Biology subjects

Klimina, K. M.

Publications and source records attributed to Klimina, K. M..

4 recordsLinked to original sources

bioRxiv2023

Systemic Metabolic Depletion of Intestine Microbiome Undermines Melanoma Immunotherapy Effectiveness

Immunotherapy has proven to be a boon for patients grappling with metastatic melanoma, significantly enhancing their clinical condition and overall quality of life. A compelling connection was discovered between the composition of the intestinal microbiome and the effectiveness of immunotherapy substantiated in both animal models and human patients. Nonetheless, the precise biological mechanisms through which gut microbes influence melanoma treatment outcomes remain poorly understood. This study conducted a high-resolution metagenomic meta-analysis, employing cutting-edge bioinformatics techniques including genome-resolved metagenomics, strain profiling, comparative genomics, and metabolic reconstruction. According to the obtained results, the systemic metabolic depletion of the gut microbiome causes a lack of response to immunotherapy. Specifically, the presence of bacteria adept at utilizing polysaccharides, as well as those responsible for cobalamin, amino acids, and fatty acids production, decreased in patients who experienced unfavorable treatment outcomes. In contrast, patients who had successful outcomes after immunotherapy exhibited a prevalence of amino acids and cobalamin prototrophs, while autotrophy in these substances characterized the microbiomes of patients with unsuccessful outcomes. The metabolic reconstruction of short-chain fatty acid biosynthesis pathways did not differentiate bacteria linked to treatment outcomes based on their ability to produce acetate, butyrate, or propionate. However, the cobalamin-dependent Wood-Ljungdahl pathway of acetate synthesis was directly associated with immunotherapy effectiveness.

bioinformatics↗

bioRxiv2023

Unlocking DNA Damage Sensitivity of Cancer Cells: The Potential of Splicing Inhibitors

Despite the growing interest in pre-mRNA alternative splicing (AS) as a therapeutic anticancer target, the potential of splicing inhibitors in treating solid tumors remains largely unexplored. We conducted a meta-analysis of transcriptome data from six different tumor types and revealed that splicing inhibitors induced similar patterns of AS, resulting in widespread exon-skipping and intron retention events that often lead to nonsense-mediated decay of the transcripts. Interestingly, in many cases exon skipping is induced by a compensatory cellular response to splicing inhibitor treatment. It involves an upregulation of multiple splicing factors and incomplete recognition of branch points by U2 snRNP. These post transcriptional changes downregulate one-third of essential DNA repair genes, thereby creating a therapeutic vulnerability that can be exploited for cancer treatment. To harness this vulnerability, we proposed a new approach to cancer treatment consisting of sequential addition of a splicing inhibitors followed by a DNA-damaging agent. Our in vitro and in vivo experiments demonstrated that this strategy exhibits promising therapeutic potential for a wide range of tumors.

cancer biology↗

bioRxiv2021

Analysis of the upper respiratory tract microbiota in mild and severe COVID-19 patients

The microbiota of the respiratory tract remains a relatively poorly studied subject. At the same time, like the intestinal microbiota, it is involved in modulating the immune response to infectious agents in the host organism. A causal relationship between the composition of the respiratory microbiota and the likelihood of development and the severity of COVID-19 may be hypothesized. We analyze biomaterial from nasopharyngeal smears from 336 patients with a confirmed diagnosis of COVID-19, selected during the first and second waves of the epidemic in Russia. Sequences from a similar study conducted in Spain were also included in the analysis. We investigated associations between disease severity and microbiota at the level of microbial community (community types) and individual microbes (differentially represented species). To search for associations, we performed multivariate analysis, taking into account comorbidities, type of community and lineage of the virus. We found that two out of six community types are associated with a more severe course of the disease, and one of the community types is characterized by high stability (very similar microbiota profiles in different patients) and low level of lung damage. Differential abundance analysis with respect to comorbidities and community type suggested association of Rothia and Streptococcus genera representatives with more severe lung damage, and Leptotrichia, unclassified Lachnospiraceae and Prevotella with milder forms of the disease.

molecular biology↗

bioRxiv2019

Long-term impact of fecal transplantation in healthy volunteers

BackgroundFecal microbiota transplantation (FMT) is now approved for the treatment of refractory recurrent clostridial colitis, but a number of studies are ongoing in inflammatory bowel diseases, i.e., Crohns disease, nonspecific ulcerative colitis, and in other autoimmune conditions. In most cases, the effects of FMT are evaluated on patients with initially altered microbiota. The aim of the present study was to evaluate effects of FMT on the gut microbiota composition in healthy volunteers and to track long-term changes.\n\nResultsWe have performed a combined analysis of three healthy volunteers before and after FMT with frozen capsules, followed by evaluation of their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene sequencing (16S seq) and shotgun sequencing (or whole-genome sequencing - WGS). The data analysis demonstrated the profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria, and persistence of this effect for almost ~1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events and systemic inflammatory response in one volunteer.\n\nConclusionsThe FMT procedure leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition, being relatively safe to the recipients without long-term adverse events.

microbiology↗