tbuckley/cabot-search huggingface dataset:
Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma
Authors: Haipeng Zhang, Kai Li, Yuan Lin, Fan Xing, Xiao Xiao, Jing Cai, Wenbo Zhu, Jiankai Liang, Yaqian Tan, Liwu Fu, Fang Wang, Wei Yin, Bingzheng Lu, Pengxin Qiu, Xingwen Su, Shoufang Gong, Xuetao Bai, Jun Hu, Guangmei Yan
Journal: Science Translational Medicine (2017)

Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus-suppressed inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential.
In utero exposure to malaria is associated with metabolic traits in adolescence: The Agogo 2000 birth cohort study
Authors: George Bedu-Addo, Marie Alicke, Justice K. Boakye-Appiah, Inusah Abdul-Jalil, Markus van der Giet, Matthias B. Schulze, Frank P. Mockenhaupt, Ina Danquah
Journal: Journal of Infection (2017)

Malaria in pregnancy (MiP) contributes to fetal undernutrition and adverse birth outcomes, and may constitute a developmental origin of metabolic diseases in the offspring. In a Ghanaian birth cohort, we examined the relationships between MiP-exposure and metabolic traits in adolescence.MiP at delivery was assessed in 155 mother-child pairs. Among the now teenaged children (mean age, 14.8 years; 53% male), we measured fasting plasma glucose (FPG), body mass index (BMI), and systolic and diastolic blood pressure (BP). Associations of MiP with the adolescents' FPG, BMI, and BP were examined by linear regression.At delivery, 45% were MiP-exposed, which increased FPG in adolescence, adjusted for mother's age at delivery, parity and familial socio-economic status (infected vs. uninfected: mean ΔFPG = 0.20 mmol/L; 95% confidence interval (CI): 0.01, 0.39; p = 0.049). As a trend,this was discernible for BP, particularly for microscopic infections (mean Δsystolic BP = 5.43 mmHg; 95% CI: 0.00, 10.88; p = 0.050; mean Δdiastolic BP = 3.67 mmHg; 95% CI: -0.81, 8.14; p = 0.107). These associations were largely independent of birth weight, gestational age and teenage BMI. Adolescent BMI was not related to MiP.In rural Ghana, exposure to malaria during fetal development contributes to metabolic conditions in young adulthood.
Circulating tumor DNA (ctDNA) to monitor treatment response and progression in patients treated with tyrosine kinase inhibitors (TKIs) and immunotherapy for EGFR-mutant non-small cell lung cancer (NSCLC).
Authors: Brian S. Henick, Sarah B. Goldberg, Azeet Narayan, Chiara Rossi, Simon Rodney, Adam J Kole, Katerina A. Politi, Scott N. Gettinger, Roy S. Herbst, Abhijit Patel
Journal: Journal of Clinical Oncology (2017)

e20652 Background: Detection of EGFR mutations in ctDNA can help determine appropriateness of TKI therapy for patients with NSCLC. We investigated whether longitudinal monitoring of ctDNA levels can be used to assess response to therapy and disease progression, with a focus on EGFR mutation-positive patients treated with immunotherapy. Methods: Serially collected blood from patients with EGFR mutation-positive NSCLC treated with TKIs and/or immunotherapy was analyzed using an ultrasensitive 24-gene next-generation sequencing assay. Clinical characteristics and outcomes were analyzed retrospectively by chart review. Results: We studied quantitative changes in ctDNA levels during treatment by analyzing somatic mutations in 91 plasma samples from 8 patients with EGFR-mutant NSCLC, including samples collected around the time of disease progression for a subset of patients. Two patients treated with PD-1 inhibitor monotherapy experienced a rise in ctDNA harboring EGFR-sensitizing mutations prior to radiographic progression. A third patient was started on anti-PD-1 monotherapy following disease progression on erlotinib. Plasma levels of L858R, T790M, and TP53 mutations were detectable on treatment initiation and decreased with radiographic response. The levels of these mutations rose at progression,fell with response to EGFR-directed therapy, and increased again before disease progression. Another patient was found to have mutations in EGFR, T790M, and TP53 that fell upon treatment with combination TKI therapy. The remaining four patients studied were treated with concurrent TKI and immunotherapy. In all of these cases, sensitizing EGFR mutations were present in plasma at low levels during response to treatment. Two of the four patients had a rise in ctDNA level at the time of radiographic progression; the other two patients had durable responses with persistently low ctDNA levels. Analysis of additional cases is ongoing. Conclusions: Monitoring quantitative changes in ctDNA may enable assessment of response or disease progression in immunotherapy- and TKI-treated EGFR-mutant NSCLC patients.
Potential Resistance Mechanisms Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs)
Authors: Jia Zhong, Lei Li, Zhijie Wang, Hua Bai, Fei Gai, Jianchun Duan, Jun Zhao, Minglei Zhuo, Yuyan Wang, Shuhang Wang, Wanchun Zang, Meina Wu, Tongtong An, Guanhua Rao, Guanshan Zhu, Jie Wang
Journal: Journal of Thoracic Oncology (2017)
Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis
Authors: Ian N. Glaspole, Alice L. Watson, Heather Allan, Sally Chapman, Wendy A. Cooper, Tamera J. Corte, Samantha Ellis, Christopher Grainge, Nicole Goh, Peter Hopkins, Gregory Keir, Sacha Macansh, Annabelle Mahar, Yuben Moodley, Paul N. Reynolds, Christopher J. Ryerson, E. Haydn Walters, Christopher J. Zappala, Anne E. Holland
Journal: European Respiratory Journal (2017)

We have recently shown that anxiety and depression are common comorbidities for people with interstitial lung disease (ILD). In a cross-sectional single-centre study, the prevalence of anxiety was 31% and the prevalence of depression was 23% [1]. Anxiety and depression were not related to physiological parameters; however, dyspnoea and number of comorbidities were important contributors. The aims of this study were to determine the frequency of prolonged anxiety and depression among sufferers of idiopathic pulmonary fibrosis (IPF), and factors contributing to their persistence. Prolonged anxiety and depression occur frequently in IPF and strongly relate to dyspnoea and cough <http://ow.ly/iWxV30cLCfl> The researchers acknowledge the support to Australian IPF registry's national and state coordinators and its data manager in obtaining the data used for this research. I. Glaspole had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. I. Glaspole and A. Holland contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. A. Watson contributed substantially to data analysis and interpretation and the writing of the manuscript. The remaining authors contributed substantially to the writing of the manuscript.
高レベルのsmall dense LDLコレステロールは安定冠動脈疾患の男性患者において将来の冠動脈事象を予測しうる
Authors: Nakamura Yuya, Koba Shinji, Sakai Koshiro, Yokota Yuya, Furuyama Fumiaki, Tsunoda Fumiyoshi, Shoji Makoto, Hirano Tsutomu, Kobayashi Youichi
Journal: Circulation (2016)
Abstract 17179: Combined Doxycycline and Tauroursodeoxycholic Acid Slows Progression of Transthyretin Cardiac Amyloidosis
Authors: Marjan Sadegh, Danielle L Trota, Rodney H Falk
Journal: Circulation (2015)

Introduction: Transthyretin (TTR) cardiac amyloidosis (CA) is a progressive infiltrative cardiomyopathy with no specific therapy. In animals, doxycycline disrupts existing amyloid fibrils and may prevent fibrillogenesis. Tauroursodeoxycholic acid (TUDCA), a bile acid, prevents extracellular TTR monomer deposits, and the 2 drugs work synergistically in a mouse model of amyloidosis to decrease tissue amyloid. We sought to determine whether a combination of TUDCA and doxycycline could slow the progression of amyloid-associated LV dysfunction in patients with TTR cardiac amyloidosis. Methods: 17 patients with biopsy-proven TTR cardiac amyloidosis, mean age 71.3 yr (all men: 16 wild-type and 1 mutant TTR), received doxycycline 100 bid and TUDCA 250 mg tid for 12 months. The primary endpoint was change in longitudinal strain (LS) at 12 months, when compared to a group of 14 patients studied serially without therapy (mean age 72.4 yr, all men). All patients had echocardiograms performed on a GE Vivid machine, and analyzed by the same investigator. LS was measured from the apical 4-chamber view. Results: Doxycycline/TUDCA was well-tolerated. Mean baseline LS was no different between treatment group and untreated patients, and both groups showed deterioration of LS at 12 months. However, deterioration of LS was less in the treated group than controls (table). NTproBNP, a marker of disease was measured in the treatment group only, and rose slightly from a mean of 3108 pg/ml to 3669 pg/ml,(p&lt;0.05) consistent with the change in LS. Conclusion: 1. TTR cardiac amyloidosis is characterized by a consistent decrease in LV strain over a 1 year period, associated with a rise in NTproBNP. 2. Although doxycycline/TUDCA combination does not entirely halt progression of LV dysfunction, it appears to significantly slow the progression of disease and offers a well-tolerated therapy for disease modification.
Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease
Authors: John W. Eikelboom, Stuart J. Connolly, Jackie Bosch, Gilles R. Dagenais, Robert G. Hart, Olga Shestakovska, Rafael Diaz, Marco Alings, Eva M. Lonn, Sonia S. Anand, Petr Widimsky, Masatsugu Hori, Alvaro Avezum, Leopoldo S. Piegas, Kelley R.H. Branch, Jeffrey Probstfield, Deepak L. Bhatt, Jun Zhu, Yan Liang, Aldo P. Maggioni, Patricio Lopez-Jaramillo, Martin O’Donnell, Ajay K. Kakkar, Keith A.A. Fox, Alexander N. Parkhomenko, Georg Ertl, Stefan Störk, Matyas Keltai, Lars Ryden, Nana Pogosova, Antonio L. Dans, Fernando Lanas, Patrick J. Commerford, Christian Torp-Pedersen, Tomek J. Guzik, Peter B. Verhamme, Dragos Vinereanu, Jae-Hyung Kim, Andrew M. Tonkin, Basil S. Lewis, Camilo Felix, Khalid Yusoff, P. Gabriel Steg, Kaj P. Metsarinne, Nancy Cook Bruns, Frank Misselwitz, Edmond Chen, Darryl Leong, Salim Yusuf
Journal: New England Journal of Medicine (2017)

We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).
Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer.
Authors: John Lu, Christopher M. Haqq, HQ Han
Journal: Journal of Clinical Oncology (2013)

2541 Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC 50 &lt; 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p&lt;0.0001) tumor growth reduction, versus the vehicle-treated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p&lt;0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p&lt;0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.
Gender and survival in essential thrombocythemia: A two‐center study of 1,494 patients
Authors: Ayalew Tefferi, Silvia Betti, Daniela Barraco, Mythri Mudireddy, Sahrish Shah, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, Giacomo Coltro, Paola Guglielmelli, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2017)

Based on suggestive information from recent epidemiologic data and earlier retrospective studies, we revisited the effect of gender on survival in 1,494 patients with essential thrombocythemia (ET). The primary study population included 904 patients from the Mayo Clinic (median age 58 years; 65% females); risk distribution, according to the international prognostic score for ET (IPSET), was 23% high, 42% intermediate and 35% low. Multivariable analysis that included IPSET-relevant risk factors identified male sex (HR 1.6, 95% CI 1.3-2.0), age ≥60 years (HR 4.3, 95% CI 3.4-5.4) and leukocyte count ≥11 × 10(9)/L (HR 1.5, 95% CI 1.3-1.9) as independent predictors of shortened survival. These findings were confirmed by analysis of a separate cohort of 590 ET patients (65% females) from the University of Florence, Italy, with corresponding HRs (95% CI) of 1.6 (1.1-2.5), 4.6 (2.2-9.5) and 1.8 (1.1-2.8). The independent prognostic effect of gender was further corroborated by a separate multivariable analysis against IPSET risk categories; HR (95% CI) for the Mayo Clinic/Florence cohorts were 1.5/1.6 (1.2/1.1-1.8/2.5) for male sex, 6.8/7.5 (5.0/3.1-9.3/18.3) for IPSET high risk and 2.8/4.1 (2.1/1.8-3.8/9.5) for IPSET intermediate risk. Furthermore, the survival disadvantage in men was most apparent in IPSET high risk category and in patients older than 60 years. In both patient cohorts, thrombosis history garnered significance in univariate, but not in multivariable analysis. The observations from the current study suggest that women with ET live longer than their male counterparts and that gender might supersede thrombosis history as a risk variable for overall survival.
Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer (mCRC).
Authors: Sukeshi R. Patel, Norma Ketchum, Brad H. Pollock, John Sarantopoulos, Steven Weitman, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2013)

3541 Background: Recently, regorafenib (RGF), an oral multikinase inhibitor, was approved for patients (pts) with mCRC who have failed standard therapies. Compared to placebo, the phase III CORRECT study showed RGF improved median overall survival (mOS) from 5.0 to 6.4 months (mo) and median progression-free survival (mPFS) from 1.7 to 1.9 mo, regardless of K-Ras status. This suggests further VEGF inhibition is crucial in controlling mCRC progression. Many mCRC pts enroll on phase I studies with efficacy reported by some; however, a collective efficacy assessment aimed solely for mCRC in relation to class of agents has not been done. Methods: A historical cohort analysis included pts with mCRC enrolled amongst 28 phase I trials at the IDD, from 7/2008 – 9/2012. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: A total of 75 pts were included. Median age 59 (33–80), males 61 %, K-ras mutated 39 %. ECOG PS 0–1 96 %. ≥3 prior lines of therapy 68 %. Class of drugs included: VEGF Inhibitors 32 %, Cytotoxic 25 %, Microenvironment Inhibitors 13 %, Apoptosis/Autophagy Inhibitors 11 %, EGFR/Growth Factor TKIs 8 %, others 11 %. For the whole cohort of 75 pts, mPFS was 2.8 mo (95% CI: 2.0–3.7). As of 12/1/12, among 65 pts, mOS was 5.6 mo (95% CI: 4.4-7.0). In subgroup analysis, mPFS was 3.4 (95% CI: 1.4–4.5) vs 2.8 months (95% CI: 2.0–3.5) for pts on VEGF and non-VEGF Inhibitors (HR 0.79, 95% CI: 0.43–1.44, p = 0.44), respectively. VEGF Inhibitor treated pts had a mOS of 5.5 months (95% CI: 1.6–10.0 months) vs 5.6 months (95% CI: 4.4–7.6) with non-VEGF Inhibitors (HR 1.02, 95% CI: 0.58–1.78, p = 0.96). Efficacy was similar regardless of K-Ras status. Conclusions: In pretreated mCRC, median PFS and OS for pts enrolled in phase I trials, irrespective of agent, was comparable to efficacy of RGF. Therefore, after failure of standard therapies, mCRC pts should be encouraged to enroll in clinical trials with efficacy reported in both VEGF and non-VEGF inhibitors.
Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
Authors: Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
Journal: Nature Medicine (2017)
The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease
Authors: Matthew J. Williams, Toshifumi Sugatani, Olga A. Agapova, Yifu Fang, Joseph P. Gaut, Marie-Claude Faugere, Hartmut H. Malluche, Keith A. Hruska
Journal: Kidney International (2017)
The evolution of fluid intelligence meets formative <i>g</i>
Authors: Kristof Kovacs, Andrew R. A. Conway
Journal: Behavioral and Brain Sciences (2017)

Abstract The argument by Burkart et al. in the target article relates to fluid (not general) intelligence: a domain-general ability involved in complex, novel problem solving, and strongly related to working memory and executive functions. A formative framework, under which the general factor of intelligence is the common consequence, not the common cause of the covariance among tests is more in line with an evolutionary approach.
P2.03b-010 EGFR Mutation Status Analysis in Cerebrospinal Fluid and Plasma of Advanced Lung Adenocarcinoma with Brain Metastases
Authors: Liang Shi, Zhe Liu, Jungfang Tang, Hongbo Wu, Lili Guo, Mingzhi Li, Li Tong, Wei Wu, Hong Tao, Weihua Wu, Hongxia Li, Qiyi Meng, Liyan Xu, Yunzhong Zhu
Journal: Journal of Thoracic Oncology (2017)
Shared epitope positivity is related to efficacy of abatacept in rheumatoid arthritis
Authors: Kensuke Oryoji, Kenji Yoshida, Yusuke Kashiwado, Keiko Tanaka, Shin-ichi Mizuki, Hiroshi Tsukamoto, Kazuo Kamada, Koichi Akashi
Journal: Annals of the Rheumatic Diseases (2017)

Abatacept, a soluble fusion protein consisting of the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the Fc portion of human IgG1, has been approved for the treatment of rheumatoid arthritis (RA). It acts by binding to cluster of differenciation (CD)80/86 (B7-1/B7-2) on antigen-presenting cells (APCs) and blocking the B7:CD28 interaction. Meanwhile, HLA-DRB1 shared epitope (SE) has been proposed to be associated with the production of anticyclic citrullinated peptide antibody (ACPA) via major histocompatibility complex-based antigen presentation.1 2 Moreover, the efficacy of abatacept is associated with positivity and titer for ACPA.3 4 Therefore, we hypothesised that the efficacy of abatacept may be associated with patients’ HLA-DRB1 SE positivity. To test this idea, we have retrospectively underwent exploratory analysis of the association between the clinical efficacy of abatacept and HLA-DRB1 genotype. HLA-DRB1 genotype could be identified in 72 patients. The study was approved by the ethics review board of Matsuyama Red Cross Hospital, Japan and was conducted as …