tbuckley/cabot-search huggingface dataset:
Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: The “Anticipate” study
Authors: Juan G. Abraldes, Christophe Bureau, Horia Stefanescu, Salvador Augustin, Michael Ney, Hélène Blasco, Bogdan Procopet, Jaime Bosch, Joan Genesca, Annalisa Berzigotti
Journal: Hepatology (2016)

In patients with compensated advanced chronic liver disease (cACLD), the presence of clinically significant portal hypertension (CSPH) and varices needing treatment (VNT) bears prognostic and therapeutic implications. Our aim was to develop noninvasive tests-based risk prediction models to provide a point-of-care risk assessment of cACLD patients. We analyzed 518 patients with cACLD from five centers in Europe/Canada with paired noninvasive tests (liver stiffness measurement [LSM] by transient elastography, platelet count, and spleen diameter with calculation of liver stiffness to spleen/platelet score [LSPS] score and platelet-spleen ratio [PSR]) and endoscopy/hepatic venous pressure gradient measurement. Risk of CSPH, varices, and VNT was modeled with logistic regression. All noninvasive tests reliably identified patients with high risk of CSPH, and LSPS had the highest discrimination. LSPS values above 2.65 were associated with risks of CSPH above 80%. None of the tests identified patients with very low risk of all-size varices, but both LSPS and a model combining TE and platelet count identified patients with very low risk (<5%) risk of VNT, suggesting that they could be used to triage patients requiring screening endoscopy. LSPS values of <1.33 were associated with a <5% risk of VNT, and 26% of patients had values below this threshold. LSM combined with platelet count predicted a risk <5% of VNT in 30% of the patients. Nomograms were developed to facilitate point-of-care risk assessment.A significant proportion of patients with a very high risk of CSPH, and a population with a very low risk of VNT can be identified with simple, noninvasive tests, suggesting that these can be used to individualize medical care. (Hepatology 2016;64:2173-2184).
AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis
Authors: Qiyuan Yang, Xingwei Liang, Xiaofei Sun, Lupei Zhang, Xing Fu, Carl J. Rogers, Anna Berim, Shuming Zhang, Songbo Wang, Bo Wang, Marc Foretz, Benoit Viollet, David R. Gang, Buel D. Rodgers, Mei-Jun Zhu, Min Du
Journal: Cell Metabolism (2016)
Fulvestrant (F) as first-line palliative treatment for hormone receptor (HR)- positive metastatic breast cancer.
Authors: R. Bartsch, C. Wenzel, R. Ziebermayr, Z. Bago-Horvath, U. Pluschnig, P. C. Dubsky, M. Rudas, M. Gnant, C. Zielinski, G. G. Steger
Journal: Journal of Clinical Oncology (2010)

1098 Background: Endocrine therapy is the preferred treatment in HR positive MBC. F is a pure ER antagonist with similar efficacy as aromatase inhibitors (AI). However, comparison with tamoxifen as first-line therapy could not establish noninferiority, due to a large subgroup of patients (pts) with unknown HR status. Here, we report data concerning efficacy and safety of first-line F in an exclusively HR positive population. Methods: 100 consecutive pts were treated at two Austrian centers with first-line F at 250 mg every four weeks. Data concerning demographics, tumor characteristics, and clinical outcome are available. Tumor status was routinely assessed every 12 weeks. Time to progression (TTP) was defined as primary endpoint and estimated with the Kaplan-Meier product limit method. A Cox proportional hazards-model was applied to control for possible confounders (age >65 years, PgR, HER2, prior adjuvant therapy, prior AI, visceral metastases). Further endpoints consisted of safety, clinical benefit rate (CBR; CR+PR+SD≥6 months), and response rate (RR; CR+PR). Results: Median age was 68 years (y), 38% were >65 y, 65% had positive PgR staining, 14% were HER2-positive, 75% had received prior adjuvant endocrine therapy (31% AI), and 41% had visceral metastases. Median TTP was 9 months (95%CI 8.48-9.52), and F yielded a CBR of 70% and RR of 27%, respectively. In the Cox regression model, none of the factors included were significantly associated with TTP. Safety: Only grade 3 toxicities observed were hot flushes and nausea (1% each); 31% experienced hot flushes grade 1 or 2. Other side effects (grade 1 and 2) consisted of joint pain (29%), injection-site reaction (9%), weight gain (2%), and fatigue (1%). Conclusions: F is an effective and safe option in MBC patients, yielding results comparable to other endocrine agents even in patients with visceral involvement. This is explained by the fact that only patients with limited visceral disease were included. Effect of F was independent of age, prior AI exposure, and HER2 status. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Prediction of lung cancer genotype noninvasively using droplet digital PCR (ddPCR) analysis of cell-free plasma DNA (cfDNA).
Authors: Adrian G. Sacher, Geoffrey R. Oxnard, Stacy L. Mach, Messineo M. Melissa, David Michael Jackman, Pasi A. Janne, Cloud Paweletz
Journal: Journal of Clinical Oncology (2014)

8059 Background: Noninvasive plasma genotyping has the potential to accelerate delivery of targeted therapies to genotype-defined cancer populations and obviate repeat biopsies, particularly following drug resistance. We recently reported on a new assay for plasma genotyping using ddPCR of cfDNA (Oxnard et al., Clinical Cancer Research, 2014). Here, we aimed to predict the genotype of tumor biopsies using plasma genotyping. Methods: We identified patients (pts) with advanced NSCLC and acquired resistance to erlotinib that underwent rebiopsy and plasma collection on three IRB-approved protocols. Rebiopsy specimens underwent clinical EGFR genotyping. Plasma was collected in EDTA tubes, cfDNA extracted, and EGFR genotype quantified using ddPCR assays for L858R, exon 19 del and T790M. Serial plasma genotyping on treatment was performed for a subset of pts. This assay was then piloted in pts with advanced NSCLC who had not yet undergone tumor genotyping. Results: A total of 32 pts undergoing rebiopsy had plasma available for analysis. Sensitivity of plasma genotyping for EGFR exon 19 del and L858R was 57%; sensitivity increased to 91% among 11 pts with symptomatic bone or visceral metastases. One additional pt with no tumor EGFR sensitizing mutation but response to erlotinib had high levels of plasma exon 19 del, suggesting that plasma genotyping may identify mutations missed by tumor genotyping. T790M was detected on rebiopsy in 16 pts (50%); plasma genotyping was concordant with rebiopsy T790M status in 27 of 32 pts (84%). Post-treatment plasma specimens were available for 12 pts; the 5 pts with a partial response on imaging had a significant decrease in plasma concentration compared to the 7 pts without a response (median 895 copies/mL decrease vs 2 copies/mL increase, p=0.01). In 17 NSCLC pts without a known genotype, we identified EGFR mutations in 3 pts with a median 3 day turnaround time, up to 19 days before tumor genotyping confirmed the result. Conclusions: Plasma genotyping of cfDNA with ddPCR can predict tumor genotype rapidly and quantitatively with a high degree of accuracy, potentially obviating the need for re-biopsy in some circumstances. Clinical development of this assay is ongoing.
Health Coaching and Chronic Obstructive Pulmonary Disease Rehospitalization. A Randomized Study
Authors: Roberto Benzo, Kristin Vickers, Paul J. Novotny, Sharon Tucker, Johanna Hoult, Pamela Neuenfeldt, John Connett, Kate Lorig, Charlene McEvoy
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Hospital readmission for chronic obstructive pulmonary disease (COPD) has attracted attention owing to the burden to patients and the health care system. There is a knowledge gap on approaches to reducing COPD readmissions.To determine the effect of comprehensive health coaching on the rate of COPD readmissions.A total of 215 patients hospitalized for a COPD exacerbation were randomized at hospital discharge to receive either (1) motivational interviewing-based health coaching plus a written action plan for exacerbations (the use of antibiotics and oral steroids) and brief exercise advice or (2) usual care.We evaluated the rate of COPD-related hospitalizations during 1 year of follow-up. The absolute risk reductions of COPD-related rehospitalization in the health coaching group were 7.5% (P = 0.01), 11.0% (P = 0.02), 11.6% (P = 0.03), 11.4% (P = 0.05), and 5.4% (P = 0.24) at 1, 3, 6, 9, and 12 months, respectively, compared with the control group. The odds ratios for COPD hospitalization in the intervention arm compared with the control arm were 0.09 (95% confidence interval [CI], 0.01-0.77) at 1 month postdischarge, 0.37 (95% CI, 0.15-0.91) at 3 months postdischarge, 0.43 (95% CI, 0.20-0.94) at 6 months postdischarge, and 0.60 (95% CI, 0.30-1.20) at 1 year postdischarge. The missing value rate for the primary outcome was 0.4% (one patient). Disease-specific quality of life improved significantly in the health coaching group compared with the control group at 6 and 12 months, based on the Chronic Respiratory Disease Questionnaire emotional score (emotion and mastery domains) and physical score (dyspnea and fatigue domains) (P < 0.05). There were no differences between groups in measured physical activity at any time point.Health coaching may represent a feasible and possibly effective intervention designed to reduce COPD readmissions. Clinical trial registered with www.clinicaltrials.gov (NCT01058486).
Endoscopic retrieval followed by compression hemostasis using a Sengstaken–Blakemore tube to manage a foreign body with suspected aortic injury
Authors: Chenguang Dai, Lili Zhao, Min Wang, Sichong Qian, Xiang Wang, Zhining Fan, Li Liu
Journal: Endoscopy (2016)

A 44-year-old woman presented with unremitting chest pain after a fish meal. A fishbone had been stuck in her esophagus overnight. A local endoscopist had tried to remove it but had failed.
Case reports in dermatology: loved by clinicians, loathed by editors, and occasionally important
Authors: I. Garcia-Doval, J.R. Ingram, L. Naldi, A. Anstey
Journal: British Journal of Dermatology (2016)

http://orcid.org/0000-0002-6881-5260 http://orcid.org/0000-0002-5257-1142 http://orcid.org/0000-0002-3160-2835 http://orcid.org/0000-0002-6345-4144 Dermatologists occupy a unique position between patients and researchers and are usually the first to recognize novel clinical features of potential importance. We learn clinical craft by studying our patients and their skin diseases under supervision from expert senior colleagues, complemented by reading and then writing what we hope will be instructive and insightful case reports. However, some leading dermatology journals now decline case reports, perhaps due to concerns about academic citation rates. This has spawned open‐access, online‐only journals dedicated to case reports. Unfortunately, the outputs of such journals may be missed by the research community. The BJD is unique among clinical dermatology journals for publishing basic and applied research of translational significance.1 Our readership is diverse, representing a continuum from clinical dermatology to laboratory science with multiple variants in between. The BJD academic community includes novices in clinical dermatology and laboratory science, as well as expert clinicians, clinical academics and leading scientists. Additionally, the BJD excels in epidemiology and qualitative research,1 attracting academic hunter–gatherers who roam outside the laboratory and clinic in their quest for big datasets and insights into patients’ behaviour and experience. Thus, the BJD has a unique and broad profile within dermatology academic publishing. This raises the question, how best to satisfy these multiple stakeholders? The answer is to ensure that the journal remains focused on disseminating high‐quality clinical research, including clinical trials, epidemiology, qualitative research and translational research of clinical relevance. Publishing interesting and rigorously prepared case reports may fit with this aspiration and with the recent BJD position statement.1 Indeed, case reports sometimes open new avenues of research, leading to unexpected and transformative insights of importance to patient care. In other words, the best case reports should interest our multiple stakeholders, particularly clinicians, clinical academics and skin scientists.
Prospective study comparing outcomes in patients with advanced malignancies on molecular alteration-matched versus non-matched therapy.
Authors: Jennifer J. Wheler, Roman Yelensky, Bettzy Stephen, David S. Hong, Ralph Zinner, Vivek Subbiah, Siqing Fu, Daniel D. Karp, Gerald Steven Falchook, Aung Naing, Apostolia Maria Tsimberidou, Sarina Anne Piha-Paul, Filip Janku, Yali Li, J. Jack Lee, Vincent A. Miller, Funda Meric-Bernstam, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2015)

11019 Background: With the paradigm shift to precision medicine, we hypothesized that matching patients to therapy based on molecular profile could significantly improve outcomes. Methods: Archival tissues from patients treated in MDACC’s Phase I clinic were sent to Foundation Medicine, where next-generation sequencing (NGS)-based comprehensive genomic profiling (236 genes) was performed. Patients with actionable molecular alterations were preferentially treated on pathway-matched therapies. A direct match was defined when the drug targeted an alteration or its immediate downstream effector; an indirect match, when the drug targeted a protein > 1 effector removed from the alteration. Based on matching and the number of alterations in patients’ tumors, an exploratory scoring system was evaluated; each direct match was given a 1, each indirect match 0.5, and no match a value of zero, normalized by the number of alterations per patient. Progression-free survival (PFS) and overall survival (OS) were analyzed (Kaplan-Meier method; log-rank test). Results: Molecular profiling was performed for 339 of 500 patients (68%) consented on the study. Ninety-five percent of those tested (322/339) had ≥ 1 molecular alteration on NGS. Patients (n=175) were treated either on pathway-matched (n = 110, 63%) or non-matched therapy (n = 65, 37%). Matched/non-matched patient characteristics were similar. The most common reasons for not profiling or not treating were inadequate tissue or early death/hospice. Outcomes are shown below. Conclusions: Patients treated on matched therapy had significantly improved PFS and OS versus those on non-matched therapy. An exploratory scoring system that included the number of matched therapies in the regimen and molecular alterations in the tumor confirms the above results. Further analyses of response rates and multivariate analyses of factors impacting outcomes are ongoing. Outcome by therapy and scoring system. Basis Treatment Patients (n = 175) Median PFS (months) p-value Median OS (months) p-value Matching Matched 110 3.9 0.002 10.8 0.018 Unmatched 65 3.3 7.5 Scoring system ≥ median score (≥ 0.13) 92 3.8 0.013 11.1 0.026 < median score (< 0.13) 83 3.3 7.5
Lifelong Gender Gap in Risk of Incident Myocardial Infarction
Authors: Grethe Albrektsen, Ivar Heuch, Maja-Lisa Løchen, Dag Steinar Thelle, Tom Wilsgaard, Inger Njølstad, Kaare Harald Bønaa
Journal: JAMA Internal Medicine (2016)

It is not clear to what extent the higher incidence of coronary heart disease (CHD) in men vs women is explained by differences in risk factor levels because few studies have presented adjusted risk estimates for sex. Moreover, the increase in risk of CHD in postmenopausal women, possibly hormone related, may eventually eliminate the sex contrast in risk, but age-specific risk estimates are scarce.To quantify the difference in risk of incident myocardial infarction (MI) between men and women.Population-based prospective study from Tromsø, Norway, comprising 33 997 individuals (51% women). Median follow-up time during ages 35 to 102 years was 17.6 years. Incidence rates (IRs) and incidence rate ratios (IRRs, relative risk) of MI were calculated in Poisson regression analysis of person-years at risk. The data analysis was performed in November 2015.Sex, age, birth cohort, serum lipid levels, blood pressure, lifestyle factors, diabetes.Incident MI.A total of 2793 individuals (886 women) received a diagnosis of MI during follow-up in the period 1979 through 2012. The IR increased with age in both sexes, with lower rates for women until age 95 years. Adjusted for age and birth cohort, the overall IRR for men vs women was 2.72 (95% CI, 2.50-2.96). Adjustment for high-density lipoprotein cholesterol and total cholesterol levels had the strongest impact on the risk estimate for sex, followed by diastolic blood pressure and smoking. However, the sex difference remained substantial even after adjustment for these factors (IRR, 2.07; 95% CI, 1.89-2.26). Men had higher risk throughout life, but the IRRs decreased with age (3.64 [95% CI, 2.85-4.65], 2.00 [95% CI, 1.76-2.28], and 1.66 [95% CI, 1.42-1.95] for age groups 35-54, 55-74, and 75-94 years, respectively). Adjustment for systolic blood pressure, diabetes, body mass index, and physical activity had no notable impact.The observed sex contrast in risk of MI cannot be explained by differences in established CHD risk factors. The gender gap persisted throughout life but declined with age as a result of a more pronounced flattening of risk level changes in middle-aged men. The minor changes in IRs when moving from premenopausal to postmenopausal age in women make it unlikely that changes in female hormone levels influence the risk of MI.
Subcutaneous Preadipocytes Are Ideal Candidate To Produce A Large Number Of Functional Platelets In a Culture System
Authors: Yukako Ono-Uruga, Tatsuya Tanaka, Atsuko Igari, Takanori Moriki, Kenji Yokoyama, Takeru Zama, Tadashi Horiuchi, Mitsuru Murata, Yasuo Ikeda, Toshio Suda, Yumiko Matsubara
Journal: Blood (2013)
Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization
Authors: Gleb Konotop, Elena Bausch, Tomoaki Nagai, Andrey Turchinovich, Natalia Becker, Axel Benner, Michael Boutros, Kensaku Mizuno, Alwin Krämer, Marc Steffen Raab
Journal: Cancer Research (2016)

Abstract Centrosome amplification is a hallmark of virtually all types of cancers, including solid tumors and hematologic malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents. We identified CP-673451 and crenolanib, two chemically related compounds originally developed for the inhibition of platelet-derived growth factor receptor β (PDGFR-β), as robust inhibitors of CC with selective cytotoxicity for cells with extra centrosomes. We demonstrate that these compounds induce mitotic spindle multipolarity by activation of the actin-severing protein cofilin, leading to destabilization of the cortical actin network, and provide evidence that this activation is dependent on slingshot phosphatases 1 and 2 but unrelated to PDGFR-β inhibition. More specifically, we found that although both compounds attenuated PDGF-BB–induced signaling, they significantly enhanced the phosphorylation of PDGFR-β downstream effectors, Akt and MEK, in almost all tested cancer cell lines under physiologic conditions. In summary, our data reveal a novel mechanism of CC inhibition depending on cofilin-mediated cortical actin destabilization and identify two clinically relevant compounds interfering with this tumor cell–specific target. Cancer Res; 76(22); 6690–700. ©2016 AACR.
Evidence of innate lymphoid cell redundancy in humans
Authors: Frédéric Vély, Vincent Barlogis, Blandine Vallentin, Bénédicte Neven, Christelle Piperoglou, Mikael Ebbo, Thibaut Perchet, Maxime Petit, Nadia Yessaad, Fabien Touzot, Julie Bruneau, Nizar Mahlaoui, Nicolas Zucchini, Catherine Farnarier, Gérard Michel, Despina Moshous, Stéphane Blanche, Arnaud Dujardin, Hergen Spits, Jörg H W Distler, Andreas Ramming, Capucine Picard, Rachel Golub, Alain Fischer, Eric Vivier
Journal: Nature Immunology (2016)
Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer
Authors: Zhong-Qiang Guo, Tong Zheng, Baoen Chen, Cheng Luo, Sisheng Ouyang, Shouzhe Gong, Jiafei Li, Liu-Liang Mao, Fulin Lian, Yong Yang, Yue Huang, Li Li, Jing Lu, Bidong Zhang, Luming Zhou, Hong Ding, Zhiwei Gao, Liqun Zhou, Guoqiang Li, Ran Zhou, Ke Chen, Jingqiu Liu, Yi Wen, Likun Gong, Yuwen Ke, Shang-Dong Yang, Xiao-Bo Qiu, Naixia Zhang, Jin Ren, Dafang Zhong, Cai-Guang Yang, Jiang Liu, Hualiang Jiang
Journal: Cancer Cell (2016)
Abstract #3977: Inhibition of p21-activated kinase 6 (PAK6) increases radiosensitivity of prostate cancer cells
Authors: Min Zhang, Michael Siedow, Gregory Saia, Arnab Chakravarti
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Purpose: For patients with high-risk localized prostate cancer, biochemical and clinical relapse after radiotherapy remains a significant problem. New therapeutic target for radiation sensitization is needed. p21-activated kinase 6 (PAK6), a serine/threonine kinase belonging to the p21-activatedkinase (PAK) family, was first identified as an androgen receptor (AR)-interactingprotein able to inhibit AR-mediated transcriptional responses.In this study, we investigated the role of PAK6 in radiation-induced cell death in human PC-3 and DU-145 prostate cancer cells. Experimental Design: We used a short hairpin RNA (shRNA) strategy to stably knock down PAK6 in PC-3 and DU-145 cells.Radiation sensitivities were compared in PAK6 stably knockdown cells and in scrambled shRNA-expressing cells. Results: 6 Gy of irradiation upregulated PAK6 mRNA and protein levels in PC-3 and DU-145 cells. Transfection with PAK6 shRNA resultedin a significant decrease of PAK6 mRNA and protein expression. After irradiation, an increased percentage of apoptoticcells and an increased cleaved caspase 3 level in parallel witha decreased cell viability and a reduced clonogenic survivalwas shown. Furthermore, transfection withPAK6 shRNA blocked cells in a more radiosensitive G2/M phaseand increased levels of DNA double-strand breaks as indicated by a higher amount of \#947;-H2AX in irradiated cells.We further explored the potential mechanisms by which PAK6 mediates resistance to radiation-induced apoptosis. Inhibition of PAK6 caused a decrease in Ser112 phosphorylation of BAD, a proapoptotic member of the Bcl-2 family, which led to enhanced binding of BAD to Bcl-2 and Bcl-XL and release ofcytochrome c culminating into caspase activation and cell apoptosis. Conclusions: The combination of PAK6 inhibition and irradiation resulted in significantly decreased survival of prostate cancer cells. The underlying mechanisms by which targeting Pak6 may improve radiation response seem to be multifaceted, and involve alterations in cell cycle distribution and impaired DNA double-strand break repair as well as relieved BAD phosphorylation. Additional studies are ongoing to validate PAK6 as a target for radiation sensitization in animal models of prostate cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3977.
P0538 : Tracing HBV genetic history in the arctic: Evidence for a central asian HBV origin in Greenland
Authors: D. Paraskevis, K. Angelis, G. Magiorkinis, C. Osiowy, M. Børresen, A. Koch, S.Y. Ho, F. Jia, J.-P. Allain, A. Hatzakis
Journal: Journal of Hepatology (2015)