We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.

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a b s t r a c tPurpose: Child abuse is a national, often hidden, epidemic. The study objective was to determine at-risk populations that have been previously hospitalized prior to their admission for child abuse. Methods: The Nationwide Readmissions Database (NRD) was queried for all children hospitalized for abuse. Outcomes were previous admissions and diagnoses. χ 2 analysis was used; significance equals p b 0.05. Results: 31,153 children were hospitalized for abuse (half owing to physical abuse) during the study period. 11% (n = 3487) of these children had previous admissions (one in three to a different hospital), while 3% (n = 1069) had multiple hospitalizations. 60% of prior admissions had chronic conditions, and 12% had traumatic injuries. Children with chronic conditions were more likely to have sexual abuse (89% vs. 57%, p b 0. 001) and emotional abuse (75% vs. 60%, p b 0. 01). 25% of chronic diagnoses were psychiatric, who were also more likely to have sexual and emotional abuse (47% vs. 5.5% and 10% vs. 1%, all p b 0. 001). Conclusion: This study uncovers a hidden population of children with past admissions for chronic conditions, especially psychiatric diagnoses that are significantly associated with certain types of abuse. Improved measures to accurately identify at-risk children must be developed to prevent future childhood abuse and trauma. Level of evidence: Level III. Type of study: Retrospective comparative study.

Despite decades of research there is no specific therapy for Acute Pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an anti-inflammatory and antifibrotic agent which is FDA-approved for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (i.e. after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP.In-vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines.Antibody-mediated IL-10 depletion, use of IL-10 Knock Out mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously.

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Background Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers. Methods In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer. Results The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases. Conclusions Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.

is a founder and equity holder of Sebastian Biopharma that holds intellectual rights for the neoantigen induction approach described in this study.