Transcriptome profiling of colorectal tumors from patients with sepsis reveals an ethnic basis for viral infection risk and sepsis progression.

Mortality from cancer-associated sepsis varies by cancer site and host responses to sepsis are heterogenous. Native Hawaiians have the highest mortality risk from cancer-associated sepsis and colorectal cancer (CRC), even though they demonstrate lower CRC incidence compared to other ethnicities. We conducted a retrospective transcriptomic analysis of CRC tumors and adjacent non-tumor tissue from adult patients of Native Hawaiian and Japanese ethnicity who died from cancer-associated sepsis. We examined differential gene expression in relation to patient survival and sepsis disease etiology. Native Hawaiian CRC patients diagnosed with sepsis had a median survival of 5 (IQR 4-49) months, compared to 117 (IQR 30-146) months for Japanese patients. Transcriptomic analyses identified two distinct sepsis gene signatures classified as early response and late response sepsis genes that were significantly altered in the Native Hawaiian cohort. Analysis of canonical pathways revealed significant up and downregulation in mechanisms of viral exit from host cells (p = 4.52E-04) and epithelial junction remodeling (p = 4.01E-05). Key genes including elongation initiation factor pathway genes, GSK3B, and regulatory associated protein of mTOR (RPTOR) genes that protect cells from infection were significantly downregulated in Native Hawaiians. Genes promoting sepsis progression including CLOCK, PPBP and Rho family GTPASE 2 (RND2) were upregulated in Native Hawaiian patients. Our transcriptomic approach advances understanding of sepsis heterogeneity by revealing a role of genetic background and defining patient subgroups with altered early and late biological responses to sepsis. This study is the first to investigate differential gene expression in CRC-associated sepsis patients in relation to ethnicity. Our findings may lead to personalized approaches in stratifying patient mortality risk for sepsis and in the development of effective targeted therapies for sepsis.

Association of Sepsis Mortality with Specific Cancer Sites and Treatment Type: The Multiethnic Cohort Study.

Sepsis is a severe dysregulated immune response to infection. Sepsis deaths represent 9% of cancer deaths in the U.S. Evidence of the effect of specific cancer sites on sepsis mortality risk remains limited, and no research has evaluated the effect of cancer treatment on the risk of sepsis death. We examined whether cancer sites and treatments differentially affect the risk of sepsis death compared to other-cause mortality, among the 94,784 Hawaii participants in the Multiethnic Cohort, including 29,255 cancer cases, using competing risk Cox proportional hazards regression. Cancer diagnosis at any site was associated with similar increases in sepsis and non-sepsis mortality risk (HR: 3.39 and 3.51, resp.). Colorectal cancer differentially affected the risk of sepsis and non-sepsis mortality with a 40% higher effect on the risk of sepsis death compared with non-sepsis mortality (RRR: 1.40; 95% CI: 1.14-1.72). Lung cancer was associated with a significantly lower increase in sepsis compared to non-sepsis mortality (HR: 1.22 and 3.0, resp.; RRR: 0.39). Radiation therapy had no effect on sepsis mortality but was associated with higher risk of non-sepsis mortality (HR: 0.90 and 1.16, resp.; RRR: 0.76), whereas chemotherapy was associated with higher risk of both sepsis and non-sepsis mortality (HR: 1.31 and 1.21, resp.). We conclude that the risk of sepsis-related mortality is differentially affected by cancer sites and treatments. These associations were consistent across sexes and ethnic groups.

Correction: Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis.

[This corrects the article DOI: 10.18632/oncotarget.24388.].

Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis.

Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca2+) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca2+ flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca2+ flux through the endoplasmic reticulum Ca2+ channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca2+ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca2+-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK-/- mice to generate the following littermates: Grm1-Tg/SELENOK-/-, Grm1-Tg/SELENOK-/+, Grm1-Tg/SELENOK+/+. SELENOK-deficiency in Grm1-Tg/SELENOK-/- male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK-/- mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.

Human Gut Microbiota: Toward an Ecology of Disease.

Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics.

Effects of glucomannan-enriched, aronia juice-based supplement on cellular antioxidant enzymes and membrane lipid status in subjects with abdominal obesity.

The aim of this study was to analyze the effects of a 4-week-long consumption of glucomannan-enriched, aronia juice-based supplement on anthropometric parameters, membrane fatty acid profile, and status of antioxidant enzymes in erythrocytes obtained from postmenopausal women with abdominal obesity. Twenty women aged 45-65 with a mean body mass index (BMI) of 36.1 ± 4.4 kg/m(2) and waist circumference of 104.8 ± 10.1 cm were enrolled. Participants were instructed to consume 100 mL of supplement per day as part of their regular diet. A significant increase in the content of n-3 (P < 0.05) polyunsaturated fatty acids in membrane phospholipids was observed, with a marked increase in the level of docosahexaenoic fatty acid (P < 0.05). Accordingly, a decrease in the n-6 and n-3 fatty acids ratio was observed (P < 0.05). The observed effects were accompanied with an increase in glutathione peroxidase activity (P < 0.05). Values for BMI (P < 0.001), waist circumference (P < 0.001), and systolic blood pressure (P < 0.05) were significantly lower after the intervention. The obtained results indicate a positive impact of tested supplement on cellular oxidative damage, blood pressure, and anthropometric indices of obesity.