tbuckley/cabot-search huggingface dataset:
Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis
Authors: Usman Barlass, Raini Dutta, Hassam Cheema, John George, Archana Sareen, Ajay Dixit, Zuobiao Yuan, Bhuwan Giri, Jingjing Meng, Santanu Banerjee, Sulagna Banerjee, Vikas Dudeja, Rajinder K Dawra, Sabita Roy, Ashok K Saluja
Journal: Gut (2017)

Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis.Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol-palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (µ) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of µ-opioid receptors in morphine's effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR.Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine's effect on severity of acute pancreatitis are mediated through the µ-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1.Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies.
Reply to «Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma: The ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CIRVIR and CO23 CUPILT cohorts)»
Authors: Philippe Kolly, Jean-François Dufour
Journal: Journal of Hepatology (2016)
Abstract 3591: Group X sPLA2 Deficiency Increases Adiposity and Adipose Tissue Inflammation in Mice
Authors: Nancy R Webb, Xia Li, Kathy Forrest, William Bailey, Boris B Boyanovsky, Preetha Shridas, Frederick C de Beer
Journal: Circulation (2007)

Introduction: Of the 10 secretory phospholipase A 2 (sPLA 2 ) enzymes expressed in humans, Group X (GX) sPLA 2 is the most potent in hydrolyzing phospholipids on cell membranes. In addition to its lipolytic activity, GX sPLA 2 is also a high affinity ligand for the M-type sPLA 2 receptor. Although numerous studies have implicated GX sPLA 2 in important biological processes in vitro , data from studies in vivo are lacking. To elucidate the physiological functions of this enzyme we recently developed C57BL/6 mice with targeted deletion of the GX sPLA 2 gene. Results : Analysis by real time RT-PCR showed that GX sPLA 2 mRNA is widely distributed in mouse tissues, with highest expression in intestine, testes, brain, thymus, spleen, fat, lung, and heart. Unlike some of the other members of the sPLA 2 family, tissue expression of GX sPLA 2 was not highly upregulated in mice injected with lipopolysaccharide. However, GX sPLA 2 was induced almost 5-fold in retroperitoneal fat of mice fed a high-fat (60 kcal%) diet for 17 weeks.Targeted disruption of GX sPLA 2 resulted in increased body weight in 1.5 year-old mice fed a normal laboratory diet (male GX sPLA 2 +/+ mice: 35.8±0.4 g; male GX sPLA 2 −/− mice: 45.033.2 g; p&lt;0.05). The increase in body weight was associated with significantly increased percent body fat (GX sPLA 2 +/+ mice: 16.0±1.0%; GX sPLA 2 −/− mice: 19.6±1%; p&lt;0.05), increased adipocyte size (GX sPLA 2 +/+ mice: 1300±26 um 2 GX sPLA 2 −/− mice: 2700±78 um 2 ; p&lt;0.001), and decreased fasting plasma triglyceride levels (GX sPLA 2 +/+ mice: 46.3±4.9 mg/dl; GX sPLA 2 −/− mice: 33.8±2.9 mg/dl; p&lt;0.05) at 3 months of age. Food consumption, fasting blood glucose, and plasma total cholesterol levels were not significantly different between GX sPLA 2 −/− and GX sPLA 2 +/+ mice. Compared to 3 month old GX sPLA 2 +/+ mice, the relative expression of IL-6 and F4/80 mRNAs in adipose tissue of age-matched GX sPLA 2 −/− mice was increased 9- and 4-fold, respectively, suggesting that the increased adiposity in GX sPLA 2 −/− mice was associated with an increase in the inflammatory profile of adipose tissue Conclusions: Our data points to a previously unrecognized role for Group X sPLA 2 in the development of obesity and associated adipose tissue inflammation.
Whole exome sequencing (WES) of multiple spatially distinct biopsies from single metastatic lesions to evaluate tumour heterogeneity and identify actionable truncal mutations (ATMs) in patients (pts) with advanced solid malignancies using a radiologically-guided single-pass percutaneous technique.
Authors: Valerie Heong, Bernard Wee, Shane Goh, Darwin Tay, Xiao Wen Lee, Ross A. Soo, Joline Si Jing Lim, Raghav Sundar, Cheng Ean Chee, Soo-Chin Lee, Samuel Guan Wei Ow, Boon C. Goh, Wei-Peng Yong, Andrea Li Ann Wong, Anil Gopinathan, Diana Lim, Brendan Pang, Mohammad Feroz, Richie Chuan Teck Soong, David Shao Peng Tan
Journal: Journal of Clinical Oncology (2017)

2550 Background: Genomic profiling of single core biopsies (bx) are confounded intratumoral heterogeneity, resulting in sampling bias. We explored the use of a novel technique to obtain multiple bx from single metastatic lesion in pts to evaluate heterogeneity and identify therapeutic ATM. Methods: 15 pts (5 NSCLC; 3 ovarian; 2 colon, 2 uterine and 1 breast, cervix and HCC) with biopsiable lesions were identified. Using a single pass radiologically guided percutaneous bx technique, we obtained multiple spatially distinct core bx samples from a single metastatic lesion. Each bx underwent DNA extraction and WES using the NextSeq500. Results: Median of 4 core bx were obtained from each lesion. Complication rate utilizing this technique was 0%. 2 pts were omitted from analysis due to poor quality DNA with 13 pts successfully sequenced. In 1 pt, only 2 of 4 cores were successfully sequenced. The median amounts of total and non-synonymous variants were 137 (27-1286) and 66 (10-649) respectively. The median (range) filtered variants detected in 1/4, 2/4, 3/4, and 4/4 bx cores was 63(16-91)%, 5(1-65)%, 4(0-30)% and 26(0-63)% respectively, suggesting significant subclonal diversity within a single lesion. ATMs were identitified in 8/13 pts. 4/13 pts (31%) had no ATM across all 4 cores. 3 pts received therapy with inhibitors targeting ATMs. A pt with AKT1_E17K ATM received an AKT inhibitor with 21% tumour shrinkage and PFS 6.1 mths. 2 NSCLC pts harbouring an EGFR_T790M ATM were treated with an EGFRT790M specific TKI. 1 withdrew due to toxicity after 2mths and another had PFS &gt; 16.5 mths. Tumour mutational burden (TMB) was consistent across multiple bx from each lesion. A NSCLC pt with the highest TMB received a checkpoint inhibitor with ongoing &gt; 4 mths stable disease. Conclusions: Utilizing a single pass radiologically guided techniqueto obtainmultiple bx is feasible, safe and informative. This allows reconstruction of a tumour’s subclonal genomic architecture, providing insights into mutational heterogeneity and help guide therapy.
Abstract 1396: Mitigation Of Cardiac Injury By Sulfaphenazole, A CYP2C9 Inhibitor Through Involvement Of Inducible Nitric Oxide Synthase (iNOS) in Post-ischemic Heart
Authors: Mahmood Khan, Iyyapu K Mohan, Damodhar Kumbala, Vijay K Kutala, Periannan Kuppusamy
Journal: Circulation (2007)

Cytochrome P450 enzymes play a significant role in ischemia-reperfusion (I/R) injury. Sulfaphenazole (SFZ), a potent CYP2C9 inhibitor, is known to reduce I/R injury. However, the mechanism of its cardioprotective effects and the role of nitric oxide (NO) is not clear. Objective : Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of I/R injury. The objective of this study was to determine how SFZ treatment modulates myocardial tissue oxygenation (pO 2 ) and RNS generation in vivo . Methods: Myocardial infarction was induced in rats by ligating the left anterior descending coronary artery (LAD) for 30 min, followed by 24 h of reperfusion. The study was divided into 4 groups: Untreated I/R control, SFZ, L-NAME, and SFZ+L-NAME. L-NAME (100 mg/kg/day), a nitric oxide synthase inhibitor, was given orally for 3 days prior to LAD ligation. SFZ (1.5 mg/kg, ip) was injected 30 min prior to LAD ligation. Oxygen-sensing crystals were implanted into the LV wall and the rat was placed in an L-band (1.2 GHz) electron paramagnetic resonance (EPR) spectrometer for measurement of myocardial tissue pO 2 during I/R injury. Hemodynamic data was collected with a microtip catheter. Infarct size was measured after 24 h of reperfusion. Superoxide generation was determined by dihydroethidium fluorescence imaging. Immunohistological staining was performed for nitrotyrosine and iNOS. Results: After LAD ligation, pO 2 decreased from 18 mmHg baseline to &lt;2 mmHg. At reperfusion, there was a significant myocardial hyperoxygenation in SFZ-treated rats compared to control group (45.0±1.3 vs. 34.0±2.0 mmHg, P&lt;0.05). In L-NAME and L-NAME+SFZ-treated rats, there was a significant reduction in pO 2 (24.0±1.6 and 26.0±2.3 mmHg, respectively). Compared to control, SFZ treatment significantly improved the left ventricular developed pressure (94.0±4.7 vs. 69.0±6.5 mmHg, P&lt;0.05), decreased infarct size % (35.0±4.2 vs. 16.0±2.5, P&lt;0.05), decreased superoxide generation and nitrotyrosine production. Conclusions: These findings demonstrate that SFZ may provide potent cardioprotection by attenuating post-ischemic ROS and RNS generation, and could serve as an attractive adjuvant therapy in the clinical setting of myocardial I/R injury.
Beliefs about lung cancer, knowledge, and interest in lung screening among community health center patients.
Authors: Sanja Percac-Lima, Jeffrey M Ashburner, Steven J Atlas, Nancy Rigotti, Emily Poles, Elyse R. Park
Journal: Journal of Clinical Oncology (2016)

e13051 Background: Lung cancer mortality in high-risk smokers can be decreased by annual computed tomography lung screening. Prior to initiating a lung screening program for community health center (CHC) patients, we surveyed eligible current and former smokers to assess their beliefs about lung cancer and knowledge and interest in screening. Methods: In 2015, we conducted a telephone survey of current and former smokers, aged 50-80, receiving care at five CHCs affiliated with an academic primary care network. We excluded patients who had a history of lung cancer or did not speak English/Spanish. Surveys assessed self-reported risk of developing lung cancer and other smoking related diseases, worry about developing lung cancer, and knowledge about and willingness to have lung screening. We compared responses among former and current smokers using logistic regression adjusting for age, sex, education, and language. Results: Overall, 253 patients completed the survey (68% response rate). Mean age was 62.1 years (SD=7.6), 57% of responders were women, 47% were Spanish speakers and 47% were former smokers. Current smokers were younger and more likely to be English speakers. There were no significant differences between current and former smokers in awareness of lung cancer screening (41.1% vs. 40.8%) or willingness to get screened if offered (59.4% vs. 63.3%). Table shows beliefs about smoking and disease. Conclusions: Among CHC patients eligible for lung screening, current smokers were more likely to be worried and believe that they will develop lung cancer yet demonstrated relatively low rates of screening awareness. Screening willingness was similar for current and former smokers. For a lung cancer screening program to be successful, patient outreach to increase screening awareness, will be needed. Current Former OR (95% CI) Likely develop lung cancer 91 (69.5%) 42 (35.6%) 4.22 (2.39- 7.43) Can do something to prevent lung cancer 85 (64.4%) 78 (65.5%) 0.95 (0.55- 1.66) Likely develop other smoking related disease 107 (81.7%) 51 (42.5%) 5.63 (3.12- 10.14) Worry about getting lung cancer 86 (65.7%) 36 (30.3%) 4.26 (2.41- 7.53) Worry about getting other smoking re lated disease 98 (74.8%) 37 (31.3%) 6.54 (3.65- 11.71)
Effect of Patent Foramen Ovale Closure on Obstructive Sleep Apnea
Authors: Stefano F. Rimoldi, Sebastian R. Ott, Emrush Rexhaj, Robert von Arx, Stefano F. de Marchi, Roman Brenner, Urs Scherrer, Bernhard Meier, Matthias Gugger, Yves Allemann, Christian Seiler
Journal: Journal of the American College of Cardiology (2015)
A Comparison of Cyclophosphamide, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma
Authors: Amarilis Figueiredo, Harold Atkins, Ranjeeta Mallick, Natasha Kekre, Andrea Kew, Arleigh McCurdy
Journal: Blood (2016)
Killer-cell Inmunoglobulin-like Receptor (KIR) genes as a predictor of response to the anti-HER therapy in solid tumors.
Authors: Cristina Morales-Estevez, Barbara Manzanares-Martin, Juan de la Haba-Rodriguez, Rafael Gonzalez-Fernandez, Javier López-González, Alberto Moreno, Ignacio Porras, Maria Jose Ortiz, María Auxiliadora Gómez-España, Maria Teresa Cano, Beatriz Chia-Delgado, Raquel Serrano, M Jesus Rubio, Enrique Aranda
Journal: Journal of Clinical Oncology (2016)

e13024 Background: KIRs are an important receptor in natural killer (NK) cells; these cells play a role in antibody-dependent cell-mediated cytotoxicity (ADCC) response due to monoclonal antibodies therapy. It is unknown whether the extensive polymorphism KIRs and/or their human leukocyte antigen (HLA) ligands might influence the response to treatment with monoclonal antibodies (MABs). Methods: We select in this study 39 patients treated with MABs, anti-human epidermal growth factor receptor (anti-HER/EGFR: Trastuzumab for advanced breast cancer and Cetuximab for advanced colorectal and advanced head and neck cancer). All the patients had progressed to the MABs therapy and were grouped in two groups taking into account the time to treatment failure (TTF) duration ( < or = 6m and > or = 10m).KIR genotyping (16 polymorphisms) was performed by PCR sequence-specific primer technique and KIR-ligand typing was performed for HLA-B & -C loci by reverse PCRSSO methodology and for HLA-C alleles by direct sequencing. Results: Subjects carrying the KIR2DS1/HLAC2C2-C1C2 showed longer TTF than non carriers (14,76 m vs 3,73 m, p < 0.001) and KIR3DS1/HLAw4w4-w4w6 (14,93 m vs 4,6 m, p = 0.005). No other significant differences were observed. Conclusions: Two activator combinations of KIRs and their HLA ligands predicts longer TTF of patients treated with anti-HER therapy. These findings increase the overall knowledge on the role of specific variants related with anti-HER treatment in solid tumors responsiveness and highlight the importance of assessing gene polymorphisms related with cancer medications. These result must be confirm in future trials.
Infectivity of <i>Plasmodium falciparum</i> sporozoites determines emerging parasitemia in infected volunteers
Authors: Matthew B. B. McCall, Linda J. Wammes, Marijke C. C. Langenberg, Geert-Jan van Gemert, Jona Walk, Cornelus C. Hermsen, Wouter Graumans, Rob Koelewijn, Jean-François Franetich, Sandra Chishimba, Max Gerdsen, Audrey Lorthiois, Marga van de Vegte, Dominique Mazier, Else M. Bijker, Jaap J. van Hellemond, Perry J. J. van Genderen, Robert W. Sauerwein
Journal: Science Translational Medicine (2017)

Infectivity of P. falciparum sporozoites determines the course of primary malaria infection in human volunteers.
Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease
Authors: Siddhartha Jaiswal, Pradeep Natarajan, Alexander J. Silver, Christopher J. Gibson, Alexander G. Bick, Eugenia Shvartz, Marie McConkey, Namrata Gupta, Stacey Gabriel, Diego Ardissino, Usman Baber, Roxana Mehran, Valentin Fuster, John Danesh, Philippe Frossard, Danish Saleheen, Olle Melander, Galina K. Sukhova, Donna Neuberg, Peter Libby, Sekar Kathiresan, Benjamin L. Ebert
Journal: New England Journal of Medicine (2017)

Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.
TULA-2 Inhibits the Platelet FcγRIIA-Syk Pathway and Heparin-Induced Thrombocytopenia in Mice
Authors: Yuhang Zhou, Shaji Abraham, Leonard C. Edelstein, Carol Dangelmaier, Alexander Tsygankov, Satya P. Kunapuli, Paul F. Bray, Steven McKenzie
Journal: Blood (2016)
Inhibition of WEE1 Induces Cell Death of Both Bortezomib- and Lenalidomide-Resistant Multiple Myeloma Cells: A Novel Therapeutic Approach Targeting Cell-Cycle Checkpoint Kinase
Authors: Takayuki Tabayashi, Yuka Tanaka, Yasuyuki Takahashi, Yuta Kimura, Tatsuki Tomikawa, Morihiko Sagawa, Tomoe Anan-Nemoto, Reiko Watanabe, Michihide Tokuhira, Masahiro Kizaki
Journal: Blood (2016)
Implementation of reflexive genomic profiling in non-squamous NSCLC: Results of single center experience.
Authors: Jacqueline T Brown, Andrew R Moore, Joshua E Reuss, Nicholas I Simon, Ryan D. Gentzler, Richard Delmar Hall
Journal: Journal of Clinical Oncology (2017)

e13010 Background: Identification of oncogenic driver mutations (ODM) and targeted therapies have increased the number of treatment options for patients (pts) with non-squamous non-small cell lung cancer (ns-NSCLC). Different methods exist to detect ODM and there is no standard approach. This study examines the changes in detection of ODM over a 2-year period before and after implementing reflexive genomic testing using next generation sequencing (NGS) in January 2015. Methods: We retrospectively reviewed ns-NSCLC cases (stages I-IV) in 2014 and 2015 using the UVA Cancer Registry. We identified pts with pathologically-confirmed ns-NSCLC and reviewed any genotyping - single gene pyrosequencing, NGS, or FISH for gene rearrangements - within 90 days of pathologic confirmation. Comprehensive genomic profiling (CGP) was defined as both NGS and ALK/ROS1 FISH. Chi-square analyses were generated using SAS 9.4. Results: A total of 360 pts were included. 60% had genotyping while 19% underwent CGP. Mutations are summarized in the table below. From 2014 to 2015, genotyping increased from 50% to 69% (p&lt;0.001), with CGP increasing from 2% to 48% of testing performed (p&lt;0.001). Detection of oncogene driver mutations increased from 28% to 46% (p=0.009). Doubletons (pts with 2 driver mutations) increased from 0% to 5% (p=0.036). Conclusions: Reflexive CGP significantly increased the rate of detection of ODM at our center with results similar to previous studies. Previous studies detected low rates of doubleton mutations, perhaps due to lack of uniform NGS testing. Utilization of NGS may increase detection of doubleton mutations, for which further study is necessary to evaluate efficacy of targeted therapies. For centers without reflexive CGP, implementing this approach is likely to increase rates of ODM detection and expand treatment options. [Table: see text]
Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: A retrospective analysis on 32 patients
Authors: N. Milpied, B. Vasseur, N. Parquet, J.L. Garnier, C. Antoine, P. Quartier, A.S. Carret, D. Bouscary, A. Faye, B. Bourbigot, Y. Reguerre, A.M. Stoppa, P. Bourquard, B. Hurault de Ligny, F. Dubief, A. Mathieu-Boue, V. Leblond
Journal: Annals of Oncology (2000)
Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function
Authors: Haijiao Zhang, Sophie Means, Anna Reister Schultz, Kevin Watanabe-Smith, Bruno C. Medeiros, Daniel Bottomly, Beth Wilmot, Shannon K. McWeeney, Tim Kükenshöner, Oliver Hantschel, Jeffrey W. Tyner
Journal: Cancer Research (2017)

Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients. Cancer Res; 77(16); 4258-67. ©2017 AACR.