Diagnostics of lung cancer by fragmentated blood circulating cell-free DNA based on machine learning methods

IntroductionMinimally invasive diagnostics based on liquid biopsy makes it possible early detection of lung cancer (LC). The blood plasma circulating cell-free DNA (cfDNA) fragments reflect the genome and chromatin status and are considered as integral cancer biomarkers and the biological entities for ‘cancer-of-origin’ prediction. The aim of this work is to create a method for processing next-generation sequencing (NGS) data and an interpretable binary classification model (CM), which analyzed cfDNA fragmentation features for distinguishing healthy subjects and subjects with LC.Methods148 healthy subjects and 138 subjects with LC were included in the study. cfDNA fractions, isolated from blood plasma biospecimens, were used for DNA libraries preparations and NGS on the NovaSeq 6,000 Illumina system with a coverage of 100 million reads/sample. Twelve variables, describing the abundance and length distribution of cfDNA fragments within each genomic interval, and 40 variables based on the values of position-weight matrices, describing combinations of 5-bp-long terminal motifs of cfDNA fragments, were used to characterize genomic fragmentation. Classification models of the first phase of machine learning were based either on logistic regression with L1- and L2-regularization or were probabilistic CMs based on Gaussian processes. The second phase CM was based on kernel logistic regression.ResultsThe final CM can distinguish healthy subjects and subjects with LC with AUC values of 0.872–0.875. The performance of developed CM was evaluated using datum and testing sets for each LC stage category. Sensitivity values ranged from 66.7 to 85.7%, from 77.8 to 100%, and from 70 to 80% for LC stages I, II, and III, respectively. Specificity values ranged from 79.3 to 90.0%.DiscussionThus, the CM has a good diagnostic value and does not require clinical or other data on tumor-associated biomarkers. The current method for LC detection has some advantages for future clinical implementation as a decision-making support system due to the performance of the CM requires data exclusively from NGS-analysis of blood plasma cfDNA fragmentation; the accuracy of the CM does not depend on any additional clinical data; the CM is highly interpretable and traceable; CM has appropriate modular architecture

Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study

Background: Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia. Methods: This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m2) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression. Findings: Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55–98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04–117·73]) than in those in the lowest risk category (aged 18–38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57–38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67–104·02) for those with obesity in the highest risk category and OR 20·07 (12·73–31·65) for those without obesity. Interpretation: Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population. Funding: Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron

Analysis of methods for reducing the signal PAPR under the influence of the Doppler effect in hybrid communication networks

Background. For further development of communication networks, it is planned to use hybrid satellite networks for traffic transmission. However, satellite communication channels have features such as distortion caused by the Doppler effect and increased energy efficiency requirements. Aim of this study is to analyze variants of orthogonal frequency multiplexing methods and modulation methods in order to choose the most stable technology, taking into account destabilizing factors. Method. Comparing different signal processing technologies and studying their resistance to bit errors is the imitation modeling of the communication channel in the Matlab environment. This approach allows creating a model of the communication network, taking into account the main parameters of communication channels, such as the Doppler effect, energy deficiency and destabilizing factors. Results. The distribution of the bit error coefficient for various signal processing technologies, depending on the signal-to-noise ratio, is compared. The method of frequency multiplexing is defined, providing the minimum peak factor and the most resistant to bit error. It is also noted that the effectiveness of all the studied technologies depends on the spacing and modulation constellations, and that it is necessary to adjust the characteristics of the system for each case. Conclusion. The results of this study can be used to improve the quality of communication in difficult interference conditions of hybrid mobile networks of 5 and 6 generations using the satellite segment

Genetic Diversity of HIV-1 in Krasnoyarsk Krai: Area with High Levels of HIV-1 Recombination in Russia

More than a quarter of HIV-infected individuals registered in Russia live in Siberia. Unlike Central Russia where HIV-1 subtype A6 is predominant, in most Siberian regions since 2012, a new HIV-1 CRF63_02A1 genetic variant has spread, with the share of this variant attaining 75–85% among newly identified HIV cases. Krasnoyarsk Krai is considered to be a high-risk territory according to morbidity rate and HIV infection incidence among the population. The current paper aims to study the molecular epidemiologic characteristics of HIV-1 spreading in Krasnoyarsk Krai. Phylogenetic and recombination analyses ofpol(PR-RT, IN) andenvregions of the virus were used for genotyping 159 HIV-1 isolated in Krasnoyarsk Krai. 57.2% of the isolates belonged to subtype A (A6) specific to Russia, 12.6% to CRF63_02A1, and 0.6% to CRF02_AGСА, and in 29.6% HIV-1 URFs were detected, including URF63/А (23.9%), URFА/В (4.4%), and URF02/А (1.3%). In 6 of 7, HIV-1 URFА/В identical recombination model was detected; the origin of 38 URF63/А was proven to be the result of individual recombination events. Since 2015, a share of the population with newly diagnosed HIV who were infected with HIV-1 URF reached an exceptionally high rate of 38.6%. As distinct from adjacent Siberian regions, the HIV-1 CRF63_02A1 prevalence rate in Krasnoyarsk Krai is within 16%; however, the increased contribution of new HIV-1 into the regional epidemic development was observed due to the recombination of viruses of subtypes А, В, and CRF63_02A1. The difference between the described molecular epidemiologic picture in Krasnoyarsk Krai and in adjacent areas is likely caused by differences in predominant routes of HIV transmission and by more recent HIV-1 CRF63_02A1 transmission in the PWID group, which had a high prevalence of HIV-1 subtype A by the time of the new virus transmission, resulting in increased possibility of coinfection with various HIV-1 genetic variants.</jats:p

Current Approaches to Epigenetic Therapy

Epigenetic therapy is a promising tool for the treatment of a wide range of diseases. Several fundamental epigenetic approaches have been proposed. Firstly, the use of small molecules as epigenetic effectors, as the most developed pharmacological method, has contributed to the introduction of a number of drugs into clinical practice. Secondly, various innovative epigenetic approaches based on dCas9 and the use of small non-coding RNAs as therapeutic agents are also under extensive research. In this review, we present the current state of research in the field of epigenetic therapy, considering the prospects for its application and possible limitations

Characterization of HIV-1 Epidemic in Kyrgyzstan

Kyrgyzstan has one of the highest rates of HIV-1 spread in Central Asia. In this study, we used molecular–epidemiological approaches to examine the HIV-1 epidemic in Kyrgyzstan. Samples were obtained from HIV-positive individuals who visited HIV/AIDS clinics. Partial pol gene sequences were used to identify HIV-1 subtypes and drug resistance mutations (DRMs) and to perform phylogenetic analysis. Genetic diversity and history reconstruction of the major HIV-1 subtypes were explored using BEAST. This study includes an analysis of 555 HIV-positive individuals. The study population was equally represented by men and women aged 1–72 years. Heterosexual transmission was the most frequent, followed by nosocomial infection. Men were more likely to acquire HIV-1 during injection drug use and while getting clinical services, while women were more likely to be infected through sexual contacts (p &amp;lt; 0.01). Heterosexual transmission was the more prevalent among individuals 25–49 years old; individuals over 49 years old were more likely to be persons who inject drugs (PWID). The major HIV-1 variants were CRF02_AG, CRF63_02A, and sub-subtype A6. Major DRMs were detected in 26.9% of the study individuals; 62.2% of those had DRMs to at least two antiretroviral (ARV) drug classes. Phylogenetic analysis revealed a well-defined structure of CRF02_AG, indicating locally evolving sub-epidemics. The lack of well-defined phylogenetic structure was observed for sub-subtype A6. The estimated origin date of CRF02_AG was January 1997; CRF63_02A, April 2004; and A6, June 1995. A rapid evolutionary dynamic of CRF02_AG and A6 among Kyrgyz population since the mid-1990s was observed. We observed the high levels of HIV-1 genetic diversity and drug resistance in the study population. Complex patterns of HIV-1 phylogenetics in Kyrgyzstan were found. This study highlights the importance of molecular–epidemiological analysis for HIV-1 surveillance and treatment implementation to reduce new HIV-1 infections.</jats:p

Diversities in the Gut Microbial Patterns in Patients with Atherosclerotic Cardiovascular Diseases and Certain Heart Failure Phenotypes

To continue progress in the treatment of cardiovascular disease, there is a need to improve the overall understanding of the processes that contribute to the pathogenesis of cardiovascular disease (CVD). Exploring the role of gut microbiota in various heart diseases is a topic of great interest since it is not so easy to find such reliable connections despite the fact that microbiota undoubtedly affect all body systems. The present study was conducted to investigate the composition of gut microbiota in patients with atherosclerotic cardiovascular disease (ASCVD) and heart failure syndromes with reduced ejection fraction (HFrEF) and HF with preserved EF (HFpEF), and to compare these results with the microbiota of individuals without those diseases (control group). Fecal microbiota were evaluated by three methods: living organisms were determined using bacterial cultures, total DNA taxonomic composition was estimated by next generation sequencing (NGS) of 16S rRNA gene (V3&ndash;V4) and quantitative assessment of several taxa was performed using qPCR (quantitative polymerase chain reaction). Regarding the bacterial culture method, all disease groups demonstrated a decrease in abundance of Enterococcus faecium and Enterococcus faecalis in comparison to the control group. The HFrEF group was characterized by an increased abundance of Streptococcus sanguinus and Streptococcus parasanguinis. NGS analysis was conducted at the family level. No significant differences between patient&rsquo;s groups were observed in alpha-diversity indices (Shannon, Faith, Pielou, Chao1, Simpson, and Strong) with the exception of the Faith index for the HFrEF and control groups. Erysipelotrichaceae were significantly increased in all three groups; Streptococcaceae and Lactobacillaceae were significantly increased in ASCVD and HFrEF groups. These observations were indirectly confirmed with the culture method: two species of Streptococcus were significantly increased in the HFrEF group and Lactobacillus plantarum was significantly increased in the ASCVD group. The latter observation was also confirmed with qPCR of Lactobacillus sp. Acidaminococcaceae and Odoribacteraceae were significantly decreased in the ASCVD and HFrEF groups. Participants from the HFpEF group showed the least difference compared to the control group in all three study methods. The patterns found expand the knowledge base on possible correlations of gut microbiota with cardiovascular diseases. The similarities and differences in conclusions obtained by the three methods of this study demonstrate the need for a comprehensive approach to the analysis of microbiota