Commensals Suppress Intestinal Epithelial Cell Retinoic Acid Synthesis to Regulate Interleukin-22 Activity and Prevent Microbial Dysbiosis.

Retinoic acid (RA), a vitamin A metabolite, regulates transcriptional programs that drive protective or pathogenic immune responses in the intestine, in a manner dependent on RA concentration. Vitamin A is obtained from diet and is metabolized by intestinal epithelial cells (IECs), which operate in intimate association with microbes and immune cells. Here we found that commensal bacteria belonging to class Clostridia modulate RA concentration in the gut by suppressing the expression of retinol dehydrogenase 7 (Rdh7) in IECs. Rdh7 expression and associated RA amounts were lower in the intestinal tissue of conventional mice, as compared to germ-free mice. Deletion of Rdh7 in IECs diminished RA signaling in immune cells, reduced the IL-22-dependent antimicrobial response, and enhanced resistance to colonization by Salmonella Typhimurium. Our findings define a regulatory circuit wherein bacterial regulation of IEC-intrinsic RA synthesis protects microbial communities in the gut from excessive immune activity, achieving a balance that prevents colonization by enteric pathogens.

Infectious hepatitis E virus excreted into the vagina.

Hepatitis E virus (HEV) persists in the male genital tract that associates with infertility. However, the presence of HEV in the female genital tract is unreported. Vaginal secretions, cervical smears, and cervix uteri were collected to explore the presence of HEV in the female genital tract. HEV RNA and/or antigens were detected in the vaginal secretions, cervical smears, and the cervix uteri of women. The infectivity of HEV excreted into vaginal secretions was further validated in vitro. In addition, HEV replicates in the female genital tract were identified in HEV-infected animal models by vaginal injection or vaginal mucosal infection to imitate sexual transmission. Serious genital tract damage and inflammatory responses with significantly elevated mucosal innate immunity were observed in women or animals with HEV vaginal infection. Results demonstrated HEV replicates in the female genital tract and causes serious histopathological damage and inflammatory responses.

Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo.

Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.

Ultra-processed food consumption and the risk of pancreatic cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Whether ultra-processed food consumption is associated with the risk of pancreatic cancer has not been determined. We performed a prospective study to fill this gap. A population-based cohort of 98 265 American adults was identified from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Ultra-processed foods were defined by the NOVA classification. Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer incidence. Subgroup analysis was performed to identify the potential effect modifiers. During a mean follow-up of 8.86 years, 387 pancreatic cancer cases occurred. High consumption of ultra-processed foods was found to be associated with an increased risk of pancreatic cancer (fully adjusted HRquartile 4 vs 1 :1.49; 95% confidence interval [CI]: 1.07-2.07; Ptrend  = .021) in a linear dose-response manner (Pnonlinearity  = .075). Subgroup analysis further found that the positive association of ultra-processed food consumption with the risk of pancreatic cancer was more pronounced in subjects aged <65 years (HRquartile 4 vs 1 :2.17; 95% CI: 1.14-4.15) than in those aged ≥65 years (HRquartile 4 vs 1 :1.32; 95% CI: 0.88-1.94), though the interaction test failed to achieve the statistical significance (Pinteraction  = .061). These findings suggest that reducing ultra-processed food consumption may be beneficial in decreasing pancreatic cancer incidence.

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

OBJECTIVES: To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. METHODS: Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. RESULTS: A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. CONCLUSIONS: A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

Prognosis of hepatitis E infection in patients with chronic liver disease: A meta-analysis.

In individuals with underlying chronic liver disease (CLD), hepatitis E virus (HEV) infection is a potential trigger of acute-on-chronic liver failure. In this systematic review, seven electronic databases were searched. Pooled incidence rates with 95% confidence intervals (95% CIs) were calculated by the Freeman-Tukey double arcsine transformation method. The association between death or liver failure and HEV superinfection in CLD patients was estimated by the odds ratios (OR) with a 95% CI. A total of 18 studies from 5 countries were eligible for systematic review. The prevalence of acute HEV infection in hospitalized CLD patients with clinical manifestations of hepatitis was 13.6%, which was significantly higher than that in CLD patients from the community (pooled prevalence 1.1%). The overall rates of liver failure and mortality in CLD patients with HEV superinfection were 35.8% (95% CI: 26.7%-45.6%) and 14.3% (95% CI: 10.6%-18.5%), respectively, with the rates in cirrhotic patients being approximately 2-fold and 4-fold higher than those in noncirrhotic patients, respectively. The risks of liver failure (OR = 5.5, 95% CI: 1.5-20.1) and mortality (OR = 5.0, 95% CI: 1.9-13.3) were significantly higher in CLD patients with HEV superinfection than in those without HEV superinfection. HEV testing in hospitalized CLD patients is necessary due to the high prevalence of HEV infection observed in hospitalized CLD patients. HEV superinfection could accelerate disease progression in patients with underlying CLD and increase mortality in these patients. HEV vaccination is appropriate for patients with pre-existing CLD.

Retinoic acid regulates pyruvate dehydrogenase kinase 4 (Pdk4) to modulate fuel utilization in the adult heart: Insights from wild-type and ß-carotene 9',10' oxygenase knockout mice.

Regulation of the pyruvate dehydrogenase (PDH) complex by the pyruvate dehydrogenase kinase PDK4 enables the heart to respond to fluctuations in energy demands and substrate availability. Retinoic acid, the transcriptionally active form of vitamin A, is known to be involved in the regulation of cardiac function and growth during embryogenesis as well as under pathological conditions. Whether retinoic acid also maintains cardiac health under physiological conditions is unknown. However, vitamin A status and intake of its carotenoid precursor ß-carotene have been linked to the prevention of heart diseases. Here, we provide in vitro and in vivo evidence that retinoic acid regulates cardiac Pdk4 expression and thus PDH activity. Furthermore, we show that mice lacking ß-carotene 9',10'-oxygenase (BCO2), the only enzyme of the adult heart that cleaves ß-carotene to generate retinoids (vitamin A and its derivatives), displayed cardiac retinoic acid insufficiency and impaired metabolic flexibility linked to a compromised PDK4/PDH pathway. These findings provide novel insights into the functions of retinoic acid in regulating energy metabolism in adult tissues, especially the heart.

UCMSCs-derived exosomal circHIPK3 promotes ulcer wound angiogenesis of diabetes mellitus via miR-20b-5p/Nrf2/VEGFA axis.

AIMS: Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. METHODS: Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. RESULTS: CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. CONCLUSION: UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.

Severe maternal-fetal pathological damage and inflammatory responses contribute to miscarriage caused by hepatitis E viral infection during pregnancy.

BACKGROUND: Hepatitis E virus (HEV) infection causes serious adverse pregnancy outcomes during pregnancy. However, the maternal and fetal damage induced by HEV infection is rarely reported. METHODS: A BALB/c pregnant mouse model was established to explore the maternal and fetal pathological damage and inflammatory responses caused by HEV infection. RESULTS: Notably, miscarriages and stillbirths were observed in HEV-infected pregnant mice. HEV infections were identified by qRT-PCR, immunohistochemical analysis and immunofluorescence assay in the uterus, placenta, umbilical cords and livers and brains of fetuses. Serious inflammatory responses and pathological damage were triggered in the uterus and placenta of HEV-infected pregnant mice. Vertical transmission of HEV resulted in severe pathological damage and inflammatory responses in the livers and brains of fetuses, as well as emerging apoptosis cells in the brains of fetuses. Most of the cytokines/chemokines in the sera were significantly increased in the HEV-infected pregnant mice. Remarkably, cytokines/chemokines were significantly different between HEV-infected pregnant and miscarriage mice; IL9, GM-CSF and IL1α were the most important three cytokines/chemokines in determining the pregnancy outcomes. CONCLUSION: HEV infections cause serious maternal/fetal pathological damage, inflammatory responses and apoptosis, which may be responsible for adverse pregnancy outcomes.

Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation.

BACKGROUND/AIMS: The activation of the complement system and subsequent inflammatory responses are important features of myocardial ischemia/reperfusion (I/R) injury. Exosomes are nanoscale extracellular vesicles that play a significant role in remote ischemic preconditioning (RIPC) cardioprotection. The present study aimed to test whether RIPC-induced plasma exosomes (RIPC-Exo) exert protective effects on myocardial I/R injury by inhibiting complement activation and inflammation and whether exosomal heat shock protein 90 (HSP90) mediates these effects. METHODS: Rat hearts underwent 30 min of coronary ligation followed by 2 h of reperfusion. Plasma exosomes were isolated from RIPC rats and injected into the infarcted myocardium immediately after ligation. Sixty rats were randomly divided into Sham, I/R, I/R + RIPC-Exo (50 µg/µl), and RIPC-Exo + GA (geldanamycin, 1 mg/kg, administration 30 min before ligation) groups. Cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB), infarct size, the expression of HSP90, complement component (C)3, C5a, c-Jun N-terminal kinase (JNK), interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule -1 (ICAM-1) were assessed. RESULTS: RIPC-Exo treatment significantly reduced I/R-induced cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB) and infarct size. These beneficial effects were accompanied by decreased C3 and C5a expression, decreased inflammatory factor levels (IL-1ß, TNF-α, and ICAM-1), decreased JNK and Bax, and increased Bcl-2 expression. Meanwhile, the expression of HSP90 in the exosomes from rat plasma increased significantly after RIPC. However, treatment with HSP90 inhibitor GA significantly reversed the cardioprotection of RIPC-Exo, as well as activated complement component, JNK signalling and inflammation, indicating that HSP90 in exosomes isolated from the RIPC was important in mediating the cardioprotective effects during I/R. CONCLUSION: Exosomal HSP90 induced by RIPC played a significant role in cardioprotection against I/R injury, and its function was in part linked to the inhibition of the complement system, JNK signalling and local and systemic inflammation, ultimately alleviating I/R-induced myocardial injury and apoptosis by the upregulation of Bcl-2 expression and the downregulation of proapoptotic Bax.

Long-term outcomes of chemoradiotherapy versus radiotherapy alone in patients with intermediate-risk nasopharyngeal carcinoma: a population-based analysis.

PURPOSE: To investigate the efficacy of chemotherapy among intermediate-risk (stage II/T3N0) nasopharyngeal carcinoma (NPC) patients receiving radiotherapy (RT). METHODS: We identified stage II/T3N0 NPC patients who received radiotherapy with or without chemotherapy from the Surveillance, Epidemiology and End Results database (2004-2019). Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan-Meier method with log-rank test and Cox proportional hazards models to evaluate the efficacy of chemotherapy. Subgroup analysis was also conducted based on the baseline characteristics. Propensity score matching (PSM) was performed to balance the intergroup covariates. RESULTS: A total of 1623 patients were enrolled in the study, 1444 received chemoradiotherapy (CRT) and 179 received RT alone. CRT, compared to RT alone, was independently associated with a better OS (HR 0.57, 95% CI 0.45-0.71) and CSS (HR 0.55, 95% CI 0.39-0.79). After PSM, similar results were obtained, and CRT was superior to RT alone in terms of OS (HR 0.60, 95% CI 0.39-0.92) and CSS (HR 0.60, 95% CI 0.40-0.91). Subgroup analysis revealed that OS benefits from CRT were mainly observed in T0-2N1(HR 0.51, 95% CI 0.38-0.70) and T3N0 (HR 0.64, 95% CI 0.42-0.98) rather than T2N0 (HR 1.00, 95% CI 0.51-1.94). Interestingly, after PSM, OS benefits were still seen in T0-2N1 (HR 0.44, 95% CI 0.24-0.82), while not seen in T2N0 (HR 1.83, 95% CI 0.56-5.97) and T3N0 (HR 0.56, 95% CI 0.28-1.12). CONCLUSION: For T0-2N1 NPC patients, CRT was superior to RT alone with better survival, whereas, for T2-3N0 patients, CRT was comparable to RT alone. Prospective large studies should be encouraged to verify the results.

A modified Blumgart anastomosis with a simple and practicable procedure after laparoscopic pancreaticoduodenectomy: our center's experience.

BACKGROUND: Laparoscopic pancreaticoduodenectomy(LPD) has become the goal of lots of minimally invasive surgical centers in recent years. Postoperative pancreatic fistula(POPF) is still the barrier to attaining the above goal. Thus, improving anastomosis techniques to reduce the rate of POPF has been a hotspot of surgery. Blumgart pancreaticojejunostomy is considered one of the best anastomosis procedures, with low rates of POPF. However, the original Blumgart pancreaticojejunostomy method is not easy for laparoscopic operation. In consequence, we modified a Blumgart pancreaticojejunostomy technique with a simple and practicable procedure and applied to LPD. METHODS: We collected and retrospectively analyzed the perioperative clinical data of patients who underwent modified Blumgart anastomosis from February 2017 to September 2022. The above patients included 53 cases in open pancreaticojejunostomy(OPD) and 58 cases in LPD. After propensity score matching, 44 cases were included for comparison in each group. RESULTS: After propensity score matching, the average time for pancreaticojejunostomy was about 30 min in the LPD group. The Clinically relevant POPF(CR-POPF) rate was 9.1%. The length of postoperative hospitalization was 13.1 days. Compared with the OPD group, The CR-POPF rate in the LPD group are not significant differences. But the postoperative length of hospital stay was significantly shorter in the LPD group. Besides, there were no other severely postoperative complications between two groups. CONCLUSION: The modified Blumgart anastomosis technique applied to LPD in our Center not only has simple and convenient properties but also low rate of CR-POPF. And this method may be a good choice for surgeons to begin to carry out LPD.

Frequently expressed glypican-3 as a promising novel therapeutic target for osteosarcomas.

Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican-3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti-GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer-targeted next-generation sequencing (NGS) and three-dimensional patient-derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT-PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti-GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS-08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3-positive cells was variable in the focal (+; 10%-30%; 8/45), partial (++; 31%-70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10-10 ). The anti-GPC3 antibody efficiently inhibits Wnt/ß-catenin signaling and induces apoptosis in GPC3-positive PDOs and PDXs, as opposed to GPC3-negative PDOs and PDXs. The high frequency of GPC3 and CD133 co-expression and the effectiveness of anti-wild-type GPC3-Ab therapy in GPC3-positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma.

Type 2 Diabetes-Prevention Diet and All-Cause and Cause-Specific Mortality: A Prospective Study.

We aimed to examine whether type 2 diabetes-prevention diet, a dietary pattern previously developed for reducing type 2 diabetes risk, was associated with mortality in a US population. A population-based cohort of 86,633 subjects was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2015). Dietary information was collected with a food frequency questionnaire. A dietary diabetes risk-reduction score was calculated to reflect adherence to this dietary pattern, with higher scores representing better adherence. Hazard ratios (HRs) and absolute risk differences (ARDs) in mortality rates per 10,000 person-years were calculated. After a mean follow-up of 13.6 years, 17,532 all-cause deaths were observed. Participants with the highest versus the lowest quintiles of dietary diabetes risk-reduction score were observed to have decreased risks of death from all causes (HR = 0.76, 95% CI: 0.72, 0.80; ARD: -81.94, 95% CI: -93.76, -71.12), cardiovascular disease (HR = 0.73, 95% CI: 0.66, 0.81; ARD: -17.82, 95% CI: -24.81, -11.30), and cancer (HR = 0.85, 95% CI: 0.78, 0.94; ARD: -9.92, 95% CI: -15.86, -3.59), which were modified by sex, smoking status, or alcohol consumption in subgroup analyses (P for interaction < 0.05 for all). In conclusion, a type 2 diabetes-prevention diet confers reduced risks of death from all causes, cardiovascular disease, and cancer in this US population.

Discovery and Visualization of Uncharacterized Drug-Protein Adducts Using Mass Spectrometry.

Drugs are often metabolized to reactive intermediates that form protein adducts. Adducts can inhibit protein activity, elicit immune responses, and cause life-threatening adverse drug reactions. The masses of reactive metabolites are frequently unknown, rendering traditional mass spectrometry-based proteomics approaches incapable of adduct identification. Here, we present Magnum, an open-mass search algorithm optimized for adduct identification, and Limelight, a web-based data processing package for analysis and visualization of data from all existing algorithms. Limelight incorporates tools for sample comparisons and xenobiotic-adduct discovery. We validate our tools with three drug/protein combinations and apply our label-free workflow to identify novel xenobiotic-protein adducts in CYP3A4. Our new methods and software enable accurate identification of xenobiotic-protein adducts with no prior knowledge of adduct masses or protein targets. Magnum outperforms existing label-free tools in xenobiotic-protein adduct discovery, while Limelight fulfills a major need in the rapidly developing field of open-mass searching, which until now lacked comprehensive data visualization tools.

Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18.

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs.

Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis.

BACKGROUND: Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction. METHODS: The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis. RESULTS: A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis. CONCLUSION: ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity.

Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKIα, an essential regulator of spinogenesis. CaMKK1/CaMKIα signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor ßPIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKIα/ßPIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.

Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

BACKGROUND: Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. METHODS: Intranasal dexmedetomidine 2 µg · kg-1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. RESULTS: A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors' study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h-1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h-1. The simulation indicated that at the dose of 2 µg · kg-1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml-1 within 20 min, and the average peak concentration of 0.563 ng · ml-1 could be attained at 61 min. CONCLUSIONS: The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg-1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h.

Effect of bovine lactoferricin on the growth performance, digestive capacity, immune responses and disease resistance in Pacific white shrimp, Penaeus vannamei.

The present study evaluated the growth performance, digestive enzyme activity, non-specific immunity, immunity and growth genes in Penaeus vannamei fed diets supplemented with Bovine lactoferricin (the basal diet without Bovine lactoferricin, the control; 1.0‰ Bovine lactoferricin，LCB1; 1.5‰ Bovine lactoferricin，LCB1.5; 2.0‰ Bovine lactoferricin, LCB2; 2.5‰ Bovine lactoferricin, LCB2.5) for 56 days. The feeding trial showed that the final weight, weight gain rate, and specific growth rate of the shrimp were improved significantly, while the feed conversion ratio was reduced significantly in the LCB1.5 group compared to the control (P < 0.05). The challenge test of Vibrio parahaemolyticus showed that the cumulative mortalities of shrimp in the LCB1.5, LCB2 and LCB2.5 groups were significantly lower than that in the control (P < 0.05). Compared with the control, Lipase and Trypsin activities in the hepatopancreas of LCB1.5 and LCB2 groups were significantly enhanced (P < 0.05). Compared with the control, alkaline phosphatase, acid phosphatase activities in the hepatopancreas and the relative expression levels of Relish, Toll, JAK, STAT, TOR, Raptor, 4E-BP, eIF4E1α, eIF4E2 genes in the hepatopancreas of LCB1.5, LCB2 and LCB2.5 groups were all significantly enhanced (P < 0.05). These results suggested that dietary Bovine lactoferricin could improve the growth performance, digestive capacity and immune responses of shrimp. When resistance against Vibrio parahaemolyticus in shrimp is considered, high dosage of Bovine lactoferricin showed a better effect than low dosage of Bovine lactoferricin. However, high dosage of Bovine lactoferricin can have a negative impact on the growth performance of shrimp. Considering collectively the above, Bovine lactoferricin could improve the growth performance, digestive enzymes activities, immune responses and disease resistance of P. vannamei.