CCR9+ T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9+ cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity–responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9+CD8+ T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell–dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein–1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9+CD8+ T cell tumor infiltration.

Trace elements play a critical role in the pathogenesis of autism spectrum disorders (ASD). The aim of this study was to investigate the serum levels of zinc (Zn) and copper (Cu) in Chinese children with ASD. Sixty patients (48 males, 12 females) diagnosed with ASD and 60 healthy sex-matched and age-matched control participants were assessed for serum Zn and Cu content at admission. The severity of ASD was also evaluated using the Childhood Autism Rating Scale (CARS) score. The results indicated that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases (P<0.001, respectively), whereas serum Cu levels were significantly higher (P<0.001). There was a significant negative association between Zn/Cu and CARS scores (r=-0.345, P=0.007). On the basis of the receiver operating characteristic curve, the optimal cut-off value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943-0.993). In conclusion, these results suggested an association between serum levels of Zn and Cu and ASD among Chinese patients, and the Zn/Cu ratio could be considered a biomarker of ASD.

Background A growing body of evidence suggests that E2Fs, by regulating gene expression related to cell cycle progression and other cellular processes, play a pivotal role in human cancer. However, the distinct roles of each E2F in the development and treatment of hepatocellular carcinoma (HCC) remain unknown. In the present study, the mRNA expression and prognostic value of different E2Fs in HCC are analyzed. Materials and methods Transcriptional and survival data related to E2F expression in patients with HCC were obtained through ONCOMINE and UALCAN databases. Survival analysis plots were drawn with Kaplan–Meier Plotter. The sequence alteration data for E2Fs were obtained from The Cancer Genome Atlas and c-BioPortal. Gene functional enrichment analyses were performed in Database for Annotation, Visualization and Integrated Discovery. Results The mRNA expression levels of E2F1–E2F8 were all significantly upregulated in HCC patients, and high expression of each E2F was obviously related to poor prognosis. Similarly, the expression of E2Fs showed prognostic prediction value in HCC patients with different cancer stages and pathological grades. Moreover, the mutation rate of E2Fs was relatively high in HCC patients, and the DNA sequence alterations primarily occurred in E2F5, E2F3, and E2F6, which were associated with worse overall survival and disease-free survival in HCC patients. Network analysis confirmed that the expression levels of cell cycle-related genes were mostly affected by E2F mutations. Conclusion High expression of individual E2Fs was associated with poor prognosis in all liver cancer patients. E2Fs may be exploited as good prognostic targets for comprehensive management of HCC patients, but this notion should be further evaluated in clinical studies.

Background: The use of direct oral anticoagulant (DOAC) off-label doses in atrial fibrillation (AF) patients may result in poor clinical outcomes. However, the true prevalence remains scarce. This study aims at estimating the prevalence of DOAC off-label doses in AF patients.Methods: Databases of MEDLINE, EMBASE, and COCHRANE were searched from inception through February 2020 for real-world studies that reported the off-label definition and prevalence data of AF patients using DOACs. The primacy outcomes were the overall prevalence of DOAC off-label doses and the corresponding underdose and overdose. The random-effects model was used for data synthesis. Variations on individual DOAC and different regions were examined by subgroup analyses.Results: A total of 23 studies involving 162,474 AF patients were finally included. The overall prevalence of DOAC off-label doses was 24% (95% CI, 19–28%), with 18% for dabigatran, 27% for rivaroxaban, 24% for apixaban, and 26% for edoxaban. The prevalence of underdosed DOACs was 20% (95% CI, 16–24%) with significant difference among individual anticoagulants (13% for dabigatran, 22% for rivaroxaban, 22% for apixaban, and 18% for edoxaban; Pinteraction=0.02). The prevalence of overdosed DOACs was 5% (95% CI, 3–7%), with the lowest prevalence observed in apixaban (2%). Subgroup analyses by regions demonstrated that the prevalence of DOAC off-label doses was higher in Asia (32%) than in North America (14%) and in Europe (22%), with underdose being predominant. Regardless of different regions, the prevalence of overdose was relatively low (4–6%).Conclusion: This study provides an estimation of DOAC off-label doses in the real-world setting. The prevalence rate of DOAC off-label doses in AF patients was relatively high, with underdose being predominant. Clinicians in Asia preferred to prescribe underdose of DOACs to AF patients. More evidence about the appropriateness of DOAC off-label doses in AF patients is urgently needed. Education programs concerning the appropriate prescription of DOACs within the drug labels and accepted guidelines are necessary to DOAC prescribers to ensure the safety and effectiveness of anticoagulation therapy for patients with AF.

Adverse environment in early life can modulate the adult phenotype, including blood pressure. Lipopolysaccharide (LPS) exposure in utero results in increased blood pressure in the offspring, but the exact mechanisms are not clear. Studies have shown that the renal dopamine D1 receptor (D1R) plays an important role in maintaining sodium homeostasis and normal blood pressure; dysfunction of D1R is associated with oxidative stress and hypertension. In this study, we determined if dysfunction of the renal D1R is involved in fetal-programmed hypertension, and if oxidative stress contributes to this process. Pregnant Sprague-Dawley (SD) rats were intraperitoneally injected with LPS (0.79 mg/kg) or saline at gestation days 8, 10, and 12. As compared with saline-injected (control) dams, offspring of LPS-treated dams had increased blood pressure, decreased renal sodium excretion, and increased markers of oxidative stress. In addition, offspring of LPS-treated dams had decreased renal D1R expression, increased D1R phosphorylation, and G protein-coupled receptor kinase type 2 (GRK2) and type 4 (GRK4) protein expression, and impaired D1R-mediated natriuresis and diuresis. All of the findings in the offspring of LPS-treated dams were normalized after treatment with TEMPOL, an oxygen free radical scavenger. In conclusion, prenatal LPS exposure, via an increase in oxidative stress, impairs renal D1R function and leads to hypertension in the offspring. Normalization of renal D1R function by amelioration of oxidative stress may be a therapeutic target of fetal programming of hypertension.

Background Controversies exist concerning the association between serum lipids and ischemic stroke.Objective To investigate the relationship between serum lipid, apolipoprotein E (apoE) genotype and risk of ischemic stroke. MethodsWe measured the concentrations of serum lipids, lipoprotein (a) [Lp(a)], and apoE genotype, as well as the distribution of other potential risk factors, in 90 pairs of age-and sex-matched ischemic stroke patients and stroke-free controls. ResultsThe prevalence of hypertension, family history of stroke and hypertension, and smoking and drinking habits were significantly higher in cases than in controls. Total cholesterol, low-density lipoprotein cholesterol, and Lp(a) levels were higher in ischemic stroke patients than in controls (5.7 ± 1.2 versus 5.3± 1.2mmol/I, P<0.05; 3.7± 1.0 versus 3.1 ± 1.0mmol/I, P< 0.0 1; and 197.6 ± 30.6 versus 9004 ± 11.2 mg/I, P< 0.0 1, respectively). The cases had lower high-density lipoprotein cholesterol and apolipoprotein A-I concentrations compared with the controls. The apoE e3/e4 genotype was more frequent in cases (21.1 %) than in controls (8.9%, P< 0.05). ConclusionThe results of the study indicate that serum Lp(a) level and apoE e4 are the prominent lipidic predictors for ischemic stroke in addition to the general risk factors such as history of hypertension, family history of stroke and cigarette smoking.

Constipation is a major health concern worldwide, requiring effective and safe treatment options. This study mainly focused on three species and nine strains of Bifidobacteria from different sources to study...

Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27Kip1 was investigated by western blotting and immunofluorescence.Results: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth in vitro and in vivo. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27Kip1-S10D but not P27Kip1-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.