Colon volvulus in rhesus macaques (Macaca mulatta) at the Oregon National Primate Research Center-Retrospective analysis.

Colonic volvulus is an uncommon, often life-threatening condition, in non-human primates. Twenty-six cases of colonic volvulus in rhesus macaques (Macaca mulatta) were identified in necropsy records spanning 38 years at the Oregon National Primate Research Center (ONPRC). This report represents the largest collection of colonic volvuli in rhesus macaques.

Functions of Thrombospondin-1 in the Tumor Microenvironment.

The identification of thrombospondin-1 as an angiogenesis inhibitor in 1990 prompted interest in its role in cancer biology and potential as a therapeutic target. Decreased thrombospondin-1 mRNA and protein expression are associated with progression in several cancers, while expression by nonmalignant cells in the tumor microenvironment and circulating levels in cancer patients can be elevated. THBS1 is not a tumor suppressor gene, but the regulation of its expression in malignant cells by oncogenes and tumor suppressor genes mediates some of their effects on carcinogenesis, tumor progression, and metastasis. In addition to regulating angiogenesis and perfusion of the tumor vasculature, thrombospondin-1 limits antitumor immunity by CD47-dependent regulation of innate and adaptive immune cells. Conversely, thrombospondin-1 is a component of particles released by immune cells that mediate tumor cell killing. Thrombospondin-1 differentially regulates the sensitivity of malignant and nonmalignant cells to genotoxic stress caused by radiotherapy and chemotherapy. The diverse activities of thrombospondin-1 to regulate autophagy, senescence, stem cell maintenance, extracellular vesicle function, and metabolic responses to ischemic and genotoxic stress are mediated by several cell surface receptors and by regulating the functions of several secreted proteins. This review highlights progress in understanding thrombospondin-1 functions in cancer and the challenges that remain in harnessing its therapeutic potential.

ECMO hospital volume and survival in congenital diaphragmatic hernia repair.

PURPOSE: This study examined survival in newborn patients after congenital diaphragmatic hernia (CDH) repair. METHODS: We analyzed the Kids' Inpatient Database Years 2000, 2003, and 2006 for patients admitted at fewer than 8 d of age undergoing CDH repair. We analyzed patient demographics, clinical characteristics, socioeconomic measures, hospital type, operative case volume, and survival using Fisher's exact test and a multivariate binary logistic regression model. RESULTS: Of 847 patients identified, most were male (61%) and white (57%), were treated at urban (99.8%) and teaching (96%) hospitals, and had private insurance (57%). Survival to discharge was 95% in non-extracorporeal membrane oxygenation (ECMO) patients versus 51% for those requiring ECMO (P < 0.0001). Univariate analysis revealed significantly lower survival rates in blacks, Medicaid patients, and patients undergoing repair after 7 d of life. Among ECMO patients, we noted higher survival rates at hospitals conducting four or more ECMO cases per year (66% versus 47%; P = 0.03). Multivariate analysis identified ECMO (hazards ratio [HR] 16.23, P < 0.001), CDH repair at >7 d of age (HR 2.70, P = 0.004), and ECMO patients repaired at hospitals performing <4 CDH ECMO cases per year (HR 3.59, P = 0.03) as independent predictors of mortality. CONCLUSIONS: We conclude that ECMO hospital volume is associated with survival in patients requiring ECMO for CDH repair.

Metabolic Implications of Immune Checkpoint Proteins in Cancer.

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

Discrete Correlation Summation Clustering Reveals Differential Regulation of Liver Metabolism by Thrombospondin-1 in Low-Fat and High-Fat Diet-Fed Mice.

Thrombospondin-1 (TSP1) is a matricellular protein with many important roles in mediating carcinogenesis, fibrosis, leukocyte recruitment, and metabolism. We have previously shown a role of diet in the absence of TSP1 in liver metabolism in the context of a colorectal cancer model. However, the metabolic implications of TSP1 regulation by diet in the liver metabolism are currently understudied. Therefore Discrete correlation summation (DCS) was used to re-interrogate data and determine the metabolic alterations of TSP1 deficiency in the liver, providing new insights into the role of TSP1 in liver injury and the progression of liver pathologies such as nonalcoholic fatty liver disease (NAFLD). DCS analysis provides a straightforward approach to rank covariance and data clustering when analyzing complex data sets. Using this approach, our previous liver metabolite data was re-analyzed by comparing wild-type (WT) and Thrombospondin-1 null (Thbs1-/-) mice, identifying changes driven by genotype and diet. Principal component analysis showed clustering of animals by genotype regardless of diet, indicating that TSP1 deficiency alters metabolite handling in the liver. High-fat diet consumption significantly altered over 150 metabolites in the Thbs1-/- livers versus approximately 90 in the wild-type livers, most involved in amino acid metabolism. The absence of Thbs1 differentially regulated tryptophan and tricarboxylic acid cycle metabolites implicated in the progression of NAFLD. Overall, the lack of Thbs1 caused a significant shift in liver metabolism with potential implications for liver injury and the progression of NAFLD.

Diet Alters Entero-Mammary Signaling to Regulate the Breast Microbiome and Tumorigenesis.

Obesity and poor diet often go hand-in-hand, altering metabolic signaling and thereby impacting breast cancer risk and outcomes. We have recently demonstrated that dietary patterns modulate mammary microbiota populations. An important and largely open question is whether the microbiome of the gut and mammary gland mediates the dietary effects on breast cancer. To address this, we performed fecal transplants between mice on control or high-fat diets (HFD) and recorded mammary tumor outcomes in a chemical carcinogenesis model. HFD induced protumorigenic effects, which could be mimicked in animals fed a control diet by transplanting HFD-derived microbiota. Fecal transplants altered both the gut and mammary tumor microbiota populations, suggesting a link between the gut and breast microbiomes. HFD increased serum levels of bacterial lipopolysaccharide (LPS), and control diet-derived fecal transplant reduced LPS bioavailability in HFD-fed animals. In vitro models of the normal breast epithelium showed that LPS disrupts tight junctions (TJ) and compromises epithelial permeability. In mice, HFD or fecal transplant from animals on HFD reduced expression of TJ-associated genes in the gut and mammary gland. Furthermore, infecting breast cancer cells with an HFD-derived microbiome increased proliferation, implicating tumor-associated bacteria in cancer signaling. In a double-blind placebo-controlled clinical trial of patients with breast cancer administered fish oil supplements before primary tumor resection, dietary intervention modulated the microbiota in tumors and normal breast tissue. This study demonstrates a link between the gut and breast that mediates the effect of diet on cancer. SIGNIFICANCE: This study demonstrates that diet shifts the microbiome in the gut and the breast tumor microenvironment to affect tumorigenesis, and oral dietary interventions can modulate the tumor microbiota in patients with breast cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/14/3890/F1.large.jpg.

Hospital preference of laparoscopic versus open appendectomy: Effects on outcomes in simple and complicated appendicitis.

PURPOSE: We hypothesize that laparoscopic (LA) or open appendectomy (OA) outcomes are associated with hospital procedure preference. METHODS: We queried Kids' Inpatient Database (1997-2009) for simple (ICD-9-CM 540.9) and complicated (540.0, 540.1) appendicitis. RESULTS: On PS-matched analysis of simple appendicitis (91,118 LA vs. 97,496 OA), LA had increased transfusion (1.7) rates, but lower wound infection (0.6) and perforation/laceration (0.3) rates. LA had shorter length of stay (LOS; 1.7 vs. 2.1days), but higher total charges (TC; 19,501 vs. 13,089 USD) and cost (7121 vs. 5968) vs. OA. For complicated appendicitis (28,793 LA vs. 30,782 OA), LA had increased nausea/vomiting rates (1.9), but lower wound infection (0.5) and transfusion (0.6) rates. LA had shorter LOS (5.1 vs. 5.9), but higher TC (32,251 vs. 28,209). MVA demonstrated shorter LOS (0.9) for LA at laparoscopic-preferring hospitals vs. open-preferring hospitals for simple appendicitis. For complicated appendicitis, higher complication rates (1.1) were associated with OA at laparoscopic-preferring hospitals. Laparoscopic-preferring hospitals had higher TC in all categories. CONCLUSION: Complications and resource utilization for appendicitis are associated with surgical technique and hospital procedure preference. Laparoscopic-preferring hospitals had higher complication rates with OA for complicated appendicitis and higher charges regardless of appendectomy technique or appendicitis type. LEVEL OF EVIDENCE: 2c, Outcomes Research.

Survival disparities in newborns with congenital diaphragmatic hernia: a national perspective.

PURPOSE: The aim of the study was to examine national outcomes for congenital diaphragmatic hernia (CDH). METHODS: We analyzed the Kids' Inpatient Database for patients admitted at less than 8 days of age. RESULTS: Overall, 2774 hospitalizations were identified. Most patients were white and had private insurance. Most patients were treated at urban (96%), teaching (75%), and not identified as children's hospital (NIACH) (50%). Birth was the most common admission source at NIACH (91%) and children's unit in general hospital (CUGH) (59%), compared to hospital transfer at children's general hospital (CGH) (81%). Most CDH were repaired through the abdomen (81%), and 25% required extracorporeal membrane oxygenation (ECMO). Most NIACH patients were transferred to another hospital, whereas most at CGH and CUGH were discharged home. Survival to discharge was 66% after excluding hospital transfers. Univariate analysis revealed higher survival for males, birth weight (BW) of 3 kg or more, whites, patients with private insurance, and those in the highest median household income quartile. Survival was 86% after CDH repair but 46% for ECMO. Multivariate analysis identified black race (hazard ratio [HR], 1.536; P = .03) and other race (HR, 1.515; P = .03) as independent predictors of mortality. CONCLUSIONS: Hospital survival for CDH is related to sex, BW, race, and socioeconomic status. Blacks and other non-Hispanic minorities have higher mortality rates.