tbuckley/cabot-search huggingface dataset:
CD1d-dependent CLL progression?
Authors: Mark L. Lang
Journal: Blood (2017)

Moreover, current knowledge with regard to major immune subsets in different human and mouse tissue sites has not been well elucidated.It remains unknown if humans have similar immune subsets in different tissues compared with mouse tissue sites.It may be possible that tumor-reactive T cells to CLL antigens are present in Tcl-1-tg mouse spleen but may not be present in human lymph nodes or other tissues.Taken together, it may not be surprising that the immunotherapy results observed in this relevant CLL mouse model do not recapitulate the human disease.Despite the promise of PD-1 blockade in RT patients, this approach did not prevent the progression of underlying clonally related CLL, suggesting that these interesting anti-PD-1 findings might be best translated to combination therapies for RT/CLL patients.To this end, early work in a pilot study from the MD Anderson Cancer Center using BTKi therapy with PD-1 blockade has been ongoing and may add to these results. 8Nonetheless, to establish further advances for RT therapy, there remains a great need for a better understanding of the mechanisms involved in the development of RT.The important work described by Ding et al may be the initial step by demonstrating single-agent PD-1 blockade can benefit RT patients with modest improvements of survival.While other earlyphase trials are ongoing, these results clearly must be confirmed in a larger phase 3 study testing the efficacy of checkpoint inhibition in RT patients.Overall PD-1 blockade may finally be the next move toward significant progress in the treatment of RT since conventional chemoimmunotherapy.
Abstract 097: Recombinant Human Erythropoietin Prevents Reactive Oxygen Species - Induced Apoptosis Via Akt and p38 MAPK Pathway During Hypoxia/ Reperfusion Injury
Authors: Asiya Parvin Allaudeen, Ajay Devendran, John E Baker, Anuradha Dhanasekaran
Journal: Circulation Research (2013)

Erythropoietin (EPO) is a cytokine produced primarily in the kidney that is essential for red blood cell production. Apart from playing a role in hematopoiesis, EPO also has a protective role in heart myocytes, ovarian, glial cells brain and retinal diseases. In this study we observed that recombinant human EPO (rhEPO) reduces Hypoxia/ Reperfusion (H/R) injury by virtue of its effect on EPO receptor prosurvival signaling pathway, which ultimately leads to reduced expression of apoptotic proteins and increased survival of cardiomyocytes. H9C2 cells were exposed to H/R with or without pretreatment using 10, 15 and 20 U/ml of rhEPO. We determined viability using MTT, nuclear fragmentation by Hoechst staining, apoptotic nuclei by Acridine orange and Ethidium bromide, Reactive Oxygen Species (ROS) by Dicholorofluoresin Diacetate and activity of late apoptotic protease, Caspase-3 by colorimetric Caspase-3 assay. The expression of mitochondrial superoxide dismutase (MnSOD) by RT-PCR and Western blot, phospho-Akt and p38 MAPK by Confocal microscopy were analyzed. Cell viability is increased in cells pretreated with rhEPO compared to cell exposed to H/R. Cells subjected to H/R showed early apoptotic and late apoptotic cells but showed normal nuclei with intact cell membrane in cells pretreated with rhEPO. Intracellular production of ROS and Caspase-3 activity was decreased in cells pretreated with rhEPO compared to cells exposed to H/R. The expression of MnSOD RNA and protein was up-regulated in response to rhEPO, but not in H/R. The phosphorylative activation of Akt, p38MAPK progressively diminished during H/R but increased in rhEPO pretreated cells. We show that rhEPO prevents apoptosis in cardiomyocytes, subjected to H/R injury via phosphorylation of Akt and p38MAPK. These results it is hoped would help us distinguish the cell signaling pathways involved in cardioprotection and thus would open new avenues in cardiovascular therapy.
Pattern of risks of systemic lupus erythematosus among statin users: a population-based cohort study
Authors: Hilda J I De Jong, Tjeerd P van Staa, Arief Lalmohamed, Frank de Vries, Rob J Vandebriel, Henk Van Loveren, Olaf H Klungel, Jan Willem Cohen Tervaert
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To examine the association between the use of statins and the risk of systemic lupus erythematosus <b>(</b>SLE) with focus on describing the patterns of risks over time. <h3>Setting</h3> A population-based cohort study using the UK Clinical Practice Research Datalink. <h3>Participants</h3> All patients aged 40 years or older who had at least one prescription of statins during the period 1995–2009 were selected and matched by age, sex, practice and date of first prescription to non-users. The follow-up period of statin users was divided into periods of current, recent and past exposure, with patients moving among these three exposure categories over time. Current statin users were also stratified into ≤1 year or &gt;1 year of use. <h3>Main outcome measures</h3> Time-dependent Cox models were used to calculate HRs of SLE, adjusted for disease history and previous drug exposure. <h3>Results</h3> We included 1 039 694 patients, of whom 519 847 were statin users. Current statin users did not have an increased risk of developing SLE among patients aged ≥40 years (HR<sub>adjusted</sub> 0.75, 95% CI 0.53 to 1.07). Current statin users who continued the therapy for &gt;1 year had a 38% lower risk of developing SLE (HR<sub>adjusted</sub> 0.62, 95% CI 0.42 to 0.93). When more specific definitions for SLE were used, this latter finding, however, was not observed. <h3>Conclusions</h3> Our findings showed no effect of statins on the risk of developing SLE among patients aged ≥40 years. Further research is needed to study the long-term effects of statins on SLE.
Genotype–covariate interaction effects and the heritability of adult body mass index
Authors: Matthew R Robinson, Geoffrey English, Gerhard Moser, Luke R Lloyd-Jones, Marcus A Triplett, Zhihong Zhu, Ilja M Nolte, Jana V van Vliet-Ostaptchouk, Harold Snieder, Tonu Esko, Lili Milani, Reedik Mägi, Andres Metspalu, Patrik K E Magnusson, Nancy L Pedersen, Erik Ingelsson, Magnus Johannesson, Jian Yang, David Cesarini, Peter M Visscher
Journal: Nature Genetics (2017)
Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox
Authors: Jun Yang, Sandra Milasta, Dongli Hu, Alaa M. AlTahan, Rodrigo B. Interiano, Junfang Zhou, Jesse Davidson, Jonathan Low, Wenwei Lin, Ju Bao, Pollyanna Goh, Amit C. Nathwani, Ruoning Wang, Yingdi Wang, Su Sien Ong, Vincent A. Boyd, Brandon Young, Sourav Das, Anang Shelat, Yinan Wu, Zhenmei Li, Jie J. Zheng, Ashutosh Mishra, Yong Cheng, Chunxu Qu, Junmin Peng, Douglas R. Green, Stephen White, R. Kiplin Guy, Taosheng Chen, Andrew M. Davidoff
Journal: Cancer Research (2017)

Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy. Cancer Res; 77(17); 4626-38. ©2017 AACR.
Abstract 40: Discovery and Characterization of the Novel Muscle-Specific Membrane Protein Smco1
Authors: James B Papizan, John R McAnally, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2015)

Mutations in numerous membrane proteins cause debilitating myopathies. The discovery of novel muscle-specific, membrane proteins would likely provide insight into mechanisms of disease and potentially yield new therapeutic targets. Through bioinformatics screening for muscle-specific membrane proteins with unknown function, we identified C3orf43 or single-pass membrane protein with coiled-coil domains 1 (Smco1). Consistent with bioinformatics predictions, Smco1 is expressed exclusively in cardiac and skeletal muscle. We demonstrate with chromatin immunoprecipitation and luciferase promoter assays that Smco1 is a Mef2-regulated gene with robust expression occurring shortly after birth. Immunofluorescent analysis demonstrates Scmo1 localizes to the cardiomyocyte sarcolemma and intercalated disks. Talen-mediated disruption of Smco1 in mice results in stunted postnatal growth, cardiac hypoplasia and skeletal muscle myopathy as early as postnatal day 15. While studies are on going to determine the function of Smco1, our findings reveal an essential role of Smco1 in striated muscle structure and function. The identification of heart- and muscle-specific membrane proteins will likely illuminate the mechanisms of muscular membrane diseases.
Desmoid Tumors and Celecoxib with Sorafenib
Authors: Nicolas Benech, Thomas Walter, Jean-Christophe Saurin
Journal: New England Journal of Medicine (2017)

Desmoid tumors are difficult to treat when not amenable to resection. Two cases are reported in which there was regression of desmoid tumors in response to treatment with sorafenib and celecoxib.
Cobimetinib (C) + paclitaxel (P) as first-line treatment in patients (pts) with advanced triple-negative breast cancer (TNBC): Updated results and biomarker data from the phase 2 COLET study.
Authors: Adam Brufsky, Sung-Bae Kim, Thierry J. Velu, Jose Angel Garcia Saenz, Elizabeth Tan-Chiu, Joohyuk Sohn, Luc Yves Dirix, Jaroslav Vanasek, Marleen V. Borms, J. Ignacio Delgado Mingorance, Mei-Ching Liu, Mehdi M. Moezi, Mark Kozloff, Joseph A. Sparano, Jessie J. Hsu, Matthew Wongchenko, Brian P. Simmons, V. A. McNally, David Miles
Journal: Journal of Clinical Oncology (2016)

1074 Background: C is a highly selective MEK inhibitor. Up-regulation of the MAPK pathway may confer resistance to taxane therapy. Because resistance to taxanes occurs in most TNBC pts and many TNBC tumors harbor genetic alterations in the MAPK pathway, the combination of C+P may be beneficial. Methods: COLET (NCT02322814) is evaluating the safety and efficacy of C+P in pts with metastatic/locally advanced TNBC and no prior systemic therapy for metastatic disease. There are 2 stages: a safety run-in (n≈12) followed by a 1:1 randomized stage (n≈100 pts) to C+P or placebo (PBO) + P. Pts receive P 80 mg/m2 on Days 1, 8, and 15 and C/PBO 60 mg/d on Days 3-23 of each 28-d cycle until disease progression or unacceptable toxicity. Safety stage is complete and the randomized stage is enrolling. Results: Between Mar 12, 2015, and Jun 8, 2015, 16 pts were enrolled in the safety stage. All were women (median age, 55 years). At data cutoff (Dec 1, 2015), 14 pts had completed ≥1 cycle; all 16 pts received ≥1 dose of study treatment and were included in the safety review. Median time on treatment was 135 d (range, 1-245). 94% of pts had ≥1 adverse event (AE). Most common (≥20%) AEs of any grade were diarrhea (63%), rash (50%), nausea (44%), alopecia (31%), and pyrexia, blood CPK level increase, asthenia, dyspnea, edema peripheral, stomatitis, vomiting, and constipation (all 25%). 9 pts (56%) had grade 3 AEs; there were no grade 4-5 AEs. Serous retinopathy is a known AE of C; in this study, 2 pts reported one grade 1 AE each. Preliminary efficacy from safety run-in included unconfirmed partial response (n = 8), stable disease (n = 3), and progressive disease (n = 3); 2 pts had not completed a tumor assessment. Mutation and copy number changes in oncogenes, tumor suppressors, and other genes associated with TNBC will be reported. Conclusions: This is the first study to evaluate C+P in TNBC. The safety profile of C+P is consistent with known safety profiles. Initial results are promising, and enrollment in the randomized stage is ongoing (primary efficacy outcome of progression-free survival). Pts in the safety stage continue to be followed up for long-term safety and disease progression. Clinical trial information: NCT02322814.
Restorative Proctocolectomy: Is it Safe in a District General Hospital?
Authors: KL Kirkpatrick, S Thomson, S Khan, RI Hallan
Journal: Endoscopy (2006)

Results: Twenty-eight patients (11 female, 17 male) underwent RP over 11 years. Median age was 35 (16–63). Median follow-up is 50 months (2–129). All patients had a diagnosis of colitis, nine were taking steroids peri-operatively. Eleven patients had simultaneous colectomy and RP with ileostomy. Seventeen patients had undergone previous colectomy (10 as an emergency); at the time of RP, 4 of these also had a covering ileostomy. A catheter was sited for pouch decompression in the thirteen patients without a covering ileostomy until a contrast study showed no pouch-anal leak. Eight patients had early complications including DVT (n=1), high output stomas (n=3), prolonged ileus (n=2), post-operative bleeding (n=1). Late complications were pouchitis (n=6), incisional hernia (n=3), significant anaemia (n=2), pouch-vaginal fistulation (n=1), significant pouch-anal stenosis (n=4), bowel obstruction (n=2). Fifteen patients (54%) open their bowels less than six times in 24 hours, although ten (36%) take constipating drugs regularly and four open their bowels at night. Patients are generally satisfied with bowel function.
Abstract P311: Differential Changes in Caveolin Levels in Lung and Heart from Ozone-Exposed Adult Healthy Rats
Authors: Rajat Sethi, Magdalena Ramirez, Ashoka Bandla, Shubham Manchanda, Carlos Garcia, David Dostal
Journal: Circulation Research (2011)

Acute exposure to ozone (O 3 ) has been reported to possess beneficial effects in the injured myocardium. We have demonstrated that chronic O 3 exposure elicits cardiac dysfunction in rats. These results suggest that acute and chronic exposures to O 3 have different effects on myocardial function. On the contrary exposure to acute ozone levels has shown to cause lung injury. Although effects of chronic exposure to ozone on the lung has not been determined, it is reasonable to suggest that ozone mediated toxicity may be tissue specific. It appears that in chronic cardiac injury subsequent to an ischemic insult, lipid raft proteins such as caveolin-1 and caveolin-3 play vital roles in the generation of death and survival signaling in the heart. In lung injury subsequent to acute O 3 exposure, dramatic reductions in caveolin-1 levels were associated with increases in lung TNF-α. Our previous studies showed increased expressions of myocardial TNF-α after chronic O 3 exposure. In the present study we wanted to determine the regulatory role of caveolin-1 and caveolin-3 in hearts and lungs from rats exposed to chronic O 3 levels. Sprague Dawley rats were exposed 8 hrs/day for 28 and 56 days to filtered air or 0.8 ppm O 3 . In order to assess the chronic effects to O 3 , levels of caveolin-1 and caveolin-3 in the lung and heart tissue were measured 24 hrs after termination of the O 3 exposure. Caveolin-1 levels in hearts from the ozone exposed groups were significantly decreased compared to air exposed rats; while caveolin-1 levels in lungs from the same animals were not different from the air exposed group. On the other hand caveolin-3 levels in hearts from the ozone exposed groups increased and decreased after 4 and 8 week of ozone exposure compared to air exposed rats; while caveolin-3 levels in lungs from the same animals were not different from the air exposed group. These novel findings suggest the interesting possibility that caveolin expressions subsequent to chronic ozone exposure may be tissue specific.
Pre-treatment endogenous interleukin-1 receptor antagonist (IL-1Ra) levels in metastatic colorectal cancer (mCRC) patients are associated with clinical outcomes after anti-interleukin-1a therapy (MABp1)
Authors: Razelle Kurzrock, Tamas Hickish, Lucjan Wyrwicz, Thierry André, Tomasz Sarosiek, Judit Kocsis, Radim Nemecek, Qian Wu, Prasant Mohanty, Mike Stecher, John Simard, Charles Dinarello
Journal: Annals of Oncology (2017)
Quality of Life Assessment after Laparoscopic Nissen Rossetti Fundoplication – A Prospective Study
Authors: PC Munipalle, B Gurney, YKS Viswanath
Journal: Endoscopy (2006)

Aims: Gastro-oesophageal reflux disease (GORD) is a common disorder in the Western world and currently antireflux surgery is an established treatment. This study aims at evaluating the postoperative results and compare pre- and postoperative quality of life with laparoscopic Nissen-Rossetti fundoplication (LNRF).
Complications of Diabetes Diagnosed in Children and Adolescents—Reply
Authors: Dana Dabelea, Ralph D’Agostino, Elizabeth J. Mayer-Davis
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 163: Inhibition of p38a Regulates SERCA2a Function
Authors: Leena Kaikkonen, Johanna Magga, Veli-Pekka Ronkainen, Elina Koivisto, ábel Perjes, Kurt Chuprun, Leif E Vinge, Jani Aro, Johanna Ulvila, Tarja Alakoski, James Bibb, Istvan Szokodi, Walter J Koch, Heikki Ruskoaho, Risto Kerkelä
Journal: Circulation Research (2013)

Rationale: p38 MAPK is a negative regulator of cardiac contractile function, but the underlying molecular mechanism is not well understood. Objective: To determine the molecular mechanism mediating the positive inotropic effect of p38 inhibition. Methods and Results: The effect of p38 inhibition on calcium regulatory proteins and calcium cycling was investigated in isolated neonatal and adult rodent cardiomyocytes using chemical inhibitors, recombinant adenoviruses and RNAi. Chemical inhibition of p38 enhanced phospholamban (PLB) phosphorylation at serine 16 residue. This was recapitulated with dominant negative p38α adenovirus and by p38α RNAi, but not with dominant negative p38β adenovirus. Chemical inhibition of p38 and dominant negative p38α resulted in significant decrease in Ca 2+ -transient decay time in adult rat cardiomyocytes. Inhibition of p38α, but not p38β, induced an increase in phosphorylation of protein phosphatase inhibitor-1 at the protein kinase A site threonine 35. Analysis of underlying mechanisms revealed that p38 inhibition increased phosphorylation of G protein-coupled receptor kinase 2 (GRK2), but not GRK3 or GRK5. p38 inhibition- induced PLB phosphorylation was abolished in cardiomyocytes overexpressing wild type GRK2. In contrast, increased PLB phosphorylation upon p38 inhibition was not reduced in cardiomyocytes overexpressing GRK2 harboring a non-phosphorylatable mutation in serine 670 residue. Finally, p38 inhibition-induced shortening of Ca 2+ -transient decay time was absent in cardiomyocytes overexpressing wild type GRK2. Conclusions: Inhibition of p38α regulates protein phosphatase inhibitor-1 resulting in increased PLB phosphorylation and enhanced SERCA2a function.
Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).
Authors: Apurva Jain, Rachna T. Shroff, Mingxin Zuo, Jacqueline Weatherly, Funda Meric-Bernstam, Randi Isaacs, Siraj Mahamed Ali, Tanios S. Bekaii-Saab, Milind M. Javle
Journal: Journal of Clinical Oncology (2017)

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; &lt; 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p &lt; 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p &lt; 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.
Modification of the cytotoxic activity of cerium oxide nanoparticles (CNP) in relation to pH (physiological vs tumoral)
Authors: Amador Garcia Fuente, Jose Vazquez Villa, Daniel Martinez Perez, Rebeca Fernandez Fernandez, García Alonso Francisco J, Martin Carbajo Jose I, Alejandro Criado, Luis Barneo, Paula Fonseca, de Prado Jose Maria Vieitez, Jaime Ferrer
Journal: Annals of Oncology (2017)