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Ondřej Fiala,1,2 Pavel Ostašov,3 Aneta Rozsypalová,4 Milan Hora,5 Ondřej Šorejs,1,2 Jan Šustr,1 Barbora Bendová,5 Ivan Trávníček,5 Jan Filipovský,6 Jindřich Fínek,1 Tomáš Büchler4 1Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 2Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech, Czech Republic; 3Laboratory of Tumor Biology and Immunotherapy, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech, Czech Republic; 4Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic; 5Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 6 2nd Department of Internal Medicine, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech RepublicCorrespondence: Ondřej FialaDepartment of Oncology and Radiotherapy, Faculty of Medicine and University Hospital Pilsen, Charles University Prague, Alej Svobody 80, Pilsen, CZ-304 60, Czech RepublicTel +42 0728655488Email fialao@fnplzen.czBackground: The anticancer properties of metformin have been suggested in numerous experimental studies and several retrospective clinical studies show that its use is associated with improved outcome of patients with cancer. However, limited data are available for patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. The aim of this retrospective study was to assess the impact of the metformin use on survival of mRCC patients treated with sunitinib or pazopanib.Methods: Clinical data from 343 patients with mRCC treated with sunitinib or pazopanib in the first line were analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of metformin.Results: The median PFS and OS for patients using metformin was 31.1 (95% CI 20.6– 35.1) and 51.6 (95% CI 44.7-NR) months compared to 9.3 (95% CI 8.0– 12.0) and 22.4 (95% CI 19.4– 26.8) months for patients not using metformin (p< 0.0001 and p=0.0002, respectively). Cox multivariate analysis shows that the use of metformin remains a significant factor for PFS (HR=0.55 [95% CI 0.343– 0.883], p=0.013) and also for OS (HR=0.45 [95% CI 0.256– 0.794], p=0.006).Conclusion: The present study results suggest that the use of metformin was associated with favorable outcome of mRCC patients treated with sunitinib or pazopanib.Keywords: renal cell carcinoma, metformin, sunitinib, pazopanib, tyrosine kinase inhibitors, outcome

Microbiome research has gained much attention in recent years as the importance of gut microbiota in regulating host health becomes increasingly evident. However, the impact of radiation on the microbiota in the murine bone marrow transplantation model is still poorly understood. In this paper, we present key findings from our study on how radiation, followed by bone marrow transplantation with or without T cell depletion, impacts the microbiota in the ileum and caecum. Our findings show that radiation has different effects on the microbiota of the two intestinal regions, with the caecum showing increased interindividual variation, suggesting an impaired ability of the host to regulate microbial symbionts, consistent with the Anna Karenina principle. Additionally, we observed changes in the ileum composition, including an increase in bacterial taxa that are important modulators of host health, such as Akkermansia and Faecalibaculum . In contrast, radiation in the caecum was associated with an increased abundance of several common commensal taxa in the gut, including Lachnospiraceae and Bacteroides . Finally, we found that high doses of radiation had more substantial effects on the caecal microbiota of the T-cell-depleted group than that of the non-T-cell-depleted group. Overall, our results contribute to a better understanding of the complex relationship between radiation and the gut microbiota in the context of bone marrow transplantation and highlight the importance of considering different intestinal regions when studying microbiome responses to environmental stressors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kreisinger, Dooley, Singh, Čížková, Schmiedová, Bendová, Liston and Moudra.)

The gut microbiota of vertebrates is acquired from the environment and other individuals, including parents and unrelated conspecifics. In the laboratory mouse, a key animal model, inter-individual interactions are severely limited and its gut microbiota is abnormal. Surprisingly, our understanding of how inter-individual transmission impacts house mouse gut microbiota is solely derived from laboratory experiments. We investigated the effects of inter-individual transmission on gut microbiota in two subspecies of house mice (Mus musculus musculus and M. m. domesticus) raised in a semi-natural environment without social or mating restrictions. We assessed the correlation between microbiota composition (16S rRNA profiles), social contact intensity (microtransponder-based social networks), and mouse relatedness (microsatellite-based pedigrees). Inter-individual transmission had a greater impact on the lower gut (colon and cecum) than on the small intestine (ileum). In the lower gut, relatedness and social contact independently influenced microbiota similarity. Despite female-biased parental care, both parents exerted a similar influence on their offspring's microbiota, diminishing with the offspring's age in adulthood. Inter-individual transmission was more pronounced in M. m. domesticus, a subspecies, with a social and reproductive network divided into more closed modules. This suggests that the transmission magnitude depends on the social and genetic structure of the studied population., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

The gastrointestinal microbiota (GM) is considered an important component of the vertebrate holobiont. GM-host interactions influence the fitness of holobionts and are, therefore, an integral part of evolution. The house mouse is a prominent model for GM-host interactions, and evidence suggests a role for GM in mouse speciation. However, previous studies based on short 16S rRNA GM profiles of wild house mouse subspecies failed to detect GM divergence, which is a prerequisite for the inclusion of GM in Dobzhansky-Muller incompatibilities. Here, we used standard 16S rRNA GM profiling in two mouse subspecies, Mus musculus musculus and M. m. domesticus, including the intestinal mucosa and content of three gut sections (ileum, caecum, and colon). We reduced environmental variability by sampling GM in the offspring of wild mice bred under seminatural conditions. Although the breeding conditions allowed a contact between the subspecies, we found a clear differentiation of GM between them, in all three gut sections. Differentiation was mainly driven by several Helicobacters and two H. ganmani variants showed a signal of codivergence with their hosts. Helicobacters represent promising candidates for studying GM-host coadaptations and the fitness effects of their interactions., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Background: Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear., Objective: Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC., Methods: The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors., Results: The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001)., Conclusions: The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The vertebrate gastrointestinal tract is colonised by microbiota that have a major effect on the host's health, physiology and phenotype. Once introduced into captivity, however, the gut microbial composition of free-living individuals can change dramatically. At present, little is known about gut microbial changes associated with adaptation to a synanthropic lifestyle in commensal species, compared with their non-commensal counterparts. Here, we compare the taxonomic composition and diversity of bacterial and fungal communities across three gut sections in synanthropic house mouse (Mus musculus) and a closely related non-synanthropic mound-building mouse (Mus spicilegus)., Results: Using Illumina sequencing of bacterial 16S rRNA amplicons, we found higher bacterial diversity in M. spicilegus and detected 11 bacterial operational taxonomic units with significantly different proportions. Notably, abundance of Oscillospira, which is typically higher in lean or outdoor pasturing animals, was more abundant in non-commensal M. spicilegus. ITS2-based barcoding revealed low diversity and high uniformity of gut fungi in both species, with the genus Kazachstania clearly dominant., Conclusions: Though differences in gut bacteria observed in the two species can be associated with their close association with humans, changes due to a move from commensalism to captivity would appear to have caused larger shifts in microbiota.