tbuckley/cabot-search huggingface dataset:
Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals
Authors: Pei Zhang, Jilian Wu, Fengmei Xiao, Dujuan Zhao, Yuxia Luan
Journal: Medicinal Research Reviews (2018)

Abstract Increasing numbers of disulfide linkage‐employing polymeric drug carriers that utilize the reversible peculiarity of this unique covalent bond have been reported. The reduction‐sensitive disulfide bond is usually employed as a linkage between hydrophilic and hydrophobic polymers, polymers and drugs, or as cross‐linkers in polymeric drug carriers. These polymeric drug carriers are designed to exploit the significant redox potential difference between the reducing intracellular environments and relatively oxidizing extracellular spaces. In addition, these drug carriers can release a considerable amount of anticancer drug in response to the reducing environment when they reach tumor tissues, effectively improving antitumor efficacy. This review focuses on various disulfide linkage‐employing polymeric drug carriers. Important redox thiol pools, including GSH/GSSG, Cys/CySS, and Trx1, as well as redox environments in mammals, will be introduced.
T-cell biomarkers for diagnosis of tuberculosis: candidate evaluation by a simple whole blood assay for clinical translation
Authors: Munyaradzi Musvosvi, Darragh Duffy, Elizabeth Filander, Hadn Africa, Simbarashe Mabwe, Lungisa Jaxa, Nicole Bilek, Alba Llibre, Vincent Rouilly, Mark Hatherill, Matthew Albert, Thomas J. Scriba, Elisa Nemes
Journal: European Respiratory Journal (2018)

Diagnosis of pulmonary tuberculosis (TB) disease, the most common cause of death due to infection globally [1], depends on direct detection of Mycobacterium tuberculosis , typically from a sputum specimen. However, up to half of individuals with microbiologically proven TB do not have a prolonged productive cough [2], required to produce sputum. To address this challenge, investigators have identified candidate blood-based host biomarkers for TB diagnosis, based on M. tuberculosis -specific T-cell memory phenotypes, activation or cytokine expression profiles [3–9]. Such biomarkers have also shown potential as surrogates to monitor TB treatment response [3, 10]. Here, we aimed to: 1) compare the diagnostic performance of several blood-based T-cell biomarkers in TB patients and controls; 2) determine if combinations of these biomarkers improve diagnostic performance; 3) identify the minimal number of flow cytometry parameters required to distinguish active TB patients from persons with latent M. tuberculosis infection (LTBI); and 4) translate measurement of these biomarkers from peripheral blood mononuclear cells to whole blood to enable a simplified application in field studies. We compared candidate T-cell-based TB biomarkers and identified HLA-DR on Mtb-specific T-cells as a priority marker <http://ow.ly/TyHa30iwVbL>
EFFECT OF OBESITY ON LEFT ATRIAL STRAIN IN MIDDLE AGE: THE ASKLEPIOS STUDY
Authors: Julio A. Chirinos, Marc De Buyzere, Jugal Chahwala, Vaibhav Satija, Patrick Segers, Dirk De Bacquer, Thierry Gillebert, Ernst Rietzschel
Journal: Journal of the American College of Cardiology (2018)
“Tragedy” of 35 deaths from measles in Europe last year is unacceptable, says WHO
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

There were 21 315 cases of measles and 35 deaths recorded in Europe in 2017—a 400% increase on the previous year when there was a record low of 5273 cases, World Health Organization figures show.1

Large outbreaks of measles (100 or more cases) have affected 15 of the 53 countries in the WHO European region, with the highest numbers seen in Romania (5562), Italy (5006), and Ukraine (4767). Vaccination rates (2nd dose) in these …
DIRECT PULMONARY VEIN ABLATION WITHOUT STENOSIS: CHRONIC EFFICACY OF A NOVEL ELECTROPORATION TECHNIQUE
Authors: Chance M. Witt, Alan Sugrue, Deepak Padmanabhan, Sarah Gruba, James Rohl, Christopher DeSimone, Ammar Killu, Niyada Naksuk, Suraj Kapa, Samuel Asirvatham
Journal: Journal of the American College of Cardiology (2018)
Abstract 210: The Association of Body Mass Index with Time to Target Temperature and Outcomes in Postarrest Patients Treated with Therapeutic Hypothermia via an External Cooling System
Authors: Marion Leary, Marisa J Cinousis, Kelsey Sheak, Stephen Iannacone, Daniel Kolansky, Mark Mikkelsen, Benjamin S Abella, Barry Fuchs
Journal: Circulation (2012)

Background: Regarding the use of TH for post-cardiac arrest patients, preliminary evidence suggests that more rapid attainment of target temperature (32-34 o C) may improve outcomes. We hypothesized that the time to achieve target temperature is increased as Body Mass Index (BMI) increases and that this may impact clinical outcomes. Objective: To assess for an association of BMI with time to target temperature, skin complications, survival to hospital discharge, and good neurologic outcome (GCS 14-15) in survivors. Methods: Single-center retrospective cohort of cardiac arrest patients who underwent TH using an external cooling system between 7/2007 - 6/2012. We examined the association between BMI (weight in kilograms divided by height in meters squared) and time from initiation of cooling to attainment of target temperature. The cohort was categorized into two groups based on their BMI, (see table 1). The Wilcoxon rank-sum was used to compare time to target temperature by BMI status, categorized as obese and non-obese and the chi-squared was used to compare categorical variables. Results: Of the 179 patients treated with TH, 135 were evaluable. The median age of the cohort was 60 yrs, (IQR 46, 69); 64/135 (47%) were female and 37/135 (27%) had VF/VT as the initial rhythm. Mean time to target temperature was 216 min (IQR 135, 359). Obese compared to non-obese patients required a longer time to achieve target temperature (p=0.07) and obese patients were significantly more likely to have skin breakdown (p=0.01). There was no survival difference between obese and non-obese patients in terms of discharge (53% vs. 45%, p=0.39), nor good neurologic outcome (76% vs. 62%, p=0.26). Conclusions: Obese patients were significantly more likely to experience skin breakdown as a result of TH. There was a suggestion that time to target temperature was prolonged in obese patients. Whether outcomes could have been improved in obese patients if time to target temperature was reduced, is unknown.
Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy
Authors: Rina Nishii, Takaya Moriyama, Laura J. Janke, Wenjian Yang, Chase C. Suiter, Ting-Nien Lin, Lie Li, Kentaro Kihira, Hidemi Toyoda, Ute Hofmann, Matthias Schwab, Masatoshi Takagi, Tomohiro Morio, Atsushi Manabe, Shirley Kham, Nan Jiang, Karen R. Rabin, Motohiro Kato, Katsuyoshi Koh, Allen Eng-Juh Yeoh, Hiroki Hori, Jun J. Yang
Journal: Blood (2018)
INCIDENCE, PATTERNS AND ASSOCIATIONS BETWEEN DUAL ANTIPLATELET THERAPY CESSATION AND RISK FOR ADVERSE EVENTS IN HIGH-RISK PATIENTS: INSIGHTS FROM THE PARIS REGISTRY
Authors: Sabato Sorrentino, Usman Baber, Gennaro Giustino, Samantha Sartori, Jaya Chandrasekhar, Clayton Snyder, Serdar Farhan, Birgit Vogel, Ge Zhen, Ariti Cono, C. Michael Gibson, Mitchell Krucoff, David J. Moliterno, Alaide Chieffo, Timothy Henry, Giora Weisz, Ioannis Iakovou, Antonio Colombo, Thomas Stuckey, Annapoorna Subhash Kini, Bernhard Witzenbichler, Philippe G. Steg, George Dangas, Stuart Pocock, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Letter by Tampaki et al Regarding Article, “Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)”
Authors: Ekaterini Christina Tampaki, Athanasios Tampakis, Costas Pantos
Journal: Circulation (2018)
Complement-Mediated Activation of the NLRP3 Inflammasome and Its Inhibition by AAV-Mediated Delivery of CD59 in a Model of Uveitis
Authors: Binit Kumar, Siobhan M. Cashman, Rajendra Kumar-Singh
Journal: Molecular Therapy (2018)

Uveitis is an inflammatory disorder of the eye responsible for approximately 10%–15% of blindness in the US. In this study, we examined the role of the complement membrane attack complex (MAC) and the NLRP3 inflammasome in the pathogenesis of experimental autoimmune uveitis (EAU) in normal and C9−/− mice that are incapable of assembling the MAC. We discovered that the MAC and the NLRP3 inflammasome and associated production of IL-1β are elevated in EAU mice and that MAC may be involved in regulation of Th1 and Th17 cell differentiation. In contrast, MAC and the NLRP3 inflammasome were not elevated in C9−/− mice. However, EAU-associated pathophysiology including retinal structure and function were not rescued in C9−/− mice. Unexpectedly, AAV-mediated delivery of sCD59, an inhibitor of C9 incorporation into the MAC, successfully attenuated activation of the NLRP3 inflammasome and EAU pathology as well as MAC. Our studies provide an improved understanding of the role of the MAC and the NLRP3 inflammasome in EAU as well as suggest a novel approach for the treatment of uveitis. Uveitis is an inflammatory disorder of the eye responsible for approximately 10%–15% of blindness in the US. In this study, we examined the role of the complement membrane attack complex (MAC) and the NLRP3 inflammasome in the pathogenesis of experimental autoimmune uveitis (EAU) in normal and C9−/− mice that are incapable of assembling the MAC. We discovered that the MAC and the NLRP3 inflammasome and associated production of IL-1β are elevated in EAU mice and that MAC may be involved in regulation of Th1 and Th17 cell differentiation. In contrast, MAC and the NLRP3 inflammasome were not elevated in C9−/− mice. However, EAU-associated pathophysiology including retinal structure and function were not rescued in C9−/− mice. Unexpectedly, AAV-mediated delivery of sCD59, an inhibitor of C9 incorporation into the MAC, successfully attenuated activation of the NLRP3 inflammasome and EAU pathology as well as MAC. Our studies provide an improved understanding of the role of the MAC and the NLRP3 inflammasome in EAU as well as suggest a novel approach for the treatment of uveitis.
Tuberculosis and tobacco: is there any epidemiological association?
Authors: Eva Padrão, Olena Oliveira, Óscar Felgueiras, Ana Rita Gaio, Raquel Duarte
Journal: European Respiratory Journal (2018)

Tobacco smoking has been suspected to be a risk factor for tuberculosis (TB) for more than a century, but only recently has consistent epidemiological evidence between tobacco and TB been established [1, 2]. Smokers are more likely to be infected with TB, progress to active disease and die from TB [3–5]. However, there are few worldwide studies regarding a dose–response relationship between the number of smoked cigarettes per day (CPD) and TB risk. Excessive tobacco consumption in men (20 or more cigarettes per day) is a risk factor for tuberculosis <http://ow.ly/AWdK30hdZOq>
PREDICTORS FOR NEOATHEROSCLEROSIS IN SIROLIMUS-ELUTING STENTS OVER 10 YEARS AFTER IMPLANTATION
Authors: Eisuke Usui, Taishi Yonetsu, Yoshinori Kanno, Rikuta Hamaya, Tadashi Fukuda, Hiroaki Ohya, Yohei Sumino, Masahiro Hada, Masao Yamaguchi, Masahiro Hoshino, Yoshihisa Kanaji, Tsunekazu Kakuta
Journal: Journal of the American College of Cardiology (2018)
YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis
Authors: Shuai Ye, Matthew A. Lawlor, Adrian Rivera-Reyes, Shaun Egolf, Susan Chor, Koreana Pak, Gabrielle E. Ciotti, Avery C. Lee, Gloria E. Marino, Jennifer Shah, David Niedzwicki, Kristy Weber, Paul M.C. Park, Md. Zahidul Alam, Alison Grazioli, Malay Haldar, Mousheng Xu, Jennifer A. Perry, Jun Qi, T.S. Karin Eisinger-Mathason
Journal: Cancer Research (2018)

Abstract To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment. Significance: A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705–20. ©2018 AACR.
From genome-wide association studies to Mendelian randomization: novel opportunities for understanding cardiovascular disease causality, pathogenesis, prevention, and treatment
Authors: Marianne Benn, Børge G Nordestgaard
Journal: Cardiovascular Research (2018)

The Mendelian randomization approach is an epidemiological study design incorporating genetic information into traditional epidemiological studies to infer causality of biomarkers, risk factors, or lifestyle factors on disease risk. Mendelian randomization studies often draw on novel information generated in genome-wide association studies on causal associations between genetic variants and a risk factor or lifestyle factor. Such information can then be used in a largely unconfounded study design free of reverse causation to understand if and how risk factors and lifestyle factors cause cardiovascular disease. If causation is demonstrated, an opportunity for prevention of disease is identified; importantly however, before prevention or treatment can be implemented, randomized intervention trials altering risk factor levels or improving deleterious lifestyle factors needs to document reductions in cardiovascular disease in a safe and side-effect sparse manner. Documentation of causality can also inform on potential drug targets, more likely to be successful than prior approaches often relying on animal or cell studies mainly. The present review summarizes the history and background of Mendelian randomization, the study design, assumptions for using the design, and the most common caveats, followed by a discussion on advantages and disadvantages of different types of Mendelian randomization studies using one or more samples and different levels of information on study participants. The review also provides an overview of results on many of the risk factors and lifestyle factors for cardiovascular disease examined to date using the Mendelian randomization study design.
EAACI Position paper on the standardization of nasal allergen challenges
Authors: J. Augé, J. Vent, I. Agache, L. Airaksinen, P. Campo Mozo, A. Chaker, C. Cingi, S. Durham, W. Fokkens, P. Gevaert, A. Giotakis, P. Hellings, M. Herknerova, V. Hox, L. Klimek, C. La Melia, J. Mullol, N. B. Muluk, A. Muraro, K. Naito, O. Pfaar, H. Riechelmann, C. Rondon, M. Rudenko, B. Samolinski, I. Tasca, P. Tomazic, K. Vogt, M. Wagenmann, G. Yeryomenko, L. Zhang, R. Mösges
Journal: Allergy (2018)

Abstract Nasal allergen challenge (NAC) is an important tool to diagnose allergic rhinitis. In daily clinical routine, experimentally, or when measuring therapeutic success clinically, nasal allergen challenge is fundamental. It is further one of the key diagnostic tools when initiating specific allergen immunotherapy. So far, national recommendations offered guidance on its execution; however, international divergence left many questions unanswered. These differences in the literature caused EAACI to initiate a task force to answer unmet needs and find a consensus in executing nasal allergen challenge. On the basis of a systematic review containing nasal allergen challenges of the past years, task force members reviewed evidence, discussed open issues, and studied variations of several subjective and objective assessment parameters to propose a standardized way of a nasal allergen challenge procedure in clinical practice. Besides an update on indications, contraindications, and preparations for the test procedure, main recommendations are a bilaterally challenge with standardized allergens, with a spray device offering 0.1 mL per nostril. A systematic catalogue for positivity criteria is given for the variety of established subjective and objective assessment methods as well as a schedule for the challenge procedure. The task force recommends a unified protocol for NAC for daily clinical practice, aiming at eliminating the previous difficulty of comparing NAC results due to unmet needs.
A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers
Authors: Haiyan Zhu, Xiang Gu, Lu Xia, You Zhou, Hakim Bouamar, Junhua Yang, Xiaofei Ding, Christian Zwieb, Jianan Zhang, Andrew P. Hinck, Lu-Zhe Sun, Xueqiong Zhu
Journal: Clinical Cancer Research (2018)

Abstract Purpose: We investigated the mechanisms of how TGFβ pathway is activated by chemotherapeutics and whether a novel TGFβ trap called RER can block chemotherapeutics-induced TGFβ pathway activation and enhance their antitumor activity in gynecologic cancer. Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGFβ signaling and function, and the effects of RER on chemotherapy-induced TGFβ signaling were determined in gynecologic cancer cells. Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGFβ signaling activation. Chemotherapy was found to activate TGFβ signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGFβ1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial–mesenchymal transition (EMT) and cancer stem cells (CSC). These TGFβ-like effects were due to the stimulation of TGFβ1 expression and secretion, and could all be abrogated by TGFβ inhibitors including a novel TGFβ trap protein called RER both in vitro and in vivo. Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer. Conclusions: Chemotherapeutics can stimulate TGFβ1 production and consequently enhance TGFβ signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGFβ inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. Clin Cancer Res; 24(12); 2780–93. ©2018 AACR.
Eosinophils in COPD: how many swallows make a summer?
Authors: Ghassan Ahmed Hamad, Wesley Cheung, Michael G. Crooks, Alyn H. Morice
Journal: European Respiratory Journal (2018)

There is considerable controversy over the place of the blood eosinophil as a biomarker in chronic obstructive pulmonary disease (COPD). Recent literature suggests its use in assessing responsiveness to inhaled corticosteroids (ICS) [1, 2] and in predicting exacerbations [3, 4]. Other studies either wholly or partially refute these associations [5–7]. We suggest that what underlies this confusion is the failure to understand the temporal variation in the biomarker, and the inherent imprecision in the collection of associated end-point data. Repeated measures of eosinophil counts increased the proportion of eosinophilic patients <http://ow.ly/LhnV30hlR5j>
Government reiterates goal of limiting impact of European Working Time Directive
Authors: Helen Jaques
Journal: BMJ (2013)

The government has reiterated its commitment to limiting the application of the Working Time Directive in the NHS, after a review of the balance of power between the United Kingdom and the European Union.

The review of the “balance of competences” in the area of health1 is one of 36 studies commissioned by the government to assess how EU legislation affects the UK. Evidence was provided by MPs, government departments, and the royal colleges.

A report of the review concludes that the current balance of power between the UK and the EU is …
Association of Cardiac Rehabilitation With Decreased Hospitalizations and Mortality After Ventricular Assist Device Implantation
Authors: Justin M. Bachmann, Meredith S. Duncan, Ashish S. Shah, Robert A. Greevy, JoAnn Lindenfeld, Steven J. Keteyian, Randal J. Thomas, Mary A. Whooley, Thomas J. Wang, Matthew S. Freiberg
Journal: JACC Heart Failure (2018)
Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer.
Authors: Yosuke Togashi, Yasuko Tada, Daisuke Kotani, Akihito Kawazoe, Toshihiko Doi, Hiroyoshi Nishikawa, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

98 Background: Ramucirumab (RAM), a monoclonal antibody against VEGFR2, was recently approved for the treatment of advanced gastric cancer (GC). However, little is known about the immunological effects in advanced GC patients. Methods: Patients with advanced GC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to September 2016. Paired samples were obtained from peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in primary tumors pre- and post-RAM therapy to investigate immune profiles. Results: A total of 59 PBMCs and TILs from 18 patients were collected. Higher frequencies of FOXP3 high CD45RA - CD4 + T cells (effector regulatory T cells: eTregs) were detected in TILs compared with PBMCs (19.05±10.48% vs 1.89±1.0%, P &lt; 0.0001), and the presence of high eTreg in TILs was not reflected in PBMCs. eTregs of TILs, but not of PBMC were significantly decreased after RAM-containing therapies (22.67±11.19% vs. 16.33±8.44%, P = 0.034). Expressions of immune checkpoint (IC) molecules (PD-1, CTLA-4, LAG-3, and ICOS) were much higher in TILs than those in PBMCs, and all these molecules exhibited higher expressions on eTregs than on CD8 + T cells. Among them, ICOS was specifically expressed by eTregs in TILs. PD-1 + CD8 + T cells in TILs were significantly decreased after RAM-containing therapies (54.99±19.06% vs. 39.23±17.15%, P = 0.0005), but not in PBMC. Patients with partial responses had significantly higher frequency of eTreg in pre-treatment TIL than those with progression disease (32.56±12.11% vs. 14.83±3.18%, P = 0.036). Furthermore, patients with high eTreg frequency had significantly longer progression-free survival than those with low frequency (161 days vs. 76 days, P = 0.024). Conclusions: There was significant difference in immune profile between PBMC and TIL in GC patients. eTregs and PD-1 expression on CD8 + T cells in TILs, not in PBMCs were decreased after RAM-containing therapies. This observation suggests the importance of TIL analyses and might be a rationale to use RAM as an immunomodulator in combination with IC inhibitors.