tbuckley/cabot-search huggingface dataset:
Senescent cells and osteoarthritis: a painful connection
Authors: Ok Hee Jeon, Nathaniel David, Judith Campisi, Jennifer H. Elisseeff
Journal: Journal of Clinical Investigation (2018)

Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells’ relevance to disease was unclear. In this Review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.
Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria
Authors: Sonia Fargue, Dawn S. Milliner, John Knight, Julie B. Olson, W. Todd Lowther, Ross P. Holmes
Journal: Journal of the American Society of Nephrology (2018)

Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [ 15 N, 13 C 5 ]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13 C 2 -oxalate and 13 C 2 -glycolate formed using ion chromatography coupled to mass detection. Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and &lt;13% in subjects with PH2 or PH3. Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.
Phenomenological Load on Model Parameters Can Lead to False Biological Conclusions
Authors: Christopher T Jones, Noor Youssef, Edward Susko, Joseph P Bielawski
Journal: Molecular Biology and Evolution (2018)

When a substitution model is fitted to an alignment using maximum likelihood, its parameters are adjusted to account for as much site-pattern variation as possible. A parameter might therefore absorb a substantial quantity of the total variance in an alignment (or more formally, bring about a substantial reduction in the deviance of the fitted model) even if the process it represents played no role in the generation of the data. When this occurs, we say that the parameter estimate carries phenomenological load (PL). Large PL in a parameter estimate is a concern because it not only invalidates its mechanistic interpretation (if it has one) but also increases the likelihood that it will be found to be statistically significant. The problem of PL was not identified in the past because most off-the-shelf substitution models make simplifying assumptions that preclude the generation of realistic levels of variation. In this study, we use the more realistic mutation-selection framework as the basis of a generating model formulated to produce data that mimic an alignment of mammalian mitochondrial DNA. We show that a parameter estimate can carry PL when 1) the substitution model is underspecified and 2) the parameter represents a process that is confounded with other processes represented in the data-generating model. We then provide a method that can be used to identify signal for the process that a given parameter represents despite the existence of PL.
TRACHEA ESOPHAGEAL FISTULA CLOSURE WITH THERMOCOAGULATION AND FIBRIN GLUE USING DUODENOSCOPE
Authors: V Abishek, V Leelakrishnan, M Swaminathan
Journal: Endoscopy (2018)

To demonstrate the usefulness of side viewing endoscope in trachea oesophageal fistula closure and to demonstrate the efficacy of combined modality for endoscopic fistula closure.
ENDOSCOPIC MANAGEMENT OF THE INGESTION OF PINS
Authors: FZ Chabib, I Benelbarhdadi, FZ Ajana
Journal: Endoscopy (2018)

Ingestion of foreign bodies is a frequent emergency especially found in psychotics patients and children. Ingested objects can be dangerous because of their sharpness and their location in the digestive tract. The purpose of the work is to draw attention to the possibility of occurrence of such accidents.
EXTREME ENDOSCOPY: DIRECT JEJUNOSTOMY, ENDOSCOPIC RE-ANASTOMOSIS OF INTESTINES, PERCUTANEOUS ASSISTED TRANSPROSTHETIC THERAPY (PATENT) IN PATIENT ANASTOMOTIC DEHISCENCE AND COMPLEX PLEUROPERITONEAL ABSCESS AFTER PANCREATIC SURGERY
Authors: A Martínez-Alcalá García, TP Kroner, AM Ahmed, I Jovanovic, L Fry, MA D'Assunção, K Mönkemüller
Journal: Endoscopy (2018)

A 52-year old female with history of Roux-en-Y gastric bypass underwent resection of a huge pancreatic cystic tumor of the pancreas. Postoperatively an amylase-rich pleural and retroperitoneal fluid collection was noted, which was drained radiologically. Her clinical status was poor, she was septic and her albumin was 1.2 g/L (normal > 3.5). The patient was referred for double balloon (DEB)-ERCP for a suspected pancreatic duct leak. During endoscopy it became evident that the jejunogastric anastomosis was completely disrupted, communicating with a large peritoneo-pleural abscess.
Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without <i>NPM1</i> Mutations
Authors: Sylvie D. Freeman, Robert K. Hills, Paul Virgo, Naeem Khan, Steve Couzens, Richard Dillon, Amanda Gilkes, Laura Upton, Ove Juul Nielsen, James D. Cavenagh, Gail Jones, Asim Khwaja, Paul Cahalin, Ian Thomas, David Grimwade, Alan K. Burnett, Nigel H. Russell
Journal: Journal of Clinical Oncology (2018)

Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD-. Patients without high-risk factors, including Flt3 internal tandem duplication wt/- NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD-; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD-, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD- (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.
Abstract 16815: Novel Orally Active Hydrogen Sulfide-releasing Compound, SG1002, Attenuates QT Interval Prolongation and Improves LV Function and Survival in a Murine Model of Ischemic Cardiomyopathy
Authors: Bharat Balan, Adolfo G Mauro, Chad Cain, David J Polhemus, David J Lefer, Fadi N Salloum
Journal: Circulation (2017)

Background:  Hydrogen sulfide (H 2 S) has been shown to be cardioprotective in the settings of acute myocardial infarction (MI)- and pressure overload-induced heart failure; however, the use of inorganic H 2 S-donor salts lacks precision and control over H 2 S release. We sought to determine if the novel, orally active, slow-releasing H 2 S-compound SG1002 attenuates MI-induced adverse remodeling and left ventricular (LV) dysfunction. We also tested the impact of SG1002 on changes in QT interval as well as 28-day survival post MI in mice.   Methods and Results:  After baseline echocardiography, adult male C57BL mice underwent MI by permanent ligation of the left anterior descending coronary artery. Mice received SG1002 in the diet to achieve a dosage of 40 mg/kg/day in 2 different treatment groups: Pretreatment (Pre-Tx) starting 7 days before MI or immediate Treatment (Tx) after MI and treatment was continued for 4 weeks post MI. The vehicle group received normal chow. SG1002 improved survival at 28 days post MI in the Pre-Tx and Tx groups compared to vehicle (Fig. A). LV ejection fraction (EF) was significantly improved in the Tx group compared to vehicle (Fig. B). LV scar size as measured by Trichrome staining was significantly reduced in the Tx group compared to vehicle (Fig. C). Although LVEF preservation and scar reduction did not reach statistical significance with Pre-Tx vs. vehicle, there was a clear tendency towards improvement in both. ECG analysis revealed significant prolongation in QT interval in the vehicle group post MI, which was significantly attenuated with either Pre-Tx or Tx with SG1002 (Fig. D).   Conclusion:  SG1002 protects against ischemic cardiomyopathy in mice by attenuating LV dysfunction and scar size. Interestingly, the improvement in survival observed with SG1002 may be due to mitigation of QT interval prolongation and lethal arrhythmias post MI. We propose that SG1002 may be a promising pharmacological tool for treatment of ischemic heart failure.
Concordance assessment of a cognitive computing system in Thailand.
Authors: Suthida Suwanvecho, Harit Suwanrusme, Montinee Sangtian, Andrew D Norden, Alexandra Urman, Annette Hicks, Irene Dankwa-Mullan, Kyu Rhee, Narongsak Kiatikajornthada
Journal: Journal of Clinical Oncology (2017)

6589 Background: IBM Watson for Oncology (WFO) was trained by Memorial Sloan Kettering and is a cognitive computing system that uses natural language processing to ingest patient data in structured and unstructured formats. The system provides physicians with treatment options that are derived from established guidelines, the medical literature, and training from patient cases. In this study, we assessed the degree of concordance between treatment recommendations proposed by WFO and oncologists at Bumrungrad International Hospital (BIH). BIH is a 580-bed multispecialty hospital in Bangkok, Thailand. Methods: Data from breast, colorectal, gastric, and lung cancer patients treated at BIH were entered into WFO in 2015 and 2016. Retrospective cases were entered after a treatment plan had been determined, and prospective cases were entered during patients’ treatment planning sessions. WFO recommendations were provided in 3 categories: “Recommended”, “For Consideration”, and “Not Recommended.” Concordance was analyzed by comparing the decisions made by the oncologists to those proposed by WFO. Concordance was achieved when the oncologist’s treatment suggestion was in the “Recommended” or “For Consideration” categories given by WFO. Results: A total of 211 cases were assessed, 92 were retrospective and 119 were prospective. The overall concordance rate was 83%; 89% for colorectal, 91% for lung, 76% for breast, and 78% for gastric cancer. Similar concordance rates were observed when retrospective and prospective cases were analyzed separately. Discordance was attributable in part to local oncologists’ preferences for non-U.S. guidelines for certain cancers, especially gastric cancer. Conclusions: There was a high degree of concordance between WFO treatment options and the decisions made by local oncologists. Similar results were recently reported in a breast cancer concordance study conducted using WFO in India (San Antonio Breast Cancer Symposium 2016, Somashekhar et al). WFO’s capabilities as a cognitive decision support tool can be further improved by incorporating regional guidelines. Future work will analyze reasons for discordance such as cost, insurance requirements, and patient and physician preference.
Persistance de l'effet d'un ballon intra-gastrique chez des sujets obèses morbides 6 et 12 mois aprés son ablation
Authors: M Potier, G Airinei, A Pernot, JL Fournier, R Cohen, D Sfedj, A Baglieri, JJ Raynaud, B Bejou, C Bon, R Benamouzig
Journal: Endoscopy (2009)

Introduction: La pose d'un ballon intragastrique est une des modalités thérapeutiques proposées pour la prise en charge des patients obèses morbides résistant à une prise en charge diététique adaptée lorsqu'ils ne relèvent pas d'une éventuelle chirurgie bariatrique. Peu d'études prospectives se sont intéressées à l'évolution sur le long terme après ablation du ballon intragastrique. Le but de ce travail a été d'évaluer prospectivement la persistance de l'efficacité du ballon intragastrique sur la perte de poids, la composition corporelle et l'évolution du comportement alimentaire en fonction de l'évolution des dépenses énergétiques. Cette étude est unique par la précision des méthodes employées pour évaluer l'évolution de ces paramètres.
Hyperpolarized [1-13C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer <i>In Vivo</i> Predicts Efficacy of Targeting the Warburg Effect
Authors: Bradley T. Scroggins, Masayuki Matsuo, Ayla O. White, Keita Saito, Jeeva P. Munasinghe, Carole Sourbier, Kazutoshi Yamamoto, Vivian Diaz, Yoichi Takakusagi, Kazuhiro Ichikawa, James B. Mitchell, Murali C. Krishna, Deborah E. Citrin
Journal: Clinical Cancer Research (2018)

Purpose: To evaluate the potential of hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect.Experimental Design: Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts. The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-13C]-pyruvate MRSI after systemic delivery of [1-13C] pyruvic acid. Steady-state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady-state lactate concentrations were measured with proton (1H) MRS. Perfusion and oxygenation of xenografts were measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 μg/mouse/day for 5 days × 2 weekly cycles). Lactate production, pyruvate uptake, extracellular acidification rates, and oxygen consumption of the prostate cancer cell lines were analyzed in vitro LDH activity was assessed in tumor homogenates.Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-13C]-pyruvate MRSI compared with PC3 and a corresponding greater sensitivity to LDH inhibition. No difference was observed between PC3 and DU145 xenografts in steady-state measures of pyruvate fermentation, oxygenation, or perfusion. The two cell lines exhibited similar sensitivity to FX-11 in vitro LDH activity correlated to FX-11 sensitivity.Conclusions: Hyperpolarized [1-13C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect. Clin Cancer Res; 24(13); 3137-48. ©2018 AACR.
EUS AND CT SCAN ACCURACY IN ESTABLISHING THE T STAGE IN SURGICALLY RESECTED PANCREATIC CANCER BASED ON THE UPCOMING TNM 8TH EDITION
Authors: L Archibugi, M Chiara Petrone, D Tamburrino, S Crippa, E Dabizzi, A Mariani, R Nicoletti, C Doglioni, G Capurso, M Falconi, PG Arcidiacono
Journal: Endoscopy (2018)

Pancreatic cancer (PC) patients with tumors > 2 cm might harbor micrometastases already at diagnosis. In fact, the new proposed AJCC-Staging-System-TNM-8th edition differs from the 7th mostly for T evaluation, giving high importance to PC diameter, predicting survival more efficiently. A correct preoperative evaluation of the T might shift therapeutic decision from upfront surgery to neoadjuvant chemotherapy, that could be preferred in tumors> 2 cm (T2). Few studies compared CT vs. EUS in evaluating PC dimension with heterogeneous results and dated machines, and no study adopted the new TNM system. The aim was to evaluate the accuracy of CT vs. EUS in establishing the T stage as defined by the new upcoming TNM 8th edition and to discriminate T1 from more advanced stages.
Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.
Authors: Jianzhen Lin, Weiwei Shi, Songhui Zhao, Jinwei Hu, Zheng Hou, Ming Yao, Gungwei Chrin, Jie Pan, Ke Hu, Lin Zhao, Milind Javle, Kai Wang, Haitao Zhao
Journal: Journal of Clinical Oncology (2018)

500 Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had &gt; = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease &gt; = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( &gt; 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.
A CASE OF AN IMPRISONED HOT-AXIOS STENT
Authors: L Venezia, P Cortegoso Valdivia, CG De Angelis
Journal: Endoscopy (2018)

Hot-Axios stent are indicated to facilitate transgastric or transduodenal endoscopic drainage of pancreatic pesudocystys. The removal of the stent is programmed after 4 – 6 weeks. Up to now, no case of imprisoned Hot-Axios has been reported.
The TORC1-Regulated CPA Complex Rewires an RNA Processing Network to Drive Autophagy and Metabolic Reprogramming
Authors: Hong-Wen Tang, Yanhui Hu, Chiao-Lin Chen, Baolong Xia, Jonathan Zirin, Min Yuan, John M. Asara, Leonard Rabinow, Norbert Perrimon
Journal: Cell Metabolism (2018)
ESGE POST-POLYPECTOMY SURVEILLANCE GUIDELINES: ADHERENCE AND RELATION WITH HIGH RISK LESIONS
Authors: J Pereira Rodrigues, R Pinho, S Leite, C Fernandes, T Freitas, J Silva, A Ponte, M Sousa, JC Silva, J Carvalho
Journal: Endoscopy (2018)

Colorectal cancer (CRC) is one of the main causes of cancer-related death in the western world. Adenoma resection allows reduction of the incidence and mortality caused by CRC. Some patients are still at an increased risk of developing CRC post-polypectomy so an adequate surveillance is essential for its prevention. The aim of this study was to evaluate the adherence to European Society of Gastrointestinal Endoscopy (ESGE) post-polypectomy surveillance guidelines and its relation with the diagnosis of high risk lesions.