tbuckley/cabot-search huggingface dataset:
Abstract MP62: Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels
Authors: Zhe Wang, Han Chen, Daniel I Chasman, Ching-Ti Liu, Raymond Noordam, Eric Boerwinkle, Alanna C Morrison
Journal: Circulation (2018)

Introduction: Alcohol intake modifies plasma lipid levels and such effects may be modulated by genetic variants. We use emerging statistical methods that extend well-established common variant approaches to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: Up to 247,870 exonic variants on the Illumina HumanExome BeadChip and fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 46,443 European Americans from 4 studies (the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study, the Netherlands Epidemiology of Obesity Study and the Women’s Genome Health Study) of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Using the gene-based rareGE method, we conducted exome-wide gene-environment (GxE) tests with genetic main effects estimated as fixed and random effects, and a joint analysis of genetic main and GxE interaction effects. Rare and low-frequency (minor allele frequency ≤ 5%) functional variants, (i.e. frameshift, nonsynonymous, stop/gain, stop/loss, and splicing) were aggregated by genes. Two dichotomous self-reported alcohol consumption variables, current drinker (at least 1 drink per week, yes/no) and regular drinker (at least 2 drinks per week, yes/no) were considered. A sample size weighted Z-test (weighted Stouffer’s method) was used to meta-analyze study-specific p -values. Exome-wide significance level was set at p &lt; 3.7*10 -6 (0.05/13368 genes), using a Bonferroni procedure to correct for multiple testing. Results: We identified 24 gene-lipid associations at 13 known lipid loci (within 500kb) harboring rare and low-frequency variants through the joint analysis. In ARIC, numerous genes ( PCSK9, LPL, LIPG, ANGPTL4, APOB, APOC3-A5 ) remained significant after conditioning on common index single nucleotide polymorphisms (SNPs), suggesting an independent role for rare variants at loci highlighted by previous genome-wide association studies. However, no significant gene-alcohol interactions were observed with rare and low-frequency variants on TG, HDL-c or LDL-c. Conclusion: This study applied new statistical approaches to investigate the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels. Results show promise for other larger scale studies analyzing rare variant GxE interactions.
Review of the impact of MALDI-TOF MS in public health and hospital hygiene, 2018
Authors: Belén Rodríguez-Sánchez, Emilia Cercenado, Alix T. Coste, Gilbert Greub
Journal: Eurosurveillance (2019)

IntroductionMALDI-TOF MS represents a new technological era for microbiology laboratories. Improved sample processing and expanded databases have facilitated rapid and direct identification of microorganisms from some clinical samples. Automated analysis of protein spectra from different microbial populations is emerging as a potential tool for epidemiological studies and is expected to impact public health.AimTo demonstrate how implementation of MALDI-TOF MS has changed the way microorganisms are identified, how its applications keep increasing and its impact on public health and hospital hygiene.MethodsA review of the available literature in PubMED, published between 2009 and 2018, was carried out.ResultsOf 9,709 articles retrieved, 108 were included in the review. They show that rapid identification of a growing number of microorganisms using MALDI-TOF MS has allowed for optimisation of patient management through prompt initiation of directed antimicrobial treatment. The diagnosis of Gram-negative bacteraemia directly from blood culture pellets has positively impacted antibiotic streamlining, length of hospital stay and costs per patient. The flexibility of MALDI-TOF MS has encouraged new forms of use, such as detecting antibiotic resistance mechanisms (e.g. carbapenemases), which provides valuable information in a reduced turnaround time. MALDI-TOF MS has also been successfully applied to bacterial typing.ConclusionsMALDI-TOF MS is a powerful method for protein analysis. The increase in speed of pathogen detection enables improvement of antimicrobial therapy, infection prevention and control measures leading to positive impact on public health. For antibiotic susceptibility testing and bacterial typing, it represents a rapid alternative to time-consuming conventional techniques.
A novel patient derived orthotopic xenograft model of gastro-esophageal junction cancer: Key platform for translational discoveries.
Authors: Omkara Lakshmi Veeranki
Journal: Journal of Clinical Oncology (2019)

64 Background: Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. Current GEJ models have limited applications in tumor microenvironment, immune oncology and metastatic studies. Methods: A novel patient derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via surgical implantation. Patient tumor was compared to subcutaneously implanted PDX and PDOX by H&amp;E, IHC, and next generation sequencing (T200.1 panel). Drug efficacy studies of 5-flurouracil with and without radiotherapy are being performed. Results: Mechanical abrasion of mouse GEJ prior to implantation of patient derived tumor in situ promotes tumor engraftment (100%, n = 6). Complete PDOX engraftment was observed with rapid intra and extra luminal tumor growth as evidenced by MRI. Patient derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Next generation sequencing with the T200.1 revealed that the loss of heterozygosity of NOTCH3, TGFβ1, EZH2, and MLL3 are maintained with similar allelic frequency between the patient tumor and the xenografts. Additional somatic SNVs such as ARID1A, NSD1 (CDS157-158), NSD1 (CDS158-159), KDM6A, XPO1, MAPK1 and EGFR were found to be acquired in xenograft tumor tissues that were not observed in patient tumor. Drug and radiation efficacy studies are ongoing, tumor response to radiation was observed. Conclusions: A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating to clinics. This model can be applied to address importance of tumor microenvironment in metastatic and immunological studies, and to develop novel therapeutic approaches for the treatment of GEJ cancer.
Abstract 18277: Role of Local Low Endothelial Shear Stress in Coronary Microvascular and Epicardial Endothelial Dysfunction in Patients With Non-obstructive Coronary Atherosclerosis
Authors: Gerasimos Siasos, Jaskanwal D Sara, Marina Zaromytidou, Kyoung H Park, Ahmet U Coskun, Lilach O Lerman, Evangelos Oikonomou, Dimitrios Fotiadis, Kostas Stefanou, Michail Papafaklis, Lambros Michalis, Charles Feldman, Amir Lerman, Peter H Stone
Journal: Circulation (2017)

Introduction: Local hemodynamic factors are important determinants of atherosclerotic plaque development and progression. Hypothesis: Low endothelial shear stress (ESS) is associated with epicardia...
Resection of primary tumor in liver only metastatic midgut neuroendocrine tumors.
Authors: Nicholas Manguso, Jaewon Lee, Andrew Eugene Hendifar, Richard Tuli, Alexandra Gangi
Journal: Journal of Clinical Oncology (2019)

446 Background: Surgical management of metastatic midgut neuroendocrine tumors (NET) remains controversial. Resection of primary tumor only without liver resection is advocated only in select patients, frequently for palliation. Additionally, no standard algorithm exists, and the risk profile for these patients is not well documented in the literature. We evaluated these midgut NETs with liver metastasis in the National Cancer Data Base (NCDB) to determine if resection of the primary tumor only affected survival outcomes. Methods: The NCDB was queried to identify patients with liver only metastatic midgut NET tumors between 2010 and 2015. Patients who underwent surgery of their liver metastasis were excluded. The cohort was separated into two groups, those who underwent resection of the primary tumor and those who did not. Patient demographics, year of diagnosis, clinicopathologic tumor characteristics and Charlson/Deyo comorbidity index were compared among the two groups. The primary outcome was overall survival (OS). Kaplan-Meier estimates were used to predict OS. Results: One-thousand nine hundred fifty-two patients with median age of 63 were identified. Median tumor size was 2.4 cm. Of these, 1,295 (66.0%) patients underwent resection of the primary tumor and 667 (34.0%) did not. Patients undergoing resection were younger (median age 63 vs. 65, p &lt; 0.001) and had smaller tumors (median 2.3 cm vs. 3.0 cm, p &lt; 0.001). There was no difference between the groups with respect to sex, year of diagnosis or Charlson/Deyo Comorbidity Score. Median follow up time was 42.8 months (IQR 29.7). A total of 483 deaths occurred in the entire cohort with a 5-year OS of 60.8%. The 5-year OS for patients undergoing resection of the primary tumor was 65.9% and 49.3% for those not undergoing resection (p &lt; 0.001). Conclusions: Patients with liver only metastatic midgut neuroendocrine tumors had an overall survival advantage when the primary tumor was resected. Patients with liver only metastatic midgut NET may benefit from surgical resection and should be evaluated for surgery at the time of diagnosis.
Syncope in a Patient With Wolff-Parkinson-White Pattern
Authors: Bryce Alexander, Sohaib Haseeb, Adrian Baranchuk
Journal: JAMA Internal Medicine (2019)

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 Internal Medicine 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 Internal Medicine journal
The hyperprogressive disease during nivolumab treatment or irinotecan treatment in patients with advanced gastric cancer.
Authors: Masahiko Aoki, Hirokazu Shoji, Hiroshi Imazeki, Takahiro Miyamoto, Hidekazu Hirano, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Atsuo Takashima, Ken Kato, Narikazu Boku
Journal: Journal of Clinical Oncology (2019)

124 Background: Nivolumab has demonstrated a survival benefit as a single agent in patients with advanced gastric cancer (AGC) refractory to, or intolerant of, two or more previous regimens in phase III study (ATTRACTION-2). However, an acceleration of tumor growth during immunotherapy, (hyperprogressive disease: HPD), was reported in advanced cancers treated with immunotherapy. The frequency and outcome of HPD in AGC comparing between immunotherapy and cytotoxic agents are little known. The aim of this study was to clarify the prevalence and background of HPD in patients treated with nivolumab or irinotecan. Methods: The subjects of this retrospective study were AGC patients with measurable disease defined by RECIST version 1.1 who were treated with nivolumab or irinotecan at our institution between June 2009 and September 2018, and whose tumors were assessed at least 3 times (during prior therapy, immediately before and after initiating nivolumab or irinotecan). The tumor growth rates (TGR) both before and after nivolumab or irinotecan were calculated as reported (Stéphane Champiat, Clin Cancer Res 2017). HPD was defined as an increase in the TGR exceeding 50% after nivolumab or irinotecan compared with prior therapy. Results: 32 and 66 patients received nivolumab and irinotecan (20 patients received both irinotecan and nivolumab). There were more prior chemotherapy before nivolumab than irinotecan (median: 3 vs 2). The median overall survival (MST) was 4.1 months (95%CI; 4.6-9.3 months) after nivolumab, and 7.0 months (95%CI; 6.3-9.3 months) after irinotecan. There were 9 patients showing HPD (28.1%) after initiating nivolumab and 9 patients (13.5%) after irinotecan (p = 0.0824). There were no differences in background between patients with and without HPD either after nivolumab or irinotecan. 9 patients with HPD showed shorter survival than those without HPD after nivolumab (median: 1.9 vs 6.4 months, p = 0.0007) while there was no such difference after irinotecan (median: 7.3 vs 7.0 months, p = 0.3345). Conclusions: HPD was observed more frequently after initiating nivolumab compared with irinotecan, and was associated with a poor prognosis after nivolumab but not after irinotecan.
Effect of Lanadelumab on Coagulation Parameters in Patients With Hereditary Angioedema: Findings From The Phase 3 HELP Study
Authors: Alvin H. Schmaier, Kenneth A. Bauer, Marco Cicardi, Jacques Hebert, Douglas T. Johnston, Paula J. Busse, Kim Paes, Daniel J. Sexton, Jon Kenniston, Christina Nurse, Rafael H. Zaragoza
Journal: Journal of Allergy and Clinical Immunology (2019)
Undetectable-Minimal Residual Disease (U-MRD6) (10-6 sensitivity) Is Associated with Best Progression-Free Survival for Patients Who Achieve Bone Marrow Undetectable MRD4 (10-4 sensitivity) with First-Line FCR
Authors: Philip A. Thompson, Jaya Srivastava, Paolo Strati, Jeffrey L. Jorgensen, Joyce Breaker, Tyler Hether, Michael J Keating, Susan M. O'Brien, Alessandra Ferrajoli, Jan A. Burger, Zeev E. Estrov, Nitin Jain, William G. Wierda
Journal: Blood (2018)
A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma
Authors: Michael Fricker, Peter G. Gibson, Heather Powell, Jodie L. Simpson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James, Christine Jenkins, Matthew J. Peters, Guy B. Marks, Melissa Baraket, Katherine J. Baines
Journal: Journal of Allergy and Clinical Immunology (2019)
Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome
Authors: John‐Paul Berauer, Anya I. Mezina, David T. Okou, Aniko Sabo, Donna M. Muzny, Richard A. Gibbs, Madhuri R. Hegde, Pankaj Chopra, David J. Cutler, David H. Perlmutter, Laura N. Bull, Richard J. Thompson, Kathleen M. Loomes, Nancy B. Spinner, Ramakrishnan Rajagopalan, Stephen L. Guthery, Barry Moore, Mark Yandell, Sanjiv Harpavat, John C. Magee, Binita M. Kamath, Jean P. Molleston, Jorge A. Bezerra, Karen F. Murray, Estella M. Alonso, Philip Rosenthal, Robert H. Squires, Kasper S. Wang, Milton J. Finegold, Pierre Russo, Averell H. Sherker, Ronald J. Sokol, Saul J. Karpen
Journal: Hepatology (2019)

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.
Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity
Authors: María Martínez-López, Salvador Iborra, Ruth Conde-Garrosa, Annalaura Mastrangelo, Camille Danne, Elizabeth R. Mann, Delyth M. Reid, Valérie Gaboriau-Routhiau, Maria Chaparro, María P. Lorenzo, Lara Minnerup, Paula Saz-Leal, Emma Slack, Benjamin Kemp, Javier P. Gisbert, Andrzej Dzionek, Matthew J. Robinson, Francisco J. Rupérez, Nadine Cerf-Bensussan, Gordon D. Brown, David Bernardo, Salomé LeibundGut-Landmann, David Sancho
Journal: Immunity (2019)
Dissecting the spatial heterogeneity of single circulating tumor cells reveals immune evasion through MAX regulated CCL5 overexpression in hepatocellular carcinoma.
Authors: Yun-Fan Sun, Xin-Rong Yang, Fan Jia
Journal: Journal of Clinical Oncology (2019)

246 Background: The transcriptional heterogeneity and immune evasion mechanisms of CTCs during systemic circulation are not well defined. Methods: Blood was drawn from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) of 10 localized HCC patients. Single CTCs were isolated by negative enrichment and robotic micromanipulator, followed by single-cell RNA-sequencing (sc-RNAseq). After filtering, 113 CTCs with qualified data remained were subjected to further bioinformatics analysis. The scRNA-seq results were further validated in three independent cohorts of HCC patients. Results: Our scRNA-seq data revealed remarkable intra- and inter-vascular heterogeneity among CTCs from four vascular sites. We determined CTC transcriptional dynamics during transportation through consecutive vascular compartments and revealed their adaptation mechanisms under biomechanical stress during circulation. We further classified CTCs from different vascular sites into two subsets, namely dormant CTCs and activated CTCs. Dormant CTCs were associated with a non-cycling state and upregulation of EMT/angiogenic signatures and showed stronger prognostic ability for early recurrence than activated CTCs did. Furthermore, we discovered an immune escape mechanism by which CTCs recruited regulatory T cells (Tregs) via expression of CCL5, consequently promoting the formation of an immunosuppressive microenvironment favorable for their survival in the bloodstream and seeding in secondary organs. We proved that MAX, activated through the p38 pathway, was the key transcriptional factor regulating CCL5 overexpression, which was validated by ChIP, luciferase reporter gene and in vitro/vivo knockdown assays. And we further determined that Tregs-derived TGF-β1 can heighten MAX expression, thus amplifying the CCL5 expression. Conclusions: Collectively, our results reveal a previously unappreciated spatial heterogeneity of CTCs and a CTC immune-escape mechanism, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
Abstract A098: Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents
Authors: Sarah To, Edmond Kwan, Heidi Fettke, Maria Docanto, Nicole Ng, Andrew Mant, Phillip Parente, Carmel Pezaro, Lisa Horvath, Lisa Graham, Tilman Todenhofer, Arun Azad
Journal: Cancer Research (2018)

Abstract Background: The expression of AR-v7 in circulating tumor cells (CTCs) of mCRPC patients potentially confers treatment resistance to AR-axis targeting agents, though recent data from the ARMOR3-SV study as well as other publications challenge this hypothesis. Due to the potential barriers of developing a reliable CTC platform, our aim was to develop a rapid assay for AR-v7 detection in patient whole blood samples. Method: We created and optimized a whole blood quantitative real-time polymerase chain reaction assay to correlate outcomes of patients on AR-axis targeting agents with expression of AR-v7. The expression of AR-v7 mRNA in whole blood from 47 patients with mCRPC was obtained prior to commencing therapy. Each sample was run in triplicate; positivity was defined as at least two replicates reaching cycle threshold within a standard deviation between cycles of ≤ 0.25. Gene expression was correlated with PSA response rate using Fisher’s exact test. Results: In our cohort, 10 of 47 patients (21%) were AR-v7+. Of patients commencing abiraterone or enzalutamide (37/47 patients, 79%), we observed similar response rates in the AR-v7+ (4/7) patients, compared to the AR-v7 (20/30) patients (57% vs. 66%, P=0.63; Fisher’s exact test). In two patients, early onset of acquired resistance was associated with conversion from AR-v7 to AR-v7+. AR-v7 was not detected in any of the 13 normal male controls. Conclusion: We developed a specific assay for AR-v7 detection in whole blood from mCRPC patients. Similar PSA response rates were seen in AR-v7+ and AR-v7 patients, inconsistent with literature characterizing AR-v7 as a predictive biomarker, but in support of ARMOR3-SV data demonstrating moderate response rates to an AR-axis targeting agent in AR-v7+ patients. Future directions will include cohort expansion, interrogation of other AR variants, and examination of other clinically meaningful endpoints. Citation Format: Sarah To, Edmond Kwan, Heidi Fettke, Maria Docanto, Nicole Ng, Andrew Mant, Phillip Parente, Carmel Pezaro, Lisa Horvath, Lisa Graham, Tilman Todenhofer, Arun Azad. Whole blood assay for rapid detection of AR-v7 in metastatic castration-resistant prostate cancer: No correlation with response to androgen-axis targeting agents [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A098.
Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study
Authors: Aránzazu García Mateo, Maria-Victoria Mateos, Alberto Orfao, Teresa Contreras Sanfeliciano, Luzalba del Carmen Contreras Sanfeliciano, Mª Del Rosario Caro Narros, Noemi Puig, José Antonio Queizan, Carmen Olivier
Journal: Blood (2018)