AIMTo investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer (CAC).METHODSC57BL/6 mice received an intraperitoneal injection of azoxymethane (10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water (5% w/v). Probiotic group received daily a mixture of Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum. Microbiota composition was assessed by 16S rRNA Illumina HiSeq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR (Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two-sided. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software GraphPad Prism 5.0. The project was approved by the institutional review board committee.RESULTSAt day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size (< 2 mm) (P < 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera Lactobacillus, Bifidobacterium, Allobaculum, Clostridium XI and Clostridium XVIII increased in the probiotic group (P < 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p-IKK and TNF-α and increased IL-10 expression in the colon.CONCLUSIONOur results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC.

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Insulin and insulin-like growth factors (IGFs) are mitogenic and prosurvival factors to many different cell types, including acute lymphoblastic leukemia (ALL). Circulating IGFs are bound by IGF binding proteins (IGFBPs) that regulate their action. IGFBP7 is an IGFBP-related protein (IGFBP-rP) that in contrast to other IGFBPs/IGFBP-rPs features higher affinity for insulin than IGFs and was shown to bind the IGF1 receptor (IGF1R) as well. The role of IGFBP7 in cancer is controversial: on some tumors, it functions as an oncogene, whereas in others, it functions as a tumor suppressor. In childhood ALL, higher IGFBP7 expression levels were associated with worse prognosis. Here we show that IGFBP7 exerts mitogenic and prosurvival autocrine effects on ALL cells that were dependent on insulin/IGF. IGFBP7 knockdown or antibody-mediated neutralization resulted in significant attenuation of ALL cell viability in vitro and leukemia progression in vivo. IGFBP7 was shown to prolong the surface retention of the IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) phosphorylation. Conversely, the insulin receptor was readily internalized and dephosphorylated on insulin stimulation, despite IGFBP7 addition. The affinity of homodimeric IGF1R for insulin is reportedly &gt;100 times lower than for IGF1. In the presence of IGFBP7, however, 25 ng/mL insulin resulted in IGF1R activation levels equivalent to that of 5 ng/mL IGF1. In conclusion, IGFBP7 plays an oncogenic role in ALL by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGF stimulation. Preclinical data demonstrate that IGFBP7 is a valid target for antibody-based therapeutic interventions in ALL.

BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease. In accordance, chronic inflammation has recently been implicated in the development of cancer stem cells (CSCs). However, the mechanism whereby anti-inflammatory drugs act in the prevention of colitis-associated cancer (CAC) is only partially understood. AIM To evaluate the role of diacerein (DAR), an anti-inflammatory drug that mainly acts through the inhibition of interleukin (IL)-1β expression in the development of CSCs and CAC. METHODS The effects of DAR on colon inflammation in mice with CAC were evaluated by inflammatory index, reverse real-time transcription polymerase chain reaction and western blot. Cytokine levels were measured by enzyme-linked immunosorbent assay. Cells assays evaluated the effects of DAR on CSCs. Immunohistochemistry and apoptosis assays were also used to evaluate the effects of DAR on tumorigenesis associated with inflammation. RESULTS DAR treatment reduced colon inflammation as well as the number and size of tumors in azoxymethane plus dextran sulphate sodium-treated animals. Accordingly, DAR treatment was associated with reduced intracellular signals of inflammation (inhibitor of nuclear factor kappa B kinase and c-Jun N-terminal kinase phosphorylation) in the colon. In addition, DAR treatment was associated with a decrease in colon CSC formation, suggesting that besides reducing colonic inflammation, DAR has a direct effect on the inhibition of colon carcinogenesis. CONCLUSION Together, these data indicate that DAR-mediated IL-1β suppression attenuates inflammation-induced colon cancer and CSC formation, highlighting DAR as a potential candidate for the chemoprevention of CAC.

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method was used to determine cutoff points for SMA and NLR, and their prognostic values were assessed via univariate and multivariate logistic regression analyses and the Kaplan-Meier curve. Study approved by our local IRB (CAAE: 36276620.2.0000.5404). Results: A total of 202 patients were included. The median age was 59 years, 58% of patients were men and 45% required ICU. A total of 45 (22.4%) patients died. Low SMA was associated with high death rates (HR: 3.55; 95% CI: 1.45 e 8.69, p¼0.005) and high NLR had higher risk of overall mortality (OR 4.20; 95% CI: 1.39 e 12.70, p¼0.011). The presence of myosteatosis and high NLR simultaneously was also significantly associated with death (OR 27.62; 95% CI: 2.83 e 269.34, p¼0.004). Conclusion: In our cohort, both myosteatosis and high NLR were associated with higher risk of death.

In epidemiological studies, higher calcium intake has been associated with decreased colorectal cancer (CRC) incidence. However, whether circulating calcium concentrations are associated with CRC prognosis is largely unknown. In this retrospective cohort analysis, we identified 498 patients diagnosed with stage I–IV CRC between the years of 2000 and 2018 in whom calcium and albumin level measurements within 3 months of diagnosis had been taken. We used the Kaplan–Meier method for survival analysis. We used multivariate Cox proportional hazards regression to identify associations between corrected calcium levels and CRC survival outcomes. Corrected calcium levels in the highest tertile were associated with significantly lower progression-free survival rates (hazard ratio (HR) 1.85; 95% confidence interval (CI) 1.28–2.69; p = 0.001) and overall survival (HR 1.86; 95% CI 1.26–2.74, p = 0.002) in patients with stage IV or recurrent CRC, and significantly lower disease-free survival rates (HR 1.44; 95% confidence interval (CI) 1.02–2.03; p = 0.040) and overall survival rates (HR 1.72; 95% CI 1.18–2.50; p = 0.004) in patients with stage I–III disease. In conclusion, higher corrected calcium levels after the diagnosis of CRC were significantly associated with decreased survival rates. Prospective trials are necessary to confirm this association.