Circular RNAs as biomarkers and therapeutic targets for gastrointestinal cancers.

Circular RNAs are a class of noncoding RNAs with covalently linked 5' and 3' ends that arise from backsplicing events. The absence of a 5' cap and a 3' poly(A) tail makes circular RNAs relatively more stable than their linear counterparts. They are evolutionary conserved and tissue-specific, and some show disease-specific expression patterns. Although their biological functions remain largely unknown, circular RNAs have been shown to play regulatory roles by acting as microRNA sponges, regulators of RNA-binding proteins, alternative splicing, and parental gene expression, and they could even encode proteins. Over the past few decades, circular RNAs have attracted wide attention in oncology owing to their implications in various tumors. Many circular RNAs have been characterized as key players in gastrointestinal cancers and influence cancer growth, progression, metastasis, and therapeutic resistance. Accumulating evidence reveals that their unique characteristics, coupled with their critical roles in tumorigenesis, make circular RNAs promising non-invasive clinical biomarkers for gastrointestinal cancers. In the present review, we summarized the biological roles of the emerging circular RNAs and their potential as biomarkers and therapeutic targets, which may help better understand their clinical significance in the management of gastrointestinal cancers.

Connexin 40 regulates lung endothelial permeability in acute lung injury via the ROCK1-MYPT1- MLC20 pathway.

Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung microvascular endothelium. Yet, the role of Cx40 in the regulation of lung vascular permeability and its underlying mechanisms are unclear. Here, we tested the hypothesis that Cx40 participates in regulation of lung endothelial permeability via a mechanism involving a Rho-associated protein kinase (ROCK) dependent regulation of myosin light chain (MLC). In murine models of intratracheal acid- or LPS-induced lung injury, genetic deficiency of Cx40 attenuated key features of ALI including vascular barrier failure. In human pulmonary microvascular endothelial cells (PMVECs), thrombin-induced loss of transendothelial electrical resistance was attenuated by a Cx40-inhibiting mimetic peptide (40GAP27), Cx40-specific shRNA, or ROCK inhibitor Y27632. In isolated perfused mouse lungs, platelet-activating factor-induced lung weight gain was abrogated by gap junction blocker carbenoxolone, 40GAP27, Y27632, or genetic deficiency of Cx40. Phosphorylation of MLC20 increased drastically in both LPS-treated PMVECs and HCl-treated mouse lungs. Expression of ROCK1 was increased in both LPS-treated PMVECs and HCl-treated mouse lungs, and paralleled by phosphorylation of MLC20. Coimmunoprecipitation experiments revealed protein-protein interaction between ROCK1 and Cx40. LPS-induced upregulation of ROCK1 and phosphorylation of MLC20 were blocked by knockdown of Cx40. LPS caused phosphorylation of myosin phosphatase targeting subunit 1, which could be abrogated by Y27632 or Cx40-shRNA. Our findings reveal a role of Cx40 in regulation of ROCK1 and MLC20 that contributes critically to lung vascular barrier failure in ALI.

Short-term evaluation of immune levels and nutritional values of EN versus PN in gastric cancer: a systematic review and a meta-analysis.

BACKGROUND: Postsurgical patients' oral feeding begins with clear fluids 1-3 days after surgery. This might not be sufficiently nutritious to boost the host immune system and provide sufficient energy in gastric neoplastic patients to achieve the goal of enhanced recovery after surgery (ERAS). Our objective was to analyze the significance of early postoperative feeding tubes in boosting patients' immunity and decreasing incidence of overall complications and hospital stay in gastric cancer patients' post-gastrectomy. METHODS: From January 2005 to May 24, 2019, PubMed and Cochrane databases were searched for studies involving enteral nutrition (EN) feeding tubes in comparison to parenteral nutrition (PN) in gastric cancer patients undergoing gastrectomy for gastric malignancies. Relative risk (RR), mean difference (MD), or standard mean difference (SMD) with 95% confidence interval (CI) were used to estimate the effect sizes, and heterogeneity was assessed by using Q and χ2 statistic with their corresponding P values. All the analyses were performed with Review Manager 5.3 and SPSS version 22. RESULTS: Nine randomized trials (n = 1437) and 5 retrospective studies (n = 421) comparing EN feeding tubes and PN were deemed eligible for the pooled analyses, with a categorized time frame of PODs ≥ 7 and PODs < 7. Ratio of CD4+/CD8+ in EN feeding tubes was the only outcome of PODs < 7, which showed significance (MD 0.22, 95% CI 0.18-0.25, P < 0.00001). Regarding other immune indicators, significant outcomes in favor of EN feeding tubes were measured on POD ≥ 7: CD3+ (SMD 1.71; 95% CI 0.70, 2.72; P = 0.0009), CD4+ (MD 5.84; 95% CI 4.19, 7.50; P < 0.00001), CD4+/CD8+ (MD 0.28; 95% CI 0.20; 0.36, P < 0.00001), NK cells (SMD 0.94; 95% CI 0.54, 1.30; P < 0.00001), nutrition values, albumin (SMD 0.63; 95% CI 0.34, 0.91; P < 0.001), prealbumin (SMD 1.00; 95% CI 0.52, 1.48; P < 0.00001), and overall complications (risk ratio 0.73 M-H; fixed; 95% CI 0.58, 0.92; P = 0.006). CONCLUSION: EN feeding tube support is an essential intervention to elevate patients' immunity, depress levels of inflammation, and reduce the risk of complications after gastrectomy for gastric cancer. Enteral nutrition improves the innate immune system and nutrition levels but has no marked significance on certain clinical outcomes. Also, EN reduces the duration of hospital stay and cost, significantly.