tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study
Authors: Hyun Cheol Chung, Willeke Ros, Jean-Pierre Delord, Ruth Perets, Antoine Italiano, Ronnie Shapira-Frommer, Lyudmila Manzuk, Sarina A. Piha-Paul, Lei Xu, Susan Zeigenfuss, Scott K. Pruitt, Alexandra Leary
Journal: Journal of Clinical Oncology (2019)

KEYNOTE-158 ( ClinicalTrials.gov identifier: NCT02628067) is a phase II basket study investigating the antitumor activity and safety of pembrolizumab in multiple cancer types. We present interim results from patients with previously treated advanced cervical cancer.Patients received pembrolizumab 200 mg every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors (version 1.1) by independent central radiologic review. Safety was a secondary end point.Ninety-eight patients were treated. Median age was 46.0 years (range, 24 to 75 years), and 65.3% of patients had Eastern Cooperative Oncology Group performance status of 1. Eighty-two patients (83.7%) had programmed death-ligand 1 (PD-L1)-positive tumors (combined positive score ≥ 1), 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. Median follow-up was 10.2 months (range, 0.6 to 22.7 months). ORR was 12.2% (95% CI, 6.5% to 20.4%), with three complete and nine partial responses. All 12 responses were in patients with PD-L1-positive tumors, for an ORR of 14.6% (95% CI, 7.8% to 24.2%); 14.3% (95% CI, 7.4% to 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Median duration of response was not reached (range, ≥ 3.7 to ≥ 18.6 months). Treatment-related adverse events occurred in 65.3% of patients, and the most common were hypothyroidism (10.2%), decreased appetite (9.2%), and fatigue (9.2%). Treatment-related grade 3 to 4 adverse events occurred in 12.2% of patients.Pembrolizumab monotherapy demonstrated durable antitumor activity and manageable safety in patients with advanced cervical cancer. On the basis of these results, the US Food and Drug Administration granted accelerated approval of pembrolizumab for patients with advanced PD-L1-positive cervical cancer who experienced progression during or after chemotherapy.
Functional brain alterations in acute sleep deprivation: An activation likelihood estimation meta-analysis
Authors: Nooshin Javaheripour, Niloofar Shahdipour, Khadijeh Noori, Mojtaba Zarei, Julia A. Camilleri, Angela R. Laird, Peter T. Fox, Simon B. Eickhoff, Claudia R. Eickhoff, Ivana Rosenzweig, Habibolah Khazaie, Masoud Tahmasian
Journal: Sleep Medicine Reviews (2019)
Erratum. Secular TRends in DiabEtes in India (STRiDE–I): Change in Prevalence in Ten Years Among Urban and Rural Populations in Tamil Nadu. Diabetes Care 2019;42:476–485
Authors: Arun Nanditha, Chamukuttan Snehalatha, Krishnamoorthy Satheesh, Priscilla Susairaj, Mary Simon, Lakshminarayanan Vijaya, Arun Raghavan, Ramachandran Vinitha, Ambady Ramachandran
Journal: Diabetes Care (2019)

In the article cited above, changes have been made in Table 2 on page 480 (for values under “Self-reported” and “New”) and in …
The seroprevalence of untreated chronic hepatitis C virus (HCV) infection and associated risk factors in male Irish prisoners: a cross-sectional study, 2017
Authors: Desmond Crowley, John S Lambert, Graham Betts-Symonds, Walter Cullen, Mary Keevans, Enda Kelly, Eamon Laird, Tina McHugh, Susan McKiernan, Sarah Jayne Miggin, Carol Murphy, Ross Murtagh, Deirdre O'Reilly, Ciara Tobin, Marie Claire Van Hout
Journal: Eurosurveillance (2019)

IntroductionData on chronic hepatitis C (HCV) infection prevalence in European prisons are incomplete and impact the public health opportunity that incarceration provides.AimsWe aimed to estimate the seroprevalence of untreated chronic HCV infection and to identify associated risk factors in an Irish male prison.MethodsWe conducted a cross-sectional study involving a researcher-administered questionnaire, review of medical records and HCV serology.ResultsOf 422 prisoners (78.0% of the study population) who participated in the study, 298 (70.6%) completed the questionnaire and 403 (95.5%) were tested for HCV antibodies. Of those tested, 92 (22.8%) were HCV antibody-positive, and of those, 53 (57.6%) were HCV RNA-positive, 23 (25.0%) had spontaneous clearance, 16 (17.4%) had a sustained viral response, 10 (11.0%) were co-infected with HIV and six (6.0%) with HBV. The untreated chronic HCV seroprevalence estimate was 13.1% and the seroprevalence of HCV among prisoners with a history of injecting drug use (IDU) was 79.7%. Risk factors significantly associated with past HCV infection were IDU (p < 0.0001), having received a prison tattoo (p < 0.0001) or a non-sterile community tattoo (p < 0.0001), sharing needles and other drug-taking paraphernalia (p < 0.0001). Small numbers of prisoners had a history of sharing razors (n=10; 3.4%) and toothbrushes (n=3; 1.0%) while incarcerated. On multivariable analysis, history of receiving a non-sterile community tattoo was the only significant risk factor associated with HCV acquisition (after IDU was removed from the model) (p = 0.005, β = 0.468).ConclusionThe level of untreated chronic HCV infection in Irish prisons is high, with IDU the main associated risk.
Hepatic Glucagon Signaling Regulates PCSK9 and LDL-Cholesterol
Authors: Stefano Spolitu, Haruka Okamoto, Wen Dai, John A Zadroga, Erika S Wittchen, Jesper Gromada, Lale Ozcan
Journal: Circulation Research (2018)

Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism, however, the molecular pathways underlying this effect are incompletely understood. Objective: We sought to determine the role of hepatic glucagon receptor (Gcgr) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. Methods and Results: We show that Gcgr signaling plays an essential role in low-density lipoprotein (LDL) cholesterol homeostasis through regulating the proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDL receptor protein and increased plasma LDL-cholesterol. Conversely, treatment of WT mice with glucagon lowered LDL-cholesterol levels, whereas this response was abrogated in Pcsk9-/- and Ldlr-/- mice. Our gain- and los...
Response to: ‘Circulating microbiome in blood of different circulatory compartments’ by Schierwagen <i>et al</i>
Authors: Bastian Volker Helmut Hornung, Romy Danielle Zwittink, Quinten Raymond Ducarmon, Ed J Kuijper
Journal: Gut (2019)

We read with interest the article by Schierwagen et al ,1 who reported on their findings regarding the blood microbiome. Since our research group is working in a hospital setting, recently, we have also considered investigating the blood microbiome using collected blood samples that are potentially available. However, based on recent literature,2 3 we considered the presence of a blood microbiome very unlikely and did not further venture in this direction. We were therefore extremely excited to read this work, but the results quickly raised concerns in our research group. In another area of microbiota research, we recently …
Re: Diagnostic and Prognostic Value of Using 18F-FDG PET/CT for the Evaluation of Bone Marrow Involvement in Peripheral T-Cell Lymphoma
Authors: Domenico Rubello, Patrick M. Colletti
Journal: Clinical Nuclear Medicine (2019)

∗Department of Nuclear Medicine S. Maria della Misericordia Hospital Rovigo, Italy [email protected] †Department of Radiology University of Southern California, Los Angeles, CA Conflicts of interest and sources of funding: none declared.
Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial
Authors: Philippe Merle, Jean-Frederic Blanc, Jean-Marc Phelip, Gilles Pelletier, Jean-Pierre Bronowicki, Yann Touchefeu, Georges Pageaux, René Gerolami, François Habersetzer, Eric Nguyen-Khac, Andrea Casadei-Gardini, Ivan Borbath, Albert Tran, Henning Wege, Amr Shafik Saad, Massimo Colombo, Armand Abergel, Carine Richou, Imam Waked, Nelson S Yee, Audrey Molé, Pierre Attali, Julie Le Boulicaut, Bérangère Vasseur, Driffa Moussata, Jean-Didier Grangé, Vlad Ratziu, Faiza Khemissa-Akouz, Hélène Regnault, Barbara Dauvois, Jean-Pierre Zarski, Isabelle Ollivier-Hourmand, Sylvain Manfredi, Marilyne Debette-Gratien, Alice Gangloff, Thierry Fontanges, Aurore Baron, Mohamed Bouattour, Julie Vincent, Wolfgang Sieghart, Andreas Maieron, Marc Peeters, Jean Delwaide, Luc Lasser, Thomas Berg, Michael Schultheiß, Alexander Zipprich, Joerg Trojan, Ursula Ehmer, Gabriele Luppi, Giovanni Luca, Stefano Tamberi, Domenico Amoroso, Oscar Alabiso, Angela Buonadonna, Pierluigi Toniutto, Emiliano Tamburini, Antonio Cubillo, Andrés Muñoz, Carmen Guillén, Gloria Sánchez, Hermini Manzano, Victor Navarro, Inmaculada Ales, Bartomeu Massuti, Magdolna Dank, György Bodoky, Zsuzsanna Kahan, Zsolt Horváth, Nashat Gabrail, Howard Ozer, Christos Galanopoulos, Ralph Hauke, Moses Raj, Hakan Harputluoglu, Alper Sevinc, Erdem Goker, Ahmet Coker, Suayib Yalcin, Muhammet Ali, Ozlem Ata, Ilkay Tugba, Mohammed El Kassas, Amr Abdel, Imam Wakid, Sameh Shamaa, Nasr El Lahlouby, Hanaa Kohail, Jawad Makarem, Issam Chehade, Fadi Farhat, Carlos López, Miguel Marín
Journal: The Lancet. Gastroenterology & hepatology (2019)
Clever-1 contributes to lymphocyte entry into the spleen via the red pulp
Authors: Sina Tadayon, Johannes Dunkel, Akira Takeda, Olga Halle, Marika Karikoski, Heidi Gerke, Pia Rantakari, Reetta Virtakoivu, Oliver Pabst, Marko Salmi, Maija Hollmén, Sirpa Jalkanen
Journal: Science Immunology (2019)

Lymphocyte entry into the spleen is initiated by their binding to Clever-1–expressing vessels in the red pulp.
Adiponectin accounts for gender differences in hepatocellular carcinoma incidence
Authors: Elisa Manieri, Leticia Herrera-Melle, Alfonso Mora, Antonia Tomás-Loba, Luis Leiva-Vega, Delia I. Fernández, Elena Rodríguez, Laura Morán, Lourdes Hernández-Cosido, Jorge L. Torres, Luisa M. Seoane, Francisco Javier Cubero, Miguel Marcos, Guadalupe Sabio
Journal: The Journal of Experimental Medicine (2019)

Hepatocellular carcinoma (HCC) is the sixth most common cancer type and the fourth leading cause of cancer-related death. This cancer appears with higher incidence in men and during obesity; however, the specific mechanisms underlying this correlation are unknown. Adipose tissue, a key organ in metabolic syndrome, shows evident gender disparities in the production of adipokines. Levels of the important adipokine adiponectin decrease in men during puberty, as well as in the obese state. Here, we show that this decrease in adiponectin levels is responsible for the increased liver cancer risk in males. We found that testosterone activates the protein JNK in mouse and human adipocytes. JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation, since adiponectin protects against liver cancer development through the activation of AMP-activated protein kinase (AMPK) and p38α. This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics.
Unique CDR3 epitope targeting by CAR-T cells is a viable approach for treating T-cell malignancies
Authors: Jinqi Huang, Stepanov Alexey, Jian Li, Terri Jones, Geramie Grande, Lacey Douthit, Jun Xie, Danna Chen, Xiaolei Wu, Maschan Michael, Changchun Xiao, Jiangning Zhao, Xuehua Xie, Jia Xie, Xiao Lei Chen, Guo Fu, Gabibov Alexander, Chi-Meng Tzeng
Journal: Leukemia (2019)
HIV and Sexually Transmitted Infection Vulnerability Among Heterosexual Couples Involved in the Criminal Justice System—The Corrections Connection
Authors: Tim W. Menza, Kenneth H. Mayer
Journal: JAMA Network Open (2019)

Nabila El-Bassel, PhD; Louisa Gilbert, PhD; Dawn Goddard-Eckrich, EdD; Mingway Chang, PhD; Elwin Wu, PhD; Sharun Goodwin, BS; Richard Tibbetts, MS; Maria Almonte-Weston, MSW; Timothy Hunt, PhD
Standardized Team-Based Care for Cardiogenic Shock
Authors: Behnam N. Tehrani, Alexander G. Truesdell, Matthew W. Sherwood, Shashank Desai, Henry A. Tran, Kelly C. Epps, Ramesh Singh, Mitchell Psotka, Palak Shah, Lauren B. Cooper, Carolyn Rosner, Anika Raja, Scott D. Barnett, Patricia Saulino, Christopher R. deFilippi, Paul A. Gurbel, Charles E. Murphy, Christopher M. O’Connor
Journal: Journal of the American College of Cardiology (2019)

Cardiogenic shock (CS) is a multifactorial, hemodynamically complex syndrome associated with high mortality. Despite advances in reperfusion and mechanical circulatory support, management remains highly variable and outcomes poor.This study investigated whether a standardized team-based approach can improve outcomes in CS and whether a risk score can guide clinical decision making.A total of 204 consecutive patients with CS were identified. CS etiology, patient demographic characteristics, right heart catheterization, mechanical circulatory support use, and survival were determined. Cardiac power output (CPO) and pulmonary arterial pulsatility index (PAPi) were measured at baseline and 24 h after the CS diagnosis. Thresholds at 24 h for lactate (<3.0 mg/dl), CPO (>0.6 W), and PAPi (>1.0) were determined. Using logistic regression analysis, a validated risk stratification score was developed.Compared with 30-day survival of 47% in 2016, 30-day survival in 2017 and 2018 increased to 57.9% and 76.6%, respectively (p < 0.01). Independent predictors of 30-day mortality were age ≥71 years, diabetes mellitus, dialysis, ≥36 h of vasopressor use at time of diagnosis, lactate levels ≥3.0 mg/dl, CPO <0.6 W, and PAPi <1.0 at 24 h after diagnosis and implementation of therapies. Either 1 or 2 points were assigned to each variable, and a 3-category risk score was determined: 0 to 1 (low), 2 to 4 (moderate), and ≥5 (high).This observational study suggests that a standardized team-based approach may improve CS outcomes. A score incorporating demographic, laboratory, and hemodynamic data may be used to quantify risk and guide clinical decision-making for all phenotypes of CS.
Pivotal role of membrane substrate transporters on the metabolic alterations in the pressure-overloaded heart
Authors: Ilvy M E Geraets, Jan F C Glatz, Joost J F P Luiken, Miranda Nabben
Journal: Cardiovascular Research (2019)

Cardiac pressure overload (PO), such as caused by aortic stenosis and systemic hypertension, commonly results in cardiac hypertrophy and may lead to the development of heart failure. PO-induced heart failure is among the leading causes of death worldwide, but its pathological origin remains poorly understood. Metabolic alterations are proposed to be an important contributor to PO-induced cardiac hypertrophy and failure. While the healthy adult heart mainly uses long-chain fatty acids (FAs) and glucose as substrates for energy metabolism and to a lesser extent alternative substrates, i.e. lactate, ketone bodies, and amino acids (AAs), the pressure-overloaded heart is characterized by a shift in energy metabolism towards a greater reliance on glycolysis and alternative substrates. A key-governing kinetic step of both FA and glucose fluxes is at the level of their substrate-specific membrane transporters. The relative presence of these transporters in the sarcolemma determines the cardiac substrate preference. Whether the cardiac utilization of alternative substrates is also governed by membrane transporters is not yet known. In this review, we discuss current insight into the role of membrane substrate transporters in the metabolic alterations occurring in the pressure-overloaded heart. Given the increasing evidence of a role for alternative substrates in these metabolic alterations, there is an urgent need to disclose the key-governing kinetic steps in their utilization as well. Taken together, membrane substrate transporters emerge as novel targets for metabolic interventions to prevent or treat PO-induced heart failure.
EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma
Authors: Jens-Martin Hübner, Torsten Müller, Dimitris N Papageorgiou, Monika Mauermann, Jeroen Krijgsveld, Robert B Russell, David W Ellison, Stefan M Pfister, Kristian W Pajtler, Marcel Kool
Journal: Neuro-Oncology (2019)

Abstract Background Posterior fossa A (PFA) ependymomas are one of 9 molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of chromosome X open reading frame 67 (CXorf67) as a hallmark of PFA ependymoma and showed that CXorf67 can interact with enhancer of zeste homolog 2 (EZH2), thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear. Methods We performed mass spectrometry and peptide modeling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot, and methyltransferase assays. Results We find that the inhibitory mechanism of CXorf67 is similar to diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain (Su(var)3-9/enhancer-of-zeste/trithorax) of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function, causing de-repression of PRC2 target genes, including genes involved in neurodevelopment. Conclusions Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 as “EZH Inhibitory Protein” (EZHIP).
Endoscopic submucosal dissection using an SB Knife Jr. with clip traction method for esophageal cancer at the anastomotic site after total gastrectomy
Authors: Yoshiyasu Kitagawa, Rino Nankinzan, Takuto Suzuki, Taketo Yamaguchi
Journal: Endoscopy (2019)

Endoscopic submucosal dissection (ESD) enables the operator to achieve R0 resection regardless of the tumor size. However, ESD for lesions with severe fibrosis remains technically challenging. Here, we describe a patient who underwent successful ESD of an esophageal cancer using the Stag Beetle (SB) Knife Jr. with the clip traction method.
Lifelong Congenital Urology: The Challenges for Patients and Surgeons
Authors: Dan Wood, Andrew Baird, Luca Carmignani, Gunter De Win, Piet Hoebeke, Gundela Holmdahl, Gianantonio Manzoni, Rien J.M. Nijman, Claire Taylor, Serdar Tekgul
Journal: European Urology (2019)
Interleukin-1 alpha increases anti-tumor efficacy of cetuximab in head and neck squamous cell carcinoma
Authors: Madelyn Espinosa-Cotton, Samuel N. Rodman III, Kathleen A. Ross, Isaac J. Jensen, Kenley Sangodeyi-Miller, Ayana J. McLaren, Rachel A. Dahl, Katherine N. Gibson-Corley, Adam T. Koch, Yang-Xin Fu, Vladimir P. Badovinac, Douglas Laux, Balaji Narasimhan, Andrean L. Simons
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Despite the high prevalence of epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinomas (HNSCCs), incorporation of the EGFR inhibitor cetuximab into the clinical management of HNSCC has not led to significant changes in long-term survival outcomes. Therefore, the identification of novel therapeutic approaches to enhance the clinical efficacy of cetuximab could lead to improved long-term survival for HNSCC patients. Our previous work suggests that EGFR inhibition activates the interleukin-1 (IL-1) pathway via tumor release of IL-1 alpha (IL-1α), although the clinical implications of activating this pathway are unclear in the context of cetuximab therapy. Given the role of IL-1 signaling in anti-tumor immune response, we hypothesized that increases in IL-1α levels would enhance tumor response to cetuximab. <h3>Methods</h3> Parental and stable myeloid differentiation primary response gene 88 (MyD88) and IL-1 receptor 1 (IL-1R1) knockdown HNSCC cell lines, an IL-1R antagonist (IL-1RA), neutralizing antibodies to IL-1α and IL-1β, and recombinant IL-1α and IL-1β were used to determine cytokine production (using ELISA) in response to cetuximab in vitro. IL-1 pathway modulation in mouse models was accomplished by administration of IL-1RA, stable overexpression of IL-1α in SQ20B cells, administration of rIL-1α, and administration of a polyanhydride nanoparticle formulation of IL-1α. CD4<sup>+</sup> and CD8<sup>+</sup> T cell-depleting antibodies were used to understand the contribution of T cell-dependent anti-tumor immune responses. Baseline serum levels of IL-1α were measured using ELISA from HNSCC patients treated with cetuximab-based therapy and analyzed for association with progression free survival (PFS). <h3>Results</h3> Cetuximab induced pro-inflammatory cytokine secretion from HNSCC cells in vitro which was mediated by an IL-1α/IL-1R1/MyD88-dependent signaling pathway. IL-1 signaling blockade did not affect the anti-tumor efficacy of cetuximab, while increased IL-1α expression using polyanhydride nanoparticles in combination with cetuximab safely and effectively induced a T cell-dependent anti-tumor immune response. Detectable baseline serum levels of IL-1α were associated with a favorable PFS in cetuximab-based therapy-treated HNSCC patients compared to HNSCC patients with undetectable levels. <h3>Conclusions</h3> Altogether, these results suggest that IL-1α in combination with cetuximab can induce a T cell-dependent anti-tumor immune response and may represent a novel immunotherapeutic strategy for EGFR-positive HNSCCs.
Renal Perfusion and Renal Nerve Activity
Authors: Meyer D. Lifschitz
Journal: Journal of the American Society of Nephrology (2019)

In the study by Haddock et al.,1 it was both interesting and exciting to see that such differences in regional kidney blood flow could be shown in humans over short time intervals. They suggest in their discussion that this tool could be useful in studies of renal denervation, because the changes that they observed are caused by increased renal nerve activity. This conclusion is questionable, because the changes that they observed could be caused by differences in circulating neurotransmitters rather than specific effects of renal nerve activity. Although they suggest that work of others shows an effect of handgrip on renal nerve activity, a review of these references does not show specific observations on renal nerve activity. Disclosures None.