Precision Medicine for CRC Patients in the Veteran Population: State-of-the-Art, Challenges and Research Directions.

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA\u27s research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC

Colonic Stasis and Chronic Constipation: Demystifying Proposed Risk Factors for Colon Polyp Formation in a Spinal Cord Injury Veteran Population

Background and Aims: Patients with spinal cord injury (SCI) suffer significant morbidity from neurogenic bowel. Chronic constipation has long-been a proposed risk factor for polyp development. We performed a retrospective cohort study in veterans with SCI to assess polyp presence in the setting of colonic stasis. Methods: All consecutive patients at the James A. Haley Veterans Affairs Hospital with SCI and neurogenic bowel who completed screening colonoscopy between January 1, 2004 to June 30, 2013 were included. Colonoscopies were excluded if they were aborted, not completed to the cecum, of less than adequate preparation, or if polypectomy was precluded. Patient data included level, duration, and completeness of SCI. Polyp data included number, location, and histology. Results: 325 patients ultimately met inclusion criteria. Most were male (96%). The average age at screening colonoscopy was 62.8 years. The majority of patients had injury to the cervical spine (41.5%). Colon polyps were detected in 130 patients (40%). Adenomatous change was seen in 95 (73%) of these patients. The adenoma detection rate (ADR) across all patients was 29.2%. Polyp presence and ADR demonstrated no statistically significant correlation with level, degree, or duration of SCI. Only patient age at time of screening colonoscopy had a significant correlation with polyp and adenoma presence (P\u3c0.05). Conclusions: SCI had no statistically significant correlation with polyp or adenoma presence. The ADR in our veteran SCI population with chronic constipation is comparable with that reported in the general population

Long Noncoding RNA GAS5 Contained in Exosomes Derived from Human Adipose Stem Cells Promotes Repair and Modulates Inflammation in a Chronic Dermal Wound Healing Model

Chronic recalcitrant wounds result from delayed or slowed healing processes. Underlying inflammation is a substantial risk factor for impaired dermal wound healing and often leads to chronic wound-related sequelae. Human adipose stem cells (hASCs) have shown tremendous potential in regenerative medicine. The goal of this project was to improve the outcome of chronic wounds by harvesting the exosomes from hASCs for therapeutic intervention. The results demonstrate that long noncoding RNA GAS5 is highly enriched in hASC exosomes and, further, that GAS5 is central to promoting wound repair in vitro. To evaluate the outcome of wound healing in a chronic low-grade inflammatory environment, lipopolysaccharide-treated HDF cells were evaluated for their response to hASC exosome treatment. Ingenuity pathway analysis identified inflammation pathways and genes affected by exosomes in a GAS5-dependent manner. Using siRNA to deplete GAS5 in HDF, the results demonstrated that Toll-like receptor 7 (TLR7) expression levels were regulated by GAS5. Importantly, the results demonstrate that GAS5 regulates inflammatory pathway genes in a chronic inflammation environment. The results presented here demonstrate that hASC exosomes are a viable therapeutic that accelerate the healing of chronic recalcitrant wounds

Multilevel Regulation of Protein Kinase CδI Alternative Splicing by Lithium Chloride.

Lithium chloride (LiCl) is commonly used in treatment of mood disorders; however, its usage leads to weight gain, which promotes metabolic disorders. Protein kinase C delta (PKCδ), a serine/threonine kinase, is alternatively spliced to PKCδI and PKCδII in 3T3-L1 cells. We previously demonstrated that PKCδI is the predominantly expressed isoform in 3T3-L1 preadipocytes. Here, we demonstrate that LiCl treatment decreases PKCδI levels, increases formation of lipid droplets, and increases oxidative stress. Hence, we investigated the molecular mechanisms underlying the regulation of PKCδI alternative splicing by LiCl. We previously demonstrated that the splice factor SFRS10 is essential for PKCδI splicing. Our results demonstrate that glycogen synthase kinase 3 beta (GSK3β) phosphorylates SFRS10, and SFRS10 is in a complex with long noncoding RNA NEAT1 to promote PKCδI splicing. Using PKCδ splicing minigene and RNA immunoprecipitation assays, our results demonstrate that upon LiCl treatment, NEAT1 levels are reduced, GSK3β activity is inhibited, and SFRS10 phosphorylation is decreased, which leads to decreased expression of PKCδI. Integration of the GSK3β signaling pathway with the ribonucleoprotein complex of long noncoding RNA (lncRNA) NEAT1 and SFRS10 enables fine-tuning of PKCδI expression during adipogenesis. Knowledge of the molecular pathways impacted by LiCl provides an understanding of the ascent of obesity as a comorbidity in disease management

Reduction of Video Capsule Endoscopy Reading Times Using Deep Learning with Small Data

Video capsule endoscopy (VCE) is an innovation that has revolutionized care within the field of gastroenterology, but the time needed to read the studies generated has often been cited as an area for improvement. With the aid of artificial intelligence, various fields have been able to improve the efficiency of their core processes by reducing the burden of irrelevant stimuli on their human elements. In this study, we have created and trained a convolutional neural network (CNN) capable of significantly reducing capsule endoscopy reading times by eliminating normal parts of the video while retaining abnormal ones. Our model, a variation of ResNet50, was able to reduce VCE video length by 47% on average and capture abnormal segments on VCE with 100% accuracy on three VCE videos as confirmed by the reading physician. The ability to successfully pre-process VCE footage as we have demonstrated will greatly increase the practicality of VCE technology without the expense of hundreds of hours of physician annotated videos