Frequency of Occurrence of Risk Factors for Carbohydrate Metabolism among Patients with Arterial Hypertension

Today, in the structure of causes of death in the economically developed countries of the world, more than 55% are accounted for by cardiovascular diseases. Among the main cardiovascular diseases leading to severe diseases of the heart, brain and other organs, the leading place belongs to hypertension. According to the WHO, 12,8% of deaths in the world are due to hypertension Оbesity, overweight and dyslipidemia are the most common among the factors of carbohydrate metabolism disorders among patients with arterial hypertension. In this regard, among patients with arterial hypertension, it is necessary to expand preventive measures at the medical site aimed at early recognition of pathology, the formation of risk groups and timely treatment

Integrated Identification and Efficient Use of Biodiversity in Mountainous Regions

The article studies the comprehensive identification and efficient use of biodiversity (geothermal sources) in mountainous regions. Discussion of the ways to solve the most acute problems affecting mountainous regions with complex relief has always been on the agenda as a topical issue. The purpose of the presented work is to determine the quantitative, qualitative and thermodynamic parameters of geothermal sources in these territories, as well as the spatial structure of the foci of formation of their migration routes. Conducting a comprehensive assessment of the biodiversity of deforested mountainous regions substantiates the need to ensure the protection of these unique ecosystems. The issue of determining the direction of the integrated use of geothermal resources is studied not only by its structure and characteristics, but also by the level of development of complex technological processes for the extraction and processing of hydromineral raw materials and the technology of thermal energy processes. Using a number of analytical research methods (hydrogeological, geochemical, geophysical, isotope, computer (mathematical) modeling and others) to solve these problems, we determine the foci of formation of reservoir conditions in individual horizons, migration routes, as well as quantitative and qualitative parameters of thermal waters. The following issues were studied: hydrogeological research methods will help to identify the development zone of the intensive circulation aquifer (active water exchange) and the base of the development zone of the deep underground flow aquifer (impeded exchange) in the underground hydrosphere zones, and to assess their hydrodynamic and hydrothermal conditions and parameters. Based on the data from drilled exploratory oil wells, the conditions for the formation of thermal water layers in various hydrogeological structures will be determined; hydrochemical research methods will be aimed at assessing the macro- and microcomponent composition and radiation background of thermal waters at various intervals of migration routes by determining various indicators at different depths of their formation (based on the petrochemical structure of the geological part); isotopic studies of the gas composition of thermal waters will help to identify their genesis and use them as a marker when determining the points of formation; computer modeling of the underground hydrosphere of a representative object was carried out using mathematical programs

Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma

Neuroblastoma is an embryonal malignancy of the sympathetic nervous system. Spontaneous regression and differentiation of neuroblastoma is observed in a subset of patients, and has been suggested to represent delayed activation of physiologic molecular programs of fetal neuroblasts. Homeobox genes constitute an important family of transcription factors, which play a fundamental role in morphogenesis and cell differentiation during embryogenesis. In this study, we demonstrate that expression of the majority of the human HOX class I homeobox genes is significantly associated with clinical covariates in neuroblastoma using microarray expression data of 649 primary tumors. Moreover, a HOX gene expression-based classifier predicted neuroblastoma patient outcome independently of age, stage and MYCN amplification status. Among all HOX genes, HOXC9 expression was most prominently associated with favorable prognostic markers. Most notably, elevated HOXC9 expression was significantly associated with spontaneous regression in infant neuroblastoma. Re-expression of HOXC9 in three neuroblastoma cell lines led to a significant reduction in cell viability, and abrogated tumor growth almost completely in neuroblastoma xenografts. Neuroblastoma growth arrest was related to the induction of programmed cell death, as indicated by an increase in the sub-G1 fraction and translocation of phosphatidylserine to the outer membrane. Programmed cell death was associated with the release of cytochrome c from the mitochondria into the cytosol and activation of the intrinsic cascade of caspases, indicating that HOXC9 re-expression triggers the intrinsic apoptotic pathway. Collectively, our results show a strong prognostic impact of HOX gene expression in neuroblastoma, and may point towards a role of Hox-C9 in neuroblastoma spontaneous regression

Comparison of performance of one-color and two-color gene-expression analyses in predicting clinical endpoints of neuroblastoma patients

Microarray-based prediction of clinical endpoints may be performed using either a one-color approach reflecting mRNA abundance in absolute intensity values or a two-color approach yielding ratios of fluorescent intensities. In this study, as part of the MAQC-II project, we systematically compared the classification performance resulting from one- and two-color gene-expression profiles of 478 neuroblastoma samples. In total, 196 classification models were applied to these measurements to predict four clinical endpoints, and classification performances were compared in terms of accuracy, area under the curve, Matthews correlation coefficient and root mean-squared error. Whereas prediction performance varied with distinct clinical endpoints and classification models, equivalent performance metrics were observed for one- and two-color measurements in both internal and external validation. Furthermore, overlap of selected signature genes correlated inversely with endpoint prediction difficulty. In summary, our data strongly substantiate that the choice of platform is not a primary factor for successful gene expression based-prediction of clinical endpoints

Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.)

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B

High-level MET amplification (METamp) is a primary driver in-1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median dura-tion of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early mo-lecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides anti-tumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992).Pathogenesis and treatment of chronic pulmonary disease

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial

BackgroundPatients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population.MethodsThis open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703(enrolment complete).FindingsBetween Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9–20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7–60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.InterpretationTepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.Pathogenesis and treatment of chronic pulmonary disease