The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the care of cancer patients. However, the response to ICI therapy exhibits substantial interindividual variability. Efforts have been directed to identify biomarkers that predict the clinical response to ICIs. In recent years, the gut microbiome has emerged as a critical player that influences the efficacy of immunotherapy. An increasing number of studies have suggested that the baseline composition of a patient's gut microbiota and its dysbiosis are correlated with the outcome of cancer immunotherapy. This review tackles the rapidly growing body of evidence evaluating the relationship between the gut microbiome and the response to ICI therapy. Additionally, this review highlights the impact of antibiotic-induced dysbiosis on ICI efficacy and discusses the possible therapeutic interventions to optimize the gut microbiota composition to augment immunotherapy efficacy.

Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity.

Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Advanced Proteomics-bioinformatics analysis of the protein cargo of exosomes isolated from C2C12 myoblasts transduced with P3F fusion gene revealed 52 deregulated proteins compared to control cells, with 26 enriched and 26 depleted proteins. Using both PANTHER gene classification and Ingenuity Pathway Analysis (IPA) software, we found that the main biological processes in which the 52 deregulated proteins are involved, include "catalytic activity," "binding," "metabolic process," and "cellular process." The pathways engaging the 26 enriched proteins include the "14-3-3 mediated signaling," "cell cycle," and "ERK5, VEGF, IGF1,and p70S6K signaling." Furthermore, the main nodes in which deregulated exosome proteins and miRNAs intersected revealed pathways conferring protection from stress and promoting plasticity. Based on the bioinformatics analysis and the altered exosome proteome profile, we performed biochemical functional analysis to study the diverse properties of these exosomes where angiogenesis, stemness, and anti-oxidative stress properties were validated using different platforms. P3F-modulated exosomes activated ERK, 4-EBP1, and MMP-2 in recipient cells, and enhanced angiogenesis and stemness. In addition, P3F led to lower cellular reactive oxygen species levels and enhanced resistance against oxidative stress; and treatment of stromal cells with P3F-modulated exosomes also conferred protection against exogenous oxidative stress. Our findings highlight the role of P3F fusion protein in modulating exosome cargo to confer a protective effect on recipient cells against oxidative stress and to promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of RMS.

Long-Term Patency of Individual Segments of Different Internal Thoracic Artery Graft Configurations.

BACKGROUND: Internal thoracic artery (ITA) grafts are the most durable conduits available for coronary artery bypass grafting (CABG). However, little is known about long-term angiographic outcomes of ITA grafts used in different configurations and whether sequential or Y grafting compromises patency of the inflow ITA graft. METHODS: From January 1972 to August 2016, 60,500 patients underwent primary isolated CABG, of whom 326 received ITA grafts placed in sequential or Y configuration and were studied angiographically (median 4.8 years to first follow-up angiogram). Each sequential or Y segment was studied individually using a mixed-effects longitudinal model with the patient as the random effect. RESULTS: At 15 years, patency of the proximal ITA segment (n = 331) was 99%; of a sequential segment (n = 222), 97%; and of the segment beyond anastomosis of a Y graft (n = 109), 99%. Patency of the Y grafts (n = 109) was 92% at 5 years, 91% at 10 years, and 90% at 15 years. After adjusting for proximal stenosis and graft location, Y grafts were associated with greater occlusion than the inflow segment of ITA grafts (odds ratio; 51, 95% confidence interval, 6.1 to 422; p = 0.003) and of sequential grafts (odds ratio, 12; 95% confidence interval, 1.14 to 120; p = 0.04). CONCLUSIONS: Long-term patency of ITA grafts in sequential or Y configuration is similar qualitatively, but not quantitatively, to the known patency of single ITA-to-left anterior descending grafts. Sequential or Y grafting does not compromise patency of the inflow portion of an ITA graft. Y-graft patency is lower than sequential graft patency but is still better than known patency of saphenous vein grafts.