tbuckley/cabot-search huggingface dataset:
Abstract 3970: Targeting the adenosine immunosuppressive pathway for cancer immunotherapy with small molecule agents
Authors: Pierre Fons, Michael Esquerré, Stéphanie Versluys, Gigliola Mambrini, Michael Paillasse, Andy Bell, Adrian Schreyer, Richard Cox, Richard Bickerton, Joanna Lisztwan, Mark Whittaker, Françoise Bono, Craig Johnstone, Andrew Hopkins
Journal: Cancer Research (2017)

Abstract Standard Immune Checkpoint Therapies, such as anti-CTLA-4 or anti-PD-1/PD-L1 mAb, demonstrate long progression-free-survival for responding patients but with a low response rate. This can be due to additional immunosuppressive mechanisms developed by resistant tumors. The adenosine pathway is one of the main drivers of tumor progression by acting on two key features of the TME (Tumor Micro-Environment); immunity and angiogenesis. Expression of CD73 on tumor cells and on immunosuppressive cell subsets leads to the generation of adenosine from AMP. Adenosine inhibits the biological functions of T lymphocytes infiltrating the tumor by binding to the A2AR (receptor). Evotec and Exscientia are collaborating to accelerate small molecule drug discovery in the field of Immuno-Oncology by integrating a unique biophysical screening approach to the adenosine receptors and CD73 to drive automated medicinal chemistry design with a translational-focused screening cascade, to discover novel agents that target the adenosinergic pathway in immuno-oncology. We have firstly sought to generate novel A2AR antagonists and secondly to create A2AR/CD73 bi-specific inhibitory molecules with a dual pharmacological profile, from fragment screening and de novo design approaches. In vivo combination study demonstrate the advantages of targeting CD73 and A2AR. We have obtained active molecules illustrated by in vitro data on primary human T lymphocytes. These results, have paved the way to an optimized process to identify adenosinergic pathway inhibitors with properties optimized for immuno-oncology. Citation Format: Pierre Fons, Michael Esquerré, Stéphanie Versluys, Gigliola Mambrini, Michael Paillasse, Andy Bell, Adrian Schreyer, Richard Cox, Richard Bickerton, Joanna Lisztwan, Mark Whittaker, Françoise Bono, Craig Johnstone, Andrew Hopkins. Targeting the adenosine immunosuppressive pathway for cancer immunotherapy with small molecule agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3970. doi:10.1158/1538-7445.AM2017-3970
Abstract 4417: The role of EBV infection in aerobic glycolysis in nasopharyngeal carcinoma
Authors: George S. Tsao, Jun Zhang, Lin Xia, C Tsang, Weitao Lin, Y Yip, W Deng, K Lo, M Lung
Journal: Cancer Research (2017)

Abstract Accumulating evidence indicates that oncogenic viral protein exerts a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a trans-membrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-κB is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-κB signaling to mediate aerobic glycolysis. NF-κB activation is involved for LMP1-induced upregulation of glucose transptor-1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Collectively, blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-κB activation and Glut-1 transcription. Interfering NF-κB signaling has no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that Glut-1 is a direct target gene of NF-κB signaling. Furthermore, we demonstrated that the LMP1 C-terminal activating region (CTAR) 2 is the key domain involved in mTORC1 activation, mainly through IKKβ-mediated phosphorylation of TSC2 at Ser939. Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-κB/Glut-1 represents a novel therapeutic target against NPC. Acknowledgement: 96 800x600 This project was supported by the General Research Fund (HKU 779810M, 17120814 and 17161116), CRF equipment grant (1061402980, Health and Medical Research Fund of Hong Kong (12110782), AoE grant (AoE/M-06/08) and TBRS grant (T12-401/13-R). We thank Prof. Dongyan Jin (Department of Biochemistry, The University of Hong Kong) for the kind gifts of IKK related plasmids and Prof. Zhenguo Wu (Division of Life Science, The Hong Kong University of Science and Technology) for the discussion and interpretation of the data. We also thank Mr. Tony Chan for his technical support. Note: This abstract was not presented at the meeting. Citation Format: George S. Tsao, Jun Zhang, Lin Xia, C Tsang, Weitao Lin, Y Yip, W Deng, K Lo, M Lung. The role of EBV infection in aerobic glycolysis in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4417. doi:10.1158/1538-7445.AM2017-4417
Medical Education Theme Issue 2008
Authors: Robert M. Golub
Journal: JAMA (2007)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 2845: A Rb phosphorylation code associated with lung cancer metastasis
Authors: Jaileene Perez-Morales, Darielys Mejias-Morales, Bryan Torres-Collazo, Harry Negron-Pagan, Pedro Santiago-Cardona
Journal: Cancer Research (2017)

Abstract Lung cancer is characterized by its poor prognosis, aggressiveness, and proclivity for early metastasis. Non-small cell lung cancer (NSCLC) it’s the most common type of lung cancer with a five-year survival rate of 18%. Most predictors of metastasis and recurrence of NSCLC rely on post-resection evaluation of tumor histology, which is a severe limitation since only 15% of the patients are diagnosed with resectable disease. Hence, there is a need to characterize biomarkers with metastasis-predicting value in pre-resection small biopsy specimens. In addition to the proclivity for metastasis, another feature of lung cancers is the inactivation of the retinoblastoma protein (Rb). The retinoblastoma protein (Rb) is a tumor suppressor inactivated due to hyper-phosphorylation in most human cancers, including NSCLC. Our preliminary data relates the Rb S249/T821 phosphorylation signature to an epithelial-to-mesenchymal transition (EMT), a trait strongly associated to metastasis. We found that cells that have hyperphosphorylated Rb in residues S249/T821 express EMT markers such as decreased expression of E-cadherin and integrin α5 as well as increased expression of N-cadherin, Vimentin, and p-FAK. We propose to focus on the cell adhesion and migration-related kinase Cdk5 with its activator p39 as the kinase responsible for engendering the Rb S249/T821 phosphorylation signature. Our hypothesis is that Rb phosphorylation in S249 and T821 due to CDK5 activity can have prognostic value by being associated with a metastatic phenotype and EMT. Studies performed in a tissue microarray in a population of NSCLC adenocarcinoma that had undergone EMT found an up-regulation in p39 and that its expression is correlated with metastasis. Knockdown of CDK5 induced a decrease in phosphorylation of Rb S249/T821 with a decrease in E-cadherin expression. These data suggest that CDK5-dependent phosphorylation of Rb can affect cell adhesion by regulating E-cadherin. Introducing p39 into Rb hypo-phosphorylated cell line induced an increase in phosphorylation of Rb residues. Furthermore, the CDK5-p39-Rb axis might point to the explanation and prediction of the metastatic phenotype in lung cancer. Citation Format: Jaileene Perez-Morales, Darielys Mejias-Morales, Bryan Torres-Collazo, Harry Negron-Pagan, Pedro Santiago-Cardona. A Rb phosphorylation code associated with lung cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2845. doi:10.1158/1538-7445.AM2017-2845
Plans for major NHS cuts are shrouded in secrecy, warns BMA
Authors: Abi Rimmer
Journal: BMJ (2017)

Health service leaders have refused to publish details of their plans to make severe cuts to NHS services, the BMA has said.

The association attempted to obtain details of the plans, formulated by 13 areas around England, to make considerable cuts as part of the capped expenditure process (CEP).

The cuts, said the BMA, could extend waiting times, reduce access to services, cut prescriptions and treatments, and even merge or close hospitals and facilities. The CEP was introduced …
Abstract 110: Quantitative high throughput screening as a tool to identify novel therapies in bladder cancer
Authors: Reema Railkar, Thomas Sanford, L. Spencer Krane, Piyush K. Agarwal
Journal: Cancer Research (2017)

Abstract Introduction: Bladder cancer (CaB) is the 4th most common cancer among men in the US. It is the most expensive malignancies to treat from diagnosis to death. No new pharmacological agents have been approved for treatment of bladder cancer since the approval of BCG in 1990. Thus, there is an urgent need for development of new treatment therapies. Quantitative high throughput screening (qHTS) of representative cancer lines with oncology drugs may identify new treatments or re-purpose already existing therapies for different disease. We utilized this technique to identify new therapies in two primary bladder lines (T24 and UMUC3) and their metastatic lines (T24T, SLT3 and FL3 of T24 and LUL-2 for UMUC3). Methods: We screened 7 bladder cancer cell lines against 1,912 oncology drugs using a 48 hour cell proliferation assay with an ATP−based readout (CellTiterGlo) to determine activity and potency of compounds in a dose response manner. One of the candidate drugs inhibitory in all cell lines tested is flavopiridol, a pan CDK inhibitor. We further characterized the mechanism of action and in vivo effects of flavopiridol using various cell based assays and mouse xenograft studies. Results: The initial screen identified 95 compounds active in 7 cell lines. The top 50 compounds were further analyzed for molecular size of &amp;gt;200 g/mol and TPSA&amp;lt;90. This identified mitomycin C and 8 novel compounds. Further testing revealed Flavopiridol to be most consistent with qHTS data having IC50 of 100-300nM in all the cell lines tested. Flavopiridol induces G2/M arrest; however, very little apoptosis was seen suggesting cytostatic rather than cytotoxic mechanism of flavopiridol action. Flavopiridol showed dose dependent inhibition of migration, invasion and colony formation in CaB cell lines tested. Xenograft studies in rapidly growing UMUC-3 cells showed slowing of tumor growth but not complete reduction indicating cytostatic mechanism of flavopiridol. However, in slow growing cells, 5637, 5/8 treated mice showed complete tumor reduction. Conclusions: qHTS can identify novel compounds. Flavopiridol seems to be a very effective inhibitor both in vitro and in vivo. Physical properties of Flavopiridol are most suited for intravesical use which may lead to it being an effective inhibitor of CaB in the bladder at higher doses without any/few systemic toxicities. Studies are underway to elucidate the use of flavopiridol as a single intravesical agent. Citation Format: Reema Railkar, Thomas Sanford, L. Spencer Krane, Piyush K. Agarwal. Quantitative high throughput screening as a tool to identify novel therapies in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 110. doi:10.1158/1538-7445.AM2017-110
Abstract 2305: Residential airborne heavy metal concentrations and breast cancer characteristics
Authors: Jacob K. Kresovich, Serap Erdal, Maria Argos, Hua Yun Chen, Peter H. Gann, Garth H. Rauscher
Journal: Cancer Research (2017)

Abstract Background: Ambient air metal concentrations have recently been implicated in the etiology of breast cancer. Previous studies have shown airborne concentrations of arsenic and cadmium are associated with the development of estrogen receptor-negative tumors. This study aims to replicate these findings and examine the role of other toxic and essential heavy metals. Methods: Participants were women who were diagnosed with breast cancer in Chicago between 2005 and 2008. We examined estrogen and progesterone receptor-negative (ER-/PR-) and high-grade tumors as markers of aggressive breast cancer, and estimated 15-year markers of exposure of 11 heavy metals. Exposures were calculated using census tract-level airborne concentrations from the National-scale Air Toxics Assessment and participants’ residential histories. We adjusted all models for socioeconomic status and reproductive factors. Results: We found that prevalent ER-/PR- tumors were associated with increased residential exposure to airborne concentrations of antimony (Q4 vs Q1: OR= 1.81; 95% CI: 0.95, 3.44; Ptrend= 0.04), cobalt (Q4 vs Q1: OR= 2.37; 95% CI: 1.26, 4.45; Ptrend &amp;lt; 0.01), manganese (Q4 vs Q1: OR= 2.55; 95% CI: 1.24, 5.24; Ptrend= 0.04), and selenium (Q4 vs Q1: OR= 1.85; 95% CI: 1.03, 3.29; Ptrend= 0.05), and also identified marginally significant trends for arsenic (Ptrend= 0.06), chromium (Ptrend= 0.08), lead (Ptrend= 0.08), and mercury (Ptrend= 0.07). We did not identify any overall associations with high-grade tumors, however when stratifying by menopausal status we found that antimony (Q4 vs Q1: OR= 6.97, 95% CI: 1.61-30.19) and arsenic (Q4 vs Q1: OR= 6.97, 95% CI: 1.61-30.19) were associated with prevalent high-grade tumors in premenopausal women only. Discussion: This study found further support for a role of airborne arsenic concentrations, and novel evidence implicating other airborne estrogen-pathway disrupting metal concentrations, in the development of aggressive breast cancer subtypes. Additionally, this is the first study to implicate heavy metal exposure in the etiology of high-grade tumors. These results suggest that long-term, low-dose exposures to certain heavy metals play a role in the etiology of aggressive breast cancer characteristics. Airborne exposures have the ability to affect large populations and findings from this and similar studies have large public health implications. Citation Format: Jacob K. Kresovich, Serap Erdal, Maria Argos, Hua Yun Chen, Peter H. Gann, Garth H. Rauscher. Residential airborne heavy metal concentrations and breast cancer characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2305. doi:10.1158/1538-7445.AM2017-2305
Abstract 2467: Mutation analysis using next-generation sequencing in histologically heterogeneous of primary lung cancers
Authors: Hayato Koba, Hideharu Kimura, Kazuo Kasahara
Journal: Cancer Research (2017)

Abstract Rare cases of primary lung cancer are known to have different histological types. Recently, small cell carcinoma was reported to be developed in adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations after EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. The purposes of this study are to evaluate mutational status in two different histological types separately, and to further understand the molecular pathogenesis. Twelve tumor samples from 6 patients were collected in our institution. 4 patients had primary adenocarcinoma and small cell carcinoma transformed after EGFR-TKI. One patient had primary adenocarcinoma and squamous cell carcinoma transformed after EGFR-TKI. The other one patient had carcinosarcoma in a surgically resected tumor. Two samples per patient were collected from histologically different areas within a resected tumor or the 2 distinct metastatic sites. DNA was extracted from formalin-fixed, paraffin-embedded tumor tissues. Next-generation sequencings in the 12 samples were performed on 160 cancer-related genes using GeneRead™ DNAseq Targeted Panels V2 Human comprehensive Cancer Panel (QIAGEN). In a carcinosarcoma case with deletional mutation in EGFR gene, a total 504 in adenocarcinoma and 595 in sarcoma variants in 160 genes were detected with high confidence. The gene of identical alterations, as truncal alterations, were EGFR, CBLB, TP53 and MEN1 and the number of that as an unique alteration corresponding to each histology is 25 for adenocarcinoma and 85 for sarcoma. We show relations between the histological types and the genomic alterations, identical alterations and unique alterations, in each patient. Furthermore, we raise essential factors for the histological transformation. Citation Format: Hayato Koba, Hideharu Kimura, Kazuo Kasahara. Mutation analysis using next-generation sequencing in histologically heterogeneous of primary lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2467. doi:10.1158/1538-7445.AM2017-2467
Connecting Cancer to Its Causes Requires Incorporation of Effects on Tissue Microenvironments
Authors: James DeGregori
Journal: Cancer Research (2017)

Abstract In a recent article in Science, Tomasetti and colleagues present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment, and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context. Cancer Res; 77(22); 6065–8. ©2017 AACR.
Abstract 5758: Elevated level of estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells
Authors: Yu-Wei Chang, Kamaleshwar Singh
Journal: Cancer Research (2017)

Abstract Effectiveness of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen sensitive and the levels of ovarian estrogen are age-dependent variable among the breast cancer patients. Whether this variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is unclear. Therefore, the objective of this study was to determine the effects of natural estrogen 17 beta-estradiol on the efficacy of chemotherapy in breast cancer cells. Estrogen responsive MCF-7 breast cancer cells were long-term exposed to 100 pg/ml estrogen for three months. Using these estrogen exposed MCF-7 cells, the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased efficacy of doxorubicin and cisplatin in estrogen-exposed MCF-7 cells as compared to control MCF-7 cells. Gene expression analysis of marker genes for cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-Aza-2-deoxycytidine and Trichostatin A before doxorubicin and cisplatin treatments. The enhanced efficacy of doxorubicin and cisplatin in estrogen-treated cells was significantly decreased by 5-aza-2 deoxycytidine pre-treatment, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In conclusion, results of this study demonstrate that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the type and dose of chemotherapy in breast cancer patients depending on the serum estrogen levels that varies in between pre- and post-menopausal age of the patients. Citation Format: Yu-Wei Chang, Kamaleshwar Singh. Elevated level of estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5758. doi:10.1158/1538-7445.AM2017-5758