Currently the main way of curable treatment of hepatocellular carcinomas (HCC)* is a liver resection. Candidates for surgery are patient with good score of liver function (Child-Pugh A group), without destruction of great vessels and distant metastases. Hemihepatectomy is associated with a high risk of postoperative liver failure (including portal hypertension, cirrhosis, portal vein thrombosis). This reason leads to premature failure of the operation. According to current clinical guidelines, system therapy is more suitable, despite of the lack of reliable data on its effectiveness in such clinical situations. The presented cases may support the selection of advanced hemihepatectomy as a treatment for hepatocellular cancer C stage BCLC classification.

Background: The role of CREBBP and EP300 mutations in hypermutation and immunotherapy response in gastroesophageal adenocarcinomas is poorly defined and needs further investigation. Methods: We conducted an in silico analysis of 12 publicly available studies (n = 1871; cBioPortal), stratifying samples by CREBBP/EP300 status to assess associations with TMB-High, MSI, co-mutation patterns, and mutation localization. Clinical validation was performed in an independent pan-cancer cohort treated with ICIs (n = 1610) and a gastric cancer cohort with WES data (n = 55). Results: Coding mutations in CREBBP and/or EP300 were significantly associated with TMB-high and MSI-high phenotypes (p < 0.001). All studied samples carrying coding mutations in both CREBBP and EP300 exhibited a TMB-high status. PTVs in functional HAT and bromodomain regions were exclusively associated with TMB-high. Incorporating CREBBP and/or EP300 mutation status improved identification of ultra-hypermutated tumors compared with single-gene biomarkers (p < 0.001). Clinically, these mutations predicted improved overall survival in the pan-cancer cohort (median OS 34 vs. 17 months; HR = 0.68, 95% CI 0.52–0.87, p = 0.0026), as well as in bladder (HR = 0.55, p = 0.0337) and gastrointestinal cancer cohorts (HR = 0.31, p = 0.0021) treated with ICIs. In the gastric cancer validation cohort, all tumors with PTVs demonstrated a partial response to anti-PD-1 therapy. Conclusions: We report CREBBP and EP300 coding mutations as novel potential surrogate biomarkers for hypermutation in gastroesophageal adenocarcinomas and demonstrate their association with favorable immunotherapy outcomes, supporting their potential clinical utility for patient stratification.

Background: Cardiovascular diseases remain a leading cause of death worldwide, yet the prevalence of pathogenic and likely pathogenic genetic variants associated with them is still underassessed in some populations. This study aimed to assess the frequency and geographic distribution of such variants within a representative sample of the Russian population. Additionally, it explored potential links between genotype and phenotype in a cohort of long-lived adults. Methods: We analyzed whole-genome sequencing data from 75,144 adults and 2,872 individuals aged 90 and older. Variants within 37 ACMG v3.1 genes were examined using InterVar, focusing on nonsynonymous variants and indels across exons and splicing sites. Variants were grouped based on ClinVar (as of 24 April 2023) annotations, with most subjected to manual review to confirm their significance. Results: Among the adult participants, 3,817 (5.1%) carried at least one of the variants under consideration. Of these, 141 (0.19%) carried pathogenic, 580 (0.77%) likely pathogenic, and 3,127 (4.16%) variants of uncertain significance. Variants not registered in ClinVar were found in 1,782 individuals (2.37%). Notably, one participant with cardiomyopathy carried a heterozygous TTN variant. In the long-lived cohort, 15 variants were classified as pathogenic or likely pathogenic, alongside 72 uncertain variants; overall, 19 individuals (0.66%) carried pathogenic or likely pathogenic variants. No significant difference was observed in variant frequency between the adult and long-lived groups. Conclusions: This study provided essential insights into the prevalence and geographic distribution of cardiovascular disease-related variants in Russia, laying the foundation for targeted genetic screening disease prevention strategies within this population.

Transplantability of allogeneic mesenchymal stem cells (MSCs) as a stable engraftment and participation in physiological renewal of bone marrow (BM) stroma remains an open question. We hypothesized that a necessary condition for successful MSC transplantation is the prior significant damage to the recipient’s BM stroma. To test this, BM derived from male B10 mice was injected intravenously into syngeneic female mice irradiated with 6.5 Gy and 13 Gy, and unirradiated individuals. We measured donor chimerism 30 days after irradiation in recipients’ bones by RQ-PCR and in BM CFU-Fs by ddPCR. The ratio of PCR signals from single-copy Y chromosome-linked Prssly gene and autosomal Gapdh gene was used to determine donor chimerism. None of the non-irradiated recipients had donor cells in the subpopulation under study. In the group of recipients irradiated at a dose of 6.5 Gy, donor cells were detected at 0.16% in BM of only one animal. Increasing the radiation dose resulted in a significant increase in donor chimerism among BM stromal cells: it was 11% and 14% in two survived animals of this group. Donor chimerism in the bones of unirradiated recipients was not observed in any of the 15 samples. It was detected in only 2/18 bones of recipients irradiated with 6.5 Gy (0.8% and 1%). The median donor chimerism in bones of recipients irradiated with 13 Gy was 15%. We conclude that the condition for successful engraftment of donor stromal progenitor cells is prior damage to the recipient's BM stroma.

Aim. To study the proportion of coronavirus disease 2019 (COVID-19) survivors and hospitalization cases of the Russian population for the period 2020-2022, depending on socio-demographic characteristics.Material and methods. The work was performed on random samples of the population aged 35-74 years from 15 regions participating in the Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation-3 (ESSE-RF3) study. The examination was carried out from February 2020 to March-April 2022 (n=28718, 47% men).Results. According to a survey of sample participants, the proportion of respondents who had COVID-19 by the spring of 2022 among all surveyed was 26,0%. Among 45-54-year-old respondents, this parameter was maximum (28,0%), while among those aged 65-74-year-old — minimal (22,3%). The following categories of people were more likely to have COVID-19: women (27,9 vs 23,9% of men, p<0,001), persons with higher education (30 vs 22,6% persons without higher education, p<0,001), persons with high income (30,0 vs 24,3% low-income, p=0,002), persons with family (26,6 vs 24,8% single, p<0,001), employed persons (28,4 vs 21,7% non-employed, p<0,001), as well as those living in urban areas (26,5 vs 24,5% country people, p=0,003). But those less likely to have COVID-19 (men, people without higher education, low-income, single, unemployed or rural residents) had more severe disease course. The following categories of people had higher hospitalization rates: men (26,0 vs 20,9% women, p<0,001), patients without higher education (27,1 vs 19,6% those with higher education, p<0,001), non-employed (34,3 vs 18,4% workers), p<0,001) and rural residents (27,2 vs 22,0% of city residents, p<0,001). Hospitalization rate was not associated with the level of income and marital status. However, low-income and single people were more likely to require mechanical ventilation.Conclusion. The results obtained by survey reflect the following population data: the proportion of patients after COVID-19, hospitalization rate and the development of severe acute respiratory failure requiring mechanical ventilation among Russians for the period 2020-2022. This can complement the population data demonstrated by state statistics. Special attention from the healthcare system, both during treatment and prevention of COVID-19, requires males, people aged ≥65 years, low-income people, single people (widowers, divorced), unemployed people (pensioners, disabled people, nonemployed), rural residents and people without higher education.

Identifying immunotherapy biomarkers for colorectal cancer (CRC) beyond MSI-high status is challenging. We evaluated CREBBP/EP300 and POLE/POLD1 mutations as candidate markers using public cohorts (MSK-CHORD, n = 5493; TCGA, n = 528; MetTropism, n = 24,496; ICI-treated, n = 1610). Regression with SHAP attribution, survival analyses, and pan-cancer transcriptomic profiling (n = 7628) were performed. CREBBP/EP300 mutations were independently associated with TMB-high MSS tumors (p < 0.00001). The co-mutation group (CREBBP/EP300 + POLE/POLD1; CoMut) was the strongest predictor of elevated TMB level (β = 3.63; p < 10⁻¹⁶; exp(β) = 37.7) with a median TMB of 155.9 vs. 7.4 and 5.4 Mut/Mb in single-mutation groups. CoMut also associated with improved survival (HR = 0.57, p = 0.035). In the ICI-treated cohort, both single-mutation groups (CREBBP/EP300-MUT-only; POLE/POLD1-MUT-only) and showed longer overall survival than wild type (34 and 28 vs. 17 months; p < 0.05), but only CREBBP/EP300 mutations independently reduced mortality risk (HR = 0.71, p = 0.0025). All groups shared immune-inflammatory transcriptomic enrichment. These findings support CREBBP/EP300 mutations as candidate immunotherapy biomarkers, and co-mutations with POLE/POLD1 define a TMB-high MSS subgroup that could refine TMB testing, pending prospective validation.