tbuckley/cabot-search huggingface dataset:
Sintilimab for relapsed/refractory classical Hodgkin’s lymphoma: Extended follow-up on the multicenter, single-arm phase II ORIENT-1 study.
Authors: Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Shan Zeng, Peng Liu, Yuankai Shi, Hui Zhou, Shuyan Wang
Journal: Journal of Clinical Oncology (2019)

7533 Background: Classical Hodgkin’s lymphoma (cHL) is characterized by chromosome 9p24.1 alterations and PD-1 ligand overexpression. Sintilimab, a programmed death-1 checkpoint inhibitor, has demonstrated efficacy in relapsed/refractory cHL after the primary analysis of the ORIENT-1 study. Here, we report the updated safety and efficacy prolines after extended follow-up. Methods: ORIENT-1 is a multicenter, single-arm, phase II study in China. Classical Hodgkin’s lymphoma patients who had failed ≥2 lines of systemic therapy, including autologous hematopoietic stem cell transplantation (HSCT) were enrolled. Sintilimab, 200 mg IV was given every 3 weeks, until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) according to 2007 IWG criteria. Results: 96 patients were treated. As of the data cutoff on 16 October, 2018 72.9% of patients were continuing treatment with a median follow-up of 14 months. Median number of treatment cycles was 20 (range: 1 to 26). ORR was 85.4% (82/96, 95%CI: 76.7 to 91.8) based on IRRC review. Twenty-eight patients (29.2%) achieved complete response (CR) by PET scan. At the time of analysis, 59 out of 82 patients who had achieved complete or partial response continued to have an on-going response. The median duration of response (DoR) and progression free survival (PFS) have not been reached. The most common treatment-related adverse event (TRAE) was pyrexia (40.6%, 39/96), 92.3% of which was grade 1 or 2. The most common grade 3 or 4 TRAEs were pyrexia (3.1%) and anemia (3.1%). One death occurred which was not considered treatment related. Conclusions: ORIENT-1 study has the largest cohort of cHL patients in China treated with a PD-1. In addition to a high rate of response, sintilimab also demonstrated durable efficacy and favorable long-term safety profile after extended follow-up. Clinical trial information: NCT03114683.
Alcohol-dependent effect of <i>PRSS1-PRSS2</i> haplotype in chronic pancreatitis
Authors: Eszter Hegyi, Anna Zsófia Tóth, Áron Vincze, Andrea Szentesi, Péter Hegyi, Miklós Sahin-Tóth
Journal: Gut (2019)

We read with great interest the studies by Derikx et al ,1 Boulling et al 2 and Masson et al ,3 in which the authors report that a commonly occurring haplotype spanning the PRSS1-PRSS2 locus (encoding human cationic and anionic trypsinogen) is associated with chronic pancreatitis with an allelic OR of 0.7 in European cohorts (figure 1). Tagged by the c.-408C>T variant (rs10273639), this haplotype was first identified in a GWAS by the Whitcomb laboratory.4 The small but significant protective effect is likely due to the c.-204C>A promoter variant (rs4726576) in PRSS1 , which decreases trypsinogen expression and thereby reduces the risk of premature trypsin activation in the pancreas.2 Curiously, Derikx et al 1 found a clear association of the PRSS1-PRSS2 haplotype with alcoholic pancreatitis only, whereas no association was evident with non-alcoholic disease. Whitcomb et al also noted that the effect of the haplotype seemed to be amplified by alcohol.4 The French study did not specify disease aetiology.2 …
Magnetic Sphincter Augmentation Superior to Proton Pump Inhibitors for Regurgitation in a 1-Year Randomized Trial
Authors: Reginald Bell, John Lipham, Brian E. Louie, Valerie Williams, James Luketich, Michael Hill, William Richards, Christy Dunst, Dan Lister, Lauren McDowell-Jacobs, Patrick Reardon, Karen Woods, Jon Gould, F. Paul Buckley, Shanu Kothari, Leena Khaitan, C. Daniel Smith, Adrian Park, Christopher Smith, Garth Jacobsen, Ghulam Abbas, Philip Katz
Journal: Clinical Gastroenterology and Hepatology (2019)

Regurgitative gastroesophageal reflux disease (GERD) refractive to medical treatment is common and caused by mechanical failure of the anti-reflux barrier. We compared the effects of magnetic sphincter augmentation (MSA) with those of proton-pump inhibitors (PPIs) in a randomized trial.Patients with moderate to severe regurgitation (assessed by the foregut symptom questionnaire) despite once-daily PPI therapy (n = 152) were randomly assigned to groups given twice-daily PPIs (n = 102) or laparoscopic MSA (n = 50) at 20 sites, from July 2015 through February 2017. Patients answered questions from the foregut-specific reflux disease questionnaire and GERD health-related quality of life survey about regurgitation, heartburn, dysphagia, bloating, diarrhea, flatulence, and medication use, at baseline and 6 and 12 months after treatment. Six months after PPI therapy, MSA was offered to patients with persistent moderate to severe regurgitation and excess reflux episodes during impedance or pH testing on medication. Regurgitation, foregut scores, esophageal acid exposure, and adverse events were evaluated at 1 year.Patients in the MSA group and those who crossed over to the MSA group after PPI therapy (n = 75) had similar outcomes. MSA resulted in control of regurgitation in 72/75 patients (96%); regurgitation control was independent of preoperative response to PPIs. Only 8/43 patients receiving PPIs (19%) reported control of regurgitation. Among the 75 patients who received MSA, 61 (81%) had improvements in GERD health-related quality of life improvement scores (greater than 50%) and 68 patients (91%) discontinued daily PPI use. Proportions of patients with dysphagia decreased from 15% to 7% (P < .005), bloating decreased from 55% to 25%, and esophageal acid exposure time decreased from 10.7% to 1.3% (P < .001) from study entry to 1-year after MSA (Combined P < .001). Seventy percent (48/69) of patients had pH normalization at study completion. MSA was not associated with any peri-operative events, device explants, erosions, or migrations.In a prospective study, we found MSA to reduce regurgitation in 95% of patients with moderate to severe regurgitation despite once-daily PPI therapy. MSA is superior to twice-daily PPIs therapy in reducing regurgitation. Relief of regurgitation is sustained over 12 months. ClinicalTrials.gov no: NCT02505945.
Abstract 15276: Identification of a Novel Sarcomeric TPM1 Variant in Familial Atrial Septal Defect
Authors: Polakit Teekakirikul, Wenjuan Zhu, Xinxiu Xu, Amanda M Smith, Chengdong Wang, George Gabriel, Daniel Sonnenberg, Anne Moreau de Bellaing, Michael X Wang, Honglan Gou, Yijen L Wu, Abha Bais, Omar Khalifa, Maliha Zahid, Hui Zhao, Stephanie M Ware, Brian Feingold, Cecilia W Lo
Journal: Circulation (2018)

Introduction: Atrial septal defect (ASD) accounts for 13% of all congenital heart defects (CHD). Despite well-described genetic contribution to ASD, the genetic etiology of ASD remains poorly under...
TCF12 promotes the tumorigenesis and metastasis of hepatocellular carcinoma via upregulation of CXCR4 expression
Authors: Jing Yang, Lili Zhang, Zhiyuan Jiang, Chao Ge, Fangyu Zhao, Jingyi Jiang, Hua Tian, Taoyang Chen, Haiyang Xie, Ying Cui, Ming Yao, Hong Li, Jinjun Li
Journal: Theranostics (2019)

TCF12, which is known to be involved in the regulation of cell growth and differentiation, has been reported to function as an oncogene or a tumor suppressor gene in the progression of various malignant tumors. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. Methods: Stable ectopic TCF12 expression or knockdown in HCC cell lines was established by lentiviral infection. Then, MTT, colony formation, migration, invasion and HUVECs tube formation assays as well as an orthotopic xenograft model were used to investigate the biologic function of TCF12 in HCC cells in vitro and in vivo. Subsequently, RNA-Seq analysis was utilized to explore the target genes regulated by TCF12. RT-qPCR, western blotting, a dual-luciferase reporter assay, Ch-IP, CHIP-Seq and functional rescue experiments were used to confirm the target gene regulated by TCF12. Finally, RT-qPCR, western blot and immunohistochemical (IHC) staining were performed to detect the expression level of TCF12 and to analyze the correlation of TCF12 with downstream genes as well as the clinical significance of TCF12 in human primary HCC. Results: Our functional studies revealed that stable overexpression of TCF12 in human HCC cells enhanced cell proliferation, migration and invasion in vitro and in vivo, whereas knockdown of TCF12 showed opposing effects. Mechanistically, CXCR4 was a downstream target of TCF12, and TCF12 directly bound to the CXCR4 promoter to regulate its expression. Moreover, CXCR4, with its ligand CXCL12, played a critical role in tumor progression induced by TCF12 via activation of the MAPK/ERK and PI3K/AKT signaling pathways. Clinically, IHC analysis revealed that TCF12 was significantly associated with poor survival of HCC patients and that TCF12 expression was closely correlated with CXCR4 expression in primary HCC tissues. Conclusion: Our findings are the first to indicate that TCF12 could promote the tumorigenesis and progression of HCC mainly by upregulating CXCR4 expression and is a prognostic indicator for patients with HCC.
Abstract 15990: Microbubble-Mediated Sonothrombolysis With Long Tone Burst Ultrasound for the Treatment of Microvascular Microembolization: An in vivo Study
Authors: John Pacella, Xucai Chen, Judith Brands, Frederick Schnatz, Thomas Porter, Flordeliza Villanueva
Journal: Circulation (2013)

Background: Despite successful epicardial coronary artery reperfusion by percutaneous coronary intervention (PCI), microembolization (mEMB) of thrombotic debris into the microcirculation limits myo...
A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice
Authors: Di Zhang, Paige Baldwin, Ana S. Leal, Sarah Carapellucci, Srinivas Sridhar, Karen T. Liby
Journal: Theranostics (2019)

Two recently approved PARP inhibitors provide an important new therapeutic option for patients with BRCA-mutated metastatic breast cancer.PARP inhibitors significantly prolong progression-free survival in patients, but conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and off-target toxicities, thus compromising the therapeutic benefits and quality of life for patients.Here, we developed a new delivery system, in which the PARP inhibitor Talazoparib is encapsulated in the bilayer of a nano-liposome, to overcome these limitations.Methods: Nano-Talazoparib (NanoTLZ) was characterized both in vitro and in vivo.The therapeutic efficacy and toxicity of Nano-Talazoparib (NanoTLZ) were evaluated in BRCA-deficient mice.The regulation of NanoTLZ on gene transcription and immunomodulation were further investigated in spontaneous BRCA-deficient tumors.Results: NanoTLZ significantly (p<0.05)prolonged the overall survival of BRCA-deficient mice compared to all of the other experimental groups, including saline control, empty nanoparticles, and free Talazoparib groups (oral and i.v.).Moreover, NanoTLZ was better tolerated than treatment with free Talazoparib, with no significant weight lost or alopecia as was observed with the free drug.After 5 doses, NanoTLZ altered the expression of over 140 genes and induced DNA damage, cell cycle arrest and inhibition of cell proliferation in the tumor.In addition, NanoTLZ favorably modulated immune cell populations in vivo and significantly (p<0.05)decreased the percentage of myeloid derived suppressor cells in both the tumor and spleen compared to control groups.Conclusions: Our results demonstrate that delivering nanoformulated Talazoparib not only enhances treatment efficacy but also reduces off-target toxicities in BRCA-deficient mice; the same potential is predicted for patients with BRCA-deficient breast cancer.
Imitation: Neither instinct nor gadget, but a cultural starting point?
Authors: Lindsey J Powell
Journal: Behavioral and Brain Sciences (2019)

Abstract Heyes asks whether cultural learning mechanisms are cognitive instincts or cognitive gadgets. I argue that imitation does not fall into either category. Instead, its acquisition is promoted by its value in social interactions, which is evident across phylogeny and ontogeny and does not depend on the role of imitation in cultural learning.
Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care
Authors: Elisabetta Patorno, Ajinkya Pawar, Jessica M. Franklin, Mehdi Najafzadeh, Anouk Déruaz-Luyet, Kimberly G. Brodovicz, Steven Sambevski, Lily G. Bessette, Adrian J. Santiago Ortiz, Martin Kulldorff, Sebastian Schneeweiss
Journal: Circulation (2019)

The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor.Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis.After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings.The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease.URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.
Activation of mitogen-activated protein kinases in satellite glial cells of the trigeminal ganglion contributes to substance P-mediated inflammatory pain
Authors: Yanyan Zhang, Ning Song, Fei Liu, Jiu Lin, Mengke Liu, Chaolan Huang, Daqing Liao, Cheng Zhou, Hang Wang, Jiefei Shen
Journal: International Journal of Oral Science (2019)

Abstract Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1β and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund’s adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1β and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1β and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1β and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.
Decrease in 18F-Florbetapir Accumulation in the Cerebral Hemisphere With Hypoperfusion and Misery Perfusion Due to Chronic Atherosclerotic Occlusion of the Internal Carotid Artery
Authors: Tatsuhiko Takahashi, Masakazu Kobayashi, Shunrou Fujiwara, Yoshitaka Kubo, Kazunori Terasaki, Kuniaki Ogasawara
Journal: Clinical Nuclear Medicine (2019)

Abstract A 67-year-old man had a slowly progressing impairment of recent memory. Cerebral angiography showed atherosclerotic occlusion of the right internal carotid artery with insufficient collateral circulation. Positron emission tomography (PET) using 15 O 2 gas showed reduced cerebral blood flow, reduced cerebral metabolic rate of oxygen, and elevated oxygen extraction fraction in the precentral region of the right cerebral hemisphere. Use of 18 F-florbetapir PET depicted amyloid β deposition as decreased tracer uptake in the precentral region in the right cerebral hemisphere when compared with the contralateral hemisphere.
A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model
Authors: Stephen R. Yant, Andrew Mulato, Derek Hansen, Winston C. Tse, Anita Niedziela-Majka, Jennifer R. Zhang, George J. Stepan, Debi Jin, Melanie H. Wong, Jill M. Perreira, Eric Singer, Giuseppe A. Papalia, Eric Y. Hu, Jim Zheng, Bing Lu, Scott D. Schroeder, Kevin Chou, Shekeba Ahmadyar, Albert Liclican, Helen Yu, Nikolai Novikov, Eric Paoli, Daniel Gonik, Renee R. Ram, Magdeleine Hung, William M. McDougall, Abraham L. Brass, Wesley I. Sundquist, Tomas Cihlar, John O. Link
Journal: Nature Medicine (2019)
Biomarker-Driven Drug Discovery in Cancer—Trastuzumab Development
Authors: H. Michael Shepard
Journal: JAMA (2019)

In this Viewpoint, 2019 Lasker-DeBakey Clinical Medical Research Award winner H. Michael Shepard discusses development of trastuzumab, the first fully humanized monoclonal antibody for solid tumor treatment and the first tyrosine kinase inhibitor, for treatment of breast cancer.
Humean replies to Regard for Reason
Authors: Neil Sinhababu
Journal: Behavioral and Brain Sciences (2019)

First, I argue that the Humean theory is compatible with the commonsense psychological explanations May invokes against it. Second, I explain why desire provides better-integrated explanations than the mental states May describes as sharing its effects. Third, I defend individuating processes by relata, which May rejects in arguing that anti-Humean views are as parsimonious as the Humean theory.
Regional lymph node irradiation in early stage breast cancer: An EBCTCG meta-analysis of 13,000 women in 14 trials
Authors: D Dodwell, C Taylor, P McGale, C Coles, F Duane, R Gray, T Kuehn, C Hennequin, S Oliveros, Y Wang, J Overgaard, P Poortmans, T Whelan
Journal: Cancer Research (2019)
hs-CRP Is Associated With Incident Diabetic Nephropathy: Findings From the Jackson Heart Study
Authors: Satyesh K. Sinha, Susanne B. Nicholas, Jung Hye Sung, Adolfo Correa, Tripathi B. Rajavashisth, Keith C. Norris, Jae Eun Lee
Journal: Diabetes Care (2019)

OBJECTIVE African Americans (AA) suffer disproportionately from diabetic nephropathy (DN). C-reactive protein (CRP) has been associated with prevalent DN, but its association with incident DN in AA is unknown. We examined hs-CRP and incident DN in AA. RESEARCH DESIGN AND METHODS We conducted a longitudinal analysis of data from exams 1, 2, and 3 in 4,043 eligible Jackson Heart Study (JHS) participants. Participants with DN or without hs-CRP at exam 1 were excluded. Incident DN was defined as urinary albumin-to-creatinine ratio (ACR) &amp;gt;30 mg/g or self-reported dialysis/transplantation and type 2 diabetes mellitus (DM) or HbA1c &amp;gt;6.5% by exam 2 or 3 among participants free of DN at exam 1. Kaplan-Meier curves examined DN event-free survival probability by hs-CRP. With Cox proportional hazards regression we estimated hazard ratios (HRs) and 95% CI for DN by hs-CRP tertiles, adjusting for demographics and clinical and laboratory data. RESULTS During 7.8 years of median follow-up time, participants who developed DN had significantly higher baseline hs-CRP, age, fasting glucose, triglycerides, ACR, systolic blood pressure, waist circumference, and duration of DM (P &amp;lt; 0.05). The overall incident rate of DN was 7.9%. The mean time to incident DN was shorter for participants with hs-CRP in the high tertile (&amp;gt;4.24 mg/L) than in the low tertile (&amp;lt;1.46 mg/L); P &amp;lt; 0.001. Participants with high hs-CRP had higher incidence of DN (HR 2.34, 95% CI 1.04–5.24) versus the reference group. CONCLUSIONS Inflammation, as measured by hs-CRP levels, may be associated with incident DN in AA. Further studies are warranted to replicate and elucidate the basis for this association.