tbuckley/cabot-search huggingface dataset:
Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis
Authors: Alexander E. Weber, Omid Jalali, Sean Limfat, Ruzanna Shkhyan, Robert Van Der Horst, Siyoung Lee, Yucheng Lin, Liangliang Li, Erik N. Mayer, Liming Wang, Nancy Q. Liu, Frank A. Petrigliano, Jay R. Lieberman, Denis Evseenko
Journal: Arthritis & Rheumatology (2020)

Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA.Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage.Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls).The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.
Understanding the pathophysiological mechanisms of cardiometabolic complications in obstructive sleep apnoea: towards personalised treatment approaches
Authors: Silke Ryan, Eoin P. Cummins, Ramon Farre, Alex Gileles-Hillel, Jonathan C. Jun, Henrik Oster, Jean-Louis Pepin, David W. Ray, Sirimon Reutrakul, Manuel Sanchez-de-la-Torre, Renaud Tamisier, Isaac Almendros
Journal: European Respiratory Journal (2020)

In January 2019, a European Respiratory Society research seminar entitled "Targeting the detrimental effects of sleep disturbances and disorders" was held in Dublin, Ireland. It provided the opportunity to critically review the current evidence of pathophysiological responses of sleep disturbances, such as sleep deprivation, sleep fragmentation or circadian misalignment and of abnormalities in physiological gases such as oxygen and carbon dioxide, which occur frequently in respiratory conditions during sleep. A specific emphasis of the seminar was placed on the evaluation of the current state of knowledge of the pathophysiology of cardiovascular and metabolic diseases in obstructive sleep apnoea (OSA). Identification of the detailed mechanisms of these processes is of major importance to the field and this seminar offered an ideal platform to exchange knowledge, and to discuss pitfalls of current models and the design of future collaborative studies. In addition, we debated the limitations of current treatment strategies for cardiometabolic complications in OSA and discussed potentially valuable alternative approaches.
Development and Validation of a Prognostic Survival Model With Patient-Reported Outcomes for Patients With Cancer
Authors: Hsien Seow, Peter Tanuseputro, Lisa Barbera, Craig Earle, Dawn Guthrie, Sarina Isenberg, Rosalyn Juergens, Jeffrey Myers, Melissa Brouwers, Rinku Sutradhar
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Existing prognostic cancer tools include biological and laboratory variables. However, patients often do not know this information, preventing them from using the tools and understanding their prognosis. <h3>Objective</h3> To develop and validate a prognostic survival model for all cancer types that incorporates information on symptoms and performance status over time. <h3>Design, Setting, and Participants</h3> This is a retrospective, population-based, prognostic study of data from patients diagnosed with cancer from January 1, 2008, to December 31, 2015, in Ontario, Canada. Patients were randomly selected for model derivation (60%) and validation (40%). The derivation cohort was used to develop a multivariable Cox proportional hazards regression model with baseline characteristics under a backward stepwise variable selection process to predict the risk of mortality as a function of time. Covariates included demographic characteristics, clinical information, symptoms and performance status, and health care use. Model performance was assessed on the validation cohort by C statistics and calibration plots. Data analysis was performed from February 6, 2018, to November 6, 2019. <h3>Main Outcomes and Measures</h3> Time to death from diagnosis (year 0) recalculated at each of 4 annual survivor marks after diagnosis (up to year 4). <h3>Results</h3> A total of 255 494 patients diagnosed with cancer were identified (135 699 [53.1%] female; median age, 65 years [interquartile range, 55-73 years]). The cohort decreased to 217 055, 184 822, 143 649, and 109 569 patients for each of the 4 years after diagnosis. In the derivation cohort year 0, and the most common cancers were breast (30 855 [20.1%]), lung (19 111 [12.5%]), and prostate (18 404 [12.0%]). A total of 47 614 (31.1%) had stage III or IV disease. The mean (SD) time to death in year 0 was 567 (715) days. After backward stepwise selection in year 0, the following factors were associated with increased risk of death by more than 10%: being hospitalized; having congestive heart failure, chronic obstructive pulmonary disease, or dementia; having moderate to high pain; having worse well-being; having functional status in the transitional or end-of-life phase; having any problems with appetite; receiving end-of-life home care; and living in a nursing home. Model discrimination was high for all models (C statistic: 0.902 [year 0], 0.912 [year 1], 0.912 [year 2], 0.909 [year 3], and 0.908 [year 4]). <h3>Conclusions and Relevance</h3> The model accurately predicted changing cancer survival risk over time using clinical, symptom, and performance status data and appears to have the potential to be a useful prognostic tool that can be completed by patients. This knowledge may support earlier integration of palliative care.
Gene Duplication in the Honeybee: Patterns of DNA Methylation, Gene Expression, and Genomic Environment
Authors: Carl J Dyson, Michael A D Goodisman
Journal: Molecular Biology and Evolution (2020)

Gene duplication serves a critical role in evolutionary adaptation by providing genetic raw material to the genome. The evolution of duplicated genes may be influenced by epigenetic processes such as DNA methylation, which affects gene function in some taxa. However, the manner in which DNA methylation affects duplicated genes is not well understood. We studied duplicated genes in the honeybee Apis mellifera, an insect with a highly sophisticated social structure, to investigate whether DNA methylation was associated with gene duplication and genic evolution. We found that levels of gene body methylation were significantly lower in duplicate genes than in single-copy genes, implicating a possible role of DNA methylation in postduplication gene maintenance. Additionally, we discovered associations of gene body methylation with the location, length, and time since divergence of paralogous genes. We also found that divergence in DNA methylation was associated with divergence in gene expression in paralogs, although the relationship was not completely consistent with a direct link between DNA methylation and gene expression. Overall, our results provide further insight into genic methylation and how its association with duplicate genes might facilitate evolutionary processes and adaptation.
Randomized Comparison of Ridaforolimus- and Zotarolimus-Eluting Coronary Stents in Patients With Coronary Artery Disease
Authors: David E. Kandzari, Pieter C. Smits, Michael P. Love, Ori Ben-Yehuda, Shmuel Banai, Simon D. Robinson, Michael Jonas, Ran Kornowski, Rodrigo Bagur, Andres Iniguez, Haim Danenberg, Robert Feldman, Rajiv Jauhar, Harish Chandna, Manish Parikh, Gidon Y. Perlman, Mercedes Balcells, Peter Markham, Melek Ozgu Ozan, Philippe Genereux, Elazer R. Edelman, Martin B. Leon, Gregg W. Stone
Journal: Circulation (2017)

The safety and efficacy of a novel cobalt alloy-based coronary stent with a durable elastomeric polymer eluting the antiproliferative agent ridaforolimus for treatment of patients with coronary artery disease is undetermined.
Autoantibodies and interstitial lung disease in rheumatoid arthritis: towards a ‘mix-and-match’ approach?
Authors: Alessia Alunno, Onelia Bistoni, Angelo Francesco Bonifacio, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the article by Castellanos-Moreira et al who identified for the first time an association between anticarbamylated protein antibodies and interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA).1 The reported prevalence of ILD in RA ranges from 4% to 70% according to different cohorts and inclusion criteria. The clinical spectrum is rather broad ranging from mild reversible lung inflammatory disease to rapidly progressing fibrotic conditions with poor prognosis and frequent cause of death. On this basis, clinicians should be alert and promptly identify, classify and manage ILD according to its features and severity. However, whether a patient with RA will develop or not ILD, depends on several genetic, demographic, environmental and immunological factors that interact with each other and reliable markers able to predict ILD development are currently lacking.2 The increasing …
Abstract 15435: Oxidative Stress Induced Enos Thiol Oxidation: a Novel Mechanism Regulating Enos and Cardiovascular Function
Authors: Chun-An Chen, Cho-Hao Lin, Jay L Zweier
Journal: Circulation (2011)

Previously, we have demonstrated that eNOS S-glutathionylation uncouples eNOS, leading to increase superoxide (•O2-) generation from the purified enzyme, oxidant-induced endothelium, and hypertensi...
Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy
Authors: Chongxian Pan, Hongtao Liu, Elizabeth Robins, Wenru Song, Delong Liu, Zihai Li, Lei Zheng
Journal: Journal of Hematology & Oncology (2020)

Abstract Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.
Unilateral outward-turning leg in infancy.
Journal: BMJ (1981)

An unreported condition of the legs in infants was found in more than 130 children referred to one hospital from 1973 to 1979.One hundred of these children were studied.One leg, usually the right, lay in external rotation.Although there was no loss or restriction of movement at the hip joints, in most cases there was a difference in the arc of rotation.Eleven children also had mild hooking of the forefoot on the unaffected side.Hip radio- graphs were normal in all cases.Obstetric records were reviewed in 70 cases, but no relation was found between presenting position at birth and side of the affected limb.The condition resolved spontaneously in most of the children who were followed up.This condition may cause anxiety to parents and doc- tors but it seems to be a variant of normal with an excellent prognosis.
Characterization of amoxicillin and clavulanic acid specific T‐cell clones from patients with immediate drug hypersensitivity
Authors: Adriana Ariza, Rubén Fernández‐Santamaría, Xiaoli Meng, María Salas, Monday O. Ogese, Arun Tailor, Gádor Bogas, María José Torres, Dean J. Naisbitt
Journal: Allergy (2020)

Betalactam (BL) antibiotics are the most common cause of drug hypersensitivity. Amoxicillin (AX), which is often prescribed alongside clavulanic acid (Clav), is the most common elicitor. The aim of this study was to determine whether AX and Clav-responsive T-cells are detectable in patients with immediate hypersensitivity to AX-Clav, to assess whether these T-cells display the same specificity as that detected in skin and provocation testing, and to explore T-cell activation pathways.
Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients aged ≥ 80 years with hypertension
Authors: J Sheppard, J Burt, M Lown, E Temple, R Lowe, R Fraser, J Allen, G Ford, C Heneghan, F Hobbs, S Jowett, S Kodabuckus, P Little, J Mant, J Mollison, R Payne, M Williams, Yu L-M., R McManus
Journal: JAMA (2020)
Abstract MP96: Long Sleep and Evening Chronotype Associated with Poor Cardiovascular Health Behaviors
Authors: Freda Patterson, Susan K Malone, Alicia Lozano, Michael A Grandner, Christina Calamaro, Alexandra Hanlon
Journal: Circulation (2016)

Sleep duration and circadian preference (morningness/eveningness preference or “chronotype”) have separately been associated with cardiovascular risk behaviors including tobacco use and physical inactivity. Interactive effects are plausible, resulting from combinations of sleep homeostatic and circadian influences. But these have not been explored previously. To address this, associations between combinations of sleep duration (short [≤6h], adequate [7-8h], long [&gt;9h]) and chronotype (morning, intermediate, evening) were examined relative to tobacco use, physical inactivity, sedentary behavior, and overweight, in a cross-sectional sample of 439,933 adults enrolled in the United Kingdom Biobank project. The study sample was 56% female, 95% white, and the mean age was 56.5 (SD=8.1) years. Most participants engaged in 1 (39%) or 2 (35%) risk behaviors; 10% engaged in 3, 1% engaged in 4 while 15% engaged in 0. Compared to morning types with adequate sleep (referent group), evening types with long sleep had 1.98-fold odds of not meeting physical activity recommendations, 1.47-fold odds of being overweight, and 2.19-fold odds of high sedentary behavior. Evening types with short sleep had 3.36-fold odds of being smokers as compared to morning types with adequate sleep. All models were adjusted for age, sex, race, college attendance and shift work. These data suggest an interactive relationship between sleep duration and chronotype, such that evening types who do not get adequate sleep may be most at risk for poor heart health behaviors. Further work is needed to determine the effects of chronotherapeutic interventions (i.e., shifting evening toward morning preference) on heart health behaviors.
SP0052 FATIGUE IN RHEUMATOID ARTHRITIS: WHAT IT IS AND HOW TO ASSESS IT?
Authors: Jos&etilde; Antonio P. da Silva
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Fatigue is a frequent and important symptom in rheumatoid arthritis (RA), and it is associated with significantly reduced health-related quality of life, thus contributing to the impact of disease upon patients9 lives. <h3>Objectives:</h3> To collect, summarise and interpret available evidence on the nature of fatigue and the best ways to assess it in Rheumatoid Arthritis <h3>Methods:</h3> A systematic literature research was performed in trying to (i) to synthesize the role of fatigue in the global impact of rheumatoid arthritis; (ii) describe validated instruments and their psychometric properties as measures of fatigue among patients with RA; and finally (iii) propose a clinically meaningful, valid and feasible process to measure fatigue in clinical practice. <h3>Results:</h3> Fatigue has a major relevance in the overall burden of disease in RA. Several instruments have been validated o measure it, but no consensus has yet been reached to recommend a "gold-standard". <h3>Conclusion:</h3> Although fatigue is recognized by the rheumatology community as an important consequence of RA and a major gap in its current management of the disease, it has not been easy to measure and grasp. The problem seems to reside in the multidimensional causality and subjetive nature of this phenomenon, which may warrant dedicated measures and interventions. <h3>Disclosure of Interests:</h3> None declared
Abstract 10920: Quantifying the Risk of Ischemic Stroke Attributed to Lack of Oral Anticoagulation Use in the Southern Part of the US Among Atrial Fibrillation Patients
Authors: Jingchuan Guo, Meiqi He, Jared W Magnani, Walid F Gellad, Inmaculada Hernandez
Journal: Circulation (2019)

Background: Prior research has shown that oral anticoagulation (OAC) use is lowest in the southern part of the US, however, it remains unknown how this lower OAC use contributes to the higher rates...
Abstract 11051: Soluble Fms-Like Tyrosine Kinase 1 is a Novel Predictor of Cardiovascular Disease Progression in Patients with Coronary Artery Disease
Authors: Ryo Kameda, Minako Yamaoka-Tojo, Taiki Tojo, Kazuki Wakaume, Shinji Nemoto, Lisa Kitasato, Yuki Yoshida, Takao Shimohama, Yoji Machida, Tohru Izumi
Journal: Circulation (2011)

Purpose: Soluble Fms-like tyrosine kinase 1 (sFlt-1) is an endogenous inhibitor of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), which are involved in cardiovascular...
<i>PRKDC</i>: new biomarker and drug target for checkpoint blockade immunotherapy
Authors: Kien Thiam Tan, Chun-Nan Yeh, Yu-Chan Chang, Jen-Hao Cheng, Wen-Liang Fang, Yi-Chen Yeh, Yu-Chao Wang, Dennis Shin-Shian Hsu, Chiao-En Wu, Jiun-I Lai, Peter Mu-Hsin Chang, Ming-Han Chen, Meng-Lun Lu, Shu-Jen Chen, Yee Chao, Michael Hsiao, Ming-Huang Chen
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings. Methods Mutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide ( PRKDC ) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor. Results From the published literature, we found that among patients whose tumors harbored PRKDC mutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that a PRKDC mutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboring PRKDC mutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor ( PRKDC encodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model. Conclusions PRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.
A Network of Sputum MicroRNAs Is Associated with Neutrophilic Airway Inflammation in Asthma
Authors: Jose L. Gomez, Ailu Chen, Maria Paula Diaz, Nicholas Zirn, Amolika Gupta, Clemente Britto, Maor Sauler, Xiting Yan, Emma Stewart, Kyle Santerian, Nicole Grant, Qing Liu, Rebecca Fry, Julia Rager, Lauren Cohn, Neil Alexis, Geoffrey L. Chupp
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.
Diffuse alveolar haemorrhage secondary to e-cigarette “vaping” associated lung injury (EVALI) in a young European consumer
Authors: Thomas Villeneuve, Grégoire Prevot, Aurélie Le Borgne, Magali Colombat, Samia Collot, Stephanie Ruiz, Thomas Lanot, Laurent Brouchet, Audrey Rabeau, Elise Noel-Savina, Alain Didier
Journal: European Respiratory Journal (2020)

<b>A notable case of EVALI not involving cannabis derivatives in a 28-year-old woman who developed an intra-alveolar haemorrhage without differential diagnosis after surgical lung biopsy and requiring extracorporeal membrane oxygenation</b>http://bit.ly/2TXx79K
Updating the diagnostic criteria of COVID-19 “suspected case” and “confirmed case” is necessary
Authors: Yun-Yun Wang, Ying-Hui Jin, Xue-Qun Ren, Yi-Rong Li, Xiao-Chun Zhang, Xian-Tao Zeng, Xing-Huan Wang
Journal: Military Medical Research (2020)

Abstract On 6 February 2020, our team had published a rapid advice guideline for diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infection, and this guideline provided our experience and make well reference for fighting against this pandemic worldwide. However, the coronavirus disease 2019 (COVID-19) is a new disease, our awareness and knowledge are gradually increasing based on the ongoing research findings and clinical practice experience; hence, the strategies of diagnosis and treatment are also continually updated. In this letter, we answered one comment on our guideline and provided the newest diagnostic criteria of “suspected case” and “confirmed case” according to the latest Diagnosis and Treatment Guidelines for COVID-19 (seventh version) that issued by the National Health Committee of the People’s Republic of China.