TAZ is indispensable for c-MYC-induced hepatocarcinogenesis.

BACKGROUND & AIMS: Mounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ to c-MYC-induced liver tumor development. METHODS: The requirement for YAP and/or TAZ in c-Myc-driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. An hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples. RESULTS: We found that the Hippo cascade is inactivated in c-Myc-induced mouse HCC. Intriguingly, TAZ mRNA levels and activation status correlated with c-MYC activity in human and mouse HCC, but YAP mRNA levels did not. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc-induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc-driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc-driven HCC progression. CONCLUSIONS: TAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of patients with HCC and c-MYC activation. LAY SUMMARY: The identification of novel treatment targets and approaches for patients with hepatocellular carcinoma is crucial to improve survival outcomes. We identified TAZ as a transcriptional target of c-MYC which plays a critical role in c-MYC-dependent hepatocarcinogenesis. TAZ could potentially be targeted for the treatment of patients with c-MYC-driven hepatocellular carcinoma.

Transcription factor BZR2 activates chitinase Cht20.2 transcription to confer resistance to wheat stripe rust.

The brassinosteroid pathway promotes a variety of physiological processes in plants and the brassinosteroid insensitive1-ethylmethane sulfonate suppressor (BES)/brassinazole-resistant (BZR) functions as one of its key regulators. We previously showed that the BES/BZR-type transcription factor TaBZR2 mediates the drought stress response in wheat (Triticum aestivum) by directly upregulating the transcriptional activity of glutathione S-transferase 1. However, the function of TaBZR2 in plants under biotic stresses is unknown. In this study, we found that transcript levels of TaBZR2 were upregulated in response to inoculation with wheat stripe rust fungus (Puccinia striiformis f. sp. tritici, Pst) and treatment with flg22 or an elicitor-like protein of Pst, Pst322. Wheat lines overexpressing TaBZR2 conferred increased resistance, whereas TaBZR2-RNAi lines exhibited decreased resistance to multiple races of Pst. TaBZR2 targeted the promoter of the chitinase gene TaCht20.2, activating its transcription. Knockdown of TaCht20.2 in wheat resulted in enhanced susceptibility to Pst, indicating the positive role of TaCht20.2 in wheat resistance. Upon Pst infection in vivo, the overexpression of TaBZR2 increased total chitinase activity, whereas RNAi-mediated silencing of TaBZR2 reduced total chitinase activity. Taken together, our results suggest that TaBZR2 confers broad-spectrum resistance to the stripe rust fungus by increasing total chitinase activity in wheat.

Adverse event and treatment completion rates of a 12-dose weekly isoniazid and rifapentine course for South Korean healthcare workers.

PURPOSE: We investigated the adverse events (AEs) and treatment completion rates of a 3 month course of once-weekly isoniazid and rifapentine (3H1P1) in South Korean health care workers (HCWs) with latent tuberculosis infection (LTBI). METHODS: HCWs who were candidates for LTBI treatment were enrolled from two tertiary referral centers between December 2016 and October 2017. From December 2016 through March 2017, HCWs who agreed were treated with the 3H1P1 regimen (3H1P1 group). Their compliance and AEs were prospectively collected. From April 2017 onward, HCWs who required LTBI treatment received 3 months of isoniazid plus rifampin (3HR group), and their medical records were retrospectively reviewed. RESULTS: During the study period, 406 HCWs were treated, 226 (55.7%) in the 3H1P1 group, and 180 (44.3%) in the 3HR group. The number of subjects with AEs was significantly greater in the 3H1P1 group (75.2% vs 56.7%, P < 0.001), in particular a flu-like syndrome (19.0% vs. 0%, P < 0.001). However, hepatotoxicity occurred less frequently in those receiving 3H1P1 (7.5% vs. 20.0%, P < 0.001). Per protocol definition, anaphylaxis developed in 1.8% of the 3H1P1 group. The overall treatment completion rate was greater in the 3H1P1 group (92.9% vs 86.7%, P = 0.036). CONCLUSIONS: The 3H1P1 regimen had a higher treatment completion rate and lower hepatotoxicity compared with the 3HR regimen. However, it resulted in a higher rate of flu-like syndromes. Additionally, a few subjects had anaphylaxis, although there were no fatalities.

Predicting transcription factor binding using ensemble random forest models.

Background: Understanding the location and cell-type specific binding of Transcription Factors (TFs) is important in the study of gene regulation. Computational prediction of TF binding sites is challenging, because TFs often bind only to short DNA motifs and cell-type specific co-factors may work together with the same TF to determine binding. Here, we consider the problem of learning a general model for the prediction of TF binding using DNase1-seq data and TF motif description in form of position specific energy matrices (PSEMs). Methods: We use TF ChIP-seq data as a gold-standard for model training and evaluation. Our contribution is a novel ensemble learning approach using random forest classifiers. In the context of the ENCODE-DREAM in vivo TF binding site prediction challenge we consider different learning setups. Results: Our results indicate that the ensemble learning approach is able to better generalize across tissues and cell-types compared to individual tissue-specific classifiers or a classifier built based upon data aggregated across tissues. Furthermore, we show that incorporating DNase1-seq peaks is essential to reduce the false positive rate of TF binding predictions compared to considering the raw DNase1 signal. Conclusions: Analysis of important features reveals that the models preferentially select motifs of other TFs that are close interaction partners in existing protein protein-interaction networks. Code generated in the scope of this project is available on GitHub: https://github.com/SchulzLab/TFAnalysis (DOI: 10.5281/zenodo.1409697).

[Association between grainyhead-like 2 gene polymorphisms and noise-induced hearing loss].

OBJECTIVE: To investigate association between genetic polymorphism in the grainyhead-like 2 gene (GRHL2) and noise-induced hearing loss (NIHL) in the Chinese population. METHODS: A matched case-control association study was employed, In which, 3 790 workers exposed to continuous and steady-state occupational noise in a steel factory participated. The questionnaires were adopted to collect individual features and audiometry tests performed. In the sstudy, 286 subjects were diagnosed as cases, Which were each designated on the basis of the matched criterion, and 286 paired samples were selected finally. Noise intensity was measured according to the standards given in 'Measurement of Noise in the Workplace'(Occupational Health Standard of the People's Republic of China, GBZ/T189.8-2007). Cumulative noise exposure (CNE) was calculated, according to monitoring data on A-weighed sound pressure level and employment time. Genomic DNA was obtained from peripheral blood samples using 2 mL DNA extraction Kit following the manufacturer's protocol. Five single nucleotide polymorphisms (SNPs) of GRHL2 were genotyped by multiplex SNP genotyping kit. The continuous variables and categorical variables were analyzed by t-test and chi-square test respectively. Multivariate Logistic regression was used to test the association between genetic frequency and disease status, with adjustments for the possible confounding variables. The haplotypes were established and their frequencies in the two groups were assessed by haploview and phase softwares. RESULTS: All the five SNPs (rs3735713, rs3824090, rs3735714, rs3735715 and rs611419) were in Hardy-Weinberg equilibrium (HWE) (P>0.05). The subjects carrying rs3735715 GG genotype had a higher NIHL risk than those carrying the GA genotype under the co-dominant model (OR=0.644, 95% CI: 0.442-0.939, P=0.022) after adjustment for height, blood pressure, drinking status and smoking status. After being stratified by CNE, in the CNE ≥ 98 dB (A) group, rs3735715 polymorphism was associated with the NIHL under the co-dominant model (OR=0.509, 95% CI: 0.281-0.923, P=0.026) after adjustment for height, blood pressure, drinking status and smoking status as well. However, no statistical significant difference was found in variant genotypes of the other SNPs between the case and control subjects. Four-locus (rs3735713, rs3824090, rs3735714 and rs3735715) haplotypes were constructed, and no risk or protective haplotypes was identified. CONCLUSION: It is suggested that GRHL2 polymorphisms may be associated with development of NIHL.

Therapeutic potential of regulatory T cells in autoimmune disorders.

Regulatory T cells (Tregs) play a dominant role in the regulation of immune responses. Quantitative and/or qualitative abnormalities of Tregs were observed in patients with autoimmune diseases and therapeutic interventions focusing Tregs are an attractive new target with the potential to cure these disorders. Biological agents approved for treatment of inflammatory rheumatic diseases transiently influence Treg prevalences and function and experimental therapies including novel biological agents, gene therapy, activation and ex vivo expansion of purified Tregs as well as substances influencing tolerogenic dendritic cells will be developed for selective Treg therapy. Although many of these interventions are effective in vitro, in animal models as well as in early clinical trials, significant concerns exist regarding the stability of Treg modifications as well as the long-term safety of Treg-based therapies.

H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse.

Spinocerebellar ataxia type 3 (SCA3) caused by polyglutamine-expanded ataxin-3 is the most prevalent subtype of spinocerebellar ataxias. A compound, which decreases protein level of mutant ataxin-3 in SCA3 affected CNS regions, should be a promising therapeutic agent for SCA3. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. Rho-kinase (ROCK) inhibitor Y27632 reduced brain level of polyglutamine-expanded huntingtin in HD transgenic mouse. Therefore, we tested the possibility that ROCK inhibitors, Y27632, H1152 and GSK429286, downregulate protein expression of polyglutamine-expanded ataxin-3-Q79. Y27632 or H1152 reduced protein level of HA-tagged ataxin-3-Q79 (ATX-3-Q79HA) expressed in HEK 293 cells. Compared to Y27632, H1152 decreased ATX-3-Q79HA protein level with a significantly more potency and efficacy. H1152 also reduced protein level of HA-tagged polyglutamine-expanded ataxin-7-Q52 (ATX-7-Q52HA), which causes spinocerebellar ataxia type 7 (SCA7). H1152 decreased ATX-3-Q79HA or ATX-7-Q52HA protein level in vitro by augmenting proteasome activity and promoting ATX-3-Q79HA or ATX-7-Q52HA degradation. GSK429286, which is structurally different from H1152 but equally inhibits ROCK, failed to affect protein level of ATX-3-Q79HA or ATX-7-Q52HA. Furthermore, shRNA-mediated suppression of ROCK1 or ROCK2 expression in 293 cells did not affect protein level of ATX-3-Q79HA or ATX-7-Q52HA and H1152 reduction of ATX-3-Q79HA. Daily intraperitoneal administration of H1152 significantly decreased protein level of ATX-3-Q79HA in the cerebellum, pontine nuclei and spinal cord of SCA3 transgenic mice. H1152 also ameliorated pontine neuronal death and neurological phenotype of SCA3 transgenic mice. Our results suggest that H1152 might be an effective therapeutic agent for SCA3 or SCA7.

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia.

AIMS: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. METHODS AND RESULTS: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). CONCLUSION: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

Therapeutic approaches for control of transcription factors in allergic disease.

The inflammatory response observed in allergic disease involves multiple cell types but is orchestrated in part by the T(H)2 cytokines IL-4, IL-5, and IL-13. In recent years, the transcription factors that control the expression and function of these cytokines have been elucidated, including signal transducer and activator of transcription 6, GATA3, nuclear factor of activated T cells, and nuclear factor kappaB. These molecules are attractive targets for therapeutic intervention because they regulate the expression of numerous effector molecules and functions simultaneously. For instance, the immunosuppressive agents glucocorticoids and cyclosporin A both function by repressing the activity of transcription factors through a variety of mechanisms. In this review we examine the role of each transcription factor in allergic disease and discuss approaches that have been taken to therapeutically interfere with transcription factor function in allergic disease.

Hypoxia-inducible factor 1-related diseases and prospective therapeutic tools.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. HIF-1 regulates the expressions of the proteins that increase oxygen delivery, which enables cells to survive in oxygen-deficient conditions. Based on information as to which types of genes are controlled by HIF-1, it appears that HIF-1 provides pathological tissues with survival in hypoxic regions or angiogenic activity. Therefore, HIF-1 inhibitors could be useful as therapeutic agents for various diseases associated with the over-activation of HIF-1, such as cancers, cardiovascular remodeling, preeclampsia, and other angiogenesis-related diseases. In this review, we summarize the oxygen-dependent and -independent regulation of HIF-1 and introduce prospective HIF-1 inhibitors that might be useful in the treatment of HIF-1-related diseases.

Peroxisome proliferator-activated receptor gamma (PPargamma) as a novel target for prostate cancer.

Peroxisome proliferator activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARgamma is expressed at high levels in adipose tissue and plays a central role in adipocyte differentiation. Recent studies have implicated PPARgamma in the pathogenesis of several human malignancies. Here we review the evidence that PPARgamma contributes to prostate carcinogenesis and the potential for PPARgamma as a novel therapeutic target for prostate cancer.

The role of PPAR alpha in obesity.

Obesity is a rapidly increasing health problem in all developed countries. Overweight rarely occurs in isolation but as part of a complex pattern of metabolic abnormalities ("metabolic syndrome" or "syndrome X") consisting of hyperlipidemia, hypoalphalipoproteinemia, type II diabetes and atherosclerosis. The disorder is considerably influenced by genetic, behavioural and nutritional factors. Recent data indicate that a group of closely related nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), may be involved in the metabolic changes ultimately leading to obesity. This review summarises the latest developments in the PPAR field, with particular emphasis being placed on the physiological function of PPAR alpha during various nutritional states, and the possible role of PPAR alpha in obesity.