ORCID Profile
0000-0002-0271-781X
Current Organisations
University of Kansas
,
University of Queensland
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Molecular Evolution | Gene Expression | Protein Targeting And Signal Transduction | Genetics
Aquaculture | Ceramics, glass and industrial mineral products not elsewhere classified | Primary animal products not elsewhere classified |
Publisher: Elsevier BV
Date: 07-2008
Publisher: Rockefeller University Press
Date: 19-05-1997
Abstract: We have recently shown that two proteins related to two of the adaptor subunits of clathrincoated vesicles, p47 (μ3) and β-NAP (β3B), are part of an adaptor-like complex not associated with clathrin (Simpson, F., N.A. Bright, M.A. West, L.S. Newman, R.B. Darnell, and M.S. Robinson, 1996. J. Cell Biol. 133:749–760). In the present study we have searched the EST database and have identified, cloned, and sequenced a ubiquitously expressed homologue of β-NAP, β3A, as well as homologues of the α/γ and σ adaptor subunits, δ and σ3, which are also ubiquitously expressed. Antibodies raised against recombinant δ and σ3 show that they are the other two subunits of the adaptor-like complex. We are calling this complex AP-3, a name that has also been used for the neuronalspecific phosphoprotein AP180, but we feel that it is a more appropriate designation for an adaptor-related heterotetramer. Immunofluorescence using anti-δ antibodies reveals that the AP-3 complex is associated with the Golgi region of the cell as well as with more peripheral structures. These peripheral structures show only limited colocalization with endosomal markers and may correspond to a postTGN biosynthetic compartment. The δ subunit is closely related to the protein product of the Drosophila garnet gene, which when mutated results in reduced pigmentation of the eyes and other tissues. Because pigment granules are believed to be similar to lysosomes, this suggests either that the AP-3 complex may be directly involved in trafficking to lysosomes or alternatively that it may be involved in another pathway, but that missorting in that pathway may indirectly lead to defects in pigment granules.
Publisher: EMBO
Date: 25-06-2012
Publisher: Wiley
Date: 05-02-2015
DOI: 10.1002/IJC.29450
Abstract: Patients receiving immunosuppression to prevent organ transplant rejection are at a greatly increased risk of developing nonmelanoma skin cancer. In recent years a correlation has been identified between the class of immunosuppressant that these patients receive and their subsequent cancer risk in particular, patients switched from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors not only displayed a dramatic reduction in new tumor formation but also in some cases a regression of their existing lesions. Studies of cancer models in mice and cell lines in the laboratory have attributed these discrepancies in cancer risk to the ability of immunosuppressants such as mTOR inhibitors to elicit direct anticancer effects, including suppressing angiogenesis and increasing autophagy-mediated DNA repair. Recent evidence from the immunological literature however, suggests a significant alternative contribution of mTOR inhibitors namely the promotion of memory T-cell function. Recent advances in understanding memory T-cell establishment and the demonstration of their critical role in long-term immunity make it timely to review the available evidence as to whether the improved nonmelanoma skin cancer outcome shown by patients switched to mTOR inhibitor treatment regimens may be associated with the retainment of memory T-cell function.
Publisher: Wiley
Date: 09-11-2021
DOI: 10.1002/HED.26529
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.MODGEP.2006.05.006
Abstract: In a screen for genes expressed in the embryonic mouse facial primordia, we identified the gene sequence annotated as KIAA0101, which has previously been shown to encode a novel proliferating cell nuclear antigen (PCNA)-interacting protein named p15(PAF). We have since demonstrated that this protein also interacts in a complex with the tumour suppressor product p33ING1b, and that overexpression results in a decrease in UV-induced cell death. Although available data suggest widespread or ubiquitous expression in the adult, here we report highly restricted expression of the p15(PAF) gene in a spatio-temporal manner during mouse embryogenesis. Major sites of expression include the facial prominences, limbs, somites, brain, spinal cord and hair follicles. Based on the nature of its interacting partners, p15(PAF) is proposed to play a role in tumorigenesis. Our data also suggest a role in embryonic development, consistent with findings that a wide range of tumours result from aberrant activity of key developmental pathways.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432824
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2202
DOI: 10.1158/0008-5472.22432821
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432788
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432782
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432782.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Wiley
Date: 18-06-2020
DOI: 10.1111/BCP.14338
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432818.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: The Endocrine Society
Date: 2010
DOI: 10.1210/ME.2009-0133
Abstract: Adiponectin is an adipocyte-secreted, insulin-sensitizing hormone the circulating levels of which are reduced in conditions of insulin resistance and diabetes. Previous work has demonstrated the importance of posttranslational modifications, such as proline hydroxylation and lysine hydroxylation/glycosylation, in adiponectin oligomerization, secretion, and function. Here we describe the first functional characterization of adiponectin sialylation. Using a variety of biochemical approaches we demonstrated that sialylation occurs on previously unidentified O-linked glycans on Thr residues of the variable domain in human adiponectin. Enzymatic removal of sialic acid or its underlying O-linked sugars did not affect adiponectin multimer composition. Expression of mutant forms of adiponectin (lacking the modified Thr residues) or of wild-type adiponectin in cells defective in sialylation did not compromise multimer formation or secretion, arguing against a structural role for this modification. Activity of desialylated adiponectin was comparable to control adiponectin in L6 myotubes and acute assays in adiponectin−/− mice. In contrast, plasma clearance of desialylated adiponectin was accelerated compared with that of control adiponectin, implicating a role for this modification in determining the half-life of circulating adiponectin. Uptake of desialylated adiponectin by isolated primary rat hepatocytes was also accelerated, suggesting a role for the hepatic asialoglycoprotein receptor. Finally, after chronic administration in adiponectin−/− mice steady-state levels of desialylated adiponectin were lower than control adiponectin and failed to recapitulate the improvements in glucose and insulin tolerance tests observed with control adiponectin. These data suggest an important role for sialic acid content in the regulation of circulating adiponectin levels and highlight the importance of understanding mechanisms regulating adiponectin sialylation/desialylation.
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.YEXCR.2005.09.020
Abstract: The KIAA0101 15(PAF)/OEATC-1 protein was initially isolated in a yeast two-hybrid screen for proliferating cell nuclear antigen (PCNA) binding partners, and was shown to bind PCNA competitively with the cell cycle regulator p21(WAF). PCNA is involved in DNA replication and damage repair. Using polyclonal antisera raised against a p15(PAF) fusion protein, we have shown that in a range of mammalian tumor and non-tumor cell lines the endogenous p15(PAF) protein localises to the nucleus and the mitochondria. Under normal conditions no co-localisation with PCNA could be detected, however following exposure to UV it was possible to co-immunoprecipitate p15(PAF) and PCNA from a number of cell lines, suggesting a UV-enhanced association of the two proteins. Overexpression of p15(PAF) in mammalian cells was also found to protect cells from UV-induced cell death. Based on similarities between the behaviour of p15(PAF) and the potential tumor suppressor product p33ING1b, we have further shown that these two proteins interact in the same complex in cell cultures. This suggests that p15(PAF) forms part of a larger protein complex potentially involved in the regulation of DNA repair, apoptosis and cell cycle progression.
Publisher: American Association for Cancer Research (AACR)
Date: 14-01-2015
DOI: 10.1158/1078-0432.CCR-14-1962
Abstract: Purpose: Head and neck squamous cell carcinomas (HNSCC) are frequently drug resistant and have a mortality rate of 45%. We have previously shown that E2F7 may contribute to drug resistance in SCC cells. However, the mechanism and pathways involved remain unknown. Experimental Design: We used transcriptomic profiling to identify candidate pathways that may contribute to E2F7-dependent resistance to anthracyclines. We then manipulated the activity/expression of the candidate pathway using overexpression, knockdown, and pharmacological inhibitors in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and a downstream effector in a tissue microarray (TMA) generated from HNSCC patient s les. Results: E2F7-deficient keratinocytes were selectively sensitive to doxorubicin and this was reversed by overexpressing E2F7. Transcriptomic profiling identified Sphingosine kinase 1 (Sphk1) as a potential mediator of E2F7-dependent drug resistance. Knockdown and overexpression studies revealed that Sphk1 was a downstream target of E2F7. TMA studies showed that E2F7 overexpression correlated with Sphk1 overexpression in human HNSCC. Moreover, inhibition of Sphk1 by shRNA or the Sphk1-specific inhibitor, SK1-I (BML-EI411), enhanced the sensitivity of SCC cells to doxorubicin in vitro and in vivo. Furthermore, E2F7-induced doxorubicin resistance was mediated via Sphk1-dependent activation of AKT in vitro and in vivo. Conclusion: We identify a novel drugable pathway in which E2F7 directly increases the transcription and activity of the Sphk1/S1P axis resulting in activation of AKT and subsequent drug resistance. Collectively, this novel combinatorial therapy can potentially be trialed in humans using existing agents. Clin Cancer Res 21(2) 417–27. ©2014 AACR.
Publisher: Public Library of Science (PLoS)
Date: 19-04-2017
Publisher: Springer Science and Business Media LLC
Date: 2020
DOI: 10.1007/S11864-019-0697-3
Abstract: Recent studies have evidenced the potential of combining anti-EGFR therapies with anti-PD-1/PD-L1 checkpoint therapies. Both anti-EGFR and anti-PD-1/PD-L1 have been separately tested in the treatment of cutaneous SCC (cSCC). Here, we review recent data on EGFR in the context of cancer progression, as a prognostic and as a therapeutic target in cSCC. Anti-EGFR/checkpoint immunotherapy and other combination therapy approaches are discussed. With the advent of immunotherapy, EGFR is still a valid cSCC target.
Publisher: Wiley
Date: 28-01-2020
DOI: 10.1002/IJC.32869
Abstract: Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87% CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432785
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Informa UK Limited
Date: 30-07-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432824.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Cold Spring Harbor Laboratory
Date: 02-06-2023
DOI: 10.1101/2023.05.30.542966
Abstract: Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills basal-like breast cancer cells. We used CAP-activated media (PAM) to capture the multi-modal chemical species of CAP. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in upregulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells, such that a strategy based on the synergism of CAP and EGF therapy may provide new opportunities to improve the clinical management of TNBC.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432809.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432776.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 10-2014
Abstract: Although advanced cutaneous squamous cell carcinoma (CSCC) is quite common, there are few prospective trials regarding its optimal management. This study evaluated the efficacy and safety of single-agent panitumumab in the treatment of patients with CSCC not suitable for local therapy. Sixteen patients received single-agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of three cycles and continued until progression, a maximum of nine cycles or dose-limiting toxicity. The primary end point was the best overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) criteria. Secondary end points included evaluation of safety, toxicity and progression-free survival (PFS). Between May 2010 and May 2012, 16 patients were recruited. Fourteen patients were male and the median age was 68 years. Fifteen patients had locoregionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 receiving previous cytotoxic chemotherapy. The best ORR [partial (PR) or complete response (CR)] was 31% (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD. The median PFS and overall survival were 8 and 11 months respectively. Grade 3 or 4 events were observed in five patients (four being skin toxicity) with one patient ceasing due to skin toxicity. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, one patient with no evidence of disease at the time of analysis. Single-agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.
Publisher: Elsevier BV
Date: 06-2007
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432770.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Impact Journals, LLC
Date: 13-01-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432818
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Wiley
Date: 21-02-2013
DOI: 10.1111/AJD.12025
Abstract: Squamous cell carcinoma (SCC) of the skin is an increasingly common diagnosis worldwide. Together with precursor lesions, SCC carry a significant morbidity, particularly in regions with high solar UV radiation levels. Advanced lesions are locally or sometimes widely metastatic and may be resistant to treatment. Drugs targeting the epidermal growth factor receptor (EGFR) are currently the only significant non-surgical option for advanced SCC beyond radiotherapy and conventional chemotherapy. The role of the EGFR in skin cancer is described and the outcomes of targeted anti-EGFR therapy published to date are summarised. The future of anti-EGFR targeted therapies in the treatment of skin cancer is discussed. Targeted molecular therapies are becoming increasingly widespread and an understanding of the evidence for their use as well as their side effect profile is important in order to offer patients informed and current advice.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2015
DOI: 10.1158/1535-7163.MCT-15-0076
Abstract: We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient s les. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicin-insensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin. Mol Cancer Ther 14(8) 1939–50. ©2015 AACR.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2006
Abstract: Instructions to fabricate mineralized structures with distinct nanoscale architectures, such as seashells and coral and vertebrate skeletons, are encoded in the genomes of a wide variety of animals. In mollusks, the mantle is responsible for the extracellular production of the shell, directing the ordered biomineralization of CaCO 3 and the deposition of architectural and color patterns. The evolutionary origins of the ability to synthesize calcified structures across various metazoan taxa remain obscure, with only a small number of protein families identified from molluskan shells. The recent sequencing of a wide range of metazoan genomes coupled with the analysis of gene expression in non-model animals has allowed us to investigate the evolution and process of biomineralization in gastropod mollusks. Here we show that over 25% of the genes expressed in the mantle of the vetigastropod Haliotis asinina encode secreted proteins, indicating that hundreds of proteins are likely to be contributing to shell fabrication and patterning. Almost 85% of the secretome encodes novel proteins remarkably, only 19% of these have identifiable homologues in the full genome of the patellogastropod Lottia scutum . The spatial expression profiles of mantle genes that belong to the secretome is restricted to discrete mantle zones, with each zone responsible for the fabrication of one of the structural layers of the shell. Patterned expression of a subset of genes along the length of the mantle is indicative of roles in shell ornamentation. For ex le, Has-sometsuke maps precisely to pigmentation patterns in the shell, providing the first case of a gene product to be involved in molluskan shell pigmentation. We also describe the expression of two novel genes involved in nacre (mother of pearl) deposition. The unexpected complexity and evolvability of this secretome and the modular design of the molluskan mantle enables ersification of shell strength and design, and as such must contribute to the variety of adaptive architectures and colors found in mollusk shells. The composition of this novel mantle-specific secretome suggests that there are significant molecular differences in the ways in which gastropods synthesize their shells.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2019
DOI: 10.1038/S41598-019-54435-0
Abstract: Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432779
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432812
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432800.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: MDPI AG
Date: 14-05-2021
Abstract: Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers has two distinct mechanisms: either a kinase-activating mutation in EGFR (EGFR-mutant) and/or an overexpression of wild-type EGFR (wt-EGFR). The underlying mechanism of EGFR dysregulation influences the efficacy of anti-EGFR therapy as well as the nature of resistance patterns and secondary mutations. This review will critically analyse the mechanisms of EGFR expression in NSCLC, its relevance to currently approved targeted treatment options, and the complex nature of secondary mutations and intrinsic and acquired resistance patterns in NSCLC.
Publisher: Wiley
Date: 26-08-2005
DOI: 10.1111/J.1600-0854.2005.00328.X
Abstract: The mammalian retromer protein complex, which consists of three proteins--Vps26, Vps29, and Vps35--in association with members of the sorting nexin family of proteins, has been implicated in the trafficking of receptors and their ligands within the endosomal/lysosomal system of mammalian cells. A bioinformatic analysis of the mouse genome identified an additional transcribed paralog of the Vps26 retromer protein, which we termed Vps26B. No paralogs were identified for Vps29 and Vps35. Phylogenetic studies indicate that the two paralogs of Vps26 become evident after the evolution of the chordates. We propose that the chordate Vps26-like gene published previously be renamed Vps26A to differentiate it from Vps26B. As for Vps26A, biochemical characterization of Vps26B established that this novel 336 amino acid residue protein is a peripheral membrane protein. Vps26B co-precipitated with Vps35 from transfected cells and the direct interaction between these two proteins was confirmed by yeast 2-hybrid analysis, thereby establishing Vps26B as a subunit of the retromer complex. Within HeLa cells, Vps26B was found in the cytoplasm with low levels at the plasma membrane, while Vps26A was predominantly associated with endosomal membranes. Within A549 cells, both Vps26A and Vps26B co-localized with actin-rich lamellipodia at the cell surface. These structures also co-localized with Vps35. Total internal reflection fluorescence microscopy confirmed the association of Vps26B with the plasma membrane in a stable HEK293 cell line expressing cyan fluorescent protein (CFP)-Vps26B. Based on these observations, we propose that the mammalian retromer complex is located at both endosomes and the plasma membrane in some cell types.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432815
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: The Company of Biologists
Date: 10-2006
DOI: 10.1242/JCS.03167
Abstract: We report that phosphoinositol-binding sorting nexin 5 (SNX5) associates with newly formed macropinosomes induced by EGF stimulation. We used the recruitment of GFP-SNX5 to macropinosomes to track their maturation. Initially, GFP-SNX5 is sequestered to discrete subdomains of the macropinosome these subdomains are subsequently incorporated into highly dynamic, often branched, tubular structures. Time-lapse videomicroscopy revealed the highly dynamic extension of SNX5-labelled tubules and their departure from the macropinosome body to follow predefined paths towards the perinuclear region of the cell, before fusing with early endosomal acceptor membranes. The extension and departure of these tubular structures occurs rapidly over 5-10 minutes and is dependent upon intact microtubules. As the tubular structures depart from the macropinosome there is a reduction in the surface area and an increase in tension of the limiting membrane of the macropinosome. In addition to the recruitment of SNX5 to the macropinosome, Rab5, SNX1 and EEA1 are also recruited by newly formed macropinosomes, followed by the accumulation of Rab7. SNX5 forms heterodimers with SNX1 and this interaction is required for endosome association of SNX5. We propose that the departure of SNX5-positive tubules represents a rapid mechanism of recycling components from macropinosomes thereby promoting their maturation into Rab7-positive structures. Collectively these findings provide a detailed real-time characterisation of the maturation process of the macropinocytic endosome.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432785.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432770
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432779.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432776
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432815.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432773
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432821.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: MDPI AG
Date: 20-05-2021
Abstract: The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.
Publisher: Rockefeller University Press
Date: 15-05-1996
Abstract: Coat proteins are required for the budding of the transport vesicles that mediate membrane traffic pathways, but for many pathways such proteins pathways, but for many pathways such proteins have not yet been identified. We have raised antibodies against p47, a homologue of the medium chains of the adaptor complexes of clathrin-coated vesicles (Pevsner, J., W. Volknandt, B.R. Wong, and R.H. Scheller. 1994. Gene (Amst.). 146:279-283), to determine whether this protein might be a component of a new type of coat. p47 coimmunoprecipitates with three other proteins: two unknown proteins of 160 and 25 kD, and beta-NAP, a homologue of the beta/beta'-adaptins, indicating that it is a subunit of an adaptor-like heterotetrameric complex. However, p47 is not enriched in preparations of clathrin-coated vesicles. Recruitment of the p47-containing complex onto cell membranes is stimulated by GTP gamma S and blocked by brefeldin A, indicating that, like other coat proteins, its membrane association is regulated by an ARF. The newly recruited complex is localized to non-clathrin-coated buds and vesicles associated with the TGN. Endogenous complex in primary cultures of neuronal cells is also localized to the TGN, and in addition, some complex is associated with the plasma membrane. These results indicate that the complex is a component of a novel type of coat that facilitates the budding of vesicles from the TGN, possibly for transporting newly synthesized proteins to the plasma membrane.
Publisher: Public Library of Science (PLoS)
Date: 13-08-2012
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432809
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JID.2018.06.190
Abstract: EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in three-dimensional culture. These studies have been completed via genetic sequencing, cell line, or three-dimensional in vitro and in vivo murine models. Here, we describe an imaging method that allows ex vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumors. We analyzed sets of tumor s les from advanced cutaneous squamous cell carcinoma and head and neck squamous cell carcinoma, actinic keratosis, intraepidermal carcinoma, and cutaneous squamous cell carcinoma. We show that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intraepidermal carcinoma, and well-differentiated cutaneous squamous cell carcinoma, different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex vivo human tumors confirm that endocytosis dysregulation is a physiological event in human tumors and has therapeutic implications.
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0960-9822(98)00022-0
Abstract: Receptor-mediated endocytosis via clathrin-coated vesicles has been extensively studied and, while many of the protein players have been identified, much remains unknown about the regulation of coat assembly and the mechanisms that drive vesicle formation [1]. Some components of the endocytic machinery interact with inositol polyphosphates and inositol lipids in vitro, implying a role for phosphatidylinositols in vivo [2] [3]. Specifically, the adaptor protein complex AP2 binds phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), PtdIns(3)P, PtdIns(3,4,5)P3 and inositol phosphates. Phosphatidylinositol binding regulates AP2 self-assembly and the interactions of AP2 complexes with clathrin and with peptides containing endocytic motifs [4] [5]. The GTPase dynamin contains a pleckstrin homology (PH) domain that binds PtdIns(4,5)P2 and PtdIns(3,4,5)P3 to regulate GTPase activity in vitro [6] [7]. However, no direct evidence for the involvement of phosphatidylinositols in clathrin-mediated endocytosis exists to date. Using well-characterized PH domains as high affinity and high specificity probes in combination with a perforated cell assay that reconstitutes coated vesicle formation, we provide the first direct evidence that PtdIns(4,5)P2 is required for both early and late events in endocytic coated vesicle formation.
Publisher: Elsevier BV
Date: 02-2014
Publisher: Elsevier BV
Date: 10-1999
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432794.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: IMR Press
Date: 2006
DOI: 10.2741/1997
Abstract: Craniofacial anomalies are a common feature of human congenital dysmorphology syndromes, suggesting that genes expressed in the developing face are likely to play a wider role in embryonic development. To facilitate the identification of genes involved in embryogenesis, we previously constructed an enriched cDNA library by subtracting adult mouse liver cDNA from that of embryonic day (E)10.5 mouse pharyngeal arch cDNA. From this library, 273 unique clones were sequenced and known proteins binned into functional categories in order to assess enrichment of the library (1). We have now selected 31 novel and poorly characterised genes from this library and present bioinformatic analysis to predict proteins encoded by these genes, and to detect evolutionary conservation. Of these genes 61% (19/31) showed restricted expression in the developing embryo, and a subset of these was chosen for further in silico characterisation as well as experimental determination of subcellular localisation based on transient transfection of predicted full-length coding sequences into mammalian cell lines. Where a human orthologue of these genes was detected, chromosomal localisation was determined relative to known loci for human congenital disease.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.GENE.2006.01.027
Abstract: Cdca4 (Hepp) was originally identified as a gene expressed specifically in hematopoietic progenitor cells as opposed to hematopoietic stem cells. More recently, it has been shown to stimulate p53 activity and also lead to p53-independent growth inhibition when overexpressed. We independently isolated the murine Cdca4 gene in a genomic expression-based screen for genes involved in mammalian craniofacial development, and show that Cdca4 is expressed in a spatio-temporally restricted pattern during mouse embryogenesis. In addition to expression in the facial primordia including the pharyngeal arches, Cdca4 is expressed in the developing limb buds, brain, spinal cord, dorsal root ganglia, teeth, eye and hair follicles. Along with a small number of proteins from a range of species, the predicted CDCA4 protein contains a novel SERTA motif in addition to cyclin A-binding and PHD bromodomain-binding regions of homology. While the function of the SERTA domain is unknown, proteins containing this domain have previously been linked to cell cycle progression and chromatin remodelling. Using in silico database mining we have extended the number of evolutionarily conserved orthologues of known SERTA domain proteins and identified an uncharacterised member of the SERTA domain family, SERTAD4, with orthologues to date in human, mouse, rat, dog, cow, Tetraodon and chicken. Immunolocalisation of transiently and stably transfected epitope-tagged CDCA4 protein in mammalian cells suggests that it resides predominantly in the nucleus throughout all stages of the cell cycle.
Publisher: American Association for Cancer Research (AACR)
Date: 2016
DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-B055
Abstract: Organ transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) development. Immunosuppressive agents, given to these patients to prevent organ rejection, are widely recognized to play a key role in the increased incidence of malignancy. However, different immunosuppressive agents, such as rapamycin and tacrolimus, which both prevent organ rejection, convey different risks of tumor formation. Using a UV-induced murine model of squamous cell carcinoma (SCC) HPV38 E6E7, we aim to determine whether these discrepancies are due to differences in the mechanism of immune suppression, in contrast to the much discussed direct effects of these drugs on tumor cells (i.e. immune-independent). Using customized rapamycin- and tacrolimus-incorporated feed to allow long-term administration, clinically relevant whole blood drug concentrations were obtained and validated using LC-MS/MS. Both systemic and local immunosuppression was functionally determined via adoptively transferred transgenic T-cell assay and skin allograft rejection profile, respectively. Notably however, preliminary data suggests phenotypic and functional differences of skin-residing T-cell subpopulations may exist when mice are treated with either rapamycin or tacrolimus, alluding to their potential role in the pathogenesis of NMSC. Short-term contact hypersensitivity responses (CHS) to OVA were abrogated in both rapamycin and tacrolimus-treated mice. However, prolonging the challenge phase enhanced the long-term CHS response in rapamycin-treated but not in tacrolimus-treated mice compared to normal feed controls. This enhanced response was correlated with an increased number of effector memory CD8+ T-cell population in the challenged ear skin. Using established chronic UV dosing schedules for SCC development in HPV38 E6E7 mice, tumor s les along with surrounding UV-exposed skin and fur-covered UV-protected skin s les were analyzed with FACs under the influence of these drugs. Preliminary data suggests that the formation of resident-memory CD8+ T-cells may be favored when treated with rapamycin, as higher percentages of CD8+ T-cells were present in the lesions of rapamycin-treated mice compared to tacrolimus and controls. In addition, LC-MS/MS analysis indicated that the concentration of rapamycin in the skin was significantly lower when compared to tacrolimus, whilst clinically relevant immunosuppressive concentrations of both drugs were maintained in the blood and kidneys. Through this project, we will expand our knowledge base regarding mechanisms of SCC formation in immunosuppressed patients. Citation Format: Ji-Won Jung, Paul J. Taylor, Fiona Simpson, Ian H. Frazer, James W. Wells. The impact of rapamycin and tacrolimus treatment on resident CD8+ T-cell populations in cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival September 16-19, 2015 New York, NY. Philadelphia (PA): AACR Cancer Immunol Res 2016 (1 Suppl):Abstract nr B055.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432803.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432788.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432800
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432806
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432803
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: MDPI AG
Date: 21-11-2022
Abstract: Lysosome-related organelles (LROs) are a group of functionally erse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Springer Science and Business Media LLC
Date: 13-02-2009
DOI: 10.1038/CDD.2009.2
Abstract: After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101 15(PAF). We further show that the expressions of ATF3 and p15(PAF) is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15(PAF) compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15(PAF) expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15(PAF) expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15(PAF) as novel gatekeepers of genomic integrity after UV exposure.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2014
Publisher: Springer Science and Business Media LLC
Date: 22-05-2023
Publisher: Springer Science and Business Media LLC
Date: 19-10-2020
Publisher: Elsevier BV
Date: 11-2005
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432812.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.MOD.2009.01.007
Abstract: Embryogenesis is mediated by a relatively small number of developmental signaling pathways, and the morphogens, receptors and transcription factors integral to these cascades are considered the master regulators of development. However, superimposed on this is an additional layer of control by complex intracellular trafficking networks. The importance of trafficking in controlling the processes of morphogenesis and development is highlighted by recent data regarding the transport and localisation of the morphogen sonic hedgehog (Shh) and the machinery that leads to its secretion, modification, cellular internalisation and signal transduction. Here we review the regulation of hedgehog signaling by intracellular trafficking, including the role of the primary cilium and lipids in mediating pathway activity.
Publisher: Wiley
Date: 18-08-2004
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432791.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Wiley
Date: 2001
DOI: 10.1034/J.1600-0854.2001.020102.X
Abstract: GLUT4 is a mammalian facilitative glucose transporter that is highly expressed in adipose tissue and striated muscle. In response to insulin, GLUT4 moves from intracellular storage areas to the plasma membrane, thus increasing cellular glucose uptake. While the verification of this 'translocation hypothesis' (Cushman SW, Wardzala LJ. J Biol Chem 1980 : 4758-4762 and Suzuki K, Kono T. Proc Natl Acad Sci 1980 : 2542-2545) has increased our understanding of insulin-regulated glucose transport, a number of fundamental questions remain unanswered. Where is GLUT4 stored within the basal cell? How does GLUT4 move to the cell surface and what mechanism does insulin employ to accelerate this process? Ultimately we require a convergence of trafficking studies with research in signal transduction. However, despite more than 30 years of intensive research we have still not reached this point. The problem is complex, involving at least two separate signal transduction pathways which feed into what appears to be a very dynamic sorting process. Below we discuss some of these complexities and highlight new data that are bringing us closer to the resolution of these questions.
Publisher: American Association for Cancer Research (AACR)
Date: 07-09-2022
DOI: 10.1158/0008-5472.CAN-22-0948
Abstract: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations.
Publisher: Rockefeller University Press
Date: 16-08-2010
Abstract: Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432797.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Wiley
Date: 19-01-2007
DOI: 10.1002/DVDY.21064
Abstract: The locus for autosomal recessive infantile cerebellar ataxia (CLA3 or SCAR6) has been mapped to chromosome 20q11-q13 in a single Norwegian pedigree. We identified a relatively uncharacterised mouse gene Tp53inp2, and showed that its human orthologue mapped within this candidate interval. Tp53inp2 appears to encode a mammalian-specific protein with homology to the two Tp53inp1 isoforms that respond to cellular stress and interact with p53. We show that Tp53inp2 expression is highly restricted during mouse embryogenesis, with strong expression in the developing brain and spinal cord, as well as in the sensory and motor neuron tracts of the peripheral nervous system. Given this expression pattern, the neurological phenotype of CLA3 and the chromosomal localisation of TP53INP2, we searched the coding region for mutations in s les from in iduals from the CLA3 pedigree. Our failure to detect causative mutations suggests that alterations in the coding region of TP53INP2 are not responsible for ataxia in this family, although we cannot rule out changes in non-coding elements of this gene.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432806.V1
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Public Library of Science (PLoS)
Date: 10-01-2022
DOI: 10.1371/JOURNAL.PPAT.1010166
Abstract: A hallmark of Listeria (L . ) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L . monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L . monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria -containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L . monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L . monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L . monocytogenes in macrophages is not inevitably tied to bacterial persistence.
Publisher: S. Karger AG
Date: 18-12-2015
DOI: 10.1159/000367959
Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase. Its correct function is required for normal skin development and homeostasis, while dysregulation of EGFR signalling results in cellular hyper-proliferation and defects in differentiation, leading to impaired wound healing, the development of psoriasis-like lesions, structural and functional defects of hair follicles and tumourigenesis. Actinic keratosis, which is also known as solar keratosis, develops in sun-exposed areas of the skin. These are often called 'premalignant lesions' and are said to represent early squamous cell carcinoma (SCC) in situ, although debate over their classification continues. Anti-EGFR therapies have been approved for the treatment of several malignancies and are undergoing trials for others [1], including advanced cutaneous squamous cell carcinoma (CSCC). However, a number of questions remain regarding the treatment of CSCC with anti-EGFR inhibitors. A lower number of CSCC tumours are EGFR positive in comparison to other types of tumours, such as head and neck SCC (HNSCC), and it has been suggested that patients should be selected on the basis of high tumour EGFR expression. However, there are reports of patients with tumours showing no EGFR-positive staining responding to anti-EGFR therapy. EGFR is an oncogenic driver in many tumours. Does it drive the transformation of actinic keratosis to a tumourigenic phenotype? Many such questions remain, and here, we discuss the role of EGFR in SCC and its functions during the different stages of skin cancer development.
Publisher: MDPI AG
Date: 16-11-2020
Abstract: Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors h ering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6514248.V1
Abstract: Abstract Patient-derived xenograft (PDX) models are an effective preclinical i in vivo /i platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non–small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both i de novo /i and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research. Significance: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432794
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432791
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432797
Abstract: Supplementary Figure from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.BIOCEL.2009.12.021
Abstract: Adiponectin is an adipokine (adipocyte-derived hormone) with multiple salutary effects. It is secreted into the circulation as low molecular weight (LMW) and high molecular weight (HMW) multimers with the latter being more metabolically active. Extensive post-translational modifications (PTMs) are required for efficient adiponectin multimerisation and secretion. Recent studies have identified novel PTMs that contribute to the efficacy of adiponectin production and clearance. Thiol-mediated retention of adiponectin occurs during transit through the ER, via direct interactions with chaperones including ERp44 and DsbA-L, and facilitates multimerisation and secretion. Interestingly, this appears to be in direct competition with adiponectin succination. Adiponectin is also subject to O-glycosylation/sialylation which affects clearance from the circulation. In contrast to most adipokines, reduced adiponectin levels, particularly HMW, contribute to the aetiology of obesity-related diseases such as type 2 diabetes and cardiovascular disease. Strategies that modulate processes governing PTM of adiponectin represent attractive therapeutic approaches.
Publisher: Springer Science and Business Media LLC
Date: 15-05-1999
DOI: 10.1038/10091
Abstract: Several SH3-domain-containing proteins have been implicated in endocytosis by virtue of their interactions with dynamin however, their functions remain undefined. Here we report the efficient reconstitution of ATP-, GTP-, cytosol- and dynamin-dependent formation of clathrin-coated vesicles in permeabilized 3T3-L1 cells. The SH3 domains of intersectin, endophilin I, syndapin I and hiphysin II inhibit coated-vesicle formation in vitro through interactions with membrane-associated proteins. Most of the SH3 domains tested selectively inhibit late events involving membrane fission, but the SH3A domain of intersectin uniquely inhibits intermediate events leading to the formation of constricted coated pits. These results suggest that interactions between SH3 domains and their partners function sequentially in endocytic coated-vesicle formation.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22432773.V1
Abstract: Supplementary Table from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2005
End Date: 2007
Funder: Australian Research Council
View Funded ActivityStart Date: 2000
End Date: 2002
Funder: Juvenile Diabetes Research Foundation
View Funded ActivityStart Date: 2007
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2007
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2005
End Date: 12-2007
Amount: $370,000.00
Funder: Australian Research Council
View Funded Activity