Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy.

Redistribution, homing and organ-invasion of neoplastic stem cells in myeloid neoplasms.

The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a drug-resistant terminal phase. Organ-invasion may occur in any stage, but is usually associated with advanced disease and a poor prognosis. Sometimes, extra-medullary organ invasion shows a metastasis-like or even sarcoma-like destructive growth of neoplastic cells in local tissue sites.

Communication of CD8 T cells with mononuclear phagocytes in multiple sclerosis.

Objective: CD8 T cells are the most prevailing lymphocyte population in inflammatory lesions of patients with multiple sclerosis (MS) but it is not even known whether they are merely passive bystanders or actively communicate with other cells in the brain. To identify their potential interaction partners, we analyzed CD8 T cells that contained vectorially oriented cytotoxic granules and analyzed the areas to which the granules pointed.

Methods: We stained cryo-sections of active MS lesions of an index patient with antibodies to CD8 and perforin, searched for vectorially oriented perforin granules, and isolated target areas opposing the granules and control areas by laser-microdissection.

Dynamic Survival Analysis Using In-Memory Technology.

In the field of oncology, survival analysis is one of the most important tools in terms of measuring therapy success, evaluating risk or prognostic factors. Within this work, a variety of common survival analyses were embedded into a real-time analysis platform based on a comprehensive oncological dataset. The analysis platform utilizes an in-memory database, therefore allowing spontaneous adjustments of the survival curves to selections and stratifications.

Cardiorenal sodium MRI at 7.0 Tesla using a 4/4 channel H/ Na radiofrequency antenna array.

Purpose: Cardiorenal syndrome describes disorders of the heart and the kidneys in which a dysfunction of 1 organ induces a dysfunction in the other. This work describes the design, evaluation, and application of a 4/4-channel hydrogen-1/sodium ( H/ Na) RF array tailored for cardiorenal MRI at 7.0 Tesla (T) for a better physiometabolic understanding of cardiorenal syndrome.

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

A semi-automated, isotope-dilution high-resolution mass spectrometry assay for therapeutic drug monitoring of antidepressants.

Background: Therapeutic drug monitoring (TDM) of antidepressants is important to ensure compliance and to rule out pharmacokinetic abnormalities. Therefore, reliable methods for quantification are important for clinical laboratories. Most of the currently used mass spectrometry methods use triple quadrupoles as mass analyzers.

Shared T cell receptor chains in blood memory CD4 T cells of narcolepsy type 1 patients.

Convergent evidence points to the involvement of T cells in the pathogenesis of narcolepsy type 1 (NT1). Here, we hypothesized that expanded disease-specific T cell clones could be detected in the blood of NT1 patients. We compared the TCR repertoire of circulating antigen-experienced CD4 and CD8 T cells from 13 recently diagnosed NT1 patients and 11 age-, sex-, and HLA-DQB1*06:02-matched healthy controls.

Fiend and friend in the renin angiotensin system: An insight on acute kidney injury.

Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 1-7)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI.

Validation of the MCL35 gene expression proliferation assay in randomized trials of the European Mantle Cell Lymphoma Network.

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g.

Neuroendocrine tumors of the small intestine causing a desmoplastic reaction of the mesentery are a more aggressive cohort.

Background: Desmoplastic reaction of the mesentery is commonly seen in patients with neuroendocrine tumors of the small intestine. However, it is not clear whether desmoplastic reaction is associated with tumor-specific characteristics and diminished prognosis. Therefore, the aim of this study was to investigate whether the presence of a desmoplastic reaction correlates with prognostic and molecular markers of neuroendocrine tumors of the small intestine.

DNA methylation-based reclassification of olfactory neuroblastoma.

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

Background: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma.

Methods: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups.

Results: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group.

How could the topic patient safety be embedded in the curriculum? A recommendation by the Committee for Patient Safety and Error Management of the GMA.

The topic of patient safety is of fundamental interest for the health care sector. In view of the realisation of the National Competence-Based Learning Objectives Catalogue for Undergraduate Medical Education (NKLM) this topic now has to be prepared for medical education. For a disciplinary and content-related orientation the GMA Committee developed the Learning Objectives Catalogue Patient Safety for Undergraduate Medical Education (GMA-LZK).

Cub domain-containing protein 1 negatively regulates TGF-β signaling and myofibroblast differentiation.

Fibroblasts are thought to be the prime cell type for producing and secreting extracellular matrix (ECM) proteins in the connective tissue. The profibrotic cytokine transforming growth factor-β1 (TGF-β1) activates and transdifferentiates fibroblasts into α-smooth muscle actin (α-SMA)-expressing myofibroblasts, which exhibit increased ECM secretion, in particular collagens. Little information, however, exists about cell-surface molecules on fibroblasts that mediate this transdifferentiation process.

Distinct niches within the extracellular matrix dictate fibroblast function in (cell free) 3D lung tissue cultures.

Cues from the extracellular matrix (ECM) and their functional interplay with cells play pivotal roles for development, tissue repair, and disease. However, the precise nature of this interplay remains elusive. We used an innovative 3D cell culture ECM model by decellularizing 300-µm-thick ex vivo lung tissue scaffolds (d3D-LTCs) derived from diseased and healthy mouse lungs, which widely mimics the native (patho)physiological in vivo ECM microenvironment.

MiRIAD update: using alternative polyadenylation, protein interaction network analysis and additional species to enhance exploration of the role of intragenic miRNAs and their host genes.

http://www.miriad-database.org.

Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group.

Background: A high proportion of patients with relapsed classical Hodgkin's lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocol's efficacy.

Methods: We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany.

Ultrasensitive SPR detection of miRNA-93 using antibody-enhanced and enzymatic signal amplification.

MiRNAs are endogenous noncoding RNA molecules. They play important gene-regulatory roles by binding to the mRNA of target genes thereby leading to either transcript degradation or translational repression. In virtually all diseases, distinct alterations of miRNA expression profiles have been found thus suggesting miRNAs as interesting biomarkers.

The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease.

The pulmonary extracellular matrix (ECM) determines the tissue architecture of the lung, and provides mechanical stability and elastic recoil, which are essential for physiological lung function. Biochemical and biomechanical signals initiated by the ECM direct cellular function and differentiation, and thus play a decisive role in lung development, tissue remodelling processes and maintenance of adult homeostasis. Recent proteomic studies have demonstrated that at least 150 different ECM proteins, glycosaminoglycans and modifying enzymes are expressed in the lung, and these assemble into intricate composite biomaterials.

Biphenyl based stationary phases for improved selectivity in complex steroid assays.

The measurement of steroid hormones and their corticoid precursors is an important aspect in endocrinology since these analytes are biomarkers for several endocrine disorders. Over the last few years, HPLC-MS/MS has become the method of choice to analyze these compounds. There are already several methods using stationary phases modified with C18 groups.