WNT3 promotes chemoresistance to 5-Fluorouracil in oral squamous cell carcinoma via activating the canonical ß-catenin pathway.

BACKGROUND: 5-Fluorouracil (5FU) is a primary chemotherapeutic agent used to treat oral squamous cell carcinoma (OSCC). However, the development of drug resistance has significantly limited its clinical application. Therefore, there is an urgent need to determine the mechanisms underlying drug resistance and identify effective targets. In recent years, the Wingless and Int-1 (WNT) signaling pathway has been increasingly studied in cancer drug resistance; however, the role of WNT3, a ligand of the canonical WNT signaling pathway, in OSCC 5FU-resistance is not clear. This study delved into this potential connection. METHODS: 5FU-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells underwent RNA sequencing analysis, which was then substantiated via Real-time quantitative PCR (RT-qPCR) and western blot tests. The influence of the WNT signaling on OSCC chemoresistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor methyl 3-benzoate (MSAB) was probed for its capacity to boost 5FU efficacy. RESULTS: In this study, the WNT/ß-catenin signaling pathway was notably activated in 5FU-resistant OSCC cell lines, which was confirmed through transcriptome sequencing analysis, RT-qPCR, and western blot verification. Additionally, the key ligand responsible for pathway activation, WNT3, was identified. By knocking down WNT3 in resistant cells or overexpressing WNT3 in parental cells, we found that WNT3 promoted 5FU-resistance in OSCC. In addition, the WNT inhibitor MSAB reversed 5FU-resistance in OSCC cells. CONCLUSIONS: These data underscored the activation of the WNT/ß-catenin signaling pathway in resistant cells and identified the promoting effect of WNT3 upregulation on 5FU-resistance in oral squamous carcinoma. This may provide a new therapeutic strategy for reversing 5FU-resistance in OSCC cells.

Exposure to Polybrominated Diphenyl Ethers and Risk of All-Cause and Cause-Specific Mortality.

Importance: Polybrominated diphenyl ethers (PBDEs) are an important group of persistent organic pollutants with endocrine-disrupting properties. However, prospective cohort studies regarding the association of PBDE exposure with long-term health outcomes, particularly mortality, are lacking. Objective: To examine the association of environmental exposure to PBDEs with risk of all-cause and cause-specific mortality. Design, Setting, and Participants: This nationally representative cohort study used data from the National Health and Nutrition Examination Survey 2003 to 2004 and linked mortality information through December 31, 2019. Adults aged 20 years or older with available data on PBDE measurements and mortality were included. Statistical analysis was performed from February 2022 to April 2023. Exposures: PBDE analytes in serum samples were measured using solid phase extraction and isotope dilution gas chromatography high-resolution mass spectrometry. Main Outcomes and Measures: All-cause mortality, cancer mortality, and cardiovascular mortality. Results: This study included 1100 participants (mean [SE] age, 42.9 [0.6] years; proportion [SE] female, 51.8% [1.6%]; proportion [SE] Hispanic, 12.9% [2.7%]; proportion [SE] non-Hispanic Black, 10.5% [1.6%]; proportion [SE] non-Hispanic White, 70.8% [3.7%]; proportion [SE] other race and ethnicity, 5.8% [1.1%]). During 16 162 person-years of follow-up (median [IQR] follow-up, 15.8 [15.2-16.3] years; maximum follow-up, 17 years), 199 deaths occurred. Participants with higher serum PBDE levels were at higher risk for death. After adjustment for age, sex, and race and ethnicity, lifestyle and socioeconomic factors, and body mass index, participants with the highest tertile of serum PBDE levels had an approximately 300% increased risk of cancer mortality (HR, 4.09 [95% CI, 1.71-9.79]) compared with those with the lowest tertile of serum PBDE levels. No significant association of PBDE exposure with all-cause mortality (HR, 1.43 [95% CI, 0.98-2.07]) or cardiovascular mortality (HR, 0.92 [95% CI, 0.41-2.08]) was observed. Conclusions and Relevance: In this nationally representative cohort study, PBDE exposure was significantly associated with an increased risk of cancer mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.

Investigating diagnostic potential of long non-coding RNAs in head and neck squamous cell carcinoma using TCGA database and clinical specimens.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and prognostically challenging cancer worldwide. The role of long non-coding RNAs (lncRNAs) in cancer regulation is progressively being understood. This study aims to identify lncRNAs with diagnostic potential as biomarkers for HNSCC. Statistical analysis was performed on expression data from the Cancer Genome Atlas (TCGA) database to identify potential lncRNAs associated with HNSCC. Four selected lncRNAs were validated using real-time quantitative reverse transcription polymerase chain reaction and correlated with clinical factors. Functional roles were further investigated. A total of 488 differentially expressed lncRNAs were identified in TCGA-HNSC. After rigorous evaluation based on p-values, survival analysis, and ROC analysis, 24 lncRNAs were prioritized for additional investigation. LINC00460, LINC00941, CTC-241F20.4, and RP11-357H14.17 were established as candidate diagnostic biomarkers. These lncRNAs exhibited elevated expression in HNSCC tissues and were associated with poor prognosis. Combining them showed high diagnostic accuracy. Notably, LINC00460 and CTC-241F20.4 demonstrated a significant elevation in the advanced stages of HNSCC. We constructed an lncRNA-mRNA regulatory network, and the array of significant regulatory pathways identified included focal adhesion, regulation of epithelial cell migration, and others. Additionally, these lncRNAs were found to influence immune responses by modulating immune cell infiltration in the HNSCC microenvironment. Our research indicates that LINC00460, LINC00941, RP11-357H14.17, and CTC-241F20.4 may have diagnostic and prognostic importance in HNSCC. Furthermore, we have gained insights into their potential functional roles, particularly about immune responses and interactions in the microenvironment.

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector.

The p53 tumor suppressor protein plays an important role in physiological and pathological processes. MDM2 and its homolog MDMX are the most important negative regulators of p53. Many studies have shown that MDMX promotes the growth of cancer cells by influencing the regulation of the downstream target gene of tumor suppressor p53. Studies have found that inhibiting the MDMX-p53 interaction can effectively restore the tumor suppressor activity of p53. MDMX has growth-promoting activities without p53 or in the presence of mutant p53. Therefore, it is extremely important to study the function of MDMX in tumorigenesis, progression and prognosis. This article mainly reviews the current research progress and mechanism on MDMX function, summarizes known MDMX inhibitors and provides new ideas for the development of more specific and effective MDMX inhibitors for cancer treatment.

Single-cell RNA sequencing to explore cancer-associated fibroblasts heterogeneity: "Single" vision for "heterogeneous" environment.

Cancer-associated fibroblasts (CAFs), a phenotypically and functionally heterogeneous stromal cell, are one of the most important components of the tumour microenvironment. Previous studies have consolidated it as a promising target against cancer. However, variable therapeutic efficacy-both protumor and antitumor effects have been observed not least owing to the strong heterogeneity of CAFs. Over the past 10 years, advances in single-cell RNA sequencing (scRNA-seq) technologies had a dramatic effect on biomedical research, enabling the analysis of single cell transcriptomes with unprecedented resolution and throughput. Specifically, scRNA-seq facilitates our understanding of the complexity and heterogeneity of diverse CAF subtypes. In this review, we discuss the up-to-date knowledge about CAF heterogeneity with a focus on scRNA-seq perspective to investigate the emerging strategies for integrating multimodal single-cell platforms. Furthermore, we summarized the clinical application of scRNA-seq on CAF research. We believe that the comprehensive understanding of the heterogeneity of CAFs form different visions will generate innovative solutions to cancer therapy and achieve clinical applications.

Engineered Plant-Derived Nanovesicles Facilitate Tumor Therapy: Natural Bioactivity Plus Drug Controlled Release Platform.

Tumors are the second-most common disease in the world, killing people at an alarming rate. As issues with drug resistance, lack of targeting, and severe side effects are revealed, there is a growing demand for precision-targeted drug delivery systems. Plant-derived nanovesicles (PDNVs), which arecomposed of proteins, lipids, RNA, and metabolites, are widely distributed and readily accessible. The potential for anti-proliferative, pro-apoptotic, and drug-resistant-reversing effects on tumor cells, as well as the ability to alter the tumor microenvironment (TME) by modulating tumor-specific immune cells, make PDNVs promising anti-tumor therapeutics. With a lipid bilayer structure that allows drug loading and a transmembrane capacity readily endocytosed by cells, PDNVs are also expected to become a new drug delivery platform. Exogenous modifications of PDNVs enhance their circulating stability, tumor targeting ability, high cell endocytosis rate, and controlled-release capacity. In this review, we summarize PDNVs' natural antitumor activity, as well as engineered PDNVs as efficient precision-targeted drug delivery tools that enhance therapeutic effects. Additionally, we discuss critical considerations related to the issues raised in this area, which will encourage researchers to improve PDNVs as better anti-tumor therapeutics for clinic applications.

Association between hypertriglyceridemic-waist phenotype and circadian syndrome risk: a longitudinal cohort study.

Recently, circadian syndrome (CircS) has been proposed as a new predictor of cardiometabolic risk. We aimed to investigate the relationship between the hypertriglyceridemic-waist phenotype and its dynamic status with CircS in China. We conducted a two-stage study based on the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2015. Multivariate logistic regression models in cross-sectional analysis and Cox proportional hazards regression models in longitudinal analysis were used to estimate the associations of hypertriglyceridemic-waist phenotypes with CircS and its components. We then applied multiple logistic regression analysis to evaluate the odds ratios (ORs) and 95% confidence intervals (CIs) for CircS risk by transformation into the hypertriglyceridemic-waist phenotype. A total of 9863 participants were included in the cross-sectional analysis and 3884 participants in the longitudinal analysis. Compared with normal waist circumference (WC) and normal triglyceride (TG) level (NWNT), CircS risk was increased with enlarged WC and high TG level (EWHT) (hazard ratio (HR) 3.87 [95% CI: 2.38, 5.39]). Similar results were observed in subgroup analyses by sex, age, smoking status, and drinking status. During follow-up, CircS risk was increased in group K (stable EWNT during follow-up) (OR 9.97 [95% CI: 6.41, 15.49]) compared with group A (stable NWNT during follow-up), while group L (baseline enlarged WC and normal TG level transformed to follow-up EWHT) had the highest risk of CircS (OR 116.07 [95% CI: 72.77, 185.14]). In conclusion, the hypertriglyceridemic-waist phenotype and its dynamic status were associated with the risk of developing CircS in Chinese adults.

In-stent restenosis after vertebral artery origin stenosis stenting: a nomogram for risk assessment.

OBJECTIVE: To propose a nomogram for individual risk assessment of in-stent restenosis (ISR) after vertebral artery origin stenosis (VAOS) stenting. METHODS: We included 793 patients with VAOS treated with stenting from October 2006 to May 2013, with a median follow-up of 27.8 months. Cox regression and the least absolute shrinkage and selection operator (LASSO) regression were adopted for variable selection. The nomogram was formulated and validated by concordance indexes (C-indexes) and calibration curves. An in-stent restenosis risk table (ISR-RT) was subsequently generated for risk stratification. Differences between low-, intermediate-, and high-risk levels were shown by Kaplan-Meier curves and compared by log-rank test. RESULTS: The training and validation set included 594 and 199 patients, with a mean ISR rate of 37.2% and 35.2%, respectively. Stent type (HR=1.64, 95% CI 1.26 to 2.14), stent diameter (HR=2.48, 95% CI 1.77 to 3.48), history of peripheral vascular disease (HR=2.17, 95% CI 1.17 to 4.00), history of transit ischemic attack (HR=1.45, 95% CI 1.05 to 2.14), and left-side involvement (HR=1.33, 95% CI 1.04 to 1.69) were included in the nomogram. The C-indexes at 6 and 12 months were 0.650 and 0.611 in the training set, and 0.713 and 0.603 in the validation set, respectively. Compared with low-risk patients, the intermediate- and high-level group had 1.46 (95% CI 1.05 to 2.04; p=0.0235) and 2.28 (95% CI 1.64 to 3.17; p<0.0001) higher chances of developing ISR in 2 years, respectively. CONCLUSIONS: A nomogram and a risk evaluation table were developed with good predictive ability for in-stent restenosis among patients with VAOS, which could serve as a practical approach for individualized risk evaluation.

FAT1 Upregulates in Oral Squamous Cell Carcinoma and Promotes Cell Proliferation via Cell Cycle and DNA Repair.

Objective: Previous studies have revealed that FAT atypical cadherin 1 (FAT1) plays a tumor-suppressive or oncogenic role in a context-dependent manner in various cancers. However, the functions of FAT1 are ambiguous in tumorigenesis owing to inconsistent research in oral squamous cell carcinoma (OSCC). The present study aimed at gaining an insight into the role of FAT1 in the tumor genesis and development. Methods: The expression, mutant, and survival data analyses were done using data from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database, verified with clinical samples via real-time polymerase chain reaction (qRT-PCR), Western blot (WB), and immunohistochemical (IHC) staining. OSCC cells transfected with siRNA were employed for in vitro assessment in cell proliferation, apoptosis, and migration ability in appropriate ways. The underlying mechanism was explored by RNA sequencing after FAT1 silencing. Results: Overall, FAT1 significantly increased in OSCC with a poor prognosis outcome. The in vitro experiment showed the promoting effect of FAT1 in the proliferation and migration of OSCC cells. FAT1 can also inhibit both the early and late apoptosis of OSCC cells. RNA-sequencing analysis of FAT1 silencing revealed that the cell cycle, DNA replication, and some core genes (MCM2, MCM5, CCNE1 SPC24, MYBL2, KIF2C) may be the potential mechanism in OSCC. Conclusions: FAT1 may act as an oncogene in OSCC with potential mechanism influencing the cell cycle and DNA repair.

Trends of cancer mortality in Xi'an City, China: 2005-2020.

PURPOSE: Describe and predict the malignant tumor deaths in Xi'an so as to provide evidence for the government to formulate the prevention and treatment plans. METHODS: Overall malignant tumor death in Xi'an in the past 16 years was described. The multi-decrease life table was used to calculate cumulative mortality risk by cause and life expectancy reduction years by cause of malignant tumors in 2020. The join point regression models were used to analyze the change trend of standard mortality of malignant tumors in Xi'an from 2005 to 2020. The appropriate gray models were selected to predict the death of malignant tumors in Xi'an in the next decade. RESULTS: The mortality of total malignant tumors in Xi'an showed that men are higher than women and the elderly are higher than other groups. As for 2020, lung cancer had the highest risk of death for both men and women, while leukemia had the highest life expectancy reduction years by cause. From 2005 to 2020, standardized mortality of majority malignant tumors showed downward trends, which were particularly obvious in recent years. The prediction results of several major malignant tumors showed that in the next decade, the mortality of most malignant tumors had downward trends, but combined with the increase of population in the future, the number of malignant tumor deaths in Xi'an will continue to increase. CONCLUSIONS: Malignant tumors in Xi'an have decreasing mortality trends in recent years, and effective measures to prevent and treat tumors should be strengthened in the future.

Os LncRNAs Estão Envolvidos no Processo de Aterosclerose em Diversos Níveis / LncRNAs are Involved in the Process of Atherosclerosis at Diverse Levels

Resumo A aterosclerose é a causa mais comum de doença cardiovascular em todo o mundo, ela está associada a uma alta incidência de eventos clínicos. O acúmulo de evidências elucidou que os RNAs longos não codificantes (LncRNAs) são uma nova classe de transcritos com papéis críticos nos processos fisiopatológicos da aterosclerose. Nesta revisão, resumimos o progresso recente dos LncRNAs no desenvolvimento da aterosclerose. Descrevemos principalmente os diversos mecanismos regulatórios dos LncRNAs nos níveis transcricionais e pós-transcricionais. Este estudo pode fornecer informações úteis sobre os LncRNAs como alvos terapêuticos ou biomarcadores para o tratamento da aterosclerose.

Abstract Atherosclerosis is the most common cause of cardiovascular disease globally, associated with a high incidence of clinical events. Accumulating evidence has elucidated that long non-coding RNAs (lncRNAs) as a novel class of transcripts with critical roles in the pathophysiological processes of atherosclerosis. In this review, we summarize the recent progress of lncRNAs in the development of atherosclerosis. We mainly describe the diverse regulatory mechanisms of lncRNAs at the transcriptional and post-transcriptional levels. This study may provide helpful insights about lncRNAs as therapeutic targets or biomarkers for atherosclerosis treatment.

BLU-554, A selective inhibitor of FGFR4, exhibits anti-tumour activity against gastric cancer in vitro.

BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) plays a key role in cancer progression, including tumour proliferation, invasion, and metastasis. Recent studies have shown that the FGFR4 selective inhibitor BLU-554 has clinical benefits on tumour regression in hepatocellular carcinoma patients. However, the effect of BLU-554 on gastric cancer remains unknown. METHODS: Changes in cell proliferation, apoptosis and cell cycle, migration, and invasion capabilities of MKN-45 cells treated with FGFR4 selective inhibitors were detected by CCK-8 assay, flow cytometry, transwell assay, and wound healing assay, respectively. Western blotting was used to detect the effect of BLU-554 on the expression of FGFR4, FRS2α, and p-ERK1/2. RESULTS: As the concentration of the inhibitor increased, the survival rate of gastric cancer cells decreased, and the trend of BLU-554 was more obvious; a high dose of BLU-554 caused significant cell apoptosis and cell cycle arrest as well as reduced cell invasion ability. The expression levels of FGFR4, FRS2α, and p-ERK1/2 were also significantly reduced when cells were treated with medium and high doses of BLU-554. CONCLUSION: BLU-554 inhibited the mitogen-activated protein kinase (RAS-RAF-MEK-ERK) pathway by inhibiting FGFR4, ultimately impeding the proliferation and invasion of gastric cancer cells and promoting cell apoptosis and cell cycle arrest.

All around suboptimal health - a joint position paper of the Suboptimal Health Study Consortium and European Association for Predictive, Preventive and Personalised Medicine.

First two decades of the twenty-first century are characterised by epidemics of non-communicable diseases such as many hundreds of millions of patients diagnosed with cardiovascular diseases and the type 2 diabetes mellitus, breast, lung, liver and prostate malignancies, neurological, sleep, mood and eye disorders, amongst others. Consequent socio-economic burden is tremendous. Unprecedented decrease in age of maladaptive individuals has been reported. The absolute majority of expanding non-communicable disorders carry a chronic character, over a couple of years progressing from reversible suboptimal health conditions to irreversible severe pathologies and cascading collateral complications. The time-frame between onset of SHS and clinical manifestation of associated disorders is the operational area for an application of reliable risk assessment tools and predictive diagnostics followed by the cost-effective targeted prevention and treatments tailored to the person. This article demonstrates advanced strategies in bio/medical sciences and healthcare focused on suboptimal health conditions in the frame-work of Predictive, Preventive and Personalised Medicine (3PM/PPPM). Potential benefits in healthcare systems and for society at large include but are not restricted to an improved life-quality of major populations and socio-economical groups, advanced professionalism of healthcare-givers and sustainable healthcare economy. Amongst others, following medical areas are proposed to strongly benefit from PPPM strategies applied to the identification and treatment of suboptimal health conditions:Stress overload associated pathologiesMale and female healthPlanned pregnanciesPeriodontal healthEye disordersInflammatory disorders, wound healing and pain management with associated complicationsMetabolic disorders and suboptimal body weightCardiovascular pathologiesCancersStroke, particularly of unknown aetiology and in young individualsSleep medicineSports medicineImproved individual outcomes under pandemic conditions such as COVID-19.

Identification of Circulating hsa_circ_0063425 and hsa_circ_0056891 as Novel Biomarkers for Detection of Type 2 Diabetes.

CONTEXT: Circular RNAs (circRNAs), which are involved in the development of diseases by regulating gene expression, have become promising novel biomarkers for diseases. OBJECTIVE: The aim of the present study was to identify the circulating circRNA biomarkers for early detection of type 2 diabetes (T2D). METHODS: The circRNA expression profiles were screened by microarray and compared between 5 new T2D cases and 5 healthy controls. The expression of candidate circRNAs that may be involved in the insulin phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway were validated by RT-qPCR in a second sample with 30 T2D cases and 30 controls. The association between circRNAs and T2D and their clinical significances were further assessed by logistic regression model, correlation analysis, and ROC curve in a large cohort comprising 313 subjects. The microRNA (miRNA) targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG), and insulin resistance. The 2-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significant positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels. CONCLUSION: Downregulated hsa_circ_0063425 and hsa_circ_0056891 might contribute to the pathogenesis of T2D. They are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling.

Ginseng polysaccharide inhibits MDA-MB-231 cell proliferation by activating the inflammatory response.

Ginseng polysaccharide (GPS) is known for its efficacy in cancer therapy; however, its regulatory mechanism in breast cancer (BC) remains unclear. To analyze the effect of GPS on BC cell proliferation, cell proliferation rate calculations, western blotting, plasmid transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays were performed. GPS treatment in the culture cell medium inhibited cell proliferation in the BC cell line MDA-MB-231. In addition, the E-cadherin level was enhanced while the vimentin level was suppressed following GPS treatment (both P<0.05). Furthermore, the levels of apoptotic markers, including cleaved-Caspase-3 and p53, and inflammatory response markers, including plasminogen activator inhibitor and TNF-α, were induced by GPS treatment in MDA-MB-231 cells (all P<0.05). These results indicated that GPS supplementation activated the inflammatory response and apoptosis in BC cells. GPS treatment activated the phosphorylation levels of c-Jun N-terminal kinase, Akt and NF-κB. In MDA-MB-231 cells, GPS resulted in the accumulation of the NF-κB components p65, p50 and Ikaros family zing finger protein 1 (IKZF1; all, P<0.05). Chromatin immunoprecipitation and electrophoretic mobility shift assays indicated that p65 bound to the IKZF1 promoter. The overexpression of IKZF1 or p65 inhibited MDA-MB-231 cell proliferation (P<0.05), indicating that GPS treatment may inhibit BC cell proliferation by the activation of IKZF1. Taken together, these results suggested that GPS significantly inhibited BC cell proliferation via the control of the biological processes, including the activation of p65-IKZF1 signaling and apoptosis. The data indicated a novel mechanism for further understanding of cancer cell proliferation.

Bioinformatics analysis of the regulatory lncRNA­miRNA­mRNA network and drug prediction in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a complex inherited cardiovascular disease. The present study investigated the long noncoding (lnc)RNA/microRNA (mi)RNA/mRNA expression pattern of patients with HCM and aimed to identify key molecules involved in the development of this condition. An integrated strategy was conducted to identify differentially expressed miRNAs (DEmiRs), differentially expressed lncRNAs (DElncs) and differentially expressed genes (DEGs) based on the GSE36961 (mRNA), GSE36946 (miRNA), GSE68316 (lncRNA/mRNA) and GSE32453 (mRNA) expression profiles downloaded from the Gene Expression Omnibus datasets. Bioinformatics tools were employed to perform function and pathway enrichment analysis, protein­protein interaction, lncRNA­miRNA­mRNA and hub gene networks. Subsequently, DEGs were used as targets to predict drugs. The results indicated that a total of 2,234 DElncs (1,120 upregulated and 1,114 downregulated), 5 DEmiRs (2 upregulated and 3 downregulated) and 42 DEGs (35 upregulated and 7 downregulated) were identified in 4 microarray profiles. Gene ontology analysis revealed that DEGs were mainly involved in actin filament and stress fiber formation and in calcium ion binding, whereas Kyoto Encyclopedia of Genes and Genomes pathway analysis identified the hypoxia inducible factor­1, transforming growth factor­ß and tumor necrosis factor signaling pathways as the main pathways involved in these processes. The hub genes were screened using cytoHubba. A total of 1,086 lncRNA­miRNA­mRNA interactions including 67 lncRNAs, 5 miRNAs and 25 mRNAs were mined in the present study based on prediction websites. Drug prediction indicated that the targeted drugs mainly included angiotensin converting enzyme inhibitors or ß­blockers. A comprehensive bioinformatics analysis of the molecular regulatory lncRNA­miRNA­mRNA network was performed and potential therapeutic applications of drugs were predicted in HCM patients. The data may unravel the future molecular mechanism of HCM.

Insight into ponatinib resistance mechanisms in rhabdomyosarcoma caused by the mutations in FGFR4 tyrosine kinase using molecular modeling strategies.

Novel efficacious treatment of Rhabdomyosarcoma (RMS) with less toxicity has yet to emerge. Genomic analysis of RMS has reported that the receptor tyrosine kinase FGFR4 is highly expressed and frequently mutated in the tumor tissue. The V550E/L and N535D/K mutations of FGFR4 in RMS can lead to strong drug resistance to almost all of the type-I inhibitors. Previous report has demonstrated the type-II inhibitor ponatinib is the most potentially effective agent for RMS but still hard to starboard the V550E/L mutants. In this case, an ensemble of molecular modeling strategies was employed to theoretically uncover the resistance mechanisms. The binding free energy calculation results predicted by various strategies show that the V550E/L rather than N535D/K mutations indeed weaken the binding affinity of ponatinib, which are in good agreement with the experimental observations. Subsequently, the energy decomposition analysis mapped a knock-on effect on the diverse energy components of some key residues. Moreover, it is of great importance to report that there is an effective channel for type-II inhibitors sliding along the A-loop to prevent FGFR4 from phosphorylation and activation. Our results provide new insight into drug binding process and guide the development of effective inhibitors to surmount drug resistance in RMS.

The association between CD28 gene rs3116496 polymorphism and breast cancer risk in Chinese women.

T-lymphocyte activation plays an important role in suppressing the development of human cancers including breast cancer (BC). Cluster of differentiation 28 (CD28) is the primary T-cell costimulatory molecule and enhances T-cell activation and proliferation. To examine the role of CD28 gene polymorphism in BC, we conducted a case-control study involving 312 BC patients and 312 controls in a Chinese Han population. Bioinformatics analyses were conducted to analyze the expression level of CD28 and its association with overall survival (OS) of BC. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymorphism (SNP) Scan™ Kit. Our results indicated that CD28 mRNA level was down-regulated in the BC patients, whereas high expression of CD28 showed better OS for BC. In addition, an increased risk of BC was associated with the rs3116496 CC genotype of CD28 gene (CC vs. TT). The significant association was also observed in the recessive model. In conclusion, CD28 may be a tumor suppressor gene and rs3116496 polymorphism of CD28 gene showed positively correlation with the increased risk of BC. However, larger studies with more diverse ethnic populations are needed to confirm these results.

Expression of miR-18a and miR-34c in circulating monocytes associated with vulnerability to type 2 diabetes mellitus and insulin resistance.

Chronic stress may facilitate the development of metabolic disorders including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). MiR-18a and miR-34c modulate central cell responsiveness to stress by targeting glucocorticoid receptor (GR) and corticotropin-releasing factor receptor type 1 (CRFR1) mRNA, which are important regulators of the hypothalamus-pituitary-adrenal (HPA) axis. This study explored the relationship between T2DM/IR and expression of miR-18a and miR-34c in peripheral blood mononuclear cells (PBMCs) in an occupational sample. Three groups of study subjects were involved, including T2DM patients, impaired fasting glucose (IFG) individuals and healthy controls. The degree of IR was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR). The expression of miR-18a and miR-34c in PBMCs was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Expression levels of miR-18a and miR-34c were significantly correlated with cortisol, corticotropin-releasing factor (CRF) and interleukin 6 (IL-6) (P < 0.05). The increased levels of miR-18a were associated with risk of T2DM (adjusted OR = 1.48, 95% CI: 1.25-1.75, P < 0.001) and IFG (adjusted OR = 1.33, 95% CI: 1.09-1.63, P = 0.005). By contrast, the decreased levels of miR-34c were associated with risk of T2DM (adjusted OR = 0.81, 95% CI: 0.75-0.88, P < 0.001) and IFG (adjusted OR = 0.87, 95% CI: 0.81-0.94, P < 0.001). After adjusting for potential confounders, miR-18a and miR-34c were independent positive and negative predictors of HOMA-IR, respectively (P < 0.001). The miRNA panel with the two miRNAs demonstrated high accuracy in the diagnosis of T2DM (AUC = 0.851, 95% CI: 0.786-0.800, P < 0.001). MiR-18a and miR-34c in PBMCs may be important marker of stress reaction and may play a role in vulnerability to T2DM as well as IR.

The Uyghur population and genetic susceptibility to type 2 diabetes: potential role for variants in CDKAL1, JAZF1, and IGF1 genes.

Substantial evidence suggests that type 2 diabetes mellitus (T2DM) is a multi-factorial disease with a strong genetic component. A list of genetic susceptibility loci in populations of European and Asian ancestry has been established in the literature. Little is known on the inter-ethnic contribution of such established functional polymorphic variants. We performed a case-control study to explore the genetic susceptibility of 16 selected T2DM-related SNPs in a cohort of 102 Uyghur objects (51 cases and 51 controls). Three of the 16 SNPs showed significant association with T2DM in the Uyghur population. There were significant differences between the T2DM and control groups in frequencies of the risk allelic distributions of rs7754840 (CDKAL1) (p=0.014), rs864745 (JAZF1) (p=0.032), and rs35767 (IGF1) (p=0.044). Carriers of rs7754840-C, rs35767-A, and rs864745-C risk alleles had a 2.32-fold [OR (95% CI): 1.19-4.54], 2.06-fold [OR (95% CI): 1.02-4.17], 0.48-fold [OR (95% CI): 0.24-0.94] increased risk for T2DM, respectively. The cumulative risk allelic scores of these 16 SNPs differed significantly between the T2DM patients and the controls [17.1±8.1 vs. 15.4±7.3; OR (95%CI): 1.27(1.07-1.50), p=0.007]. This is the first study to evaluate genomic variation at 16 SNPs in respective T2DM candidate genes for the Uyghur population compared with other ethnic groups. The SNP rs7754840 in CDKAL1, rs864745 in JAZF1, and rs35767 in IGF1 might serve as potential susceptibility loci for T2DM in Uyghurs. We suggest a broader capture and study of the world populations, including who that are hitherto understudied, are essential for a comprehensive understanding of the genetic/genomic basis of T2DM.