Analysis of potential biomarkers and immune infiltration in autism based on bioinformatics analysis.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by both environmental and genetic factors. However, its etiology and pathogenesis remain unclear. The purpose of this study was to establish an immune-related diagnostic model for ASD using bioinformatics methods and to identify ASD biomarkers. Two ASD datasets, GSE18123 and GSE29691, were integrated into the gene expression Database to eliminate batch effects. 41 differentially expressed genes were identified by microarray data linear model (limma package). Based on the results of the immune infiltration analysis, we speculated that neutrophils, B cells naive, CD8+ T cells, and Tregs are potential core immune cells in ASD and participate in the occurrence of ASD. Finally, the differential genes and immune infiltration in ASD and non-ASD patients were compared, and the most relevant genes were selected to construct the first immune correlation prediction model of ASD. After the calculation, the model exhibited better accuracy. The calculations show that the model has good accuracy.

Machine learning predictive models for grading bronchopulmonary dysplasia: umbilical cord blood IL-6 as a biomarker.

Objectives: This study aimed to analyze the predictive value of umbilical cord blood Interleukin-6 (UCB IL-6) for the severity-graded BPD and to establish machine learning (ML) predictive models in a Chinese population based on the 2019 NRN evidence-based guidelines. Methods: In this retrospective analysis, we included infants born with gestational age <32 weeks, who underwent UCB IL-6 testing within 24 h of admission to our NICU between 2020 and 2022. We collected their medical information encompassing the maternal, perinatal, and early neonatal phases. Furthermore, we classified the grade of BPD according to the 2019 NRN evidence-based guidelines. The correlation between UCB IL-6 and the grades of BPD was analyzed. Univariate analysis and ordinal logistic regression were employed to identify risk factors, followed by the development of ML predictive models based on XGBoost, CatBoost, LightGBM, and Random Forest. The AUROC was used to evaluate the diagnostic value of each model. Besides, we generated feature importance distribution plots based on SHAP values to emphasize the significance of UCB IL-6 in the models. Results: The study ultimately enrolled 414 preterm infants, with No BPD group (n = 309), Grade 1 BPD group (n = 73), and Grade 2-3 BPD group (n = 32). The levels of UCB IL-6 increased with the grades of BPD. UCB IL-6 demonstrated clinical significance in predicting various grades of BPD, particularly in distinguishing Grade 2-3 BPD patients, with an AUROC of 0.815 (95% CI: 0.753-0.877). All four ML models, XGBoost, CatBoost, LightGBM, and Random Forest, exhibited Micro-average AUROC values of 0.841, 0.870, 0.851, and 0.878, respectively. Notably, UCB IL-6 consistently appeared as the most prominent feature across the feature importance distribution plots in all four models. Conclusion: UCB IL-6 significantly contributes to predicting severity-graded BPD, especially in grade 2-3 BPD. Through the development of four ML predictive models, we highlighted UCB IL-6's importance.

A m6A methyltransferase-mediated immune signature determines prognosis, immune landscape and immunotherapy efficacy in patients with lung adenocarcinoma.

BACKGROUND: As the most abundant modification in mRNA, the N6-methyladenosine (m6A) RNA modification is involved in the occurrence and development of various tumors. However, the underlying functions of this alteration in the immune microenvironment of lung adenocarcinoma (LUAD) remain unknown. METHODS: We identified m6A-mediated immune genes by performing a correlation analysis. Next, a m6A-mediated immune model was constructed using multiple machine learning algorithms, including univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. The potential of this model to predict the immune landscapes, drug sensitivities, and immunotherapy responses of different LUAD risk groups was studied. RESULTS: A m6A-mediated immune model containing 13 m6A-mediated immune genes was established and found to be an independent predictor of survival time. The prognosis of low-risk patients was significantly better than that of high-risk patients. These two risk groups displayed different immune environments, genomic backgrounds, chemotherapy responses and immunotherapy response tendencies. The low- and high-risk groups strongly corresponded to the immune-hot and immune-cold phenotypes, respectively. The low-risk group was more enriched in immune-related biological processes, and the high-risk group was more enriched in proliferation-related biological processes. Furthermore, low-risk patients responded better to immunotherapy based on the results obtained from the tumor immune dysfunction and exclusion (TIDE) algorithm and subclass mapping algorithm using five external independent immunotherapy cohorts. CONCLUSIONS: Our results suggest that the m6A modification participates in regulating the tumor microenvironment. The m6A-mediated immune model may be useful to predict the immunotherapy responses and outcomes of patients with LUAD.

The Relationship Between Cord Blood Cytokine Levels and Perinatal Characteristics and Bronchopulmonary Dysplasia: A Case-Control Study.

Objective: To establish the association between serial levels of inflammatory cytokines in cord blood and perinatal characteristics and bronchopulmonary dysplasia (BPD) in preterm infants. Methods: 147 premature infants with gestational age ≤32 weeks who were born and hospitalized in the First Affiliated Hospital of Zhengzhou University between July 2019 and August 2021 were enrolled in this retrospective case-control study. Multiple microsphere flow immunofluorescence was used to detect seven cytokines in cord blood collected within 24 h of birth. Demographics, delivery characteristics, maternal factors, neonatal characteristics, and clinical outcomes were collected for the two groups. An unconditional logistic regression model was used in this study to assess the clinical variables. Results: IL-6 cord blood levels at birth were significantly higher in the BPD group than in the non-BPD group, but the odds ratio (OR) was very small (OR = 1). No differences in other cytokine concentrations were observed between the two groups. Multivariable logistic regression analysis demonstrated that increased maternal white blood cell (WBC) count on admission and lower birth weight increased the risk of BPD progression. Conclusions: Increased IL-6 cord blood levels at birth in preterm infants may have trivial significance for predicting BPD. Furthermore, higher maternal WBC count on admission and lower birth weight increased the risk of BPD.

Development of a Nomogram for Moderate-to-Severe Bronchopulmonary Dysplasia or Death: Role of N-Terminal Pro-brain Natriuretic Peptide as a Biomarker.

Objectives: This study aimed to explore the clinical value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in predicting moderate-to-severe bronchopulmonary dysplasia (BPD)/death, and to establish an effective clinical predictive nomogram. Methods: We retrospectively analyzed very low birth weight infants (VLBWs) with gestational age ≤ 32 weeks. The NT-proBNP values were determined on the 1st, 3rd, 7th, 14th, 21st, and 28th days after birth. The correlation between NT-proBNP level and moderate-to-severe BPD/death was evaluated. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction ability. Then, we used multivariable logistic regression to build the prediction model and nomogram, and calibration of the model was assessed by calibration curve. Results: In total, 556 VLBWs were involved, among whom 229 developed BPD (mild: n = 109; moderate: n = 68; severe: n = 52) and 18 died. The NT-proBNP level in the moderate-to-severe BPD/death group was significantly higher than that in the no-to-mild BPD group from the 3rd to 28th day (P < 0.001). When the natural logarithm of the serum NT-ProBNP level increased by 1 unit at day 7 (±2 days) of life, the risk of moderate and severe BPD/death was the highest (OR = 3.753; 95% CI: 2.984~4.720), and ROC analysis identified an optimal cutoff point of 3360 ng/L (sensitivity: 80.0%; specificity: 86.2%; AUC: 0.861). After adjusting for confounding factors, the level of NT-proBNP at day 7 (±2 days) of life still had important predictive value for the development of moderate-to-severe BPD/death, significantly improving the predictive ability of the model. Conclusion: The level of NT-proBNP at day 7 (±2 days) of life can be used as an early promising biomarker for VLBWs to develop moderate-to-severe BPD/death. We constructed an early predictive nomogram to help clinicians identify high-risk populations.

A Good Way to Reduce Screening for Retinopathy of Prematurity: Development of the ROP Model in a China Preterm Population.

Importance: Retinopathy of prematurity (ROP) is a preventable cause of blindness in children. Without treatment, more than 45% of eyes may suffer permanent vision loss. Current ROP screening guidelines, which include a range of birth weights (BWs) and gestational ages (GAs), may require screening many low-risk preemies who might develop severe ROP. Method: All high-risk infants in the neonatal intensive care unit (NICU) of the First Affiliated Hospital of Zhengzhou University from 2017 to 2021 were included in this retrospective cohort study. Each of the 27 candidate risk factors was evaluated in univariate analysis and adjusted for known risk factors (i.e., GA and BW). The significant results were analyzed in a backward selection multivariate logistic regression model. Receiver operating characteristic (ROC) curves and a nomogram were drawn. Results: The study included 2,040 infants who underwent ROP screening. The weight gain rate [OR, 2.65; 95% confidence interval (CI), 1.49-1.21 ≤ 12 g/d vs. > 18 g/d; P = 0.001], blood transfusion (OR, 2.03; 95% CI, 1.14-3.64; P = 0.017), invasive mechanical ventilation (OR, 1.74; 95% CI, 1.15-2.66; P = 0.009) and N-terminal segment of pro-B-type natriuretic peptide (NT-proBNP) ≥ 25,000 ng/L (OR, 1.51; 95% CI, 1.00-2.28; P = 0.048) were four new statistically independent risk factors in addition to GA and BW. The area under the curve (AUC) of the final multivariate model was 0.90 (95% CI, 0.88-0.92; P < 0.001). Conclusions and Relevance: These findings add to our understanding of ROP screening because they include all eligible infants rather than only high-risk infants, as in previous studies. Under the control of BW and GA, low weight gain rate, increased number of blood transfusion, invasive mechanical ventilation and NT-proBNP ≥ 25,000 ng/L were "new" statistically independent risk factors for ROP. The ROP risk can be calculated manually or represented by a nomogram for clinical use.

Development and Validation of a Nomogram for Predicting Bronchopulmonary Dysplasia in Very-Low-Birth-Weight Infants.

Background: Bronchopulmonary dysplasia is a common pulmonary disease in newborns and is one of the main causes of death. The aim of this study was to build a new simple-to-use nomogram to screen high-risk populations. Methods: In this single-center retrospective study performed from January 2017 to December 2020, we reviewed data on very-low-birth-weight infants whose gestational ages were below 32 weeks. LASSO regression was used to select variables for the risk model. Then, we used multivariable logistic regression to build the prediction model incorporating these selected features. Discrimination was assessed by the C-index, and and calibration of the model was assessed by and calibration curve and the Hosmer-Lemeshow test. Results: The LASSO regression identified gestational age, duration of ventilation and serum NT-proBNP in the 1st week as significant predictors of BPD. The nomogram-illustrated model showed good discrimination and calibration. The C-index was 0.853 (95% CI: 0.851-0.854) in the training set and 0.855 (95% CI: 0.77-0.94) in the validation set. The calibration curve and Hosmer-Lemeshow test results showed good calibration between the predictions of the nomogram and the actual observations. Conclusion: We demonstrated a simple-to-use nomogram for predicting BPD in the early stage. It may help clinicians recognize high-risk populations.

Association Between NT-proBNP and Prolonged Length of Stay in Hospital Among Preterm Infants Born at 28-31 Weeks' Gestation.

OBJECTIVE: In the early life of preterm infants, the relationship between heart function and length of hospitalization is unclear. This study aims to examine the association between serum NT-proBNP level on the 7th day (NT-proBNP7) after birth and length of hospitalization among preterm infants. METHODS: A retrospective cohort study was conducted. Patients included 709 preterm infants born at 28-31 weeks' gestational age (GA) admitted to the NICU of the First Affiliated Hospital of Zhengzhou University between December 20, 2016, to April 31, 2021. Main outcome: Late discharge (postmenstrual age at discharge was in the fourth quartile (highest) among infants born at the same GA). Exposure factor: NT-proBNP7. RESULTS: We observed increased prevalence ratios for late discharge among the tertile of logarithm of NT-proBNP7 level (LnNT-proBNP7) which was positive. Compared with the lowest tertile, infants in the highest tertile of LnNT-proBNP7 had an 8.4-fold increased probability of late discharge, and the results were consistent for the subgroups. Next, a non-linear (S-shaped) relationship between LnNT-proBNP7 and late discharge was observed, whose turning points were 7.5 and 9. The effect sizes and the confidence intervals on the left of the first turning point, between two turning points and on the right of the second turning point, were 0.6 (95% CI, 0.2-1.6), 5.0 (95% CI, 2.4-10.6), and 1.1 (95% CI, 0.2-6.1), respectively. In addition, the prevalence of BPD, NEC, nosocomial infection, or any of them was highest in the group of LnNT-proBNP7 ≥ 9, lowest in the group of LnNT-proBNP7 < 7.5. CONCLUSION: Higher NT-proBNP7 levels were associated with longer hospitalization. The relationship between LnNT-proBNP7 and late discharge was S-shaped. LnNT-proBNP7 was positively related with late discharge when LnNT-proBNP7 was between 7.5 and 9.

Expression and functional analysis of the Follistatin-like 3 (FSTL3) gene in the sheep ovary during the oestrous cycle.

Follistatin-like 3 (FSTL3) is a regulator of cellular apoptosis and was previously identified via RNA-Seq to be associated with follicular development in mammalian ovaries. However, the mechanism underlying the FSTL3 regulation of oestrus in sheep remained poorly understood. In this study, the oestrogen (E2) and progesterone (P4) concentrations in blood were detected, and the expression level and functional analysis of FSTL3 in the ovary were studied during the different reproductive stage in Aohan fine wool sheep (seasonal breeding breed in China). The concentrations of E2 and P4 at the anestrus were significantly lower compared to dioestrus, proestrus and oestrus stages. Higher expression levels of FSTL3 were observed in the sheep ovary, hypothalamus, and thyroid. During different reproductive stages, higher expression levels were found during the stages of dioestrus and proestrus, while lower levels were found during the oestrus and anestrus stages. Functional analysis of FSTL3 was performed in primary granulosa cells (GCs) of sheep. The concentration of E2 increased significantly after RNAi interference of FSTL3, while the P4 level decreased. FSTL3 can decrease P4 levels, which might be involved in mediating oestrous cycle in sheep.

Congenital Myasthenic Syndrome Caused by a Novel Hemizygous CHAT Mutation.

Congenital myasthenic syndrome (CMS) is a neuromuscular transmission disorder caused by mutations in genes encoding neuromuscular junction proteins. CMS due to choline acetyltransferase (CHAT) gene mutation is characterized by episodic apnoea. To date, 52 cases of CMS caused by CHAT gene mutations have been reported. Here, we report a neonate with the third hemizygous mutation [a 4.9 Mb deletion [10q11.22-10q11.23 (chr10: 46123781-51028772)] containing the whole CHAT gene and c.1976A>T (p.Gln659Leu in the CHAT gene)]. The c.1976A>T (p.Gln659Leu) variant had not been reported in the ExAC or gnomAD databases and was predicted to be pathogenic. The alignment of amino acid sequences revealed that glutamine at codon 659 is highly conserved in different species and causes structural changes in the substrate-binding site. Our female patient with neonate-onset CMS presented with apnoea, dyspnoea, feeding difficulties, weak crying, and seizure-like episodes, and her respiration was ventilator dependent. The prostigmine test was positive. This case may help to further elucidate clinical features and treatment methods in neonate-onset CMS caused by CHAT gene mutations.

Synthesis and assessment of CTAB and NPE modified organo-montmorillonite for the fabrication of organo-montmorillonite/alginate based hydrophobic pharmaceutical controlled-release formulation.

The research goal of the present study was to develop a carrier for loading and controlled -release of the hydrophobic drug with the combined use of organo-montmorillonite (OMMT) and alginate. The OMMT was synthesized through the intercalation modification of sodium montmorillonite (Na-MMT) with cationic cetyltrimethylammonium bromide (CTAB), nonionic nonylphenol polyoxyethylene ether (NPE) and the mixture of them via simple and convenient wet ball-milling method. Furthermore, the organo-montmorillonite/alginate (OMMT/Alg) composite hydrogel beads with slow and controlled release properties were constructed by using alginate as a coating material under the exogenous cross-linking of calcium ions. The physical and chemical properties of OMMT were comparatively evaluated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), thermogravimetric analyzer (TGA), BET-specific surface area measurements, and drug adsorption experiments. Experimental results showed that the presence of CTAB was able to facilitate the intercalation of CTAB/NPE into Na-MMT through the cation exchange reaction. And the cationic CTAB and nonionic NPE were adsorbed or intercalated into the MMT lamellar structure through the wet ball-milling process, which could change the hydrophilic nature of Na-MMT and improve its affinity to the hydrophobic drug molecules. In addition, the OMMT/Alg composite hydrogel beads displayed superior sustained-release properties than Na-MMT/Alg, mainly ascribed to the good affinity of OMMT to hydrophobic drug that retarded the drug diffusion. In particular, CTA/NPE-MMT/Alg with the highest loading capacity (LC) and encapsulation efficiency (EE) revealed the optimal controlled performance for the release of hydrophobic ibuprofen. The release followed the Korsmeyer-Peppas model suggested non-Fickian diffusion release mechanism. Based on the high drug loading capacity and excellent controlled drug release properties, the CTA/NPE-MMT/Alg incorporating hydrophobic drugs into hydrophilic matrices could be a highly promising material for use in hydrophobic drug delivery.

Development and Validation of a Dynamic Nomogram to Predict the Risk of Neonatal White Matter Damage.

PURPOSE: White matter damage (WMD) was defined as the appearance of rough and uneven echo enhancement in the white matter around the ventricle. The aim of this study was to develop and validate a risk prediction model for neonatal WMD. MATERIALS AND METHODS: We collected data for 1,733 infants hospitalized at the Department of Neonatology at The First Affiliated Hospital of Zhengzhou University from 2017 to 2020. Infants were randomly assigned to training (n = 1,216) or validation (n = 517) cohorts at a ratio of 7:3. Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to establish a risk prediction model and web-based risk calculator based on the training cohort data. The predictive accuracy of the model was verified in the validation cohort. RESULTS: We identified four variables as independent risk factors for brain WMD in neonates by multivariate logistic regression and LASSO analysis, including gestational age, fetal distress, prelabor rupture of membranes, and use of corticosteroids. These were used to establish a risk prediction nomogram and web-based calculator (https://caowenjun.shinyapps.io/dynnomapp/). The C-index of the training and validation sets was 0.898 (95% confidence interval: 0.8745-0.9215) and 0.887 (95% confidence interval: 0.8478-0.9262), respectively. Decision tree analysis showed that the model was highly effective in the threshold range of 1-61%. The sensitivity and specificity of the model were 82.5 and 81.7%, respectively, and the cutoff value was 0.099. CONCLUSION: This is the first study describing the use of a nomogram and web-based calculator to predict the risk of WMD in neonates. The web-based calculator increases the applicability of the predictive model and is a convenient tool for doctors at primary hospitals and outpatient clinics, family doctors, and even parents to identify high-risk births early on and implementing appropriate interventions while avoiding excessive treatment of low-risk patients.

Systematic construction and validation of an immune prognostic model for lung adenocarcinoma.

Lung adenocarcinoma (LUAD), the most common non-small-cell lung cancer, is characterized by a dense lymphocytic infiltrate, which indicates that the immune system plays an active role in the development and growth of this cancer. However, no investigations to date have proposed robust models for predicting survival outcome for patients with LUAD in terms of tumour immunology. A total of 761 LUAD patients were included in this study, in which the database of The Cancer Genome Atlas (TCGA) was utilized for discovery, and the Gene Expression Omnibus (GEO) database was utilized for validation. Bioinformatics analysis and R language tools were utilized to construct an immune prognostic model and annotate biological functions. Lung adenocarcinoma showed a weakened immune phenotype compared with adjacent normal tissues. Immune-related gene sets were profiled, an immune prognostic model based on 2 immune genes (ANLN and F2) was developed with the TCGA database to distinguish cases as having a low or high risk of unfavourable prognosis, and the model was verified with the GEO database. The model was prognostically significant in stratified cohorts, including stage I-II, stage III-IV and epidermal growth factor receptor (EGFR) mutant subsets, and was considered to be an independent prognostic factor for LUAD. Furthermore, the low- and high-risk groups showed marked differences in tumour-infiltrating leucocytes, tumour mutation burden, aneuploidy and PD-L1 expression. In conclusion, an immune prognostic model was proposed for LUAD that is capable of independently identifying patients at high risk for poor survival, suggesting a relationship between local immune status and prognosis.

Increased risk of intracranial hemorrhage in preterm infants with OPRM1 gene A118G polymorphism.

BACKGROUND: To investigate the relationship between the OPRM1 gene A118G polymorphism and intracranial hemorrhage (ICH) in premature infants and identify the relevant genes in disease occurrence. METHODS: In the present case study analysis, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of the OPRM1 gene All8G single nucleotide polymorphism (SNP) in a case group of premature infants with ICH (n=167) and a control group of premature infants (n=163) without ICH. RESULTS: In the case group, 73 (43.7%) wild type A118 homozygous (A/A), 82 (49.1%) mutant heterozygous (A/G), and 12 (7.2%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 68.3% and 31.7% respectively. In the control group, 89 (54.6%) wild type A118 homozygous (A/A), 68 (41.7%) mutant heterozygous (A/G), and 6 (3.7%) mutant G118 homozygous (G/G) individuals were observed. The frequencies of A and G alleles were 75.5% and 24.5% respectively. There was no significant difference in the frequency distribution of the OPRM1 gene A118G polymorphism between the two groups (χ2=4.839, P=0.089). There was a significant difference in the positive rate of wild-type AA and mutant-type (A/G + G/G) between the two groups (χ2=3.913, P=0.048). Carrying the G allele of the individual was 1.5 times more frequent suffering from the risk of ICH than carrying the A allele [odds ratio (OR): 1.549; 95% confidence interval (CI): 1.003-2.391], indicating that the OPRM1 118G allele was positively correlated with ICH and can increase the risk of ICH occurrence. CONCLUSIONS: The OPRM1 gene A118G polymorphism is associated with ICH in premature infants. The OPRM1 gene A118G may play a critical role in the occurrence of ICH.

Generation and identification of a thyroid cancer cell line with stable expression of CCDC67 and luciferase reporter genes.

Coiled-coil domain containing 67 (CCDC67) gene is a tumor suppressor gene that exhibits a significant inhibitory effect on a variety of tumors. Our previous study demonstrated that the upregulation of CCDC67 gene in TPC-1 cells inhibited cell proliferation, migration and invasion, and promoted apoptosis in vitro. However, due to the lack of a suitable cell tool, these results were not validated in vivo. In the present study, a thyroid cancer cell line with stable expression of CCDC67 and luciferase reporter genes was generated and identified. Firstly, cDNA clones of the CCDC67 gene were obtained by reverse transcription using a custom-designed primer. The results of subsequent electrophoresis analysis and sequencing revealed that the cDNA clones of CCDC67 gene were obtained successfully, with a length of 1,862 bp. The lentiviral vectors, containing the CCDC67, luciferase reporter and puromycin acetyltransferase genes, were co-transfected with two plasmids that encode lentiviral structural proteins and envelope proteins into 293T cells. Following ultracentrifugation, the titer of lentivirus was determined by ELISA to be 5.0×108 TU/ml. The constructed lentiviral vector was used to transfect TPC-1 thyroid cancer cells, and stabilization was achieved by puromycin screening. The expression of CCDC67 gene, luciferase activity and tumorigenic ability of the generated cell line were detected. Reverse transcription-qPCR results demonstrated that the expression levels of CCDC67 gene in TPC-1 cells following transfection were increased 194,46.782-fold compared with those in the negative control group (P<0.01). A higher fluorescence intensity was detected in the generated cell line, while no detectable fluorescence was observed in untransfected TPC-1 cells. The tumorigenic ability of TPC-1-Luc-Puromycin-CCDC67 cells was verified by bioluminescence imaging and histopathological analysis using a pulmonary metastasis model. These results demonstrated that a thyroid cancer cell line with stable expression of CCDC67 and luciferase reporter genes was generated successfully. The TPC-1-Luc-Puromycin-CCDC67 cell line may be a helpful tool for further research on CCDC67 in vivo.

The association between thyroid cancer and insulin resistance, metabolic syndrome and its components: A systematic review and meta-analysis.

BACKGROUND: Thyroid cancer is rapidly increasing in incidence worldwide in the past several decades, same as the incidence of metabolic syndrome. We performed a system review and meta-analysis of the association between metabolic syndrome, its components and insulin resistance and thyroid cancer incidence. METHODS: We searched several computer-assisted databases PUBMED, EMBASE and ISI Web of Science to identify studies published before 31st January 2018. Every study must report either risk estimates of thyroid cancer incidence with 95% confidence interval (CI) or related data can speculate. Two investigators independently identified eligible studies and extracted data. Evaluating the summaries of relative risk estimates use both fixed and random effects methods. RESULTS: We found 42 articles met the inclusion criteria of this review. There is an increased risk for thyroid cancer for patients with insulin resistance (relative risk [RR] = 1.59, 95%confidence interval [CI] = 1.12-2.27, P = 0.01), dysglycemia (RR = 1.40, 95%CI = 1.15-1.70,P < 0.001), high BMI (RR = 1.35,95%CI = 1.23-1.48,P < 0.001) and hypertension(RR = 1.34,95%CI = 1.22-1.47, p < 0.001). However, patients with dyslipidemia, both total cholesterol (RR = 1.09, 95%CI = 0.98-1.21, P = 0.13) and triglyceride (RR = 1.01, 95%CI = 0.91-1.12, P = 0.82) was not associated with thyroid cancer. CONCLUSIONS: Our meta-analysis showed Insulin Resistance, dysglycemia, high BMI and hypertension significantly increased the thyroid cancer risk. These results may help identify people with high risk of thyroid cancer and change to healthy life style.

The Chinese herb Prunella vulgaris promotes apoptosis in human well-differentiated thyroid carcinoma cells via the B-cell lymphoma-2/Bcl-2-associated X protein/caspase-3 signaling pathway.

Prunella vulgaris (PV), a traditional Chinese herb, has been shown to be rich in bioactive chemicals and possess anti-proliferative and pro-apoptotic effects on tumor cells. The effect of PV on human well-differentiated thyroid carcinoma (WDTC), which accounts for the majority of common endocrine malignancies, remains to be elucidated. The present study aimed to investigate the function of PV on WDTC cell lines and apoptosis-associated signaling pathway activity. Additional studies demonstrated that PV may induce apoptosis in WDTC TPC-1 and FTC-133 cell lines, using the Cell Counting Kit-8 assay. Morphological changes of apoptotic cells were observed by Hoechst 33342 and acridine orange/ethidium bromide staining. In addition, ladder pattern of fragmented DNA was observed by DNA gel electrophoresis. It was also observed that PV significantly increased Bcl-2-associated X protein and caspase-3 expression, and downregulated B-cell lymphoma-2 expression in TPC-1 and FTC-133 by reverse transcription-quantitative polymerase chain reaction (P<0.05). Thus, the present results indicated that PV has the potential to be a future WDTC therapeutic agent.

Prognostic impact of minimal extrathyroidal extension in papillary thyroid carcinoma.

BACKGROUND: It is widely accepted that maximal extrathyroidal extension (ETE) plays a vital role in the prognosis of papillary thyroid carcinoma (PTC). However, there is no consensus among researchers about the meaning of minimal ETE (mETE) in PTC. Herein, we conducted a systematic review and meta-analysis to examine the role of mETE in the prognosis of PTC. METHODS: We searched PubMed, EMBASE, and Cochrane search trials databases in English to identify studies comparing data on disease recurrence in PTC patients with mETE and those with no ETE. To summarize the data related to mETE status, risk ratios and hazard ratios adjusted for potential confounders were used to assess the number of recurrence and time-dependent risks related to mETE status, respectively. RESULTS: According to the inclusion criteria, a total of 7951 patients from 9 studies were included. The recurrence rate in patients with mETE is significantly higher when compared with those with no ETE (risk ratio = 1.70, 95% confidence interval: 1.26-2.28, I = 56%). According to the data summarized with hazard ratios, PTC patients with mETE showed a significantly increased risk of disease recurrence. CONCLUSION: mETE is a risk factor for poor prognosis in patients with PTC. Our innovative classification of ETE has its value in assessing the prognosis of PTC.

Clinicopathological significance of TERT promoter mutation in papillary thyroid carcinomas: a systematic review and meta-analysis.

BACKGROUND: The prognostic value of the telomerase reverse transcriptase (TERT) promoter mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma (PTC), has been generally confirmed. To data, there is no high-level evidence approving the association of TERT promoter mutation and aggressive clinical behaviours in PTC. To systematically evaluate it, a systematic review and meta-analysis of the published literatures were carried out. METHODS: We conducted a systematic search in PubMed, EMBASE, OVID and Web of Science databases for relevant studies. We selected all the studies that reported clinicopathological features of PTC patients with information available on TERT promoter mutation status. Individual study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies. RESULTS: Eight eligible trials involved 2035 patients were included in the analysis. The average prevalence of the TERT promoter mutation was 10·32%. Compared with the wild-type TERT promoter gene, the TERT promoter mutation was associated with male gender, lymph node metastasis, extrathyroidal extension, distant metastasis, advanced TNM stage III/IV, poor clinical outcome (persistence or recurrence) and mortality. The associations were generally consistent across the different study populations. CONCLUSIONS: Thus, our findings from this large meta-analysis definitively demonstrate that TERT promoter mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT promoter mutation is likely to be useful in assisting the risk stratification and management of PTC.

Characterization of the novel tumor-suppressor gene CCDC67 in papillary thyroid carcinoma.

BACKGROUND: Some studies showed an association of coiled-coil domain-containing (CCDC) genes with cancers. Our previous limited data specifically suggested a possible pathogenic role of CCDC67 in papillary thyroid cancer (PTC), but this has not been firmly established. The present study was to further investigate and establish this role of CCDC67 in PTC. RESULTS: The expression of CCDC67, both at mRNA and protein levels, was sharply down-regulated in PTC compared with normal thyroid tissues. Lower CCDC67 expression was significantly associated with aggressive tumor behaviors, such as advanced tumor stages and lymph node metastasis, as well as BRAF mutation. Introduced expression of CCDC67 in TPC-1 cells robustly inhibited cell proliferation, colony formation and migration, induced G1 phase cell cycle arrest, and increased cell apoptosis. METHODS: Primary PTC tumors and matched normal thyroid tissues were obtained from 200 unselected patients at the initial surgery for detection of CCDC67 mRNA and protein by RT-PCR and Western blotting analyses, respectively. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. Clinicopathological data were retrospectively reviewed for correlation analyses. PTC cell line TPC-1 with stable transfection of CCDC67 was used to investigate the functions of CCDC67. CONCLUSIONS: This large study demonstrates down-regulation of CCDC67 in PTC, an inverse relationship between CCDC67 expression and PTC aggressiveness and BRAF mutation, and a robust inhibitory effect of CCDC67 on PTC cellular activities. These results are consistent with CCDC67 being a novel and impaired tumor suppressor gene in PTC, providing important prognostic and therapeutic implications for this cancer.