tbuckley/cabot-search huggingface dataset:
Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety in Japanese patients across two global randomized phase III studies (REACH-2 and REACH).
Authors: Masatoshi Kudo, Takuji Okusaka, Kenta Motomura, Izumi Ohno, Manabu Morimoto, Satoru Seo, Yoshiyuki Wada, Shinpei Sato, Tatsuya Yamashita, Masayuki Furukawa, Takeshi Aramaki, Seijin Nadano, Kazuyoshi Ohkawa, Hirofumi Fujii, Toshihiro Kudo, Junji Furuse, Hiroki Takai, Gosuke Homma, Reigetsu Yoshikawa, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2019)

320 Background: Ramucirumab (RAM), a human IgG1 monoclonal antibody, inhibits ligand activation of VEGFR2. REACH and REACH-2 were two global, randomized, double-blind, placebo (PBO)-controlled multicenter, phase III studies of RAM versus PBO in patients with HCC after prior sorafenib. REACH-2 confirmed RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. Methods: Other than AFP levels, study designs and eligibility for both studies were similar. All patients received RAM (8 mg/kg) I.V. or PBO every 14 days. Pooled analyses were performed to further support the assessments of efficacy and safety in Japanese patients with baseline AFP ≥ 400 ng/mL. Results: In total, 101 Japanese patients were pooled from REACH and REACH-2 (n = 61 RAM; n = 40 PBO). Pooled baseline patient characteristics were balanced between arms including baseline AFP and etiology. As in the individual studies, improvement in OS (median OS 10.78 vs 4.47 mo; HR 0.555; 95% CI 0.348, 0.885; p = .0124) was observed. Improvements in PFS (median PFS 3.88 vs 1.41 mo; HR 0.341; 95% CI 0.212, 0.550; p &lt; .0001), ORR (9.8% vs 2.5%, p = .1285), and disease control rate (67.2% vs 35.0%, p = .0035) were also observed. Consistent with individual study results, hypertension was the only grade 3 or higher adverse events of special interest among ≥ 5% patients that was more frequently observed in the RAM arm (13.1%) compared with the PBO arm (5.0%). Conclusions: Pooled analysis of two phase III trials of RAM as second-line treatment in patients with HCC following first-line sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Japanese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the Japanese subpopulation were consistent with the entire population (median OS 8.1 vs 5.0 mo; HR 0.694; p = .0002. Zhu AX et al., World GI 2018). Further analysis to characterize the Japanese patients compared to the non-Japanese population is planned. Clinical trial information: NCT01140347 (REACH), NCT02435433 (REACH-2).
Berberine May Correct Corticosteroid Resistance Induced By Gut Microbiota Dysbiosis in Immune Thrombocytopenia
Authors: Ya-Nan Wang, Xiao Liu, Yun He, Qian-Ming Wang, Xiao-Lu Zhu, Chen-Cong Wang, Hai-Xia Fu, Meng Lv, Ying-Jun Chang, Xiao-Su Zhao, Xiang-Yu Zhao, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang, Xiaohui Zhang
Journal: Blood (2018)
The impact of sidedness of colorectal cancer in tumor immunity.
Authors: Masaaki Nishi, Mitsuo Shimada, Hideya Kashihara, Jun Higashijima, Kozo Yoshikawa, Takuya Tokunaga, Tomohiko Miyatani, Chie Takasu, Shoko Iwahashi
Journal: Journal of Clinical Oncology (2019)

584 Background: Clinical and molecular characteristics are different between Right-side and left-sided colorectal cancer (CRC). The aim of this study was to clarify the significance of the correlation of the Sidedness of CRC and tumor immunity. Methods: A total of 116 patients who underwent curative colectomy for stage II/III CRC were included in this study. The expression of PD-1, PD-L1, FoxP3, TGF-b, and IDO was examined by immunohistochemistry and the relationship of sidedness to several prognostic factors was examined. Results: In clinicopathological factors, there were no significant difference between right sided and left sided CRC except for differentiation. Regarding tumor immunity, there were no significant difference in PD-1 and IDO expression. However, Fox P3 (right side 72% vs. left side 59%) and TGFβ (right side 72% vs. left side 57%) tended to be highly expressed in right side(p &lt; 0.1). PDL1 was significantly highly expressed in right side(right side 65% vs. left side 35%, p &lt; 0.05). In OS and DFS, the patients with right sided tumor tended to have poor prognosis compared with left side (p &lt; 0.1). The PD-L1 positive patients of right-sided tumor had poor prognosis (p &lt; 0.05). Conclusions: Sidedness is associated with tumor immunity in colorectal cancer.
Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma
Authors: Linda von Hoff, Eva Kärgel, Vedran Franke, Erik McShane, Kathrin W. Schulz-Beiss, Giannino Patone, Nikolai Schleussner, Marina Kolesnichenko, Norbert Hübner, Oliver Daumke, Matthias Selbach, Altuna Akalin, Stephan Mathas, Claus Scheidereit
Journal: Blood (2019)
The BRISC deubiquitinating enzyme complex limits hematopoietic stem cell expansion by regulating JAK2 K63-ubiquitination
Authors: Ryan Donaghy, Xu Han, Krasimira Rozenova, Kaosheng Lv, Qinqin Jiang, Miriam Doepner, Roger A. Greenberg, Wei Tong
Journal: Blood (2019)
The Toxin–Antidote Model of Cytoplasmic Incompatibility: Genetics and Evolutionary Implications
Authors: John F. Beckmann, Manon Bonneau, Hongli Chen, Mark Hochstrasser, Denis Poinsot, Hervé Merçot, Mylène Weill, Mathieu Sicard, Sylvain Charlat
Journal: Trends in Genetics (2019)
Efficacy Of 100 Mg SC Mepolizumab For Severe Eosinophilic Asthma (SEA) Across Body Weight: Meta-Analysis
Authors: Eric S. Bradford, Camille Taillé, Daniel J. Bratton, Steven W. Yancey, Namhee Kwon, Frank Albers, Alberto Papi
Journal: Journal of Allergy and Clinical Immunology (2019)
Biodegradable thermal imaging-tracked ultralong nanowire-reinforced conductive nanocomposites elastomers with intrinsical efficient antibacterial and anticancer activity for enhanced biomedical application potential
Authors: Yannan Li, Na Li, Juan Ge, Yumeng Xue, Wen Niu, Mi Chen, Yaping Du, Peter X. Ma, Bo Lei
Journal: Biomaterials (2019)
Abstract 20354: Modeling Premature Cardiac Aging by Induced Pluripotent Stem Cell From a Patient With Hutchinson-Gilford Progeria Syndrome
Authors: Gustavo Monnerat, Fernanda C Mesquita, João P Simões, Marianna M Américo, Camila Wendt, João Paulo Albuquerque, Danubia S dos Santos, Karina D Asensi, Tais H Brunswick, Adriana B Carvalho, Antonio C Campos-de-Carvalho
Journal: Circulation (2017)

Introduction: Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder with high incidence of accelerated aging and cardiovascular complications. Hypothesis: Cardiomyocytes...
Abstract P5-08-04: Defining chromatin accessibility profiles of partial and reversible EMT
Authors: KS Johnson, S Hussein, Y Lin, JH Taube
Journal: Cancer Research (2019)

Abstract The epithelial-to-mesenchymal transition (EMT) reversible cellular reprogramming event, used repeatedly throughout development, is hypothesized to be involved in the cell migration and consequently metastasis that ultimately contributes to most breast cancer-related fatalities. In this process, cuboidal epithelial cells, marked by the presence of tight junction proteins and cell-cell adhesions, lose their apicobasal polarity and acquire a spindle-like morphology and migratory traits. EMT was originally regarded to have only two states, with cells exhibiting either epithelial or mesenchymal phenotypes; however, recently, researchers have demonstrated the existence of a dual epithelial/mesenchymal state, termed hybrid- or partial-EMT. Due to its inherent plasticity, it is believed that EMT and its reversal mesenchymal-to-epithelial transition (MET) is, at least, partly regulated by epigenetic means such as alterations in chromatin structure. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a novel technique that employs the use of a mutant Tn5 transposase to cleave nucleosome-free DNA regions in a non-biased manner. In this investigation, we induced MCF10A mammary epithelial cells to undergo a short-term (&amp;lt;4 days) or long-term (&amp;gt;4 days) EMT. Addition and withdrawal of exogenous TGFβ1 produced partial- or full-EMT and MET conditions which were interrogated by ATAC- and RNA-seq. Hierarchical clustering of ATAC cleavage peaks revealed that pre-EMT and short- and long-term MET conditions demonstrate similar chromatin accessibility profiles with cleavage sites enriched for specific binding motifs. Notably, transcription factors typically not associated with EMT displayed dynamic enrichment in the accessible chromatin at various timepoints in our assay. Correlation with RNA-seq data reveals highly dynamic changes in gene expression suggesting dynamic and reversible use of regulatory programs. Importantly, partial-EMT cells were characterized by unique accessibility patterns, motif enrichment, and gene expression supporting the conclusion that this is not merely an intermediate but a unique state. Citation Format: Johnson KS, Hussein S, Lin Y, Taube JH. Defining chromatin accessibility profiles of partial and reversible EMT [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-04.
A current understanding of drug-induced QT prolongation and its implications for anticancer therapy
Authors: Dan M Roden
Journal: Cardiovascular Research (2019)

The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.
Abstract 118: Ischemic Postconditioning with Controlled Pause at the Beginning of CPR Improves the Hemodynamic Effects of Epinephrine After 15 Minutes of Untreated Ventricular Fibrillation
Authors: Timothy Matsuura, Mohammad Sarraf, Nicolas Segal, James Kolbeck, Emily Caldwell, Scott McKnite, Demetris Yannopoulos
Journal: Circulation (2012)

Background: Ischemic postconditioning (IPC), by intermittent initiation of flow during the first minutes of re-establishment of blood flow, protects the heart from injury and improves outcomes in a...
Abstract P353: New Evidence on the Association of Physical Activity and Chronic Kidney Disease: ORISCAV-LUX Study
Authors: Ala’a Alkerwi, Nicolas Sauvageot, Saverio Stranges, Charles Delagardelle, Jean Beissel
Journal: Circulation (2017)

Background: Evidence on stages of renal impairment and related risk factors in Luxembourg adults is lacking. This study aimed to assess the prevalence of chronic kidney disease (CKD) and identify potential correlates among general population in Luxembourg, using the recent definition suggested by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Methods: Analyses were based on data from 1361 adult participants aged 18-69 years, enrolled in the Observation of Cardiovascular Risk Factors in Luxembourg (ORISCAV-LUX) study, 2007-2008. Descriptive and multivariable logistic regression analyses were performed to identify demographic, socio-economic, clinical and behavioral factors associated with CKD, defined as single estimated glomerular filtration rate (eGFR) measure &lt;60 ml/min/1.73m 2 and/or urinary albumin creatinine ratio (ACR)&gt;30mg/g. Results: Overall, 6.3% had CKD, including 4.4% and 0.7% presented with moderate and severe macroalbuminuria respectively, and 0.1% had kidney failure (eGFR &lt; 15 mL/min/1.73 m 2 ). CKD risk increased significantly with age; the odds ratio increased more than two folds among subjects aged 50-69 years, with no sex-specific difference. CKD was higher among subjects with primary education. Hypertension and diabetes were associated with more than 3-fold and 4-fold higher risk of CKD [adjusted odd ratio (95%CI): 3.11 (1.76, 5.52); P&lt;0.001] and [adjusted odd ratio (95%CI): 4.69 (2.35, 9.36), P&lt;0.001] respectively. Increased physical activity measured as total MET-hour/week was independently associated with a lower odd of CKD (P=0.035). Conclusion: The prevalence estimate of CKD in Luxembourg may represent a neglected public health issue, stressing the benefit of early detection of CKD, particularly in subjects with hypertension, diabetes, lipid disorders and obesity. Promoting physical activity among these high-risk subjects should be considered to prevent CKD. These measures altogether could defray costs related to eventual complications and decrease risk of associated cardiovascular events.
Obesity Negatively Impacts Outcome in Female Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Fludarabine, Cyclophosphamide and Rituximab (FCR): An Analysis of Three Phase III Studies of the German CLL Study Group (GCLLSG)
Authors: Moritz Fürstenau, Georg Hopfinger, Sandra Robrecht, Anna-Maria Fink, Othman Al-Sawaf, Petra Langerbeins, Paula Cramer, Julia Von Tresckow, Christian Maurer, Nadine Kutsch, Manuela Hoechstetter, Martin Dreyling, Elisabeth Lange, Michael Kneba, Stephan Stilgenbauer, Hartmut Döhner, Manfred Hensel, Michael G. Kiehl, Ulrich Jaeger, Clemens-Martin Wendtner, Valentin Goede, Kirsten Fischer, Michael Hallek, Barbara Eichhorst, Sebastian Theurich
Journal: Blood (2018)
Abstract 12894: P-Wave Centric Patch Monitors May Reduce Need for Implantable Monitors Following Cryptogenic Stroke
Authors: Jared A Collins, Matthew L Ortman, John A Andriulli, Andrea M Russo
Journal: Circulation (2018)

Introduction: Cryptogenic stroke may be caused by subclinical atrial fibrillation (AF) or atrial flutter (AFL). Atrial arrhythmias may be subsequently diagnosed by external monitoring or implantabl...
Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort
Authors: Erik L. Bao, Caleb A. Lareau, Carlo Brugnara, Isabel R. Fulcher, Caroline Barau, Stephane Moutereau, Anoosha Habibi, Bouchra Badaoui, Jugurtha Berkenou, Pablo Bartolucci, Frédéric Galactéros, Orah S. Platt, Michael Mahaney, Vijay G. Sankaran
Journal: American Journal of Hematology (2019)

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family‐based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family‐based studies to better understand modifiers of SCD.
First-in-human phase I and pharmacokinetic study of DTS-108 in patients with advanced carcinomas.
Authors: Romain Coriat, Sandrine J. Faivre, Chantal Dreyer, Olivier Mir, Mohamed Bouattour, Francois Goldwasser, Eric Raymond
Journal: Journal of Clinical Oncology (2012)

2557 Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite of irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, while reducing diarrhea. Methods: This trial identified the pharmacokinetics, the adverse event (AE) profile (NCI-CTCv3 criteria), the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas, ECOG:0-1, and adequate hepatic, marrow, and kidney functions. Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416 mg/m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). Grade 3 diarrhea was only reported in two pts with either partial bowel obstruction or recent history of a total colectomy. Neutropenia was the dose limiting toxicity of DTS-108. Neutropenia started to be observed at doses &gt;56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Infusion related reactions (itching urticaria) were observed with increasing frequency and severity at doses &gt;75 mg/m2 and required antihistamine premedications. At 313 mg/m2 and 416 mg/m2, infusion skin reactions were 2/6 pts and 6/6 pts, respectively. Fluorescence HPLC was initially used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this method showed that SN38 values were inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUC INF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. Conclusions: DTS induced neutropenia and infusion skin reactions but no dose-limiting diarrhea. The MTD was 416 mg/m2 and the RD was 313 mg/m2 q2w.
Deficiency of Both Farnesoid X Receptor and Takeda G Protein–Coupled Receptor 5 Exacerbated Liver Fibrosis in Mice
Authors: Jessica M. Ferrell, Preeti Pathak, Shannon Boehme, Tricia Gilliland, John Y. L. Chiang
Journal: Hepatology (2019)

Activation of the nuclear bile acid receptor farnesoid X receptor (FXR) protects against hepatic inflammation and injury, while Takeda G protein–coupled receptor 5 (TGR5) promotes adipose tissue browning and energy metabolism. Here, we examined the physiological and metabolic effects of the deficiency of these two bile acid receptors on hepatic metabolism and injury in mice. Fxr/Tgr5 double knockout mice (DKO) were generated for metabolic phenotyping. Male DKO mice fed a chow diet had reduced liver lipid levels but increased serum cholesterol levels. Liver cholesterol 7α‐hydroxylase ( Cyp7a1 ) activity and sterol 12α‐hydroxylase mRNA levels were induced, while ileum FXR target genes were suppressed in DKO mice compared to wild‐type (WT) mice. Bile acid pool size was increased in DKO mice, with increased taurocholic acid and decreased tauromuricholic acids. RNA sequencing analysis of the liver transcriptome revealed that bile acid synthesis and fibrosis gene expression levels are increased in chow‐fed DKO mice compared to WT mice and that the top regulated pathways are involved in steroid/cholesterol biosynthesis, liver cirrhosis, and connective tissue disease. Cholestyramine treatment further induced Cyp7a1 mRNA and protein in DKO mice and increased bile acid pool size, while cholic acid also induced Cyp7a1 in DKO mice, suggesting impaired bile acid feedback regulation. A Western diet containing 0.2% cholesterol increased oxidative stress and markers of liver fibrosis but not hepatic steatosis in DKO mice. Conclusion: FXR and TGR5 play critical roles in protecting the liver from inflammation and fibrosis, and deficiency of both of these bile acid receptors in mice increased cholic acid synthesis and the bile acid pool, liver fibrosis, and inflammation; FXR and TGR5 DKO mice may be a model for liver fibrosis.
Crizotinib in Advanced ALK+ Anaplastic Large Cell Lymphoma in Children and Adults: Results of the Acs© Phase II Trial
Authors: Laurence Brugières, Roch Houot, Nathalie Cozic, Christelle De La Fouchardière, Franck Morschhauser, Pauline Brice, Nina Arakelyan Laboure, Anne Auvrignon, Nathalie Aladjidi, Brigitte Kolb, Laurence Blanc, Anne Pagnier, Julia Arfi-Rouche, Anne Ségolène Cottereau, Céline Ait Oukhatar, Natalie Hoog Labouret, Gilles Vassal
Journal: Blood (2017)
Legal and Policy Challenges to Addressing Cognitive Impairment in Federal Officials
Authors: Jalayne J. Arias, Melanie L. Stephens, Gil D. Rabinovici
Journal: JAMA Neurology (2019)

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Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses
Authors: Antoine Besnard, Yuan Gao, Michael TaeWoo Kim, Hannah Twarkowski, Alexander Keith Reed, Tomer Langberg, Wendy Feng, Xiangmin Xu, Dieter Saur, Larry S. Zweifel, Ian Davison, Amar Sahay
Journal: Nature Neuroscience (2019)