Male-Biased Gut Microbiome and Metabolites Aggravate Colorectal Cancer Development.

Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex-biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/ + mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo-germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo-germ mice receiving fecal sample from male mice. Sex-biased gut metabolites in pseudo-germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex-biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex-biased gut microbiota and metabolites could be a potential sex-targeting therapeutic strategy of CRC.

STAT3 as a target for sensitizing prostate cancer cells to irradiation.

Radioresistance of prostate cancer (PCa) is a major factor leading to local failure of radiotherapy. STAT3 is an oncogenic protein that was recently found to be activated in PCa tumors. This study aimed to investigate the radiosensitization effect of targeting STAT3 in PCa tumors. Here, the radiosensitization effect of STAT3 blockade was investigated by clonogenic assay, flow cytometry and western blot analysis in human PCa cells in vitro and in vivo. We demonstrated that STAT3 blockade with a STAT3 inhibitor or siRNA increased the radiosensitivity of PCa cells and that radiation together with STAT3 blockade induced more apoptosis and double-strand breaks (DSBs) than radiation alone in LNCaP cells. In addition, radiation induced STAT3 activation and survivin expression in PCa cells, which was inhibited by STAT3 blockade. Transfection with survivin cDNA attenuated the radiosensitization effect of STAT3 blockade. These effects were further confirmed by in vivo studies, which showed that the STAT3 inhibitor enhanced the treatment efficacy of radiation on LNCaP xenografts with decreased STAT3 activation and survivin expression. These findings suggest that STAT3 blockade radiosensitizes PCa cells through regulation of survivin. Thus, our study has revealed STAT3 as a potential sensitizer for irradiation in PCa cells. Its clinical application as an adjuvant in radiotherapy of PCa should be explored in the future.

Inflammation-Immunity-Nutrition Score: A Novel Prognostic Score for Patients with Resectable Colorectal Cancer.

PURPOSE: This study was designed to investigate the prognostic value of the combination of high-sensitivity C-reactive protein, lymphocyte, and albumin in patients with resectable colorectal cancer. PATIENTS AND METHODS: Seven-hundred-and-nineteen patients who underwent colorectal cancer resection in Hubei Cancer Hospital were included. Inflammation-Immunity-Nutrition score (0-6) was constructed based on preoperative high-sensitivity C-reactive protein, lymphocyte, and albumin. Time-dependent receiver operating characteristic curve, decision curve, Kaplan-Meier survival curve, Cox regression, and C-index were conducted to detect the prognostic values of inflammation-immunity-nutrition score. The prognostic values of inflammation-immunity-nutrition score in different subgroups by sex, location of tumor, pathologic stage, and KRAS mutation were also explored. The prognostic performance of inflammation-immunity-nutrition score was further compared with that of other traditional prognostic indicators. RESULTS: The median follow-up time was 40 months. High inflammation-immunity-nutrition score (>2 scores) presented worse survival, with the adjusted hazard ratios (95% confidence intervals) of 3.106 (2.202-4.380) for overall survival and 2.105 (1.604-2.764) for disease-free survival. Besides, the associations of high inflammation-immunity-nutrition score with overall survival were even stronger in cases with wild type KRAS, with the adjusted hazard ratios (95% confidence intervals) of 4.018 (2.355-6.854). Considering the AUCs, C-indices, and hazard ratios estimates, inflammation-immunity-nutrition score presented better prognostic performance than high-sensitivity modified Glasgow prognostic score, high-sensitivity C-reactive protein to albumin ratio, prognostic nutrition index, carcinoembryonic antigen, and carbohydrate antigen 19-9 for overall survival. CONCLUSION: Inflammation-immunity-nutrition score might serve as a powerful prognostic score in patients with colorectal cancer for overall survival, particularly in patients with wild type KRAS.

Nuclear Her2 contributes to paclitaxel resistance in breast cancer cells.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin ß1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin ß1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

Predictive Values of Postoperative and Dynamic Changes of Inflammation Indexes in Survival of Patients with Resected Colorectal Cancer.

The aim of the present study was to evaluate the prognostic potential of postoperative scores of inflammation indexes and the dynamic changes of scores before and after tumor resection in colorectal cancer patients. The study included 516 colorectal cancer patients with primary colorectal tumor resection. Cox regression was applied to estimate the associations of postoperative and dynamic changes of inflammation indexes with progression-free survival and overall survival. As results, we found that higher postoperative neutrophil to lymphocyte ratio (NLR), neutrophil and monocyte to lymphocyte ratio (NMLR), platelet to lymphocyte ratio (PLR) and systemic immune inflammation index (SII) were associated with shorter progression-free survival. The increased NLR, NMLR, PLR, SII and C-reaction protein (CRP) to albumin (ALB) ratio (CAR) were associated with poor progression-free survival, with HRs (95% CIs) of 1.92 (1.27-2.90), 1.46 (1.11-2.09), 2.10 (1.34-3.30), 1.81 (1.22-2.70) and 1.65 (1.03-2.67), respectively. Postoperative NMLR, SII, CAR, and their dynamic changes were also significantly correlated with overall survival, with the HRs (95% CIs) of 2.63 (1.30-3.97), 2.44 (1.43-4.17), 2.74 (1.31-5.74), 2.08 (1.21-3.60), 1.97 (1.12-3.45) and 2.55 (1.21-5.38) respectively. In conclusion, postoperative inflammation indexes and their dynamic changes, particularly for NMLR, SII and CAR are promising prognostic predictors of CRC patients.

Rosiglitazone enhances the proliferation of neural progenitor cells and inhibits inflammation response after spinal cord injury.

It has been previously shown that peroxisome proliferators-activated receptor gamma (PPAR-γ) is beneficial for nervous system injury. In present study, we examined the effect of rosiglitazone, a PPAR-γ agonist, on spinal cord injury (SCI) in rats. SCI was induced by dropping a 10g weight rod at a height of 25mm. The animals were randomly divided into vehicle group, rosiglitazone treated group, and G3335 treated group. Locomotor function recovery was evaluated by the Basso-Beattie-Bresnahan locomotor rating scale (BBB scale), NF-κB expression and endogenous neural progenitor cells (NPCs) proliferation and differentiation was assessed by flow cytometry and immunohistochemistry. Compared with the vehicle groups, we found that the rosiglitazone could significantly ameliorate locomotor recovery, reduce NF-κB expression, and increase the proliferation of endogenous NPCs. when the PPAR-γ antagonist was use, these effects were abolished. However, neurons differentiating from endogenous NPCs were inhibited when PPAR-γ was activated. Our results suggest that the activation of PPAR-γ may be a potential alternative treatment for spinal cord injury.