Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1ß/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Slow skeletal muscle troponin T acts as a potential prognostic biomarker and therapeutic target for hepatocellular carcinoma.

Slow skeletal muscle troponin T (TNNT1) as a poor prognostic indicator is upregulated in colon and breast cancers. However, the role of TNNT1 in the disease prognosis and biological functions of hepatocellular carcinoma (HCC) is still unclear. The Cancer Genome Atlas (TCGA), real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to evaluate the TNNT1 expression of human HCC. The impact of TNNT1 levels on disease progression and survival outcome was studied using TCGA analysis. Moreover, the bioinformatics analysis and HCC cell culture were used to investigate the biological functions of TNNT1. Besides, the immunoblot analysis and enzyme-linked immunosorbent assay (ELISA) were used to detect the extracellular TNNT1 of HCC cells and circulating TNNT1 of HCC patients, respectively. The effect of TNNT1 neutralization on oncogenic behaviors and signaling was further validated in the cultured hepatoma cells. In this study, tumoral and blood TNNT1 was upregulated in HCC patients based on the analyses using bioinformatics, fresh tissues, paraffin sections, and serum. From the multiple bioinformatics tools, the TNNT1 overexpression was associated with advanced stage, high grade, metastasis, vascular invasion, recurrence, and poor survival outcome in HCC patients. By the cell culture and TCGA analyses, TNNT1 expression and release were positively correlated with epithelial-mesenchymal transition (EMT) processes in HCC tissues and cells. Moreover, TNNT1 neutralization suppressed oncogenic behaviors and EMT in hepatoma cells. In conclusion, TNNT1 may serve as a non-invasive biomarker and drug target for HCC management. This research finding may provide a new insight for HCC diagnosis and treatment.

Evaluation of Bodily Pain Associated with Polycystic Ovary Syndrome: A Review of Health-Related Quality of Life and Potential Risk Factors.

Polycystic ovary syndrome (PCOS) is the most common reproductive disease affecting the hormone and metabolic status of women. Its associated symptoms are diverse among the patients, including hyperandrogenism, insulin resistance, anovulation, infertility, obesity, hirsutism, acne, and more. In addition, PCOS can potentially increase the risk of dysmenorrhea, endometriosis, endometrioma, and irritable bowel syndrome, which are highly related to pelvic pain and sexual difficulty. However, little known is whether PCOS exacerbates other chronic bodily pain or contributes to hyperalgesia. Health-related quality of Life (HRQoL) reflects the life satisfaction and quality derived by an individual from mental, physical, emotional, and social activities under specific conditions. In this study, we reviewed pain perception from HRQoL of PCOS patients (SF-36). The review data evidently indicated that pain perception is significantly more prevalent in patients with PCOS than in healthy controls, and obesity and infertile status could be the rationales associated with pain development. Nevertheless, underlying causes remain undetermined due to the limited information from SF-36. Furthermore, we reviewed pathophysiologic factors to pain development or exacerbation, such as the deregulation of inflammation levels, adipokines, and insulin resistance. Although current evidence of pain perception and pathophysiologic risk factors are solid in PCOS, patients' pain perception is often ignored in clinical settings. Clinicians should note the perception and treatment of pain in PCOS patients. The correlation or causality between pain and PCOS warrants further clinical examination and basic studies, thereby providing new insights into this topic in the context of clinical diagnosis and health care.

DLK2 Acts as a Potential Prognostic Biomarker for Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis.

Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with a high mortality. It has been reported that delta-like 1 homologue (DLK1) participates in the tumor microenvironmental remodeling of ccRCC, but the relationship between delta-like 2 homologue (DLK2, a DLK1 homologue) and ccRCC is still unclear. Thus, this study aims to investigate the role of DLK2 in the biological function and disease prognosis of ccRCC using bioinformatics analysis. The TNMplot database showed that DLK2 was upregulated in ccRCC tissues. From the UALCAN analysis, the overexpression of DLK2 was associated with advanced stage and high grade in ccRCC. Moreover, the Kaplan-Meier plotter (KM Plotter) database showed that DLK2 upregulation was associated with poor survival outcome in ccRCC. By the LinkedOmics analysis, DLK2 signaling may participated in the modulation of ccRCC extracellular matrix (ECM), cell metabolism, ribosome biogenesis, TGF-ß signaling and Notch pathway. Besides, Tumor Immune Estimation Resource (TIMER) analysis showed that the macrophage and CD8+ T cell infiltrations were associated with good prognosis in ccRCC patients. Finally, DLK2 overexpression was associated with the reduced macrophage recruitments and the M1-M2 polarization of macrophage in ccRCC tissues. Together, DLK2 may acts as a novel biomarker, even therapeutic target in ccRCC. However, this study lacks experimental validation, and further studies are required to support this viewpoint.

Bioinformatics Analyses Identify the Therapeutic Potential of ST8SIA6 for Colon Cancer.

Sialylation of glycoproteins is modified by distinct sialyltransferases such as ST3Gal, ST6Gal, ST6GalNAc, or ST8SIA with α2,3-, α2,6-, or α2,8-linkages. Alteration of these sialyltransferases causing aberrant sialylation is associated with the progression of colon cancer. However, among the ST8- sialyltransferases, the role of ST8SIA6 in colon cancer remains poorly understood. In this study, we explored the involvement of ST8SIA6 in colon cancer using multiple gene databases. The relationship between ST8SIA6 expression and tumor stages/grades was investigated by UALCAN analysis, and Kaplan-Meier Plotter analysis was used to analyze the expression of ST8SIA6 on the survival outcome of colon cancer patients. Moreover, the biological functions of ST8SIA6 in colon cancer were explored using LinkedOmics and cancer cell metabolism gene DB. Finally, TIMER and TISMO analyses were used to delineate ST8SIA6 levels in tumor immunity and immunotherapy responses, respectively. ST8SIA6 downregulation was associated with an advanced stage and poorly differentiated grade; however, ST8SIA6 expression did not affect the survival outcomes in patients with colon cancer. Gene ontology analysis suggested that ST8SIA6 participates in cell surface adhesion, angiogenesis, and membrane vesicle trafficking. In addition, ST8SIA6 levels affected immunocyte infiltration and immunotherapy responses in colon cancer. Collectively, these results suggest that ST8SIA6 may serve as a novel therapeutic target towards personalized medicine for colon cancer.

Callous-Unemotional Traits among Adolescents with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, or Typical Development: Differences between Adolescents' and Parents' Views.

This study examined parent-adolescent agreement on the callous, uncaring, and unemotional dimensions of callous-unemotional (CU) traits and the differences in adolescent-reported and parent-reported CU traits among 126 adolescents with autism spectrum disorder (ASD), 207 adolescents with attention-deficit/hyperactivity disorder (ADHD), and 203 typically developing (TD) adolescents. Adolescent-reported and parent-reported CU traits on the three dimensions of the Inventory of Callous and Unemotional Traits were obtained. The strength of CU traits and the differences between adolescent-reported and parent-reported traits were compared among the three groups using analysis of covariance. Parent-adolescent agreement was examined using intraclass correlation. The results reveal that both adolescent-reported and parent-reported callousness and uncaring traits in the ASD and ADHD groups were significantly stronger than those in the TD group. Parent-adolescent agreement on the uncaring trait was fair across the three groups, whereas that on callousness was poor across all three groups. Parent-adolescent agreement on unemotionality was fair in the TD group but poor in the ADHD and ASD groups. ASD and ADHD groups had significantly greater differences in scores reported by parents and adolescents on the callousness trait than the TD group. The parent-adolescent score differences in the uncaring trait were also larger in the ASD group than in the TD group. Thus, these results support the application of a multi-informant approach in CU trait assessment, especially for adolescents with ASD or ADHD.

Gender Disparity in the Risk of Hypertension in Subjects With Major Depressive Disorder.

Objects: The aim of our study was to investigate whether major depressive disorder (MDD) increased the risk of hypertension using propensity score matching (PSM) in patients with MDD in Taiwan. Methods: In this study, we recruited all samples from a random sample sub-dataset of one million insured individuals from 2005. A total of 743,114 outpatients were included in our study. We used PSM (nearest neighbor matching) stratified by age, hospital level, insurance amount, and Charlson Comorbidity Index score. Results: The hazard ratio (HR) of hypertension was significantly greater in the male MDD outpatients (HR = 1.116, P = 0.004) than in the female MDD outpatients (HR = 0.93, P = 0.02). Using PSM, we selected 27,988 outpatients with hypertension and 27,988 outpatients without hypertension for a nested case-control study. In this analysis, female outpatients with MDD (relative risk = 0.852) had lower risks of hypertension. Male outpatients without/with MDD (relative risk = 1.987/3.018) showed a synergistic interaction with gender in which male patients had a higher risk of hypertension in a multiplicative model. Furthermore, MDD appeared to have an interaction effect with gender (HR = 1.82, P < 0.001) in the proportional hazards model analysis. Antidepressant use also increased the risk of hypertension (HR = 1.16, P < 0.001). Conclusions: There was gender disparity in the risk of hypertension in subjects with MDD. MDD outpatients who used antidepressants had a higher risk of suffering from hypertension. A large-scale, population-based study is warranted to generalize these results in the future.

5-HTT mRNA level as a potential biomarker of treatment response in patients with major depression in a clinical trial.

OBJECTIVES: To investigate whether the serotonin transporter (5-HTT or SERT or SLC6A4) mRNA level could be used as a biomarker of treatment response in patients with major depression treated with different antidepressants while controlling related factors. METHODS: One hundred and nineteen patients with major depression were recruited; all genotyped for the 5-HTT polymorphism concerning 5-HTTLPR, rs25531, and STin2 VNTR, provided demographic data and completed relevant questionnaires. Duloxetine and paroxetine were administered over 32 weeks to these patients. The Hamilton depression rating scale (HDRS) and 5-HTT mRNA level were evaluated at baseline (Week 0), and at 8, 16, 24 and 32 weeks. RESULTS: Improvement in depressive symptoms (HDRS score declined) and increasing in 5-HTT mRNA level were found with longer duration of antidepressant treatment in patients with major depression. Patients with more 5-HTTPR long-form alleles and STin2.12 alleles had poor antidepressant treatment response. Duloxetine may give a better treatment response than paroxetine. Using structural equation modeling (SEM), the 5-HTTLPR long-form had a direct positive association with the 5-HTT mRNA level and an indirect adverse relationship with the 5-HTT mRNA level through neuroticism and previous suicide attempts. CONCLUSION: The 5-HTT mRNA level increased and correlated with the treatment response (HDRS score improvement) under 32-weeks antidepressants treatment clinical trial. We speculate that the 5-HTT mRNA level may be used as a potential biomarker of antidepressant treatment response.

A Systemic Review and Experts' Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder.

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician's clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms.

No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment.

The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the ApoE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that ApoE4 genotype (ß = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (ß = 15.361; p = 0.003); and age had a positive effect on the TG level (ß = 1.317; p = 0.030). Smoking (ß = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of ApoE gene polymorphism.

Glutamate-mediated signaling and autism spectrum disorders: emerging treatment targets.

Autism spectrum disorders (ASD) are developmental disorders that are characterized by deficits in reciprocal social interactions and communication, as well as by the presence of impairing repetitive behaviors and restricted interests. Prior work examining human pathology, and model systems and genetic studies have all led to the current conceptualization of ASD as a disorder of synaptic formation and functioning (a "synapsopathy"). In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission, with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of the structure and function of glutamate receptors, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the development of novel drugs for ASD treatment, and reports on glutamate- related clinical trials. We will also present promising new techniques using human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotypes, cellular responses and glutamate involvement in ASD.

Wechsler Intelligence Scale for Children 4th edition-Chinese version index scores in Taiwanese children with attention-deficit/hyperactivity disorder.

AIM: The Wechsler Intelligence Scale for Children 4th edition-Chinese version (WISC-IV-Chinese) has been in clinical use in Taiwan since 2007. Research is needed to determine how the WISC-IV, modified from its earlier version, will affect its interpretation in clinical practice in a Mandarin-speaking context. METHODS: We attempted to use WISC-IV-Chinese scores to identify the cognitive strengths and weaknesses in 334 Taiwanese children with attention-deficit/hyperactivity disorder (ADHD). Comparison of cognitive profiles of WISC-IV-Chinese scores between subtypes of ADHD was also performed. RESULTS: The results indicated that the four-factor model of the WISC-IV-Chinese fitted well for Taiwanese children with ADHD. The profiles showed that performance in the index score of the Processing Speed Index was the weakness domain for the Taiwanese children with ADHD, as confirmed by two different kinds of analytic methods. Cognitive profile analysis of ADHD subtypes revealed children with inattentive subtypes to have a greater weakness in processing speed performance. CONCLUSION: The implications of the profiles of the index scores on the WISC-IV-Chinese version for Taiwanese children with ADHD were explored.

Adaptive behaviors in high-functioning Taiwanese children with autism spectrum disorders: an investigation of the mediating roles of symptom severity and cognitive ability.

We investigated the relationship among cognitive level, autistic severity and adaptive function in a Taiwanese sample of 94 high-functioning children with autism spectrum disorders (ASD) (mean full scale intelligent quotients FSIQ = 84.8). Parents and teachers both completed the Adaptive Behavior Assessment System-II and the Social Responsiveness Scale. Correlational and regression analyses were used to explore the relationships among the constructs of cognitive, symptomatic and adaptive domains. Results revealed that average General Adaptive Composites of these children (home: 74.0; school: 74.6) was below average FSIQ. Profile analysis revealed that Social domain was the weakness among the adaptive abilities assessed at school and home. Cognitive abilities had positive relationship with adaptive function, while autistic severity had a weak negative relationship with adaptive function. Also, the younger the age the child got diagnosed, the less severe the current symptoms of autism were. The implication for emphasizing adaptive skills intervention was discussed.

Determination of binding affinity for chenodeoxycholate in equilibrium with sulfobutylether-ß-cyclodextrin.

A kinetic dialysis technique together with a radiolabeled chenodeoxycholate (CDC) was used to determine the existence of a relationship between the monomer concentration of CDC and the total CDC concentration in different CDC solutions containing 1 or 5 mM sulfobutylether (SBE)-ß-cyclodextrin. On the basis of the nature of the relationship and a binding model with binding constants of K1 and K2, the binding affinity for the solutions was quantified at the best curve fitting using a least-squares technique. The very high binding affinity of K1 and the very low (i.e., negligible) binding affinity of K2 indicate the formation of 1:1 inclusion complexes. In addition, the values of K1 and K2 were reasonably interpreted. Similar analysis showed that the formation of 1:2 inclusion complexes and the self-association of the SBE-ß-cyclodextrin molecules in the solutions are unlikely. The present study provides a basis for investigating the self-association, quantifying the binding affinity, and interpreting the quantified values.

Treatment effectiveness and adherence in patients with schizophrenia treated with risperidone long-acting injection.

This study investigated the variables related to the effectiveness and adherence to treatment with risperidone long-acting injection (RLAI) in patients with schizophrenia. We performed a retrospective medical chart review of 137 patients with schizophrenia who were prescribed RLAI between July 2004 and December 2006. Cox regression analysis showed that the effectiveness of treatment in patients treated with RLAI was affected significantly by the provision of home care and the use of illicit drugs. The adherence of patients to treatment with RLAI was affected most by the provision of home care. Bayesian analysis showed that patients who received the provision of home care or who had no history of illicit drug use continued treatment for, on average, 15.27 and 17.14days longer, respectively, than those who did not receive such care or take illicit drugs. Patients who received the provision of home care adhered to treatment for 343.98 more days than those who did not. Even though patients taking RLAI show better adherence than those taking oral risperidone, home care services can have a significant additional effect on adherence. Randomized clinical follow-up trial studies are necessary to explore the risk factors for nonadherence in more detail.

Toxic epidermal necrolysis after sun-exposure probably due to lamotrigine and chlorpromazine.

Toxic epidermal necrolysis is a life-threatening disease. It may be induced by many kinds of drugs especially anti-epileptics such as lamotrigine, but less sun-exposure related. Lamotrigine has been effective for partial complex seizure and bipolar disorder and caused serious side effects such as Stevens-Johnson syndrome or toxic epidermal necrolysis. We reported a case of the patient who developed the manic episode and received lamotrigine and chlorpromazine drugs. After combination of lamotrigine and chlorpromazine, the patient developed skin rash to toxic epidermal necrolysis after sun-exposure. We had discontinued both drugs, given supportive treatment, and let him prevent sun-exposure greatly. The disease process got subsided nearly 4 weeks later. Clinicians should carefully prescribe mood stabilizer and photo-toxic or photosensitivity medications with higher drug-eruption rate.