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Previous studies have indicated that sirolimus (SRL) may be effective for HCC patients undergoing liver transplantation (LT). However, the following results are still contradictory and do not have a clear conclusion. Therefore, we conducted an updated meta-analysis by retrieving published data in EMBASE, PubMed, and the Cochrane Library up to October 2017. Both efficiency and safety of SRL were analyzed using pooled odds ratio (ORs) with 95% confidence interval (CIs). A total of 11 studies involving 7,695 HCC patients were included. Compared with control group, SRL prolonged 1-year (OR = 2.44; CI = 1.66–3.59), 3 year (OR = 1.67; CI = 1.08–2.58) and 5-year (OR = 1.68; CI = 1.21–2.33) overall survival, as well as 1-year (OR = 2.13; CI = 1.19–3.81) disease-free survival. Pooled results found that SRL-treated patients had lower recurrence (OR = 0.60; CI = 0.37–0.98), lower recurrence-related mortality (OR = 0.58; CI = 0.42–0.81) and lower overall mortality (OR = 0.62; CI = 0.44–0.89). Moreover, fewer SRL-treated patients suffered from portal vein thrombosis (OR = 0.29; CI, 0.09–0.91) and diabetes (OR = 0.23; CI = 0.12–0.47), while SRL-treated patients were more vulnerable to acne compared with the control group (OR = 4.44; CI = 1.56–12.60). No significant differences in other adverse effects were found between two groups. Taken together, SRL-based immunosuppression is safe and effective in improving survival, as well as reducing recurrence and mortality for HCC patients following LT.

Background: MicroRNA-133b (miR-133b) has been shown to play a critical role in spinal cord regeneration. The aim of this study was to investigate the cellular role of miR-133b in neural cells. Methods: PC12 cells and primary cortical neurons (PCNs) were transfected with lenti-miR-133b, lenti-miR-133b inhibitor, plasmid-shRNA-RhoA, plasmid-RhoA and their negative controls. After 48 hours of transfection, the levels of proteins and mRNA or miRNA were evaluated by Western blotting and qRT-PCR, respectively. Moreover, the neurite outgrowth was analyzed by Image J. For pharmacological experiments, inhibitors of MEK1/2 kinase (PD98059), phosphoinositide-3 kinase (PI3K) (LY294002) and ROCK (Y27632) were added into the culture medium. Results: Overexpression of miR-133b in PC12 cells enhanced neurite outgrowth. Conversely, inhibition of miR-133b reduced neurite length. We further identified RhoA as a target and mediator of mir-133b for neurite extension by Western blot and knockdown experiment. Moreover, overexpression of RhoA could attenuate the neurite growth effects of miR-133b. Also, we observed that miR-133b activated MEK/ERK and PI3K/Akt signaling pathway by targeting RhoA. Finally, in PCNs, miR-133b also increased axon growth and attenuated axon growth restrictions from chondroitin sulfate proteoglycans (CSPG). Conclusions: In summary, our study suggested that miR-133b regulated neurite outgrowth via ERK1/2 and PI3K/Akt signaling pathway by RhoA suppression.

Background: Neurogenin2 (Ngn2) is a proneural gene that directs neuronal differentiation of progenitor cells during development. Here, we investigated whether Ngn2 can reprogram MSCs to adopt a neural precursor fate and enhance the therapeutic effects of MSCs after experimental stroke. Methods: In vitro, MSCs were transfected with lenti-GFP or lenti-Ngn2. Following neuronal induction, cells were identified by immunocytochemistry, Western blot and electrophysiological analyses. In a stroke model induced by transient right middle cerebral artery occlusion (MCAO), PBS, GFP-MSCs or Ngn2-MSCs were injected 1 day after MCAO. Behavioral tests, neurological and immunohistochemical assessments were performed. Results: In vitro, Ngn2-MSCs expressed neural stem cells markers (Pax6 and nestin) and lost the potential to differentiate into mesodermal cell types. Following neural induction, Ngn2-MSCs expressed higher levels of neuron-specific proteins MAP2, Tuj1 and NeuN, and also expressed voltage-gated Na+ channel, which was absent in GFP-MSCs. In vivo, after transplantation, Ngn2-MSCs significantly reduced apoptotic cells, decreased infarct volume, and increased the expression of VEGF and BDNF. Finally, Ngn2-MSCs treated animals showed the highest functional recovery among the three groups. Conclusions: Ngn2 was sufficient to convert MSCs into a neural precursor fate and transplantation of Ngn2-MSCs was advantageous for the treatment of stroke rats.

Abstract Background Epidemiological studies have reported that polymorphisms of folate-metabolizing genes have a significant impact on male infertility. However, the results of published studies have come to different conclusions. Objective To determine an association between folate-metabolizing gene polymorphisms and the risk of male infertility. Methods The meta-analysis was conducted according to the PRISMA 2020 statement. The protocol was registered with PROSPERO (CRD42023412251). Studies were searched from PubMed, Google Scholar, Embase, Scopus, and the Cochrane Library up to 24st October2023. Articles that satisfied the inclusion criteria were evaluated for their quality using the Newcastle–Ottawa Scale. Data were extracted from the eligible studies and were analyzed for pooled up odds ratio (OR) with 95% confidence interval (CI). Meta-analysis was conducted using STATA 12. Results Forty-six case–control studies were included in the meta-analysis which comprised 20,639 participants. The pooled analysis revealed that the MTHFR C677T polymorphism was significantly associated with male infertility and abnormospermia.Three-fifths of the model showed there was a significant association between the MTR A2756G polymorphism and male infertility. Both MTHFR A1298C and MTRR A66G polymorphisms were not significantly associated with male fertility. Furthermore, subgroup analysis revealed a significant association between the MTHFR C677T polymorphism and male fertility in Asian countries. Conclusion This meta-analysis suggests that the MTHFR C677T and MTR A2756G polymorphisms may be a potential risk factor for male infertility.

The pH value, glucose content, glycolytic potential, and expression levels of five glycolytic enzymes in lamb longissimus dorsi muscle at different time after slaughter were compared and analyzed, which treated at different cooling rates and stored at different temperatures. The impact of two steps in the process of ultra-fast chilling on the expression levels of glycolytic enzymes was determined. The regulatory mechanism of ultra-fast chilling on the glycolytic rate was elucidated from the perspective of protein expression. The results showed that ultra-fast chilling treatment significantly delayed the decrease of pH and the increase of glycolytic rate, promoted the expression levels of aldolase (ALDOA), glycogen phosphorylase (PYGM), and triosephosphate isomerase (TPI1), and inhibited the expression levels of phosphofructokinase (PFKM) and phosphoglycerate kinase (PGK). After cooling treatment, refrigeration and controlled freezing-point storage delayed glycolysis by inhibiting the expression level of PGK, without altering the effect of ultra-fast chilling. The expression level of PFKM was positively correlated with the rate of glycolysis at different temperatures. It was found that different glycolytic enzymes had different responses to temperature changes. Ultra-fast chilling affected energy supply and demand by changing the expression of enzymes involved in glycolysis. The high expression level of PFKM was associated with fast glycolysis. PFKM can be regarded as a key enzyme in the ultra-fast chilling process.

BACKGROUND: Polymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results. METHODOLOGY/ PRINCIPAL FINDINGS: The PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn's disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2 × 10(-10), OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC). CONCLUSIONS/ SIGNIFICANCE: These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.

The observation of a kilonova AT2017gfo associated with the gravitational wave event GW170817 provides the first strong evidence that neutron star mergers are dominant contributors to the production of heavy r -process elements. Radioactive gamma-ray lines emitted from neutron star merger remnants provide a unique probe for investigating the nuclide composition and tracking its evolution. In this work, we studied the gamma-ray line features arising from the radioactive decay of heavy nuclei in the merger remnants based on the r -process nuclear reaction network and the astrophysical inputs derived from numerical relativity simulations. The decay chain of ${}_{50}^{126}$ Sn ( T _1/2 = 230 kyr) → ${}_{51}^{126}$ Sb ( T _1/2 = 12.35 days) → ${}_{52}^{126}$ Te (stable) produces several bright gamma-ray lines with energies of 415, 667, and 695 keV, making it the most promising decay chain during the remnant phase. The photon fluxes of these bright gamma-ray lines reach ∼10 ^−5 γ cm ^−2 s ^−1 for Galactic merger remnants with ages less than 100 kyr, which can be detected by the high energy resolution MeV gamma-ray detectors like the MASS mission.

Aim: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population‐based cohort with type 2 diabetes (T2DM). Methods: Patients aged ≥18 years with new‐onset T2DM, without renal disease or HF at baseline, were identified from the territory‐wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all‐cause mortality. Results: Among 102 488 patients (median age 66 years, 45.7% women, median follow‐up 7.5 years), new‐onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new‐onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5‐3.6) years and was 1.2 (0.2‐3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3‐17.9) vs. 10.6 (95% CI 10.4‐10.9)/1000 person‐years, respectively, but incident HF was associated with a higher adjusted‐mortality than incident CKD. The presence of either condition (vs. CKD/HF‐free status) was associated with a three‐fold hazard of death, whereas concomitant HF and CKD conferred a six to seven‐fold adjusted hazard of mortality. Conclusion: Cardiorenal complications are common and are associated with high mortality risk among patients with new‐onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the association between prediabetes and heart failure (HF) and the association of HF with changes in glycemic status. RESEARCH DESIGN AND METHODS: Patients newly diagnosed with atrial fibrillation (AF) between 2015 and 2018 were divided into three groups (normoglycemia, prediabetes, and type 2 diabetes) according to their baseline glycemic status. The primary outcome was incident HF. The Fine and Gray competing risks model was applied, with death defined as the competing event. RESULTS: Among 17,943 patients with AF (mean age 75.5 years, 47% female), 3,711 (20.7%) had prediabetes, and 10,127 (56.4%) had diabetes at baseline. Over a median follow-up of 4.7 years, HF developed in 518 (14%) patients with normoglycemia, 646 (15.7%) with prediabetes, and 1,795 (17.7%) with diabetes. Prediabetes was associated with an increased risk of HF compared with normoglycemia (subdistribution hazard ratio [SHR] 1.12, 95% CI 1.03–1.22). In patients with prediabetes at baseline, 403 (11.1%) progressed to diabetes, and 311 (8.6%) reversed to normoglycemia at 2 years. Compared with remaining prediabetic, progression to diabetes was associated with an increased risk of HF (SHR 1.50, 95% CI 1.13–1.97), whereas reversion to normoglycemia was associated with a decreased risk (SHR 0.61, 95% CI 0.42–0.94). CONCLUSIONS: Prediabetes was associated with an increased risk of HF in patients with AF. Compared with patients who remained prediabetic, those who progressed to diabetes at 2 years experienced an increased risk of HF, whereas those who reversed to normoglycemia incurred a lower risk of HF. [ABSTRACT FROM AUTHOR]

Background: Orthotopic liver transplantation (OLT) is a life-saving option for patients with hepatocellular carcinoma (HCC), but the expanded OLT criteria remain controversial. Objective: The study aimed to explore whether expanded OLT criteria can be applied to Chinese cirrhotic patients with HCC. Methods: This retrospective study analyzed risk factors for HCC recurrence and death and compared patients' tumor characteristics and outcomes in groups of Milan, "Up-to-seven," and Hangzhou criteria, and groups between met and unmet the combinative criteria of "Up-to-seven" and AFP of < 1000 ng/mL. Results: Among 153 patients who underwent OLT for HCC from January 2015 to February 2019 in 4 years of follow-up, 20 (13.1%) patients had HCC recurrence, and 11 (7.2%) had HCC-related death. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein (AFP) of > 1000 ng/mL (hazard ratio [HR]: 10.05, 95% confidence interval [CI]: 2.45-41.13, P = 0.001) was an independent risk factor for HCC recurrence and HCC-related death (HR: 6.63, 95%CI: 1.31-33.52, P = 0.022). Patients who did not meet Milan criteria but satisfied the "Up-to-seven" criteria had no differences in overall survival (OS) (P = 0.69) and disease-free survival (DFS) (P = 0.35) than patients who met the Milan criteria. The combination of "Up-to-seven" criteria and AFP of < 1000 ng/mL differed significantly (HR: 18.9; 95% CI: 4.0-89.2; P < 0.001). Patients with HCC who met the "Up-to-seven" criteria and AFP of < 1000 ng/mL (n = 121) had excellent survival with 4-year OS of 91.6% (P < 0.001) and DFS of 90.8% (P < 0.001), which is significantly better compared to the other group (n = 32) (OS of 67.5% and DFS of 46.5%) and patients who met the Milan criteria (n = 108, OS of 89.8%, DFS of 89.6%), allowing 28.9% (13/45) of patients who did not meet the Milan criteria to benefit from OLT. Conclusion: Chinese cirrhotic patients with HCC who met the combinative criteria of "Up-to-seven" and AFP of < 1000 ng/mL had better survival than those who met the Milan criteria, and these combinative criteria benefited more patients and may become a better option for OLT. [ABSTRACT FROM AUTHOR]

Objective(s): Lysine-specific demethylase1 (LSD1), an important class of histone demethylases, plays a crucial role in regulation of mammalian biology. The up-regulated LSD1 expression was frequently associated with progress and oncogenesis of multiple human cancers, including non-small cell lung cancer (NSCLC). Therefore, inhibition of LSD1 may provide an attractive strategy for cancer treatment. We investigated the effect of sanguinarine against lung cancer cells as a natural alkaloid LSD1 inhibitor. Materials and Methods: The inhibition properties of sanguinarine to the recombinant LSD1 were evaluated by a fluorescence-based method. Subsequently, assays such as viability, apoptosis, clonogenicity, wound healing, and transwell were performed on H1299 and H1975 cells after treatment with sanguinarine. Results: Upon screening our in-house natural chemical library toward LSD1, we found that sanguinarine possessed a potent inhibitory effect against LSD1 with the IC50 value of 0.4 μM in a reversible manner. Molecular docking simulation suggested that sanguinarine may inactivate LSD1 by inserting into the binding pocket of LSD1 to compete with the FAD site. In H1299 and H1975 cells, sanguinarine inhibited the demethylation of LSD1, validating its cellular activity against the enzyme. Further studies showed that sanguinarine exhibited a strong capacity to suppress colony formation, inhibit migration and invasion, as well as induce apoptosis of H1299 and H1975 cells. Conclusion: Our findings present a new chemical scaffold for LSD1 inhibitors, and also provide new insight into the anti-NSCLC action of sanguinarine. [ABSTRACT FROM AUTHOR]

Aims: Previous studies have demonstrated that moderate/severe tricuspid regurgitation (TR) is associated with adverse outcome in patients with heart failure (HF) with reduced ejection fraction. Little is known about the prevalence and prognostic value of TR in patients of stage B HF and those with stage C HF with preserved ejection fraction (HFpEF). We aimed to investigate the prevalence and prognosis of TR in patients with HFpEF. Methods and results: From 2013 to 2017, 2014 patients with stage B (n = 1341) or C (n = 673) HFpEF were enrolled in the study. Detailed transthoracic echocardiogram was performed, and the severity of TR was graded as no, mild, moderate, and severe. The mean age of the study population was 66.7 ± 14.1 years old, and 46% were men. Mean left ventricular ejection fraction was 62.2 ± 5.5%. The prevalence of moderate/severe TR increased from stage B to C HF (8% to 16%, respectively, P < 0.01). Older age, hyperlipidaemia, atrial fibrillation, left ventricular mass, and right ventricular systolic pressure were independently associated with moderate/severe TR (P < 0.05 for all). With a median follow‐up of 3.8 (2.9–4.7) years, 346 patients died and 234 developed HF requiring hospitalization. Kaplan–Meier curve revealed that the presence of moderate/severe TR was associated with all‐cause mortality, HF requiring hospitalization and cardiovascular death (log‐rank test P < 0.01). Multivariable analysis demonstrated that moderate (hazard ratio = 1.5; 95% confidence interval: 1.1–2.2; P < 0.05) and severe TR (hazard ratio = 2.1; 95% confidence interval: 1.3–3.3; P < 0.01) were independently associated with mortality, HF requiring hospitalization and cardiovascular death. Conclusions: The presence of moderate/severe TR is not uncommon in patients with stage B HF and stage C HFpEF. Importantly, moderate/severe TR was independently associated with mortality and HF requiring hospitalization. [ABSTRACT FROM AUTHOR]

The sintering behaviors and dielectric properties of the Li2MgTiO4 ceramics at microwave frequency were investigated as a function of BaCu(B2O5) in this paper. The addition of BaCu(B2O5) dramatically decreased the sintering temperature of Li2MgTiO4 ceramics from 1250 to 900 °C. No secondary phase was detected and single phase Li2MgTiO4 with NaCl structure in the 1.0–4.0 wt% BaCu(B2O5) doped Li2MgTiO4 ceramics was confirmed, while a small amount of BaCu(B2O5) phase was found in the 8.0 wt% BaCu(B2O5) doped Li2MgTiO4 ceramics. No much deterioration of dielectric properties at microwave frequency of the BaCu(B2O5) doped Li2MgTiO4 ceramics sintered at 900 °C for 3 h occurs and favorable dielectric properties (εr = 15.8, Qf = 74,790 GHz and τf = − 24.3 ppm/°C) at microwave frequency were obtained for the Li2MgTiO4 ceramics with 4.0 wt% BaCu(B2O5) addition. Accordingly, such a favorable 4.0 wt% BaCu(B2O5)-doped Li2MgTiO4 ceramic might be a potential candidate material for LTCC applications. [ABSTRACT FROM AUTHOR]

A novel low-fired microwave dielectric ceramic, BaCu(B2O5)-added 0.6Ca3/5La4/15TiO3-0.4Li1/2Nd1/2TiO3 (abbreviated CLT-LNT), was prepared by solid state route. The influence of BaCu(B2O5) on the phase composition, sintering behavior and microwave dielectric properties of as-synthesized CLT-LNT ceramics was investigated. All the BaCu(B2O5)-added CLT-LNT ceramic samples exhibited single phase orthorhombic perovskite structure. BaCu(B2O5) dramatically decreased the sintering temperature of CLT-LNT ceramics from 1400 to 930 °C. Favorable microwave dielectric properties (εr = 87.6, Q × f = 6530 GHz, τf = 3.2 ppm/°C) as well as the maximum relative density (97.9%) were obtained for the 1.6 wt% BaCu(B2O5)-added CLT-LNT ceramic sintered at 930 °C for 3 h. Therefore, such a novel BaCu(B2O5)-added CLT-LNT ceramic would be a promising candidate for low-temperature co-fired ceramics applications. [ABSTRACT FROM AUTHOR]

The health risk of potentially toxic elements (PTEs) via contamination of the food chain has attracted widespread concern. The aim of this study is to evaluate the effects of PTEs in environment and human body (fingernail, hair, and blood) of people living in agricultural soil near arsenic coal mining areas in Xingren County (Guizhou, southwest China). 89 crop samples which included vegetables, rice, maize, and coix seed and their corresponding soils and 17 local surface water and biological tissue samples (41 × 3) in near arsenic coal mining areas were collected, and the concentrations of potentially toxic elements (As, Cd, Cu, Cr, and Pb) in all the samples were determined. The health risk assessment methods developed by the United States Environmental Protection Agency were employed to explore the potential health hazards of PTEs in soils growing crops. Results showed that 4 toxic elements, Cd, Cu, As, and Cr, were found to have different degrees of contamination in soils in the studied area. The total concentration of toxic elements (As, Cr, Cu, and Pb) in fingernail, hair, and blood samples were 90.50, 69.31, and 6.90 mg·kg−1, respectively. Fingernail samples from females were more likely to show exposure to trace metals compared to males. As the age of the subject increased, the concentration of As also increased in all three biological samples. The risk assessment for the mean hazard index value from the consumption of local food crops was 14.81, indicating that consumers may experience adverse, noncarcinogenic health effects. The estimated mean total cancer risk value of was 5.3 × 10−3, which was approximately 10 to 1000 times higher than the acceptable range of 10−6–10−4, indicating serious carcinogenic risks for local people consuming crops from the area. This study provides evidence that local residents in this study area may be at a high risk of disease caused from toxic element exposure. [ABSTRACT FROM AUTHOR]