tbuckley/cabot-search huggingface dataset:
Abstract 4478: EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma
Authors: Bernard Staumont, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Céline Mascaux, Arnaud Scherpereel, Bernard Duysinx, Renaud Louis, Philippe Delvenne, Pascale Hubert, Luc Willems
Journal: Cancer Research (2016)

Abstract Background: Malignant pleural mesothelioma (MPM) is a cancer of the pleura mainly caused by exposure to asbestos fibers. Current treatments are unsatisfactory due to intrinsic chemoresistance of the tumor. We hypothesized that chemoresistance was due to epigenetic errors and evaluated the ability of HDAC inhibitors to improve treatment efficacy. We previously showed that valproic acid (VPA) improves the first line regimen of MPM both in vitro and in vivo (Vandermeers et al, 2009, Clinical Cancer Research 15: 2818). A clinical trial also demonstrated that VPA in combination with doxorubicin increases the response rate of second line patients (Scherpereel et al, 2011, European Respiratory Journal 37:129). Methods: Transcriptomic profiling was performed by microarray analyses (Agilent). Gene expression was validated by quantitative RT-qPCR. Modulation of TGFα expression was performed by shRNA interference and transfection of a cDNA vector. Onset of apoptosis was assessed with the Annexin V assay. Results: To evaluate the mechanisms associated with the response to chemotherapy, we compared two types of MPM cell lines (M14K and H28) characterized by a difference in sensitivity to doxorubicin+VPA. Microarray analyses and bioinformatic modeling of gene expression profiles revealed the most relevant candidate genes associated with sensitivity or resistance to this regimen. Among these, TGFα expression was associated with resistance to doxorubicin + VPA in a series of MPM cell lines. Silencing of TGFα by RNA interference in H28 cells correlated with a significant increase in apoptosis. On the other hand, overexpression of TGFα desensitized M14K cells to doxorubicin+VPA -induced apoptosis. Since TGFα interacts with the EGF receptor, we evaluated pharmacological inhibition using EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) and the dual HDAC/EGFR inhibitor CUDC-101. As predicted, these TKI inhibitors improved efficacy of doxorubicin+VPA. Conclusions: Our data demonstrate that TGFα is involved in resistance of MPM to chemotherapy and that TKI inhibitors overcome resistance to second line regimen. Citation Format: Bernard Staumont, Chrisostome Costa, Fabian Vandermeers, Sathya Neelature Sriramareddy, Céline Mascaux, Arnaud Scherpereel, Bernard Duysinx, Renaud Louis, Philippe Delvenne, Pascale Hubert, Luc Willems. EGFR tyrosine kinase inhibitors overcome resistance to chemotherapy in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4478.
Diverting tampon taxes will not solve the issue of violence against women
Authors: Karen Lorimer, Kelly Babchishin
Journal: BMJ (2016)

Shanti argues that tampon makers could help reduce violence against women.1 In the UK, tampons and other sanitary products are taxed at 5%. Recently, European regulations have given EU states the power to tax feminine hygiene products.2 3 This meant that the UK could change taxation rates for these products …
Contrasting Factors Determine the Kinetics of Disease Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukaemia (AML): a Survey from the Acute Leukaemia Working Party of the EBMT
Authors: Charles Craddock, Myriam Labopin, Gerard Socie, Anne Huyn, Eric Deconinck, Liisa Volin, Noel Milpied, Jean-Henri Bourhis, Alessandro Rambaldi, Patrice Chevallier, Jan J. Cornelissen, Didier Blaise, Johann Maertens, Christoph Schmid, Arnon Nagler, Mohamad Mohty
Journal: Blood (2014)
Phase (Ph) 1 study of oral seviteronel (VT-464), a dual CYP17-Lyase (L) inhibitor and androgen receptor (AR) antagonist, in patients (pts) with advanced AR+ triple negative (TNBC) or estrogen receptor (ER)+ breast cancer (BC).
Authors: Aditya Bardia, Noshir Anthony Dacosta, Nashat Y. Gabrail, Stephen Lemon, Michael A. Danso, Haythem Y. Ali, Ronald Alan Fleming, Michael R Kurman, Joel Robert Eisner, William Richard Moore, Ayca Gucalp, Tiffany A. Traina
Journal: Journal of Clinical Oncology (2016)

1088 Background: Seviteronel (Sevi), a CYP17-L inhibitor (reduces androgen and estrogen biosynthesis) and AR antagonist, has activity in castration resistant prostate cancer (CRPC) at a dose of 750 mg nightly. Sevi potently and dose-dependently inhibits the growth of ER(+)/AR(+) tamoxifen-resistant (TAMR) MCF7 and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth > enzalutamide, an AR antagonist (Ellison et al. SABCS 2015). Approximately 80% of BCs, including a subset of TNBC that expresses AR, are potential targets for Sevi based on its mechanism of action (MOA). The primary objective of this Ph 1 study is to establish the recommended Ph 2 dose (RP2D) in women with BC (NCT02580448). Methods: Eligible pts have AR(+) TNBC or ER(+)/HER2-normal metastatic BC. ER(+) pts must have had ≥ 1 prior line of endocrine therapy; no limit to prior treatment for TNBC. Sevi start dose was 750 mg, administered nightly with dinner (28 d cycle) (n = 6/cohort). AR(+) status was confirmed using central IHC analysis with ≥ 10% staining used for evaluable TNBC pts. Tumor samples and blood for CTC, ctDNA and steroid biomarker analysis were collected. Scans were performed every 2-3 mo to estimate 16 and 24 wk clinical benefit rate. Results: As of 1/28/14, 13 pts received Sevi with 5 in screening. 8 pts are on study between Cycle 1 and 6 (median Cycle 2). Sevi systemic exposure appears inversely dependent on body mass in women and is greater than historical data in men. Exploratory lower dose cohorts were enrolled at 600 and 450 mg. Single dose Cmax was 17.4±4.4 vs. 14.9±4.3 µM and AUC 0-8h was 99.8±17.9 vs. 78.9±14.1 µM*h at 750 and 600 mg. Most adverse events (AEs) were Grade 1 or 2, including fatigue (31%), tremor (31%) and vomiting (23%). One Grade 3 related AE was reported (confusion at 750 mg and was a DLT). Conclusions: Sevi is overall well-tolerated in women with an AE profile similar to that in men. With higher exposures, the RP2D in women is likely to be lower than in men. The dual Sevi MOA (reduced sex-steroid production and AR antagonism) may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Clinical trial information: NCT02580448.
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
Authors: Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell, Ari M. Melnick
Journal: Journal of Clinical Investigation (2016)

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.
Abstract 2887: Autonomous nucleolar mechanism of colon cancer cell survival through induction of perinuclear ribosomal protein translation
Authors: Tattym E. Shaiken, Antone R. Opekun
Journal: Cancer Research (2016)

Abstract Hypertrophic and irregularly shaped nucleoli are characteristic of gastroitinal cancers with poor prognosis. The role of nucleolar hypertrophy in cancer cell survival has not been studied well. By suppressing several cellular pathways we observed a common cellular response mechanism that involves acceleration of perinuclear ribosomal protein synthesis and multifocal nucleoli hypertrophy. Paradoxically, the induction of perinuclear ribosomal protein biosynthesis was observed by inhibition of protein translation, suppression of protein degradation and mitochondrial activity. Acceleration of perinuclear protein translation in combination of nuclear hypertrophy was detected not only in actively dividing cells but also in quiescent, cell cycle arrested cells, and when cytotoxic effects were manifested. Intensification of perinuclear ribosomal protein translation and nucleolar hypertrophy by Rotenone-mediated damage of mitochondria supported a century long Otto Warburg observation that most cancer cells predominantly produce energy by high rate of glycolysis. Cell fractionation permitted detection of a perinuclear wall that provides a structural basis for the perinuclear protein translation. We found that that rapid- and slow-growing colon cancer cells significantly differ by abundance of ribosomes in the perinuclear region. Therefore, the perinuclear set of protein translation is an important mechanism of cancer cell survival that rescues ribosome biogenesis and leads to the drug resistance through nuclear transformation. Citation Format: Tattym E. Shaiken, Antone R. Opekun. Autonomous nucleolar mechanism of colon cancer cell survival through induction of perinuclear ribosomal protein translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2887.
Resensitizing Refractory ALK+ NSCLC: A Case Study
Authors: Alissa Poh
Journal: Cancer Discovery (2016)

Abstract A case report shows that drug resistance in ALK-positive non–small cell lung cancer is a dynamic process. In this patient, an acquired mutation conferring resistance to the highly selective investigational ALK inhibitor lorlatinib unexpectedly restored responsiveness to crizotinib, an older and less potent drug.
Results of a phase I-II trial using tri-modality therapy in patients with post-prostatectomy high risk pathologic (p) T2-3N0M0 prostate cancer.
Authors: Parvesh Kumar, Peter Van Veldhuizen, Mark Thompson, Xinglei Shen, Jacek K. Pinski
Journal: Journal of Clinical Oncology (2016)

e16620 Background: A phase I-II trial was conducted to determine the safety and feasibility of post-prostatectomy radiation therapy (RT), concurrent docetaxel and hormonal therapy (HT) in patients with high risk pathologic (p) T2-3N0M0 prostate cancer. Methods: Post-prostatectomy high risk prostate cancer was defined as non-metastatic disease with either an undetectable, persistent or rising PSA with 1 or more of the following features: (1) pT2-T3aN0 disease, positive or negative margins, with either (a) a gleason score (GS) of ≥ 8, and/or (b) a PSA doubling time of ≤ 10 months, and/or (c) with a pre-RT PSA of ≥ 1.0 ng/ml; and/or (2) pT3bN0 disease. The tri-modality treatment consisted of 6 months of HT [Casodex (50 mg po daily), and Lupron (22.5 mg im q 3 mos x 2)], RT to 66.0 Gy at 2.0 Gy/fraction (fx) once daily, and concurrent weekly docetaxel at 20 mg/m2 x 7 infusions. Results: Between October 2008 and July 2014, a total of 32 patients were enrolled. The clinical and disease characteristics of the 32 patients were as follows: Median age, years (range) = 64 (44 - 74); pathologic T-stage was as follows: pT2a = 2 patients, pT2c = 5, pT3a = 13 and pT3b = 12. 9 were in the adjuvant group while 23 patients were in the salvage category. One of the 32 patients withdrew consent shortly after receiving one injection of Lupron due to “hot flashes” but before starting his chemoradiation therapy treatments. Among the other 31 patients, all have completed their trimodality therapy. All of these 31 patients completed their full dose of RT (66 Gy). These 31 patients also received a median of 7 weekly docetaxel infusions (range = 5 - 8). Only 3 of these 31 patients experienced acute grade 3 diarrhea during the chemoradiation therapy, which was diet related in 1 patient. Among the other 2 patients who experienced grade 3 diarrhea, one was using excessive stool softners due to constipation, and the other patient was using excessive laxatives / prune juice. There have been no acute grade ≥ 3 GU toxicity. Conclusions: Theresults of our completed phase I-II clinical trial indicate that our post-prostatectomy tri-modality therapy is well tolerated with a very high feasibility rate in patients with high risk pT2-3N0M0 prostate cancer. Clinical trial information: NCT00669162.
Abstract SY15-02: Identification of novel oncogenic mechanisms in brain tumors with quiet genomes through mapping the enhancer landscape
Authors: Serap Erkek, Kristian W. Pajtler, Pascal D. Johann, Paul A. Northcott, Lukas Chavez, Marcel Kool, Stefan M. Pfister
Journal: Cancer Research (2016)

Abstract Malignant pediatric brain tumors, including ependymoma, medulloblastoma and atypical teratoid/rhabdoid tumors, frequently demonstrate a very “quiet” genome with very few nonsynonyomous single nucleotide variants or indels and a stable copy number profile. The recent advance of integrative genomics approaches from primary tumor tissue including whole-genome sequencing, RNA sequencing, whole-genome bisulfite sequencing, and ChIP sequencing for core histone marks and important transcription factors and chromatin configuration have enabled the discovery of new tumor-driving pathways and potentially druggable alterations in these cancers with quiet genomes. This knowledge after functional validation in vitro and in vivo provides critical insight in the search for the cell of origin in these tumors, the understanding of underlying pathomechanisms, and the identification of new treatment options. Citation Format: Serap Erkek, Kristian W. Pajtler, Pascal D. Johann, Paul A. Northcott, Lukas Chavez, Marcel Kool, Stefan M. Pfister. Identification of novel oncogenic mechanisms in brain tumors with quiet genomes through mapping the enhancer landscape. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY15-02.
Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone–Related Protein
Authors: Wonnam Kim, Farzin M. Takyar, Karena Swan, Jaekwang Jeong, Joshua VanHouten, Catherine Sullivan, Pamela Dann, Herbert Yu, Nathalie Fiaschi-Taesch, Wenhan Chang, John Wysolmerski
Journal: Cancer Research (2016)

Parathyroid hormone-related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR-PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27(kip1) levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR-PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348-60. ©2016 AACR.
National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13–17 Years — United States, 2014
Authors: Sarah Reagan-Steiner, David Yankey, Jenny Jeyarajah, Laurie D. Elam-Evans, James A. Singleton, C. Robinette Curtis, Jessica MacNeil, Lauri E. Markowitz, Shannon Stokley
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Routine immunization is recommended for adolescents aged 11-12 years by the Advisory Committee on Immunization Practices (ACIP) for protection against diseases including pertussis, meningococcal disease, and human papillomavirus (HPV)-associated cancers. To assess vaccination coverage among adolescents, CDC analyzed data collected regarding 20,827 adolescents through the 2014 National Immunization Survey-Teen (NIS-Teen). From 2013 to 2014, coverage among adolescents aged 13-17 years increased for all routinely recommended vaccines: from 84.7% to 87.6% for ≥1 tetanus-diphtheria-acellular pertussis (Tdap) vaccine dose, from 76.6% to 79.3% for ≥1 meningococcal conjugate (MenACWY) vaccine dose, from 56.7% to 60.0% and from 33.6% to 41.7% for ≥1 HPV vaccine dose among females and males, respectively.† Coverage differed by state and local area. Despite overall progress in vaccination coverage among adolescents, HPV vaccination coverage continues to lag behind Tdap and MenACWY coverage at state and national levels. Seven public health jurisdictions achieved significant increases in ≥1- or ≥3-dose HPV vaccination coverage among females in 2014, demonstrating that substantial improvement in HPV vaccination coverage is feasible.
NCCN Guidelines Insights: Melanoma, Version 3.2016
Authors: Daniel G Coit, John A Thompson, Alain Algazi, Robert Andtbacka, Christopher K Bichakjian, William E Carson, Gregory A Daniels, Dominick DiMaio, Ryan C Fields, Martin D Fleming, Brian Gastman, Rene Gonzalez, Valerie Guild, Douglas Johnson, Richard W Joseph, Julie R Lange, Mary C Martini, Miguel A Materin, Anthony J Olszanski, Patrick Ott, Aparna Priyanath Gupta, Merrick I Ross, April K Salama, Joseph Skitzki, Susan M Swetter, Kenneth K Tanabe, Javier F Torres-Roca, Vijay Trisal, Marshall M Urist, Nicole McMillian, Anita Engh
Journal: Journal of the National Comprehensive Cancer Network (2016)

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.
A Dynamic Alternative Splicing Program Regulates Gene Expression In A Differentiation Stage-Specific Manner During Terminal Erythropoiesis
Authors: Harold Pimentel, Marilyn Parra, Jie Li, Sherry Gee, Dana Ghanem, Jingping Hu, Xiuli An, Mohandas Narla, Lior Pachter, John G. Conboy
Journal: Blood (2013)
Defining Septic Shock
Authors: Glenn Hernández, Flávia Machado, Gustavo Ospina-Tascón
Journal: JAMA (2016)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications 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) 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
Development of a microphysiological model of human kidney proximal tubule function
Authors: Elijah J. Weber, Alenka Chapron, Brian D. Chapron, Jenna L. Voellinger, Kevin A. Lidberg, Catherine K. Yeung, Zhican Wang, Yoshiyuki Yamaura, Dale W. Hailey, Thomas Neumann, Danny D. Shen, Kenneth E. Thummel, Kimberly A. Muczynski, Jonathan Himmelfarb, Edward J. Kelly
Journal: Kidney International (2016)

The kidney proximal tubule is the primary site in the nephron for excretion of waste products through a combination of active uptake and secretory processes and is also a primary target of drug-induced nephrotoxicity. Here, we describe the development and functional characterization of a 3-dimensional flow-directed human kidney proximal tubule microphysiological system. The system replicates the polarity of the proximal tubule, expresses appropriate marker proteins, exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with proximal tubule function in vivo. This microphysiological system can serve as an ideal platform for ex vivo modeling of renal drug clearance and drug-induced nephrotoxicity. Additionally, this novel system can be used for preclinical screening of new chemical compounds prior to initiating human clinical trials.
Vitamin D Supplementation and Progression of Knee Osteoarthritis—Reply
Authors: Xingzhong Jin, Changhai Ding
Journal: JAMA (2016)

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 Publications 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