tbuckley/cabot-search huggingface dataset:
Piercing Fishes: Porin Expansion and Adaptation to Hematophagy in the Vampire Snail Cumia reticulata
Authors: Marco Gerdol, Manuela Cervelli, Marco Oliverio, Maria Vittoria Modica
Journal: Molecular Biology and Evolution (2018)

Cytolytic pore-forming proteins are widespread in living organisms, being mostly involved in both sides of the host-pathogen interaction, either contributing to the innate defense or promoting infection. In venomous organisms, such as spiders, insects, scorpions, and sea anemones, pore-forming proteins are often secreted as key components of the venom. Coluporins are pore-forming proteins recently discovered in the Mediterranean hematophagous snail Cumia reticulata (Colubrariidae), highly expressed in the salivary glands that discharge their secretion at close contact with the host. To understand their putative functional role, we investigated coluporins' molecular diversity and evolutionary patterns. Coluporins is a well-diversified family including at least 30 proteins, with an overall low sequence similarity but sharing a remarkably conserved actinoporin-like predicted structure. Tracking the evolutionary history of the molluscan porin genes revealed a scattered distribution of this family, which is present in some other lineages of predatory gastropods, including venomous conoidean snails. Comparative transcriptomic analyses highlighted the expansion of porin genes as a lineage-specific feature of colubrariids. Coluporins seem to have evolved from a single ancestral porin gene present in the latest common ancestor of all Caenogastropoda, undergoing massive expansion and diversification in this colubrariid lineage through repeated gene duplication events paired with widespread episodic positive selection. As for other parasites, these findings are congruent with a "one-sided arms race," equipping the parasite with multiple variants in order to broaden its host spectrum. Overall, our results pinpoint a crucial adaptive role for coluporins in the evolution of the peculiar trophic ecology of vampire snails.
Abstract 17598: More Than One in Five Older Veterans are Hospitalized for Bleeding Following Initiation of Warfarin for Atrial Fibrillation
Authors: John A Dodson, Andrew Petrone, David Gagnon, Mary E Tinetti, Harlan M Krumholz, J. Michael Gaziano
Journal: Circulation (2015)

Introduction: Clinicians are hesitant to prescribe oral anticoagulants to older adults with atrial fibrillation (AF) due to concerns over bleeding risk. Hypothesis: As many data on bleeding events are from trials of rigorously selected patients, we hypothesized that major bleeding events (requiring hospitalization) would be more common than previously reported. Methods: We created a retrospective cohort of 31,951 Veterans with AF aged ≥75 years who were new referrals to VA anticoagulation clinics (warfarin) from 1/1/02 - 12/31/12. Patients with comorbid conditions requiring warfarin (e.g. pulmonary embolus) were excluded. Data were extracted from the VA electronic medical record and linked with Medicare claims data for subsequent hospitalizations. The primary outcome was any hospitalization for bleeding. We identified bleeding subtypes by source, and compared characteristics of patients with and without bleeding hospitalizations. Results: Mean population age was 81.1 years, 98.1% were male, and 8.4% were nonwhite. Over a median follow-up period of 2.62 years, 7288 patients (22.8%) were hospitalized for bleeding. There were 12,004 total bleeding events; overall, 980 (13.4%) patients experienced multiple events. The most common bleeding sources (first event) were gastrointestinal (50.8%), genitourinary (21.6%), and intracranial (9.4%) (Figure). The median time to first bleeding event was 1.59 years. Patients hospitalized for bleeding were more likely to have coronary disease (48.4% vs. 40.9%, P&lt;0.01); COPD (28.4% vs. 24.7%, P&lt;0.01); chronic kidney disease (17.8% vs. 16.0%, P&lt;0.01); CHF (34.7% vs. 29.5%, P&lt;0.01), and labile INR (63.3% vs. 53.7%, P&lt;0.01). The rate of hospitalization for stroke over the same time period was 5.0%. Conclusions: After initiating warfarin, over one in five older Veterans are hospitalized for bleeding, most commonly from a gastrointestinal source. Comorbidity burden and labile INR place these patients at increased risk.
Abstract 11008: Ezetimibe Enhances Macrophage Reverse Cholesterol Transport in Hamsters Independent of Transintestinal Cholesterol Efflux Pathway
Authors: Tomohiro Komatsu, Makoto Ayaori, Harumi Uto-Kondo, Makiko Yogo, Makoto Sasaki, Shunichi Takiguchi, Emi Yakushiji, Masatsune Ogura, Yasuhiro Endo, Kazuhiro Nakaya, Katsunori Ikewaki
Journal: Circulation (2013)

Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. RCT fr...
Modulation of Nociception in Multiple Brain Systems—The Strain in Pain
Authors: David Spiegel
Journal: JAMA Neurology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Underutilization of Combined-Modality Therapy in Limited-Stage Small Cell Lung Cancer
Authors: Sara R. Alcorn, David B. Miller, Russell K. Hales
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 4355: Identification and functional characterization of glioma structural variants
Authors: Kevin C. Johnson, Floris P. Barthel, Ming Tang, Samirkumar Amin, Qianghu Wang, Erik P. Sulman, Kunal Rai, Roel G.W Verhaak
Journal: Cancer Research (2018)

Abstract Adult diffuse gliomas are a diverse class of brain tumors that ultimately result in fatal malignant progression. The highly variable disease progression intervals and poor treatment response observed in glioma have been explained, in part, by the extent of heterogeneity within and across gliomas. Somatic structural variants such as deletions, duplications, insertions, inversions, translocations, and extrachromosomal DNA contribute to glioma heterogeneity by generating genomic instability, a hallmark of cancer genomes. While comprehensive approaches such as whole genome sequencing have begun to catalog the glioma structural variant landscape, the molecular mechanisms by which they contribute to tumor progression remains poorly understood. Here, we identified genomic rearrangements in the whole genomes of 147 gliomas and glioma cell lines. Among the whole-genome sequencing samples were 62 glioblastomas (TCGA), 52 low-grade gliomas (TCGA), and our own set of 33 patient-derived glioma sphere-forming cells. On average, glioblastomas demonstrated a greater frequency of high-confidence structural variants (162 per tumor) than low-grade gliomas (130 per tumor, P=0.02) with two glioblastomas displaying evidence of chromothripsis. Across the World Heath Organization's molecular classifications, the IDH-mutant 1p/19q co-deleted tumors demonstrated the lowest structural variant burden when compared with both IDH-wildtype and IDH-mutant non-co-deleted tumors. Structural variant frequencies were found to be similar between patient tumors and an independent set of patient-derived cell lines. Across all samples, a majority of the structural variant breakpoints were found in intronic (42%) and intergenic regions (55%) suggesting that rearrangements predominantly impact distal regulatory regions. To investigate the functional consequences of structural variants in these regions we integrated these samples with available RNA-sequencing and epigenetic data to characterize deregulated transcriptional circuits. Analyses examining the association between genomic rearrangements and chromatin states to determine potential mechanisms of oncogene activation in select tumor and cell line samples are now underway. Together, our study demonstrates the importance of integrating structural variant calls from whole genome sequencing with expression and epigenetic data to define functional genomic rearrangements. Citation Format: Kevin C. Johnson, Floris P. Barthel, Ming Tang, Samirkumar Amin, Qianghu Wang, Erik P. Sulman, Kunal Rai, Roel G.W Verhaak. Identification and functional characterization of glioma structural variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4355.
Abstract 3300: Network analysis of the human protein-protein interactome: Tumorigenic signaling mechanisms
Authors: Diana Murray, Kamrun N. Begum, Andrea Califano, Barry Honig
Journal: Cancer Research (2018)

Abstract The dysregulated signaling responsible for tumor cell state implementation and maintenance has been shown to be mediated by the concerted action of master regulator (MR) proteins. Highly connected MR protein modules serve as “tumor checkpoints” by translating upstream genetic alterations into aberrant protein activity that drives pathophysiological cellular phenotypes. Direct pathways for information flow among MR proteins, and between individual MR proteins and their upstream modulators and downstream effectors, are largely unknown. The Prediction of Protein-Protein Interactions (PrePPI) database contains 1.4M predictions for ~85% of the human proteome; of these, ~300K are predicted to be physical, i.e. direct one-to-one, interactions.We apply network analysis concepts, as implemented in the R package igraph, to the PrePPI interactome to predict structural mechanisms underlying tumorigenic signal transduction. Shortest path and random walk with restart algorithms elucidate 1) physical interactions between MR proteins, 2) physical interactions that connect MR proteins that do not directly bind to each other, 3) upstream signaling proteins with recurrent and patient-specific mutations that physically interact with MR proteins, and 4) downstream cofactors and transcription factors that may be involved in effecting a dysregulated phenotype.Our analysis predicts that physical interactions fully connect BACH2, BCL6, IRF8, and SPIB, established germinal center MR proteins. 1) BACH2 and BCL6 are predicted to interact directly through their BTB/POZ domains; BTB domains are known to mediate heterodimeric protein-protein interactions. 2) Additional proteins, including IBTK, ANFY1, PAX7, ZEB1, GABPB1/B2, connect SPIB to BACH2 and to BCL6, in some cases through ankyrin repeats, which are structural protein-protein interaction motifs. Several of the PrePPI-predicted proteins, e.g. IBTK, ZEB1, GABP, have previously been implicated in B-cell biology. The possible implications of our analyses for a wide range of MR proteins modules will be presented.The computational prediction of physical protein-protein interactions within the regulatory architecture of a tumor cell is a powerful approach to discovering novel tumorigenic signaling mechanisms, formulating specific experimentally testable hypotheses of function, including compound mechanisms of action, and prioritizing novel drug targets. Citation Format: Diana Murray, Kamrun N. Begum, Andrea Califano, Barry Honig. Network analysis of the human protein-protein interactome: Tumorigenic signaling mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3300.
Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis
Authors: Hiroyuki Nakamura, Sanae Shimamura, Shinsuke Yasuda, Michihito Kono, Michihiro Kono, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tomohiro Shimizu, Norimasa Iwasaki, Tatsuya Atsumi
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Rheumatoid arthritis (RA) is an autoimmune polyarthritis, in which fibroblast-like synoviocytes (FLS) play a key role in cartilage and bone destruction through tumour-like proliferation and invasiveness. Considering still unsatisfactory remission rate in RA even under treatment with biological disease-modifying antirheumatic drugs, novel therapeutic strategy for treatment-resistant RA is still awaited. In this study, we analysed the expression and function of Ras guanine nucleotide-releasing proteins (RASGRPs), guanine exchange factors for small GTPase Ras, in FLS as a potential therapeutic target for RA. Methods The expression of RASGRPs mRNA was quantified by a real-time PCR assay in FLS isolated from synovial tissue samples. RASGRP2 protein was also evaluated immunohistochemically. Then, we transiently transfected FLS with RASGRP2 expression vector and assessed their proliferation, adhesion, migration and invasion by cellular functional assays and downstream signalling activation using immunoblot. Finally, the therapeutic effect of RASGRP2 silencing was evaluated in type-II collagen-induced arthritis rats. Results RASGRP2 was abundantly expressed in FLS from RA synovium, whereas scarcely found in those from osteoarthritis. Expression of RASGRP2 in RA-FLS was enhanced by transforming growth factor-beta. RASGRP2 activated RAP-1, subsequently affecting nuclear factor kappa-light-chain-enhancer of activated B cells pathway and actin dynamics in FLS. RASGRP2-overexpressed FLS had increased abilities of adhesion, migration and interleukin (IL)-6 production. Silencing of RASGRP2 using the intra-articular injection of Rasgrp2 -specific siRNAs dampened experimental arthritis in rats by inhibiting pannus formation. Conclusions RASGRP2 was identified to be involved in the pathogenesis of RA by promoting adhesion, migration and IL-6 production from FLS, proposed as a potential novel non-immunosuppressive therapeutic target for RA.
Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure
Authors: OliverZolk, JessikaQuattek, GerhardSitzler, ThomasSchrader, GeorgNickenig, PetraSchnabel, KoheiShimada, MasaakiTakahashi, MichaelBöhm
Journal: Circulation (1999)

Background—Elevated plasma levels of endothelin (ET)-1 have been reported in association with heart diseases, including heart failure. Furthermore, it has been suggested that ET-1 acts as a local autocrine/paracrine factor with biological activities such as vasoconstriction, mitogenesis, and inotropic effects on the heart. This study investigated alterations of ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in left ventricular myocardium from patients with end-stage heart failure. Methods and Results—mRNA concentrations of ETA and ETB receptors, prepro-ET-1 (ppET-1), and ECE in left ventricles from nonfailing donors hearts (NF) and from patients with end-stage chronic heart failure (NYHA functional class IV) due to dilated cardiomyopathy (DCM) were compared by use of a competitive reverse transcription–polymerase chain reaction technique. There was no significant difference in mRNA expression for ppET-1, ECE-1, and ETA receptors, whereas a significant reduction of ETB-receptor mRNA w...
Abstract 2623: CHP-IL12 combined with surgery suppresses tumor metastasis and prolongs survival
Authors: Qingnan Zhao, Jiemiao Hu, Jeffry J. Cutrera, Abhisek Mitra, Xueqing Xia, Shulin Li
Journal: Cancer Research (2018)

Abstract Interleukin 12 (IL-12) is the most promising cytokine for treating tumors by itself or arming immunogenic cells but its toxicity and moderate response limit its clinical use. To avoid or minimize the toxicity issue and boost the anti-tumor immune response, our lab has discovered a comprehensive tumor-targeting carcinoma homing peptide (CHP). Fusion of this peptide encoding DNA sequence to IL12 encoding sequence in frame yields the proprietary product—CHP-IL12 (US patent 9,657,077 B2), or tumor-targeting IL12, which increased the accumulation of IL12 in tumor environment and decreased liver toxicity compared to wild-type IL12 (wt-IL12) gene therapy. Here, we report the therapeutic efficacy of this CHP-IL12 on metastasis and to comprehend the underlying mechanism description between CHP-IL12 and wildtype (wt)-IL12 for boosting anti-tumor response, two orthotopic and spontaneous tumor metastasis models (one adult and one pediatric tumor) were utilized. CHP-IL12 gene therapy showed greater efficacy in controlling growth of established tumors compared to wt-IL12. CHP-IL12 gene therapy, in combination with surgery, reduced number of metastatic nodules in lungs, livers and bones. CHP-IL12, compared to wt-IL12, conferred a potential immunostimulatory effect involving 1) reduction of T-reg cells, myeloid-derived suppressor cells (MDSC) and tumor associated macrophages (TAM); 2) recruitment of activated CD8+ T cells to the tumor. Moreover, CHP-IL12 increased IL12, IFNγ level in tumor environment and decreased IL12, IFNγ level in serum, which is the major cause of toxicity. Furthermore, in combination with surgery, CHP-IL12 gene therapy led to long-term survival and enhanced immunological memory development of tumor bearing mice compared to wt-IL12 gene therapy. These results collectively indicate that CHP-IL12 fusion gene therapy coupled with surgery has a powerful potency in inhibition of tumor metastasis and prolonging survival and a low potency in inducing toxicity. Therefore, CHP-IL12 fusion gene therapy in combination with surgery may translate into clinic as a promising anti-tumor strategy for both adult and pediatric tumors. Citation Format: Qingnan Zhao, Jiemiao Hu, Jeffry J. Cutrera, Abhisek Mitra, Xueqing Xia, Shulin Li. CHP-IL12 combined with surgery suppresses tumor metastasis and prolongs survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2623.
Abstract 1099: Molecular drivers of neutrophil recruitment to primary non-small cell lung cancer
Authors: Claire Wang, Roni Rayes, Jack Mouhanna, Betty Giannias, Arvind Chandrasekaran, Rachel Mot, Christopher Moraes, Sidong Huang, Jonathan Cools-Lartigue, Nicholas Bertos, Lorenzo Ferri, Jonathan Spicer
Journal: Cancer Research (2018)

Abstract Neutrophils are associated with developing cancer lesions and are the main immune component of primary non-small cell lung cancer (NSCLC). Multiple studies support the notion that tumor associated neutrophils (TANs) can promote tumor progression. We hypothesize that there is a hierarchy of molecular cues produced by developing lung cancers that guide circulating neutrophils to infiltrate the tumor microenvironment and become TANs. Identifying these cues may permit modulation of neutrophil infiltration within developing lung cancers and may thereby act as an immunotherapeutic tool to suppress cancer progression and improve response to existing therapeutics. To this end, we profiled 5 established NSCLC cell lines representing the common NSCLC subtypes using a qRT-PCR 84 gene panel (A549; KRAS mutant, PC9; EGFR mutant, H1993; MET amplification, H3122; EML4-ALK translocation, HCC78; ROS1 translocation). We focused on 4 of the most commonly upregulated genes in all cell lines, which were osteopontin (Spp1), vascular endothelial growth factor A (VEGF-A), macrophage inhibitory factor (MIF), and C-X-C motif ligand 1 (CXCL1). After confirming protein expression of these targets by western blot, we performed shRNA knock down (KD) of these genes and tested the migration of neutrophils towards treated and control cell lines in a novel microfluidic device that allows increased throughput studies of neutrophil attractants. Findings from KD experiments were confirmed via antibody-mediated inhibition. We observed a 3-fold increase of neutrophil migration to the A549 cancer cell line compared to the serum free control (p=0.0265). Furthermore, this increase was inhibited in Spp1 (64% decrease), MIF (84%), VEGF (82%) KDs and their corresponding neutralizing antibodies. We have therefore identified 4 proteins that play a key role in neutrophil recruitment to NSCLC cell lines in vitro and have demonstrated the application of a simple microfluidic device to test neutrophil migration patterns. This data provides the basis for in vivo investigations to elucidate the key molecular cues for neutrophil infiltration within developing lung cancers. Citation Format: Claire Wang, Roni Rayes, Jack Mouhanna, Betty Giannias, Arvind Chandrasekaran, Rachel Mot, Christopher Moraes, Sidong Huang, Jonathan Cools-Lartigue, Nicholas Bertos, Lorenzo Ferri, Jonathan Spicer. Molecular drivers of neutrophil recruitment to primary non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1099.