Trends and projections of the global burden of thyroid cancer from 1990 to 2030.

Background: We aimed to explore the burden of thyroid cancer worldwide from 1990 to 2019 and to project its future trends from 2020 to 2030. Methods: Based on annual data on thyroid cancer cases from 1990 to 2019 available in the Global Burden of Disease (GBD) database, we calculated the age-standardised incidence, death, and disability-adjusted life year (DALY) rates for thyroid cancer. We used the estimated annual percentage change (EPAC) to quantify the temporal trends in these age-standardised rates from 1990 to 2019 and applied generalised additive models to project the disease burden from 2020 to 2030. Results: The global age-standardised incidence rate (ASIR) of thyroid cancer increased from 1990 to 2019, with a higher overall disease burden in women than in men at both study time points. The male-to-female ratios for the ASIR increased from 0.41 in 1990 to 0.51 in 2019, while the ratio for the age-standardised death rate (ASDR) increased from 0.60 to 0.82. The models predicted the United Arab Emirates would have the fastest rising trend in both the ASIR (estimated annual percentage changes (EAPC) = 4.19) and age-standardised DALY rate (EAPC = 4.36) in 2020-30, while Saint Kitts and Nevis will have the fastest rising trend in the ASDR (EAPC = 2.29). Meanwhile, the growth trends for the ASDR and age-standardised DALY rate are projected to increase across countries in this period. A correlation analysis of the global burden of thyroid cancer between 1990-2019 and 2020-30 showed a significant positive correlation between the increase in the ASIR and socio-demographic index (SDI) in low-SDI and low-middle-SDI countries. Conclusions: The global burden of thyroid cancer is increasing, especially in the female population and in low-middle-SDI regions, underscoring a need to target them for effective prevention, diagnosis, and treatment.

Design of a Dual Agonist of Exendin-4 and FGF21 as a Potential Treatment for Type 2 Diabetes Mellitus and Obesity.

Background: Fibroblast growth factor 21 (FGF21) is a metabolic, endocrine hormone regulating insulin sensitivity, energy expenditure, and lipid metabolism. It has significant potential as a therapeutic drug for treating type 2 diabetes and obesity. However, the clinical efficacy of FGF21 analogs is limited due to their instability and short half-life. Glucagon-like peptide 1 (GLP-1) receptor agonists have been recognized as effective medications for type 2 diabetes mellitus and obesity over the past two decades. Methods: This study designed a new long-acting dual-agonist, exendin-4/FGF21, utilizing albumin-binding-designed ankyrin repeat proteins (DARPins) as carriers. The purified fusion proteins were subcutaneously injected into mice for pharmacokinetic and biological activity studies. Results: Ex-DARP-FGF21 had a high binding affinity for human serum albumin (HSA) in vitro and a prolonged half-life of 27.6 hours in vivo. Bioactivity results reveal that Ex-DARP-FGF21 significantly reduced blood glucose levels in healthy mice. Moreover, compared to Ex-DARP alone, the Ex-DARP-FGF21 dual agonist displayed enhanced blood glucose lowering bioactivity and superior body weight management in the diet-induced obesity (DIO) mouse model. Conclusions: These results indicate that the long-acting dual agonist of exendin-4 and FGF21 holds considerable potential as a treatment for type 2 diabetes mellitus (T2DM) and obesity in the future.

Design, Synthesis and Antibacterial Activities of Novel Amide Derivatives Bearing Dioxygenated Rings as Potential ß-Ketoacyl-acyl Carrier Protein Synthase III (FabH) Inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, ß-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. FabH would trigger the initiation of fatty acid biosynthesis and it is highly conserved among Gram-positive and -negative bacteria. A series of novel amide derivatives bearing dioxygenated rings were synthesized and developed as potent inhibitors of FabH. These compounds were determined by 1H-NMR, 13C-NMR, MS and further confirmed by crystallographic diffraction study for compound 19. Furthermore, these compounds were evaluated strong broad-spectrum antibacterial activity. Some compounds with potent antibacterial activities were tested for their Escherichia coli (E. coli) FabH inhibitory activity. Especially, compound 19 showed the most potent antibacterial activity with minimum inhibitory concentration (MIC) values of 1.56-3.13 mg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.4 µM. Docking simulation was performed to position compound 19 into the E. coli FabH active site to determine the probable binding conformation.

Identification of functional lncRNAs based on competing endogenous RNA network in osteoblast differentiation.

Adult human mesenchymal stem cells have the potential to differentiate into osteoblast, which plays crucial roles in bone regeneration and repair. Some transcriptional factors (TFs), such as BMP-2 and RUNX2, have been demonstrated to control the differentiation processes. It is important to discover more key regulators in osteoblast differentiation. Recently, some studies found long noncoding RNAs (lncRNAs) participating in osteoblast differentiation, such as MALAT1, DANCR, and ANCR. In this study, we performed a network-based computational analysis to investigate the lncRNA-messenger RNA (mRNA) crosstalks via integrating microRNA (miRNA)-RNA interactions, gene coexpression, and protein-protein interactions. First, multiple topology analyses were performed to osteoblast-differentiation-related lncRNA-mRNA network (ODLMN). Several lncRNAs with central topology structures were identified as key regulators. Results showed that these lncRNAs participated in osteoblast differentiation via phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase, and Ras signals. Previous studies have demonstrated that lncRNAs exert functions by involving in close modules. Second, after performing module searching in ODLMN, two functional modules were identified, which played crucial roles through involving in PI3K/protein kinase B, cyclic adenosine 3',5'-monophosphate, and hypoxia-inducible factor 1 pathways. Third, a subset of core lncRNA-TF crosstalks that might form feedback loops to control the biological processes in osteoblast differentiation was identified. These core lncRNA-TF feedback loops showed more TF binding affinity than other lncRNAs. All these results can help us to uncover the molecular mechanism and provide new targets for bone regeneration and repair.

A P53-related microRNA model for predicting the prognosis of hepatocellular carcinoma patients.

Studies have shown that microRNAs (miRNAs) play a vital role in tumor progression and patients' prognosis. Therefore, we aimed to construct a miRNA model for forecasting the survival of hepatocellular carcinoma (HCC) patients. The gene expression data of 433 patients with HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus public databases were remined by survival analysis and receptor manipulation characteristic curve (ROC). A prognostic model including six miRNAs (hsa-mir-26a-1-3p, hsa-mir-188-5p, hsa-mir-212-5p, hsa-mir-149-5p, hsa-mir-105-5p, and hsa-mir-132-5p) were constructed in the training dataset (TCGA, n = 333). HCC patients were stratified into a high-risk group and a low-risk group with significantly different survival (median: 2.75 vs. 8.93 years, log-rank test p < .001). Then we proved its performance of stratification in another independent dataset (GSE116182, median: 2.55 vs 6.96 years, log-rank test p = .008). Cox regression analysis showed that the prognostic model was an independent prognostic indicator for HCC patients. Then time-dependent ROC analyses were performed to test the prognostic ability of the model with that of TNM staging, we found the model had a better performance, especially at 5 years (AUC = 0.76). Functional prediction showed that the genes targeted by the six prognostic miRNAs in the prognostic model were highly expressed in the P53-related pathway. In conclusion, we constructed a prognostic miRNA model that could indicate the survival of HCC patients.

Microarray Analysis of Long Noncoding RNAs in Female Diabetic Peripheral Neuropathy Patients.

BACKGROUND/AIMS: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Because of its controversial pathogenesis, DPN is still not diagnosed or managed properly in most patients. METHODS: In this study, human lncRNA microarrays were used to identify the differentially expressed lncRNAs in DM and DPN patients, and some of the discovered lncRNAs were further validated in additional 78 samples by quantitative realtime PCR (qRT-PCR). RESULTS: The microarray analysis identified 446 and 1327 differentially expressed lncRNAs in DM and DPN, respectively. The KEGG pathway analysis further revealed that the differentially expressed lncRNA-coexpressed mRNAs between DPN and DM groups were significantly enriched in the MAPK signaling pathway. The lncRNA/mRNA coexpression network indicated that BDNF and TRAF2 correlated with 6 lncRNAs. The qRT-PCR confirmed the initial microarray results. CONCLUSION: These findings demonstrated that the interplay between lncRNAs and mRNA may be involved in the pathogenesis of DPN, especially the neurotrophin-MAPK signaling pathway, thus providing relevant information for future studies.

Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the "neurotrophin-MAPK signaling pathway" was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment.

Gender-Specific Association of ATP2B1 Variants with Susceptibility to Essential Hypertension in the Han Chinese Population.

Previous genome-wide association studies (GWASs) found that several ATP2B1 variants are associated with essential hypertension (EHT). But the "genome-wide significant" ATP2B1 SNPs (rs2681472, rs2681492, rs17249754, and rs1105378) are in strong linkage disequilibrium (LD) and are located in the same LD block in Chinese populations. We asked whether there are other SNPs within the ATP2B1 gene associated with susceptibility to EHT in the Han Chinese population. Therefore, we performed a case-control study to investigate the association of seven tagSNPs within the ATP2B1 gene and EHT in the Han Chinese population, and we then analyzed the interaction among different SNPs and nongenetic risk factors for EHT. A total of 902 essential hypertensive cases and 902 normotensive controls were involved in the study. All 7 tagSNPs within the ATP2B1 gene were retrieved from HapMap, and genotyping was performed using the Tm-shift genotyping method. Chi-squared test, logistic regression, and propensity score analysis showed that rs17249754 was associated with EHT, particularly in females. The MDR analysis demonstrated that the interaction of rs2070759, rs17249754, TC, TG, and BMI increased the susceptibility to hypertension. Crossover analysis and stratified analysis indicated that BMI has a major effect on the development of hypertension, while ATP2B1 variants have a minor effect.