Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

Air pollution weaken your muscle? Evidence from a cross-sectional study on sarcopenia in central China.

BACKGROUND: As the world experiences a demographic shift towards aging populations, there will be a significant surge in the number of sarcopenia patients, along with an unprecedented expansion in the associated economic burden. The multitudinous risk factors for sarcopenia have been reported, but evidence for air pollution remains rare. METHODS: This cross-sectional study employed multi-stage random sampling to select 1592 participants over 40 years of age from Hubei Province. Daily mean concentrations of air pollutants were collected ChinaHighAirPollutants dataset. Unconditional logistic regression models were utilized to investigate the associations between air pollution and sarcopenia. RESULTS: For each 1 µg/m3 increase in PM2.5, PM10, SO2 and O3, there were corresponding elevations of 11.1% [95% confidence interval (CI): 4.9, 17.7], 4.3% (95% CI: 1.4, 7.2), 22.6% (95% CI: 7.2, 40.1) and 9.3% (95% CI: 0.7, 18.7) in the risk of sarcopenia, respectively. The associations of PM2.5/PM10/O3-sarcopenia were more pronounced in females, with corresponding odds ratios (ORs) and 95% CIs of 1.179 (1.062, 1.310), 1.079 (1.027, 1.135) and 1.180 (1.026, 1.358), separately. Additionally, individuals residing in rural areas were more susceptible to the effects of PM2.5 and PM10. Current/ever smokers or drinkers were also at higher risk of developing sarcopenia caused by PM2.5, PM10 and O3 exposure. Mixture analyses show a surge of 48.4% (95% CI: 3.6%, 112.5%) in the likelihood of suffering from sarcopenia, and the joint impacts of the air pollution were mainly driven by PM2.5. CONCLUSIONS: Our results produced evidence for a relationship between air pollution exposure and the increased prevalence of sarcopenia in China. Public health and relevant departments should make efforts to prevent sarcopenia, particularly in China experiencing rapid demographic aging.

Synthesis, Stepwise Bromination, and Functionalization of Picene Diimide.

Materials Synthesis and Processing Polycyclic aromatic hydrocarbon (PAH) diimides are indispensable candidates for n-type organic semiconductors in organic optoelectronic devices. Developing new PAH diimide building blocks are of remarkable significance for material diversity and further advance in organic semiconductors. In this contribution, 4,5,8,9-picene diimide (PiDI) was designed and synthesized. Controllable stepwise bromination of PiDI were accomplished to afford 13-monobromo-, 13,14-dibromo-, 2,13,14-tribromo- and 2,11,13,14-tetrabromo-PiDI. Moreover, cyanation of 2,11,13,14-tetrabromo-PiDI gave the corresponding tetracyanated PiDI, which can be utilized as n-type semiconductor with OFET electron mobility up 0.073 cm2 V-1 s-1 . This result demonstrates the potential of PiDI as a building block for constructing new high-performance electronic-transporting materials.

hsa-miR-34a-5p Ameliorates Hepatic Ischemia/Reperfusion Injury Via Targeting HNF4α.

BACKGROUND: To investigate the relationship between the expression level of hsa-miR-34a-5p and liver injury and to further explore its regulatory signaling pathways Methods: Liver tissue and blood were collected from 60 patients undergoing hepatectomy. We constructed a rat HIRI model and treated it with an intraperitoneal injection of agomir-miR-34a-5p or agomir-normal control (NC) for 7 days after the surgery. The pathological changes of agomir-miR-34a-5p or agomir-normal control (NC) groups were compared. 7702 and AML12 cells were transfected with mimics NC or miR-34a-5p mimics and then treated with H2O2 for 6 hours. Cell apoptosis was detected by flow cytometry, Western blot, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, respectively. Furthermore, the target genes of miR- 34a-5p were identified by luciferase reporter gene assay and were verified in vitro. RESULTS: The relatively high miR-34a-5p expression group revealed a lower level of alanine aminotransferase and aspartate aminotrans- ferase compared with the relatively low miR-34a-5p expression group. HIRI+agomir-miR-34a-5p rats exhibited significantly higher miR-34a-5p expression, lower serum alanine aminotransferase, aspartate aminotransferase, alleviated hepatic necrosis, reduced hepa- tocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI+agomir-NC rats (P < .05). After hydrogen peroxide treatment, alpha mouse liver-12 cell (AML-12) and normal liver cell line LO2 (LO2) cells transfected with miR-34a-5p mimics had significantly lower apoptosis rate compared with miR-34a-5p mimics NC group (P < .05). Hepatocyte nuclear factor 4α was identified as a miR-34a-5p target gene. Hepatocyte nuclear factor 4α expression was significantly downregulated in AML12 and HL-7702 (7702) cells transfected with miR-34a-5p (P < .05). Moreover, AML12 and 7702 cells transfected with miR-34a-5p signifi- cantly showed higher c-Jun N-terminal kinase (JNK), P38, cleavage cas-3, and BCL2 associated X (Bax) protein levels compared with AML12 and 7702 cells transfected with agomir-NC. CONCLUSION: miR-34a-5p possibly protected the liver from I/R injury through downregulating Hepatocyte nuclear factor 4α to inhibit the JNK/P38 signaling pathway.

Development and Validation of a Differential Diagnosis Model for Acute Appendicitis and Henoch-Schonlein Purpura in Children.

Objective: To study and develop a predictive model for the differential diagnosis of acute appendicitis (AA) and Henoch-Schonlein purpura (HSP) in children and to validate the model internally and externally. Methods: The complete data of AA and HSP cases were retrospectively analyzed and divided into internal and external verification groups. SPSS software was used for single-factor analysis and screening of independent variables, and R software was used for the development and verification of the diagnostic model. Lasso regression analysis was used to screen predictors and Lasso-logistic regression model was constructed, and K-fold cross-validation was used for the internal verification. In addition, nonfever patients were selected for model development and validation in the same way. Receiver operating characteristic (ROC) curves and calibration curves were drawn, respectively, to evaluate the 2 models. Results: Internal development and validation of the model showed that fever, neutrophil ratio (NEUT%), albumin (ALB), direct bilirubin (DBIL), C-reactive protein (CRP), and K were predictive factors for the diagnosis of HSP. The model was presented in the form of a nomogram, and the area under ROC curve of the development group and verification group was 0.9462 (95% confidence interval [CI] = 0.9402-0.9522) and 0.8931 (95% CI = 0.8724-0.9139), respectively. In the model of patients without fever, NEUT%, platelets (PLT), ALB, DBIL, alkaline phosphatase (ALP), CRP, and K were predictive factors for the diagnosis of HSP, and the area under ROC curve of the development group and verification group was 0.9186 (95% CI = 0.908-0.9293) and 0.8591 (95% CI = 0.8284-0.8897), respectively. Conclusion: In this study, 2 diagnostic models were constructed for fever or not, both of which had good discrimination and calibration, and were helpful to distinguish AA and HSP in children.

ZnSe Nanorods-CsSnCl3 Perovskite Heterojunction Composite for Photocatalytic CO2 Reduction.

Utilizing sunlight to convert CO2 into chemical fuels could simultaneously address the greenhouse effect and fossil fuel crisis. ZnSe nanocrystals are promising candidates for photocatalysis because of their low toxicity and excellent photoelectric properties. However, pristine ZnSe generally has low catalytic activities due to serious charge recombination and the lack of efficient catalytic sites for CO2 reduction. Herein, a ZnSe nanorods-CsSnCl3 perovskite (ZnSe-CsSnCl3) type II heterojunction composite is designed and prepared for photocatalytic CO2 reduction. The ZnSe-CsSnCl3 type II heterojunction composite exhibits enhanced photocatalytic activity for CO2 reduction with respect to pristine ZnSe nanorods. The experimental characterizations and theoretical calculations reveal that the efficient charge separation and lowered free energy of CO2 reduction facilitate the CO2 conversion on the ZnSe-CsSnCl3 heterojunction composite. This work presents a type II heterojunction composite photocatalyst based on ecofriendly metal chalcogenides and metal halide perovskites. Our study has also promoted the understanding of the CO2 reduction mechanisms on perovskite nanocrystals, which could be valuable for the development of metal halide perovskite photocatalysts.

USP1 Promotes GC Metastasis via Stabilizing ID2.

Gastric cancer (GC) is one of the most common malignant tumors all over the world. And recurrence and metastasis are still the main causes of low survival rate for advanced GC. USP1 has been shown overexpressed in multiple cancers, which indicate its important biomarker in tumorigenesis and development. Our study is aimed at defining the exact role of USP1 on GC metastasis and the underlying mechanism. USP1 was firstly found overexpressed in GC tissues and relatively high-expression levels conferred poor survival rates. Then, real-time cellular analysis (RTCA) showed that USP1 knockdown inhibited GC metastasis both in vitro and in vivo. Mechanically, we demonstrated that USP1 promoted GC metastasis via upregulating ID2 expression and further confirmed that USP1 stabilized ID2 expression through deubiquitinating ID2 in GC. In conclusion, our study showed that USP1 promoted GC metastasis via stabilizing ID2 expression, which provides a potential biomarker and therapy target for GC.

Development and Validation of Diagnostic Models for Hand-Foot-and-Mouth Disease in Children.

OBJECTIVE: To find risk markers and develop new clinical predictive models for the differential diagnosis of hand-foot-and-mouth disease (HFMD) with varying degrees of disease. METHODS: 19766 children with HFMD and 64 clinical indexes were included in this study. The patients included in this study were divided into the mild patients' group (mild) with 12292 cases, severe patients' group (severe) with 6508 cases, and severe patients with respiratory failure group (severe-RF) with 966 cases. Single-factor analysis was carried out on 64 indexes collected from patients when they were admitted to the hospital, and the indexes with statistical differences were selected as the prediction factors. Binary multivariate logistic regression analysis was used to construct the prediction models and calculate the adjusted odds ratio (OR). RESULTS: SP, DP, NEUT#, NEUT%, RDW-SD, RDW-CV, GGT, CK/CK-MB, and Glu were risk markers in mild/severe, mild/severe-RF, and severe/severe-RF. Glu was a diagnostic marker for mild/severe-RF (AUROC = 0.80, 95% CI: 0.78-0.82); the predictive model constructed by temperature, SP, MOMO%, EO%, RDW-SD, GLB, CRP, Glu, BUN, and Cl could be used for the differential diagnosis of mild/severe (AUROC > 0.84); the predictive model constructed by SP, age, NEUT#, PCT, TBIL, GGT, Mb, ß2MG, Glu, and Ca could be used for the differential diagnosis of severe/severe-RF (AUROC > 0.76). CONCLUSION: By analyzing clinical indicators, we have found the risk markers of HFMD and established suitable predictive models.

Varied thyroid disrupting effects of perfluorooctanoic acid (PFOA) and its novel alternatives hexafluoropropylene-oxide-dimer-acid (GenX) and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA) in vitro.

Due to its potential adverse effects on human health, perfluorooctanoic acid (PFOA), one of the once widely used legacy per- and polyfluoroalkyl substances (PFASs), has been recently replaced by its novel alternatives including hexafluoropropylene-oxide-dimer-acid (GenX) and ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA). These alternative PFASs are detected in water and exposed workers. PFASs can enter organs like thyroids, however, it is yet unknown whether the new alternatives are safer than PFOA. In the current study, we compared the thyroid disrupting effects of PFOA and its alternatives GenX and ADONA in vitro with both rat thyroid cell line FRTL5 and primary normal human thyroid (NHT) cells. Cells were exposed to ascendant doses of PFOA, GenX or ADONA for various incubation time and cell viability was assessed by WST-1 assay and LDH assay. The proliferation rate of survived cells was determined by crystal violet-based cell proliferation assay and MTT assay. The gene expression of thyroid hormone regulation-related genes in thyroid cells after exposure was quantified by RT-PCR and Western blot. Our data showed that both PFOA and GenX reduced thyroid cell viability in both dose and time dependent manner, with GenX being more toxic than PFOA at the same condition. Similarly, the proliferation rate of cells survived exposure to PFOA and GenX was considerably impaired, with GenX showing more profound adverse effect than PFOA. Unlike PFOA and GenX, ADONA showed no apparent adverse effects on the viability and proliferation of both thyroid cell types. Gene expression data revealed that all three PFASs altered gene expression in both thyroid cells and the altered gene expression seemed to be PFAS and cell type dependent. Taken together, our data reveal that the thyroid disrupting effects is increased in the order of GenX > PFOA > ADONA. Our findings will be beneficial for the guidance of the future usage of PFASs and development of better alternatives.

Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1.

The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC.

Hepatitis B virus induces sorafenib resistance in liver cancer via upregulation of cIAP2 expression.

BACKGROUND: HBV promotes cell survival by upregulating the expression of the cellular inhibitor of apoptosis protein 2 (cIAP2), however whether it is involved in HBV-induced sorafenib resistance in liver cancer remains unclear. METHODS: cIAP2 overexpression and knockdown was adopted to assess the involvement of cIAP2 in HBV-induced sorafenib resistance. Anti-HBV drug lamivudine and Akt inhibitor were used to investigate the impact of HBV replication on cIAP2 expression and sorafenib resistance. Xenotransplantation mouse model was used to confirm the data on cell lines in vitro. RESULTS: Liver cancer cell line HepG2.215 showed increased cIAP2 expression and enhanced resistance to sorafenib. Upon sorafenib treatment, overexpression of cIAP2 in HepG2 lead to decreased cleaved caspase 3 level and increased cell viability, while knockdown of cIAP2 in HepG2.215 resulted in increased level of cleaved caspase 3 and decreased cell viability, suggesting the involvement of cIAP2 in HBV-induced sorafenib resistance. Furthermore, anti-HBV treatment reduced cIAP2 expression and partially restored sorafenib sensitivity in HepG2.215 cells. Xenotransplantation mouse model further confirmed that co-treatment with lamivudine and sorafenib could reduce sorafenib-resistant HepG2.215 tumor cell growth. CONCLUSION: cIAP2 is involved in HBV-induced sorafenib resistance in liver cancer and anti-HBV treatments reduce cIAP2 expression and partially restore sorafenib sensibility.

Direct Z-Scheme 0D/2D Heterojunction of CsPbBr3 Quantum Dots/Bi2WO6 Nanosheets for Efficient Photocatalytic CO2 Reduction.

Photocatalytic CO2 reduction is an appealing approach to convert solar energy into high value-added chemicals. All-inorganic CsPbBr3 quantum dots (QDs) have emerged as a promising photocatalyst for reducing CO2. However, pristine CsPbBr3 has a low catalytic performance, mainly due to severe charge recombination. Herein, a 0D/2D heterojunction of CsPbBr3 QDs/Bi2WO6 nanosheet (CPB/BWO) photocatalysts is fabricated for photocatalytic CO2 reduction. The CPB/BWO photocatalyst achieves excellent photocatalytic performance: the total yield of CH4/CO is 503 µmol g-1, nearly 9.5 times higher than the pristine CsPbBr3. The CPB/BWO heterojunction also exhibits much-improved stability during photocatalytic reactions. On the basis of various characterization techniques, our investigations verified a direct Z-scheme charge migration mechanism between CsPbBr3 QDs and Bi2WO6 nanosheets. The improved photocatalytic performance is originated from the high spatial separation of photoexcited charge carriers in CPB/BWO, which can also preserve strong individual redox abilities of two components. This work reports an efficient direct Z-scheme heterojunction photocatalytic system based on metal halide perovskites. The novel strategy we proposed may bring up new opportunities for the development of metal halide perovskite photocatalysts with greatly enhanced activities.