Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.
This study was designed to mainly evaluate the anti-infective effects of perioperative probiotic treatment in patients receiving confined colorectal cancer (CRC) respective surgery. From November 2011 to September 2012, a total of 60 patients diagnosed with CRC were randomly assigned to receive probiotic (n = 30) or placebo (n = 30) treatment. The operative and post-operative clinical results including intestinal cleanliness, days to first - flatus, defecation, fluid diet, solid diet, duration of pyrexia, average heart rate, length of intraperitoneal drainage, length of antibiotic therapy, blood index changes, rate of infectious and non-infectious complications, postoperative hospital stay, and mortality were investigated. The patient demographics were not significantly different (p > 0.05) between the probiotic treated and the placebo groups. The days to first flatus (3.63 versus 3.27, p = 0.0274) and the days to first defecation (4.53 versus 3.87, p = 0.0268) were significantly improved in the probiotic treated patients. The incidence of diarrhea was significantly lower (p = 0.0352) in probiotics group (26.67%, 8/30) compared to the placebo group (53.33%, 16/30). There were no statistical differences (p > 0.05) in other infectious and non-infectious complication rates including wound infection, pneumonia, urinary tract infection, anastomotic leakage, and abdominal distension. In conclusion, for those patients undergoing confined CRC resection, perioperative probiotic administration significantly influenced the recovery of bowel function, and such improvement may be of important clinical significance in reducing the short-term infectious complications such as bacteremia.
The correlation between the rate of TEC index (ROTI) and scintillation indices 𝑆 4 and 𝜎 Φ for low latitude region is analyzed in this study, using data collected from a Global Positioning System (GPS) scintillation monitoring receiver installed at the south of Hong Kong for the periods June-August of 2012 and May-December of 2013. The analysis indicates that the correlation coefficient between ROTI and 𝑆 4 /𝜎 Φ is about 0.6 if data from all GPS satellites are used together. If each individual satellite is considered, the correlation coefficients are above 0.6 on average and sometimes above 0.8. The analysis also shows that the ratio of ROTI and 𝑆 4 varies between 1 and 4. The ratio ROTI/𝜎 Φ , varies between 2 and 9. In addition, it is also found that there is a good consistency between the temporal variations of ROTI with scintillation activity under different ionospheric conditions. ROTI has a high correlation relationship with scintillation indices on geomagnetically disturbed days or in solar active months. Moreover, the data observed at low elevation angles have weak correlation between ROTI and scintillation indices. These results demonstrate the feasibility of using ROTI derived from GPS observations recorded by common non-scintillation GPS receivers to characterize ionospheric scintillations.
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