Understanding the impact of parental involvement subtypes on Chinese preschool children's language ability.

Parental involvement, especially home-based involvement and home‒school communication, is an important factor affecting the development of preschool children's language abilities. Although previous studies suggest that parents are important catalysts in shaping children's language achievement, it is still unclear how types of parental involvement affect children's language abilities. This study surveys 874 preschool children in China and finds that home-based involvement boosts children's language abilities via improved approaches to learning. Surprisingly, we also find that home‒school communication negatively predicts children's language abilities via decreased approaches to learning. Moreover, school-based involvement has no significant association with children's language abilities. This study contributes new insights to the literature on children's language abilities by uncovering the various impacts of the subtypes of parental involvement and providing a process explanation accordingly.

Zyxin (ZYX) promotes invasion and acts as a biomarker for aggressive phenotypes of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.

Tumor mutational burden is associated with poor outcomes in diffuse glioma.

BACKGROUND: Tumor mutational burden (TMB) is a potential biomarker for immune checkpoint therapy and prognosis. The impact of TMB on clinical outcomes and the correlation coefficient between exome sequencing and targeted sequencing in glioma have not yet been explored. METHODS: Somatic mutations in the coding regions of 897 primary gliomas and the clinical and RNA-seq data of 654 patients in The Cancer Genome Atlas (TCGA) database were analyzed as a training set, while another 286 patients in the Chinese Glioma Genome Atlas (CGGA) database were used for validation. Descriptive and correlational analyses were conducted with TMB. Enrichment map analysis and gene set enrichment analysis (GSEA) were also performed. RESULTS: TMB was higher for the group of mutant genes that are frequently mutated in glioblastomas (GBMs) and lower for the group of mutant genes that are frequently mutated in lower-grade gliomas (LGGs). Patients with a higher TMB exhibited shorter overall survival. TMB was associated with grade, age, subtype and mutations affecting genomic structure. Moreover, univariate and multivariate analyses showed that TMB was an independent prognostic factor for glioma. The signaling pathways of the cell cycle were enriched in the TMBHigh group. TMB was higher in the mismatch repair (MMR) gene mutant group than in the wild-type group, but the MMR pathway was enriched in the TMBHigh group of gliomas without mutations in classical MMR genes. The correlation between TMBs calculated through exome sequencing and targeted sequencing was moderate, and panel-based TMB was not correlated with prognosis. CONCLUSIONS: TMB is associated with poor outcomes in diffuse glioma. The high proliferative activity in the TMBHigh group could account for the shorter survival of these patients. This association was not reflected by a pan-cancer targeted sequencing panel.

Phosphorylated mTOR and YAP serve as prognostic markers and therapeutic targets in gliomas.

Glioma is the most prevalent type of tumor in the brain and is comprised of grades I-IV, according to the WHO classification system. Grade IV glioma is also known as glioblastoma multiforme (GBM), the most malignant type of glioma. Glioma is characterized by a complex molecular background, and gene profiling studies have disclosed critical genetic events in human gliomas, which make targeted therapies the most promising therapeutic strategy. However, crosstalk between the targeted signaling pathways may hinder the efficacy of targeted therapies in gliomas. Therefore, it is necessary to identify effective markers to stratify patients for specific therapeutic procedures. Although several mechanisms have been proposed based on the crosstalk between PI3K/AKT/mTORC1 and Hippo/YAP pathways, the clinical significance of the two pathways has not yet been assessed in a combinatorial manner. In this study, we evaluated the two pathways in human glioma specimens and observed the positive correlation between protein levels of p-mTORS2448 and YAP in gliomas. The findings indicated that high expression of p-mTORS2448 and YAP correlated with poor overall survival of glioma patients. As p-mTORS2448 is a specific marker of mTORC1 activation, our results reveal a potential interaction between mTORC1 and YAP, which might functionally participate in the development and progression of gliomas. In support of this hypothesis, a combination of inhibitors targeting mTORC1 and YAP showed a better inhibitory effect on growth of glioma cell lines. Altogether, our work, for the first time, reveals that p-mTORS2448 and YAP can be used as markers of PI3K/AKT/mTORC1 and Hippo/YAP pathway activity to predict prognosis and are target candidates for personalized medicine.

Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells.

Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2minutes to 7hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.

Benzoxazine: A Privileged Scaffold in Medicinal Chemistry.

BACKGROUND: Benzoxazine is one of the most important privileged scaffolds in medicinal chemistry. Compounds bearing benzoxazine moiety usually have a variety of biological activities, such as anti-inflammatory, anti-microbial, anti-tuberculosis, anti- oxidant and anti-cancer activities. The fascinating bioactivity profile of benzoxazine scaffold in various fields has prompted medicinal chemists to design and discover novel benzoxazine derivatives as potential therapeutic candidates with the desired biological properties. OBJECTIVE: This review aimed to provide a comprehensive elucidation on the recent advances of benzoxazine derivatives in medicinal chemistry. METHODS: We have searched the recent literature about benzoxazine derivatives from the online resources and databases, such as PubMed, SciFinder and Google Scholar. RESULTS: Many benzoxazine derivatives with a wide range of bioactivities, such as anti- microbial, anti-cancer, anti-tuberculosis, anti-oxidant and anti-inflammatory, were summed up. Many compounds displayed good biological activities. CONCLUSION: Benzoxazine is a versatile structure and building block in medicinal chemistry. Benzoxazine derivatives have gained considerable attention from medicinal chemists due to their various pharmacological properties and multiple modification sites. This review might help medicinal chemists to seek new drug candidates with better bioactivities and pharmacokinetics properties.

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD-L1 expression and tumor-infiltrating lymphocytes.

AIMS: The aim of this study was to investigate the tumor microenvironment immune types (TMIT) based on tumor cell programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) distribution and whether distinct TMIT subtypes (TMIT I, PD-L1high /TILhigh ; TMIT II, PD-L1low /TILlow ; TMIT III, PD-L1high /TILlow ; and TMIT IV, PD-L1low /TILhigh ) differentially affect clinical outcomes of patients with lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). METHODS AND RESULTS: Immunohistochemistry (IHC) was applied to evaluate the expression of PD-L1 and the spatial distribution of programmed cell death 1 (PD-1) and CD8 TILs on the surgically resected specimens from 205 cases of LAC and 149 cases of SCC. PD-1 and CD8 TILs were more frequently distributed in SCC than those in LAC, regardless of their infiltrating in the tumor islets or stroma. The density of TILs was a poor prognostic factor in LAC but a favorable one in SCC. PD-L1 levels and its clinical prognostic significance differed in LAC vs SCC. LAC patients with TMIT III and SCC patients with TMIT I had the longest survival, respectively (P = .0197 and .0049). Moreover, TMIT stratification based on tumor cell PD-L1 expression and stromal CD8+ TILs could be considered as an independent prognostic factor of SCC patients' survival as determined by both univariate and multivariate analysis. CONCLUSION: Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of LAC and SCC patients and highlights the importance of the integrative assessment of PD-L1 status and TILs' spatial distribution to predict patients' prognosis.