tbuckley/cabot-search huggingface dataset:
Abstract 9121: Does AF Burden Measured By Implantable Loop Recorder During Post-ablation Blanking Period Predict Response At 12 Month Follow-up?
Authors: Evgeny Pokushalov, Alexander Romanov, Denis Losik, Sergey Artyomenko, Alexey Turov, Natalia Shirokova, Alexander Karaskov, Suneet Mittal, Jonathan S Steinberg
Journal: Circulation (2012)

Introduction: The aim of this study was to identify if there is a threshold of AF burden during the first months post-ablation obtained through continuous subcutaneous monitoring that can identify patients at risk of subsequent AF recurrences. Methods: 613 patients with symptomatic drug refractory AF (17% with persistent AF) were enrolled in this retrospective analysis. All patients underwent circumferential pulmunary vein isolation (PVI) and were implanted with an ILR for collecting data on AF burden during 12-month follow-up. AF freedom (Responders) was defined as AF%&lt;0.5% during follow-up period. A ROC curve analysis was performed to identify the value of AF burden during the first 2 months post ablation (Blanking Period, BP) that was predictive of late recurrence of AF. Results: After the first ablation procedure, 396 (65%) of the 613 patients were AF-free at 12-month: 346 out of 508 (68%) in the paroxysmal AF group and 50 out of 105 (47%) in the persistent AF group. Using the ROC curve (Fig 1), the specificity corresponding to 90% sensitivity was 75%. The corresponding threshold in the AF burden during the blanking period able to identify patients at risk of late recurrences was 7.1%, corresponding to 102h (= 4.25 days) in AF during the 2 months BP. At the multivariate analysis, a threshold in the AF burden &lt;7.1% during BP was still highly significant (p&lt;0.0001) and the odds of responders/non-responders was 21.5 (10.8 - 42.9). Conclusions: The BP AF pattern predicted response to catheter ablation. An AF burden ≥7.1% assessed by continuous monitoring was a powerful predictor of subsequent AF recurrence after initial ablation, and thus be an appropriate guide for early re-intervention.
Clinical benefit of next generation sequencing in soft tissue and bone sarcoma: Rush University Medical Center’s experience.
Authors: Mia C. Weiss, Alan Blank, Steven Gitelis, Mary J. Fidler, Marta Batus
Journal: Journal of Clinical Oncology (2019)

e22552 Background: The overall survival for metastatic sarcoma has remained at only 18-20%. In the era of next generation sequencing (NGS), much research is ongoing on identifying optimal treatments. The MULTISARC trial aims to determine if NGS can lead to improved overall survival by randomizing patients with metastatic STS to receive NGS (followed by possible NGS-guided therapy) or not. We present our center’s experience with NGS in sarcomas patients. Methods: Patients with soft tissue and bone sarcomas at Rush that had the Foundation Medicine assay sent on tumor samples between August 2017 and August 2018 were analyzed retrospectively. The impact of NGS on clinical decision making was determined based on patients being prescribed off-label FDA-approved therapy targeting identified mutation. Results: Thirty-four patients with bone/soft tissue sarcomas that had NGS sent on specimens were identified. Median age at diagnosis: 43 (18-78 years); 18 males, 16 females. Histologic subtypes: synovial sarcoma, myxofibrosarcoma, leiomyosarcoma, chondrosarcoma, sclerosing epitheloid fibrosarcoma, PEcoma, pleomorphic undifferentiated sarcoma, MPNST, liposarcoma- well and de-differentiated, angiosarcoma, osteosarcoma. 16/34 patients had targetable mutations with approved therapies in tumor types other than sarcoma. Four of these patients had therapy changed based on NGS results, 1 patient with metastatic chondrosarcoma (PTEN mutation, everolimus added), 1 patient with metastatic liposarcoma (CDK4 mutation, palbociclib added), 1 patient with metastatic osteosarcoma (CCD1/CDK4 and a PDGFRA mutation for which palbociclib followed by imatinib was added), and 1 patient with metastatic pleomorphic undifferentiated sarcoma (CDK4 mutation, palbociclib added). Targetable mutations for which clinical trials are available were identified in 25/34 (73%) of the cases. Conclusions: NGS was readily able to identify actionable mutations in close to 50% of patients with clinical trial opportunities in close to 75%. Four patients had therapy changed as a result of NGS testing. Although our study size is small, our data show potential for the use of genomic profiling to identify actionable targets, tailor therapy, and hopefully improve outcomes. [Table: see text]
Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality in a Japanese Cohort
Authors: Sanjeev Budhathoki, Norie Sawada, Motoki Iwasaki, Taiki Yamaji, Atsushi Goto, Ayaka Kotemori, Junko Ishihara, Ribeka Takachi, Hadrien Charvat, Tetsuya Mizoue, Hiroyasu Iso, Shoichiro Tsugane
Journal: JAMA Internal Medicine (2019)

Epidemiological evidence regarding the long-term effects of higher dietary protein intake on mortality outcomes in the general population is not clear.To evaluate the associations between animal and plant protein intake and all-cause and cause-specific mortality.This prospective cohort study included 70 696 participants in the Japan Public Health Center-based Prospective Cohort who were aged 45 to 74 years and had no history of cancer, cerebrovascular disease, or ischemic heart disease at study baseline. Data were collected from January 1, 1995, through December 31, 1999, with follow-up completed December 31, 2016, during which 12 381 total deaths were documented. Dietary intake information was collected through a validated food frequency questionnaire and used to estimate protein intake in all participants. Participants were grouped into quintile categories based on their protein intake, expressed as a percentage of total energy. Data were analyzed from July 18, 2017, through April 10, 2019.Hazard ratios (HRs) and 95% CIs for all-cause and cause-specific mortality were estimated using Cox proportional hazards regression models with adjustment for potential confounding factors.Among the 70 696 participants, 32 201 (45.5%) were men (mean [SD] age, 55.6 [7.6] years) and 38 495 (54.5%) were women (mean [SD] age, 55.8 [7.7] years). Intake of animal protein showed no clear association with total or cause-specific mortality. In contrast, intake of plant protein was associated with lower total mortality, with multivariable-adjusted HRs of 0.89 (95% CI, 0.83-0.95) for quintile 2; 0.88 (95% CI, 0.82-0.95) for quintile 3; 0.84 (95% CI, 0.77-0.92) for quintile 4; and 0.87 (95% CI, 0.78-0.96) for quintile 5, with quintile 1 as the reference category (P = .01 for trend). For cause-specific mortality, this association with plant protein intake was evident for cardiovascular disease (CVD)-related mortality (HRs, 0.84 [95% CI, 0.73-0.96] to 0.70 [95% CI, 0.59-0.83]; P = .002 for trend). Isocaloric substitution of 3% energy from plant protein for red meat protein was associated with lower total (HR, 0.66; 95% CI, 0.55-0.80), cancer-related (HR, 0.61; 95% CI, 0.45-0.82), and CVD-related (HR, 0.58; 95% CI, 0.39-0.86) mortality; substitution for processed meat protein was associated with lower total (HR, 0.54; 95% CI, 0.38-0.75) and cancer-related (HR, 0.50; 95% CI, 0.30-0.85) mortality.In this large prospective study, higher plant protein intake was associated with lower total and CVD-related mortality. Although animal protein intake was not associated with mortality outcomes, replacement of red meat protein or processed meat protein with plant protein was associated with lower total, cancer-related, and CVD-related mortality.
Specific Inhibition of the NLRP3 Inflammasome as an Antiinflammatory Strategy in Cystic Fibrosis
Authors: Oliver J. McElvaney, Zbigniew Zaslona, Katrin Becker-Flegler, Eva M. Palsson-McDermott, Fiona Boland, Cedric Gunaratnam, Erich Gulbins, Luke A. O’Neill, Emer P. Reeves, Noel G. McElvaney
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective antiinflammatory therapies for people with CF (PWCF) represents a significant challenge.Objectives: To identify altered immunometabolism in the CF neutrophil and investigate the feasibility of specific inhibition of the NLRP3 (NOD-, LRR-, and pyrin domain–containing protein 3) inflammasome as a CF antiinflammatory strategy in vivo.Methods: Key markers of increased aerobic glycolysis, known as a Warburg effect, including cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, succinate, HIF-1α (hypoxia-inducible factor-1α), lactate, and the IL-1β precursor pro–IL-1β, as well as caspase-1 activity and processing of pro–IL-1β to IL-1β by the NLRP3 inflammasome, were measured in neutrophils from blood and airway secretions from healthy control subjects (n = 12), PWCF (n = 16), and PWCF after double-lung transplantation (n = 6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed in vivo.Measurements and Main Results: CF neutrophils display increased aerobic glycolysis in the systemic circulation. This effect is driven by low-level endotoxemia, unaffected by CFTR (cystic fibrosis transmembrane conductance regulator) modulation, and resolves after transplant. The increased pro–IL-1β produced is processed to its mature active form in the LPS-rich CF lung by the NLRP3 inflammasome via caspase-1. Specific NLRP3 inhibition in vivo with MCC950 inhibited IL-1β in the lungs of CF mice (P < 0.0001), resulting in significantly reduced airway inflammation and improved Pseudomonas clearance (P < 0.0001).Conclusions: CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an antiinflammatory and anti-infective role in CF.
A Multicenter Nonrandom Clinical Study of Induction Regimen of FLAG-ID and Dae in the Treatment of Childhood De Novo Acute Myeloid Leukemia in South of China:the Early Report of Efficacy and Safety
Authors: Jian Li, Chunfu Li, Hua Jiang, Mincui Zheng, Xiangling He, Honggui Xu, Chun Chen, Hong Wen, Changgang Li, Xiaoqin Feng
Journal: Blood (2017)
Unraveling the high cost of end-of-life care: An oncology care model experience.
Authors: J. Russell Hoverman, Cynthia B. Taniguchi, Jad Hayes, Kathryn Eagye, B. Brooke Mann, Marcus A. Neubauer
Journal: Journal of Clinical Oncology (2019)

11534 Background: Simply put, cancer care in the last 30 days of life (30DAY) is often aggressive and expensive without best meeting the wishes and needs of patients and caregivers. In this study, we evaluated total and 30DAY cost data for patients who died while enrolled from July 1, 2016 to June 30, 2017 in the Oncology Care Model (OCM), a Medicare (CMS) program initiated by the Center for Medicare and Medicaid Innovation. Methods: CMS provided claims data on 16 OCM-participating US Oncology Network practices. We measured 30DAY OCM episode expenditures (“EXP30”) for n = 5017 deceased patients, as well as patient demographics, clinical outcomes (hospital, ICU, and ER visits) and 30DAY treatments . The population was divided into two cohorts: those with ≥ 3 days of hospice care (“HC”) and those without (“NOHC”). EXP30 was compared between HC and NOHC at the univariate level using Wilcoxon Rank-sums; categorical variables were compared using Chi-squared tests. Multivariate regression was used to determine the effect of HC on EXP30 adjusted for demographic and disease factors. Results: HC had mean EXP30 reduction of $7,192 vs. NOHC [95%CI -$7,628, -$6,730] adjusted for demographics and disease. HC had lower rates of death in hospital (0.03% vs. 43.3%, p &lt; .0001). Mean expense by days before death: NOHC values 0-30 days = $20,701; 31-60 days = $12,962; 61-90 days = $9,952 and HC values 0-30 days = $10,877; 31-60 days = $10,376; 61-90 days = $9,064. Conclusions: All categories of care except HC are associated with significantly higher cost in the last 30 days of life. The dramatic and steep trajectory in the last 30 days suggests high expense but also loss of choices as to how best to live the end of one’s life. The results will be updated as new data become available. [Table: see text]
Unusual Patterns of Mitochondrial Inheritance in the Brown Alga Ectocarpus
Authors: Laure Mignerot, Chikako Nagasato, Akira F Peters, Marie-Mathilde Perrineau, Delphine Scornet, Florian Pontheaux, Walid Djema, Yacine Badis, Taizo Motomura, Susana M Coelho, J Mark Cock
Journal: Molecular Biology and Evolution (2019)

Most eukaryotes inherit their mitochondria from only one of their parents. When there are different sexes, it is almost always the maternal mitochondria that are transmitted. Indeed, maternal uniparental inheritance has been reported for the brown alga Ectocarpus but we show in this study that different strains of Ectocarpus can exhibit different patterns of inheritance: Ectocarpus siliculosus strains showed maternal uniparental inheritance, as expected, but crosses using different Ectocarpus species 7 strains exhibited either paternal uniparental inheritance or an unusual pattern of transmission where progeny inherited either maternal or paternal mitochondria, but not both. A possible correlation between the pattern of mitochondrial inheritance and male gamete parthenogenesis was investigated. Moreover, in contrast to observations in the green lineage, we did not detect any change in the pattern of mitochondrial inheritance in mutant strains affected in life cycle progression. Finally, an analysis of field-isolated strains provided evidence of mitochondrial genome recombination in both Ectocarpus species.
Both<i>HLA</i>class I and II regions identified as genome-wide significant susceptibility loci for adult-onset Still's disease in Chinese individuals
Authors: Zhiqiang Li, Hong-Lei Liu, Jianhua Chen, Ting Zeng, Lin He, Meihang Li, Cainan Luo, Shuang Liu, Ting-Ting Ding, Kuerbanjiang Yimaiti, Jialin Teng, Xingwang Li, Yonghe Ding, Xiaobing Cheng, Juan Zhou, Junna Ye, Jue Ji, Yu-Tong Su, Hui Shi, Yue Sun, Chengwen Gao, Qiongyi Hu, Huihui Chi, Xuan Yuan, Zhuochao Zhou, Dong Wang, Ke Wang, Chang-Gui Li, Yuanchao Sun, Yujuan Niu, Lin-Jie Chen, Jian Xu, Lijun Wu, Zhaowei Zhou, Dun Pan, Haitao Niu, Yongyong Shi, Chengde Yang
Journal: Annals of the Rheumatic Diseases (2019)

Adult-onset Still's disease (AOSD) is a rare autoinflammatory condition with unclear aetiology and highly heterogeneous manifestations, such as spiking fever, skin rash and arthralgia (or arthritis).1 2 AOSD is usually the result of both genetic and environmental factors. However, only a few genetic loci have been associated with AOSD, and none of them have reached the threshold for genome-wide significance (GWS) of p<5×10−8.2 3 For example, HLA-DRB1 was strongly associated with AOSD in previous studies (the p value for the most significant association was 8.60×10−6).3 HLA-DRB1 also influences the risk of systemic juvenile idiopathic arthritis (JIA),4 which presents similarly to AOSD but differs in age of onset. In addition, functional variations in periodic fever syndrome genes have been identified in some AOSD patients (Bonferroni corrected p values ranged from 2.34×10−3 to 2.40×10−4).5

In this study, for the first time, we conducted a genome-wide association study (GWAS) to systematically screen genetic factors influencing susceptibility to AOSD (online supplementary text). Principal component analysis was adopted to evaluate population stratification between cases and controls and to detect outliers for removal (online supplementary figure S1). After quality control and imputation, a total of 3 547 931 variants in 264 AOSD cases and 2420 controls (discovery: 247 cases vs 2163 controls; replication: 17 cases vs 257 controls; online supplementary text and table S1) from China …
Role of Interferon‐γ–Producing Th1 Cells in a Murine Model of Type I Interferon–Independent Autoinflammation Resulting From <scp>DN</scp>ase <scp>II</scp> Deficiency
Authors: Sudesh Pawaria, Kerstin Nündel, Kevin M. Gao, Stephanie Moses, Patricia Busto, Kevin Holt, Rohit B. Sharma, Michael A. Brehm, Ellen M. Gravallese, Merav Socolovsky, Anette Christ, Ann Marshak‐Rothstein
Journal: Arthritis & Rheumatology (2019)

Objective Patients with hypomorphic mutations in DN ase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DN ase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response. Methods To avoid embryonic death, Dnase2 −/− mice were intercrossed with mice that lacked the type I interferon ( IFN ) receptor ( Ifnar −/− ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme‐linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2 −/− × Ifnar −/− double‐knockout ( DKO ) mice into Rag1 −/− mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice. Results In Dnase2 −/− × Ifnar −/− DKO mice, many of the disease features found in DN ase II –deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2 +/+ × Rag1 −/− mice (n &gt; 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFN γ‐producing T cell subset from the spleens of donor Dnase2 −/− × Ifnar −/− DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes ( STING ) pathway but was highly dependent on the chaperone protein Unc93B1. Conclusion Dnase2 −/− × Ifnar −/− DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE 2 ‐hypomorphic patients. In this murine model, IFN γ is required for T cell activation and the development of clinical manifestations. The role of IFN γ in DNASE 2 ‐deficient patient populations remains to be determined, but the ability of Dnase2 −/− mouse T cells to transfer disease to Rag1 −/− mice suggests that T cells may be a relevant therapeutic target in patients with IFN ‐related systemic autoinflammatory diseases.
Application of micro-RNA (miRNA) expression profiles for prognostication in low-risk endometrial carcinoma (LEC).
Authors: Johanne Ingrid Weberpals, Jaime Snowdon, Olga Bougie, Xiao Zhang, Victor Tron, Timothy Childs, Ian Garfield Bambury, Harriet Feilotter
Journal: Journal of Clinical Oncology (2012)

5032 Background: Reliably predicting which LEC patients are most likely to recur is a challenge for the clinician with implications on adjuvant therapy. MiRNAs have been exploited for diagnosis and prognostication in a number of malignancies. We hypothesize that miRNA expression profiles differ in tumors from patients with recurrence compared to those without recurrence. Methods: The inclusion criteria for this study are informed consent, stage 1 disease, grade 1 or 2 tumors and endometrioid histology. RNA was extracted from formalin-fixed paraffin-embedded tissues and miRNA profiling was done using Agilent Human miRNA. Differentially expressed miRNAs were identified using GeneSpring GX software and the two groups were compared using the student t-test. Results: The expression levels of 866 miRNAs were determined from LEC patients with recurrence (n=15) and without recurrence (n=16). The mean follow-up interval was 61.5 months. The average age of cancer diagnosis for patients with and without recurrence was 60.2 (range 42-75) and 59.7 (range 44-86), respectively (p=0.91). Three of 15 patients with recurrence and 6 of 16 patients without recurrence received adjuvant brachytherapy following their primary surgery (p=0.43). 17 miRNAs were identified which can distinguish between the tumors with recurrence and those without recurrence (p&lt;0.05). MiR-146a, miR-18a, miR-222, and miR-30a showed the highest fold change difference (&gt;5 fold) in the tumors with recurrence compared to that did not recur. A decision tree prediction model for recurrent LEC was developed where a miRNA cutoff was used as a branch in the decision tree. This model identified those patients who were most likely to recur based on the expression of 4 dysregulated miRNAs (miR-222, miR-361-3p, miR-181c and miR-125b). Conclusions: These preliminary results show the miRNA expression profile differs among LEC and can be used to distinguish an aggressive sub-group. Should future validation studies confirm this result, this information would be valuable in the design of a biomarker study to help decide which patients would benefit most from extended adjuvant treatment.
Rheumatology: A Primary Care Approach.
Journal: Annals of Internal Medicine (1983)

The first quarter of the 230 or so pages is devoted to 'A M. Rothschild.Pp. 416.£41-75.Yorke Medical: new look at rheumatoid arthritis'.This is a stimulating and New York. 1983.informative, if somewhat indigestible, dissertation by T. Bitter of Lausanne, in support of more precise diagnostic This volume aims to help the primary care physician provide criteria and more aggressive drug therapy in rheumatoid continuing care for his rheumatological patients.The title arthritis.The use of drug combinations, their mode of could be misleading to the English reader, in that 'primary action, and the semantic and conceptual questions raised by care' in the United States is given by a wide variety of rheumatoid-factor-negative polyarthritis, are all discussed.
MPRAnalyze: statistical framework for massively parallel reporter assays
Authors: Tal Ashuach, David S. Fischer, Anat Kreimer, Nadav Ahituv, Fabian J. Theis, Nir Yosef
Journal: Genome biology (2019)

Massively parallel reporter assays (MPRAs) can measure the regulatory function of thousands of DNA sequences in a single experiment. Despite growing popularity, MPRA studies are limited by a lack of a unified framework for analyzing the resulting data. Here we present MPRAnalyze: a statistical framework for analyzing MPRA count data. Our model leverages the unique structure of MPRA data to quantify the function of regulatory sequences, compare sequences' activity across different conditions, and provide necessary flexibility in an evolving field. We demonstrate the accuracy and applicability of MPRAnalyze on simulated and published data and compare it with existing methods.