tbuckley/cabot-search huggingface dataset:
PTH-017 Optical characterisation of lesions in ibd colitis: a systematic review and meta-analysis
Authors: R Lord, N Burr, N Mohammed, V Subramanian
Journal: Endoscopy (2017)

<h3>Introduction</h3> Optical imaging is increasingly advocated for characterisation of polyps during colonoscopy. Accuracy of these techniques during surveillance colonoscopy in colonic inflammatory bowel disease (IBD-C) is unclear, with variable results reported. We performed a systematic review and meta-analysis of the diagnostic accuracy of optical imaging techniques including dye-based chromoendoscopy (DCE), virtual chromoendoscopy (VCE), magnification endoscopy and confocal laser endomicroscopy (CLE). <h3>Method</h3> We searched Medline and Embase for relevant papers. Full articles or abstracts were eligible when characterisation performance of DCE, VCE (narrow-band imaging [NBI], i-scan, Fujinon intelligent chromoendoscopy [FICE]), magnification endoscopy and CLE had been compared with histopathology, as the reference standard. Enough information had to be required to obtain 2 × 2 contingency table. Pooled analysis was done using random-effects model. Sub-group analysis was performed at real-time (RT) Kudo pit pattern based and real-time (RT) CLE for characterisation of visible lesions. Heterogeneity was assessed using X<sup>2</sup> and I<sup>2</sup> statistics. <h3>Results</h3> Our search stratergy identified 172 studies of which 20 met the inclusion criteria. Pooled results are outlined in the table. <h3>Conclusion</h3> Real-time CLE and magnification endoscopy had best performance characteristics. However there is a lot of herterogeneity in the results. Most CLE and magnification studies were single centre, single expert user which could explain the results. CLE studies were also affected by attrition bias with some studies reporting non-interpretable images in a significant proportion. <h3>Disclosure of Interest</h3> None Declared
Identification of Tigit on Intra-Tumor T Cells As a New Target for Immune Checkpoint Blockade in Follicular Lymphoma
Authors: Sarah Gothberg, Kanutte Huse, Arne Kolstad, Ole Christian Lingjærde, Bjørn Østenstad, Erlend Smeland, Ronald Levy, Jonathan Michael Irish, June Helen Myklebust
Journal: Blood (2016)
Radiologist convicted of fraud is suspended for 12 months
Authors: Clare Dyer
Journal: BMJ (2017)

A consultant radiologist who was convicted of fraud over NHS overtime claims has been suspended for 12 months by a medical practitioners tribunal.

The judge who gave John Coffey a suspended sentence of 15 months’ imprisonment told him at his trial that “there is little doubt that your career as a doctor is likely to be finished.” But a panel of the Medical Practitioners Tribunal Service opted instead for the maximum period of suspension from the medical register.

Coffey’s conviction at …
Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis
Authors: Yun-Chi Tang, Hui Yuwen, Kaiying Wang, Peter M. Bruno, Kevin Bullock, Amy Deik, Stefano Santaguida, Marianna Trakala, Sarah J. Pfau, Na Zhong, Tao Huang, Lan Wang, Clary B. Clish, Michael T. Hemann, Angelika Amon
Journal: Cancer Research (2017)

Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens. Cancer Res; 77(19); 5272-86. ©2017 AACR.
Phase 1-2 open-label, multiple-dose, dose-escalation study to evaluate the safety and tolerability of intravenous infusion of SNS01-T, a first-in-class modulator of eukaryotic translation initiation factor 5A (eIF5A) in patients (pts) with relapsed or refractory B-cell malignancies.
Authors: Michael Craig, William Bensinger, David Samuel DiCapua Siegel, Frits Van Rhee, Nicolas Novitzky, Andrew Mcdonald, Martin Gutierrez, Edward N. Libby, John Thompson, Alice Susannah Bexon, Charles Barranco, Catherine Taylor, Richard Dondero, Leslie J. Browne, Michael R. Kurman, John Anthony Lust
Journal: Journal of Clinical Oncology (2014)

TPS8616 Background: eIF5A has been implicated in the regulation of cell proliferation, apoptosis, and inflammation. It is the only known protein to be modified by hypusination, and is highly conserved across species and is active in plants and animals. Hypusinated eIF5A, the predominant form in normal and cancer cells, is involved in cell survival and inflammatory pathway activation. siRNAs targeting eIF5A inhibit NF-kB activation and reduce pro-inflammatory cytokine production. Accumulation of the unhypusinated lysine form of eIF5A is associated with apoptosis. Mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic in vitro and have anti-tumoral activity in vivo in multiple cancer types including melanoma and lung cancer. SNS01-T is a novel therapeutic with a dual mechanism of eIF5A modulation: inducing cell death via siRNA-mediated inhibition of hypusinated eIF5A while simultaneously causing over-expression of pro-apoptotic eIF5AK50R via a DNA plasmid with a B-cell promoter to induce tumor cell death. SNS01-T significantly inhibited tumor growth and increased survival in mouse models of myeloma (MM), mantle cell and diffuse large B-cell lymphoma. Methods: This is an open label, phase 1-2 dose escalation study in pts with refractory B-cell cancers. The study has 4 dose cohorts: 0.0125, 0.05, 0.2 and 0.375 mg/kg twice weekly IV for 6 weeks. Main inclusion criteria are: MM per IMWG criteria or lymphomas or plasma cell leukemia with histologic confirmation; measurable disease; relapsed or refractory disease after ≥2 prior regimens; life expectancy ≥3 months; not eligible for any other standard therapy known to extend life expectancy. Primary endpoints are safety and tolerability of SNS01-T. Secondary endpoints include pharmacokinetics, tumor response (M protein, % plasma cells, radiologic response) and time to relapse or progression. To date, 15 patients have been included in the study. Enrolment (n=6) at the highest dose cohort has commenced (1 pt enrolled). Cohort 4 is expected to be completed in 1H2014. Clinical trial information: NCT01435720.
PTH-121 The humanistic and economic burden of irritable bowel syndrome with diarrhoea among patients in the uk
Authors: A Marciniak, JL Abel, RT Carson, NM Flores, R Liebert
Journal: Gut (2017)

Introduction  Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a chronic gastrointestinal disorder associated with significant economic burden in Europe; however, data specific to the UK are limited. This study assessed the impact of IBS-D on health-related quality of life (HRQoL), work and activity impairment, and healthcare resource utilisation (HCRU) among adults in the UK.  Method  UK respondents were identified from the 2013 EU5 National Health and Wellness Survey (NHWS). Diagnosed IBS-D patients reported a physician diagnosis of IBS, with diarrhoea as the predominant symptom; undiagnosed IBS-D patients reported IBS-D symptoms without a physician diagnosis. Controls included all respondents without IBS or inflammatory bowel disease. IBS-D severity (mild/moderate/severe) was also patient-reported for those diagnosed and undiagnosed. HRQoL (via the 36-Item Short Form Health Survey version 2 Mental and Physical Component Summary [MCS; PCS] scores), work and activity impairment (via the Work Productivity and Activity Impairment: General Health Questionnaire), and HCRU (via the number of patient-reported visits to healthcare providers in the past 6 months) were assessed. Multivariable generalised linear models assessed HRQoL, work and activity impairment, and HCRU by IBS-D status and severity, controlling for demographic and health characteristics.  Results  13 478 patients were included (335 diagnosed; 146 undiagnosed; 12 997 controls). Diagnosed IBS-D patients had significantly lower HRQoL compared to controls as measured by MCS and PCS scores (both p  Conclusion  Diagnosed IBS-D patients in the UK had significantly greater impairments in HRQoL and daily activities and higher HCRU use compared to controls. Similar results were observed in patients with severe IBS-D compared to patients with mild or moderate IBS-D. These results highlight the substantial burden of illness and the need for effective treatments to manage IBS-D symptoms.  Disclosure of Interest  A. Marciniak Conflict with: Pfizer, Amgen, Allergan plc, Conflict with: Allergan plc, J Abel Conflict with: Allergan plc, Conflict with: Allergan plc, R Carson Conflict with: Allergan plc, Conflict with: Allergan plc, N Flores Conflict with: Kantar Health, paid consultants to Allergan plc, R Liebert Conflict with: Kantar Health, paid consultants to Allergan plc
WHAT DOES RETURN TO PRE-INJURY RISK MEAN?
Authors: Ian Shrier, Meng Zhao, Alexandre Piché, Pavel Slavchev, Russell J. Steele
Journal: British Journal of Sports Medicine (2017)

Background Previous injury is the strongest predictor of subsequent injury. Some authors suggest injury always causes permanent structural damage, or that rehabilitation programs are grossly inadequate. Objective To describe the limitations of commonly used analyses assessing subsequent injury risk, and to explicitly define what “100% effective rehabilitation” means. Design Simulated studies based on observed data professional sport and performing arts. Setting Simulations were conducted with 100% rehabilitation post first injury (return to pre-injury state), in contexts where injury risk was stable over the season, and increased over the season. Patients (or Participants) Simulated data. Interventions (or Assessment of Risk Factors) The main independent variables are previous injury, time of first injury, and position. We included “participant” as a random effect. Main Outcome Measurements Injury risk expressed as injuries per games played. Results When our simulated data with 100% effective rehabilitation was based on constant injury risk during the season, traditional analyses found that previous injury was still strongly associated with subsequent injury. A causal analysis that included the participant as a random effect correctly showed that the injury risk for participants remained constant. When injury risk increased over the season, the traditional analysis found that previous injury was even more strongly associated with subsequent injury. A causal analysis that only included the participant as a random effect also suggested a higher injury risk. However, when the appropriate control group was chosen for comparison, the causal analysis correctly illustrated that pre-injury risk did not increase following an initial injury. Conclusions Conclusions about the effectiveness of rehabilitation programs using traditional risk factor analysis will always show an increased risk of subsequent injury even if none exists. A causal analytical approach correctly identifies when the risk is present, but requires careful consideration about what is the appropriate control group for the given question.
MSH2 Loss in Primary Prostate Cancer
Authors: Liana B. Guedes, Emmanuel S. Antonarakis, Michael T. Schweizer, Nooshin Mirkheshti, Fawaz Almutairi, Jong Chul Park, Stephanie Glavaris, Jessica Hicks, Mario A. Eisenberger, Angelo M. De Marzo, Jonathan I. Epstein, William B. Isaacs, James R. Eshleman, Colin C. Pritchard, Tamara L. Lotan
Journal: Clinical Cancer Research (2017)

Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
Abstract 3283: Proximity of Lead Position to Site of Latest Mechanical Activation is Associated With Improvements in Ventricular Dyssynchrony and Function Following Resynchronization Therapy
Authors: Glen Miske, John Gorcsan, Masaki Tanabe, Samir Saba
Journal: Circulation (2007)

Background: Left ventricular (LV) lead position for resynchronization therapy (CRT) is routinely done empirically by targeting the posterior-lateral region. Our objective was to test the hypothesis that acute improvements in dyssynchrony and LV function are related to LV lead proximity to site of latest radial activation. Methods: We studied 42 consecutive heart failure patients referred for CRT with ejection fraction (EF) 19±13%, and QRS 155±26ms (57% Ischemic) before and 24 hours after CRT. Speckle tracking radial strain (GE Corp.) was used to map mechanical activation time from 12 radial sites; 6 at basal and 6 at mid-LV levels. LV lead tip was localized using anatomic landmarks of the coronary sinus from multiple fluoroscopic views during CRT. Concordance was defined as LV lead tip matching the same site as the latest mechanical activation from the 12 radial sites. Results: Overall, group mean radial dyssynchrony improved from 253±127ms to 53±127ms (p&lt;0.05) after CRT. Among the 34 patients with significant baseline radial dyssynchrony (defined as septal-posterior wall delay ≤ 130 ms), lead position was concordant in 24 and discordant in 10. Concordant lead position resulted in greater improvements in dyssynchrony than discordant lead position (58±80ms* vs. 211±120ms) and a greater acute increase in EF (Δ 6±7%* vs. Δ 2±3%) *p&lt; 0.05 vs discordant lead. Conclusions: Although empiric LV lead placement for CRT results in acute improvement in LV dyssynchrony overall, concordance of lead position with site of latest activation is associated with greater improvements in dyssynchrony and LV function. These observations have potential clinical implications.
Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC).
Authors: Gini F. Fleming, Leisha A. Emens, Joseph Paul Eder, Erika Paige Hamilton, Joyce F. Liu, Bo Liu, Luciana Molinero, Marcella Fasso, Carol O'Hear, Fadi S. Braiteh
Journal: Journal of Clinical Oncology (2017)

5585 Background: The prognosis for patients (pts) with rEC remains poor, with a 5-y OS of 20%-26%. We report safety, clinical activity and biomarker data from a Phase Ia study of atezo (anti–PD-L1) monotherapy in rEC. Methods: Atezo 1200 mg or 15 mg/kg IV q3w was administered until toxicity or loss of clinical benefit. Pts were initially eligible based on PD-L1 status ( &gt; 5% of tumor-infiltrating immune cells [IC; IC2/3], VENTANA SP142 IHC assay) and then enrolled regardless of PD-L1 status. Tumor-infiltrating lymphocytes (TILs) were assessed by H&amp;E. The FoundationOne NGS panel was used for microsatellite instability (MSI) and tumor mutation load analyses. Confirmed ORR and PFS were assessed by RECIST v1.1. Results: As of March 31, 2016, 15 pts were evaluable for safety and efficacy (minimum follow-up, 11.2 mo). The median age was 61 y (range, 20-74 y), 53% were ECOG PS 1 and 93% had ≥ 2 prior systemic therapies; 10 (67%) pts had prior RT. Pts were MSI-H (1/15), MSS (7/15) or MSI unknown (7/15). EC subtypes were endometrioid (5/15), serous (5/15), ER+ leiomyosarcoma (1/15) or unknown (4/15). Five (33%) pts were IC2/3, and 10 (67%) pts were IC0/1. Seven (47%) pts had any related AE, mainly G1-2 (5 pts). No G4-5 related AEs occurred. Two pts had related SAEs (colitis; rash). ORR was 13% (2/15) by RECIST. Both pts achieved PR and were IC2/3. ORR for IC2/3 pts was 40% (2/5). One responder was MSS and heavily infiltrated with TILs (IC3, 70% TILs, 1.8 Mut/Mb, unknown subtype); the other responder was hypermutated, MSI-H and moderately infiltrated with TILs (IC2, 10% TILs, 237 Mut/Mb, endometrioid). DOR in the 2 responders was 7.3 and 8.1+ mo. mPFS was 1.7 mo (range, 0.6-11+ mo); mOS was 9.6 mo (range, 0.6-11.8+ mo). Of the remaining pts, 2 had SD, 9 had PD and 2 were non-evaluable. DCR (PR + SD) was 27%. A trend for higher PFS and OS was seen in IC2/3 vs IC0/1 pts. Conclusions: Atezo had a favorable safety profile in rEC, with durable clinical benefit in some pts. Clinical benefit appeared to increase with higher PD-L1 expression, suggesting a link between PD-L1 status and response. Hypermutation and/or high immune infiltration may be linked to response to PD-L1 blockade, and further evaluation is merited. Clinical trial information: NCT01375842.
思春期:ゲノム配列解析によって初潮年齢に関連する数百のバリアントが同定され,思春期の時期ががん発症リスクに関与することが示された
Authors: Day Felix R, Langenberg Claudia, Luan Jian’an, Scott Robert A, Zhao Jing Hua, Wareham Nicholas J, Ong Ken K, Perry John R B, Thompson Deborah J, Bolla Manjeet K, Dennis Joe, Michailidou Kyriaki, Pharoah Paul D P, Wang Qin, Easton Douglas F, Helgason Hannes, Sulem Patrick, Gudbjartsson Daniel F, Thorsteindottir Unnur, Stefansson Kari, Chasman Daniel I, Rose Lynda M, Buring Julie E, Ridker Paul M, Karasik David, Finucane Hilary, Loh Po‐Ru, DE Vivo Immaculata, Hunter David J, Stampfer Meir, Kraft Peter, Price Alkes L, Ruth Katherine S, Murray Anna, Whalen Sean, Pollard Katherine S, Sarkar Abhishek K, Kellis Manolis, Albrecht Eva, Strauch Konstantin, Altmaier Elisabeth, Grallert Harald, Meisinger Christa, Peters Annette, Gieger Christian, Stoeckl Doris, Amini Marzyeh, Nolte Ilja M, Alizadeh Behrooz Z, Snieder Harold, Barbieri Caterina M, Sala Cinzia F, Traglia Michela, Toniolo Daniela, Boutin Thibaud, Navarro Pau, Vitart Veronique, Hayward Caroline, Wilson James F, Campbell Archie, Porteous David, Demerath Ellen, Giri Ayush, Edwards Digna R Velez, HE Chunyan, Hottenga Jouke J, Mbarek Hamdi, Willemsen Gonneke, Boomsma Dorret I, Karlsson Robert, Brand Judith S, Czene Kamila, Gabrielson Marike, Hall Per, LI Jingmei, Pedersen Nancy, Magnusson Patrik K E, Kolcic Ivana, Polasek Ozren, Palotie Aarno, Esko Tonu, Lunetta Kathryn L, Murabito Joanne M, Mangino Massimo, Lachance Genevieve, Menni Cristina, Spector Tim D, Marco Brumat, Gandin Ilaria, Mcmahon George, Paternoster Lavinia, Smith George Davey, Ring Susan M, Timpson Nicholas J, Lawlor Debbie A, Medland Sarah E, Lind Penelope A, Martin Nicholas G, Noordam Raymond, Nutile Teresa, Ruggiero Daniela, Sorice Rossella, Ciullo Marina, Perjakova Natalia, Maegi Reedik
Journal: Nature Genetics (2017)
Targeted Proteomics Identifies Proteomic Signatures in Liquid Biopsies of the Endometrium to Diagnose Endometrial Cancer and Assist in the Prediction of the Optimal Surgical Treatment
Authors: Elena Martinez-Garcia, Antoine Lesur, Laura Devis, Silvia Cabrera, Xavier Matias-Guiu, Marc Hirschfeld, Jasmin Asberger, Jan van Oostrum, María de los Ángeles Casares de Cal, Antonio Gómez-Tato, Jaume Reventos, Bruno Domon, Eva Colas, Antonio Gil-Moreno
Journal: Clinical Cancer Research (2017)

Purpose: Endometrial cancer (EC) diagnosis relies on the observation of tumor cells in endometrial biopsies obtained by aspiration (i.e., uterine aspirates), but it is associated with 22% undiagnosed patients and up to 50% of incorrectly assigned EC histotype and grade. We aimed to identify biomarker signatures in the fluid fraction of these biopsies to overcome these limitations.Experimental Design: The levels of 52 proteins were measured in the fluid fraction of uterine aspirates from 116 patients by LC-PRM, the latest generation of targeted mass-spectrometry acquisition. A logistic regression model was used to assess the power of protein panels to differentiate between EC and non-EC patients and between EC histologic subtypes. The robustness of the panels was assessed by the "leave-one-out" cross-validation procedure performed within the same cohort of patients and an independent cohort of 38 patients.Results: The levels of 28 proteins were significantly higher in patients with EC (n = 69) compared with controls (n = 47). The combination of MMP9 and KPYM exhibited 94% sensitivity and 87% specificity for detecting EC cases. This panel perfectly complemented the standard diagnosis, achieving 100% of correct diagnosis in this dataset. Nine proteins were significantly increased in endometrioid EC (n = 49) compared with serous EC (n = 20). The combination of CTNB1, XPO2, and CAPG achieved 95% sensitivity and 96% specificity for the discrimination of these subtypes.Conclusions: We developed two uterine aspirate-based signatures to diagnose EC and classify tumors in the most prevalent histologic subtypes. This will improve diagnosis and assist in the prediction of the optimal surgical treatment. Clin Cancer Res; 23(21); 6458-67. ©2017 AACR.
01.09 Myeloid cells drive early inflammation and orchestrate salivary glands tertiary lymphoid structures formation in a model of inducible sialadenitis
Authors: Davide Lucchesi, Elena Pontarini, Costantino Pitzalis, Domenico Mavilio, Michele Bombardieri
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Tertiary lymphoid structures (TLS) are leukocytes aggregates forming in non-lymphoid tissues in response to chronic inflammation. Salivary glands (SG) of patients with Sjögren's syndrome (SS) develop TLS characterised by B/T cell compartmentalization, specialised vasculature (HEV), functional B cell activation and local differentiation of autoreactive plasma cells. Although TLS presence in SS SG associates with an aggressive disease progression, the mechanisms triggering their formation in SS are largely unknown. We recently developed a model of inducible TLS formation, breach of self-tolerance and salivary hypofunction upon delivery of a replication­deficient adenovirus­5 (AdV5) into C57BL/6 mice SG. In this model, 3 weeks after infection, we observed fully formed and functional TLS, breach of self-tolerance and loss of salivary function. Here we characterised the presence, function and relevance in TLS formation of the myeloid compartment in the first month post-infection. <h3>Materials and methods</h3> A luciferase-encoding AdV5 was delivered to the SG, glands were collected between 1 and 4 weeks post-cannulation (WPC), embedded for immunofluorescence staining and/or digested for FACS analysis, and stained for various markers. Sorted myeloid cells were analysed my Q-PCR. Infiltration and differentiation of monocytes was followed via adoptive transfer. <h3>Results</h3> During the first WPC, innate cells infiltrated the gland in sequential waves, as shown by FACS. Neutrophils and eosinophils were rapidly recruited to the SG and likely contributed to the histological damage observed. Inflammatory monocytes were recruited from the periphery and progressively differentiated into macrophages <i>in-situ</i>. NK and pDC also increased in number in response to viral infection. Gene expression analysis of sorted myeloid cells showed early upregulation of inflammatory mediators (eg, CCL5, IFNg) and a later production of lymphoneogenetic signals (eg, Lt-b, CXCL13) mRNA. <h3>Conclusions</h3> In our model of inducible ialadenitis, innate immune cells not only mediate early inflammation in the SG, but also take part in driving the lymphocytic infiltration, thus playing a pivotal role in tertiary lymphoid formation.
Topical Sinecatechins, 10%, Ointment for Superficial Basal Cell Carcinoma
Authors: Janneke Kessels, Lotte Voeten, Patty Nelemans, Jack Cleutjens, Lisa Maria Hillen, Klara Mosterd, Nicole W. J. Kelleners-Smeets
Journal: JAMA Dermatology (2017)

This randomized clinical trial compares topical sinecatechins ointment, 10%, vs placebo in the treatment of superficial basal cell carcinoma.
Ribavirin, an eIF4E Inhibitor, As a Potential Anti-Lymphoma Therapeutic - Preclinical and Early Clinical Data
Authors: Sarah C. Rutherford, Eric Stewart, Tharu M Fernando, Biljana Culjkovic-Kraljacic, Katherine L. B. Borden, Koen van Besien, Peter Martin, Richard R Furman, John P. Leonard, Leandro Cerchietti
Journal: Blood (2016)