Eugenia Boulygina

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.

The aim of this study was to assess the genetic diversity of peach (Prunus persica (L.)) cultivars in the Nikitsky Botanical Garden collection using ddRAD-seq technology to establish molecular genetic passports and analyze the relationship between genetic structure and phenotypic traits. Leaves from 56 peach cultivars of different origin were used. DNA was isolated using the CTAB buffer method, libraries for sequencing were prepared using MspI and PstI restriction enzymes, and sequencing was performed on an Illumina NovaSeq6000 platform. Data processing included alignment to the P. persica reference genome and SNP filtering using the Stacks2, bowtie2, and R software packages. UPGMA, PCA, and DAPC methods were used to assess genetic relationships. Several thousand SNPs were obtained, allowing us to identify 14 genetic clusters reflecting the high intraspecific diversity of the collection. The genetic structure partially correlated with fruit ripening time, with a pronounced distinction between early- and late-ripening varieties. Forty informative SNP markers, localized primarily on chromosomes 1, 4, and 8, were identified, sufficient to identify all studied genotypes. The ddRAD sequencing method has proven effective for mass genotyping of peach varieties. The obtained results provide the basis for developing a SNP panel suitable for cultivar certification, varietal purity monitoring, and optimization of breeding programs.

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.

Understanding the transcriptional responses of plants under cold stress conditions is critical for olive cultivation, particularly in regions prone to extreme weather fluctuations and especially with increasing threats from climate change. In controlled experiments, we subjected leaves of three cold-tolerant and three cold-susceptible cultivars to moderate (−7 °C) and severe (−12 °C) freezing stress, followed by recovery at baseline temperatures. The study measured photosynthetic efficiency and enzymatic activity and showed physiological and gene expression changes using different methods. Distinct transcriptomic adaptations were revealed. Cultivars displayed enhanced differential expression associated with photosynthetic recovery and gene regulation in metabolic pathways. Two overlapping DEGs with increased expression were found in all cultivars during initial freezing.

High-grade B-cell lymphoma (HGBL), not otherwise specified (NOS), is a rare entity within the spectrum of B-cell lymphomas. HGBL, NOS remains a diagnosis of exclusion with limited data available on the optimal clinical approach. We report a case of a 67-year-old man with HGBL, NOS with a germinal center B-cell (GCB) immunophenotype. The disease was characterized by an aggressive clinical course, refractory to multiple lines of cytotoxic chemotherapy, immunotargeted treatment, therapy with a PD-1 inhibitor, and haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Ultimately, the disease progression led to the patient’s death nine months post-diagnosis. A FISH assay identified a sole genetic rearrangement: BCL2/IGH. Whole-exome sequencing revealed a number of significant somatic mutations, such as TP53 p.C238G, B2M p.L12R, STAT6 p.D419G, STAT3 p.S614R, TREX1 p.T49fs, and CREBBP p.C367Ter, as well as a high focal amplification of the MUC3A gene and the deletion of the short arm of chromosome 17 (del(17p)). An inactivating somatic mutation in the TREX1 gene (p.T49fs) has not been previously described in patients with non-Hodgkin lymphomas. Additionally, our analysis uncovered a key cancer hallmark: tumor genomic instability, manifested as a high tumor mutational burden, which likely contributed to the aggressive disease course.

This paper reports on a proto-Maeotian burial complex of a horseman warrior discovered in 2023 in the foothills of Adygea (N 44.22787800, E 40.12983900). The burial assemblage included weaponry, notably an axe-scepter, a Colchian fibula, an equine skeleton, and a set of bronze horse bridles contemporary with the Novocherkassk treasure. Based on these findings, the authors date the burial to the late 8th century BC. Comprehensive analyses, including natural science methods, were conducted on the burial. Anthropological examination determined the interred individual to be a male over 55 years of age who had sustained a cranial injury during his lifetime, potentially in military engagements. The authors propose that this elderly proto-Maeot horseman warrior may have participated in the “Cimmerian campaigns” in the Transcaucasia and Western Asia. Strontium isotope analysis of human and equine tooth enamel samples did not corroborate their habitation in the immediate vicinity of the burial site, nor did it indicate an origin in Western Transcaucasia. The unusual proportions of the horse skeletal remains prompted an investigation into a potential hybrid origin for the animal. However, detailed morphometric and molecular genetic analyses did not confirm the presence of a mule or hinny. Establishing definitive evidence for a specific local horse breed in the Early Iron Age of the North Caucasus necessitates dedicated genomic research.

Background: Cerebral cavernous malformations (CCMs) are vascular lesions linked to mutations in the CCM1, CCM2, and CCM3 genes, resulting in angiogenesis dysregulation. This case study highlights the clinical course of a child with severe CCMs and explores the genetic basis of the condition. Methods: We used comprehensive clinical assessment and magnetic resonance imaging (MRI) to monitor the patient’s neurological status and CCM progression and genetic analysis by whole-exome sequencing to identify mutations in CCM-related genes. Results: The patient presented with developmental delays, multiple CCMs, and recurrent hemorrhagic events, requiring five surgical interventions. Genetic analysis revealed a novel frameshift mutation in the PDCD10 gene. Despite surgical efforts, the patient developed significant disability by age 13. Conclusions: This case illustrates the aggressive clinical course associated with CCMs, particularly in patients with CCM3 mutations. It underscores the importance of genetic screening and monitoring in understanding hereditary CCM progression and guiding treatment strategies.

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.

More than ten species of the Actinidia Lindl. genus bear edible fruits rich in biologically active compounds, which are essential and beneficial for human health. The most popular cultivars today are the large-fruited Actinidia species, A. deliciosa and A. chinensis, commonly known as kiwi. However, small-fruited kiwi cultivars are gaining prominence due to their high nutritional value, superior cold resistance, and suitability for temperate climates. In Russia, these are represented by Far Eastern species: A. arguta, A. kolomikta, and A. polygama. Despite increasing consumer interest, Russian Actinidia cultivars remain little studied, with fragmented genetic data available for breeding purposes. Our objective was to analyze the Actinidia collection at the Federal Horticultural Center for Breeding, Agrotechnology, and Nursery and the N.V. Tsitsin Main Botanical Garden (MBG RAS, Moscow), which includes samples from four species, A. kolomikta, A. arguta, A. polygama, A. purpurea, interspecific hybrids, and derived varieties, using RAD sequencing. We assessed the genetic variability of all species, identified population groups within A. kolomikta and A. arguta based on origin, determined ploidy levels across the collection, and identified a set of SNP markers associated with valuable agronomic traits.