Malondialdehyde, Antioxidant Defense System Components and Their Relationship with Anthropometric Measures and Lipid Metabolism Biomarkers in Apparently Healthy Women.

Cardiovascular diseases are the leading cause of mortality worldwide. Since atherosclerosis, an inflammatory, lipid-driven disease, is an underlying basis for the development of cardiovascular disease, it is important to understand its relationship with confounding factors, such as oxidative lipid degradation. In contrast, circulating antioxidants prevent oxidative lipid damage, and therefore, may be associated with reduced development of atherosclerosis. We aimed to assess oxidative lipid degradation biomarker malondialdehyde (MDA) and antioxidant defense system components, total antioxidant capacity (TAC) and superoxide dismutase (SOD) inhibition rate levels, in healthy women and evaluate their relationships with age, anthropometric measures, and lipid metabolism biomarkers. The study included 86 healthy middle-aged women. MDA in human serum samples was evaluated by HPLC, and the TAC and SOD inhibition rates were measured by photometric methods. MDA was found to be associated with age, total cholesterol, non-HDL cholesterol, apolipoprotein B and triacylglycerols. TAC was shown to be associated with age, BMI, and waist circumference, as well as lipid metabolism biomarkers apolipoprotein B and triacylglycerol, while SOD inhibition rate was only associated with total cholesterol, apolipoprotein B and triacylglycerols. In conclusion, the association of oxidative status indices, MDA, TAC and SOD, with cardiovascular risk factors suggests that they could be additional useful biomarkers in the research of aging, obesity, and atherosclerosis pathogenesis.

Association of hair glucocorticoid levels with sleep quality indicators: a pilot study in apparently healthy perimenopausal and menopausal women.

Background: Poor sleep quality is associated with different physical and mental health diseases. It is proposed that increased hypothalamic-pituitary-adrenal axis activity is a potential contributor affecting sleep pattern and quality. We aimed to analyze the relationship between subjective sleep quality indicators and hair glucocorticoid levels among relatively healthy perimenopausal and postmenopausal women. Methods: A total of 145 women aged 50-64 y.o. were enrolled in the cross-sectional pilot study. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index, while stress level was measured using the Perceived Stress Scale. Hair cortisol and cortisone levels were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Results: Statistically significant positive relationship was found between hair cortisol concentration and Pittsburgh sleep quality index score. Similarly, statistically significant positive associations were observed between hair total glucocorticoid level and Pittsburgh sleep quality index, sleep disturbance, and Perceived Stress Scale scores. Subjects with prolonged sleep latency had significantly higher hair cortisol and total hair glucocorticoid concentrations compared with individuals whose sleep latency is not disturbed. Additionally, Chi-squared test indicated that lower hair cortisol concentration was significantly related to better sleep efficiency. Conclusion: Increased hair glucocorticoid (cortisol, cortisone) levels were found to be related with worse sleep quality measured by Pittsburgh sleep quality index score.

A De Novo 8q22.2q22.3 Interstitial Microdeletion in a Girl with Developmental Delay and Congenital Defects.

Background and Objectives: Only nine patients with interstitial de novo 8q22.2q22.3 microdeletions have been reported to date. The objective of this report is to present clinical features of a new patient with an 8q22.2q22.3 microdeletion, to compare her phenotype to other previously reported patients, and to further expand the phenotype associated with this microdeletion. Materials and Methods: We describe an 8½-year-old girl with developmental delay, congenital hip dysplasia, a bilateral foot deformity, bilateral congenital radioulnar synostosis, a congenital heart defect, and minor facial anomalies. Results: Chromosomal microarray analysis revealed a 4.9 Mb deletion in the 8q22.2q22.3 region. De novo origin was confirmed by real-time PCR analysis. Conclusions: Microdeletions in the 8q22.2q22.3 region are characterized by moderate to severe intellectual disability, seizures, distinct facial features and skeletal abnormalities. In addition to one already reported individual with an 8q22.2q22.3 microdeletion and unilateral radioulnar synostosis, this report of a child with bilateral radioulnar synostosis provides additional evidence, that radioulnar synostosis is not an incidental finding in individuals with an 8q22.2q22.3 microdeletion. Additional patients with similar microdeletions would be of a great importance for more accurate phenotypic description and further analysis of the genotypic-phenotypic relationship.

Computational pharmacology: New avenues for COVID-19 therapeutics search and better preparedness for future pandemic crises.

The COVID-19 pandemic created an unprecedented global healthcare emergency prompting the exploration of new therapeutic avenues, including drug repurposing. A large number of ongoing studies revealed pervasive issues in clinical research, such as the lack of accessible and organised data. Moreover, current shortcomings in clinical studies highlighted the need for a multi-faceted approach to tackle this health crisis. Thus, we set out to explore and develop new strategies for drug repositioning by employing computational pharmacology, data mining, systems biology, and computational chemistry to advance shared efforts in identifying key targets, affected networks, and potential pharmaceutical intervention options. Our study revealed that formulating pharmacological strategies should rely on both therapeutic targets and their networks. We showed how data mining can reveal regulatory patterns, capture novel targets, alert about side-effects, and help identify new therapeutic avenues. We also highlighted the importance of the miRNA regulatory layer and how this information could be used to monitor disease progression or devise treatment strategies. Importantly, our work bridged the interactome with the chemical compound space to better understand the complex landscape of COVID-19 drugs. Machine and deep learning allowed us to showcase limitations in current chemical libraries for COVID-19 suggesting that both in silico and experimental analyses should be combined to retrieve therapeutically valuable compounds. Based on the gathered data, we strongly advocate for taking this opportunity to establish robust practices for treating today's and future infectious diseases by preparing solid analytical frameworks.

Higher Levels of Stress-Related Hair Steroid Hormones Are Associated with the Increased SCORE2 Risk Prediction Algorithm in Apparently Healthy Women.

Cardiovascular diseases (CVDs) are the major cause of death worldwide. Although the importance of conventional CVD risk factors, including older age, male gender, hypertension, obesity, dyslipidemia and hyperglycemia, is well-studied, psychosocial stress, which is considered an independent CVD risk factor, requires further investigation. Thus, we aimed to investigate the association between long-term secretion of stress-related steroid hormones, including cortisol, cortisone and dehydroepiandrosterone, and the 10-year fatal and non-fatal CVD risk estimated by the SCORE2 risk prediction algorithm, as well as traditional CVD risk factors in a group of apparently healthy women. A total of 145 women (aged 50-64 years) participating in the national CVD prevention program were enrolled in the study. Sociodemographic, lifestyle, health-related characteristics, stress, anxiety and sleep quality indicators were evaluated using specific questionnaires. Anthropometric and arterial blood pressure measures were assessed by trained personnel, lipid and glucose metabolism biomarkers were measured using routine methods, and hair steroid hormone levels were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. The results showed that higher levels of hair cortisol and cortisone are associated with increased SCORE2 values. Moreover, significant associations between hair glucocorticoids and individual cardiovascular risk factors, including obesity, hypertension, dyslipidemia and hyperglycemia, were found. These findings indicate that stress-related hair steroid hormones might be valuable biomarkers for CVD prediction and prevention.

Association between hair cortisol concentration and metabolic syndrome.

Metabolic syndrome (MetS) is a highly prevalent disorder defined as a cluster of cardiometabolic risk factors including obesity, hyperglycemia, hypertension, and dyslipidemia. It is believed that excessive cortisol secretion due to psychosocial stress-induced hypothalamic-pituitary-adrenal axis activation might be involved in the pathogenesis of MetS. We sought to explore the association between MetS and psychosocial risk factors, as well as cortisol concentration measured in different biological specimens including saliva, blood serum, and hair samples. The study was conducted on a sample of 163 young and middle-aged men who were divided into groups according to the presence of MetS. Hair cortisol concentration (HCC) was determined using high performance liquid chromatography with UV detection, while blood serum and salivary cortisol levels were measured by enzyme-linked immunoassay. Lipid metabolism biomarkers were determined using routine laboratory methods. Anthropometric and lifestyle characteristics, as well as self-reported psychosocial indicators, were also examined. Significantly higher HCC and lower social support level among participants with MetS compared with individuals without MetS were found. However, no significant differences in blood serum and salivary cortisol levels were observed between men with and without MetS. In conclusion, chronically elevated cortisol concentration might be a potential contributing factor to the development of MetS.

Insights into therapeutic targets and biomarkers using integrated multi-'omics' approaches for dilated and ischemic cardiomyopathies.

At present, heart failure (HF) treatment only targets the symptoms based on the left ventricle dysfunction severity; however, the lack of systemic 'omics' studies and available biological data to uncover the heterogeneous underlying mechanisms signifies the need to shift the analytical paradigm towards network-centric and data mining approaches. This study, for the first time, aimed to investigate how bulk and single cell RNA-sequencing as well as the proteomics analysis of the human heart tissue can be integrated to uncover HF-specific networks and potential therapeutic targets or biomarkers. We also aimed to address the issue of dealing with a limited number of samples and to show how appropriate statistical models, enrichment with other datasets as well as machine learning-guided analysis can aid in such cases. Furthermore, we elucidated specific gene expression profiles using transcriptomic and mined data from public databases. This was achieved using the two-step machine learning algorithm to predict the likelihood of the therapeutic target or biomarker tractability based on a novel scoring system, which has also been introduced in this study. The described methodology could be very useful for the target or biomarker selection and evaluation during the pre-clinical therapeutics development stage as well as disease progression monitoring. In addition, the present study sheds new light into the complex aetiology of HF, differentiating between subtle changes in dilated cardiomyopathies (DCs) and ischemic cardiomyopathies (ICs) on the single cell, proteome and whole transcriptome level, demonstrating that HF might be dependent on the involvement of not only the cardiomyocytes but also on other cell populations. Identified tissue remodelling and inflammatory processes can be beneficial when selecting targeted pharmacological management for DCs or ICs, respectively.

Biophysics is reshaping our perception of the epigenome: from DNA-level to high-throughput studies.

Epigenetic research holds great promise to advance our understanding of biomarkers and regulatory processes in health and disease. An increasing number of new approaches, ranging from molecular to biophysical analyses, enable identifying epigenetic changes on the level of a single gene or the whole epigenome. The aim of this review is to highlight how the field is shifting from completely molecular-biology-driven solutions to multidisciplinary strategies including more reliance on biophysical analysis tools. Biophysics not only offers technical advancements in imaging or structure analysis but also helps to explore regulatory interactions. New computational methods are also being developed to meet the demand of growing data volumes and their processing. Therefore, it is important to capture these new directions in epigenetics from a biophysical perspective and discuss current challenges as well as multiple applications of biophysical methods and tools. Specifically, we gradually introduce different biophysical research methods by first considering the DNA-level information and eventually higher-order chromatin structures. Moreover, we aim to highlight that the incorporation of bioinformatics, machine learning, and artificial intelligence into biophysical analysis allows gaining new insights into complex epigenetic processes. The gained understanding has already proven useful in translational and clinical research providing better patient stratification options or new therapeutic insights. Together, this offers a better readiness to transform bench-top experiments into industrial high-throughput applications with a possibility to employ developed methods in clinical practice and diagnostics.

The impact of metformin on survival in patients with melanoma-national cohort study.

PURPOSE: The primary study outcome was melanoma-specific mortality in patients with type 2 diabetes mellitus (T2DM) using metformin. METHODS: Data regarding patients were provided by the Lithuanian Cancer Registry and were linked with National Health Insurance Fund in accordance with unique personal identification numbers during the period of thirteen years. RESULTS: About 2817 patients met eligibility criteria and were included in the retrospective cohort study. About 163 patients had pre-existing T2DM and 103 of them were treated with metformin. In the multivariable analysis, there was significant risk difference in melanoma-specific survival between diabetic, metformin-using patients, and nondiabetic patients (P=0.02) in favor of metformin users. CONCLUSION: Melanoma patients with T2DM treated with metformin had lower risk of melanoma-specific mortality; however, prospective controlled studies are mandatory to confirm this finding.

Association of Platelet Membrane Fatty Acid Composition with Markers of Oxidative Stress in Healthy Men.

BACKGROUND Platelet membranes are extremely susceptible to peroxidation, forming a variety of lipid peroxides, including malondialdehyde (MDA), which has been implicated in the etiology of cardiovascular diseases. Moreover, platelet-leukocyte aggregates (PLAs) are known to contribute to advanced endothelial injury and atherogenesis. MATERIAL AND METHODS Fatty acid (FA) methyl esters of the platelet membranes of 79 apparently healthy men without any acute clinical condition at the time of the study were identified by GC/MS. MDA was measured by HPLC in blood serum, and PLAs were analyzed by whole-blood flow cytometry. Individuals were divided into quartiles according to MDA concentration and percentage of PLAs formation. The composition of platelet membrane FAs was compared to MDA concentration and the percentage of PLAs formation in apparently healthy individuals. RESULTS In quartiles (Q) with higher MDA concentration, percentage of C 16: 1ω7 (Q1 vs. Q3, p=0.021), C 20: 1ω9 (Q2 vs. Q4, p=0.028) and C 20: 5ω3 (Q2 vs. Q4, p=0.046) was lower. However, C 22: 5ω3 (Q1 vs. Q4, p=0.038) and total ω3 (Q1 vs. Q2, p=0.024) were higher. CONCLUSIONS MDA and the formation of platelet-monocyte aggregates stimulate the incorporation of monounsaturated fatty acids and polyunsaturated fatty acids in platelet phospholipid membranes, which may be a hallmark for a changed level of biologically active compounds required for the activation of future platelets.

Association of Hair Cortisol Concentration with Prevalence of Major Cardiovascular Risk Factors and Allostatic Load.

BACKGROUND The high prevalence of cardiovascular diseases cannot be explained completely by conventional risk factors such as older age, smoking, diabetes mellitus, hypertension, obesity, and dyslipidemia. Results of recent studies indicate that chronic stress may be an independent risk factor for cardiovascular morbidity and mortality. Thus, the aim of our study was to investigate the associations between the hair cortisol concentration (HCC), which is considered as a potential biomarker of long-term psychosocial stress, and traditional cardiovascular risk factors, including smoking, dyslipidemia, hypertension, and obesity. MATERIAL AND METHODS Fasting blood samples and anthropometric and lifestyle data were collected from 163 apparently healthy men. HCC was determined using high-performance liquid chromatography. Allostatic load (AL) index, defined as an integrated score of multiple interacting systems involved in the adaptation to adverse physical or psychosocial situations, was also calculated. RESULTS We found that many prevalent cardiovascular risk factors, including hypertension, smoking, higher than recommended waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C) median values, are associated with higher HCC. Hair cortisol level was also positively associated with the manifestation of individual cardiovascular risk factors such as higher-than-recommended total cholesterol, LDL-C, non-high-density lipoprotein cholesterol, body mass index, and WC median values. Moreover, a significant positive relationship between HCC and AL index was observed. CONCLUSIONS The results of this study suggest that increased prevalence of traditional cardiovascular risk factors is associated with higher HCC. Also, both HCC and AL index might be appropriate markers for the evaluation of chronic stress level.

Chronic and oxidative stress association with total count of endothelial microvesicles in healthy young male plasma.

BACKGROUND: Chronic and oxidative stress promotes injury to the endothelium. This happens early in the disease and novel biomarkers describing the rate of the damage may be important in early diagnostics and prevention. Microvesicles are shed from endothelial cells in response to oxidative stress, inflammation, coagulation, and angiogenesis. Their increased level in plasma could reflect the state of the endothelium. OBJECTIVES: The objective of this study was to test the association between oxidative and chronic stress markers, atherosclerosis risk factors and endothelial microvesicle (EMV) count in peripheral blood. MATERIAL AND METHODS: The study included 81 males, aged 25-55 years and apparently healthy. Venous blood samples were labeled with anti-CD144-FITC, anti-CD105-BV421, anti-CD42a-PerCP, anti-CD62e-PE, anti-CD31-APCy7, and anti-CD61-APC (BD Biosciences, San Jose, USA), and tested using a BD LSR Fortessa cytometer (BD Biosciences). Events were gated on forward and side-scattered light parameters. Malondialdehyde (MDA) and cortisol concentrations were measured using high-performance liquid chromatography (HPLC). RESULTS: Four populations of EMV expressing a combination of CD105+, CD31+, CD144+, and CD62e with CD42aor CD42a+ markers were examined. We found correlations between MDA concentration and hair cortisol and a total count of CD144+ microvesicles, and weak correlations with diastolic blood pressure (DBP) (p = 0.003, r = 0.324) and systolic blood pressure (SBP) (p = 0.016, r = 0.267), especially with the microvesicles carrying CD62e. There was a median difference of CD105+ microvesicle count between smoking (n = 13) and non-smoking (n = 68) individuals. A predictive model showed an association between CD144+ microvesicle counts with cortisol and MDA concentrations and waist circumference. CONCLUSIONS: In conclusion, our data and predictive model showed that the total counts of microvesicle populations were associated with stress-related parameters - cortisol and MDA concentrations; expression of CD62e in various populations of EMV and the ratio of CD144+ to CD105+/CD62e+ were associated with increased DBP and SBP, and also with total cholesterol concentration in healthy young male population.

Natural killer cell-based immunotherapy: a new fighter against melanoma?

Changes in the expression of proteins on cancer cell surface are a typical outcome of malignant transformation. Natural killers (NKs) utilize a set of activating and inhibitory receptors that enable them to recognize altered protein expression and then destroy 'stressed' cells such as cancer or virus-infected cells. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA and MICB, respectively) are expressed by various human tumors and can be recognized by activating NK cell receptor NKG2D. However, cancer frequently escapes recognition by NK cells by proteolytic shedding of MICA and MICB proteins. A study carried out by Ferrari de Andrade and colleagues showed that monoclonal antibody targeting the site of proteolytic shedding of MICA and MICB reduced the progression of melanoma in immunocompromised and immune competent mice models by activation of NKG2D. This approach prevented the reduction of essential immunostimulatory ligands (MICA/MICB) and restored NK cell-driven anticancer immunity.

Classical rather than genetic risk factors account for high cardiovascular disease prevalence in Lithuania: A cross-sectional population study.

PURPOSE: Cardiovascular disease (CVD) mortality accounts for 54% of all deaths in Lithuania, making it the highest among all of the European Union countries. We evaluated the prevalence of several CVD risk factors, including lifestyle, blood biochemistry and genetic predisposition to determine the reasons behind significantly increased CVD prevalence in Lithuania. MATERIALS AND METHODS: In total 435 volunteers of Lithuanian ethnicity and stable geographic settlement for 3 generations, had their anthropometric, biochemical and behavioural risk factors measured. A randomly selected sample of 166 volunteers had their 60 CVD risk alleles genotyped. The prevalence of risk alleles and cumulative CVD genetic risk score were compared with population of North-West European origin (CEU) using data from the phase 3 HapMap project. RESULTS: CVD was present in 33.8% of study volunteers, 84% of participants consumed alcohol, 21% were current smokers and only 30% of participants engaged in higher levels of physical activity. Also, the average BMI (males 28.3±4.3kg/m2, females 27.3±5.0kg/m2), total cholesterol (males 6.1±1.2mmol/L, females 6.2±1.0mmol/L) and LDL-cholesterol (males 4.1±1.1mmol/L, females 4.1±1.0mmol/L) were above the normal values. The cumulative genetic susceptibility to develop CVD in Lithuanians was only 1.4% higher than in CEU population. CONCLUSIONS: High BMI and poor population plasma lipid profile are the major contributing factors to high CVD mortality and morbidity in Lithuania. Smoking, alcohol consumption and preliminary genetic predisposition results do not explain the difference in CVD mortality between the Lithuanian and wider European populations. CVD prevention programmes in Lithuania should primarily focus on weight loss and improving blood lipid control.

Heterogeneity of nutritional habits of Lithuanian ethnolinguistic groups: population-based study.

BACKGROUND: Lithuania is a Northern European country consisting of two main ethnolinguistic groups: Samogitians and Highlanders. The objective of the paper is to investigate differences in nutritional habits of 18-65-year-old Lithuanians living in different ethnolinguistic regions. MATERIALS AND METHODS: A representative, population-based, random sample of the 18-65-year-old ethnic Lithuanian population was interviewed from 17 December 2008 to 20 May 2013. Lithuanians living in their ethnolinguistic region for at least three generations were included (n = 1,133). We analysed responses to 12 questions about nutritional habits of respondents. For the univariate analysis, we applied the chi-squared test. For the clusterisation of the survey questions, we employed a multiple correspondence analysis (MCA). RESULTS: Comparing Samogitians' and Highlanders' responses according to their gender, education, and place of residence, we observed more often significant differences (p < 0.05) for the urban population, respondents without higher education, and women. The nutrition of Highlanders was more consistent with national and WHO nutritional recommendations. Significant differences were obtained in the consumption of fish (p = 1.9 · 10-12), milk (p = 1.8 · 10-4) and grain products (p = 0.01). MCA revealed that all questions fall into three groups with a different composition for Samogitians and Highlanders. We failed to demonstrate the impact of different nutritional habits on the body mass index. CONCLUSIONS: According to the univariate and multivariate analysis, the nutritional habits of Lithuanian ethnolinguistic regions are heterogeneous. Dependency on an ethnolinguistic region might be considered an important factor for the preparation of appropriate health and nutrition education and disease prevention programmes. The issue of excess weight remains equally important for both ethnolinguistic groups.