TFEB SignallingRelated MicroRNAs and also Autophagy

echanisms and overlapping genetic heritability between CAD and BW.Even after multimodal therapy, the prognosis is dismal for patients with brain metastases from non-small cell lung cancer (NSCLC). Although the blood-brain barrier (BBB) limits tumor cell penetration into the brain parenchyma, some nevertheless colonize brain tissue through mechanisms that are not fully clear. Here we show that homeobox B9 (HOXB9), which is commonly overexpressed in NSCLC, promotes epithelial-to-mesenchymal transition (EMT) and tumor migration and invasion. Animal experiments showed that HOXB9 expression correlates positively with the brain metastatic potential of human NSCLC cells, while brain metastatic cells derived through in vivo selection showed greater HOXB9 expression than their cells of origin. Comparable results were obtained after immunohistochemical analysis of clinical primary NSCLC and matched brain metastasis samples obtained after surgery. Using an in vitro BBB model, knockdown and overexpression experiments showed that HOXB9-dependent expression of MMP9 in NSCLC cells leads to reduced expression of junctional proteins in cultured human vascular endothelial cells and enhanced transmigration of tumor cells. These data indicate that HOXB9 enables NSCLC cells to break away from the primary tumor by inducing EMT, and promotes brain metastasis by driving MMP9 production and degradation of intercellular adhesion proteins in endothelial cells comprising the BBB.RNA binding proteins (RBPs) are aberrantly expressed in a tissue-specific manner across many tumors. These proteins, which play a vital role in post-transcriptional gene regulation, are involved in RNA splicing, maturation, transport, stability, degradation, and translation. We set out to establish an accurate risk score model based on RBPs to estimate prognosis in hepatocellular carcinoma (HCC). RNA-sequencing data, proteomic data and corresponding clinical information were acquired from the Cancer Genome Atlas database and the Clinical Proteomic Tumor Analysis Consortium database respectively. We identified 406 differentially expressed RBPs between HCC tumor and normal tissues at the transcriptional and protein level. Overall, 11 RBPs (BRIX1, DYNC1H1, GTPBP4, PRKDC, RAN, RBM19, SF3B4, SMG5, SPATS2, TAF9, and THOC5) were selected to establish a risk score model. We divided HCC patients into low-risk and high-risk groups based on the median of risk score values. AZ32 mouse The survival analysis indicated that patients in the high-risk group had poorer overall survival compared to patients in the low-risk group. Our study demonstrated that 11 RBPs were associated with the overall survival of HCC patients. These RBPs may represent potential drug targets and can help optimize future clinical treatment.Many risk factors of cancer have been established, but the contribution of paternal age in this regard remains largely unexplored. To further understand the etiology of cancer, we investigated the relationship between paternal age and cancer incidence using PLCO cohort. Cox proportional hazards models were performed to assess the association between paternal age and the risk of cancers. During follow-up time (median 11.5 years), 18,753 primary cancers occurred. Paternal age was associated with reduced risk of cancers of the female genitalia (HR, 0.79; 95%CI, 0.66-0.94; P = 0.008) as well as cancers of the respiratory and intrathoracic organs (HR, 0.78; 95%CI, 0.63-0.97; P = 0.026). The association was stronger for lung cancer (HR, 0.67; 95%CI, 0.52-0.86; P = 0.002). The subgroup analysis suggested that age, gender, smoking and BMI were related to the decreased cancer incidence of the respiratory and intrathoracic organs, lung and the female genitalia. Positive linear associations were observed between paternal age and cancer incidence of the female genitalia, respiratory and intrathoracic organs and the lungs. These findings indicate that advanced paternal age is an independent protective factor against various cancers in offspring.
Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. Long noncoding RNA ANRIL (lncRNA-ANRIL) is critical in vascular homeostasis. Metformin produces multiple beneficial effects in atherosclerosis. However, the underlying mechanisms need to be elucidated.
Metformin increased lncRNA-ANRIL expression and AMPK activity in cultured VSMCs, and inhibited the phenotypic switching of VSMCs to the synthetic phenotype induced by platelet-derived growth factor (PDGF). Overexpression of lncRNA-ANRIL inhibited phenotypic switching and reversed the reduction of AMPK activity in PDGF-treated VSMCs. While, gene knockdown of lncRNA-ANRIL by adenovirus or silence of AMPKγ through siRNA abolished AMPK activation induced by metformin in VSMCs. RNA-immunoprecipitation analysis indicated that the affinity of lncRNA-ANRIL to AMPKγ subunit was increased by metformin.
, administration of metformin increased the levels of lncRNA-ANRIL, suppressed VSMC phenotypic switching, and prevented the development of atherosclerotic plaque in
mice fed with western diet. These protective effects of metformin were abolished by infecting
mice with adenovirus expressing lncRNA-ANRIL shRNA. The levels of AMPK phosphorylation, AMPK activity, and lncRNA-ANRIL expression were decreased in human atherosclerotic lesions.
Metformin activates AMPK to suppress the formation of atherosclerotic plaque through upregulation of lncRNA-ANRIL.
Metformin activates AMPK to suppress the formation of atherosclerotic plaque through upregulation of lncRNA-ANRIL.Bone marrow mesenchymal stem cells (BMMSCs)-based therapy has emerged as a promising novel therapy for Traumatic Brain Injury (TBI). However, the therapeutic quantity of viable implanted BMMSCs necessary to initiate efficacy is still undetermined. Increased oxidative stress following TBI, which leads to the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathway, has been implicated in accounting for the diminished graft survival and therapeutic effect. To prove this assertion, we silenced the expression of NADPH subunits (p22-phox, p47-phox, and p67-phox) and small GTPase Rac1 in BMMSCs using shRNA. Our results showed that silencing these proteins significantly reduced oxidative stress and cell death/apoptosis, and promoted implanted BMMSCs proliferation after TBI. The most significant result was however seen with Rac1 silencing, which demonstrated decreased expression of apoptotic proteins, enhanced in vitro survival ratio, reduction in TBI lesional volume and significant improvement in neurological function post shRac1-BMMSCs transplantation. Additionally, two RNA-seq hub genes (VEGFA and MMP-2) were identified to play critical roles in shRac1-mediated cell survival. In summary, we propose that knockdown of Rac1 gene could significantly boost cell survival and promote the recovery of neurological functions after BMMSCs transplantation in TBI mice.Systemic sclerosis (SSc) is a prototypic fibrotic disease characterized by localized or diffuse skin thickening and fibrosis. Tissue fibrosis is driven by myofibroblasts, and factors affecting myofibroblast activation may also be involved in the development of SSc. In this study, we examined molecular mechanisms underlying SSc by focusing on myofibroblast activation processes. Bioinformatics analysis conducted to identify differentially expressed miRNAs (DEMs) and genes (DEGs) revealed that microRNA-16-5p (miR-16-5p) was downregulated and NOTCH2 was upregulated in SSc patients. In vitro experiments confirmed that miR-16-5p was able to bind directly to NOTCH2 and inhibit myofibroblast activation. Moreover, miR-16-5p-dependent inhibition of NOTCH2 decreased collagen and α-SMA expression. MiR-16-5p downregulation and NOTCH2 upregulation was also confirmed in vivo in SSc patients, and NOTCH2 activation promoted fibrosis progression in vitro. These results indicate that miR-16-5p suppresses myofibroblast activation by suppressing NOTCH signaling.
The Affordable Care Act (ACA) gives states the option of expanding Medicaid coverage to low-income individuals; however, not all states have chosen to expand Medicaid. The ACA Medicaid expansions are particularly important for Americans with mental health conditions because they are substantially more likely than other Americans to have low incomes.
We examine the impact of Medicaid expansion on adults who were newly eligible for Medicaid using the 2008-2017 Medical Expenditure Panel Survey (MEPS).
We use the AHRQ PUBSIM model to identify low-income adults aged 19-64 who were either newly Medicaid eligible if they lived in an expansion state or would have been eligible had their state opted to expand its Medicaid program. We estimate linear probability models within a difference-in-difference framework. An additional interaction term allows us to test for differences among those with serious psychological distress (SPD) or probable depression (PD). Outcomes of interest are insurance coverage by type, beatus but the overall effect on insurance coverage was stronger among those with SPD/PD. The lack of an effect on treatment use suggests that providing insurance coverage alone may be insufficient to guarantee that people with mental illness will receive the treatment they need. Limitations include that our difference-in-difference estimator may not account for time-varying factors that change contemporaneously with the expansions. Our estimates may also be affected by other provisions of the ACA that went into effect at the same time as the Medicaid expansions. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE AND IMPLICATIONS FOR HEALTH POLICIES Although the ACA has resulted in increased coverage for low-income individuals, more outreach efforts may be needed to encourage individuals with mental illness to get the treatment they need.
Illegal drug use causes a variety of negative consequences for the society -- referred to as the social costs of illegal drug use -- and therefore they are estimated in many countries. The main purpose of social cost estimation is prevention or, at least, attenuation of the negative effects of illegal drug use.
The main aim of the study was the estimation of the basic social costs of illegal drug use in Poland in the year 2015 with the use of standardized methodology and the standardized presentation of results, which can ensure better comparison of the costs between countries. The other aim of the study was to present a method to fill the gaps in statistical data concerning the criminal justice system costs attributable to illegal drugs use.
Cost-of-illness (COI), human capital, and prevalence-based approaches were applied to costs estimation. The author proposed a method combining survey results with official statistical data, which allows for rough estimation of some of the criminal justice costs. Fur research.
A number of important issues, for example "harm to others" costs, private costs, intangible costs, lifetime productivity costs, require further research.
The inclusion of indirect spillover costs and benefits that occur in non-healthcare sectors of society is necessary to make optimal societal decisions when assessing the cost effectiveness of healthcare interventions. Education costs and benefits are relevant in the disease area of mental and behavioral disorders, but their inclusion in economic evaluations is largely neglected due to lack of methodological knowledge.
This study aims to explore, using a scoping review, the identification, measurement, and valuation methods used to assess the impact of mental and behavioural disorders on education costs and benefits.
A scoping review was conducted to identify articles that were set in the education sector and assessed education costs and benefits. An adapted 5-step approach was used (i) initating a scoping review; (ii) identifying component studies; (iii) data extraction; (iv) reporting results; (v) discussion and interpretation of findings. Results were summarized in a narrative synthesis per identification, measurement, and valuation method.