Serine Supports Epithelial and Immune Cell Function in Colitis.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, and mucosal healing is critical for remission. Serine is a nonessential amino acid that supports epithelial and immune cell metabolism and proliferation; however, whether these roles affect IBD pathogenesis is not well understood. Herein, the study showed that serine synthesis increased selectively in the epithelial cells of colons from patients with IBD and murine models of colitis. Inhibiting serine synthesis impaired colonic mucosal healing and increased susceptibility to acute injury in mice, effects associated with diminished epithelial cell proliferation. Dietary removal of serine similarly sensitized mice to acute chemically induced colitis but ameliorated inflammation in chronic colitis models. The anti-inflammatory effect of exogenous serine depletion in chronic colitis was associated with mitochondrial dysfunction of macrophages, resulting in impaired nucleotide production and proliferation. Collectively, these results suggest that serine plays an important role in both epithelial and immune cell biology in the colon and that modulating its availability could impact IBD pathogenesis.

Keratin 17 modulates the immune topography of pancreatic cancer.

BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. METHODS: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. RESULTS: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. CONCLUSIONS: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging.

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer's ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. In this study, we show that ecological habitat analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intraductal microenvironment based on oxygen diffusion distance. Then, we identify cancer cells with metabolic phenotypes attributed to their habitat conditions, such as the expression of CA9 indicating hypoxia responding phenotype, and LAMP2b indicating the acid adaptation. Traditionally these markers have shown limited predictive capabilities for DCIS upstaging, if any. However, when analyzed from an ecological perspective, their power to differentiate between pure DCIS and upstaged DCIS increased significantly. Second, using eco-evolutionary guided computational and digital pathology techniques, we discovered distinct niches with spatial patterns of these biomarkers and used the distribution of such niches to predict patient upstaging. The niches patterns were characterized by pattern analysis of both cellular and spatial features. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve (AUC) of 0.74. Our results affirm the importance of using eco-evolutionary-designed approaches in biomarkers discovery studies in the era of digital pathology by demonstrating the role of tumor ecological habitats and niches.

Induction and evaluation of murine colitis induced by T cell transfer.

Inflammatory bowel diseases (IBD) involve repetitive bouts of inflammation in the intestinal tract and can result in severe morbidity for patients. Moreover, long-standing IBD increases the risk for developing intestinal neoplasia. Although several factors including immune cell activity, microbiota and diet have been implicated in IBD pathogenesis, it is still considered a disease of idiopathic origin. Therefore, much work is needed to identify the critical mediators in IBD onset, severity and response to treatment. Mouse models are useful for identifying factors that contribute to IBD and the efficacy of therapy, which can then be tested in humans. There are currently multiple IBD models including the use of chemical induction, genetic manipulation and modulation of the immune response. The T cell transfer colitis model provides a quality mimic of human IBD that is T cell driven and results in inflammation in both the ileum and colon. Here, we have provided a detailed step-by-step protocol to induce inflammation and assess disease severity using this model. Such a detailed methodologic description will help to increase its utilization to advance IBD research.

Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome.

Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to suppress intestinal tumorigenesis. Use of ABx also impaired celecoxib's ability to shift microbial populations and gut luminal and circulating metabolites. Treatment with ABx alone markedly reduced tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of celecoxib and intestinal tumor growth. PREVENTION RELEVANCE: This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal tumor development. These findings have the potential to lead to improved cancer prevention strategies by modulating microbes and their metabolites.

Inflammatory Myofibroblastic Tumor 12 Years After Treatment for Synovial Sarcoma: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are mesenchymal neoplasms most seen in the abdominopelvic region, lung, and retroperitoneum; and less commonly seen in virtually any other site. We report a case of two lower limb masses consistent with diagnosis of IMTs. This is a 39-year-old woman with a history of right lower extremity popliteal fossa synovial sarcoma diagnosed 12 years prior and treated with chemotherapy, surgery, and radiation. She presented with two new - one anterior and one posterior - right thigh masses. Biopsies of the lesions demonstrated low-grade inflammatory spindle cell lesions at both sites. Wide resection was performed for both masses and further characterization of the surgical specimens was most consistent with IMT. At follow-up, the patient is well with no signs of recurrence 19 and 7 months postoperative to the resection of the anterior and posterior thigh masses, respectively. This case represents the first reported IMTs occurring as late as 12 years after primary cancer treatment, and the first occurring after synovial sarcoma.

Outcomes of Introducing a Mobile Interactive Learning Resource in a Large Medical School Course.

Mobile devices are an integral part of modern medical education, as convenient platforms for access to online interactive learning resources; students' use of textbooks has correspondingly declined. We designed an interactive iBook© for pre-clinical students encompassing the content of the pulmonary segment in an organ-based multidisciplinary course. We found, via a survey-based study, that students preferred the iBook to other faculty-supplied materials (PowerPoints and PDFs), mainly due to its interactive images, animations, and study questions. Students' test performance did not change significantly after introducing the iBook. This study suggests that expanded use of interactive learning resources may enhance students' engagement with pre-clinical courses.

Keratin 17 is a negative prognostic biomarker in high-grade endometrial carcinomas.

Keratin 17 (K17) has been established as a negative prognostic biomarker in cervical and ovarian cancers but has not previously been evaluated as a prognostic biomarker in endometrial adenocarcinoma. The association of K17 with decreased patient survival may be explained in part by the discovery that K17 drives tumor aggression by serving as a nuclear shuttle of p27, leading to cell cycle progression and tumor growth. The current study tests the hypothesis that K17 mRNA and protein levels correlate with decreased survival of patients with high-grade endometrial cancer. Gene expression data (mRNA) from The Cancer Genome Atlas were analyzed for 271 high-grade endometrial carcinomas and K17 immunohistochemistry (IHC) was performed on a separate cohort of 119 high-grade endometrial cancer cases from two academic medical centers. Survival analyses were determined by Cox proportional hazards regression. High K17 mRNA and IHC correlated with decreased overall survival (HR: 1.8, P = .0101, HR: 1.8, P = .0488, respectively). K17 was positive in malignant glandular cells of the endometrium but not in other tissues, including endometrial stroma, myometrium and uterine sarcoma. These results support the conclusion that K17 is a negative prognostic biomarker in high-grade endometrial carcinoma and that K17 IHC test results could be used to inform decisions related to therapeutic intervention.