Biology subjects

Evans, R. J.

Publications and source records attributed to Evans, R. J..

3 recordsLinked to original sources

bioRxiv2023

Effect of Nivolumab therapy on Metastatic Lung Cancer in Human Microbiome

Nivolumab, a type of immunotherapy, has enhanced the 5-year survival of patients with renal cell cancer, melanoma, and lung cancer which is now mechanistically understood. However, relatively sparse information assesses its relationship with shaping the gut microbiome. We aimed to assess the degree to which nivolumab treatment contributes to alterations in the species composition of the colon in lung cancer patients undergoing nivolumab treatment. Our pilot study utilized stool samples of five lung cancer patients at Inland Hematology Oncology (IHO) before administration of nivolumab and three months after initiation of treatment. 16S and ITS rRNA sequence analysis were used to assess alterations in species abundance and richness of the colon. After sequencing, statistical analysis, specifically a paired t-test, was performed to assess if any significant differences in any microbial species were observed before and after immunotherapy treatment. Although different proportions of microorganisms existed at baseline prior to treatment for each patient, a significant reduction in the Megasphaera elsdenii population was observed (p=.0488; n=4), when comparing before and after treatment. Our findings differ from that of Huang et. al (2022), who has recently posited that a positive association exists between Megasphaera elsdenii and the survival of patients with pancreatic ductal adenocarcinomas. Our conclusions suggest that different cancers may elicit differential effects on Megasphaera elsdenii in the gut microbiome. ImportanceNivolumab is a relatively new form of cancer therapy called immunotherapy, which enables the body to use its own immune system to effectively fight cancer. Due to advances in microbial sequencing in 16S rRNA, this project explores differences in the abundance of microbial communities before and three months of treatment in patients who have advanced on chemotherapy. Our findings suggest that reduction of Megasphaera elsdenii, a metabolically active bacterium, is associated with positive outcomes, which differs from findings from other literature. Our project advocates for a more robust profiling of the microbiome during lung cancer treatment, and immunotherapy, in particular, to establish a more substantive profile of the changing gut in the midst of treatment.

cancer biology↗

bioRxiv2020

Blood vessel occlusion by Cryptococcus neoformans is a mechanism for hemorrhagic dissemination of infection

Meningitis caused by infectious pathogens are associated with vessel damage and infarct formation, however the physiological cause is unknown. Cryptococcus neoformans, is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of cases, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model for in vivo live imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on there size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a single or small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel stifness via cell junctions and found increased stiffness resulted in increased dissemination. Therefore, global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction more generally in infective meningitis.

pathology↗

bioRxiv2017

Fungal derived 15-keto-prostaglandin E2 and host proliferator-activated receptor gamma (PPAR-γ) promote C. neoformans growth during infection.

Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants{Delta} plb1 and{Delta} lac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-{gamma}. C. neoformans infection of macrophages activates host PPAR-{gamma} and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-{gamma} in cryptococcosis. Author SummaryCryptococcus neoformans is an opportunistic fungal pathogen that is responsible for significant numbers of deaths in the immunocompromised population worldwide. Here we address whether eicosanoids produced by C. neoformans manipulate host innate immune cells during infection. Cryptococcus neoformans produces several eicosanoids that are notable for their similarity to vertebrate eicosanoids, it is therefore possible that fungal-derived eicosanoids may provoke physiological effects in the host. Using a combination of in vitro and in vivo infection models we identify a specific eicosanoid species - prostaglandin E2 - that is required by C. neoformans for growth during infection. We subsequently show that prostaglandin E2 must be converted to 15-keto-prostaglandin E2 within the host before it has these effects. Furthermore, we find that prostaglandin E2/15-keto-prostaglandin E2 mediated virulence is via activation of host PPAR-{gamma} - an intracellular eicosanoid receptor known to interact with 15-keto-PGE2.

microbiology↗