Sparksmccormick2682

0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.OBJECTIVE To determine the relative effectiveness of dietary macronutrient patterns and popular named diet programmes for weight loss and cardiovascular risk factor improvement among adults who are overweight or obese. DESIGN Systematic review and network meta-analysis of randomised trials. DATA SOURCES Medline, Embase, CINAHL, AMED, and CENTRAL from database inception until September 2018, reference lists of eligible trials, and related reviews. STUDY SELECTION Randomised trials that enrolled adults (≥18 years) who were overweight (body mass index 25-29) or obese (≥30) to a popular named diet or an alternative diet. OUTCOMES AND MEASURES Change in body weight, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, systolic blood pressure, diastolic blood pressure, and C reactive protein at the six and 12 month follow-up. REVIEW METHODS Two reviewers independently extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of erdiovascular risk factors, particularly blood pressure. At 12 months the effects on weight reduction and improvements in cardiovascular risk factors largely disappear. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42015027929. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a+ CD207+ LCH cells. In LCH, somatic mutations of the BRAFV600E gene have been detected in tissue LCH cells, bone marrow CD34+ hematopoietic stem cells, circulating CD14+ monocytes, and BDCA1+ myeloid DCs. Targeting BRAFV600E in clonal LCs and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF-1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAMs) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through immunohistochemistry and flow cytometry that CSF1R is normally expressed on human CD1a+CD207+ LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14+ monocytes, BDCA1+ DCs, and CD34+ cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAFV600E cells) and TAMs retained high expression of CSF1R. We also detected presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF-1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAFV600E and wild-type forms of the disease. Copyright ©2020, American Association for Cancer Research.Anti-angiogenic therapies that target the vascular endothelial growth factor (VEGF) pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining anti-angiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Here we reveal that blockade of VEGF-A with a monoclonal antibody to VEGF augments activation of CD8+ T cells within tumors and potentiates their capacity to produce cytokines. We demonstrate that this phenomenon relies on the disruption of VEGFR2 signaling in the tumor microenvironment, but does not affect CD8+ T cells directly. Instead, the augmented functional capacity of CD8+ T cells stems from increased tumor hypoxia that initiates a hypoxia-inducible factor-1α (HIF-1α) program within CD8+ T cells that directly enhances cytokine production. Lastly, combinatorial administration of anti-VEGF with an immunotherapeutic antibody, anti-OX40, improved antitumor activity over single-agent treatments. Our findings illustrate that anti-VEGF treatment enhances CD8+ T-cell effector function and provides a mechanistic rationale for combining anti-angiogenic and immunotherapeutic drugs for cancer treatment. Copyright ©2020, American Association for Cancer Research.Myeloid derived suppressor cells (MDSCs) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. Based on surface markers, three subsets of MDSCs have been defined in humans granulocytic, monocytic and early-stage (e-MDSCs). The markers attributed to e-MDSCs overlap with those of basophils, which are rare circulating myeloid cells with unrecognized roles in cancer. Thus, we asked whether e-MDSCs in circulation and the tumor microenvironment include basophils. On average 58% of cells with e-MDSC surface markers in blood and 36% in ascites from patients with ovarian cancer (OC) were basophils based on CD123high expression and cytology, whereas cells with immature features were rare. Circulating and ascites basophils did not suppress proliferation of stimulated T cells, a key feature of MDSCs. Increased accumulation of basophils and basogranulin, a marker of basophil degranulation, were observed in ascites compared to serum in patients with newly diagnosed OC. check details Basophils recruited to the tumor microenvironment may exacerbate fluid accumulation by their release of pro-inflammatory granular constituents that promote vascular leakage. No significant correlation was observed between peripheral basophil counts and survival in patients with OC. Our results suggest that studies in which e-MDSCs were defined solely by surface markers should be re-revaluated to exclude basophils. Both immaturity and suppression are criteria to define e-MDSCs in future studies. Copyright ©2020, American Association for Cancer Research.The 2018 and 2019 guidelines from the American College of Cardiology and American Heart Association reflect the complexity of individualized cholesterol management. link2 The documents address more detailed risk assessment, newer nonstatin cholesterol-lowering drugs, special attention to patient subgroups, and consideration of the value of therapy, all with the aim of creating personalized treatment plans for each patient. Overall, the guidelines recommend shared decision-making to meet the individual needs of each patient. link3 Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.Gastroesophageal reflux disease (GERD) is mainly a clinical diagnosis based on typical symptoms of heartburn and acid regurgitation. Current guidelines indicate that patients with typical symptoms should first try a proton pump inhibitor (PPI). If reflux symptoms persist after 8 weeks on a PPI, endoscopy of the esophagus is recommended, with biopsies taken to rule out eosinophilic esophagitis. This review discusses the evidence for different medical, endoscopic, and surgical therapies and presents a management algorithm. Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.The cornerstone of preventive migraine treatment has long been drugs developed for other diseases such as epilepsy, depression, and hypertension. But a new set of drugs is available for preventing migraine attacks erenumab, galcanezumab, fremanezumab, and eptinezumab. These monoclonal antibodies target calcitonin gene-related peptide (CGRP) or its receptors, each a key molecule in the pathophysiology of migraine. Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.Fracture is a major cause of morbidity and death in postmenopausal women. Dual-energy x-ray absorptiometry (DXA) measures bone mineral density, which helps in estimating fracture risk and in identifying those who may benefit from treatment. Although screening guidelines differ somewhat for postmenopausal women under age 65, in general, DXA is indicated if the patient has a high risk for fracture. Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we will focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology. Copyright © 2020 by the American Society of Nephrology.SUMMARYCaseum, the central necrotic material of tuberculous lesions, is a reservoir of drug-recalcitrant persisting mycobacteria. Caseum is found in closed nodules and in open cavities connecting with an airway. Several commonly accepted characteristics of caseum were established during the preantibiotic era, when autopsies of deceased tuberculosis (TB) patients were common but methodologies were limited. These pioneering studies generated concepts such as acidic pH, low oxygen tension, and paucity of nutrients being the drivers of nonreplication and persistence in caseum. Here we review widely accepted beliefs about the caseum-specific stress factors thought to trigger the shift of Mycobacterium tuberculosis to drug tolerance. Our current state of knowledge reveals that M. tuberculosis is faced with a lipid-rich diet rather than nutrient deprivation in caseum. Variable caseum pH is seen across lesions, possibly transiently acidic in young lesions but overall near neutral in most mature lesions. Oxygen tension is low in the avascular caseum of closed nodules and high at the cavity surface, and a gradient of decreasing oxygen tension likely forms toward the cavity wall.