BackgroundEpithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive.MethodologyEligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value.Principal FindingsA total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63–3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13–3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95–1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45–2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19–0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21–0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32–0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22–0.91, Z = 3.43, P = 0.001), respectively.ConclusionsThis study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.

Background β-catenin plays a key role in the progression of colorectal cancer (CRC). However, its prognostic significance for patients with CRC remains controversial.MethodologyIdentical search strategies were used to search relevant literatures in the PubMed, Embase and Web of Science databases. The correlation between β-catenin expression and clinicopathological features and prognosis was analyzed.Principal FindingsA total of 18 studies met the inclusion criteria, which comprised 3665 cases. Meta-analysis suggested that β-catenin overexpression in the nucleus was significantly associated with disease free survival (DFS) (n = 541 in 3 studies; HR = 1.87, 95% CI: 1.28–2.71; Z = 3.26; P = 0.001) and overall survival (OS) for CRC patients (n = 2630 in 10 studies; HR = 1.55, 95% CI: 1.12–2.14; Z = 2.62; P = 0.009). However, there was no significant association between β-catenin expression in the cytoplasm and OS (n = 1327 in 3 studies; HR = 1.04, 95% CI: 0.88–1.24, Z = 0.46, P = 0.643). The combined odds ratio (OR) of β-catenin in the nucleus indicated that β-catenin overexpression was associated with advanced stage CRC (n = 950 in 7 studies; OR = 0.71, 95% CI: 0.53–0.94; Z = 2.35; P = 0.019) and metastasis of CRC (n = 628 in 5 studies; OR = 0.49, 95% CI: 0.25–0.96, Z = 2.06, P = 0.039). β-catenin overexpression in the nucleus had no correlation with the tumor site (colon or rectum), differentiation grade, lymph node status or depth of invasion. The pooled ORs were 1.09 (95% CI: 0.41–2.91, Z = 0.18, P = 0.856), 1.27(95% CI: 0.76–2.10, Z = 0.92, P = 0.357), 0.71(95% CI: 0.46–1.09, Z = 1.58, P = 0.115) and 0.82(95% CI: 0.4–1.68, Z = 0.53, P = 0.594).ConclusionsThis study showed that β-catenin overexpression in the nucleus, rather than in the cytoplasm, appeared to be associated with progress disease and a worse prognosis for CRC patients.

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans and play a major role in the genetics of human phenotype variation and the genetic basis of human complex diseases. Recently, there is considerable interest in understanding the possible role of the CYP11B2 gene with corticosterone methyl oxidase deficiency, primary aldosteronism, and cardio-cerebro-vascular diseases. Hence, the elucidation of the function and molecular dynamic behavior of CYP11B2 mutations is crucial in current genomics. In this study, we investigated the pathogenic effect of 51 nsSNPs and 26 UTR SNPs in the CYP11B2 gene through computational platforms. Using a combination of SIFT, PolyPhen, I-Mutant Suite, and ConSurf server, four nsSNPs (F487V, V129M, T498A, and V403E) were identified to potentially affect the structure, function, and activity of the CYP11B2 protein. Furthermore, molecular dynamics simulation and structure analyses also confirmed the impact of these nsSNPs on the stability and secondary properties of the CYP11B2 protein. Additionally, utilizing the UTRscan, MirSNP, PolymiRTS and miRNASNP, three SNPs in the 3′UTR region were predicted to exhibit a pattern change in the upstream open reading frames (uORF), and eight microRNA binding sites were found to be highly affected due to 3′UTR SNPs. This cataloguing of deleterious SNPs is essential for narrowing down the number of CYP11B2 mutations to be screened in genetic association studies and for a better understanding of the functional and structural aspects of the CYP11B2 protein.

The objective of the research was to investigate the function of endothelial progenitor cells (EPCs) in the conditions of high glucose and lipids, which has been widely used to mimic the metabolic disorder that occurs in type 2 diabetic mellitus, and further to verify the role of PGC-1α and SIRT1, cellular energy metabolism regulators, in the process of senescence of EPCs with these combined stimuli. Circulating EPCs were incubated in absence or presence of high glucose (25 mM), FFA (200 µM) or both. EPCs senescence was assessed by β-galactosidase staining, EPCs telomerase activity was measured by telomeric repeat ampli-fication protocol assay, in vitro angiogenesis assay and MTT assays were performed to assess angiogenesis and proliferation ability of EPCs. The results showed that combined stimuli inhibited EPCs reendothelialization ability in vitro, accelerated EPCs senescence and decreased the telomerase activity. Meanwhile, with combined stimuli, the expression of PGC-1α increased whereas SIRT1 expression decreased in EPCs accompanied by activation of P53/P21 signaling pathway. Conversely, transfection of EPCs with PGC-1α-siRNA rescued EPCs premature senescence and up-regulated SIRT1 and decreased P53/P21 expression, correlating closely with the down-regulation of PGC-1α itself. In addition, the combined stimuli induced up-regulation of PGC-1α expression was partly mediated by ROS and P38 signaling pathway. Overall, the data presented here identify PGC-1α as a potent negative regulator of EPCs' senescence under combined stimuli, which is partly mediated by SIRT1/P53/P21 signaling pathway.

Kimura disease (KD) is a rare and benign chronic inflammatory disease of unknown cause. It is characterized by subcutaneous granuloma of soft tissues in the head and neck region, increased eosinophil count, and elevated serum IgE. Currently, no definitive treatments are recommended. A 57-year-old Chinese man was diagnosed with KD after 7 years of slow subcutaneous masses growth. The patient underwent treatment of oral glucocorticoids for 1 year, but the masses recurred as the dosage was tapered down. Subsequent anti-IgE therapy of omalizumab administered subcutaneously at 450 mg/day at a 4-week interval did not show improvement. The size of masses and serum IgE and circulating eosinophils did not decrease significantly after 19 cycles of continuous treatment. Ultimately, switched strategy of dupilumab was applied at an initial dose of 600 mg, followed by 300 mg every 2 weeks for 4 months. This treatment demonstrated dramatical effects with reduced masses in each area and fast dropdown of eosinophil counts, while the high level of serum IgE remained without changes. Recently, different biologics including anti-IgE, anti-IL-5, and anti-IL-4/IL-13 have been applied to treat KD with satisfied results and help to explore the pathogenesis of this rare disease. To our knowledge, this is the first report that demonstrates the effects of two different biologics in the same patient and reveals the impressive clinical efficacy of dupilumab to treat KD independent of IgE. Therefore, further investigation of the underlying mechanism and the development of diagnosis and treatment of KD is valuable.