tbuckley/cabot-search huggingface dataset:
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors
Authors: Jason J. Luke, Jeffrey M. Lemons, Theodore G. Karrison, Sean P. Pitroda, James M. Melotek, Yuanyuan Zha, Hania A. Al-Hallaq, Ainhoa Arina, Nikolai N. Khodarev, Linda Janisch, Paul Chang, Jyoti D. Patel, Gini F. Fleming, John Moroney, Manish R. Sharma, Julia R. White, Mark J. Ratain, Thomas F. Gajewski, Ralph R. Weichselbaum, Steven J. Chmura
Journal: Journal of Clinical Oncology (2018)

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1–treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases &gt; 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ–induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ–associated genes from post–SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1–directed immunotherapy are warranted.
A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers
Authors: Enrique Martin-Gayo, Michael B. Cole, Kellie E. Kolb, Zhengyu Ouyang, Jacqueline Cronin, Samuel W. Kazer, Jose Ordovas-Montanes, Mathias Lichterfeld, Bruce D. Walker, Nir Yosef, Alex K. Shalek, Xu G. Yu
Journal: Genome biology (2018)

Human immunity relies on the coordinated responses of many cellular subsets and functional states. Inter-individual variations in cellular composition and communication could thus potentially alter host protection. Here, we explore this hypothesis by applying single-cell RNA-sequencing to examine viral responses among the dendritic cells (DCs) of three elite controllers (ECs) of HIV-1 infection. To overcome the potentially confounding effects of donor-to-donor variability, we present a generally applicable computational framework for identifying reproducible patterns in gene expression across donors who share a unifying classification. Applying it, we discover a highly functional antiviral DC state in ECs whose fractional abundance after in vitro exposure to HIV-1 correlates with higher CD4+ T cell counts and lower HIV-1 viral loads, and that effectively primes polyfunctional T cell responses in vitro. By integrating information from existing genomic databases into our reproducibility-based analysis, we identify and validate select immunomodulators that increase the fractional abundance of this state in primary peripheral blood mononuclear cells from healthy individuals in vitro. Overall, our results demonstrate how single-cell approaches can reveal previously unappreciated, yet important, immune behaviors and empower rational frameworks for modulating systems-level immune responses that may prove therapeutically and prophylactically useful.
Abstract 20804: Models of Ischemia/Reperfusion Need to Consider Cardiac Sympathetic Nerve Injury
Authors: Ian A White, Lauro M Takeuchi, Alessia C Lavin, Wayne Balkan, Joshua M Hare
Journal: Circulation (2017)

Introduction: Substantial damage and scarring to the heart can result following a myocardial infarction (MI) even when the tissue is successfully reperfused. The physiological and biochemical cause...
Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis
Authors: Yun Zhang, Sebastian Pötter, Chih-Wei Chen, Ruifang Liang, Kolja Gelse, Ingo Ludolph, Raymund E Horch, Oliver Distler, Georg Schett, Jörg H W Distler, Clara Dees
Journal: Annals of the Rheumatic Diseases (2018)

Objectives The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. Methods The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. Results The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. Conclusion PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.
Modulation of ABCB1 (MDR1) and ABCC2 (MRP2) expression dependent on genetic polymorphisms in renal cell carcinoma.
Authors: Ingolf Cascorbi, Sierk Haenisch, Uwe Zimmermann, Peter Dazert, Rolf Warzok
Journal: Cancer Research (2004)

2035   The transmembrane transporters P-glycoprotein (PGP), encoded by MDR1 (ABCB1) gene, and multidrug resistance-related protein 2 (MRP2, ABCC2), actively excrete various substances and their organic anion conjugates. In kidney, both transporters are expressed in epithelial tubules cells and are therefore believed to be involved in the export of potential carcinogens but may also contribute to chemotherapy resistance. ABCB1 and ABCC2 mRNA expression of 40 renal cancer and adjacent tumour-free tissue samples was determined by real-time PCR and DNA was genotyped for MDR1 polymorphisms G2677T/A (Ala893Ser/Thr) and C3435T, and MRP2 C-24T in the 5’UTR region, G1249A (Val417Ile), and C3972T. In relation to 18S rRNA, MRP2 mRNA, but not MDR1, was significantly lower expressed in tumours than in healthy tissues (median 4,54 vs. 2,80; p=0,032). No significant correlation between genotypes and gene expressions of MDR1 and MRP2 was found. However, a significant increased allelic frequency of MRP2 -24T in renal cell carcinoma patients versus 197 controls could be observed (27,6% vs. 16,0%; p=0,008). Histological tumour classification and clinical outcome have to be included in further investigations.
Shorter duration of antibiotic treatment for acute bacteraemic cholangitis with successful biliary drainage: a retrospective cohort study
Authors: A. Doi, T. Morimoto, K. Iwata
Journal: Clinical Microbiology and Infection (2018)

ObjectivesTo assess the effectiveness of short duration antimicrobial therapy for acute cholangitis with bacteraemia.MethodsWe conducted a retrospective cohort study of patients with acute bacteraemic cholangitis with successful biliary duct drainage at a single centre in Japan. We compared short-course antimicrobial therapy (SCT, ≤7 days) and long-course therapy (LCT, ≥8 days), with a primary outcome of 30-day mortality. We constructed logistic regression models for mortality and a composite outcome, including mortality, recurrence, recrudescence, new bacteraemia, liver abscess or other complications related to cholangitis. We also developed a propensity score for SCT with inverse probability weighting for both the primary outcome and the composite outcome.ResultsWe identified 263 patients in our cohort; 86 (32.7%) patients received SCT and the remaining 177 (67.3%) received LCT. The median durations of SCT and LCT were 6 days (range 2–7 days) and 12 days (range 8–46 days), respectively. The 30-day mortalities of SCT and LCT were 4.7% (4/85) and 5.7% (10/176), respectively (p 1.00). Logistic regression analysis showed that the odds ratio of SCT for 30-day mortality and the composite outcome were 1.07 (95% CI 0.25–4.52, p 0.93) and 1.08 (95% CI 0.48–2.45, p 0.85), respectively. Propensity score analyses for both 30-day mortality and the composite outcome did not demonstrate a difference between SCT and LCT (p 0.65 and p 0.95, respectively).ConclusionsSCT with a median duration of 6 days did not have worse outcomes than LCT with a median duration of 12 days. Shortening the duration of antimicrobial therapy may be a reasonable option when treating acute bacteraemic cholangitis following successful biliary drainage.
Association of Heritable Cognitive Ability and Psychopathology With White Matter Properties in Children and Adolescents
Authors: Dag Alnæs, Tobias Kaufmann, Nhat Trung Doan, Aldo Córdova-Palomera, Yunpeng Wang, Francesco Bettella, Torgeir Moberget, Ole A. Andreassen, Lars T. Westlye
Journal: JAMA Psychiatry (2018)

Many mental disorders emerge during adolescence, which may reflect a cost of the potential for brain plasticity offered during this period. Brain dysconnectivity has been proposed as a common factor across diagnostic categories.To investigate the hypothesis that brain dysconnectivity is a transdiagnostic phenotype in adolescence with increased susceptibility and symptoms of psychiatric disease.We investigated clinical symptoms as well as cognitive function in 6487 individuals aged 8 to 21 years from November 1, 2009, to November 30, 2011, in the Philadelphia Neurodevelopmental Cohort and analyzed diffusion magnetic resonance imaging brain scans for 748 of the participants.Independent component analysis was used to derive dimensional psychopathology scores, and genome-wide complex trait analysis was used to estimate its heritability. Multimodal fusion simultaneously modeled contributions of the diffusion magnetic resonance imaging metrics fractional anisotropy, mean diffusivity, radial diffusivity, L1 (the principal diffusion tensor imaging eigen value), mode of anisotropy, as well as dominant and secondary fiber orientations, and structural connectivity density, and their association with general psychopathology and cognition.Machine learning with 10-fold cross-validation and permutation testing in 729 individuals (aged 8 to 22 years; mean [SD] age, 15.1 [3.3] years; 343 females [46%]) revealed significant association with general psychopathology levels (r = 0.24, P < .001) and cognition (r = 0.39, P < .001). A brain white matter pattern reflecting frontotemporal connectivity and crossing fibers in the uncinate fasciculus was the most associated feature for both traits. Univariate analysis across a range of clinical domains and cognitive test scores confirmed its transdiagnostic importance. Both the general psychopathology (16%; SE, 0.095; P = .05) and cognitive (18%; SE, 0.09; P = .01) factor were heritable and showed a negative genetic correlation.Dimensional and heritable general cognitive and psychopathology factors are associated with specific patterns of white matter properties, suggesting that dysconnectivity is a transdiagnostic brain-based phenotype in individuals with increased susceptibility and symptoms of psychiatric disorders.
African Countries Move Closer to Eradicating Guinea Worm Disease
Authors: Rita Rubin
Journal: JAMA (2018)

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
Mindful choice of endoscopic resection for large colorectal lesions
Authors: Heiko Pohl, Michal Filip Kaminski
Journal: Gut (2018)

ESD or not ESD? This question has probably come up in the minds of many advanced endoscopists in the Western world, when debating on how to approach resection of large non-pedunculated colorectal polyps. The benefit of endoscopic submucosal dissection (ESD) is twofold. First, it can achieve en bloc curative resection of low-risk colorectal cancers (CRC)1 that have only invaded the superficial (less than 1000 µm) submucosal layer (sm1 cancers), and that do not show lymphovascular invasion or poor differentiation.2 Second, the recurrence rate following ESD is only 1%–2%.3 But the procedure carries a greater risk of complications, it requires extensive training and special skill, and perhaps more importantly for Western endoscopists, it takes a long time, patience and a different mindset.3 4 The defenders of colorectal endoscopic mucosal resection (EMR) argue that it is safe and efficient and that recurrence can easily be addressed by experts, with over 90% eradication rates after a maximum of two sessions.5 The solution to the controversy therefore focuses on this question: Is colorectal ESD worthwhile to benefit the few patients with low-risk CRC?

The study by Fuccio et al 6 in Gut provides valuable insights to answer this question. The authors systematically reviewed all studies that examined the prevalence of cancer with sm1 invasion of colorectal lesions that were removed by ESD. They found an overall rate of sm invasion of 16%, of which 8% were limited …
TCT-449 Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup: An Updated Meta-analysis of 23 Studies
Authors: Joo Myung Lee, Doyeon Hwang, Jonghanne Park, Kyung-Jin Kim, Kyung Woo Park, Chul Ahn, Bon-Kwon Koo
Journal: Journal of the American College of Cardiology (2015)
Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial
Authors: Anne-Ségolène Cottereau, Annibale Versari, Annika Loft, Olivier Casasnovas, Monica Bellei, Romain Ricci, Stéphane Bardet, Antonio Castagnoli, Pauline Brice, John Raemaekers, Bénédicte Deau, Catherine Fortpied, Tiana Raveloarivahy, Emelie Van Zele, Loic Chartier, Thierry Vander Borght, Massimo Federico, Martin Hutchings, Umberto Ricardi, Marc Andre, Michel Meignan
Journal: Blood (2018)
Activation of Serine One-Carbon Metabolism by Calcineurin Aβ1 Reduces Myocardial Hypertrophy and Improves Ventricular Function
Authors: Laura Padrón-Barthe, María Villalba-Orero, Jesús M. Gómez-Salinero, Rebeca Acín-Pérez, Sara Cogliati, Marina López-Olañeta, Paula Ortiz-Sánchez, Elena Bonzón-Kulichenko, Jesús Vázquez, Pablo García-Pavía, Nadia Rosenthal, José Antonio Enríquez, Enrique Lara-Pezzi
Journal: Journal of the American College of Cardiology (2018)

In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action. Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAβ1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAβ1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAβ1. CnAβ1Δi12 mice show increased cardiac hypertrophy and declined contractility. The metabolic reprogramming induced by CnAβ1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches.
Real-World Impact of a Decision Support Tool on Colony-Stimulating Factor Use and Chemotherapy-Induced Febrile Neutropenia Among Patients With Breast Cancer
Authors: Abiy Agiro, Andrea DeVries, Jennifer Malin, Michael J. Fisch
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: White blood cell colony-stimulating factors (CSFs) decrease the incidence of chemotherapy-induced febrile neutropenia (FN). Widespread use of CSFs that is not guideline-concordant has been reported. Among patients with breast cancer receiving chemotherapy, the ability of evidence-based decision support tools to promote risk-appropriate reductions in CSF use without increased incidence of FN has not been examined. Methods: A retrospective cohort design and US commercial claims data were used. The impact of CSF decision support was analyzed among women with breast cancer receiving first-cycle chemotherapy from April 1, 2013, to March 30, 2015. The tool was implemented as part of a prior authorization process in 9 states starting July 1, 2014. Patients were assigned to intervention (ie, states where the decision support tool had been implemented) or nonintervention states (ie, 39 states where the tool had not been implemented). CSF use and subsequent incidence of FN were compared using difference-in-difference (DID) regressions adjusting for baseline differences in FN risk factors such as comorbidities and various infections. Results: The study sample of 7,224 patients (intervention states: pre-implementation, 1,991 and post-implementation, 2,010; nonintervention states: pre-implementation, 1,569 and post-implementation, 1,654) showed no significant difference in risk factors. Before and after implementation, a significant decrease in the proportion of patients with CSF use was observed in the intervention states (75% to 69%) compared with no significant change in the nonintervention (72% to 71%) states (DID, -5.4%; 95% CI, -6.0% to -4.7%; P=.006). No significance increase in FN incidence occurred in intervention (5.0% to 5.5%) and nonintervention (5.4% to 4.8%) states (DID, 0.2%; 95% CI, -0.20 to 0.30; P=.78). Similar results were obtained in subgroups by comorbidities and in sensitivity analyses by claims-based FN definitions. Conclusions: CSF use decreased modestly after implementation of the decision support tool, with no observed changes in FN rates. Such tools can reduce practice variation to improve care standards.
Delineation of the extent of early gastric cancer by magnifying narrow-band imaging and chromoendoscopy: a multicenter randomized controlled trial
Authors: Takashi Nagahama, Kenshi Yao, Noriya Uedo, Hisashi Doyama, Tetsuya Ueo, Kunihisa Uchita, Hideki Ishikawa, Takashi Kanesaka, Yasuhito Takeda, Kurato Wada, Kentaro Imamura, Hisatomi Arima, Toshio Shimokawa
Journal: Endoscopy (2018)

Abstract Background Accurate delineation of tumor margins is necessary for curative resection of early gastric cancer (EGC). The objective of this multicenter, randomized, controlled study was to compare the accuracy with which magnifying narrow-band imaging (M-NBI) and indigo carmine chromoendoscopy delineate EGC margins. Methods Patients with EGC ≥ 10 mm undergoing endoscopic or surgical resection were enrolled. The oral-side margins of the lesions were first evaluated with conventional white-light endoscopy in both groups and then delineated by either chromoendoscopy or M-NBI. Biopsies were taken from noncancerous and cancerous mucosa, each at 5 mm from the margin. Accurate delineation was judged to have been achieved when the histological findings in all biopsy samples were consistent with endoscopic diagnoses. The primary end point was the difference in rate of accurate delineation between the two techniques. Results Data on 343 patients were analyzed. The accurate delineation rate (95 % confidence interval) was 85.7 % (80.4 – 91.0) in the chromoendoscopy group (n = 168), and 88.0 % (83.2 – 92.8) in the M-NBI group (n = 175; P = 0.63). Lower third tumor location (odds ratio [OR] 2.9; P = 0.01), nonflat macroscopic type (OR 4.4; P &lt; 0.01), and high diagnostic confidence (OR 3.6; P &lt; 0.001) were associated with accurate delineation, whereas use of M-NBI was not (OR 1.2; P = 0.39). Even after adjustment for identified confounders, the difference in accurate delineation between the groups was not significant (OR 1.0; P = 0.82). Conclusions M-NBI does not offer superior delineation of EGC margins compared with chromoendoscopy; the two methods appear to be clinically equivalent.