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Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT.

Background Dual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest‐specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD. Methods and Results A total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA‐223‐3p (miR‐223‐3p) expression. Platelet‐rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR‐223‐3p expression. A dual‐luciferase reporter assay was performed to explore the interaction between miR‐223‐3p and GAS5 or P2Y12 3′‐UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG‐01 cells. Loss‐of‐function and gain‐of‐function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR‐223‐3p in MEG‐01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR‐223‐3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR‐223‐3p expressions was observed in platelets. MiR‐223‐3p mimic reduced while the miR‐223‐3p inhibitor increased the expression of GAS5 and P2Y12 in MEG‐01 cells. Knockdown of GAS5 by siRNA increased miR‐223‐3p expression and decreased P2Y12 expression, which could be reversed by the miR‐223‐3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR‐223‐3p expression and increased P2Y12 expression, which could be reversed by miR‐223‐3p mimic. Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR‐223‐3p.

This study focused on parents' relationships and involvement in their children's lives and the effects on the students' school engagement and school performance. The study used the Wave I data from the National Longitudinal Study of Adolescent Health (Add Health). The data on seventh and eighth grade students' school and family experiences were analyzed using structural equation modeling. The study examined the effect of parents' relationships and involvement on students' cognitive, emotional, and behavioral engagement in school and subsequently on school performance. The results confirmed the importance and significance of parents' involvement in middle school students' school engagement and performance. The study has implications for practice and provides empirical support for creating school structures that would foster parents' continued interest and engagement in their children's education. (Contains 5 tables and 2 figures.)

Abstract Background Chemotherapy is the primary established systemic treatment for patients with breast cancer, especially those with the triple-negative subtype. Simultaneously, the resistance of triple-negative breast cancer (TNBC) to chemotherapy remains a major clinical problem. Our previous study demonstrated that the expression levels of PTN and its receptor PTPRZ1 were upregulated in recurrent TNBC tissue after chemotherapy, and this increase was closely related to poor prognosis in those patients. However, the mechanism and function of chemotherapy-driven increases in PTN/PTPRZ1 expression are still unclear. Methods We compared the expression of PTN and PTPRZ1 between normal breast and cancer tissues as well as before and after chemotherapy in cancer tissue using the microarray analysis data from the GEPIA database and GEO database. The role of chemotherapy-driven increases in PTN/PTPRZ1 expression was examined with a CCK-8 assay, colony formation efficiency assay and apoptosis analysis with TNBC cells. The potential upstream pathways involved in the chemotherapy-driven increases in PTN/PTPRZ1 expression in TNBC cells were explored using microarray analysis, and the downstream mechanism was dissected with siRNA. Results We demonstrated that the expression of PTN and PTPRZ1 was upregulated by chemotherapy, and this change in expression decreased chemosensitivity by promoting tumour proliferation and inhibiting apoptosis. CDKN1A was the critical switch that regulated the expression of PTN/PTPRZ1 in TNBC cells receiving chemotherapy. We further demonstrated that the mechanism of chemoresistance by chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis depended on the NF-κB pathway. Conclusions Our studies indicated that chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis play a critical role in chemoresistance, which suggests a novel strategy to enhance chemosensitivity in breast cancer cells, especially in those of the triple-negative subtype.

Men are underrepresented within the ivory tower. When the intersection of race and gender is examined, enrollment gaps widen even further. Currently, more opportunities than ever before are available for African Americans and Hispanics to attend college; however, their rates of attaining a bachelor's degree are significantly lower when compared to other ethnic/gender combinations. Select personal characteristics (i.e., race, SES) are known to play a role in men's academic achievement. Beyond those, however, are issues of efficacy. The purpose of this study was to determine what efficacy factors predict persistence to graduation of male students when personal characteristics are controlled for. A modified version of the Bandura et al. (1996) theoretical model was used that identified three factors that influence self-efficacy, hence academic success: familial, peer, and self. The findings suggest that race and select parental and peer factors can have both negative and positive effects on the persistence of male students in college.

This study examined the individual, class, and school level variability of the students' science achievement. It was hypothesized that there are school or teacher effects which contribute toward explaining achievement differences, besides the student level differences. Owing to the nested structure of the data in Trends in International Mathematics and Science Study, we used the Hierarchical Linear Modeling methodology. Besides the significant effect of engagement, the teachers' teaching certification in science and the topic coverage were both significant factors as were the effect of school SES and availability of remedial and enrichment programs in science. The study makes a contribution to a better understanding of the opportunity to learn variables at classroom and school level in students' science achievement.

A series of molecular dynamics simulations were performed to investigate the phase transition during the rapid solidification of liquid metal tungsten (W). In particular, the formation and evolution of the topologically close-packed (TCP) crystals of β-W have been thoroughly investigated in terms of the newly developed largest standard cluster analysis (LaSCA), tracing method, and 3D visual analysis. Results indicate that the system solidifies into the amorphous structure that coexists with TCP crystals rather than pure amorphous ones even at high cooling rates, and the content of the TCP crystals increases with decreasing cooling rate. The defects in the TCP crystal structure are the precursor of the perfect ones; at the beginning of crystallization, both the perfect TCP crystal structure and defect ones increase quickly with decreasing temperature, however, when the perfect TCP crystal structure become dominant in the system, the defective ones begin to gradually transform into perfect ones. Interestingly, the formation and evolution of the TCP crystals of β-W experience three stages: the incubation of the crystal nuclei, formation and rapid growth of the critical nucleus, and slow growth and regulation of crystal nuclei. These findings shed new light on the understanding of the nucleation theory under rapid cooling of metal melts. [ABSTRACT FROM AUTHOR]