Combined Effect of Hypertension and Alcohol Consumption on the Risk of Death (27­Year Cohort Prospective Study).

Aim      To study the effect of arterial hypertension (AH) in combination with frequent alcohol consumption on the formation of risk for cardiovascular death and all-cause death according to results of a 27-year prospective cohort study.Material and methods  This 27­year prospective cohort study of an unorganized population of the Tomsk city (1546 people aged 20-59 years, including 630 men and 916 women) investigated AH prevalence and alcohol consumption (1988-1991) and analyzed the predictive significance of the effect of AH in combination with frequent alcohol consumption on the formation of risk for all-cause and cardiovascular death. AH was diagnosed at blood pressure ≥140 / 90 mm Hg. Frequent alcohol users were defined as those who consumed alcohol more than once a week.Results The combination of AH and frequent alcohol consumption increased the risk of all-cause death 4.1 times compared to that for persons without these risk factors (p<0.001). This was true for all age groups of the total cohort (higher relative risk, RR, was observed for persons aged 20-39 years) and for men (except for the group aged 40-59 years). RR of cardiovascular death was 5.3 (p<0.001) for frequent alcohol users with AH. It was established that frequent alcohol consumption additionally increased RR of all-cause death for persons with AH (RR 1.89; p<0.05) primarily at the expense of persons aged 20-39 years. Prediction of 27­year survival for frequent alcohol users with AH was 35.3 %.Conclusion      A combination of AH with frequent alcohol consumption considerably increases the risk of all-cause and cardiovascular death. Frequent alcohol consumption significantly impairs the prediction of 27-year survival for persons with AH by additionally (1.9 times) increasing the risk of all-cause death. Binary AH combinations with frequent alcohol consumption exert a more pronounced adverse effect on young men and women.

[Impact of hypertension, overweight, hypertriglyceridemia and their combination for mortality rate according to the results of a 27-year cohort prospective study].

AIM:  To study influence of hypertension, overweight, hypertriglyceridemia and their combinations for all-cause and cardiovascular mortality risk formation. Methods. The prevalence of hypertension, overweight and hypertriglyceridemia was studied (1988-1991) by 27-year prospective cohort study of unorganized population of Tomsk (1546 persons - 916 female and 630 male). The predictive value of these risk factors for all-cause and cardiovascular mortality risk formation were researched in 2015. Hypertension was diagnosed in persons with blood pressure greater or equal to 140/90 mm Hg, overweight was diagnosed in people with body mass index 25 kg/m2, hypertriglyceridemia was diagnosed in individuals having high blood level of triglycerides (greater or equal to 1.7).  Results.  Influence of hypertension for all-cause (relative risk (RR) 2.2) and cardiovascular mortality (RR 3.38) risk formation was detected. A hypertension related elevation of mortality risk was observed both among women and men and in all age groups with the exception of men 40-59 years (the results for cardiovascular mortality in these persons was statistically insignificant). We established that hypertension had the independent significant contribution for mortality risk formation. It is shown that RR of all-cause mortality 1.25 times (cardiovascular mortality 1.8 times) more in overweight persons. Increase of relative mortality risk was detected in overweight women, especially in women 20-39 years old. Hypertriglyceridemia increases relative risk of all-cause mortality 1.46 times, relative risk of cardiovascular mortality 2.15 times, especially in individuals 40-59 years old. It was revealed that hypertriglyceridemia is significant risk factor for all-cause mortality formation only in women. Combination of hypertension and overweight increases the risk of all-cause mortality 2.23 times and the risk of cardiovascular mortality  4.0 times, combination of hypertension and hypertriglyceridemia - 2.83 and 5.06 times,  combination of overweight and hypertriglyceridemia - 1.73 and 2.99 times, respectively. We detected the additional risk of hypertriglyceridemia in individuals with overweight for all-cause (RR 1.53) and cardiovascular (RR 2.18) mortality risk formation compared with overweight persons with normal level of triglycerides and also the additional risk of hypertriglyceridemia (RR 1.51 and 2.04, respectively) in individuals with hypertension compared with normotensive persons (p<0,05). The additional risk of overweight in individuals with hypertension for all-cause mortality was found only in women (RR 3.23). Conclusion. The independent significant impact of hypertension for all-cause and cardiovascular mortality risk formation was revealed by the results of 27-year prospective study. Combination of hypertension and hypertriglyceridemia increases the risk of all-cause mortality 2.8 times and the risk of cardiovascular mortality 5.1 times, combination of hypertension and overweight - 2.2 and 4 times, combination of overweight and hypertriglyceridemia - 1.7 and 3 times, respectively. We detected the additional risk of hypertriglyceridemia for all-cause mortality in overweight people (RR 1.5) and in individuals with hypertension (RR 1.5). Also, the additional risk of hypertriglyceridemia for cardiovascular mortality risk formation in overweight people (RR 2.2) and in persons with hypertension (RR 2.0) was found.

[Impact of Arterial Hypertension on the Formation of the Risk of Mortality. Results of a 27­Year Prospective Study].

OBJECTIVE: to investigate the impact of arterial hypertension (AH) on formation of the risk of total and cardiovascular mortality. MATERIALS AND METHODS: The 27­year cohort prospective study was conducted on the sample of unorganised population of Tomsk (n=1 546, age 20-59 years, 630 men, 916 women). At the first stage (1988-1991) we studied the prevalence of AH, at the second stage (2015) we investigated overall and cardiovascular mortality and the prognostic significance of AH in shaping mortality. Criterion of AH was blood pressure (BP) ≥140/90 mm Hg or (in persons with BP.

[Natural dynamics of blood pressure, body mass index and lipid levels in the elderly (the results of 17-year follow-up)].

AIM: to study natural dynamics of mean levels of systolic and diastolic arterial pressure (SAP, DAP), body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG) in elderly people using data of 17-year cohort prospective observation. MATERIAL AND METHODS: Primary examination of a random sample of population was carried out in 1988-1991, reexamination in 2002-2005. Here we present results of examination of 1046 persons including 136 of older age group (mean age at reexamination 69.3 ± 3.2 years). RESULTS: During the period of observation mean values of SAP in the elder group increased from 140.66 ± 23.61 to 164.58 ± 31.80 mm Hg (+17.0%; p<0,001). Values of DAP in women also rose from 87.82 ± 13.12 to 90.58 ± 13.69 mm Hg (+3.2%; p=0.029) while they did not change in the same age men. IMT values decreased from 28.78 ± 4.91 to 28.22 ± 5.17 kg/m² (-1.9%; p = 0.049). There was no dynamics of mean TC levels, while mean HDLC level lowered from 1.44 ± 0.35 to 1.29+0.34 mmol/l (-7.7%; p<0.001). Mean TG levels rose from 1.40 ± 0.78 to 1.73+1.0 mmol/I (+23.6%; p=0.002). CONCLUSION: The following changes occurred between 2 examinations of elderly persons performed with interval of 17 years: elevation of SAP, elevation of DAP in women, lowering of HDLC and BMI, elevation TG. There were no changes of TC.

[Spousal concordance of blood pressure levels (results of 17-year follow-up)].

Study aim was investigation of blood pressure levels (BP) in spouses and assessment of the role of arterial hypertension (AH) in a spouse as risk factor (RF) of AH in a 17-years prospective study. Primary study based on a random sample of citizens of Tomsk (1546 men and women aged 20-59 years) was carried out in 1988-1991. At repeat study which was carried out in 2002-2005 we obtained data on AH and end points from 81.2% of initial population. Cohort family study comprised 427 family couples. Relative risk (RR) of AH development in men in case of AH of a female spouse was 1.63 (95% confidence interval [CI] 1.14 to 2.33). RR of AH development in a women in this situation was 1.5 (95%CI 1.13 to 1.99). Husbands AH was associated with 5.2% elevation of systolic BP (SBP) (<0.001), 4.8% elevation of diastolic BP (DBP) (=0.001) in his wife. AH of a wife was associated with 5.5% elevation of SBP (<0.001) and 5% elevation of DBP (=0.003) in a husband. Coefficient of correlation (r) of SBP levels between spouses was 0.09 in age group 20-39 years (=0.041) and 0.16 in age group 40-59 years (=0.002). For DBP in age group 20-39 years r=0.14 (=0.002), in age group 40-59 years r=0.10 (=0.042). In a prospective study in men and women we found higher SBP when AH was detected in a spouse during follow-up compared with individuals whose BP had been and remained normal (by 5.4%, =0.015) or those whose BP during this period decreased to normal level (by 17.5%; =0.006). Detection of new cases of AH in men - spouses of women with AH was higher than in man - cohabitants of wives without AH (53.8 and 37.3%, respectively, =0.028). Thus we found concordance of BP levels in spouses, which was conditioned by marital assortment as well as common environment and way of life.

HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics.

BACKGROUND: Therapies targeting anti-tumor T-cell responses have proven successful in the treatment of a variety of malignancies. However, as most patients still fail to respond, approaches to augment immunotherapeutic efficacy are needed. Here, we investigated the ability of histone deacetylase 6 (HDAC6)-selective inhibitors to decrease immunosuppression and enhance immune function of melanoma patient T-cells in ex vivo cultures. METHODS: T-cells were harvested from peripheral blood or tumor biopsies of metastatic melanoma patients and cultured in the presence of pan-, class-specific or class-selective histone deacetylase (HDAC) inhibitors. Changes in cytokine production were evaluated by Luminex and intracellular flow cytometry staining. Expression of surface markers, transcription factors, protein phosphorylation, and cell viability were assessed by flow cytometry. Changes in chromatin structure were determined by ATAC-seq. RESULTS: T-cell viability was impaired with low doses of pan-HDAC inhibitors but not with specific or selective HDAC inhibitors. The HDAC6-selective inhibitors ACY-1215 (ricolinostat) and ACY-241 (citarinostat) decreased Th2 cytokine production (i.e. IL-4, IL-5, IL-6, IL-10 and IL-13). Expansion of peripheral blood T-cells from melanoma patients in the presence of these inhibitors resulted in downregulation of the Th2 transcription factor GATA3, upregulation of the Th1 transcription factor T-BET, accumulation of central memory phenotype T-cells (CD45RA-CD45RO + CD62L + CCR7+), reduced exhaustion-associated phenotypes (i.e. TIM3 + LAG3 + PD1+ and EOMES+PD1+), and enhanced killing in mixed lymphocyte reactions. The frequency, FOXP3 expression, and suppressive function of T regulatory cells (Tregs) were decreased after exposure to ACY-1215 or ACY-241. Higher frequencies of T-cells expressing CD107a + IFNγ+ and central memory markers were observed in melanoma tumor-infiltrating lymphocytes (TIL), which persisted after drug removal and further expansion. After ACY-1215 treatment, increased chromatin accessibility was observed in regions associated with T-cell effector function and memory phenotypes, while condensed chromatin was found in regions encoding the mTOR downstream molecules AKT, SGK1 and S6K. Decreased phosphorylation of these proteins was observed in ACY-1215 and ACY-241-treated T-cells. AKT- and SGK1-specific inhibition recapitulated the increase in central memory frequency and decrease in IL-4 production, respectively, similar to the observed effects of HDAC6-selective inhibition. CONCLUSIONS: HDAC6-selective inhibitors augmented melanoma patient T-cell immune properties, providing a rationale for translational investigation assessing their potential clinical efficacy.

GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF.

Identifying the spectrum of genetic alterations that cooperate with critical oncogenes to promote transformation provides a foundation for understanding the diversity of clinical phenotypes observed in human cancers. Here, we performed integrated analyses to identify genomic alterations that co-occur with oncogenic BRAF in melanoma and abrogate cellular dependence upon this oncogene. We identified concurrent mutational inactivation of the PTEN and RB1 tumor suppressors as a mechanism for loss of BRAF/MEK dependence in melanomas harboring (V600E)BRAF mutations. RB1 alterations were mutually exclusive with loss of p16(INK4A), suggesting that whereas p16(INK4A) and RB1 may have overlapping roles in preventing tumor formation, tumors with loss of RB1 exhibit diminished dependence upon BRAF signaling for cell proliferation. These findings provide a genetic basis for the heterogeneity of clinical outcomes in patients treated with targeted inhibitors of the mitogen-activated protein kinase pathway. Our results also suggest a need for comprehensive screening for RB1 and PTEN inactivation in patients treated with RAF and MEK-selective inhibitors to determine whether these alterations are associated with diminished clinical benefit in patients whose cancers harbor mutant BRAF.