tbuckley/cabot-search huggingface dataset:
AB0071 THERAPEUTIC EFFECTS OF BONE MARROW MESENCHYMAL STEM CELLS-DERIVED EXOSOMES ON OSTEOARTHRITIS
Authors: C. Dong, Y. Liu, A. Deng, J. Ji, W. Zheng, Z. Gu
Journal: Annals of the Rheumatic Diseases (2020)

Background: Mesenchymal stem cells (MSCs) have shown chondroprotective effects in clinical models of osteoarthritis (OA) [1] . Objectives: The study aimed to investigate the therapeutic potential of exosomes from human bone marrow MSCs (BM-MSCs) in alleviating OA. Methods: The anterior cruciate ligament transection (ACLT) anddestabilization of the medial meniscus (DMM) surgery were performed on the knee joints of a rat OA model, followed by intra-articular injection of BM-MSCs or their exosomes. The beneficial effects were evaluated by histological staining, OARSI scores and micro-CT. Furthermore, BM-MSCs-derived exosomes were administrated to primary human chondrocytes to observe the functional and molecular alterations. In addition, lncRNA MEG3 were investigated in chondrocytes to explore the biological contents accounting for anti-OA effects of BM-MSCs-derived exosomes. Results: Based on the observation in the rat OA model, both of BM-MSCs and BM-MSCs-derived exosomes alleviated cartilage destruction, reduced joint damage and restored the trabecular bone of OA rats. In addition, in vitro assays showed that BM-MSCs- exosomes could maintain the chondrocyte phenotype by increasing collagen type II synthesis and inhibiting IL-1β- induced senescence and apoptosis. Furthermore, exosomal lncRNA MEG3 also reduced the senescence and apoptosis of chondrocytes induced by IL-1β, indicating that lncRNA MEG3 might partially account for the anti-OA effects of BM-MSC exosomes. Conclusion: The exosomes from BM-MSCs exerted beneficial therapeutic effects on OA by reducing the senescence and apoptosis of chondrocytes, suggesting that MSCs-derived exosomes might provide a candidate therapy for OA treatment. References: [1]Mckinney J M, Doan T N, Wang L, et al. Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis[J]. Eur Cell Mater, 2019, 37: 42-59. Disclosure of Interests: None declared
A single-cell atlas of the peripheral immune response in patients with severe COVID-19
Authors: Aaron J. Wilk, Arjun Rustagi, Nancy Q. Zhao, Jonasel Roque, Giovanny J. Martínez-Colón, Julia L. McKechnie, Geoffrey T. Ivison, Thanmayi Ranganath, Rosemary Vergara, Taylor Hollis, Laura J. Simpson, Philip Grant, Aruna Subramanian, Angela J. Rogers, Catherine A. Blish
Journal: Nature Medicine (2020)
Systems Genetics for Mechanistic Discovery in Heart Diseases
Authors: Christoph D. Rau, Aldons J. Lusis, Yibin Wang
Journal: Circulation Research (2020)

Cardiovascular diseases are the leading cause of death worldwide. Complex diseases with highly heterogenous disease progression among patient populations, cardiovascular diseases feature multifactorial contributions from both genetic and environmental stressors. Despite significant effort utilizing multiple approaches from molecular biology to genome-wide association studies, the genetic landscape of cardiovascular diseases, particularly for the nonfamilial forms of heart failure, is still poorly understood. In the past decade, systems-level approaches based on omics technologies have become an important approach for the study of complex traits in large populations. These advances create opportunities to integrate genetic variation with other biological layers to identify and prioritize candidate genes, understand pathogenic pathways, and elucidate gene-gene and gene-environment interactions. In this review, we will highlight some of the recent progress made using systems genetics approaches to uncover novel mechanisms and molecular bases of cardiovascular pathophysiological manifestations. The key technology and data analysis platforms necessary to implement systems genetics will be described, and the current major challenges and future directions will also be discussed. For complex cardiovascular diseases, such as heart failure, systems genetics represents a powerful strategy to obtain mechanistic insights and to develop individualized diagnostic and therapeutic regiments, paving the way for precision cardiovascular medicine.
The Development of Kraepelin’s Concept of Dementia Praecox
Authors: Kenneth S. Kendler
Journal: JAMA Psychiatry (2020)

In 1893 and 1896, in his fourth and fifth textbook editions, Emil Kraepelin brought together 3 syndromes to form the first and second of his 2 prequels to dementia praecox (DP), a definitive version of which he would propose in his 1899 sixth textbook edition. These syndromes, which would become hebephrenic DP, catatonic DP, and paranoid DP, each had distinct histories. Hebephrenic DP was derived from syndromes first proposed by Hecker, and catatonic DP was derived from syndromes first proposed by Kahlbaum, and then both were substantially revised. Kraepelin created paranoid DP de novo from a division of his early broad delusional syndrome Verrücktheit, distinguishing it from paranoia. Two of these syndromes (catatonic DP and paranoid DP) were present in different forms in his earlier textbook editions, and 1 syndrome (hebephrenic DP) was not. In his 2 prequels, the 3 syndromes were listed together with a brief preface. In the sixth textbook edition, they became "clinical forms" of DP with a lengthy integrative introduction. Much more than in his prequels, in his sixth edition, Kraepelin stitched these 3 syndromes together, emphasizing their shared signs, symptoms, and course. Hebephrenia was the core of Kraepelin's DP concept, while the paranoid subtype fitted least comfortably within his framework. His term<i>dementia</i>was meant in a broad sense consistent with both short-term and rare long-term recoveries. Kraepelin was a pragmatist, not a purist, in his nosologic work and focused both on clinical features and course and outcome. He experimented with various nosologic categories, willing to revise earlier formulations in the light of new data. He was more tentative about his conclusions than many who followed him.
Abstract B23: PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/Nodal Nodal signaling
Authors: Marc Sprouse, Thomas Welte, Debasish Boral, Monika Vishnoi, Haowen Liu, Isabella Glitza-Oliva, Dario Marchetti
Journal: Clinical Cancer Research (2020)

Abstract Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multiparametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice coinjected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro coculturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs, and induced their protumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bidirectional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immunosuppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease. Citation Format: Marc Sprouse, Thomas Welte, Debasish Boral, Monika Vishnoi, Haowen Liu, Isabella Glitza-Oliva, Dario Marchetti. PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/Notch/Nodal Nodal signaling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B23.
Treatment persistence in paediatric and adolescent patients with psoriasis followed into young adulthood. From topical to systemic treatment: a prospective, longitudinal, observational cohort study of 448 patients*
Authors: F.M. Bruins, I.M.G.J. Bronckers, R. Cai, J.M.M. Groenewoud, M. Krol, E.M.G.J. Jong, M.M.B. Seyger
Journal: British Journal of Dermatology (2020)

Although solely topical treatment often suffices, patients with psoriasis may require more intensive treatment (phototherapy and/or systemic treatments) to control their disease. However, in paediatric, adolescent and young adult patients, little is known about persistence of topical treatment and time until switch to systemic treatment.To determine the median time from psoriasis onset until (i) discontinuation of solely topical agents and (ii) switch to systemic treatment, and to identify patient characteristics associated with switching to systemic treatments.Data were extracted from the Child-CAPTURE registry, a prospective, observational cohort of patients with paediatric-onset psoriasis followed into young adulthood from 2008 to 2018. Data prior to inclusion in the registry were collected retrospectively. Median times were determined through Kaplan-Meier survival analyses. Cox regression analysis was used to identify patient characteristics associated with switch to systemic treatment.Of 448 patients, 62·3% stayed on solely topical treatment until data lock; 14·3% switched from topicals to phototherapy, but not to systemic treatment; and 23·4% switched to systemic treatment. The median time from psoriasis onset until discontinuation of solely topical treatment was 7·3 years, and until switch to systemics was 10·8 years. Higher Psoriasis Area and Severity Index and (Children's) Dermatology Life Quality Index > 5 were independently associated with switching to systemic treatment.In a population of paediatric and adolescent patients with mild-to-severe psoriasis, one-third needed more intensive treatment than solely topical therapy to control their disease. We consider the median time until switching to systemics to be long.
Abstract IA17: Defining cancer dependency maps
Authors: William C. Hahn
Journal: Cancer Research (2020)

Abstract Although molecular profiling of human tumors is becoming increasingly routine, the use of this data to guide remains limited to a subset of patients. To complement genome characterization studies, we have used genome-scale gain- and loss-of-function approaches to identify genes required for cell survival and transformation. Specifically, we have used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome-scale RNAi and CRISPR-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. Integrating these studies with genome characterization of human tumors and protein-protein interaction databases facilitates the identification of genes and pathways required for the survival of specific cancer subtypes. In recent studies, we have expanded these efforts to patient-derived organoids and cell lines, which will expand the number and types of cancers represented and allow for the interrogation of other cancer phenotypes. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine. Citation Format: William C. Hahn. Defining cancer dependency maps [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA17.
Association between COPD exacerbations and lung function decline during maintenance therapy
Authors: Marjan Kerkhof, Jaco Voorham, Paul Dorinsky, Claudia Cabrera, Patrick Darken, Janwillem WH Kocks, Mohsen Sadatsafavi, Don D Sin, Victoria Carter, David B Price
Journal: Thorax (2020)

Background Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study. Methods The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV 1 decline. Effect modification by blood eosinophils was studied through interaction terms. Results Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV 1 decline of 19.4 mL/year (95% CI 12.0 to 26.7, p&lt;0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p&lt;0.0001) in those with BEC ≥350 cells/µL treated with ICS. Conclusion Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.
Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning
Authors: Nishan Sudheera Kalupahana, Bimba Lakmini Goonapienuwala, Naima Moustaid-Moussa
Journal: Annual Review of Nutrition (2020)

White adipose tissue (WAT) and brown adipose tissue (BAT) are involved in whole-body energy homeostasis and metabolic regulation. Changes to mass and function of these tissues impact glucose homeostasis and whole-body energy balance during development of obesity, weight loss, and subsequent weight regain. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which have known hypotriglyceridemic and cardioprotective effects, can also impact WAT and BAT function. In rodent models, these fatty acids alleviate obesity-associated WAT inflammation, improve energy metabolism, and increase thermogenic markers in BAT. Emerging evidence suggests that ω-3 PUFAs can also modulate gut microbiota impacting WAT function and adiposity. This review discusses molecular mechanisms, implications of these findings, translation to humans, and future work, especially with reference to the potential of these fatty acids in weight loss maintenance.
AB1136 THE DIAGNOSTIC VALUE OF SERUM KL-6 IN CONNECTIVE TISSUE DISEASE ASSOCIATED INTERSTITIAL LUNG DISEASE IN THE UYGUR POPULATION OF CHINA.
Authors: X. Wu, L. Wu, C. N. Luo, Y. M. Shi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Connective tissue diseases are a group of inflammatory, immune mediated disorders.Interstitial lung disease (ILD) is associated with significant morbidity and mortality.Currently,, scientists are still looking for serum markers to diagnose interstitial lung disease.Althought serum KL-6 level has been studied in ILD of various aetiologies and revealed to be an important serum marker for ILD,but differences in KL-6 expression related to ethnic and/or genetic variants may exist. Objectives: To evaluate the diagnosis of the serum Krebs von den Lungen-6 (KL-6) for CTD-ILD in the Uygur population of China. Methods: 117 Patients with CTD-ILD (CTD-ILD group) and 182 patients with CTD (CTD group) who visited the department of rheumatology and immunology of People’s Hospital of Xinjiang Uygur Autonomous Region between January, 2015 and December, 2019 were included. Serum KL-6 levels were measured by chemiluminescent enzyme immunoassay kit. Results: The significantly higher levels of KL-6 were determined in the RA-ILD group than RA group [569(287.5,984)U/ml vs 194(152,266.5)U/ml](P&lt;0.001)(figure 1).The optimal cutoff value of serum KL-6 for diagnosis of RA-ILD was 345.5 U/ml, and the sensitivity and specificity were71.8% and 90.1 %, respectively. Area Under the Curve (AUC) was 0.875.(figure 2) Figure 1. Comparison of serum KL-6 concentrations in CTD-ILD group and CTD group. Fig 2. Receiver-operating characteristic curve(ROC) of KL-6 for the diagnosis of CTD-ILD Conclusion: The serum KL-6 is a important biomarker for the diagnosis of CTD-ILD and Serum KL-6 could be a clinically useful biomarker in screening CTD-ILD in the Uygur population of China. References: [1]Woodhead F, Wells A U, Desai S R. Pulmonary Complications of Connective Tissue Diseases[J]. Clinics in Chest Medicine, 2008, 29(29):149–164. Tanaka S, Hattori N, Ishikawa N, et al. Krebs von den Lungen-6 (KL-6) is a progn -ostic biomarker in patients with surgically resected nonsmall cell lung cancer. Int J Cancer 2012; 130:377–87. [2]Ogz E O, Kucuksahin O, Turgay M, et al. Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study. Clinical Rheumatology, 2016, 35(3):663-666. Disclosure of Interests: None declared
AB0249 POSITIVE EFFECT OF ANTIRHEUMATIC THERAPY ON THE COURSE OF CHRONIC HEART FAILURE IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS
Authors: I. Kirillova, D. Novikova, T. Popkova, Y. Gorbunova, E. Markelova, A. Volkov
Journal: Annals of the Rheumatic Diseases (2020)

Background: Objectives: to evaluate the effect of antirheumatic therapy according to the “treat to target” strategy on the course of chronic heart failure (CHF) in patients with early RA. Methods: The study included 22 patients CHF with valid diagnosis of RA (criteria ACR / EULAR, 2010), 17 (77%) of women, median (Me) age - 60 years, Me disease duration - 7 months; IgM seropositive for rheumatoid factor 10 (45%) and / or antibodies to the cyclic citrulline peptide 22 (100%), DAS28-5.6 [4,8;6,5]. CHF verified in accordance the recommendations for the diagnosis and treatment of CHF Society of Specialists in Heart Failure (2013). The concentration of NT-proBNP was determined by electrochemiluminescence. For all patients was started methotrexate (MT) therapy with a rapid increase in the dose to 30 mg per week subcutaneously. If the MT was not effective enough, after 3 months a biological Disease-Modifying Anti-Rheumatic Drug (bDMARDs) was added to the therapy, predominantly TNF-alpha inhibitors. After 18 months, 10 (45%) patients were in remission and low disease activity, 6 (60%) of patients underwent MT therapy in combination with bDMARDs. Results: In baseline CHF with preserved EF was revealed in 21 (95%) patients, in 1 patient - CHF with reduced EF. After 18 months there was a positive dynamics of improvement of clinical symptoms, echocardiographic indicators (decrease the size of the left atrium (LА) and the index of end-systolic volume of LА, IVRT, E’ LV), diastolic function of the left ventricle (LV). There was no decompensation of CHF. LV diastolic function normalized in 7 (32%) patients who reached the target level of blood pressure, remission (n = 5) and low (n = 2) disease activity, mainly in the treatment of MT and bDMARDs. In patients with RA and CHF, the level of NT-proBNP decreased from 192.2 [151.4; 266.4] to 114.0 [90.4; 163.4] pg / ml (p &lt;0.001), normalized in 16 of 22 (73%) patients (p &lt;0.001) with remission or low RA activity. In 5 (22%) patients, the clinical manifestations of CHF regressed, LV diastolic function and NT-proBNP level normalized. Conclusion: In patients with early RA and CHF anti-rheumatic therapy improves the clinical course of CHF. There were an improvement in the clinical course of CHF, diastolic function of the left ventricle and a decrease in NT-proBNP. Disclosure of Interests: None declared
Infographic. What kinds of exercise are best for chronic low back pain?
Authors: Patrick J Owen, Clint T Miller, Niamh L Mundell, Simone J J M Verswijveren, Scott D Tagliaferri, Helena Brisby, Steven J Bowe, Daniel L Belavy
Journal: British Journal of Sports Medicine (2020)

Back pain is the greatest cause of disability and lost productivity worldwide.1 Back pain generates significant financial costs for society in developed countries, such as the USA, Japan, Europe and Australia (eg, US$80 billion per year in direct and indirect costs in the USA).2 Chronic low back pain (ie, ≥12 weeks’ duration) presents the greatest challenge: it generates the greatest proportion of economic burden due to back pain3 and affects 20% of the global population.4 Of these, approximately 90% of cases of chronic low back pain are non-specific (NSCLBP), meaning that a definitive diagnosis that is agreed on between clinicians cannot be made.5 Current treatment recommendations for NSCLBP include exercise (high-quality evidence), manual therapy (low-quality evidence) and psychological therapies (moderate-quality evidence).5 6 There are a …
Views and experiences of managing eczema: systematic review and thematic synthesis of qualitative studies*
Authors: E. Teasdale, I. Muller, K. Sivyer, D. Ghio, K. Greenwell, S. Wilczynska, A. Roberts, M.J. Ridd, N. Francis, L. Yardley, K.S. Thomas, M. Santer
Journal: British Journal of Dermatology (2020)

The number of qualitative studies on eczema has increased rapidly in recent years. Systematically reviewing these can provide greater understandings of people's perceptions of eczema and eczema treatments.We sought to systematically review and thematically synthesize qualitative studies exploring views and experiences of people with eczema and parents/carers of children with eczema.We searched MEDLINE, EMBASE, PsycINFO and CINAHL from the earliest date available to February 2019. We selected papers focusing on views and experiences of eczema and eczema treatments, and barriers/facilitators to eczema self-management. We excluded papers focusing on health service provision models or health professionals' views.We synthesized 39 papers (reporting 32 studies) from 13 countries. We developed four analytical themes: (1) Eczema not viewed as a long-term condition; (2) Significant psychosocial impact not acknowledged by others; (3) Hesitancy (patient/carer uncertainty) about eczema treatments; and (4) Insufficient information and advice. Our findings suggest that people with eczema and their carers experience frustration at having to manage a condition that is often seen by others as mundane but has significant psychosocial impact and is difficult to manage due to concerns about, and burden of, treatment. This frustration can be exacerbated by experiences of conflicting and/or insufficient information and advice from health professionals, family and others.Effective self-management of eczema could be supported by addressing beliefs and concerns about treatments; seeking positive ways to promote a 'control not cure' message; acknowledging psychosocial impacts of eczema and treatment burden; and providing clear consistent advice or signposting towards reliable information.