitivity/specificity for depression. BDI-II, HADS-A and BAI produced acceptable sensitivity/specificity unmodified. Pending further research for COPD patients we recommend continued use of the HADS-A with standard cut-off (≥8) and removal of Q4 of the HADS-D with lower cut-off ≥5.

Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma

Publisher: Impact Journals, LLC

Date: 22-09-2015

DOI: 10.18632/ONCOTARGET.5788

Changing Pax6 expression correlates with axon outgrowth and restoration of topography during optic nerve regeneration

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.NEUROSCIENCE.2006.07.057

Abstract: Pax6, a member of the highly conserved developmental Pax gene family, plays a crucial role in early eye development and continues to be expressed in adult retinal ganglion cells (RGCs). Here we have used Western blots and immunohistochemistry to investigate the expression of Pax6 in the formation and refinement of topographic projections during optic nerve regeneration in zebrafish and lizard. In zebrafish with natural (12-h light/dark cycle) illumination, Pax6 expression in RGCs was decreased during axon outgrowth and increased during the restoration of the retinotectal map. Rearing fish in stroboscopic illumination to prevent retinotopic refinement resulted in a prolonged decrease in Pax6 levels return to natural light conditions resulted in map refinement and restoration of normal Pax6 levels. In lizard, RGC axons spontaneously regenerate but remain in a persistent state of regrowth and do not restore topography visual training during regeneration, however, allows a stabilization of connections and return of topography. Pax6 was persistently decreased in untrained animals but remained increased in trained ones. In both species, changes in expression were not due to cell ision or cell death. The results suggest that decreased Pax6 expression is permissive for axon regeneration and extensive searching, while higher levels of Pax6 are associated with restoration of topography.

Graft outcomes influenced by co‐expression of Pax7 in graft and host tissue

Publisher: Wiley

Date: 23-02-2009

DOI: 10.1111/J.1469-7580.2009.01049.X

Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma

Publisher: Springer Science and Business Media LLC

Date: 11-06-2014

DOI: 10.1186/1471-2407-14-423

The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington's disease: An exploratory study

Publisher: Wiley

Date: 15-01-2015

DOI: 10.1002/BRB3.312

Alveolar rhabdomyosarcoma: Is the cell of origin a mesenchymal stem cell?

Publisher: Elsevier BV

Date: 07-2009

DOI: 10.1016/J.CANLET.2008.09.039

Abstract: Alveolar rhabdomyosarcoma (ARMS) is a pediatric sarcoma that typically occurs in older children predominantly arising in the trunk and extremities, and exhibits a worse prognosis than other types of rhabdomyosarcomas. Most ARMS tumors have t(2 13) or t(1 13) translocations, involving PAX3-FKHR and PAX7-FKHR fusion genes, respectively. These genetic events result in a molecular gain of function of the fusion protein which is proposed, in a yet unspecified mechanism, to perturb the differentiation of muscle progenitor cells. While a significant amount of work has been done characterizing PAX-FKHR fusion proteins in ARMS and elucidating their involvement in the sarcomagenic process, their relationship to normal skeletal muscle differentiation remains unestablished. In this manuscript we will explore a potential role for mesenchymal stem cells as the cell of origin of ARMS, and the possibility that PAX-FKHR fusion genes may commit these cells to a myogenic lineage while inhibiting terminal differentiation, thus contributing to ARMS formation. We will also review the structure and function of alternate transcripts of PAX3, PAX7, FKHR and the fusion genes PAX3-FKHR and PAX7-FKHR, and discuss the role of these genes and their downstream targets in development of ARMS. Additionally, we will review transgenic mouse models and their ability to mimic the formation of ARMS.

Differential PAX3 functions in normal skin melanocytes and melanoma cells

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.BBRC.2011.07.053

Abstract: The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as "stem" cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated "stem" cell like phenotype, PAX3 may contribute to melanoma development and progression.

Alternate PAX3 and PAX7 C-terminal isoforms in myogenic differentiation and sarcomagenesis

Publisher: Springer Science and Business Media LLC

Date: 03-2011

DOI: 10.1007/S12094-011-0640-Y

Abstract: Pax3 and Pax7 are closely related genes that are involved in commitment of cells to a myogenic lineage during skeletal muscle development and regeneration. Several Pax3 and Pax7 transcripts are expressed from the genes, generating different isoforms with potentially distinct DNA binding and transactivation properties. The aim of this study was to investigate the implication of Pax3 and Pax7 C-terminal isoforms during myogenic differentiation and tumorigenesis, since fusions involving these genes are commonly associated with alveolar rhabdomyosarcoma (ARMS). Uncommitted (mouse mesenchymal stem cells, MSCs) and committed (C2C12) myogenic precursor cells were stably transfected with PAX3/FKHR and PAXC7/ FKHR fusion genes. We analysed gene and protein expression comparing the newly generated cells with the parental cells, to determine the functional importance of Pax3 and Pax7 C-terminal isoforms. We found that the transcript Pax3c was expressed at low levels in undifferentiated C2C12 and MSCs cells, but its expression levels increased considerably at later stages of differentiation. However, expression levels of Pax3d transcript increased only slightly after differentiation. Pax7 transcripts, present before differentiation in committed C2C12 cells, but absent in uncommitted MSCs, increased noticeably in MSCs after differentiation. We also found that the presence of PAX/FKHR fusions prevented both C2C12 and MSC cells from terminal myogenic differentiation and increased the expression of discrete endogenous Pax3/7 transcripts, in particular Pax3d and Pax7B. Our results suggest that both Pax3 and Pax7 transcripts are required for commitment of cells to the myogenic lineage, with each transcript having a distinct role. More specifically, the Pax3c isoform may be required for terminal myogenic differentiation whereas the Pax3d isoform may be involved in undifferentiated cell maintenance and/or proliferation.

Respiratory muscle training on pulmonary and swallowing function in patients with Huntingtons disease: A pilot randomised controlled trial

Publisher: SAGE Publications

Date: 31-12-2015

DOI: 10.1177/0269215514564087

Abstract: To examine the effects of 4-month of respiratory muscle training on pulmonary and swallowing function, exercise capacity and dyspnoea in manifest patients with Huntington’s disease. A pilot randomised controlled trial. Home based training program. Eighteen manifest Huntington’s disease patients with a positive genetic test and clinically verified disease expression, were randomly assigned to control group ( n=9) and training group ( n=9). Both groups received home-based inspiratory (5 sets of 5 repetitions) and expiratory (5 sets of 5 repetitions) muscle training 6 times a week for 4 months. The control group used a fixed resistance of 9 centimeters of water, and the training group used a progressively increased resistance from 30% to 75% of each patient’s maximum respiratory pressure. Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, six minutes walk test, dyspnoea, water-swallowing test and swallow quality of life questionnaire were assessed before, at 2 and 4 months after training. The magnitude of increases in maximum inspiratory ( d=2.9) and expiratory pressures ( d=1.5), forced vital capacity ( d=0.8), forced expiratory volume in 1 second ( d=0.9) and peak expiratory flow ( d=0.8) was substantially greater for the training group in comparison to the control group. Changes in swallowing function, dyspnoea and exercise capacity were small ( d≤0.5) for both groups without substantial differences between groups. A home-based respiratory muscle training program appeared to be beneficial to improve pulmonary function in manifest Huntington’s disease patients but provided small effects on swallowing function, dyspnoea and exercise capacity.

A comparative analysis of shotgun-cloning and tagged-random amplification-cloning of chromatin immunoprecipitation-isolated genome fragments

Publisher: Elsevier BV

Date: 07-2006

DOI: 10.1016/J.BBRC.2006.05.145

Abstract: The cloning of transcription factor antibody-immunoprecipitated genomic fragments from chromatin immunoprecipitation (ChIP) experiments is a technically challenging procedure, especially when the input genomic DNA is isolated from whole tissues (in vivo) rather than cultured cells. Here we adapt a technique known as Tagged-Random PCR (T-PCR) to lify ChIP-immunoprecipitated DNA from mouse embryonic tissue prior to cloning. Importantly, we then compare this technique with tandem shotgun-cloning experiments in terms of its capacity to identify target genes. We find that T-PCR dramatically increases the efficiency of cloning ChIP fragments without distortion of the relative location of cloned fragments to putative target genes. Thus, T-PCR is a simple procedure which greatly enhances the efficiency of cloning tissue-derived ChIP fragments.

Expression profiles suggest a role for Pax7 in the establishment of tectal polarity and map refinement

Publisher: Springer Science and Business Media LLC

Date: 06-2004

DOI: 10.1007/S00221-003-1775-Z

Abstract: The role for Pax7 in establishing tectal polarity and map refinement was authenticated by gene expression studies in vivo and in vitro. Throughout development (stages E2-E12 were examined) a rostral(low)-caudal(high) and dorsal(high)-ventral(low) Pax7 expression gradient was detected immunohistochemically in the chick optic tectum, indicating a role for Pax7 in establishing tectal polarity. Chick retino-recipient tectal cells positive for Pax7 also co-expressed ephrin-A2, a molecule involved in the establishment and refinement of the retinotopic map. In vitro, PAX7 up-regulated ephrin-A2 when transfected into undifferentiated P19 cells cells became negative for both Pax7 and ephrin-A2 protein following treatment with anti-sense oligonucleotides. These results suggest that in addition to being involved in the early establishment of tectal polarity, Pax7 plays a later role in retino-tectal map formation and refinement.

Students reflecting on test performance and feedback: An on-line approach

Publisher: Informa UK Limited

Date: 03-06-2014

DOI: 10.1080/02602938.2013.801063

Neuroendocrine and neurotrophic signaling in Huntington’s disease: Implications for pathogenic mechanisms and treatment strategies

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.NEUBIOREV.2016.09.006

Abstract: Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways.

Bone marrow stromal cells as replacement cells for Parkinson's disease: Generation of an anatomical but not functional neuronal phenotype

Publisher: Elsevier BV

Date: 02-2011

DOI: 10.1016/J.TRSL.2010.11.001

Abstract: The focus of cell replacement therapies (CRTs) for Parkinson's disease has been on delivering dopamine-producing cells to the striatum. Fetal grafts have proven the feasibility of this approach, but an appropriate source of replacement cells has restricted the clinical translation. Bone marrow stromal cells (BMSCs) have been heralded as an ideal source of dopaminergic (DAergic) replacement cells, as they are viewed as ethically acceptable, easily procured, and readily expanded. It is known that they confer functional benefits, particularly in stroke models, through the release of neurotrophic factors, but their transdifferentiation into neurons is still under contention. We sought to evaluate the neuronal phenotype and functional capacity of adult rat BMSCs after exposure to a novel multistep in vitro differentiation protocol compared with cells exposed to other reported neuronal differentiation conditions. We employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs. Our fluorescence-activated cell sorting, immunofluorescent and semiquantitative polymerase chain reaction results confirmed that undifferentiated BMSCs isolated based on their adherence to plastic are of mesenchymal origin and express a range of lineage markers. After exposure to preinduction and neuronal induction steps, BMSCs down-regulate markers of other lineages but fail, as assessed by patch cl , to differentiate into functional neurons. Thus, for BMSCs to be considered a source of DAergic neuronal replacement cells, their ability to transdifferentiate terminally along a neuronal lineage first must be clarified before attempting to direct more complex specification process required for them to be used in Parkinson's-disease-focused CRTs.

Genome-wide discovery of Pax7 target genes during development

Publisher: American Physiological Society

Date: 03-2008

DOI: 10.1152/PHYSIOLGENOMICS.00256.2007

Abstract: Pax7 plays critical roles in development of brain, spinal cord, neural crest, and skeletal muscle. As a sequence-specific DNA-binding transcription factor, any direct functional role played by Pax7 during development is mediated through target gene selection. Thus, we have sought to identify genes targeted by Pax7 during embryonic development using an unbiased chromatin immunoprecipitation (ChIP) cloning assay to isolate cis-regulatory regions bound by Pax7 in vivo. Sequencing and genomic localization of a library of chromatin-DNA fragments bound by Pax7 has identified 34 candidate Pax7 target genes, with occupancy of a selection confirmed with independent chromatin enrichment tests (ChIP-PCR). To assess the capacity of Pax7 to regulate transcription from these loci, we have cloned alternate transcripts of Pax7 (differing significantly in their DNA binding domain) into expression vectors and transfected cultured cells with these constructs, then analyzed target gene expression levels using RT-PCR. We show that Pax7 directly occupies sites within genes encoding transcription factors Gbx1 and Eya4, the neurogenic cytokine receptor ciliary neurotrophic factor receptor, the neuronal potassium channel Kcnk2, and the signal transduction kinase Camk1d in vivo and regulates the transcriptional state of these genes in cultured cells. This analysis gives us greater insight into the direct functional role played by Pax7 during embryonic development.

Infrared spectra of o-toluidine and m-toluidine complexes of Co(II), Ni(II), Cu(II) and Zn(II) halides

Publisher: Elsevier BV

Date: 09-1978

DOI: 10.1016/0022-2860(78)87002-1

Differential expression of four alternate Pax7 paired box transcripts is influenced by organ- and strain-specific factors in adult mice

Publisher: Elsevier BV

Date: 09-1998

DOI: 10.1016/S0378-1119(98)00353-9

Abstract: The developmental paired-type gene Pax7 is expressed in skeletal muscle and brain during development and in the adult mouse. In this study, RNA was isolated from the brains and skeletal muscles of the limbs of adult BALB/c and SJL/J mice to determine whether there were alternate transcripts which could account for the biological ersity of Pax7. Four alternate transcripts have been identified, each of which differs by the presence and/or absence of a trinucleotide or a hexanucleotide in the region of Pax7 which encodes the paired domain. Inclusion of the trinucleotide and the hexanucleotide results in insertion of the amino acids glutamine (Q) and glycine (GL), respectively, into the paired domain. The insertion of GL is predicted to influence the binding specificity, whereas insertion of Q may affect the relative binding affinity of the N and C termini of the paired domain. The transcripts which include the hexanucleotide are more frequent in RNA from the hind-limb skeletal muscles of adult mice compared with the brain, suggesting that they may effect some form of myogenic function. By contrast, it is possible that transcripts which lack the hexanucleotide encode factors which are involved in neurogenesis. The proportion of the potential myogenic transcript Pax7b was found to be increased in RNA from limb skeletal muscles of adult SJL/J mice compared with that of BALB/c mice. These results provide a new basis for examination of the genetic control of skeletal-muscle formation and neurogenesis.

Variation in the methylation profile and structure of Pax3 and Pax7 among different mouse strains and during expression

Publisher: Elsevier BV

Date: 1997

DOI: 10.1016/S0378-1119(96)00572-0

Abstract: Structural alterations within the myogenic and neurogenic developmental gene Pax7 which involve TaqI recognition sequences have previously been reported. These alterations are associated with differences in the efficiency of regrowth of damaged skeletal muscle. To identify other structural features of Pax genes which may influence skeletal muscle regrowth, variation in the structure and methylation status of Pax7 and the closely related gene Pax3 has been sought among different mouse strains and during gene expression using the restriction endonucleases MspI and HpaII. Following MspI digestion, RFLPs within Pax7 have been found which most likely reflect intron size variability within the paired box. Differences in the size of MspI and HpaII fragments hybridising with Pax7 and Pax3 region specific sub-probes indicate that the paired boxes are hypomethylated, whereas the region encoding the homeodomain of each gene is highly methylated in the spleen and other tissues from adult mice. In the skeletal muscle precursor cell line C2C12, which expresses Pax7 but not Pax3, the homeodomain encoding region of Pax7 is hypomethylated. In spleen cells, the Pax7 paired box is transcribed but the homeodomain encoding region is not. By contrast, both the paired box and the homeobox of Pax3 are hypermethylated in C2C12 cells indicating that generation of alternate transcripts from Pax genes may be controlled by DNA methylation. In contrast to Pax3, reference to the size of fragments hybridising with a Pax7 homeobox specific probe provides evidence for CpNpG methylation within and immediately downstream from the region encoding the homeodomain. Interestingly, CpNpG methylation remains when the Pax7 homeobox is expressed. Structural variation recognised by MspI digestion and differences in the methylation profile of Pax7 are not associated with the ability to regrow damaged skeletal muscle.

Pax genes during neural development and their potential role in neuroregeneration

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1016/J.PNEUROBIO.2011.08.012

Abstract: Pax genes encode a family of transcription factors that have long been recognised as obligate contributors to embryonic development of the CNS, with evidence obtained from various animal models illustrating phylogenetically conserved functions. Within the CNS, Pax genes play substantial roles in cellular and regional specification, proliferation, progenitor cell maintenance, anti-apoptosis and neural differentiation. This comprehensive review details the critical functions of those Pax genes involved in pre- and post-natal CNS development, provides possible molecular mechanisms by which Pax genes contribute to proliferation and differentiation of neuronal cells, and explains observed changes in Pax gene expression in response to neurotrauma in the mature animal. Knowledge of the ability of in idual Pax genes to specify precise lineages within the CNS is beneficial for cell replacement strategies, particularly in the production of "designer" cells for the treatment of neurodegenerative disorders. The manipulation of stem or committed cells so that they express definitive Pax genes may indeed assist in the pursuit of the holy grail of regenerative medicine - that of CNS cell replacement therapies leading to functional repair. We explain here, however, that only the sophisticated and precise use of Pax genes will lead to a successful outcome.

Paramedics and pre-hospital management of acute myocardial infarction: Diagnosis and reperfusion

Publisher: BMJ

Date: 05-2006

DOI: 10.1136/EMJ.2005.028118

Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression

Publisher: Oxford University Press (OUP)

Date: 15-11-2013

DOI: 10.1111/BJD.12057

University Of Western Australia

Location: Australia

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University Of Cape Town

Location: South Africa

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Edith Cowan University

Location: Australia

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A Single-molecule Super-resolution Microscopy Facility In Western Australia

Start Date: 2016

End Date: 2016

Funder: Australian Research Council

A Core Western Australian Cell Sorting Facility - Ultra-Small Objects And Rare Cell Populations

Start Date: 2009

End Date: 2009

Funder: Australian Research Council

Expanding Capability In Western Australian Flow Cytometry For Earth, Oceans, Environmental And Biomedical Science: State-of-the-art Four Laser And 12 Colour Analysis

Start Date: 2013

End Date: 2013

Funder: Australian Research Council

Western Australia Single-cell Isolation And Genomics Preparation Facility

Start Date: 2017

End Date: 2017

Funder: Australian Research Council

A Cryopreparation Facility For Western Australia

Start Date: 2008

End Date: 2008

Funder: Australian Research Council

Melanoma Mutation Profiling For Personalised Treatment

Start Date: 2013

End Date: 2015

Funder: National Health and Medical Research Council

Autoantibody Biomarkers For Melanoma Diagnosis

Start Date: 2014

End Date: 2016

Funder: National Health and Medical Research Council

Are All Circulating Cells Metastatic?

Start Date: 2011

End Date: 2013

Funder: National Health and Medical Research Council

In-Vivo Multispectral And X-ray Micro-CT Imaging: Founding A Western Australian Small Animal Imaging Core Facility

Start Date: 2010

End Date: 2010

Funder: Australian Research Council

Mass Cytometry: A Breakthrough In Multidimensional Systems Biology

Start Date: 2015

End Date: 2015

Funder: Australian Research Council

A High-throughput Protein Production And Structure Facility

Start Date: 2012

End Date: 2012

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100225

Start Date: 2017

End Date: 12-2017

Amount: $410,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0772899

Start Date: 06-2007

End Date: 06-2011

Amount: $253,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100056

Start Date: 2018

End Date: 03-2019

Amount: $621,198.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100217

Start Date: 2010

End Date: 05-2011

Amount: $450,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE160100086

Start Date: 05-2016

End Date: 12-2016

Amount: $850,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882893

Start Date: 2008

End Date: 12-2008

Amount: $260,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100092

Start Date: 01-2012

End Date: 12-2012

Amount: $240,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989782

Start Date: 10-2009

End Date: 10-2010

Amount: $524,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE130100126

Start Date: 2013

End Date: 12-2013

Amount: $160,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100066

Start Date: 2015

End Date: 12-2015

Amount: $440,000.00

Funder: Australian Research Council