tbuckley/cabot-search huggingface dataset:
POSEIDON trial phase 1b results: Safety and preliminary efficacy of the isoform selective PI3K inhibitor taselisib (GDC-0032) combined with tamoxifen in hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC) patients (pts) - including response monitoring by plasma circulating tumor (ct) DNA.
Authors: Richard D. Baird, Annelot Van Rossum, Mafalda Oliveira, Karin Beelen, Javier Garcia-Corbacho, Ingrid A M Mandjes, Anne-Laure Vallier, Erik D. van Werkhoven, Sanjeev Srinivas Kumar, Harm van Tinteren, Emma Beddowes, Hilde Rosing, Mariette Schrier, Aurelia de Vries Schultink, Cristina Saura, Rene Bernards, Josep Tabernero, Javier Cortes, Carlos Caldas, Sabine C. Linn
Journal: Journal of Clinical Oncology (2016)

2520 Background: Endocrine therapy resistance remains a major challenge in the treatment of HR-positive breast cancer. The strategy of combining PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes (eg. BOLERO-2, BELLE-2) but at the cost of increased toxicity. Taselisib is a potent, selective, beta-isoform sparing inhibitor of PI3K designed to have a better therapeutic index than first-generation pan-PI3K inhibitors. Methods: Pts with prior exposure to endocrine therapy were enrolled using a 3+3 design, testing taselisib in combination with tamoxifen 20mg qd. A (21 day on / 7 day off) intermittent schedule was also compared with daily continuous dosing (28/28). The primary objective was to determine the recommended phase II dose and schedule. Other objectives included: pharmacokinetics (PK), pharmacodynamics (PD) and serial monitoring of plasma ctDNA using digital PCR / tagged amplicon deep-sequencing. Results: 30 pts were enrolled in 3 cohorts: taselisib 2mg (21/7), 4mg (21/7) and 4mg (28/28). The most common drug toxicities were diarrhea, nausea and anemia. No dose-limiting toxicities were seen. Three pts had reversible, late, grade ≥ 3 side effects (two colitis; one pneumonitis). Steady-state PK results: 4mg taselisib mean Cmax 66.6ng/mL, AUC 1016ng*hr/mL; mean endoxifen 7.63ng/mL; consistent with previous reports and low chance of drug-drug interaction. Three pts had a RECIST partial response; 15 pts stable disease; 4 pts not evaluated yet. The radiologic treatment responses seen in some pts were preceded by early changes in plasma PIK3CA ctDNA levels (eg. one pt with a response at 8 weeks had a >90% decrease in PIK3CAH1047R titres detected at 4 weeks). Conclusions: Taselisib in combination with tamoxifen is generally well tolerated. Preliminary evidence of anti-tumor activity was seen, in some patients preceded by a fall in plasma PIK3CA ctDNA levels. The recommended phase II dose of taselisib in combination with tamoxifen is 4mg on a daily continuous schedule. Clinical trial information: NCT02285179.
Quantification of circulating clonal plasma cells (cPCs) via multiparametric flow cytometry (MFC) to identify patients with smoldering multiple myeloma (SMM) at high risk of progression.
Authors: Wilson I. Gonsalves, S. Vincent Rajkumar, Michael Timm, William Morice, Angela Dispenzieri, Martha Lacy, Francis Buadi, David Dingli, Ronald S. Go, Nelson Leung, Prashant Kapoor, Suzanne R. Hayman, John Anthony Lust, Stephen Russell, Steven R. Zeldenrust, Taxiarchis Kourelis, Yi Lisa Hwa, Robert A. Kyle, Morie A. Gertz, Shaji Kumar
Journal: Journal of Clinical Oncology (2016)

8015 Background: The presence of high numbers of cPCs in patients with SMM, detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to multiple myeloma (MM). The significance of quantifying cPCs via MFC, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. Methods: This study evaluated patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013 and who had their peripheral blood evaluated for cPCs by six-color MFC. cPCs were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. The cPCs detected were reported out as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: There were 100 patients with a known diagnosis of SMM who had their peripheral blood evaluated by MFC for clonal cPCs prior to disease progression. The median follow up was 37 months (95% CI: 32 – 41). There were 31 (31%) patients who had progressed to MM requiring treatment at the time of last follow up. There were 24 patients who had detectable cPCs. The median number of cPCs was 78 per 150,000 events analyzed (Range: 20 – 3124). Patients with 150 or more cPCs (N = 9) had a 97% specificity and 78% PPV for progression to MM within 2 years and hence the presence of 150 or more cPCs was chosen as a cutoff to define high levels of cPCs (due to its nearly 80% PPV). The median TTP of patients with 150 or more cPCs was 9 months compared to not reached for patients with less than 150 cPCs (P < 0.001). The estimated three and five year OS was 79% and 67% for patients with 150 or more cPCs and 97% and 95% for patients with less than 150 cPCs (P = 0.043). Conclusions: Quantification of cPCs via MFC identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.
Barrett's Oesophagus (BE)Surveillance: What is its Real Role?
Authors: R Quera, K O'Sullivan, EMM Quigley
Journal: Endoscopy (2004)

The incidence of oesophageal adenocarcinoma (AC) is increasing rapidly. Although surveillance of BE, its precursor, is recommended, to detect dysplasia and early cancer, the cost-effectiveness of this approach has not been established.
Advanced technique for the treatment of chronic calculous pancreatitis using endoscopic ultrasound-guided pancreatic duct drainage
Authors: Nozomi Okuno, Kazuo Hara, Nobumasa Mizuno, Susumu Hijioka, Takamichi Kuwahara, Akashi Fujita, Yasumasa Niwa
Journal: Endoscopy (2017)

A 64-year-old man who underwent distal gastrectomy with Billroth II reconstruction for duodenal ulcer perforation was hospitalized for painful chronic pancreatitis. The recurrent pain was caused by calculous obstruction of the pancreatic duct, resulting in upstream ductal hypertension. Computed tomography showed stones and a dilated main pancreatic duct (MPD) ([Fig. 1]).
Faecal microbiota study reveals specific dysbiosis in spondyloarthritis
Authors: Maxime Breban, Julien Tap, Ariane Leboime, Roula Said-Nahal, Philippe Langella, Gilles Chiocchia, Jean-Pierre Furet, Harry Sokol
Journal: Annals of the Rheumatic Diseases (2017)

Altered microbiota composition or dysbiosis is suspected to be implicated in the pathogenesis of chronic inflammatory diseases, such as spondyloarthritis (SpA) and rheumatoid arthritis (RA).16S ribosomal RNA gene sequencing was performed on faecal DNA isolated from stool samples in two consecutive cross-sectional cohorts, each comprising three groups of adult volunteers: SpA, RA and healthy controls (HCs). In the second study, HCs comprised a majority of aged-matched siblings of patients with known HLA-B27 status. Alpha and beta diversities were assessed using QIIME, and comparisons were performed using linear discriminant analysis effect size to examine differences between groups.In both cohorts, dysbiosis was evidenced in SpA and RA, as compared with HCs, and was disease specific. A restriction of microbiota biodiversity was detected in both disease groups. The most striking change was a twofold to threefold increased abundance of Ruminococcus gnavus in SpA, as compared with both RA and HCs that was significant in both studies and positively correlated with disease activity in patients having a history of inflammatory bowel disease (IBD). Among HCs, significant difference in microbiota composition were also detected between HLA-B27+ and HLA-B27 negative siblings, suggesting that genetic background may influence gut microbiota composition.Our results suggest that distinctive dysbiosis characterise both SpA and RA and evidence a reproducible increase in R. gnavus that appears specific for SpA and a marker of disease activity. This observation is consistent with the known proinflammatory role of this bacteria and its association with IBD. It may provide an explanation for the link that exists between SpA and IBD.
Is the HFE Heterozygote State an Innocent Bystander in Alcoholic Liver Disease?
Authors: F Gleeson, P Holloway, E Ryan, J Crowe
Journal: Endoscopy (2004)

Background: The HFE gene contains two mutant alleles: C282Y and H63D. There is evidence to support that HFE heterozygosity may act as a potentially damaging co-factor in chronic liver disease. Increased ferritin is frequently found in individuals with hepatic steatosis. The significance of heterozygosity in alcohol related liver disease is unclear.
Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification
Authors: Mehdi Afshar, Kevin Luk, Ron Do, Line Dufresne, David S. Owens, Tamara B. Harris, Gina M. Peloso, Kathleen F. Kerr, Quenna Wong, Albert V. Smith, Mathew J. Budoff, Jerome I. Rotter, L. Adrienne Cupples, Stephen S. Rich, James C. Engert, Vilmundur Gudnason, Christopher J. O’Donnell, Wendy S. Post, George Thanassoulis
Journal: Journal of the American College of Cardiology (2017)
Quantitative Imaging Approaches to Study the CAR Immunological Synapse
Authors: Malini Mukherjee, Emily M. Mace, Alexandre F. Carisey, Nabil Ahmed, Jordan S. Orange
Journal: Molecular Therapy (2017)

The lytic immunological synapse (IS) is a discrete structural entity formed after the ligation of specific activating receptors that leads to the destruction of a cancerous cell. The formation of an effector cell IS in cytotoxic T lymphocytes or natural killer cells is a hierarchical and stepwise rearrangement of structural and signaling components and targeted release of the contents of lytic granules. While recent advances in the generation and testing of cytotoxic lymphocytes expressing chimeric antigen receptors (CARs) has demonstrated their efficacy in the targeted lysis of tumor targets, the contribution and dynamics of IS components have not yet been extensively investigated in the context of engineered CAR cells. Understanding the biology of the CAR IS will be a powerful approach to efficiently guide the engineering of new CARs and help identify mechanistic problems in existing CARs. Here, we review the formation of the lytic IS and describe quantitative imaging-based measurements using multiple microscopy techniques at a single cell level that can be used in conjunction with established population-based assays to provide insight into the important cytotoxic function of CAR cells. The inclusion of this approach in the pipeline of CAR product design could be a novel and valuable innovation for the field.
Prophylactic Antibiotics for ERCP: Are they Needed?
Authors: A Coss, AR Aftab, G Courtney
Journal: Endoscopy (2004)

Endoscopic retrograde cholangio-pancreatography (ERCP) is an invasive procedure associated with potentially significant morbidities including sepsis. Traditionally prophylactic antibiotics have been administered to all patients undergoing ERCP. The most important predictor of sepsis after ERCP is incomplete bile duct drainage. We have adopted a policy of omitting prophylactic antibiotics except where there is a risk of endocarditis or symptomatic bacteraemia and only administer a therapeutic course if an obstructed duct cannot be cleared or drained at ERCP.
LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer.
Authors: Karim Fizazi, Namphuong Tran, Luis Enrique Fein, Nobuaki Matsubara, Alfredo Rodríguez Antolín, Boris Y. Alekseev, Mustafa Ozguroglu, Dingwei Ye, Susan Feyerabend, Andrew Protheroe, Peter De Porre, Thian Kheoh, Youn C. Park, Mary Beth Todd, Kim N. Chi
Journal: Journal of Clinical Oncology (2017)

LBA3 Background: Pts with newly diagnosed mHNPC, particularly with high-risk characteristics, have a poor prognosis. ADT+docetaxel showed improved outcomes in mHNPC, but many pts are not candidates for docetaxel and may benefit from alternative therapy. AA+P is indicated for metastatic castration-resistant prostate cancer pts. LATITUDE evaluates clinical benefit of early intervention with AA+P added to ADT in newly diagnosed, high-risk mHNPC pts. Methods: 1199 pts with newly diagnosed (≤ 3 mos prior to randomization) mHNPC (ECOG PS 0-2) with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) were randomized 1:1 to ADT+AA (1 g QD) + P (5 mg QD) or ADT+PBOs of AA and P. Co-primary end points were overall survival (OS) and radiographic progression-free survival (rPFS). One rPFS (~565 events), 2 interim, and 1 final OS analyses (~426, ~554, and ~852 events) were planned. Results: At this first interim analysis (median follow-up of 30.4 mos; 406 deaths [48%]; 593 rPFS events), OS, rPFS, and all secondary end points significantly favored ADT+AA+P (Table). The IDMC unanimously recommended unblinding the study and crossing pts to ADT+AA+P. Grade 3/4 adverse events (ADT+AA+P vs ADT+PBOs) (%): hypertension (20.3 vs 10.0); hypokalemia (10.4 vs 1.3); increased ALT (5.5 vs 1.3) or AST (4.4 vs 1.5). Conclusions: Early use of AA+P added to ADT in pts with high-risk mHNPC yielded significantly improved OS, rPFS, and all secondary end points vs ADT+PBOs alone. ADT+AA+P had a favorable risk/benefit ratio and supports early intervention with AA+P in newly diagnosed, high-risk mHNPC. Clinical trial information: NCT01715285. [Table: see text]
ChREBP refines the hepatic response to fructose to protect the liver from injury
Authors: Angela M. Hall, Brian N. Finck
Journal: Journal of Clinical Investigation (2017)

Overconsumption of fructose and other sugars has been linked to nonalcoholic fatty liver disease (NAFLD); however, the sugar-associated effects that lead to disease are poorly defined. In this issue of the JCI, Zhang and colleagues show that the carbohydrate response element–binding protein (ChREBP) coordinates an adaptive response to a high-fructose diet in mice and that loss of this transcription factor leads to hepatic inflammation and early signs of fibrosis. Intriguingly, ChREBP-dependent effects were due to an exaggerated activation of the proapoptotic arms of the endoplasmic reticulum stress response that is probably secondary to inappropriate derepression of cholesterol biosynthesis. These findings suggest that a previously unknown link exists between ChREBP and the regulation of cholesterol synthesis that affects liver injury.
Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer
Authors: Yuichiro Yokoyama, Toshiaki Watanabe, Yusuke Tamura, Yoshinobu Hashizume, Kohei Miyazono, Shogo Ehata
Journal: Cancer Research (2017)

Abstract Poor prognoses for colorectal cancer patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here, we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human colorectal cancer cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in colorectal cancer cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of colorectal cancer cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for colorectal cancer. Cancer Res; 77(15); 4026–38. ©2017 AACR.
Using multicellular tumor spheroids as a model to study the effect of extracellular matrix on viral oncolysis
Authors: Jonathan Goodwin, Bryan Fuchs, Yakup Kulu, Kenneth Tanabe, Michael Lanuti
Journal: Cancer Research (2007)

3045   One of the major therapeutic limitations of oncolytic viral gene therapy for treatment of solid tumors is poor viral distribution within the tumor microenvironment. Recent evidence has shown that connective tissue and extracellular matrix may play a prominent role in inhibiting viral propagation. The ability of progeny virion to penetrate extracellular matrix and subsequently infect neighboring tumor cells has not been sufficiently elucidated. We have developed an  in vitro  multicellular spheroid model in order to further study the role of extracellular matrix proteins, such as collagen and fibronectin, in primary and secondary viral infection. Briefly, murine non-small cell lung cancer (L1C2) cells were cultured in a spinner flask alone or with an equal number of murine fibroblasts (NIH-3T3). Single or co-culture spheroids (>500 um) were harvested after 10 days, sectioned, and stained for extracellular matrix proteins, collagen IV and fibronectin. Co-culture L1C2/NIH-3T3 spheroids displayed elevated levels of collagen IV and fibronectin compared to single culture L1C2 spheroids. We then investigated the sensitivity of these tumor spheroids to a replication competent ICP6-deleted Herpes simplex viral mutant expressing green fluorescent protein (GFP). L1C2 and NIH-3T3 were equally sensitive to viral cytotoxicity  in vitro  when grown alone as a monolayer. Each cell line was also shown to equally support viral replication through a single-step burst assay. However, co-culture L1C2/NIH-3T3 spheroids infected with virus for 48 hours remained morphologically intact while the single culture spheroids had deteriorated. We hypothesize that the increased network of extracellular matrix proteins in the L1C2/NIH-3T3 co-culture spheroids impedes viral biodistribution and oncolysis in our  in vitro  spheroid model. Future studies will involve manipulating the extracellular matrix to increase the therapeutic efficacy of recombinant herpes viral vectors in solid tumors.
Endemic Toxin Variant Clostridium Difficile in an Irish Teaching Hospital
Authors: D Drudy, N Harnedy, S Fanning, R O'Mahony, A Baird, L Kyne
Journal: Endoscopy (2004)

Aim: To determine the prevalence of clinically important toxin-variant (A-negative, B-positive) Clostridium difficile strains in our institution; a 600-bed university-affiliated hospital in Dublin.
Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) [2] (multiple letters)
Authors: J. R Jass, Luca Roncucci, Maurizio Ponz De Leon, Piero Benatti, F. Borghi, Monica Pedroni, A. Scarselli, Carmela Di Gregorio, Lorena Losi, A. Viel, M. Genuardi, Gian Luca Abbati, G. Rossi, Mirco Menigatti, Giovanni Ponti
Journal: Gut (2004)
Accuracy of J-CTO Score Derived From Computed Tomography Versus Angiography to Predict Successful Percutaneous Coronary Intervention
Authors: Akiko Fujino, Satoru Otsuji, Katsuyuki Hasegawa, Toyohiro Arita, Shin Takiuchi, Kenichi Fujii, Masanori Yabuki, Motoaki Ibuki, Shinya Nagayama, Kasumi Ishibuchi, Toshikazu Kashiyama, Rui Ishii, Hiroto Tamaru, Wataru Yamamoto, Masahiko Hara, Yorihiko Higashino
Journal: JACC. Cardiovascular imaging (2017)
Mastocytosis: a case series of 107 consecutive patients
Authors: H. Bhullar, R. Martyres, K. Nicholls, G. Varigos, J. Douglass, A. Saracino
Journal: British Journal of Dermatology (2017)

Mastocytosis is classified by the World-Health-Organisation (WHO)1 as cutaneous-mastocytosis (CM) and systemic-mastocytosis (SM). CM is subdivided into maculopapular (MPCM), diffuse-CM and mastocytomas. SM is subdivided into indolent (ISM), with-an-associated-haematologic-neoplasm (SM-AHN)2, aggressive (ASM) and mast-cell-leukemia (MCL).

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Abstract 161: Kcne2 Gene Deletion Combines With A Western Diet To Cause Early-onset Diabetes Mellitus And Atherosclerosis In Mice
Authors: Soo-Min Lee, Ritu Kant, Geoffrey W Abbott
Journal: Circulation Research (2014)

The KCNE2 single transmembrane domain protein regulates multiple types of cardiac voltage-gated potassium (Kv) channel in vivo and its disruption causes the ventricular arrhythmia, Long QT Syndrome. Interestingly, a SNP near the human KCNE2 locus was also previously linked to early-onset myocardial infarction (MI). Because KCNE2 is also expressed outside the heart, we are interested in understanding extracardiac defects caused by Kcne2 deletion in mice, and also the potential contribution of these extracardiac defects to cardiac dysfunction. Thus, recently, we found that Kcne2 deletion creates a multifactorial substrate for sudden cardiac death (SCD) that includes diabetes mellitus and dyslipidemia. Because atherosclerosis is the most common cause of MI, here, using Kcne2 -/- mice, we investigated atherosclerosis and other potential predisposing factors in MI and SCD, and quantified the impact of a Western diet (high fat/high cholesterol) on these processes. Previously, we discovered impaired glucose tolerance in adult Kcne2 -/- mice using a standard glucose tolerance assay in which plasma glucose is quantified 0-2 hours following glucose injection. Here, we found that in Kcne2 -/- mice as young as 5 weeks, just 2 weeks on a Western diet induced impaired glucose tolerance, whereas 5-week-old wild-type mice regardless of diet, or Kcne2 -/- mice on a control diet, had normal glucose tolerance. This indicates a strong interaction between diet and Kcne2 deletion in creating early-onset diabetes mellitus. Atherosclerosis was also investigated, using Sudan IV staining of plaques in the aorta of wild-type and Kcne2 -/- mice fed on either standard (control) or Western diet. Strikingly, Kcne2 -/- mice as young as 4.5 months exhibited aortic plaques, and this was accelerated by a Western diet. In contrast, wild-type littermates did not exhibit plaques at this age, regardless of diet. Ongoing studies to determine potential metabolic defects in the liver and pancreas are aimed at understanding the molecular mechanisms underlying these findings. Our data provide further evidence of the unexpected complexity of monogenic cardiovascular syndromes caused by disruption of genes associated with cardiac arrhythmias.
Abstract 289: Cardiac-Specific Ectonucleoside Triphosphate Diphosphohydrolase 1 Overexpression Affords Protection from Myocardial Infarction and Reperfusion Injury
Authors: Zhaobin Xu, Debra G Wheeler, Shouvik D Mahamud, Karen M Dwyer, Simon C Robson, Peter J Cowan, Anthony J d'Apice, Richard J Gumina
Journal: Circulation Research (2012)

Background: During myocardial stress, extracellular levels of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) increase. These extracellular ATP and ADP levels are modulated via hydrolysis by ectonucleoside triphosphate diphosphohydrolase 1 (ENTDP-1/CD39) to adenosine monophosphate (AMP) subsequently converted by ecto-5'-nucleotidase (CD73) to the anti-thrombotic, cardioprotective nucleoside, adenosine. Previous data demonstrated significantly smaller infarcts in mice globally overexpressing CD39. The current objective was to determine whether tissue specific overexpression of CD39 in the heart would reduce myocardial ischemia/reperfusion injury. Methods: Myocardial ischemia/reperfusion (I/R) injury was evaluated in transgenic mice overexpressing human CD39 driven by the α-MHC promoter. I/R injury was induced by ligation of the left anterior descending (LAD) artery for 60 min followed by 24 hours of reperfusion. Myocardial infarct size was determined by staining with triphenyl tetrazolium chloride (TTC) and the area-at-risk was delineated by perfusion with 5% Phthalo Blue. Results: Expression of CD39 in the heart tissue was confirmed by Western blot analysis. In response to 60 minutes of ischemia followed by 24 hours of reperfusion, α-MHC CD39-OE animals displayed a marked reduction in infarct size (WT: 31.68%±4.64 vs TG: 6.14%± 2.48, N=5/group, P&lt;0.01), relative to wild-type controls (Figure). Conclusions: Overexpression of CD39 in cardiac tissue alone significantly attenuates myocardial ischemic injury.