A STABILITY OF CARDIOVASCULAR RISK FACTORS BY THE 17-YEAR OBSERVATIONAL STUDY

While planning treatment and prevention in cardiovascular disorders (CVD) it is important to take into account the data on stability of clinical course of the main risk factors (RF). Until recently there is no such data on Russian population. Aim. To study the stability of arterial hypertension (AH), overweight (OW), hypercholestrolemia (HCE), hypertriglyceridemia (HTE) among men and women in 17-year observation. Material and methods. Baseline testing on the base of randomly assigned selection from the city of Tomsk citizens was performed in 1988-1991 (1546 men and women 20-59 y.  o.). Second test was done in 2002-2005, and the data obtained on RF and endpoints in 81,2% persons from the first step. A stability factor (St) was defined as relation of repeated RF (RF2) to the general selection (RF1), in percent — St=RF2/RF1 x 100%. Also the regression of RF was calculated. As regression we defined the cases of nonfinding of RF in the second measurement while having this in the first, and calculated by 1000 person-years of observation (PEO). Results. Seventeen-years lasting prospective study, performed on the cohort of men and women 20-59 y.  o. showed a high stability of AH, OW, HCE. The St values for AH was 96,6% (regressed 2,31 cases by 1000 PEO), for HCE; St for OW — 92,7% (regressed 4,70 by 1000 PEO); St for HCE — 92,9% (regressed 4,53 by 1000 PEO). HTE was not so stable RF: St = 75,0%. In age subgroup of 20-29 y. the interrelation of lower stability for HCE and HTE was found — St for HCE was 85,0% (regression 9,37 cases by 1000 PEO); St for HTE — 50,0% (regression 30,38 per 1000 PEO). It suggests that the nonmedication methods for dyslipoproteidemia correction, as diet, physical exertion increase, smoking cessation, body mass decrease can be highly effective in young people

Huntington’s Disease protein huntingtin associates with its own mRNA

Background: The Huntington's disease (HD) protein huntingtin (Htt) plays a role in multiple cellular pathways. Deregulation of one or more of these pathways by the mutant Htt protein has been suggested to contribute to the disease pathogenesis. Our recent discovery-based proteomics studies have uncovered RNA binding proteins and translation factors associated with the endogenous Htt protein purified from mouse brains, suggesting a potential new role for Htt in RNA transport and translation. Objective: To investigate how Htt might affect RNA metabolism we set out to purify and analyze RNA associated with Htt. Methods: RNA was extracted from immunopurified Htt-containing protein complexes and analyzed by microarrays and RNA-Seq. Results: Surprisingly, the most enriched mRNA that co-purified with Htt was Htt mRNA itself. The association of Htt protein and Htt mRNA was detected independent of intact ribosomes suggesting that it is not an RNA undergoing translation. Furthermore, we identified the recently reported mis-spliced Htt mRNA encoding a truncated protein comprised of exon 1 and a portion of the downstream intron in the immunoprecipitates containing mutant Htt protein. We show that Htt protein co-localizes with Htt mRNA and that wild-type Htt reduces expression of a reporter construct harboring the Htt 3' UTR. Conclusions: HD protein is found in a complex with its own mRNA and RNA binding proteins and translation factors. Htt may be involved in modulating its expression through post-transcriptional pathways. It is possible that Htt shares mechanistic properties similar to RNA binding proteins such as TDP-43 and FUS implicated in other neurodegenerative diseases

Predictive value of cardiovascular risk factors in the formation of cardiovascular and all-cause mortality: results of a 27-year cohort prospective study

Aim. To study the prognostic significance of cardiovascular risk factors (RFs) in the formation of all-cause and cardiovascular mortality based on the results of a 27-year prospective cohort study of Tomsk population of both sexes aged 20-59 years.Material and methods. The object of study was random house-to-house sample of Tomsk population. In total, 1546 people (630 men and 916 women) aged 20-59 were examined. In 1988-1991, the prevalence of following cardiovascular RFs was studied: hypertension (HTN), overweight, smoking, alcohol consumption, hypercholesterolemia (HCE), low high-density lipoprotein cholesterol levels (hypo-HDL-emia), hypertriglyceridemia (HTG). All examination methods used were strictly standardized. To determine the RF, the criteria generally accepted in epidemiological studies were used. Over 27 years of follow-up, 330 deaths were recorded, including 142 due to cardiovascular disease.Results. In the multivariate Cox proportional hazard model, the following va­riables were studied: HTN, overweight, smoking, alcohol consumption, HCE, hypo-HDL-emia, HTG, coronary artery disease (CAD) (according to epi­demio­logical criteria), and age. The strongest predictor of of all-cause death was frequent alcohol use (relative risk (RR) 2,75). Smoking increased the risk of death by 2,72 times. Among former smokers, the risk of all-cause death was 1,9 times higher compared to non-smokers. HTN increases the death risk by 1,61 times. Each year of life lived increases the death risk by 1,06 times. The most significant risk factor for death from CVD was frequent alcohol consumption (RR 3,01). Smoking increases the cardiovascular death risk by 2,28 times. Among former smokers, the RR of cardiovascular death was 1,91. HTN increases the risk of cardiovascular mortality by 1,84 times compared with people with normal blood pressure. Each year of life lived increases the risk of cardiovascular death by 1,1 times. In multivariate analysis, overweight, HCE, hypo-HDL-emia, HTG did not have a significant independent effect on the all-cause and cardiovascular death risk.Conclusion. In a 27-year cohort prospective study, independent predictors of all-cause and cardiovascular mortality, along with hypertension and age, were lifestyle risk factors, such as smoking and frequent alcohol consumption

Spousal body weight concordance and the impact of spouse overweight on death risk: data form a 27-year cohort prospective study

Aim. To study the interdependence of spousal body mass and influence of spouse overweight on the death risk according to the 27-year cohort prospective study.Material and methods. We examined a random household sample (n=1546; married couples, 427). Overweight frequency among spouses was studied on the first stage of the study (1988-1991). In 2002-2005 (stage II), the examination was repeated and overweight dynamics were studied. In 2015 (stage III), we analyze mortality rates and significance of overweight and spousal overweight for the mortality risk formation. Overweight was detected in people with body mass index ≥25 kg/m2. Two hundred deaths were recorded during 27-year follow-up. Vital status was established for 97% of observed persons.Results. Overweight was detected in 61,1% of men who lived with overweight wife and in 45% of men whose wife had normal body mass (p<0,01). Overweight was diagnosed more often in women whose husband also had overweight comparing with women who lived with normal weight husband (76,2% vs 61,7%; p<0,001). The risk of overweight formation among individuals whose spouse’s body mass increased from norm to overweight was in 3,04 times higher than in persons whose spouse had a stable normal body mass and in 2,2 times higher than in participants whose spouse had overweight on study stages I and II. Relative risk of mortality in men who lived with overweight wife was 2,07.Conclusion. 1) We found the body mass concordance in spouses. 2) The average body mass index in men and women who lived with overweight spouse is higher than in men and women whose spouse had a normal body mass. 3) Interdependence of spousal body mass was revealed in dynamics. 4) Spousal overweight is an independent predictor of premature mortality in men

ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer

Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity

COMPOSITION OF DEATH RISK ACCORDING TO BEHAVIORAL FACTORS (SMOKING, ALCOHOL CONSUMPTION) BY THE RESULTS OF 27-YEAR PROSPECTIVE STUDY

Aim. To assess the all-cause and cardiovascular mortality by the results from prospective cohort study of non-organized inhabitants of Tomsk city depending on behavioral risk factors — smoking, alcohol consumption, in 25 years observation.Material and methods. The study was done on the model of nonorganized Tomsk city population. Totally, 1546 persons studied, of the age 20-59 y.o., 630 males, 916 females. The parameters of all-cause and cardiovascular mortality studied, as the prognostic significance of behavioral risk factors — smoking, alcohol consumption, in the all-cause mortality origin, as the mortality from cardiovascular diseases.Results. The data acquired, on the increase of all-cause mortality risk in smokers 2,34 times, 1,93 times in men and 1,99 in women. Among those having quit smoking, mortality risk was also higher comparing to nonsmokers — 1,86 in general population; 1,83 in men. Cardiovascular mortality risk is also significantly higher in those influenced by tobacco smoking: relative mortality risk 1,58, females — 1,93; no significant data for males. Relative risk increases in those consuming alcohol frequently, 2,55 times comparing to those non-drinking, especially in younger age strata. Gender analysis showed remaining of all relations for whole population in men, and in women there were significant results only for frequent alcohol intake.Conclusion. It was shown that smoking significantly increases the risk of all-cause mortality among persons of both ages; among those quit smoking risk of death is still higher as in current smokers, comparing to non-smokers. Frequent alcohol consumption increases the risk of alcohol intake 2.6 times comparing to non-drinkers. Moderate and rare alcohol intake also increases the risk of all-cause mortality

Estimating Total Quantitative Protein Content in <i>Escherichia coli</i>, <i>Saccharomyces cerevisiae</i>, and HeLa Cells

The continuous improvement of proteomic techniques, most notably mass spectrometry, has generated quantified proteomes of many organisms with unprecedented depth and accuracy. However, there is still a significant discrepancy in the reported numbers of total protein molecules per specific cell type. In this article, we explore the results of proteomic studies of Escherichia coli, Saccharomyces cerevisiae, and HeLa cells in terms of total protein copy numbers per cell. We observe up to a ten-fold difference between reported values. Investigating possible reasons for this discrepancy, we conclude that neither an unmeasured fraction of the proteome nor biases in the quantification of individual proteins can explain the observed discrepancy. We normalize protein copy numbers in each study using a total protein amount per cell as reported in the literature and create integrated proteome maps of the selected model organisms. Our results indicate that cells contain from one to three million protein molecules per µm3 and that protein copy density decreases with increasing organism complexity

Epitranscriptome: Review of Top 25 Most-Studied RNA Modifications

The alphabet of building blocks for RNA molecules is much larger than the standard four nucleotides. The diversity is achieved by the post-transcriptional biochemical modification of these nucleotides into distinct chemical entities that are structurally and functionally different from their unmodified counterparts. Some of these modifications are constituent and critical for RNA functions, while others serve as dynamic markings to regulate the fate of specific RNA molecules. Together, these modifications form the epitranscriptome, an essential layer of cellular biochemistry. As of the time of writing this review, more than 300 distinct RNA modifications from all three life domains have been identified. However, only a few of the most well-established modifications are included in most reviews on this topic. To provide a complete overview of the current state of research on the epitranscriptome, we analyzed the extent of the available information for all known RNA modifications. We selected 25 modifications to describe in detail. Summarizing our findings, we describe the current status of research on most RNA modifications and identify further developments in this field

Correlation of spouses’ body weight (results of a 15-year prospective study)

Aim. To study the cross-sectional prevalence of overweight (OW) in men and women, in regard to their spouses’ body weight (BW), as well as to assess the BW dynamics in participants and their spouses over 15 years of the prospective follow-up. Material and methods. In the screening study, body mass index (BMI) was assessed in 425 married couples. The repeat assessment, performed 15 years later, included 232 couples who were still married. OW was diagnosed in subjects with BMI ≥25 kg/m2. Results. In the wives of OW men, OW prevalence was higher (76,2%) than in the spouses of non-OW men (61,3%; p&lt;0,001). In the husbands of OW women, OW prevalence was also higher (61,3%) than in the spouses of non-OW women (43,8%; p&lt;0,001). In the prospective study, the participants with no OW at baseline, whose spouses developed OW, the incidence of OW was significantly higher (60,9%) than in participants whose spouses remained non-OW (16,4%; p&lt;0,001), or in participants whose spouses remained OW (31,7%; p&lt;0,05). Among men and women with OW at baseline, whose spouses reduced their BW and became non-OW, BW normalization was more frequent (32,0%) than in the participants whose spouses either remained OW (9,1%; p&lt;0,001), or remained nonOW (3,4%; p&lt;0,001), or increased BW and became OW (6,9%; p&lt;0,05). Conclusion. BW dynamics in spouses was characterized by parallel increases or decreases, due to shared social and intra-familial factors