tbuckley/cabot-search huggingface dataset:
I'm a consultant—get me out of here
Authors: Stephanie Young
Journal: BMJ (2005)

Organic anion-transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Here, we examined the effect of green tea (<i>Camellia sinensis</i>) catechins on the function of the four OATPs expressed in human enterocytes and hepatocytes. Uptake of the model substrate estrone-3-sulfate by cells expressing OATP1A2, OATP1B1, OATP1B3, or OATP2B1 was measured in the absence and presence of the four most abundant flavonols found in green tea. Uptake by OATP1A2, OATP1B1, and OATP2B1 was inhibited by epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) in a concentration-dependent way. In contrast, OATP1B3-mediated uptake of estrone-3-sulfate was strongly stimulated by EGCG at low substrate concentrations. The effect of EGCG on OATP1B3 was also studied with additional substrates: uptake of estradiol-17β-glucuronide was unchanged, whereas uptake of Fluo-3 was noncompetitively inhibited. Both ECG and EGCG were found to be substrates of OATP1A2 (<i>K</i><sub>m</sub> values of 10.4 and 18.8 μM, respectively) and OATP1B3 (34.1 and 13.2 μM, respectively) but not of OATP1B1 or OATP2B1. These results indicate that two of the major flavonols found in green tea have a substantial effect on the function of OATPs expressed in enterocytes and hepatocytes and can potentially alter the pharmacokinetics of drugs and other OATP substrates. In addition, the diverse effects of EGCG on the transport of other OATP1B3 substrates suggest that different transport/binding sites are involved.
Whole blood AR-V7 and AR-V9 mRNA expression and treatment response in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Edmond Michael Kwan, Sarah To, Heidi Fettke, Andrew Michael Mant, Maria Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane Graham, Phillip Parente, Carmel Jo Pezaro, Kate Lynette Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad
Journal: Journal of Clinical Oncology (2018)

252 Background: Androgen receptor splice variant (AR-V) expression has previously been regarded as a negative predictive biomarker for response to abiraterone and enzalutamide in mCRPC patients. However, recent data questions this association. We designed a whole blood assay to detect AR-V7 and AR-V9, the two most abundantly expressed AR-Vs, and correlated expression with clinical outcomes in patients commencing abiraterone or enzalutamide. Methods: We developed a quantitative real-time polymerase chain reaction assay to detect AR-V7 and AR-V9 from whole blood collected in PAXgene tubes. The assay was applied to samples prospectively collected from 37 mCRPC patients prior to commencing abiraterone or enzalutamide, and at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Assay sensitivity was determined by serially diluting RNA from VCaP prostate cancer cells (known to express AR-V7) to establish a lower limit of detection. Results: The median follow-up was 7.29 months (IQR 4.21-10.55); 9 of 37 patients (24%) were AR-V-positive. We observed similar response rates in AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p = 0.896). PSA-PFS did not differ significantly between groups (9.2 months vs. not reached, p = 0.355). Two patients converted from AR-V-negative to AR-V-positive (PSA-PFS 3.35 and 0.60 months respectively), and one patient remained AR-V-positive at baseline and end-of-treatment sampling. The lower limit of detection for AR-V7 was 0.1%, and AR-V7/V9 was not detected in any of the 13 normal male controls. Conclusions: We developed a sensitive and specific whole blood assay for AR-V7 and AR-V9 detection in patients with mCRPC. Neither PSA response rates nor PSA-PFS differed significantly between AR-V-positive and AR-V-negative patients. These data support recent literature questioning the role of AR-V expression as a negative predictive biomarker in mCRPC patients receiving abiraterone or enzalutamide.
Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer
Authors: Lifeng Li, Liping Wang, Jieyao Li, Zhirui Fan, Li Yang, Zhen Zhang, Chaoqi Zhang, Dongli Yue, Guohui Qin, Tengfei Zhang, Feng Li, Xinfeng Chen, Yu Ping, Dan Wang, Qun Gao, Qianyi He, Lan Huang, Hong Li, Jianmin Huang, Xuan Zhao, Wenhua Xue, Zhi Sun, Jingli Lu, Jane J. Yu, Jie Zhao, Bin Zhang, Yi Zhang
Journal: Cancer Research (2018)

Abstract Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α and subsequently suppressed hypoxia-inducible factor α, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients. Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779–91. ©2018 AACR.
Impact of genomic risk scores on treatment decisions following radical prostatectomy in a prospective Medicare registry.
Authors: John L. Gore, Darlene Dai, Robert Benjamin Den, Kasra Yousefi, Tiffany Le, Marguerite Du Plessis, Roanna Padre, Worlanyo Sosu-Sedzorme, Elai Davicioni, Paul L. Nguyen, Ashley Ross
Journal: Journal of Clinical Oncology (2018)

72 Background: Prostate cancer patients and providers confront uncertainty as they consider adjuvant or salvage radiation therapy (ART, SRT) after radical prostatectomy (RP). We prospectively evaluated the impact of the Decipher RP test, which predicts metastasis risk after RP, on decision-making for postoperative radiation therapy. Methods: Between October 2016 and May 2017, 1,319 patients treated with RP and considering ART or SRT were enrolled into a Medicare Certification and Training Registry (CTR). Providers submitted a management recommendation based on initial clinical and pathology findings prior to obtaining the Decipher RP test and again upon receiving test results. Only Medicare patients that met the Local Coverage Determination inclusion criteria (i.e., non-organ confined prostate cancer or positive margins or rising PSA) and whose provider was certified in the CTR registry were included in the analysis. Results: Based on clinical variables alone, treatment was recommended for 26% of adjuvant and 19% of salvage patients. Obtaining a Decipher score, changed treatment recommendations in 34% (95% CI 30-39%) and 28% (95% CI 19-38%) of men considering adjuvant or salvage therapy respectively. Among men considering ART, 9% of Decipher low risk patients and 45% of Decipher high-risk patients were recommended treatment. Multivariable logistic regression demonstrated that – independent of pathology risk factors, a high-risk Decipher score was associated with an odds ratio of 7.3 (95% CI 3.9-14.2 p &lt; 0.001) in the adjuvant and 5.5 (95% CI, 1.3-27.8, p = 0.026) in the salvage setting. Conclusions: A prospective CTR demonstrated that use of Decipher resulted in significant changes in treatment decisions for Medicare beneficiaries with PCa considering adjuvant and salvage therapies. Ongoing prospective studies aim at determining how increased use of therapy in men with high Decipher risk impacts oncologic outcomes and whether decreased use in Decipher low risk individuals improves health related quality of life without harming patient survival.
A study of intravesical bacillus Calmette-Guerin (BCG) in combination with ALT-803 in patients with non-muscle invasive bladder cancer.
Authors: Charles Joel Rosser, Karim Chamie, Amy Rock, Lydia Ferguson, Hing C. Wong
Journal: Journal of Clinical Oncology (2018)

TPS545 Background: The current standard of care for patients with high risk NMIBC is a transurethral resection of the bladder tumor (TURBT) or biopsy followed by a 6-week induction course of intravesical BCG treatment and supplementary maintenance instillations every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG treatment, 50% of patients are still expected to recur within the first 12 months (Sfakianos 2014). Thus, the pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This clinical trial evaluates the safety and efficacy of ALT-803, an IL-15 superagonist, plus BCG in BCG-naïve NMIBC patients. Methods: Patients with high-risk NMIBC (any high-grade disease, T1, or CIS) who are BCG naïve, will be randomized and enrolled into one of two study arms to be treated with either ALT-803 plus BCG or BCG alone. Patients will receive treatment via a urinary catheter in the bladder, weekly for 6 consecutive weeks during induction. A response assessment will be performed at Week 12: Patients with no disease or low-grade Ta disease will receive a maintenance course of therapy (3 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta will require a TURBT procedure. Patients with presence of high-grade Ta, CIS or low-grade T1 disease will receive a re-induction course of therapy (6 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta/T1 will require a TURBT procedure. Patients with high-grade T1 or greater disease (including disease progression) will be considered a treatment failure. Patients with no disease or low-grade Ta disease at months 6, 12, and 18 are eligible for maintenance treatment according to their assigned randomization. Patients with presence of disease greater than low-grade Ta will be considered a treatment failure. The primary endpoint of the study is the proportion of patients receiving ALT-803 plus BCG who are responders by Month 12 or earlier. Responders are defined as patients who experience a complete response (CIS patients) or no disease recurrence (defined as reappearance of high-risk disease). Enrollment is underway. Clinical trial information: NCT02138734.
Obesity results in higher PD-1-mediated T-cell suppression but greater T-cell effector functions following blockade.
Authors: Robert J. Canter, Ethan Aguilar, Ziming Wang, Catherine Le, Lam Khuat, Cordelia Dunai, Robert Rebhun, Alice Tarantal, Bruce R. Blazar, Arta Monjazeb, William J Murphy
Journal: Journal of Clinical Oncology (2018)

65 Background: Obesity is increasingly prevalent and viewed as a critical co-factor in many pathologic conditions due to metabolic, inflammatory and immune perturbations. We performed a multi-species evaluation of the impact of obesity T cell effector functions and markers of immune exhaustion. Methods: We examined the impact of obesity on PD-1 and T cell-mediated responses across different pre-clinical models (tumor, infection, and autoimmune encephalomyelitis [EAE]) and species (mouse, dog, non-human primate, and human). Results: CD4 and CD8 T cells from obese mice, dogs, non-human primates and humans displayed increases in memory T cells and PD-1 expression, as well as impaired proliferative responses compared to lean controls, indicating a greater degree of T cell exhaustion at baseline. Following immunization with myelin oligodendrocyte glycoprotein, obese mice were resistant to induction of EAE, correlating with reduced antigen-specific CD4 T cells in the central nervous system. Administration of anti-PD-1 resulted in restoration of EAE and increased antigen-specific T cell numbers in obese mice. Tumors in obese mice exhibited accelerated growth compared to lean mice, and T cells displayed higher PD-1 expression correlating with RNAseq/molecular signatures of exhaustion compared to tumor-bearing lean mice. PD-1 blockade resulted in marked anti-tumor effects only in obese mice, and not lean. Impaired viral resistance to murine cytomegalovirus (MCMV) resulted was seen in obese mice, associated with increased PD-1/PD-L1 expression, which was reversible by PD-1/PD-L1 blockade. Conclusions: Obesity results in an increase in PD-1/PD-L1 expression and inhibition of T cell responses across species, and blockade not only reverses this inhibition but also leads to markedly augmented T cell effector responses compared to lean counterparts where no effects were observed. These results highlight how the immune system has evolved to control T cell responses using checkpoints contingent on dynamic host conditions and have translational relevance for predicting both efficacy and toxicity in clinical immuno-oncology.
Typing of vancomycin-resistant enterococci with MALDI-TOF mass spectrometry in a nosocomial outbreak setting
Authors: B.J. Holzknecht, R. Dargis, M. Pedersen, M. Pinholt, J.J. Christensen, Anette M. Hammerum, Pia Littauer, Peder Worning, Henrik Westh, Claus Moser, Ulrik S. Justesen, Lars E. Lemming, Turid S. Søndergaard, Esad Dzajic, Tove Ejlertsen
Journal: Clinical Microbiology and Infection (2018)
Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines.
Authors: Gwang Hyeon Choi, Jin-Sun Kim, Yusun Jung, Kang Mo Kim, Se Jin Jang, Eun Sil Yu, Han Chu Lee
Journal: Journal of Clinical Oncology (2018)

325 Background: Despite enhancing overall survival, sorafenib resistance usually occurs and is a significant limiting factor of improved prognosis in hepatocellular carcinoma (HCC) patients. Therefore, it is important to identify the mechanism of sorafenib resistance. This study is designed to identify that causative factor for sorafenib resistance and to suggest way for overcoming sorafenib resistance. Methods: The sensitivity of sorafenib was compared in human HCC lines and patient-derived HCC primary cells. Based on its cytotoxicity, analysis was performed to examine the altered signaling pathway by sorafenib and its causative factor. It was further investigated that how sorafenib modify the sorafenib resistant inducer through gene or protein expression or stability. We also design the treatment option to overcome sorafenib resistance. Results: Sorafenib activates the Raf/MEK/ERK pathway, causing sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Reactivation of the MAPK pathway by sorafenib occurs via down-regulation of RKIP at a post-translational level. Knockdown of RKIP increased phosphorylated ERK and consequently suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy in patients with sorafenib resistance. Sequential combination of sorafenib and PD98059 significantly reduced cell viability and proliferation, while increasing apoptosis efficacy in sorafenib-resistant cells. Conclusions: Our findings suggest that reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms for sorafenib resistance in HCC. Sequential combination treatment of sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.
Reducing Overtreatment of Cancer With Precision Medicine
Authors: Steven J. Katz, Reshma Jagsi, Monica Morrow
Journal: JAMA (2018)

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Intratumor heterogeneity in epigenetic patterns
Authors: Yassen Assenov, David Brocks, Clarissa Gerhäuser
Journal: Seminars in Cancer Biology (2018)

Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. Understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.
BENEFICIAL EFFECT OF COFFEE CONSUMPTION ON ATHEROSCLEROSIS: THE CORINTHIA STUDY
Authors: Evangelos Oikonomou, George Lazaros, Evangelia Christoforatou, Christos Chasikidis, Sotirios Tsalamandris, George-Angelo Papamikroulis, Georgia Vogiatzi, Athina Goliopoulou, Petros Fountoulakis, Anastasopoulou Giota, Charilila-Loukia Ververeli, Timos Mavratzas, Evgenia Bourouki, Georgia Vavuranaki, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
The Insider's Guide to the New GP Contract: opportunities and options for general practice⇓
Authors: Dave Triffitt
Journal: BMJ (2004)

A book on the new GMS contract wouldn't normally be my first choice. Having said that, the authors of this book have tried hard to make this a friendly, non-threatening read. It's a slim volume, which I found reassuring, and the catchy title, together with the comforting red “Don't panic” label, will help to calm the fluttering nerves of prospective readers.

It's written by a panel of GPs and divided into well laid out, concise chapters. The initial overview …
Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages
Authors: Sathishkumar Baskaran, Markus Mayrhofer, Hanna Göransson Kultima, Tobias Bergström, Lioudmila Elfineh, Lucia Cavelier, Anders Isaksson, Sven Nelander
Journal: Neuro-Oncology (2018)

Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.
Characterization of urinary bladder paragangliomas in patients with germline mutations.
Authors: Kareem Rayn, Michael Daniel Weintraub, Gustavo R Pena-La Grave, Graham R. Hale, Samuel Gold, Jonathan Bloom, Sam Joseph Brancato, Piyush K. Agarwal
Journal: Journal of Clinical Oncology (2018)

508 Background: Data on the genetic characteristics of patients with urinary bladder paragangliomas (UBPGLs) is extremely limited. The primary goal of this study is to examine the clinical characteristics of a series of patients with UBPGLs, focusing particularly on their genetic profiles. Methods: We analyzed the medical records of patients who presented with UBPGLs from 2000 to 2017 to determine their presenting symptoms, clinical characteristics and outcomes. In addition, patients were stratified by the presence or absence of metastasis and the presence or absence of multiple paragangliomas (PGLs). Groups were compared using chi-square test and t-test (Stata) statistical analyses. Results: 18 of the 28 patients (64.2%) with UBPGLs had underlying genetic mutations: 15 (53.5%) in the succinate dehydrogenase subunit B gene (SDHB) and 3 (10.7%) in the von Hippel-Lindau gene (VHL). The average age at first symptoms was significantly younger in patients with germline mutations compared to those without mutations (22.3 ± 2.52 vs 37.3 ± 5.95, p = 0.01). 7 patients (38.9%) with germline mutations developed metastasis, at either first presentation or on follow-up, compared to 7 patients (70%) without germline mutations, p = 0.15. 10 patients (58.8%) with germline mutations had multiple PGLs compared to 1 patient (11.1%) without germline mutations, p = 0.02. On average, patients with germline mutations had larger lesions than patients without germline mutations based on the means of the largest diameter (3.7 ± 2.6 vs 3.1 ± 2.2, p = 0.51). Conclusions: Patients presenting with UBPGLs should be screened for underlying germline mutations as they are frequently associated. Patients with UBPGLs and underlying germline mutations present at a significantly younger age than patients without these mutations. Even though patients with UBPGLs and underlying mutations are significantly more likely to develop multiple PGLs, the risk of metastasis is not greater compared to patients without germline mutations. Therefore, all patients with UBPGLs should be followed closely for metastatic development. This research was supported by the Intramural Research Program of the National Cancer Institute, NIH and NIH Medical Research Scholars Program.