Acta Naturae最新文献

A patient with an immunophenotype characteristic of B-cell acute lymphoblastic leukemia (B-ALL) was found to carry the chromosomal translocation t(9;22)(q34;q11), or Philadelphia (Ph) chromosome and less common variant of the chimeric oncogene BCR::ABL/p210. No additional mutations in the BCR::ABL gene, including point mutations, insertions, or deletions, were identified in the disease onset characterized by elevated blast cell (77.6%) and leukocyte (48×109/L) counts. Ph+ALL-2012m chemotherapy with imatinib (600 mg) and two consolidation phases resulted in complete hematologic remission and a profound molecular response. However, six months later, the patient had relapsed (blasts: 15%, BCR::ABL/p210: 105%). Three weeks after the initiation of dasatinib therapy (100 mg), the number of blasts had decreased to 4.8%, while the expression level of BCR::ABL/p210 had dropped to 11.8%. Sanger sequencing identified two mutations in the BCR::ABL oncogene; namely, the point mutation F317L and a new insertion of nine nucleotides previously not detected. In the latter case, the amino acid lysine at position 294 was replaced by four new amino acid residues: K294SPSQ. Therapy with bosutinib and inotuzumab led to the disappearance of one leukemia clone with the F317L mutation, but the presence of another clone carrying a nine-nucleotide insertion was observed. The switch to ponatinib+blinatumomab chemotherapy was effective, resulting in the disappearance of the insertion. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an available HLA-matched unrelated donor resulted in complete clinical and hematologic remission, including a complete molecular response. Six months after allo-HSCT, minimal residual disease monitoring showed maintenance of complete remission.

Long non-coding RNAs (lncRNAs) play a crucial role in the epigenetic regulation of gene expression by recruiting chromatin-modifying proteins to specific genomic loci. Two databases, previously developed by our groups, HiMoRNA and RNA-Chrom, provide valuable insights into this process. The former contains data on epigenetic modification regions (peaks) correlated with lncRNA expression, while the latter offers genome-wide RNA-chromatin interaction data for tens of thousands of RNAs. This study integrated the two resources to generate experimentally supported, interpretable hypotheses regarding lncRNA-mediated epigenetic gene expression regulation. We adapted the web interfaces of HiMoRNA and RNA-Chrom to enable the retrieval of chromatin contacts for each "lncRNA-pigenetic modification-ssociated gene" triad from HiMoRNA, either at specific genomic loci or genome-wide via RNA-Chrom. The integration analysis revealed that for the lncRNAs MALAT1, HOXC-AS2, NEAT1, NR2F1-AS1, PVT1, and MEG3, most HiMoRNA peaks are located within 25 kb of their RNA-Chrom contacts. Further investigation confirmed the RNA-hromatin contacts of MIR31HG and PVT1 lncRNAs, with HiMoRNA peaks for H3K27ac and H3K27me3 marks in the loci of the genes GLI2 and LATS2, respectively, which are known to be regulated by these RNAs. Thus, the integration of HiMoRNA and RNA-Chrom offers a powerful platform to elucidate the role of specific lncRNAs in the regulation of histone modifications at both individual loci and genome-wide levels. We expect this integration to help significantly advance the functional annotation of human lncRNAs.

Recent advances in assisted reproductive technologies (ART) have revolutionized human reproduction, offering hope to millions of couples facing infertility issues. At the same time, concerns persist regarding the potential impact of ART on the genomic integrity of offspring conceived through these techniques. Specifically, questions abound about the effects of these techniques on the incidence of de novo mutations (DNMs), which are genetic alterations that arise spontaneously in the germline or during early embryonic development and are implicated in various human diseases. The extent to which ART directly affects the rate of de novo mutations has been the subject of ongoing debate. This review explores recent studies that have investigated the relationship between ART and DNMs. It underscores the necessity for further research to clarify the clinical implications and long-term consequences of ART.

A plant's defense response involves the accumulation of flavonoids, whose biosynthetic pathway in garlic Allium sativum L. remains not characterized. In this work, we identified eight AsCHS1-8 genes of chalcone synthases in the A. sativum genome which presumably catalyze the first stage of flavonoid synthesis in garlic plants. These genes were found to be localized on 4 chromosomes: AsCHS2, 6-8 contain 1 to 2 introns, whereas AsCHS1, 3-5 are intronless. The analysis of the organ-specific gene expression profiles revealed significant transcript levels for AsCHS3 and 8. Only AsCHS8 was shown to change its expression level in response to abiotic stressors (salinity, drought, cold) and exogenous phytohormones (abscisic acid, methyl jasmonate). These findings suggest that two out of the eight genes, AsCHS3 and 8, control flavonoid synthesis during garlic development, with AsCHS8 being the most active chalcone synthase gene. The other six genes (AsCHS1, 2, 4-7) may be involved in flavonoid biosynthesis in highly specialized cells/tissues/organs or the developmental stages of the garlic plant. Our results on the identification and characterization of garlic chalcone synthase genes AsCHS1-8 may facilitate further analysis of the mechanisms that regulate stress adaptation in A. sativum and other Allium species. A plant's defense response involves the accumulation of flavonoids, whose biosynthetic pathway in garlic Allium sativum L. remains not characterized. In this work, we identified eight AsCHS1-8 genes of chalcone synthases in the A. sativum genome which presumably catalyze the first stage of flavonoid synthesis in garlic plants. These genes were found to be localized on 4 chromosomes: AsCHS2, 6-8 contain 1 to 2 introns, whereas AsCHS1, 3-5 are intronless. The analysis of the organ-specific gene expression profiles revealed significant transcript levels for AsCHS3 and 8. Only AsCHS8 was shown to change its expression level in response to abiotic stressors (salinity, drought, cold) and exogenous phytohormones (abscisic acid, methyl jasmonate). These findings suggest that two out of the eight genes, AsCHS3 and 8, control flavonoid synthesis during garlic development, with AsCHS8 being the most active chalcone synthase gene. The other six genes (AsCHS1, 2, 4-7) may be involved in flavonoid biosynthesis in highly specialized cells/tissues/organs or the developmental stages of the garlic plant. Our results on the identification and characterization of garlic chalcone synthase genes AsCHS1-8 may facilitate further analysis of the mechanisms that regulate stress adaptation in A. sativum and other Allium species.

Tumor-infiltrating T lymphocytes (TILs) are a population of T cells present in tumor tissue and enriched in tumor antigen-specific clones. TILs participate in the adaptive antitumor immune response, which makes them a promising candidate for cancer immunotherapy. The concept framing this type of therapy involves the extraction of T cells from a patient's tumor, followed by their in vitro expansion and reinfusion into the same patient in large quantities. This approach enhances the antitumor immune response and allows one to affect cancer cells resistant to other types of treatment. In 2024, the first TIL-based drug was approved for melanoma treatment. The possibility of using TILs for treating other solid tumors is currently being considered, and novel methods aiming to increase the efficiency of generating TIL cultures from tumor tissues in vitro are being developed. However, despite the significant progress achieved in this area, there remain unresolved issues and problems, including the lack of standardized protocols for obtaining, expanding, and cryopreserving TILs, the complexity related to their isolation and the duration of that, as well as insufficient efficiency. Our review focuses on the concept of immunotherapy using TILs, the main stages involved in generating a TIL-based cellular product, associated problems, and further steps in the production of TIL cultures that aim to improve efficiency as relates to production and ensure a wider application of the therapy.

In our previous studies, we demonstrated that the Drosophila zinc finger protein Aef1 interacts with the SAGA DUB module. The Aef1 binding sites colocalize with the SAGA histone acetyltransferase complex and the dSWI/SNF chromatin remodeling complex, as well as the origin recognition complex (ORC). Aef1 predominantly localizes with the promoters of active genes (55% of all sites) and can be involved in transcriptional regulation. In this study, we showed that Aef1 binding sites in Drosophila S2 cells, located outside gene promoters, are nucleosome-depleted regions and colocalize with the SAGA, dSWI/SNF, and ORC complexes. Aef1 binding sites colocalize with the CBP protein and the H3K27Ac histone tag, which is considered to be an active enhancer mark. An RNA-Seq experiment was conducted in Drosophila S2 cells, both normal and with RNA interference targeting the Aef1 protein, to study the role played by the Aef1 protein in transcriptional regulation. The Aef1 protein was shown to affect the transcription of 342 genes, more than half of those (178 genes) containing Aef1 at their promoters or enhancers. Hence, we infer that the Aef1 protein is recruited to both promoters and enhancers and is involved, both directly and indirectly, in the regulation of the transcription of the respective genes.

Skin cancers such as squamous cell carcinoma (SCC) are among the most aggressive types of tumors. They come with a high rate of growth, metastasis, and frequently occurring chemoresistance. Smoking is one of the risk factors for SCC progression, and the α7 nicotinic acetylcholine receptor (α7-nAChR) is a promising target for SCC therapy. Human secreted protein SLURP-1 is an auto/paracrine regulator of epithelial homeostasis and a selective negative allosteric modulator of α7-nAChR. Recently, we demonstrated the high efficiency of the therapy based on the recombinant SLURP-1 in controlling SCC cell growth and metastasis in vivo. The anti-tumor effect of SLURP-1 was mediated through interaction with both α7-nAChR and the epidermal growth factor receptor (EGFR). Cytotoxic antibiotic doxorubicin has been proposed for the SCC therapy; however, its use is limited due to the high toxicity. In this study we investigated the use of an enhanced SLURP-1 dose and of a combination of SLURP-1 with low-dozen doxorubicin for SCC treatment of mice xenografted with squamous cell carcinoma A431 cells. An increased SLURP-1 dose didn't significantly enhance the efficiency of the therapy. However, the combination with doxorubicin further enhanced the anti- tumor activity of SLURP-1 and dramatically suppressed metastasis. The effect from the combined therapy was accompanied by down-regulation of EGFR expression in tumors. Direct inhibition of EGFR activation by SLURP-1 was shown. No toxicity of the combined therapy was encountered. Our data indicate that the combination of SLURP-1 with chemotherapy in lower doses is a promising approach in SCC treatment and should be further studied.

Proprotein convertases (PCs) constitute an enzyme family that includes nine highly specific human subtilisin-like serine proteases. It is known that the PCs mRNA levels vary in tumors, and that these proteases are involved in carcinogenesis. Thus, PCs may be considered as potential markers for typing and predicting the course of the disease, as well as potential targets for therapy. We used quantitative real-time PCR to evaluate the expression levels of PC genes in the paired samples of tumor and adjacent normal tissues derived from 19 patients with esophageal squamous cell carcinomas. We observed a significant enrichment of PCSK6, PCSK9, MBTPS1, and FURIN mRNAs in the tumor tissue, which may be indication of the involvement of these PCs in the development and progression of esophageal cancers. Additionally, cluster analysis of PC expression alteration patterns in tumor compared to normal adjacent tissues (esophageal and previously analyzed lung tissue samples) revealed a limited set of scenarios for the changes in PC expression. These scenarios are implemented during malignant transformation of lung and esophagus cells, as well as, probably, the cells of other organs. These findings indicate that PC genes may be important markers of human cancers.

Oxidative stress accompanies many pathologies that are characterized by neuronal degradation leading to a deterioration of the disease. The main causes are the disruption of protein homeostasis and activation of irreversible processes of cell cycle disruption and deterioration of cellular physiology, leading to senescence. In this paper, we propose a new approach to combating senescence caused by oxidative stress. This approach is based on the use of a low-molecular inducer of chaperone synthesis, one of the cell protective systems regulating proteostasis and apoptosis. We present data demonstrating the ability of the pyrrolylazine derivative PQ-29 to induce chaperone accumulation in human neuronal cells and prevent oxidative stress-induced aging.

Most clinical studies confirm the negative impact diabetes mellitus (DM) has on the course and outcome of cardiovascular complications caused by a myocardial ischemia-reperfusion injury (IRI). In this regard, the search for new approaches to IRI treatment in diabetic myocardium is of undeniable value. The aim of this work was to study the effect of galanin (G) on the size of myocardial infarct (MI), on mitochondrial functions, and on the energy state in the area at risk (AAR) in rats with type 1 diabetes mellitus (DM1) subjected to regional myocardial ischemia and reperfusion. Rat G was obtained by solid-phase synthesis using the Fmoc strategy and purified by HPLC. DM1 was induced by streptozotocin administration. Myocardial IRI was modeled by occlusion of the left anterior descending coronary artery and subsequent reperfusion. G at a dose of 1 mg/kg was administered intravenously before reperfusion. G decreased MI size and plasma creatine kinase MB (CK-MB) activity in DM rats by 40 and 28%, respectively. G injection improved mitochondrial respiration in saponin-skinned fibers in the AAR: namely, the maximal ADP-stimulated state 3, respiratory control, and the functional relationship between the mitochondrial CK-MB and oxidative phosphorylation. G provided significantly higher ATP levels, total adenine nucleotide pool, and adenylate energy charge of cardiomyocytes. It also reduced total creatine loss in myocardial AAR in DM rats. The results suggest there is a possibility of therapeutic use of G in myocardial IRI complicated by DM1.