SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake.

Beyond glycemic control, SGLT2 inhibitors (SGLT2i) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers, and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. Additionally, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of downstream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.

Multi-omics provide insights into the regulation of DNA methylation in pear fruit metabolism.

BACKGROUND: Extensive research has been conducted on fruit development in crops, but the metabolic regulatory networks underlying perennial fruit trees remain poorly understood. To address this knowledge gap, we conduct a comprehensive analysis of the metabolome, proteome, transcriptome, DNA methylome, and small RNAome profiles of pear fruit flesh at 11 developing stages, spanning from fruitlet to ripening. Here, we systematically investigate the metabolic landscape and regulatory network involved. RESULTS: We generate an association database consisting of 439 metabolites and 14,399 genes to elucidate the gene regulatory network of pear flesh metabolism. Interestingly, we detect increased DNA methylation in the promoters of most genes within the database during pear flesh development. Application of a DNA methylation inhibitor to the developing fruit represses chlorophyll degradation in the pericarp and promotes xanthophyll, ß-carotene, and abscisic acid (ABA) accumulation in the flesh. We find the gradual increase in ABA production during pear flesh development is correlated with the expression of several carotenoid pathway genes and multiple transcription factors. Of these transcription factors, the zinc finger protein PbZFP1 is identified as a positive mediator of ABA biosynthesis in pear flesh. Most ABA pathway genes and transcription factors are modified by DNA methylation in the promoters, although some are induced by the DNA methylation inhibitor. These results suggest that DNA methylation inhibits ABA accumulation, which may delay fruit ripening. CONCLUSION: Our findings provide insights into epigenetic regulation of metabolic regulatory networks during pear flesh development, particularly with regard to DNA methylation.

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice.

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients.

Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed. We selected serum interleukin-15 (sIL-15) out of four interleukins as a candidate biomarker, while most patients' sIL-15 levels were too low to be detected by conventional methods, so it was necessary to construct a highly sensitive method to detect sIL-15 in order to select NPC patients who would benefit most or least from ICIs. METHODS: Combining a primer exchange reaction (PER), transcription-mediated amplification (TMA), and a immuno-PER-TMA-CRISPR/Cas13a system, we developed a novel multiple signal amplification platform with a detection limit of 32 fg/mL, making it 153-fold more sensitive than ELISA. RESULTS: This platform demonstrated high specificity, repeatability, and versatility. When applied to two independent cohorts of 130 NPC sera, the predictive value of sIL-15 was accurate in both cohorts (area under the curve: training, 0.882; validation, 0.898). Additionally, lower sIL-15 levels were correlated with poorer progression-free survival (training, HR: 0.080, p<0.0001; validation, HR: 0.053, p<0.0001). CONCLUSION: This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.

Prevalence and risk factors for colonisation and infection with carbapenem-resistant Enterobacterales in intensive care units: A prospective multicentre study.

OBJECTIVES: This study aimed to investigate the prevalence and risk factors for carbapenem-resistant Enterobacterales colonisation/infection at admission and acquisition among patients admitted to the intensive care unit. RESEARCH METHODOLOGY/DESIGN: A prospective and multicentre study. SETTING: This study was conducted in 24 intensive care units in Anhui, China. MAIN OUTCOME MEASURES: Demographic and clinical data were collected, and rectal carbapenem-resistant Enterobacterales colonisation was detected by active screening. Multivariate logistic regression models were used to analyse factors associated with colonisation/infection with carbapenem-resistant Enterobacterales at admission and acquisition during the intensive care unit stay. RESULTS: There were 1133 intensive care unit patients included in this study. In total, 5.9% of patients with carbapenem-resistant Enterobacterales colonisation/infection at admission, and of which 56.7% were colonisations. Besides, 8.5% of patients acquired carbapenem-resistant Enterobacterales colonisation/infection during the intensive care stay, and of which 67.6% were colonisations. At admission, transfer from another hospital, admission to an intensive care unit within one year, colonisation/infection/epidemiological link with carbapenem-resistant Enterobacterales within one year, and exposure to any antibiotics within three months were risk factors for colonisation/infection with carbapenem-resistant Enterobacterales. During the intensive care stay, renal disease, an epidemiological link with carbapenem-resistant Enterobacterales, exposure to carbapenems and beta-lactams/beta-lactamase inhibitors, and intensive care stay of three weeks or longer were associated with acquisition. CONCLUSION: The prevalence of colonisation/infection with carbapenem-resistant Enterobacterales in intensive care units is of great concern and should be monitored systematically. Particularly for the 8.5% prevalence of carbapenem-resistant Enterobacterales acquisition during the intensive care stay needs enhanced infection prevention and control measures in these setting. Surveillance of colonisation/infection with carbapenem-resistant Enterobacterales at admission and during the patient's stay represents an early identification tool to prevent further transmission of carbapenem-resistant Enterobacterales. IMPLICATIONS FOR CLINICAL PRACTICE: Carbapenem-resistant Enterobacterales colonization screening at admission and during the patient's stay is an important tool to control carbapenem-resistant Enterobacterales spread in intensive care units.

Research advances in application of mainstream anammox processes: Roles of quorum sensing and microbial metabolism.

Anaerobic ammonium oxidation (anammox) is a low-carbon biological nitrogen removal process, that has been widely applied to treat high-strength wastewater. However, the practical application of mainstream anammox treatment is limited due to the slow growth rate of anammox bacteria (AnAOB). Therefore, it is important to provide a comprehensive summary of the potential impacts and regulatory strategies for system stability. This article systematically reviewed the effects of environmental fluctuations on anammox systems, summarizing the bacterial metabolisms and the relationship between metabolite and microbial functional effects. To address the shortcoming of mainstream anammox process, molecular strategies based on quorum sensing (QS) were proposed. Sludge granulation, gel encapsulation and carrier-based biofilm technologies were adopted to enhance the QS function in microbial aggregation and reduction of biomass loss. Furthermore, this article discussed the application and progress of anammox-coupled processes. Valuable insights were provided for the stable operation and development of mainstream anammox process from the perspectives of QS and microbial metabolism.

Bile acids regulate the epithelial Na+ channel in native tissues through direct binding at multiple sites.

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that regulation occurs through direct binding. Using photoaffinity labelling, we found evidence for specific binding to both the ß and γ subunits of the channel. In functional experiments, we found that the α subunit was sufficient for regulation. We also found that regulation by at least one bile acid was voltage-sensitive, suggesting that one binding site may be closely associated with the pore-forming helices of the channel. Our data provide evidence that bile acids regulate ENaC by binding to multiple sites to influence the open probability of the channel. KEY POINTS: Recent studies have shown that bile acids regulate the epithelial sodium channel (ENaC) in vitro. Here we investigated whether bile acids regulate ENaC in native tissues and whether bile acids directly bind the channel. We found that bile acids regulate ENaC expressed in the mouse cortical collecting duct and mouse colon by modulating open probability. Photoaffinity labelling experiments showed specific binding to the ß and γ subunits of the channel, while channels comprising only α subunits were sensitive to taurocholic acid in functional experiments using Xenopus oocytes. Taurocholic acid regulation of ENaC was voltage-dependent, providing evidence for binding to pore-forming helices. Our data indicate that bile acids are ENaC regulatory effectors that may have a role in the physiology and pathophysiology of several systems.

Activation by cleavage of the epithelial Na+ channel α and γ subunits independently coevolved with the vertebrate terrestrial migration.

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel's α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the α and γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange were required for terrestrial survival.

Development and external validation of a predictive nomogram model of posttraumatic epilepsy: A retrospective analysis.

OBJECTIVE: We aimed to develop and validate a predictive model of posttraumatic epilepsy (PTE). METHODS: The training cohort was patients registered at West China Hospital and diagnosed as traumatic brain injury (TBI) between January 1, 2011, and December 31, 2017. On the basis of multivariable cox proportional hazards model using a forward stepwise method, the nomogram was generated. We externally validated this instrument in 834 participants from two independent cohorts to assess its performance. RESULTS: The nomogram was built based on the results of multivariable cox proportional hazards regression analysis of 1301patients from West China Hospital. The prevalence of PTE was 12.8% (95% confidence interval [CI], 10.9-14.6%) in training cohort, 10.5% (95% CI, 7.5-13.4%) in the testing 1 cohort, and 6.1% (95% CI, 3.7-8.4%) in the testing 2 cohort. 7 independent predictors of PTE composed the nomogram (sex, time of loss of consciousness, subdural hemorrhage, contusion sites, early posttraumatic seizures, TBI severity, and treatment). The C-index was 0.846 (95% CI, 0.817-0.876), and the corresponding sensitivity and specificity were 0.867 and 0.738. External validations showed good discrimination in overall testing cohorts with a C-index of 0.895 (95% CI, 0.859-0.930), in the testing 1 cohort (C-index 0.897, 95% CI, 0.855-0.938) and testing 2 cohort (C-index, 0.883, 95% CI, 0.814-0.952). Calibration of this model was also good since the calibration plots were close to the ideal line. CONCLUSIONS: This nomogram was developed and validated in a large cohort for individualized prediction of PTE, which can identify individuals at high risk of epilepsy and help us find preventive drugs based on these targeted population.

[Inpatient Care Expenditure of Terminally Ill Patients in the Geriatric Ward of Peking Union Medical College Hospital].

Objective To describe the inpatient care expenditure of the terminally ill patients in the geriatric ward of Peking Union Medical College Hospital and facilitate future research on the economic outcomes of hospice and palliative care.Methods The histories of patients admitted to the Department of Geriatrics of Peking Union Medical College Hospital during 2018 were reviewed by trained doctors.According to the diagnosis and overall health state,terminally ill patients were selected and enrolled in the study.Demographics,health and disease information,prescriptions,and expenditure details were retrieved from the HIS system.Results In 2018,35 patients were terminally ill and eligible for hospice care,including 20 males and 15 females,with the average age of(78±8)years(59-91 years),the average age-adjusted Charlson Comorbidity Index of 10±3,and the median Barthel index of 40(10,70).These patients had malignant tumor(23 cases),heart failure(4 cases),end-stage renal disease(1 case),end-stage liver disease(2 cases),dementia(4 cases)and other severe diseases(3 cases).The patients received standard care within the scope of internal medicine and geriatrics.Finally,8 patients died during hospitalization,and 27 were discharged alive.The 35 patients had the median length of stay of 15(12,23)days,the median inpatient expenditure of CNY 21 500(13 800,37 600),and the median daily expenditure of CNY 1425(970,2503).The percentage of expenditure was(28.5±12.3)% for medication,(33.2±18.0)% for tests and examinations,and 11.5%(6.4%,15.8%)for accommodation and medical services.The medications for symptom control costed CNY(77±58)per day on average,accounting for(5.2±3.5)% of the total expenditure.Conclusions The inpatient expenditure for terminally ill patients in the tertiary grade A hospital was higher than that reported in community hospitals providing hospice care.In terms of expenditure constitution,the money spent on medications and tests/examinations were similar,and the percentage of expenditure on medications for symptom control was low.There is a need for further research on the economic impact of hospice and palliative care among terminally ill patients in China.

Prevalence and associated factors of sharps injuries and other blood/body fluid exposures among healthcare workers: A multicenter study.

A multicenter study of sharps injuries (SIs) and other blood or body fluid (OBBF) exposures was conducted among 33,156 healthcare workers (HCWs) from 175 hospitals in Anhui, China. In total, 12,178 HCWs (36.7%) had experienced at least 1 SI in the previous 12 months and 8,116 HCWs (24.5%) had experienced at least 1 OBBF exposure during the previous 12 months.

Validation of the predictive model for seizure recurrence after withdrawal of antiepileptic drugs.

PURPOSE: The purpose of this study was to validate the practicability of Lamberink's prediction model in risk assessment of antiepileptic drug (AED) withdrawal in a real, seizure-free population and to find a practical cutoff value to guide clinical withdrawal. METHODS: A group of seizure-free patients from West China Hospital was recruited. Each patient had been seizure-free for at least two years. The seizure recurrence risk among the patients was calculated by an online AED withdrawal risk calculator. The predictive ability of Lamberink's model was assessed by analyzing discrimination and calibration with receiver operating characteristic (ROC) curves and calibration plots, respectively. RESULTS: A total of 184 seizure-free patients received risk evaluation, all of whom were followed up for at least two years or had an earlier report of seizure relapse. Of these patients, 128 patients were followed up for at least five years or had an earlier report of relapse within five years. Sixty-two of 184 (33.7%) patients relapsed within two years, while 81 of 184 (44.0%) patients relapsed within five years after the start of AEDs' withdrawal. Cox regression analyses showed that seizure duration before remission and the age of seizure onset were independent predictors of relapse at two years. For predictors of recurrence at five years, seizure duration before remission, age at onset, and withdrawal were significant. For discrimination, ROC curve analysis showed that the area under the curve (AUC) for the seizure recurrence within two and five years was 0.605 (95% confidence interval [CI]: 0.518-0.692, p = 0.02) and 0.656 (95% CI: 0.563-0.749, p = 0.003), respectively. For calibration, it was poor in two-year prediction; the observed number was considerably lower than the predicted number. However, the calibration plot showed good calibration with the five-year prediction except for the second, fourth, and eighth deciles. With a cutoff two-year recurrence risk of 47%, the model had a sensitivity of 0.758 and a specificity of 0.410; the largest Youden index was 1.168. With a cutoff five-year recurrence risk of 77%, the model had a sensitivity of 0.358 and a specificity of 0.979; the largest Youden index was 1.337. CONCLUSIONS: Lamberink's prediction model has a general discrimination ability. The model overestimated the actual recurrence events when predicting the two-year recurrence risk, but it showed relatively good calibration with five-year prediction. The cutoff value found in this study may be used to guide patients and clinicians towards a decision regarding the withdrawal of AEDs. The model appears to be a useful tool for predicting seizure recurrence for the five-year recurrence risk.

Epidemiology of traumatic brain injury-associated epilepsy in western China: An analysis of multicenter data.

OBJECTIVES: This study aims to explore the probability of developing posttraumatic epilepsy (PTE) in the following 8 years after traumatic brain injury (TBI), the risk factors associated with PTE and its cumulative prevalence. METHODS: This is a retrospective follow-up study of patients with traumatic brain injury (TBI) discharged from the West China Hospital between January 1, 2011 and December 31, 2017, Chengdu Shang Jin Nan Fu Hospital and Sichuan Provincial People's Hospital from January 1, 2013 to March 1, 2015. We used forward stepwise method to build the final multivariate cox proportional hazard regression model to obtain estimates of hazard ratio (HR) of PTE and 95% confidence intervals (CI). We also conducted Kaplan-Meier survival analysis to investigate the cumulative prevalence of PTE. RESULTS: The cumulative incidence of PTE rose from 6.2% in one year to 10.6% in eight years. There were more male patients in PTE group and generally older. Besides, patients with PTE tended to have abnormal CT scan results. The risk factors of PTE were male (HR = 1.6, 95% CI: 1.1-2.2, P = 0.009), early posttraumatic seizures (HR = 2.9, 95% CI: 2.2-4.1, P < 0.001), TBI severity (moderate TBI: HR = 3.0, 95% CI: 1.8-5.0, P = 0.001; severe TBI: HR = 4.3, 95% CI: 2.3-7.6, P < 0.029), loss of consciousness (LOC) more than 30 min (30 min-24 h: HR = 1.8, 95% CI: 1.02-3.1, P = 0.041; >24 h: HR = 2.4, 95% CI: 1.4-2.4, P = 0.001), subdural hematoma (SDH) (HR = 1.9, 95% CI: 1.4-2.5, P < 0.001), brain contusion sites (frontal-temporal lobe: HR = 2.7, 95% CI: 1.9-3.9, P < 0.001; other sites: HR = 1.5, 95% CI: 1.01-2.3, P = 0.042) and cranial surgery (HR = 1.7, 95% CI: 1.3-2.3, P < 0.001). SIGNIFICANCE: The probability of developing PTE increased during the study period. In addition, the risk of developing PTE was significantly associated with gender, EPTS, LOC time, SDH, brain contusion sites, surgery and TBI severity. However, further researches may be needed to predict the risk of PTE in combination with quantitative factors.

Therapeutic effect of intravenous levetiracetam in status epilepticus: A meta-analysis and systematic review.

PURPOSE: We performed this analysis to evaluate the efficacy and safety of intravenous levetiracetam (IV LEV) in patients with status epilepticus. METHOD: Studies were searched in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for available randomized controlled trials(RCTs) comparing the efficacy and/or safety of IV LEV with other antiepileptic drugs (AEDs). Meta-analysis was performed using the random-effects model to calculate risk ratio with the RevMan 5.3 software. RESULTS: Six RCTs with a total of 543 patients were included. There was no significant differences in clinical seizure cessation and hospital mortality, either between IV LEV and IV phenytoin (PHT) or between IV LEV and IV valproate (VPA). Compared with IV PHT, IV LEV had a lower risk of poor neurological outcome. For IV LEV compared with IV lorazepam (LOR), no significant difference in efficacy was found, but IV LEV patients had significantly lower need for ventilatory assistance. Adding IV LEV to clonazepam (CNP), compared with adding placebo showed no significant differences in seizure cessation at 15 min. CONCLUSIONS: Our results suggested that IV LEV was comparable to IV PHT,VPA, or LOR in efficacy, and IV LEV as add-on therapy of CNP had no superiority in seizure cessation than CNP plus placebo. IV LEV may have a better tolerability than other AEDs do. More RCTs are needed to validate the role of IV LEV in status epilepticus.

Serum Apolipoprotein A-I Combined With C-Reactive Protein Serves As A Novel Prognostic Stratification System For Colorectal Cancer.

BACKGROUND AND OBJECTIVE: Noninvasive prognostic tools for colorectal cancer (CRC) are urgently needed. This study was designed to investigate the prognostic value of preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels retrospectively in CRC patients. METHODS: Preoperative serum lipid and lipoprotein concentrations (including ApoA-I, Apo-B, HDL-C, LDL-C, TC and TG) and CRP levels were analyzed retrospectively in 250 patients with CRC. The prognostic significance of these indexes was determined by univariate and multivariate Cox hazard models. RESULTS: CRC patients with higher levels of ApoA-I and HDL-C and lower levels of CRP had significantly longer overall survival (OS, log rank test, p<0.05). Based on univariate analysis, ApoA-I levels (p=0.002), CRP levels (p=0.007), HDL-C levels (p=0.005), pT classification (p=0.005), pN classification (p<0.001), pM classification (p<0.001) and pTNM stage (p<0.001) were significantly associated with OS. Multivariate Cox proportional hazards regression analysis indicated that ApoA-I levels (HR: 1.52, p=0.023), CRP levels (HR: 1.85, p=0.035) and pTNM stage (HR: 2.53, p< 0.001) were independent predictors of CRC survival. The included patients were then stratified into three tiers based on the ApoA-I and CRP levels. In the whole cohort, the OS and disease-free survival differed significantly between the low-risk (ApoA-I≥1.08 mg/dL and CRP<3.04 mg/dL), medium-risk (ApoA-I≥1.08 mg/dL or CRP<3.04 mg/dL), and high-risk (ApoA-I<1.08 mg/dL and CRP ≥3.04 mg/dL) groups (p=0.001 and p=0.004). CONCLUSION: Decreased levels of ApoA-I and HDL-C and increased levels of CRP were predictive of poor prognosis among patients with CRC. In addition, the combination of ApoA-I and CRP can serve as a novel prognostic stratification system for more accurate clinical staging of CRC.

Prognostic value of estrogen receptor-α and progesterone receptor in curatively resected colorectal cancer: a retrospective analysis with independent validations.

BACKGROUND: Prognostic assessment is crucial for optimal treatment. The aim of our study was to investigate the potential impact of estrogen receptor-α (ER-α) and progesterone receptor (PR) on the prognosis of colorectal cancer (CRC) patients who received curative resection. METHODS: Retrospective evaluation of two independent cohorts of CRC patients maintained prospectively in 2009-2010 (training set) (n = 148) and 2007-2009 (internal validation set) (n = 485). Furthermore, we used an external independent CRC cohort from The Cancer Genome Atlas (TCGA) (n = 511) for further validation. ER-α and PR expression as well as other potential prognostic factors were retrospectively evaluated in training set with respect to overall survival (OS), local relapse free survival (LRFS) and distant metastasis free survival (DMFS). The prognostic factors found in training set will be validated in two validation cohorts. RESULTS: On univariate analysis for the training set, OS, LRFS and DMFS were not associated with PR expression. While patients with ER-αexpression were found to have poor prognosis. In addition, multivariate analysis showed that ER-αexpression maintained significance with respect to OS (HR, 5.06; p = 0.002), LRFS (HR, 8.81; p = 0.002) and DMFS (HR, 8.07; p = 0.004). Similarly, ER-α expression showed prognostic significance with respect to OS with hazard ratios (HRs) of 1.572 (95% CI: 1.001-2.467, p = 0.049) and 1.624 (95% CI: 1.047-2.520, p = 0.031) for the internal and external validation cohort, respectively. CONCLUSION: ER-α expression was a biomarker of poor prognosis and it might inform treatment decision for high risk CRC patients. However, PR expression was not associated with survival outcomes.

Murine epithelial sodium (Na+) channel regulation by biliary factors.

The epithelial sodium channel (ENaC) mediates Na+ transport in several epithelia, including the aldosterone-sensitive distal nephron, distal colon, and biliary epithelium. Numerous factors regulate ENaC activity, including extracellular ligands, post-translational modifications, and membrane-resident lipids. However, ENaC regulation by bile acids and conjugated bilirubin, metabolites that are abundant in the biliary tree and intestinal tract and are sometimes elevated in the urine of individuals with advanced liver disease, remains poorly understood. Here, using a Xenopus oocyte-based system to express and functionally study ENaC, we found that, depending on the bile acid used, bile acids both activate and inhibit mouse ENaC. Whether bile acids were activating or inhibiting was contingent on the position and orientation of specific bile acid moieties. For example, a hydroxyl group at the 12-position and facing the hydrophilic side (12α-OH) was activating. Taurine-conjugated bile acids, which have reduced membrane permeability, affected ENaC activity more strongly than did their more membrane-permeant unconjugated counterparts, suggesting that bile acids regulate ENaC extracellularly. Bile acid-dependent activation was enhanced by amino acid substitutions in ENaC that depress open probability and was precluded by proteolytic cleavage that increases open probability, consistent with an effect of bile acids on ENaC open probability. Bile acids also regulated ENaC in a cortical collecting duct cell line, mirroring the results in Xenopus oocytes. We also show that bilirubin conjugates activate ENaC. These results indicate that ENaC responds to compounds abundant in bile and that their ability to regulate this channel depends on the presence of specific functional groups.

A Meta-Analysis of Cardiovascular Events in Systemic Lupus Erythematosus.

Objective: To identify accurate occurrence and risk of cardiovascular (CV) events (stroke and myocardial infarction [MI]) in patients with systemic lupus erythematosus (SLE). Methods: Systemic literature search in PubMed and additional manual search were performed to obtain interested studies until March 31, 2018. The pooled incidences and risk of stroke and MI were calculated. Results: A total of 24 studies were included in this meta-analysis. For MI, a total of 1,516 SLE patients were reported to had MI (n = 96,154) over a mean follow-up of 9.98 years: incidence 2.0% (95% CI: 1.7-2.4%), i.e. 0.20/100 pyrs; in the five studies, 360 SLE patients (n = 18,943) and 817 controls had MI (n = 111,525), revealing that the risk of MI in SLE population was 3.04 times higher than in the general population (RR = 3.04, 95% CI: 1.81-5.11). For stroke, the incidence of 17 studies during the 10.09 follow-up period using random model was 4.4% (95% CI: 3.6-5.1%), i.e. 0.44/100 pyrs; in the 7 studies, 694 SLE patients (n = 22,594) and 4,034 controls had stroke (n = 255,023), indicating that the risk of MI in SLE population was 1.95 times higher than that in the general population (RR = 1.95, 95% CI: 1.52-2.53). Conclusion: Based on the findings from previous reports, our meta-analysis showed that patients with SLE have been at higher risk of CV events.

Circulating Insulin-like Growth Factor-1 Levels in Patients with Rheumatoid Arthritis: A Meta-analysis.

BACKGROUND AND OBJECTIVES: Insulin-like growth factor-1 (IGF-1) levels have been investigated in rheumatoid arthritis (RA), however, produced inconsistent results. The purpose of this meta-analysis was to derive a more precise conclusion about serum/plasma IGF-1 levels in RA patients. METHODS: PubMed, Embase and the Cochrane Library databases were searched up to December 2018 in English, and the studies comparing serum/plasma IGF-1 levels between RA group and healthy control group were what we are interested in. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of the included studies. The heterogeneity test was performed by the Cochrane Q statistic and I2 -statistic. The publication bias was evaluated by the funnel plot and Egger's test. The standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the fixed-effects or random-effects model. RESULTS: A total of eleven articles with 334 cases and 261 controls were finally included. Compared with the healthy group, the RA group had lower circulating IGF-1 levels (pooled SMD= -0.936, 95% CI= -1.382 to -0.489, p<0.001). The subgroup analysis showed that RA patients from Asia (SMD= -0.645, 95% CI= -1.063 to -0.228, p= 0.002) and Europe (SMD= -1.131, 95% CI= -1.767 to -0.495, p<0.001) had lower circulating IGF-1 levels, no significant difference in plasma/serum IGF-1 levels was observed in RA patients from America. Sensitivity analysis indicated the stability and credibility of the overall effect sizes. CONCLUSION: Patients with RA have lower circulating IGF-1 level than healthy controls, particularly for patients from Asia and Europe. Further studies are necessary to elucidate the role of IGF-1 in the pathological process of RA.

Diagnostic accuracy of anti-keratin antibody for rheumatoid arthritis: a meta-analysis.

OBJECTIVES: Anti-keratin antibody (AKA) is a serum antibody for patients with rheumatoid arthritis (RA), and it has a high specificity. Diagnostic role of AKA in RA was evaluated in this study. METHODS: PubMed, EMBASE, and Web of Science were searched to acquire eligible studies. Articles published before 15 March 2018 were considered to be included. Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate the risk of bias and application concern of the included articles. Pooled analysis of diagnostic indicators of AKA for RA was conducted by using a random effects model. Subgroup analysis was employed to explore the potential influencing factors. RevMan 5.3, Stata 11.0, and Meta-DiSc 1.4 software were used in this study. RESULTS: A total of 15 studies (2350 positive and 2067 negative participants) were included. The pooled sensitivity was 0.46 (95% CI 0.44-0.48), pooled specificity was 0.94 (95% CI 0.93-0.95), and pooled diagnostic odds ratio was 15.86 (95% CI 9.48-26.52). In addition, the area under the curve was 0.7194. CONCLUSIONS: The current evidence indicated that AKA has high diagnostic specificity in RA and may be useful for RA diagnostic application in clinic.