Prior antibiotic administration disrupts outcomes of PD-1 blockade in advanced gastric cancer by altering gut microbiome and systemic immune response
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229379 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:Prior antibiotic administration disrupts outcomes of PD-1 blockade in advanced gastric cancer by altering gut microbiome and systemic immune response
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Project description:Differential responses to immune checkpoint inhibitors (ICI) may be attributed to tumor-intrinsic factors or environmental cues; however, these mechanisms cannot fully explain the variable ICI responses in different individuals. Here, we investigate the potential contribution of immunological heterogeneity with a focus on differences in T-cell receptor (TCR) repertoire to ICI responses, which has not been defined previously.
2022-10-10 | GSE214348 | GEO
Project description:ObjectiveAntibiotics have been a mainstay of chronic rhinosinusitis therapy; however, data suggest that antibiotics may also result in several adverse unintended consequences. We aimed to evaluate if greater antibiotic use prior to sinus surgery was associated with differences in surgical outcomes.MethodsAdult CRS patients enrolled in a prospective, multi-institutional, observational cohort study were asked to recall systemic antibiotic use in the 90 days prior to endoscopic sinus surgery (ESS). Antibiotic use was examined in relation to demographics, disease characteristics, and outcomes.ResultsData were collected for 271 study participants followed for a mean of 14.9 [± 5.1] months across four institutions, with a mean preoperative antibiotic use of 27.8 [± 22.7] days out of the 90 preceding ESS. After ESS, significant improvement (P < 0.001) was reported for patient-reported outcome measures and endoscopy scores for the overall cohort. No bivariate correlation between preoperative antibiotic use and degree of benefit in objective clinical measures (endoscopy, Brief Smell Identification Test) was seen. Increased preoperative antibiotic use was associated with less improvement in 22-item SinoNasal Outcome Test (SNOT-22) and its rhinologic subdomain after ESS. Prevalence of achieving a minimal clinically important difference in overall SNOT-22 symptom scores was lower in those using more preoperative antibiotics, although statistical significance was not reached when adjusting for independent covariates in multivariate modeling.ConclusionHigher amounts of previous antibiotic use do not appear to be associated with better ESS outcomes. Specific recommendations for antibiotic use as part of CRS-appropriate medical therapy prior to ESS require further study, particularly given concerns for antibiotic overuse and implications for improving outcomes in the modern healthcare era.Level of evidence2C Laryngoscope, 129:558-566, 2019.
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Project description:The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat. These adverse events are a considerable clinical problem and the mechanisms underlying them are multifactorial and poorly understood. Growing evidence suggests that the gut microbiota has a key role in energy regulation and disease states such as obesity. Moreover, we recently showed that chronic olanzapine altered the composition of the gut microbiome in the rat. It is thus possible that treatments that alter gut microbiota composition could ameliorate olanzapine-induced weight gain and associated metabolic syndrome. To this end, we investigated the impact of antibiotic-induced alteration of the gut microbiota on the metabolic effects associated with chronic olanzapine treatment in female rats. Animals received vehicle or olanzapine (2 mg kg(-1) per day) for 21 days, intraperitoneal injection, two times daily. Animals were also coadministered vehicle or an antibiotic cocktail consisting of neomycin (250 mg kg(-1) per day), metronidazole (50 mg kg(-1) per day) and polymyxin B (9 mg kg(-1) per day) by oral gavage, daily, beginning 5 days before olanzapine treatment. The antibiotic cocktail drastically altered the microbiota of olanzapine-treated rats, and olanzapine alone was also associated with an altered microbiota. Coadministration of the antibiotic cocktail in olanzapine-treated rats attenuated: body weight gain, uterine fat deposition, macrophage infiltration of adipose tissue, plasma free fatty acid levels, all of which were increased by olanzapine alone. These results suggest that the gut microbiome has a role in the cycle of metabolic dysfunction associated with olanzapine, and could represent a novel therapeutic target for preventing antipsychotic-induced metabolic disease.
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Project description:Early gastric cancers (EGC) precede advanced gastric cancers (AGC) with a favorable clinical outcome compared to advanced gastric cancers (AGC). To understand the progression mechanisms of EGC to AGC, it is required to disclose the EGC and AGC genomes in terms of the the mutational and evolutionary perspectives. In this study, we performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (5 EGC and 4 AGC) and eight MS-stable (MSS) gastric cancers (4 EGC and 4 AGC). Unexpectedly, we observed no substantial differences in the number, sequence composition and functional consequences (potential driver mutations and affected pathways) of the mutations and CNAs between EGC and AGC genomes in both MSI-H and MSS cases.
2014-06-30 | GSE57176 | GEO
Project description:mtDNA mutagenesis in somatic stem cells leads to their dysfunction and to progeria in mouse. The mechanism was proposed to involve modification of reactive oxygen species (ROS)/redox signaling. We studied the effect of mtDNA mutagenesis on reprogramming and stemness of pluripotent stem cells (PSCs) and show that PSCs select against specific mtDNA mutations, mimicking germline and promoting mtDNA integrity despite their glycolytic metabolism. Furthermore, mtDNA mutagenesis is associated with an increase in mitochondrial H2O2, reduced PSC reprogramming efficiency, and self-renewal. Mitochondria-targeted ubiquinone, MitoQ, and N-acetyl-L-cysteine efficiently rescued these defects, indicating that both reprogramming efficiency and stemness are modified by mitochondrial ROS. The redox sensitivity, however, rendered PSCs and especially neural stem cells sensitive to MitoQ toxicity. Our results imply that stem cell compartment warrants special attention when the safety of new antioxidants is assessed and point to an essential role for mitochondrial redox signaling in maintaining normal stem cell function.
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Project description:Previous studies have suggested that a relationship exists between severity and transmissibility of malaria and variations in the gut microbiome, yet only limited information exists on the temporal dynamics of the gut microbial community during a malarial infection. Here, using a rhesus macaque model of relapsing malaria, we investigate how malaria affects the gut microbiome. In this study, we performed 16S sequencing on DNA isolated from rectal swabs of rhesus macaques over the course of an experimental malarial infection with Plasmodium cynomolgi and analyzed gut bacterial taxa abundance across primary and relapsing infections. We also performed metabolomics on blood plasma from the animals at the same timepoints and investigated changes in metabolic pathways over time. Members of Proteobacteria (family Helicobacteraceae) increased dramatically in relative abundance in the animal's gut microbiome during peak infection while Firmicutes (family Lactobacillaceae and Ruminococcaceae), Bacteroidetes (family Prevotellaceae) and Spirochaetes amongst others decreased compared to baseline levels. Alpha diversity metrics indicated decreased microbiome diversity at the peak of parasitemia, followed by restoration of diversity post-treatment. Comparison with healthy subjects suggested that the rectal microbiome during acute malaria is enriched with commensal bacteria typically found in the healthy animal's mucosa. Significant changes in the tryptophan-kynurenine immunomodulatory pathway were detected at peak infection with P. cynomolgi, a finding that has been described previously in the context of P. vivax infections in humans. During relapses, which have been shown to be associated with less inflammation and clinical severity, we observed minimal disruption to the gut microbiome, despite parasites being present. Altogether, these data suggest that the metabolic shift occurring during acute infection is associated with a concomitant shift in the gut microbiome, which is reversed post-treatment.
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