tbuckley/cabot-search huggingface dataset:
Selection of patients for intra-arterial treatment for acute ischaemic stroke: development and validation of a clinical decision tool in two randomised trials
Authors: Esmee Venema, Maxim J H L Mulder, Bob Roozenbeek, Joseph P Broderick, Sharon D Yeatts, Pooja Khatri, Olvert A Berkhemer, Bart J Emmer, Yvo B W E M Roos, Charles B L M Majoie, Robert J van Oostenbrugge, Wim H van Zwam, Aad van der Lugt, Ewout W Steyerberg, Diederik W J Dippel, Hester F Lingsma
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To improve the selection of patients with acute ischaemic stroke for intra-arterial treatment using a clinical decision tool to predict individual treatment benefit. <b>Design</b>&nbsp;Multivariable regression modelling with data from two randomised controlled clinical trials. <b>Setting</b>&nbsp;16 hospitals in the Netherlands (derivation cohort) and 58 hospitals in the United States, Canada, Australia, and Europe (validation cohort). <b>Participants</b>&nbsp;500 patients from the Multicenter Randomised Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands trial (derivation cohort) and 260 patients with intracranial occlusion from the Interventional Management of Stroke III trial (validation cohort). <b>Main outcome measures</b>&nbsp;The primary outcome was the modified Rankin Scale (mRS) score at 90 days after stroke. We constructed an ordinal logistic regression model to predict outcome and treatment benefit, defined as the difference between the predicted probability of good functional outcome (mRS score 0-2) with and without intra-arterial treatment. <b>Results</b>&nbsp;11 baseline clinical and radiological characteristics were included in the model. The externally validated C statistic was 0.69 (95% confidence interval 0.64 to 0.73) for the ordinal model and 0.73 (0.67 to 0.79) for the prediction of good functional outcome, indicating moderate discriminative ability. The mean predicted treatment benefit varied between patients in the combined derivation and validation cohort from −2.3% to 24.3%. There was benefit of intra-arterial treatment predicted for some individual patients from groups in which no treatment effect was found in previous subgroup analyses, such as those with no or poor collaterals. <b>Conclusion</b>&nbsp;The proposed clinical decision tool combines multiple baseline clinical and radiological characteristics and shows large variations in treatment benefit between patients. The tool is clinically useful as it aids in distinguishing between individual patients who may experience benefit from intra-arterial treatment for acute ischaemic stroke and those who will not. <b>Trial registration</b>&nbsp;clinicaltrials.govNCT00359424 (IMS III) and isrctn.com ISRCTN10888758 (MR CLEAN).
Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 <scp>ESC</scp>/<scp>ERS</scp> guidelines and insights for future changes
Authors: Massimiliano Palazzini, Fabio Dardi, Alessandra Manes, Maria L. Bacchi Reggiani, Enrico Gotti, Andrea Rinaldi, Alessandra Albini, Enrico Monti, Nazzareno Galiè
Journal: European Journal of Heart Failure (2017)
Identification of LASEP3 as a new serological and prognostic biomarker for lung and various type of cancer.
Authors: Atsushi Takano, Yusuke Nakamura, Yataro Daigo
Journal: Journal of Clinical Oncology (2012)

e13565 Background: Identification of early cancer detection and prognostic biomarkers is urgently required to improve clinical outcome. Methods: We have screened cancer biomarkers using a strategy as follows; i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray representing 27,648 genes and 120 lung cancers, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot analysis, iii)To validate clinicopathological significance of their protein expression by tissue microarray consisting of 259 lung cancers, iv) To verify whether they are essential for the growth of cancer cells by siRNA assay, and v) To measure their serum protein levels by ELISA in patients with various type of cancers. Results: We identified LASEP3 (Lung cancer Associated Serum Protein 3) encoding secreted protein as a candidate. Immunohistochemical analysis showed that LASEP3 was frequently over-expressed in various histological types of lung cancers; positive staining of LASEP3 was observed in 198 (54.8%) of 361 NSCLCs. In addition, a high level of LASEP3 expression was associated with poor prognosis of patients with NSCLC (p=0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs; 131 (63.6%) of 206 ADCs and 29 (54.7%) of 53 SCCs, while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Serum LASEP3 levels were significantly higher in breast and colon cancer patients than in healthy volunteers, and tissue LASEP3 protein was overexpressed in breast and colon cancer tissues. Furthermore, treatment of lung cancer cells with siRNAs against LASEP3 suppressed its expression and resulted in growth suppression of cancer cells. Induction of exogenous expression of LASEP3 promoted cell mobility in vitro. We found a 50-kDa receptor (LASEPR) which interacts with LASEP3 on cancer cell surface, suggesting that LASEP3 is an autocrine/paracrine growth factor. Conclusions: LASEP3 is a potential target for the development of diagnostic and prognostic biomarkers for lung and various types of cancers
Abstract 025: Oxidative-stress Mediates Apoptosis in a Human Model of Danon Disease and Heart Failure
Authors: Cynthia N Perry, Sangyoon Han, Stacey D Clegg, Kunfu Ouyang, Dekker Deacon, Ju Chen, Qiuming Gong, Zhengfeng Zhou, Neil C Chi, Eric D Adler
Journal: Circulation Research (2013)

Emerging evidence has highlighted the importance of autophagy, an intracellular recycling pathway, in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal associated membrane protein type 2 (LAMP-2). To investigate the pathogenesis of Danon disease, we created iPS cells from a patient with a mutation in LAMP-2 who expired from heart failure. Danon iPS-derived cardiomyocytes recapitulated key features of the disease in vitro, including impaired autophagic flux, increased cell size, abnormal calcium handling, and increased expression of natriuretic peptides. Danon cells were noted to have significant amounts of mitochondrial oxidative stress and apoptosis, both of which could be abrogated by treatment with the antioxidant N-acetylcysteine. These results implicate mitochondrial oxidative stress and apoptosis in the pathogenesis of Danon disease. They also provide the basis for the use of antioxidants for Danon disease and other autophagy-related human diseases such as heart failure, diabetes, cancer, and neurodegenerative disorders.
A randomized phase II study evaluating the use of prydoxine to prevent hand-foot syndrome associated with capecitabine therapy for advanced or metastatic breast cancer.
Authors: Akiyo Yoshimura, Hiroji Iwata, Takako Hayashi, Naomi Kobayashi, Kanako Saito, Michiko Tsuneizumi, Masataka Sawaki, Masaya Hattori, Takumi Nakada, Isao Yokota, Tatsuya Toyama
Journal: Journal of Clinical Oncology (2014)

9610 Background: Pyridoxine (Pyr) is a drug of activated vitamin B6 and usually used for allergic dermatitis. Pyr is frequently used to prevent the HFS, although the evidence of benefit is lacking in Japan. The aim of this is to determine whether Pyr could reduce capecitabine (Cap)-induced HFS in advanced or metastatic breast cancer patients. This study is an open label, multicenter, randomized phase II study conducted by Tokai Breast Cancer Research Group (TBCRG) in Japan. Methods: All patients were received either concomitant pyridoxine (60mg P.O per day) or none with Cap containing regimens (Cap monotherapy, Cap plus cyclophosphamide, Cap plus weekly paclitaxel). Patients were stratified by chemotherapy regimens, line of therapy after metastases, and institutes. The study treatment was given until grade 2 HFS or incidence of other severe adverse events or progression disease. Primary endpoint is the period until the incidence of grade 2 or worse HFS from start of protocol treatment. The key secondary endpoints were incidence and period until all grade HFS and safety. Results: A total of 135 advanced and metastatic breast cancer patients were randomized the concomitant Pyr arm (n=67) and Cap alone arm (n=68). The baseline characteristics were well balanced in both arms. Grade 2 or worse HFS developed in 19 of 66 patients (28.8%) versus 21 of 67 patients (31.3%) in concomitant Pyr arm and Cap alone arm, respectively. The median HFS-free period (grade 2 or worse) was 13.6 and 10.6 months in concomitant Pyr arm and Cap alone arm, respectively (Hazard ratio=0.75 [95%CI: 0.40-1.40], P=0.364). Grade 1 HFS-free period were not significant difference in both arms (Hazard ratio=0.92 [95%CI: 0.61-1.38], P=0.659). HFS-free period in each regimens were not evaluated because of small events in combination regimens. Interestingly, leucocytopenia and neutropenia were significantly increased in concomitant Pyr arm (p=0.020 and 0.006, respectively). The ratio of other adverse events were similar with both arms. Conclusions: Prophylactic pyridoxine use may delay the period until the incidence of severe Cap-induced HFS in advanced and metastatic breast cancer patients. Clinical trial information: UMIN000002932.
Pentamidine blocks hepatotoxic injury in mice
Authors: Enpeng Zhao, Ghulam Ilyas, Francesca Cingolani, Jae Ho Choi, François Ravenelle, Kathryn E. Tanaka, Mark J. Czaja
Journal: Hepatology (2017)

Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells.VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).
Asthma and smoking-induced airway disease without spirometric COPD
Authors: Neil C. Thomson
Journal: European Respiratory Journal (2017)

Due to the high prevalence rates of cigarette smoking and asthma, current and ex-smokers frequently develop chronic airway disease without spirometric evidence of chronic obstructive pulmonary disease (COPD), either alone or associated with asthma. This review considers the classification, clinical outcomes, inflammatory and imaging variables, phenotypes, and management of current and ex-smokers with airway disease without COPD, focusing on overlaps in those with and without asthma. These individuals have more respiratory symptoms, worse quality of life, increased exacerbation rates, reduced lung function and more comorbidities than never-smokers with asthma or healthy never-smokers. As well as clinical features, airway inflammatory and structural changes in smoking-induced airway disease without COPD overlap with those found in smokers with asthma. Cigarette smoking is associated with worse clinical outcomes in some phenotypes of asthma. Management involves public health measures to control exposure to tobacco smoke, personal advice on smoking cessation and the use of appropriate targeted therapies, although evidence is limited on their effectiveness. Understanding the mechanisms, natural history and management of current and ex-smokers with asthma and smoking-induced airway disease without COPD is a priority for future research.
Abstract 15320: Prevalence of Right Atrial Non-pulmonary Vein Triggers in Atrial Fibrillation Patients Treated With Thyroid Hormone Replacement Therapy
Authors: Sanghamitra Mohanty, Prasant Mohanty, Luigi Di Biase, Chintan Trivedi, Pasquale Santangeli, Rong Bai, Amin Al-Ahmad, John D Burkhardt, Joseph G Gallinghouse, Rodney Horton, Javier Sanchez, Shane Bailey, Patrick Hranitzky, Jason Zagrodzky, Andrea Natale
Journal: Circulation (2014)

Introduction:  Thyroid hormone is known to enhance the arrhythmogenicity of the pulmonary vein cardiomyocytes by increasing automaticity and triggered activity. Patients with high-normal thyroid function have been reported to be at an increased risk of AF recurrence after catheter ablation. However, very little is known about the impact of thyroid hormone replacement therapy on AF ablation. This study aimed to assess the effect of supplemental thyroid hormone on clinical parameters during catheter ablation in AF patients.   Methods:  This study evaluated 1163 consecutive paroxysmal AF patients [160 (14%) on thyroid hormone and 1003 (86%) without] undergoing their first catheter ablation at our institution. Propensity matching, based on scores calculated using a logistic model on the basis of baseline risk factors, generated 146 patients on thyroid hormone replacement (THR) therapy (65±10 year age, female 60%, BMI 30±7, LA size 44.3±0.8 mm) and 146 patients not receiving any thyroid hormone (control group; 65±9 year age, female 60%, BMI 30±7, LA size 4.3±1.1 mm). The presence of non-PV triggers was disclosed by high-dose isoproterenol challenge.   Results:  Clinical characteristics were not different between the groups. Compared to the control group, non-PV triggers were significantly more prevalent in THR patients [112(77%) vs. 47 (32%), p   Conclusion:  Right atrial non-pulmonary vein triggers were more prevalent in AF patients treated with thyroid hormone compared to their counterparts. Our results strongly suggest the importance of personalization of the ablation strategy with identification and elimination of non-PV triggers to enhance the efficacy of ablation in AF patients on thyroid hormone replacement therapy.
"Maternal Deaths from Coccidioidomycosis."
Journal: JAMA (1949)

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Treatment Decision Regret Among Long-Term Survivors of Localized Prostate Cancer: Results From the Prostate Cancer Outcomes Study
Authors: Richard M. Hoffman, Mary Lo, Jack A. Clark, Peter C. Albertsen, Michael J. Barry, Michael Goodman, David F. Penson, Janet L. Stanford, Antoinette M. Stroup, Ann S. Hamilton
Journal: Journal of Clinical Oncology (2017)

Purpose To determine the demographic, clinical, decision-making, and quality-of-life factors that are associated with treatment decision regret among long-term survivors of localized prostate cancer. Patients and Methods We evaluated men who were age ≤ 75 years when diagnosed with localized prostate cancer between October 1994 and October 1995 in one of six SEER tumor registries and who completed a 15-year follow-up survey. The survey obtained demographic, socioeconomic, and clinical data and measured treatment decision regret, informed decision making, general- and disease-specific quality of life, health worry, prostate-specific antigen (PSA) concern, and outlook on life. We used multivariable logistic regression analyses to identify factors associated with regret. Results We surveyed 934 participants, 69.3% of known survivors. Among the cohort, 59.1% had low-risk tumor characteristics (PSA < 10 ng/mL and Gleason score < 7), and 89.2% underwent active treatment. Overall, 14.6% expressed treatment decision regret: 8.2% of those whose disease was managed conservatively, 15.0% of those who received surgery, and 16.6% of those who underwent radiotherapy. Factors associated with regret on multivariable analysis included reporting moderate or big sexual function bother (reported by 39.0%; OR, 2.77; 95% CI, 1.51 to 5.0), moderate or big bowel function bother (reported by 7.7%; OR, 2.32; 95% CI, 1.04 to 5.15), and PSA concern (mean score 52.8; OR, 1.01 per point change; 95% CI, 1.00 to 1.02). Increasing age at diagnosis and report of having made an informed treatment decision were inversely associated with regret. Conclusion Regret was a relatively infrequently reported outcome among long-term survivors of localized prostate cancer; however, our results suggest that better informing men about treatment options, in particular, conservative treatment, might help mitigate long-term regret. These findings are timely for men with low-risk cancers who are being encouraged to consider active surveillance.
Abstract 349: Functional Scaffold-Free 3D Cardiac Microtissues: A Novel Model for the Investigation of Heart Cells
Authors: Bethany Desroches, Peng Zhang, Bum-Rak Choi, Michelle E King, Angel E Maldonado, Weiyan Li, Adam Rago, GongXin Liu, Nandan Nath, Kathryn M Hartmann, Bryant Yang, Gideon Koren, Jeffrey Morgan, Ulrike Mende
Journal: Circulation Research (2012)

To bridge the gap between 2D cell culture and tissue, various 3D cell culture approaches have been developed for the investigation of cardiac myocytes (CM) and fibroblasts (CF), but limitations still exist. The goal of this study was to develop a scaffold-free cardiac culture that could easily and inexpensively create many uniform cardiac microtissues that mimic the cellular distribution and functional behavior of CM and CF in tissue. Using micromolded non-adhesive agarose hydrogels containing 822 concave recesses (800 λm deep x 400 λm wide), we demonstrate that neonatal rat ventricular CM and CF, when seeded alone or in combination, self-assembled into viable (Live/Dead® stain) spherical-shaped microtissues. Importantly, when CM and CF were seeded simultaneously or sequentially, they self-sorted to be highly interspersed, reminiscent of their distribution in ventricular tissue, as shown by cell type-specific CellTracker TM or antibody labeling. Depending on their cellular composition, microtissues expressed extracellular matrix and calcium handling proteins (including SERCA2a), featured typical I K1 and I Ca-L current densities and IV relationships, and formed functional cell-cell connections (as evidenced by spontaneous action potentials, contractions and connexin 43 expression). Microelectrode recordings and optical mapping showed characteristic triangular action potentials (AP) with a resting membrane potential of -66±7 mV (n=4) in spontaneously contracting CM microtissues. Under pacing, optically mapped AP duration at 90% repolarization and conduction velocity were 100±30 ms and 18.0±1.9 cm/s, respectively (n=5 each). The presence of CF led to a prolongation of both AP and calcium transients in CM:CF microtissues (1:1). Furthermore, cell-type-specific adenoviral gene transfer was achieved, with no impact on microtissue formation or cell viability. In conclusion, we have developed a novel scaffold-free cardiac 3D culture model, in which more than 800 homotypic (CM or CF) or heterotypic (CM:CF) microtissues can be formed in a 6-well with ease, analyzed functionally and subjected to cell-type-specific gene transfer, paving the way for future in vitro investigations of CM and CF behavior and their interactions in a 3D environment.
De novo non-alcoholic steatohepatitis is associated with a five-fold long-term increased mortality in liver transplant recipients
Authors: S. Gitto, F.D. Benedetto, N.D. Maria, G. Tarantino, V. Serra, L. Maroni, M. Cescon, A.D. Pinna, P. Andreone, E. Villa
Journal: Journal of Hepatology (2017)