tbuckley/cabot-search huggingface dataset:
Adoptive cell therapy using PD-1+ myeloma-reactive T cells eliminates established myeloma in mice
Authors: Weiqing Jing, Jill A. Gershan, Grace C. Blitzer, Katie Palen, James Weber, Laura McOlash, Matthew Riese, Bryon D. Johnson
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Adoptive cellular therapy (ACT) with cancer antigen-reactive T cells following lymphodepletive pre-conditioning has emerged as a potentially curative therapy for patients with advanced cancers. However, identification and enrichment of appropriate T cell subsets for cancer eradication remains a major challenge for hematologic cancers. <h3>Methods</h3> PD-1<sup>+</sup> and PD-1<sup>−</sup> T cell subsets from myeloma-bearing mice were sorted and analyzed for myeloma reactivity in vitro. In addition, the T cells were activated and expanded in culture and given to syngeneic myeloma-bearing mice as ACT. <h3>Results</h3> Myeloma-reactive T cells were enriched in the PD-1<sup>+</sup> cell subset. Similar results were also observed in a mouse AML model. PD-1<sup>+</sup> T cells from myeloma-bearing mice were found to be functional, they could be activated and expanded ex vivo, and they maintained their anti-myeloma reactivity after expansion. Adoptive transfer of ex vivo-expanded PD-1<sup>+</sup> T cells together with a PD-L1 blocking antibody eliminated established myeloma in Rag-deficient mice. Both CD8 and CD4 T cell subsets were important for eradicating myeloma. Adoptively transferred PD-1<sup>+</sup> T cells persisted in recipient mice and were able to mount an adaptive memory immune response. <h3>Conclusions</h3> These results demonstrate that PD-1 is a biomarker for functional myeloma-specific T cells, and that activated and expanded PD-1<sup>+</sup> T cells can be effective as ACT for myeloma. Furthermore, this strategy could be useful for treating other hematologic cancers.
Pratiques de désinfection en endoscopie digestive dans un centre référent régional: résultats d'un audit avant et après mesures correctives
Authors: S Malavaud, F Cabrespine, J Moreau, L Buscail, J Escourrou
Journal: Endoscopy (2006)

Les procédures de désinfection des endoscopes se sont, au cours du temps, allongées et complexifiées par l'ajout d'étapes et de passages obligés. Le bute de cette étude était de réaliser un audit de notre centre d'endoscopie pour évaluer les pratiques de nettoyage et de désinfection manuelle et en machine des endoscopes avant et après mesures correctives.
Функциональная диспепсия у взрослых: диагностика и лечение
Authors: Yu.I. Reshetilov, N.N. Protsenko, L.F. Kuznetsova, Ye.Yu. Vasilchenko, T.V. Bogoslav, N.P. Guz
Journal: GASTROENTEROLOGY (2013)

Целью работы явилось исследование динамики клинических проявлений функциональной диспепсии у взрослых под воздействием лечения с применением М-холинолитика (cкополамина бутилбромид). Под наблюдением находилось 45 пациентов с функциональной диспепсией; из них 30 получали дополнительно к комплексному лечению М-холинолитик (cкополамина бутилбромид). В результате применения этого препарата улучшились клинические и инструментальные показатели. При индивидуальном подборе дозы препарата и длительности его приема побочных эффектов не выявлено.
LOW STROMAL CD99 EXPRESSION IS INDEPENDENTLY ASSOCIATED WITH SHORTER SURVIVAL IN NSCLC
Authors: Karolina Edlund, Patrick Micke, Cecilia Lindskog, Akira Saito, Simon Ekman, Michael Bergqvist, Fredrik Ponten, Anders Isaksson, Hanna Goransson, Karin Jirstrom, Mats Lambe, Anders Berglund, Lars Holmberg, Arne Ostman, Johan Botling
Journal: Journal of Thoracic Oncology (2011)
Learning a Comorbidity-Driven Taxonomy of Pediatric Pulmonary Hypertension
Authors: Mei-Sing Ong, Mary P. Mullen, Eric D. Austin, Peter Szolovits, Marc D. Natter, Alon Geva, Tianxi Cai, Sek Won Kong, Kenneth D. Mandl
Journal: Circulation Research (2017)

Pediatric pulmonary hypertension (PH) is a heterogeneous condition with varying natural history and therapeutic response. Precise classification of PH subtypes is, therefore, crucial for individualizing care. However, gaps remain in our understanding of the spectrum of PH in children.
Association of Educational Attainment With Lifetime Risk of Cardiovascular Disease
Authors: Yasuhiko Kubota, Gerardo Heiss, Richard F. MacLehose, Nicholas S. Roetker, Aaron R. Folsom
Journal: JAMA Internal Medicine (2017)

Estimates of lifetime risk may help raise awareness of the extent to which educational inequalities are associated with risk of cardiovascular disease (CVD).To estimate lifetime risks of CVD according to categories of educational attainment.Participants were followed from 1987 through December 31, 2013. All CVD events (coronary heart disease, heart failure, and stroke) were confirmed by physician review and International Classification of Diseases codes. A total of 13 948 whites and African Americans who were 45 to 64 years old and free of CVD at baseline were included from 4 US communities (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and suburbs of Minneapolis, Minnesota). The data analysis was performed from June 7 to August 31, 2016.Educational attainment.We used a life table approach to estimate lifetime risks of CVD from age 45 through 85 years according to educational attainment. We adjusted for competing risks of death from underlying causes other than CVD.The sample of 13 948 participants was 56% female and 27% African American. During 269 210 person-years of follow-up, we documented 4512 CVD events and 2401 non-CVD deaths. Educational attainment displayed an inverse dose-response relation with cumulative risk of CVD, which became evident in middle age, with the most striking gap between those not completing vs completing high school. In men, lifetime risks of CVD were 59.0% (95% CI, 54.0%-64.1%) for grade school, 52.5% (95% CI, 47.7%-56.8%) for high school education without graduation, 50.9% (95% CI, 47.3%-53.9%) for high school graduation, 47.2% (95% CI, 41.5%-52.5%) for vocational school, 46.4% (95% CI, 42.8%-49.6%) for college with or without graduation, and 42.2% (95% CI, 36.6%-47.0%) for graduate/professional school; in women, 50.8% (95% CI, 45.7%-55.8%), 49.3% (95% CI, 45.1%-53.1%), 36.3% (95% CI, 33.4%-39.1%), 32.2% (95% CI, 26.0%-37.3%), 32.8% (95% CI, 29.1%-35.9%), and 28.0% (95% CI, 21.9%-33.3%), respectively. Educational attainment was inversely associated with CVD even within categories of family income, income change, occupation, or parental educational level.More than 1 in 2 individuals with less than high school education had a lifetime CVD event. Educational attainment was inversely associated with the lifetime risk of CVD, regardless of other important socioeconomic characteristics. Our findings emphasize the need for further efforts to reduce CVD inequalities related to educational disparities.
Non-classical response measured by immune-modified RECIST and post-progression treatment effects of atezolizumab in 2L/3L NSCLC: Results from the randomized phase II study POPLAR.
Authors: Julien Mazieres, Louis Fehrenbacher, Achim Rittmeyer, Alexander I. Spira, Keunchil Park, David A. Smith, Angel Artal-Cortes, Conrad R. Lewanski, Fadi S. Braiteh, Jing Yi, Pei He, Marcin Kowanetz, Daniel Waterkamp, Marcus Ballinger, Daniel S. Chen, Alan Sandler, Johan F. Vansteenkiste
Journal: Journal of Clinical Oncology (2016)

9032 Background: Cancer immunotherapy (CIT) can induce unconventional response patterns due to tumor immune infiltration or delayed response, reducing the ability of RECIST-based endpoints to predict OS benefit.Atezolizumab (atezo; MPDL3280A) demonstrated OS benefit compared with docetaxel (doc) in the ITT population of 2L/3L NSCLC patients (pts) in the POPLAR primary analysis (HR, 0.73; mOS 12.6 mo for atezo vs 9.7 mo for doc). However, PFS and ORR improvement was restricted to pts with high PD-L1 expression, suggesting that many pts experience atezo benefit after classical radiographic progression. Methods: AdvancedNSCLC pts were randomized to atezo 1200 mg IV q3w until loss of clinical benefit or doc 75 mg/m2 IV q3w until PD per RECIST v1.1 (RECIST). The primary endpoint was OS. In addition to secondary endpoints of PFS and ORR per RECIST, atezo pts were evaluated per immune-modified RECIST (imRECIST) and for post-PD radiographic changes. Both arms were evaluated for OS post PD (data cutoff, May 8, 2015; median follow up, 15 mo). Results: Of 287 pts, 144 were randomized to atezo. Among these pts, ORR per imRECIST vs RECIST was 17% and 15%, respectively; the rate of CR+PR+SD was 65% and 52%, respectively. mPFS was longer per imRECIST vs RECIST (4.2 vs 2.7 mo). Among 57 atezo arm pts continuing treatment post PD, 14% had subsequent ≥ 30% decrease in target lesions relative to baseline, and 33% had a change of +20% and −30%. mOS from the time of first RECIST PD was 11.1 mo for atezo arm pts continuing atezo post PD (n = 57) and 8.3 mo for atezo pts receiving different anti-cancer therapy post PD (n = 30). Doc arm pts receiving subsequent therapy post PD (n = 46) had mOS of 9.6 mo from the time of PD. Conclusions: ORR and PFS were increased in atezo pts per imRECIST vs RECIST, and 47% of pts continuing atezo after PD had subsequent stable/reduced target lesions relative to baseline. The mOS of 11.1 mo post PD for pts continuing atezo treatment is suggestive of atezo benefit following PD that contributes to the OS benefit vs doc in all-comer pts. These results also highlight the utility of imRECIST as response evaluation criteria to assess the efficacy of atezo/CIT. Clinical trial information: NCT01903993.
A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors
Authors: Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S.J. Elenitoba-Johnson, Vivek M. Rangnekar
Journal: Cancer Research (2017)

Abstract Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA segment, competitively bound to Fbxo45 and rescued Par-4–mediated induction of cancer cell–specific apoptosis. Collectively, our findings identify a molecular decoy naturally generated during apoptosis that inhibits a ubiquitin ligase to overcome therapy resistance in tumors. Cancer Res; 77(15); 4039–50. ©2017 AACR.
In Rotterdam, size really does matter: implications of pulmonary artery enlargement on mortality
Authors: Aline N. Zouk, J. Michael Wells
Journal: European Respiratory Journal (2017)

For quite some time, we have known that pulmonary hypertension (PH) is associated with an increased risk of death in chronic obstructive pulmonary disease (COPD) [1, 2]. The occurrence of PH in the context of chronic lung diseases is often the result of hypoxic pulmonary hypertension and is classified as Group III PH by the World Health Organization (WHO) [3]. The diagnosis of PH requires a high index of suspicion, as symptoms are often vague and nonspecific, particularly among individuals with pre-existing respiratory disease. PH is defined by hemodynamic measurement during right-sided heart catheterisation (RHC), even though RHC is not routinely performed in COPD, because of the invasive nature of the procedure and the lack of efficacious treatments [4–6]. Comorbid PH independently accounts for worsening dyspnoea, fatigue, impaired exercise tolerance and poor quality of life in COPD [7, 8], and is associated with increased risk of hospitalisation and higher mortality [2, 3, 9]. In a general population, the PA:A is associated with increased mortality in moderate to severe COPD <http://ow.ly/L9S130bNuq7>
Abstract 183: Improved Ca-cycling by Dexamethasone Preserves Contractility After Ischemia/Reperfusion in Diabetic Rat Cardiomyocytes
Authors: Christian Schach, Michael Goetz, Hendrik Busse, York Zausig, Marzena Drymalski, Lars Maier, Stefan Wagner
Journal: Circulation Research (2015)

Glucocorticoid receptor (GR) stimulation is essential for normal heart function and dexamethasone (DEX) treatment has been shown to reduce ischemia reperfusion injury (IRI). Prevalence of diabetes is increasing and myocardial infarction in such patients is more severe and risk of complications is augmented. We tested the hypothesis, that GR stimulation with DEX protects diabetic myocardium from IRI by improving Ca cycling. Cardiomyocytes from type 2 diabetic Zucker diabetic fatty rats were isolated and cultured in DEX (10 μg/mL) vs. vehicle for 24h. [Ca] i and fractional shortening (FS) was measured in electrical field-stimulated cardiomyocytes loaded with Fura-2 AM (10 μM). Compared to control, DEX-treated cells display increased Ca transient amplitude (0.33±0.03 vs. 0.46±0.04, P = 0.01, n=6 animals) and FS (fig.) DEX also significantly increased sarcoplasmic reticulum (SR) Ca content (Caffeine, 10 mM) and reduced SR Ca leak measured as Ca spark frequency (SpF), fluo-4 loaded myocytes, confocal microscopy (fig.). To test, whether DEX reduced IRI, rats were treated with DEX (2 mg/kg i.p.) 24h before measurement (vehicle as control). Left ventricular developed pressure (LVDP) was monitored in Langendorff-perfused-hearts during global ischemia for 30 min and reperfusion. During reperfusion, DEX-treated hearts showed significantly greater LVDP (P &lt; 0.05, 2way ANOVA, fig.). In diabetic rats, glucocorticoid receptor stimulation with DEX leads to a more efficient Ca cycling with reduced SR Ca leakage, which translates to an increased contractility on the cellular level and protection against ischemia reperfusion injury in the whole organ.
Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency
Authors: Daniel Petersheim, Michel J. Massaad, Saetbyul Lee, Alessia Scarselli, Caterina Cancrini, Kunihiko Moriya, Yoji Sasahara, Arjan C. Lankester, Morna Dorsey, Daniela Di Giovanni, Liliana Bezrodnik, Hidenori Ohnishi, Ryuta Nishikomori, Kay Tanita, Hirokazu Kanegane, Tomohiro Morio, Erwin W. Gelfand, Ashish Jain, Elizabeth Secord, Capucine Picard, Jean-Laurent Casanova, Michael H. Albert, Troy R. Torgerson, Raif S. Geha
Journal: Journal of Allergy and Clinical Immunology (2017)
Randomised phase 3 trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for clinically localised high-risk or node-positive prostate cancer: ENZARAD (ANZUP 1303).
Authors: Scott G. Williams, Ian D. Davis, Christopher Sweeney, Martin R. Stockler, Andrew James Martin, Wendy Hague, Xanthi Coskinas, Sonia Yip, Emily Tu, Howard Chan, Nicola Jane Lawrence, Ray McDermott, Simon Hughes, Vittorio Marchesin, Olwyn Deignan, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2016)

TPS5086 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide is more effective in metastatic disease than conventional non-steroidal anti-androgens (NSAA). We hypothesize that addition of enzalutamide to adjuvant ADT and RT will improve outcomes. Aim: To determine the efficacy of enzalutamide as part of adjuvant ADT with LHRHA in men planned for RT for localized high risk or node-positive PC. Methods: Open label, randomised, stratified, 2-arm multicentre, phase 3 clinical trial. Primary endpoint: OS. Secondary endpoints: cause-specific survival, PSA PFS, clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival, adverse events and HRQOL. Tertiary objectives: identification of prognostic/predictive biomarkers from archival tumour tissue and serial fasting blood. Treatment is LHRHA for 24 months and radiotherapy starting after week 16. Radiotherapy delivered as 78Gy in 39 Fx or 46Gy in 23Fx plus brachytherapy (nodal RT optional for N0, mandatory for N1). Participants are randomised 1:1 to enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. Assessments at baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. CT/MRI and bone scan at baseline, PSA progression, 6 monthly until re-initiation of ADT and 3 monthly until evidence of metastases. Target accrual is 800 with 2 yrs accrual + 5.5 yrs minimum followup. 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. As of Jan 2016, 43 sites open in Australia, New Zealand, Ireland, UK and USA with 164 patients recruited. EORTC sites will enter in 2016. ENZARAD is an international investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funding from Astellas. ANZUP is supported by Cancer Australia and CI NSW ClinicalTrials.gov: NCT02446444, ANZCTR: ACTRN12614000126617 Clinical trial information: NCT02446444.
Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks
Authors: Ruei-Zeng Lin, Chin Nien Lee, Rafael Moreno-Luna, Joseph Neumeyer, Breanna Piekarski, Pingzhu Zhou, Marsha A. Moses, Monisha Sachdev, William T. Pu, Sitaram Emani, Juan M. Melero-Martin
Journal: Nature Biomedical Engineering (2017)
The fate and lifespan of human monocyte subsets in steady state and systemic inflammation
Authors: Amit A. Patel, Yan Zhang, James N. Fullerton, Lies Boelen, Anthony Rongvaux, Alexander A. Maini, Venetia Bigley, Richard A. Flavell, Derek W. Gilroy, Becca Asquith, Derek Macallan, Simon Yona
Journal: The Journal of Experimental Medicine (2017)

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.
Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial
Authors: Marcia S. Brose, Francis P. Worden, Kate L. Newbold, Matthew Guo, Arti Hurria
Journal: Journal of Clinical Oncology (2017)

Purpose In the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). This prespecified subanalysis investigated the effect of age on the efficacy and safety of lenvatinib. Patients and Methods This randomized, double-blind, phase III study enrolled patients with histologically confirmed RR-DTC stratified by age (≤ 65 or &gt; 65 years). Patients (N = 392) received lenvatinib 24 mg/day (n = 261) or placebo (n = 131). The primary end point was PFS; secondary end points included overall survival (OS), objective response rate, and safety. Results In both treatment arms, median ages were 56 (younger group) and 71 years (older group). PFS benefit was maintained with lenvatinib versus placebo in the younger and older age groups, with median PFS of 20.2 versus 3.2 months (hazard ratio [HR], 0.19; 95% CI, 0.13 to 0.27; P &lt; .001) and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17 to 0.43; P &lt; .001), respectively. PFS did not differ with age in either treatment arm. OS was improved in older lenvatinib-treated patients versus placebo (HR, 0.53; 95% CI, 0.31 to 0.91; P = .020). Younger lenvatinib-treated patients showed significantly higher ORR (72% v 55%; P = .0038), longer time to first dose reduction (3.7 v 1.5 months), and lower proportion of grade ≥ 3 treatment-related adverse events (67% v 89%; P &lt; .001) compared with older patients. Conclusion This subanalysis demonstrated improved PFS with lenvatinib treatment versus placebo in both age groups, although higher toxicity was observed in older patients. Despite the allowance of crossover after disease progression, the OS benefit was observed in older patients, suggesting that lenvatinib should be considered for treatment of patients of any age with RR-DTC.
Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia
Authors: Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F. Claxton, W. Christopher Ehmann, Witold B. Rybka, Neil D. Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D. Schell, Raymond J. Hohl, Hui Zeng, Hong Zheng
Journal: Journal of Hematology & Oncology (2017)

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.