Identification of biomarkers for glycaemic deterioration in type 2 diabetes.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates.

MicroRNA Activity in Mouse Choline Acetyltransferase-Positive Neurons Is Critical for the Rate of Early and Late Paraplegia After Transient Aortic Cross-Clamping.

Aortic aneurism open repair surgery can cause spinal cord (SC) injury with 5-15% of patients developing paraparesis or paraplegia. Using a mouse model of transient aortic cross-clamping (ACC), we have previously found that the expression of proinflammatory microRNA increases in motoneurons (MNs) and endothelial cells (ECs) of ischemic SCs, and that global deletion decreases the percentage of paraplegia by 37.4% at 48-h post-ACC.

BACH2 inhibition reverses β cell failure in type 2 diabetes models.

Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question.

Histological Findings After Aortic Cross-Clamping in Preclinical Animal Models.

Spinal cord ischemic injury and paralysis are devastating complications after open surgical repair of thoracoabdominal aortic aneurysms. Preclinical models have been developed to simulate the clinical paradigm to better understand the neuropathophysiology and develop therapeutic treatment. Neuropathological findings in the preclinical models have not been comprehensively examined before.

Endovascular repair and open repair surgery of thoraco-abdominal aortic aneurysms cause drastically different types of spinal cord injury.

Both endovascular repair (EVR) and open repair (OR) surgery of thoraco-abdominal aortic aneurysms cause spinal cord (SC) injury that can lead to paraparesis or paraplegia. It has been assumed that mechanisms responsible for SC damage after EVR are similar to those after OR. This pilot study compared the pathophysiology of SC injury after EVR versus OR using a newly developed EVR dog model.

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets.

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin islet mass with concomitant increases in circulating insulin and C peptide.

Frequency and perturbations of various peripheral blood cell populations before and after eculizumab treatment in paroxysmal nocturnal hemoglobinuria.

While red blood cells (RBCs) and granulocytes have been more studied, platelets and reticulocytes are not commonly used in paroxysmal nocturnal hemoglobinuria (PNH) flow-cytometry and less is known about susceptibility to complement-mediated destruction and effects of anti-complement therapy on these populations. We performed flow-cytometry of RBCs and granulocytes in 90 PNH patients and of platelets and reticulocytes in a subgroup (N = 36), to unveil perturbations of these populations during PNH disease course before and after anti-complement treatment. We found that platelets and reticulocytes were less sensitive to complement-mediated lysis than RBCs but not as resistant as granulocytes, as shown by mean sensitive fraction (difference in a given PNH population vs.

A High-Throughput Assay for the Pancreatic Islet Beta-Cell Potassium Channel: Use in the Pharmacological Characterization of Insulin Secretagogues Identified from Phenotypic Screening.

Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.

Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human.

The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.

Long-Acting and Selective Oxytocin Peptide Analogs Show Antidiabetic and Antiobesity Effects in Male Mice.

Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT's short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXT) that is potent and selective for the OXT receptor (OXTR).

[The effect of various multimodal analgesia regimens during surgical treatment of patients with spinal stenosis on the rate of failed back surgery syndrome].

Objective: To determine the effect of various methods of perioperative analgesia on the rate of failed back surgery syndrome in patients operated on for spinal stenosis.

Material And Methods: A total of 122 patients were operated on for spinal stenosis in 2010-2016. The patients were assigned to groups according to the type of received analgesia: Group K (n=19) underwent analgesia on-demand.

Cardiorenal syndrome in the early stages of coronary bypass surgery.

Aim: Evaluate the frequency and risk factors of postoperative atrial fibrillation (pAF) in patients with chronic coronary artery disease (CHD) with acute kidney injury (AKI) developed in connection with coronary artery bypass grafting (CABG).

Materials And Methods: The study involved 90 patients (pts) undergoing CABG at age 58±7 years, duration of CHD - 6±6 years. 80% of pts had previous myocardial infarction.

Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel.

Estrogen hormones play an important role in controlling glucose homeostasis and pancreatic β-cell function. Despite the significance of estrogen hormones for regulation of glucose metabolism, little is known about the roles of endogenous estrogen metabolites in modulating pancreatic β-cell function. In this study, we evaluated the effects of major natural estrogen metabolites, catechol estrogens, on insulin secretion in pancreatic β-cells.

miR-155 expression in antitumor immunity: The higher the better?

MicroRNAs are small noncoding RNAs that modulate gene expression either directly, by impairing the stability and/or translation of transcripts that contain their specific target sequence, or indirectly through the targeting of transcripts that encode transcription factors, factors implicated in signal transduction pathways, or epigenetic regulators. Abnormal expression of micro-RNAs has been found in nearly all types of pathologies, including cancers. MiR-155 has been the first microRNA to be implicated in the regulation of the innate and adaptative immune responses, and its expression is either increased or decreased in a variety of liquid and solid malignancies.

[Prognostic models of the severity of acute dynamic pain on the first postoperative day and the likelihood of chronic postoperative pain in spine surgery].

Unlabelled: The risk factors for acute pain as well as chronic pain syndrome (CPS) in spine surgery have not been defined to date.

Purpose: To define the prognostic parameters of acute pain severity and the risk of CPS in patients operated on for spinal diseases and injuries.

Material And Methods: The study included 291 patients operated on for degenerative diseases and injuries of the spine at the Sklifosovsky Research Institute of Emergency Medicine in 2010-2016.

The management of acute myocardial infarction in the Russian Federation: protocol for a study of patient pathways.

Background: Death rates from cardiovascular disease in Russia are among the highest in the world. In recent years, the Russian government has invested substantially in the healthcare system, with a particular focus on improving access to advanced technology, especially for acute myocardial infarction (AMI). This protocol describes a study to understand the management of AMI in different Russian regions, investigating the role of patient, clinical, and health system characteristics.

GPR142 prompts glucagon-like Peptide-1 release from islets to improve β cell function.

Objective: GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action.

[Elevated Level of the Natriuretic Peptide Among Adult Population in Regions Participating in the ESSE-RF Study and Its Association With Cardiovascular Diseases and Risk Factors].

Aim: to study associations between elevated blood plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP), risk factors and cardiovascular diseases (CVD) in samples of adult population of Russian Federation (RF) aged 25-64 years.

Materials And Methods: We analyzed data of examination of representative samples of population of 5 regions of RF obtained within the framework of the multicenter ESSE-RF study (2012-2013). Number of examined subjects was 8 077 (3 176 men).

Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer.

Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood.

Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident.

Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5.

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress insulin and glucagonlike peptide-1 (GLP-1) secretion through the Gi-coupled SST receptor 5 (SSTR5) isoform in vitro, antagonism of SSTR5 may improve glycemic control via intervention in both pathways.

GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner.

Human HMGA2 protein overexpressed in mice induces precursor T-cell lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes. HMGA2 (high-mobility group AT-hook 2) gene expression is extremely low in normal adult tissues, but it is overexpressed in many tumors. To identify the biological function of HMGA2, we generated transgenic mice carrying the human HMGA2 gene under control of the VH promoter/Eμ enhancer.

[The prevalence of anxiety and depression in different regions of the Russian Federation and its association with sociodemographic factors (according to the data of the ESSE-RF study)].

Aim: To study the prevalence of anxiety and depression by psychometric methods (the Hospital Anxiety and Depression Scale (HADS) in different regions of the Russian Federation (RF), which are characterized by various climatic, geographic, economic, and demographic indicators.

Subjects And Methods: The investigation used the data of the multicenter epidemiological survey of cardiovascular diseases in different regions of the Russian Federation--the ESSE-RF study. The subjects of the study were representative samples from unorganized male and female populations aged 25-64 years from 10 RF regions.

Ectonucleotidase NTPDase3 is abundant in pancreatic β-cells and regulates glucose-induced insulin secretion.

Extracellular ATP released from pancreatic β-cells acts as a potent insulinotropic agent through activation of P2 purinergic receptors. Ectonucleotidases, a family of membrane-bound nucleotide-metabolizing enzymes, regulate extracellular ATP levels by degrading ATP and related nucleotides. Ectonucleotidase activity affects the relative proportion of ATP and its metabolites, which in turn will impact the level of purinergic receptor stimulation exerted by extracellular ATP.