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Background Although several measures have been taken to control hand foot and mouth disease (HFMD) and herpangina (HA), these two diseases have been prevalent in China for 10 years with high incidence. We suspected that adults’ inapparent infection might be the cause of the continued prevalence of HFMD/HA infection in mainland China. Methods To explore the role of adults (especially caregivers) in the transmission process of HFMD/HA among children, 330 HFMD/HA cases and 330 healthy children (controls) were selected for a case–control study. Then, data were analyzed by logistic regression. Results Single-variable analyses revealed that caregivers who tested positive for enterovirus was a significant risk factor of HFMD/HA transmission to children (adjusted odds ratio (OR) = 9.22; 95% CI, 1.16 to 73.23). In the final multivariable model, caregiver behavior, such as cooling children’s food with mouth (OR = 1.85; 95% CI, 1.11 to 3.08) and feeding children with their own tableware (OR = 2.19; 95% CI, 1.07 to 4.45), significantly increased the risk of transmitting HFMD/HA to children. On the contrary, washing hands before feeding children reduced such risk. Conclusions These results implied that the caregivers might be the infectious source or carriers of enterovirus. Therefore, preventing or treating the caregivers’ enterovirus infection and improving their hygiene habits, especially when they are in contact with children, could provide a breakthrough for the effective control of HFMD/HA.

Background. Hepatocellular carcinoma (HCC) is a common cancer with an extremely high mortality rate. Therefore, there is an urgent need in screening key biomarkers of HCC to predict the prognosis and develop more individual treatments. Recently, AATF is reported to be an important factor contributing to HCC. Methods. We aimed to establish a gene signature to predict overall survival of HCC patients. Firstly, we examined the expression level of AATF in the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the International Union of Cancer Genome (ICGC) databases. Genes coexpressed with AATF were identified in the TCGA dataset by the Poisson correlation coefficient and used to establish a gene signature for survival prediction. The prognostic significance of this gene signature was then validated in the ICGC dataset and used to build a combined prognostic model for clinical practice. Results. Gene expression data and clinical information of 2521 HCC patients were downloaded from three public databases. AATF expression in HCC tissue was higher than that in matched normal liver tissues. 644 genes coexpressed with AATF were identified by the Poisson correlation coefficient and used to establish a three-gene signature (KIF20A, UCK2, and SLC41A3) by the univariate and multivariate least absolute shrinkage and selection operator Cox regression analyses. This three-gene signature was then used to build a combined nomogram for clinical practice. Conclusion. This integrated nomogram based on the three-gene signature can predict overall survival for HCC patients well. The three-gene signature may be a potential therapeutic target in HCC.

To detect the molecular characterization of hemoglobinopathies and thalassemias in Northern Guangdong Province of China.We recruited 10,285 subjects who were screened for hemoglobin (Hb) variants and thalassaemia genotypes in the outpatient department of Yuebei People's Hospital from January 2018 to December 2020. The subjects collected venous blood samples for blood cell parameter analysis and Hb electrophoresis analysis. When the average red blood cell volume is82 fL, or the average red blood cell Hb is27 pg, or HbA2 3.5%, or HbA2 2.5%, or HbF 2.0%, the screening is positive if one of them is satisfied. All subjects who were screened positive were tested for the thalassaemia gene by gap-polymerase chain reaction, PCR-based reverse dot blot, and DNA sequencing.Among all subjects screened, the overall prevalence of hemoglobinopathies and thalassemias were 0.46% (47/10,285) and 21.02% (2162/10,285) in Northern Guangdong Province. We found that Hb Q-Thailand is the most common, and other types of hemoglobinopathies are followed by Hb E, Hb New York, Hb G-Chinese, Hb G-Coushatta, Hb J-Bangkok, Hb J-Broussais, Hb Ottawa, and Hb G-Taipei. We identified 1340 cases (13.03%) of α-thalassemia, mainly includes --SEA deletion (71.64%), -α3.7 deletion (12.01%), -α4.2 deletion (4.78%). And identified 652 cases (6.34%) of β-thalassemia, the most prevalent being CD 41/42(-TTCT) (35.89%), IVS-II-654 (C T) (33.44%), CD 17 (A T) (10.28%) and -28(A G) (9.66%). Furthermore, there are 170 cases (1.65%) of α combined β thalassaemia. In addition, we found a rare case with -80 (T A) of β-thalassemia. The results of this study found a high prevalence of hemoglobinopathies and thalassemias in Northern Guangdong Province, China. There were some differences molecular characterizations of thalassemia in different areas of China.Our results enriched the related information of hemoglobinopathies and thalassemias in the region, which provided valuable references for the prevention and control of thalassemia.

Background: Atrial fibrillation (AF) is a common arrhythmia that induces disability or death; however, the underlying pathogenesis is yet unclear. This study aimed to investigate the expression of matrix metalloproteinase-9 (MMP-9) in rheumatic valvular heart disease (RVHD) and its value in predicting AF.Methods: In this single-center, prospective case-control study, 30 patients who received valve replacement for the treatment of RVHD in the Cardiac and Major Vascular Department, Yue Bei People’s Hospital between August 2012 and January 2015 were included in this study. The patients were categorized equally into two groups according to the electrocardiogram characteristics: sinus rhythm (SR) group and chronic atrial fibrillation (AF) group. In patients hospitalized for RVHD, the fasting serum was collected on the following day in the morning, and the tissues of right auricle were collected during the operation. Hematoxylin and eosin staining and Masson staining were performed to assess the pathological structures of myocardial tissues and changes in collagen fibers. Enzyme-linked immunosorbent assay was used to measure the level of MMP-9 in serum, and the distribution of the protein in myocardial tissues was assessed by immunohistochemistry. Echocardiography was performed before the surgery to measure the left atrial diameter and ejection fraction.Results: The MMP-9 expression was significantly higher in the AF group than the SR group (4.2281 ± 0.9165 ng/mg vs. 2.7613 ± 1.2166 ng/mg, p < 0.05). The MMP-9 levels were positively associated with left atrial diameter (LAD) (p < 0.01) and collagen volume fraction (CVF) (p < 0.05).Conclusions: MMP-9 expression is elevated in AF patients and could be one of the major factors involved in the remodeling of atrial structures in AF. MMP-9 influences the metabolism of collagen and promotes the fibrosis of the myocardium, participates in cardiac structural remodeling, and plays a role in the onset and maintenance of AF.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and N6-methyladenosine (m6A) is a predominant internal modification of RNA in various cancers. We obtained the expression profiles of m6A-related genes for HCC patients from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Most of the m6A RNA methylation regulators were confirmed to be differentially expressed among groups stratified by clinical characteristics and tissues. The clinical factors (including stage, grade, and gender) were correlated with the two subgroups (cluster 1/2). We identified an m6A RNA methylation regulator-based signature (including METTL3, YTHDC2, and YTHDF2) that could effectively stratify a high-risk subset of these patients by univariate and LASSO Cox regression, and receiver operating characteristic (ROC) analysis indicated that the signature had a powerful predictive ability. Immune cell analysis revealed that the genes in the signature were correlated with B cell, CD4 T cell, CD8 T cell, dendritic cell, macrophage, and neutrophil. Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to HCC. Moreover, the nomogram was established based on the signature integrated with clinicopathological features. The calibration curve and the area under ROC also demonstrated the good performance of the nomogram in predicting 3- and 5-year OS in the ICGC and TCGA cohorts. In summary, we demonstrated the vital role of m6A RNA methylation regulators in the initial presentation and progression of HCC and constructed a nomogram which would predict the clinical outcome and provide a basis for individualized therapy.

High-throughput sequencing is gaining popularity in clinical diagnoses, but more and more novel gene variants with unknown clinical significance are being found, giving difficulties to interpretations of people’s genetic data, precise disease diagnoses, and the making of therapeutic strategies and decisions. In order to solve these issues, it is of critical importance to figure out ways to analyze and interpret such variants. In this work, BRCA1 gene variants with unknown clinical significance were identified from clinical sequencing data, and then, we developed machine learning models so as to predict the pathogenicity for variants with unknown clinical significance. Through performance benchmarking, we found that the optimized random forest model scored 0.85 in area under receiver operating characteristic curve, which outperformed other models. Finally, we applied the best random forest model to predict the pathogenicity of 6321 BRCA1 variants from both sequencing data and ClinVar database. As a result, we obtained the predictive pathogenic risks of BRCA1 variants of unknown significance.

Background: This study aims to assess the therapeutic effects of a well-known component (puerarin) obtained from a Chinese herb root in patients with polycystic ovary syndrome (PCOS). Methods: Women with premature ovarian failure (POF) were assigned to the obese group (body mass index [BMI] ≥24 kg/m2 and waist hip ratio [WHR] >0.85) or non-obese group (group 3, n = 21). Obese patients were further randomly assigned to the obese treatment group (group 1, n = 15) and obese control group (group 1, n = 15). All patients received standard treatment (Diane-35, 1 tablet/d, orally, plus metformin, 1.5 g/d, orally). In addition to the standard modality, patients in group 1 and group 3 also orally received 150 mg/d of puerarin tablets for 3 months. Venous blood was drawn before and after treatment. Then, the metabolic and antioxidant biomarkers were measured. The normality of distribution of the data was tested using the Kolmogorov–Smirnov method. The baseline characteristics were analyzed using one-factor analysis of variance (ANOVA), and post-hoc was performed using the least significance difference (LSD)-t test. Results: Significantly improved blood levels of sex hormone binding globulin (SHBG) and superoxide dismutase (SOD) were observed in patients who received the additional treatment of puerarin, regardless of their lean or obese status, while these were not observed in patients who did not receive puerarin. Furthermore, obese patients with PCOS had significantly lower systolic blood pressure, total cholesterol, and testosterone blood levels, when compared with before treatment. Conclusion: The addition of puerarin to the present treatment protocol can be considered for the management of metabolic disorders and hyperandrogenism in PCOS patients.

The difficulty of early diagnosis for ovarian cancer is an important cause of the high mortal rates of ovarian cancer patients. Instead of symptom-based diagnostic methods, modern sequencing technologies enable the access of human’s genetic information via reading DNA/RNA molecules’ nucleotide base sequences. In such way, genes’ mutations and variants could be identified and hence a better clinical diagnosis in molecular level could be expected. However, as sequencing technologies gain more popularity, novel gene variants with unknown clinical significance are found, giving difficulties to interpretations of patients’ genetic data, precise disease diagnoses as well as the making of therapeutic strategies and decisions. In order to solve these issues, it is of critical importance to figure out ways to analyze and interpret such variants. In this work, BRCA1 gene variants with unknown clinical significance were identified from clinical sequencing data, and then we developed machine learning models so as to predict the pathogenicity for variants with unknown clinical significance. Amongst, in performance benchmarking, our optimized random forest model scored 0.85 in area under receiver-operating characteristic curve, which outperformed other models. Finally, we applied the optimized random forest model to predict the pathogenic risks of 7 BRCA1 variants of unknown clinical significances identified from our sequencing data, and 6315 variants of unknown clinical significance in ClinVar database. As a result, our model predicted 4724 benign and 1591 pathogenic variants, which helped the interpretation of these variants of unknown significance and diagnosis.

Background: Nowadays, clinical treatment outcomes of patients with hepatocellular carcinoma (HCC) have been improved. However, due to the complexity of the molecular mechanisms, the recurrence rate and mortality in HCC inpatients are still at a high level. Therefore, there is an urgent need in screening biomarkers of HCC to show therapeutic effects and improve the prognosis. Methods: In this study, we aim to establish a gene signature that can predict the prognosis of HCC patients by downloading and analyzing RNA sequencing data and clinical information from three independent public databases. Firstly, we applied the limma R package to analyze biomarkers by the genetic data and clinical information downloaded from the Gene Expression Omnibus database (GEO), and then used the least absolute shrinkage and selection operator (LASSO) Cox regression and survival analysis to establish a gene signature and a prediction model by data from the Cancer Genome Atlas (TCGA). Besides, messenger RNA (mRNA) and protein expressions of the six-gene signature were explored using Oncomine, Human Protein Atlas (HPA) and the International Cancer Genome Consortium (ICGC). Results: A total of 8,306 differentially expressed genes (DEGs) were obtained between HCC (n = 115) and normal tissues (n = 52). Top 5,000 significant genes were selected and subjected to the weighted correlation network analysis (WGCNA), which constructed nine gene co-expression modules that assign these genes to different modules by cluster dendrogram trees. By analyzing the most significant module (red module), six genes (SQSTM1, AHSA1, VNN2, SMG5, SRXN1, and GLS) were screened by univariate, LASSO, and multivariate Cox regression analysis. By a survival analysis with the HCC data in TCGA, we established a nomogram based on the six-gene signature and multiple clinicopathological features. The six-gene signature was then validated as an independent prognostic factor in independent HCC cohort from ICGC. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of the six-gene signature and nomogram. Besides, overexpression of the six genes at the mRNA and protein levels was validated using Oncomine and HPA, respectively. Conclusion: The predictive six-gene signature and nomograms established in this study can assist clinicians in selecting personalized treatment for patients with HCC.

Evidence suggests that hepatitis C virus (HCV) infection is among the main causes of hepatocellular carcinoma (HCC). In addition, HCV-induced HCC (HCV-HCC) exhibits adverse clinical outcomes and limited therapeutic treatments are available for this condition. To investigate key biomarkers in the occurrence and development of HCV-HCC, microarray datasets GSE62232, GSE69715 and GSE107170 were downloaded from the Gene Expression Omnibus database for analysis. The differentially expressed genes between HCV-HCC and normal tissue were identified using the GEO2R online tool. The function enrichment analyses including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were performed using the Database for Annotation, Visualization and Integrated Discovery online tool. A protein-protein interaction network was constructed using the Search Tool for the Retrieval of Interacting Genes database and visualized using Cytoscape. A total of 368 DEGs were identified, and the top 10 hub genes with a high degree of connectivity were selected for further analysis. Subsequently, overall survival and disease-free survival analysis revealed that there was a significant association between altered expression of HMMR, CCNB1 and KIF20A, and poor clinical outcome. In summary, these results indicate that HMMR, CCNB1 and KIF20A are potential targets for diagnosis and therapy of HCV-HCC.

Background: The immune environment in primary tumor has a profound impact on immunotherapy. However, the clinical relevance of immune environment in hepatocellular carcinoma (HCC) is largely unknown. Methods: Here, the immune profile and its clinical response in HCC was investigated. The gene expression profiles of 427 HCCs from two cohorts (The Cancer Genome Atlas, TCGA, n = 257; Gene Expression Omnibus, GEO, n = 170) were used in the current study. Findings: Five gene expression subtypes (C1-C5) responsible for global immune genes were identified in HCCs at stage I/II. It was found that subtype C4 was associated with upregulation and subtype C5 was associated with downregulation of immune profiles in most metagenes. Immune-correlation analysis of the five subtypes demonstrated that C3 and C4 had higher immune score and better prognostic outcome, as compared with other subtypes. Moreover, the mutation frequencies of TP53, CTNNB1, and AXIN1 had significant difference in the five subgroups. Further, the expression of PDCD1, CD274, PDCD1LG2, CTLA4, CD86, and CD80 was higher in subtypes C4 in comparison with the other subtypes. The WGCNA of immune-related genes in the five subtypes revealed that blue and turquoise modules were positively correlated with subtype C4 and were associated with twelve common pathways in KEGG database. These results were validated in an external cohort from NCI (National Cancer Institute) cohort (GSE14520). Interpretation: In summary, one immune-enhanced subtype and one immune-decreased subtype having different immune and clinical characteristics may provide guidance for developing novel treatment strategies for immune system malfunction related cancer. Funding Statement: This work was supported by Grants from Special Science and Technology Innovation Strategy in Guangdong (201803011), the National Natural Science Foundation of China (Grant No. 81473369), and the Key R & D programs in Shandong (2016CYJS08A01-1). Declaration of Interests: The authors declared that they have no conflict of interest. Ethics Approval Statement: Not required.

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

Epidemics of hand, foot and mouth disease (HFMD) among children have caused concern in China since 2007. We have conducted a retrospective study to investigate risk factors associated with HFMD. In this non-matching case-control study, 99 HFMD patients and 126 control from Guangdong Province were enlisted as participants. Data comprising demographic, socio-economic, clinical and behavior factors were collected from children’s parents through face-to-face interviews by trained interviewers using a standardized questionnaire. Results of the primary logistic regression analyses revealed that age, history of cold food consumption, hand-washing routines, and airing out bedding were significantly associated with HFMD cases. Results of further multivariate analysis indicated that older age (OR = 0.44, 95% CI: 0.34–0.56) and hand-washing before meals (OR = 0.3, 95% CI: 0.13–0.70) are protective factors, whereas airing out bedding more than thrice a month (OR = 4.55, 95% CI: 1.19–17.37) was associated with increased risk for HFMD. Therefore, hand-washing should be recommended to prevent HFMD, and the potential threat of airing out bedding should be carefully considered. However, further studies are needed to examine other possible risk factors.

The objective of this study was to identify potential risk factors for severe hand, foot and mouth disease (HFMD). In this case-control study, 459 severe HFMD patients and 246 mild HFMD patients from Guangdong province and Henan province, China were included. Data comprising demographic characteristics, clinical symptoms and signs, laboratory findings and other factors were collected. Univariate analysis revealed 30 factors associated with severe cases. Further multivariate analysis indicated four independent risk factors: fatigue (p p = 0.03, OR = 10.44), the use of dehydrant drugs (p p p = 0.01, OR = 0.02). However, more systematic research and validation are needed to understand the underlying risk factors for severe HFMD.