tbuckley/cabot-search huggingface dataset:
LCCC 1525: Combination immunotherapy with cyclophosphamide plus pembrolizumab in patients with advanced triple negative breast cancer (TNBC).
Authors: Benjamin Garrett Vincent, Dominic T. Moore, Susan G. Moore, Rebecca Davidson Kaltman, Shannon Puhalla, Vinay K. Gudena, Lisa A. Carey, Elizabeth Claire Dees, Hyman B. Muss, Katherine Elizabeth Reeder-Hayes, Trevor Augustus Jolly, Jonathan Stuart Serody, Carey K. Anders
Journal: Journal of Clinical Oncology (2017)

TPS1125 Background: Immunotherapy is a promising strategy to treat advanced TNBC, an aggressive subtype of BC lacking expression of estrogen and progesterone receptors and HER2. TNBC response to antibodies targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) are modest (&lt; 20%); high expression of PD-L1 is associated with enhanced response. The presence of intratumoral regulatory T cells (Tregs), potent suppressors of the immune response, dampens response to checkpoint inhibitors. The capacity of cyclophosphamide (Cy), a cytotoxic with known activity in BC, to deplete Tregs is well-established. Preclinical mouse models of TNBC illustrate Treg depletion with improved outcome when Cy is administered prior to PD-1 inhibition. We are testing the hypothesis that a single dose of Cy given prior to pembrolizumab (pembro) will improve progression free survival (PFS) beyond historical control in advanced TNBC. Methods: This phase II, single-arm, multicenter study will evaluate pembro 200 mg IV every 3 weeks following a single priming dose of Cy 300 mg/m2 IV in patients (pts) with advanced TNBC who have received ≥1 prior therapy in the metastatic setting. The primary objective is to estimate PFS for Cy + pembro in advanced TNBC pts. A co-primary objective is to describe reduction in circulating Tregs. Secondary objectives include overall response rate (ORR, RECIST 1.1), duration of response (DOR), disease control rate (DCR) and overall survival (OS). Determination of ORR based on immune response criteria (irRECIST) and association of immunogenomic features with PFS are exploratory. Statistical considerations: A sample size of 36 pts has an 80% power to detect change in median PFS from 1.9 (null) to 2.9 (alternative hypothesis) months at a 0.05 significance level. Assuming 10% dropout rate, we will enroll 40 pts. We will also be able to detect a 67% reduction in Tregs with 80% power and one-sided alpha = 0.05. Correlative studies: Archival primary and/or metastatic tissues are required of all pts to evaluate molecular subtype, gene signature expression, T and B cell receptor repertoires, and PD-1 and PD-L1 expression; correlations with outcome will be performed. Clinical trial information: NCT02768701.
Erratum. Combination Therapy With Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in Patients With Poorly Controlled Type 2 Diabetes on Sulfonylurea Plus Metformin: The Qatar Study. Diabetes Care 2017;40:325–331
Authors: Muhammad Abdul-Ghani, Osama Migahid, Ayman Megahed, John Adams, Curtis Triplitt, Ralph A. DeFronzo, Mahmoud Zirie, Amin Jayyousi
Journal: Diabetes Care (2017)

In the above-mentioned article, Fig. 1 A was corrected (the colors in the panel were switched) to …
Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer
Authors: Uzma S. Asghar, Alexis R. Barr, Ros Cutts, Matthew Beaney, Irina Babina, Deepak Sampath, Jennifer Giltnane, Jennifer Arca Lacap, Lisa Crocker, Amy Young, Alex Pearson, Maria Teresa Herrera-Abreu, Chris Bakal, Nicholas C. Turner
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of breast cancer that is associated with a poor prognosis. We evaluated the activity of CDK4/6 inhibitors across the TNBC subtypes and investigated mechanisms of sensitivity. Experimental Design: A panel of cell lines representative of TNBC was tested for in vitro and in vivo sensitivity to CDK4/6 inhibition. A fluorescent CDK2 activity reporter was used for single-cell analysis in conjunction with time-lapse imaging. Results: The luminal androgen receptor (LAR) subtype of TNBC was highly sensitive to CDK4/6 inhibition both in vitro (P &amp;lt; 0.001 LAR vs. basal-like) and in vivo in MDA-MB-453 LAR cell line xenografts. Single-cell analysis of CDK2 activity demonstrated differences in cell-cycle dynamics between LAR and basal-like cells. Palbociclib-sensitive LAR cells exit mitosis with low levels of CDK2 activity, into a quiescent state that requires CDK4/6 activity for cell-cycle reentry. Palbociclib-resistant basal-like cells exit mitosis directly into a proliferative state, with high levels of CDK2 activity, bypassing the restriction point and the requirement for CDK4/6 activity. High CDK2 activity after mitosis is driven by temporal deregulation of cyclin E1 expression. CDK4/6 inhibitors were synergistic with PI3 kinase inhibitors in PIK3CA-mutant TNBC cell lines, extending CDK4/6 inhibitor sensitivity to additional TNBC subtypes. Conclusions: Cell-cycle dynamics determine the response to CDK4/6 inhibition in TNBC. CDK4/6 inhibitors, alone and in combination, are a novel therapeutic strategy for specific subgroups of TNBC. Clin Cancer Res; 23(18); 5561–72. ©2017 AACR.
Introducing Emerging Science for the Clinician
Authors: Michael S. Parmacek
Journal: JAMA Cardiology (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 Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Cardiology journal
Localization of Eosinophils to Different Subspecies of Nerves in Inflammatory Bowel Disease
Authors: CM Smyth, S Woods, M Thornton, A O'Grady, GJ Gleich, FE Murray, RW Costello
Journal: Endoscopy (2004)

Introduction: The role of the eosinophil, which is a common inflammatory cell in inflamed gastrointestinal mucosa in inflammatory bowel disease (IBD) is uncertain. Many of the symptoms of IBD are due to neural dysregulation, including increased mucous production and dysmotility. We hypothesized that an interaction between eosinophils and nerves may explain how inflammation is related to neural dysfunction in IBD. The aim of this study was to determine the interaction of eosinophils with nerves in IBD, and to define the type of nerves involved.
Monocytes Are Required for Both Optimal Anti-Leukemic Efficacy and the Cytokine Release Syndrome By CAR-T Cells: Lessons from an Innovative Xenotolerant Mouse Model
Authors: Margherita Norelli, Monica Casucci, Barbara Camisa, Laura Falcone, Catia Traversari, Claudio Bordignon, Fabio Ciceri, Chiara Bonini, Attilio Bondanza
Journal: Blood (2016)
Effect of Noninvasive Ventilation on Tracheal Reintubation Among Patients With Hypoxemic Respiratory Failure Following Abdominal Surgery
Authors: Samir Jaber, Thomas Lescot, Emmanuel Futier
Journal: JAMA (2016)

Importance  It has not been established whether noninvasive ventilation (NIV) reduces the need for invasive mechanical ventilation in patients who develop hypoxemic acute respiratory failure after abdominal surgery.

Objective  To evaluate whether noninvasive ventilation improves outcomes among patients developing hypoxemic acute respiratory failure after abdominal surgery.

Design, Setting, and Participants  Multicenter, randomized, parallel-group clinical trial conducted between May 2013 and September 2014 in 20 French intensive care units among 293 patients who had undergone abdominal surgery and developed hypoxemic respiratory failure (partial oxygen pressure <60 mm Hg or oxygen saturation [Spo2] ≤90% when breathing room air or <80 mm Hg when breathing 15 L/min of oxygen, plus either [1] a respiratory rate above 30/min or [2] clinical signs suggestive of intense respiratory muscle work and/or labored breathing) if it occurred within 7 days after surgical procedure.

Interventions  Patients were randomly assigned to receive standard oxygen therapy (up to 15 L/min to maintain Spo2 of 94% or higher) (n = 145) or NIV delivered via facial mask (inspiratory pressure support level, 5-15 cm H2O; positive end-expiratory pressure, 5-10 cm H2O; fraction of inspired oxygen titrated to maintain Spo2 ≥94%) (n = 148).

Main Outcomes and Measures  The primary outcome was tracheal reintubation for any cause within 7 days of randomization. Secondary outcomes were gas exchange, invasive ventilation–free days at day 30, health care–associated infections, and 90-day mortality.

Results  Among the 293 patients (mean age, 63.4 [SD, 13.8] years; n=224 men) included in the intention-to-treat analysis, reintubation occurred in 49 of 148 (33.1%) in the NIV group and in 66 of 145 (45.5%) in the standard oxygen therapy group within+ 7 days after randomization (absolute difference, −12.4%; 95% CI, −23.5% to −1.3%; P = .03). Noninvasive ventilation was associated with significantly more invasive ventilation–free days compared with standard oxygen therapy (25.4 vs 23.2 days; absolute difference, −2.2 days; 95% CI, −0.1 to 4.6 days; P = .04), while fewer patients developed health care–associated infections (43/137 [31.4%] vs 63/128 [49.2%]; absolute difference, −17.8%; 95% CI, −30.2% to −5.4%; P = .003). At 90 days, 22 of 148 patients (14.9%) in the NIV group and 31 of 144 (21.5%) in the standard oxygen therapy group had died (absolute difference, −6.5%; 95% CI, −16.0% to 3.0%; P = .15). There were no significant differences in gas exchange.
Abstract 11307: Interleukin-1β and Methylation of Apoptosis Associated Speck-Like Protein Containing a Caspase Recruitment Domain Are Associated With Aerobic Capacity in Heart Failure
Authors: Brittany Butts, Javed Butler, Sandra B Dunbar, Elizabeth J Corwin, Rebecca A Gary
Journal: Circulation (2016)

Background: Aerobic capacity, as measured by peak oxygen uptake (V˙O 2 ), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and the interleukin (IL)-1 cytokine IL-1β is implicated in this process. The adaptor protein ASC (apoptosis associated speck-like protein containing a caspase recruitment domain) is necessary for inflammasome activation of IL-1β. ASC expression is controlled through epigenetic modification, and lower ASC methylation is associated with worse outcomes in HF. Hypothesis: Peak V˙O 2 will be positively related to ASC methylation and negatively related to IL-1β in persons with HF. Methods: This cross-sectional study examined the relationship between ASC methylation and the inflammatory cytokine IL-1β with peak V˙O 2 in 54 stable outpatients with HF. All participants were NYHA class II or III, not currently engaged in an exercise program, and physically able to complete a symptom limited modified Balke exercise treadmill test. Results: Participants were 59 ± 10 years of age, 52% female, and 59% African American. Mean peak V˙O 2 was 16.68 ± 4.7 ml/kg/min. Peak V˙O 2 was positively associated with mean percent ASC methylation (r=.47, p=.001) and negatively associated with IL-1β (r=-.38, p=.007). Multiple linear regression models controlling for left ventricular ejection fraction and gender demonstrated that peak V˙O2 increased by 2.30 ml/kg/min for every 1% increase in mean ASC methylation and decreased by 1.91 ml/kg/min for every 1 pg/mL increase in plasma IL-1β. Conclusions: Mean percent ASC methylation and plasma IL-1β levels are associated with clinically meaningful changes in peak V˙O 2 in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF. Modification of ASC expression via behavioral interventions that increase ASC methylation may improve aerobic capacity in persons with HF.
Margaret McCartney: Remember that doctors are more trusted than journalists
Authors: Margaret McCartney
Journal: BMJ (2017)

In the past few months the Daily Mail has excoriated GPs for letting “millions” down by being “shut in the afternoon,”1 for “failing an estimated 32 000 cancer patients,”2 and for “failing to diagnose patients with early dementia.”3 It often does this on the front page in large font, and I know that these headlines hurt many GPs who work long and hard under intolerable pressure.

Free speech is important, and the press should be able to say what it likes. But it was perhaps predictable that Wikipedia would decide not to use the Daily Mail as a reference in all but exceptional circumstances because of its “reputation for poor fact checking, sensationalism, and flat-out fabrication.”4

If …
Cytogenetic Abnormalities and Treatment with New Drugs on Clinical Trials Are Important Prognostic Markers for Myeloma in the Era of ISS and FISH Analysis
Authors: Cinnie Yentia Soekojo, Adeline Lin, Michelle Poon, Liang Piu Koh, Lip Kun Tan, Melissa G. Ooi, Wee Joo Chng
Journal: Blood (2016)
Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease — United States
Authors: Natalie S. Marzec, Christina Nelson, Paul Ravi Waldron, Brian G. Blackburn, Syed Hosain, Tara Greenhow, Gary M. Green, Catherine Lomen-Hoerth, Marjorie Golden, Paul S. Mead
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks.
Abstract 8556: Inhibition of Grk2 Augments Cardiac Beta2-Adrenergic Receptor-Dependent Contractility via Prevention of Receptor Interaction with Phosphodiesterase Type 4d
Authors: Anastasios Lymperopoulos, Giuseppe Rengo, Erhe Gao, Walter J Koch
Journal: Circulation (2011)

β 1 - and β 2 -adrenergic receptors (βARs) are G-protein coupled receptors (GPCRs) that play clearly distinct roles in cardiac physiology/pathology. For instance, cardiomyocyte contraction is readily stimulated by β 1 AR but not β 2 AR signaling. This might be explained by differences in assembly of macromolecular signaling complexes: β 1 AR forms a signaling complex with phosphodiesterase (PDE) type 4D8 directly, and agonist binding dissociates this complex. Conversely, GPCR kinase (GRK)2-induced β 2 AR phosphorylation leads to recruitment of a complex consisting of β-arrestin (βarr), a universal GPCR adapter/scaffolding molecule, and another PDE4D variant, PDE4D5. This PDE4D recruitment is postulated to constrain β 2 AR pro-contractile signaling by limiting compartmentalization of 3′-5′-adenosine monophosphate signaling. Thus, herein, we sought to investigate the effect of inhibition of this complex recruitment on β 2 AR pro-contractile signaling in vivo. In order to block β 2 AR-PDE4D interaction in cardiac myocytes in vivo, we crossed β 1 AR knockout (B1KO) mice, which do not express β 1 AR, with M27 mice, which overexpress, specifically in cardiac myocytes, the GRK2 inhibitor GRK2ct (or βARKct). By blocking GRK2-mediated phosphorylation, βarr-dependent PDE4D recruitment to β 2 AR is prevented. We studied the offspring both under normal conditions and after surgically induced myocardial infarction (MI). Contractility was significantly augmented in M27/B1KO mice compared to B1KO's, both in healthy mice (ejection fraction (EF): 69+1.8% vs. 57+1.7% respectively, p&lt;0.05, n=8) and at 4 weeks after MI (EF: 42.6+0.1% vs. 25+3.9% respectively, p&lt;0.05, n=8). In addition, GRK2ct expression attenuated cardiac dilatation of B1KO's at 4 weeks post-MI. At the molecular level, M27/B1KO hearts displayed significantly less membrane recruitment of both PDE4D5 and PDE4D3 compared to B1KO hearts, as evidenced by western blotting in cardiac membrane preparations, indicating less β 2 AR-PDE4D interaction. Thus, cardiac GRK2 inhibition by GRK2ct increases β 2 AR-dependent contractility both normally and in post-MI heart failure. The underlying mechanism appears to involve inhibition of the GRK2/βarr-mediated PDE4D recruitment to the receptor.
Closing the Quality Gap After Laparoscopic Colectomy
Authors: Stefan D. Holubar, Scott R. Steele
Journal: JAMA Surgery (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 Surgery HomeNew OnlineCurrent IssueFor Authors Podcast 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 Surgery journal
Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study
Authors: Ni Jiang, Guoliang Qiao, Xiaoli Wang, Michael A. Morse, William R. Gwin, Lei Zhou, Yuguang Song, Yanjie Zhao, Feng Chen, Xinna Zhou, Lefu Huang, Amy Hobeika, Xin Yi, Xuefeng Xia, Yanfang Guan, Jin Song, Jun Ren, H. Kim Lyerly
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy. Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care. Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P &amp;lt; 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P &amp;lt; 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3+, CD3+/CD4+, and CD8+/CD28+ T-cell subsets were elevated (P &amp;lt; 0.05), while the CD3+/CD8+, CD3+/CD16+/CD56+ and CD4+/CD25+ cell subsets were significantly decreased after DC-CIK cell therapy (P &amp;lt; 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival. Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066–73. ©2017 AACR.
Half of salaried and locum GPs are stressed, BMA survey finds
Authors: Abi Rimmer
Journal: BMJ (2017)

Half of salaried and locum GPs in the UK experience work related stress, a survey by the BMA has found.

Between 1 March and 6 April the BMA emailed a survey to 13 800 of its members who it identified as working, or potentially working, as sessional (salaried and locum) GPs. The survey received 2079 responses (a 15% response rate)

Just over half (52%) of the respondents reported having felt …
Modeling the benefits and harms of surveillance for hepatocellular carcinoma: Information to support informed choices
Authors: Eleanor J. Taylor, Rebecca L. Jones, J. Ashley Guthrie, Ian A. Rowe
Journal: Hepatology (2017)

Surveillance by ultrasonography for hepatocellular carcinoma (HCC) for individuals with cirrhosis is recommended. There is debate regarding the effectiveness of surveillance in reducing mortality, and there is little information on the harms available to patients considering surveillance. The aim of this study was to provide estimates of both the benefit and harms of surveillance. A Markov model was built to simulate outcomes of individuals aged 50 years with well-compensated cirrhosis entering surveillance. Following identification of a focal lesion by ultrasound surveillance, further investigations were defined by the European Association for the Study of the Liver/European Organization for Research and Treatment of Cancer recall policy. Benefit and harm outcomes are expressed per 1,000 patients over 5 years. For every 1,000 patients in surveillance over 5 years, there are 13 fewer deaths (95% confidence interval [CI], 12-14) compared with no surveillance, equating to a number needed to screen to prevent one death from HCC of 77. In comparison, many more individuals experienced harm through surveillance. For every 1,000 patients, 150 (95% CI, 146-154) had one or more false-positive tests equating to a number needed to harm from surveillance of 7. As a consequence of a false-positive test, 65 individuals required at least one additional unnecessary computed tomography scan or magnetic resonance imaging and 39 required an unnecessary liver biopsy according to the recall policy. Surveillance benefits were sensitive to the incidence of HCC and the mortality benefit achieved by treatment. Harms were sensitive to the rates of false-positive testing and the frequency of liver biopsy.There is a balance between the small absolute mortality benefit to surveillance for HCC and the numerically more frequent harms resulting from false-positive testing. Implementation of the recently revised American Association for the Study of Liver Diseases recommendations is predicted to reduce harms from unnecessary liver biopsy. (Hepatology 2017;66:1546-1555).