Effects of prolonged face mask use among patients with hypertension or diabetes during the COVID-19 pandemic.

OBJECTIVE: We aimed to investigate the impacts of prolonged mask use on patients with hypertension or diabetes during the COVID-19 pandemic. METHODS: This study included patients with hypertension or diabetes who visited the outpatient department of Nanjing Yimin Hospital between 1 February 2022 and 31 January 2023. We compared the change in blood pressure (BP) and fasting plasma glucose in patients with hypertension or diabetes and adjustments to treatment between the group with prolonged mask-wearing group (≥20 hours/week) and the control group (<20 hours/week). RESULTS: Compared with the control group of hypertensive patients, the prolonged mask-wearing group had significantly higher diastolic blood pressure (DBP) and mean arterial pressure (MAP). These two groups had had similar DBP and MAP 1 year earlier. Likewise, the prolonged mask-wearing group of patients with diabetes had a greater need than the control group for upgraded treatment to reach their therapeutic goals. CONCLUSIONS: This study suggests that prolonged mask use by patients with hypertension or diabetes has negative effects on hypertension and plasma glucose control. BP and plasma glucose monitoring should be improved in these patient populations and their treatment should be adjusted in a timely manner.

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice.

BACKGROUND: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. METHODS: We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6f/- Tie2Cre+) and tamoxifen-inducible Arf6 knockout (Arf6f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. RESULTS: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. CONCLUSIONS: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

Activation of NFAT by HGF and IGF-1 via ARF6 and its effector ASAP1 promotes uveal melanoma metastasis.

Preventing or effectively treating metastatic uveal melanoma (UM) is critical because it occurs in about half of patients and confers a very poor prognosis. There is emerging evidence that hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1) promote metastasis and contribute to the striking metastatic hepatotropism observed in UM metastasis. However, the molecular mechanisms by which HGF and IGF-1 promote UM liver metastasis have not been elucidated. ASAP1, which acts as an effector for the small GTPase ARF6, is highly expressed in the subset of uveal melanomas most likely to metastasize. Here, we found that HGF and IGF-1 hyperactivate ARF6, leading to its interaction with ASAP1, which then acts as an effector to induce nuclear localization and transcriptional activity of NFAT1. Inhibition of any component of this pathway impairs cellular invasiveness. Additionally, knocking down ASAP1 or inhibiting NFAT signaling reduces metastasis in a xenograft mouse model of UM. The discovery of this signaling pathway represents not only an advancement in our understanding of the biology of uveal melanoma metastasis but also identifies a novel pathway that could be targeted to treat or prevent metastatic uveal melanoma.

Laparoscopic versus open surgery for colonoscopic perforation: A systematic review and meta-analysis.

BACKGROUND: The efficacy of laparoscopic surgery (LS) for the treatment of colonoscopic perforation is still controversial. The purpose of this meta-analysis was to evaluate the effectiveness and safety of LS versus open surgery (OS) for colonoscopic perforation. METHODS: All clinical trials that compared laparoscopic with OS for colonoscopic perforation published in English were identified in PubMed, EMBASE, Web of Science, and Cochrane Library searches. A modified scale was used to assess the quality of the literature. We analyzed the age, sex ratio, aim of colonoscopy, history of abdominopelvic surgery, type of procedure, size of perforation, operation time, postoperative fasting time, hospital stay, postoperative complication morbidity, and postoperative mortality. Meta-analyses were performed using weighted mean differences for continuous variables, and odds ratios for dichotomous variables. RESULTS: No eligible randomized trials were identified, but eleven nonrandomized trials were analyzed. In the pooled data of 192 patients who underwent LS and 131 OS, there were no significant differences in age, sex ratio, aim of colonoscopy, history of abdominopelvic surgery, perforation size, and operative time between the groups. LS group had shorter time of hospital stay and postoperative fasting time, less postoperative complication morbidity, but there were no significant difference in postoperative mortality rate between LS group and OS group. CONCLUSIONS: Based on the current meta-analysis, we conclude that LS is a safe and efficacious technique for colonoscopic perforation, with fewer postoperative complications, less hospital mortality, and faster recovery compared with OS.

Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis.

Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.

Endothelial specific reduction in Arf6 impairs insulin-stimulated vasodilation and skeletal muscle blood flow resulting in systemic insulin resistance.

Background: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance, however, the underlying mechanisms remain incompletely understood. ADP ribosylation factor 6 (Arf6) is a small GTPase that plays a critical role in endothelial cell (EC) function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. Methods: We used mouse models of constitutive EC-specific Arf6 deletion (Arf6 f/- Tie2Cre) and tamoxifen inducible Arf6 knockout (Arf6 f/f Cdh5Cre). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose- and insulin-tolerance tests and hyperinsulinemic-euglycemic clamps. A fluorescence microsphere-based technique was used to measure tissue blood flow. Intravital microscopy was used to assess skeletal muscle capillary density. Results: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue (WAT) and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide (NO) bioavailability but independent of altered acetylcholine- or sodium nitroprusside-mediated vasodilation. In vitro Arf6 inhibition resulted in suppressed insulin stimulated phosphorylation of Akt and endothelial NO synthase. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow fed mice and glucose intolerance in high fat diet fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. Conclusion: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

LPA2 Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction.

RATIONALE: Myocardial infarction (MI) is one of the most dangerous adverse cardiovascular events. Our previous study found that lysophosphatidic acid (LPA) is increased in human peripheral blood after MI, and LPA has a protective effect on the survival and proliferation of various cell types. However, the role of LPA and its receptors in MI is less understood. OBJECTIVES: To study the unknown role of LPA and its receptors in heart during MI. METHODS AND RESULTS: In this study, we found that mice also had elevated LPA level in peripheral blood, as well as increased cardiac expression of its receptor LPA2 in the early stages after MI. With adult and neonate MI models in global Lpar2 knockout (Lpar2-KO) mice, we found Lpar2 deficiency increased vascular leak leading to disruption of its homeostasis, so as to impaired heart function and increased early mortality. Histological examination revealed larger scar size, increased fibrosis, and reduced vascular density in the heart of Lpar2-KO mice. Furthermore, Lpar2-KO also attenuated blood flow recovery after femoral artery ligation with decreased vascular density in gastrocnemius. Our study revealed that Lpar2 was mainly expressed and altered in cardiac endothelial cells during MI, and use of endothelial-specific Lpar2 knockout mice phenocopied the global knockout mice. Additionally, adenovirus-Lpar2 and pharmacologically activated LPA2 significantly improved heart function, reduced scar size, increased vascular formation, and alleviated early mortality by maintaining vascular homeostasis owing to protecting vessels from leakage. Mechanistic studies demonstrated that LPA-LPA2 signaling could promote endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk pathway and enhanced endothelial cell tube formation via PKD1-CD36 signaling. CONCLUSIONS: Our results indicate that endothelial LPA-LPA2 signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA2 signal might have clinical therapeutic potential to protect the heart from ischemic injury.

Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.

Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1ß-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway. Inhibiting the activation of ARF6 both prevents and reverses EndoMT, stabilizes BCNSB function, reduces demyelination, and attenuates symptoms even after the establishment of severe EAE, without immunocompromising the host. Pan-inhibition of ALKs also reduces disease severity in the EAE model. Therefore, multiple components of the IL-1ß-ARF6-ALK-SMAD1/5 pathway could be targeted for the treatment of a variety of neuroinflammatory disorders.

Deletion of Arno Reduces Eosinophilic Inflammation and Interleukin-5 Expression in a Murine Model of Rhinitis.

BACKGROUND: ARF nucleotide-binding site opener (ARNO) is a guanine nucleotide-exchange factor for ADP-ribosylation factor proteins. ARF nucleotide-binding site opener also binds MyD88, and small-molecule inhibition of ARNO reduces inflammation in animal models of inflammatory arthritis and acute inflammation. However, whether genetic deletion of Arno in mice reduces pathologic inflammation has not yet been reported. Furthermore, its role in the nasal cavity has yet to be investigated. OBJECTIVE: To generate Arno knockout mice and to determine whether genetic loss of ARNO reduces eosinophilic inflammation in the ovalbumin (OVA) murine model of rhinitis. METHODS: Arno knockout mice were generated and wild type and knockout littermates were subjected to the OVA-induced mouse model of rhinosinutitis. Eosinophilic inflammation was assessed through immunofluorescent quantification of EMBP+ eosinophils in the septal mucosa and cytokine expression was assessed by quantitative polymerase chain reaction. RESULTS: Arno knockout mice are viable and fertile without any noted deficits. Arno wild type and knockout mice subjected to the OVA-induced model of rhinitis demonstrated an average of 314.5 and 153.8 EMBP+ cells per mm2 septal tissue, respectively (P < .05). Goblet cells per mm of basal lamina were assessed via Alcian blue and there was no statistically significant difference between Arno wild type and knockout mice. Ovalbumin-induced expression of interleukin-5 (IL-5) was significantly reduced in Arno knockout mice (P < .05). There was no statistically significant reduction in IL-4, IL-13, or eotaxin-1 expression. CONCLUSIONS: These data demonstrate that deletion of Arno reduces eosinophilic inflammation and IL-5 expression in an OVA-induced model of rhinitis.

Role of minimally invasive techniques in gastrointestinal surgery: Current status and future perspectives.

In recent years, the incidence of gastrointestinal cancer has remained high. Currently, surgical resection is still the most effective method for treating gastrointestinal cancer. Traditionally, radical surgery depends on open surgery. However, traditional open surgery inflicts great trauma and is associated with a slow recovery. Minimally invasive surgery, which aims to reduce postoperative complications and accelerate postoperative recovery, has been rapidly developed in the last two decades; it is increasingly used in the field of gastrointestinal surgery and widely used in early-stage gastrointestinal cancer. Nevertheless, many operations for gastrointestinal cancer treatment are still performed by open surgery. One reason for this may be the challenges of minimally invasive technology, especially when operating in narrow spaces, such as within the pelvis or near the upper edge of the pancreas. Moreover, some of the current literature has questioned oncologic outcomes after minimally invasive surgery for gastrointestinal cancer. Overall, the current evidence suggests that minimally invasive techniques are safe and feasible in gastrointestinal cancer surgery, but most of the studies published in this field are retrospective studies and case-matched studies. Large-scale randomized prospective studies are needed to further support the application of minimally invasive surgery. In this review, we summarize several common minimally invasive methods used to treat gastrointestinal cancer and discuss the advances in the minimally invasive treatment of gastrointestinal cancer in detail.

Robotic natural orifice specimen extraction surgery versus traditional robotic-assisted surgery (NOTR) for patients with colorectal cancer: a study protocol for a randomized controlled trial.

BACKGROUND: Natural orifice specimen extraction surgery for colorectal cancer has been introduced in order to reduce the abdominal incision, demonstrating major development potential in minimally invasive surgery. We are conducting this randomized controlled trial to assess whether robotic NOSES is non-inferior to traditional robotic-assisted surgery for patients with colorectal cancer in terms of primary and secondary outcomes. METHOD/DESIGN: Accordingly, a prospective, open-label, randomized controlled, parallel-group, multicenter, and non-inferiority trial will be conducted to discuss the safety and efficacy of robotic natural orifice extraction surgery compared to traditional robotic-assisted surgery. Here, 550 estimated participants will be enrolled to have 80% power to detect differences with a one-sided significance level of 0.025 in consideration of the non-inferiority margin of 10%. The primary outcome is the incidence of surgical complications, which will be classified using the Clavien-Dindo system. DISCUSSION: This trial is expected to reveal whether robotic NOSES is non-inferior to traditional robotic-assisted surgery, which is of great significance in regard to the development of robotic NOSES for patients with colorectal cancer in the minimally invasive era. Furthermore, robotic NOSES is expected to exhibit superiority to traditional robotic-assisted surgery in terms of both primary and secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04230772 . Registered on January 15, 2020.

Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/ß-catenin signaling.

Familial exudative vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/ß-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in α-catenin (CTNNA1) cause FEVR by overactivating the ß-catenin pathway and disrupting cell adherens junctions. We identified 3 heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27, and p.P893L) by exome sequencing and further demonstrated that FEVR-associated mutations led to overactivation of Norrin/ß-catenin signaling as a result of impaired protein interactions within the cadherin-catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivated ß-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung ECs, both CTNNA1-P893L and F72S mutants failed to rescue either the disrupted F-actin arrangement or the VE-cadherin and CTNNB1 distribution. Moreover, we discovered that compound heterozygous Ctnna1 F72S and a deletion allele could cause a similar phenotype. Furthermore, in a FEVR family, we identified a mutation of LRP5, which activates Norrin/ß-catenin signaling, and the corresponding knockin mice exhibited a partial FEVR-like phenotype. Our study demonstrates that the precise regulation of ß-catenin activation is critical for retinal vascular development and provides new insights into the pathogenesis of FEVR.

MicroRNAs: Multifaceted Regulators of Colorectal Cancer Metastasis and Clinical Applications.

Colorectal cancer (CRC) is the third-commonest malignant cancer, and its metastasis is the major reason for cancer-related death. The process of metastasis is highly coordinated and involves a complex cascade of multiple steps. In recent years, miRNAs, as highly conserved, endogenous, noncoding, single-stranded RNA, has been confirmed to be involved in the development of various cancers. Considering that miRNA is also involved in a series of biological behaviors, regulating CRC occurrence and development, we review and summarize the role of miRNAs and related signaling pathways in several CRC-metastasis stages, including invasion and migration, mobility, metabolism, epithelial-mesenchymal transition, tumor-microenvironment communication, angiogenesis, anoikis, premetastatic-niche formation, and cancer stemness. In addition, we review the application of miRNAs as diagnostic CRC markers and in clinical treatment resistance. This review can contribute to understanding of the mechanism of miRNAs in CRC progression and provide a theoretical basis for clinical CRC treatment.

Apigenin and Ethaverine Hydrochloride Enhance Retinal Vascular Barrier In Vitro and In Vivo.

Purpose: This study aims to develop an impedance-based drug screening platform that will help identify drugs that can enhance the vascular barrier function by stabilizing vascular endothelial cell junctions. Methods: Changes in permeability of cultured human retinal microvascular endothelial cells (HRMECs) monolayer were monitored in real-time with the xCELLigence RTCA system. Using this platform, we performed a primary screen of 2100 known drugs and confirmed hits using two additional secondary permeability assays: the transwell permeability assay and the XPerT assay. The cellular and molecular mechanisms of action and in vivo therapeutic efficacy were also assessed. Results: Eleven compounds blocked interleukin 1 beta (IL-1ß) induced hyperpermeability in the primary screen. Two of 11 compounds, apigenin and ethaverine hydrochloride, reproducibly blocked multiple cytokines induced hyperpermeability. In addition to HRMEC monolayers, the two compounds stabilized three other types of primary vascular endothelial cell monolayers. Preliminary mechanistic studies suggest that the two compounds stabilize the endothelium by blocking ADP-ribosylation factor 6 (ARF6) activation, which results in enhanced VE-cadherin membrane localization. The two compounds showed in vivo efficacy in an animal model of retinal permeability. Conclusions: We developed an impedance-based cellular phenotypic drug screening platform that can identify drugs that enhance vascular barrier function. We found apigenin and ethaverine hydrochloride stabilize endothelial cell junctions and enhance the vascular barrier by blocking ARF6 activation and increasing VE-cadherin membrane localization. Translational Relevance: The drugs identified from the phenotypic screen would have potential therapeutic efficacy in retinal vascular diseases regardless of the underlying mechanisms that promote vascular leak.

Clinical outcomes and prognostic factors of robotic assisted rectal cancer resection alone versus robotic rectal cancer resection with natural orifice extraction: a matched analysis.

Robotic rectal cancer resection with natural orifice extraction is a recently developed minimally invasive surgery used in the treatment of patients with rectal cancer. However, its safety and feasibility remain undiscussed and controversial. This study reported the clinical outcomes and prognostic factors pertaining to traditional robotic assisted rectal cancer resection alone against that of robotic rectal cancer resection with natural orifice extraction to provide a discussion on this issue. 49 patients who underwent robotic rectal cancer resection with natural orifice extraction and 49 matched patients who underwent conventional robotic assisted rectal cancer resection were systematically analyzed in this study. Regarding the baseline characteristics, after matching, no significant differences were observed between the natural orifice specimen extraction (NOSE) group and the robotic assisted rectal cancer resection (RARC) group. Patients in the NOSE group had a reduced visual analog scale (p < 0.001), passed flatus more quickly (p = 0.002) and suffered less surgical stress than those in the RARC group. Moreover, 4 complications were observed in the NOSE group and 7 complications in the RARC group with no significant difference (p = 0.337) in terms of complications. The two groups had a similar survival outcomes, where the 3-year overall survival (p = 0.738) and 3-year progression-free survival (p = 0.986) were all comparable between the two groups. Histological differentiation and T stage could be regarded as independent prognostic factors for 3-year overall survival and 3-year progression-free survival. Robotic rectal cancer resection with natural orifice extraction is a safe and feasible minimally invasive surgery for patients suffering from rectal cancer as it encompasses considerable several advantages. Histological differentiation and T stage may serve as independent prognostic factors for 3-year overall survival and 3-year progression-free survival.

Robotic- vs laparoscopic-assisted proctectomy for locally advanced rectal cancer based on propensity score matching: Short-term outcomes at a colorectal center in China.

BACKGROUND: Reports in the field of robotic surgery for rectal cancer are increasing year by year. However, most of these studies enroll patients at a relatively early stage and have small sample sizes. In fact, studies only on patients with locally advanced rectal cancer (LARC) and with relatively large sample sizes are lacking. AIM: To investigate whether the short-term outcomes differed between robotic-assisted proctectomy (RAP) and laparoscopic-assisted proctectomy (LAP) for LARC. METHODS: The clinicopathological data of patients with LARC who underwent robotic- or laparoscopic-assisted radical surgery between January 2015 and October 2019 were collected retrospectively. To reduce patient selection bias, we used the clinical baseline characteristics of the two groups of patients as covariates for propensity-score matching (PSM) analysis. Short-term outcomes were compared between the two groups. RESULTS: The clinical features were well matched in the PSM cohort. Compared with the LAP group, the RAP group had less intraoperative blood loss, lower volume of pelvic cavity drainage, less time to remove the pelvic drainage tube and urinary catheter, longer distal resection margin and lower rates of conversion (P < 0.05). However, the time to recover bowel function, the harvested lymph nodes, the postoperative length of hospital stay, and the rate of unplanned readmission within 30 days postoperatively showed no difference between the two groups (P > 0.05). The rates of total complications and all individual complications were similar between the RAP and LAP groups (P > 0.05). CONCLUSION: This retrospective study indicated that RAP is a safe and feasible method for LARC with better short-term outcomes than LAP, but we have to admit that the clinically significant of part of indicators are relatively small in the practical situation.

Preserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial Infection.

The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization's and National Institutes of Health's high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host's vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, and CPKP. We show that the pharmacological inhibition of ARF6-GTP phenocopies endothelium-specific Arf6 disruption in enhancing the survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small-molecule inhibitors acts by the restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of the TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host's vasculature with small-molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and reemerging pathogens.

Robotic- versus laparoscopic-assisted distal gastrectomy with D2 lymphadenectomy for advanced gastric cancer based on propensity score matching: short-term outcomes at a high-capacity center.

Reports in the field of robotic surgery for gastric cancer are increasing. However, studies only on patients with advanced gastric cancer (AGC) are lacking. This retrospective study was to compare the short-term outcomes of robotic-assisted distal gastrectomy (RADG) and laparoscopic-assisted distal gastrectomy (LADG) with D2 lymphadenectomy for AGC. From December 2014 to November 2019, 683 consecutive patients with AGC underwent mini-invasive assisted distal gastrectomy. Propensity-score matching (PSM) analysis was conducted to reduce patient selection bias. Short-term outcomes were compared between the two groups. The clinical features were well matched in the PSM cohort. Compared with the LADG group, the RADG group was associated with less operative blood loss, a lower rate of postoperative blood transfusion, less volume of abdominal drainage, less time to remove abdominal drainage tube, retrieved more lymph node, and lower rates of surgical complications and pancreatic fistula (P <0.05). However, the time to recovery bowel function, the length of postoperative stay, the rates of other subgroups of complications and unplanned readmission were similar between the two groups (P > 0.05). This study suggests that RADG is a safe and feasible technique with better short-term outcomes than LADG for AGC.

ROBO4 deletion ameliorates PAF-mediated skin inflammation via regulating the mRNA translation efficiency of LPCAT1/LPCAT2 and the expression of PAF receptor.

The diminished level of platelet-activating factor acetylhydrolase (PAFAH) in milk causes an enhanced level of platelet activating factor (PAF) in the skin, leading to a severe hair loss phenotype during neonatal pup's lactation. The deletion of very-low-density-lipoprotein receptor (VLDLR) prevents the expression and secretion of PAFAH. Here we revealed that deletion of Roundabout 4 (ROBO4) in mice ameliorated hair loss phenotype via reducing PAF concentration in skin. As a consequence, the neonatal pups with ROBO4 deletion lactated by mother with VLDLR deletion showed normal hair phenotype during lactation. In details,ROBO4 deletion reduced the protein but not mRNA expression of two PAF synthetic enzymes LPCAT1/LPCAT2 in macrophage as well as the expression of PAF receptor in both macrophage and ocular tissue, but increased PAFAH protein in serum. On the other hand, RNA expression profile analysis in macrophages revealed that the genes involving in oxidative phosphorylation and ribosome obviously decreased their expression in response to ROBO4 deletion. Moreover, through High Performance Liquid Chromatography (HPLC) analysis, we found that ATP concentration also reduced in ROBO4 deletion macrophages. Because ribosome and energy are very important factors for the mRNA translation, we then tested whether ROBO4 deletion affects LPCAT1/LPCAT2 mRNA translation using polyribosome assay. As expected, the mRNA level of LPCAT1/LPCAT2 significantly decreased in polyribosome in ROBO4 deletion macrophage comparing to that of wild type. Additionally, mice with ROBO4 deletion suppressed LPS-induced IL-6 expression as well as the phosphorylation of p44/42 and p65, but enhanced the AKT phosphorylation. Collectively, ROBO4 deletion alleviates PAF- and LPS-mediated inflammation. And above results also indicate PAF signal might be a crosstalk point of ROBO4- and VLDLR-activated pathways.