ALKBH5 gene polymorphisms and risk of neuroblastoma in Chinese children from Jiangsu Province.

Background: Neuroblastoma is one of the most common extracranial malignant solid tumors in children. AlkB homolog 5 (ALKBH5) is an RNA N6-methyladenosine (m6A) demethylase that plays a critical role in tumorigenesis and development. We assessed the association between single nucleotide polymorphisms (SNPs) in ALKBH5 and the risk of neuroblastoma in a case-control study including 402 patients and 473 non-cancer controls. Methods: Genotyping was determined by the TaqMan method. The association between ALKBH5 polymorphisms (rs1378602 and rs8400) and the risk of neuroblastoma was evaluated using the odds ratio (OR) and 95% confidence interval (CI). Results: We found no strong association of ALKBH5 rs1378602 and rs8400 with neuroblastoma risk. Further stratification analysis by age, sex, primary site, and clinical stage showed that the rs1378602 AG/AA genotype was associated with a lower risk of neuroblastoma in males (adjusted OR = 0.58, 95% CI = 0.35-0.97, p = 0.036) and children with retroperitoneal neuroblastoma (adjusted OR = 0.58, 95% CI = 0.34-0.98, p = 0.040). Conclusions: ALKBH5 SNPs do not seem to be associated with neuroblastoma risk. More studies are required to confirm this negative result and reveal the relationship between gene polymorphisms of the m6A modifier ALKBH5 and neuroblastoma.

Cell communication pathway prognostic model identified detrimental neurodevelopmental pathways in neuroblastoma.

Neurodevelopmental cell communication plays a crucial role in neuroblastoma prognosis. However, determining the impact of these communication pathways on prognosis is challenging due to limited sample sizes and patchy clinical survival information of single cell RNA-seq data. To address this, we have developed the cell communication pathway prognostic model (CCPPM) in this study. CCPPM involves the identification of communication pathways through single-cell RNA-seq data, screening of prognosis-significant pathways using bulk RNA-seq data, conducting functional and attribute analysis of these pathways, and analyzing the post-effects of communication within these pathways. By employing the CCPPM, we have identified ten communication pathways significantly influencing neuroblastoma, all related to axongenesis and neural projection development, especially the BMP7-(BMPR1B-ACVR2B) communication pathway was found to promote tumor cell migration by activating the transcription factor SMAD1 and regulating UNK and MYCBP2. Notably, BMP7 expression was higher in neuroblastoma samples with distant metastases. In summary, CCPPM offers a novel approach to studying the influence of cell communication pathways on disease prognosis and identified detrimental communication pathways related to neurodevelopment.

TET3 gene rs828867 G>A polymorphism reduces neuroblastoma risk in Chinese children.

Objective: Neuroblastoma (NB) is a prevalent pediatric tumor originating from primordial neural crest cells. As one of the latest epigenetics investigations focuses, RNA 5-methylcytosine (m5C) is closely related to cancer risk. TET methylcytosine dioxygenase 3 (TET3) is a demethylase for m5C modification. Whether there is an association between TET3 gene polymorphisms and neuroblastoma risk remains unclear. Methods: We conducted an epidemiological study in 402 patients and 473 controls to evaluate the relationship between TET3 gene SNPs (rs7560668 T > C, rs828867 G > A, and rs6546891 A > G) and NB susceptibility. Results: Our results showed that rs828867 G > A significantly reduced NB risk in Chinese children [GA vs. GG, adjusted odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.52-0.98, P=0.040; GA/AA vs. GG, adjusted OR = 0.74, 95% CI = 0.55-0.998, P=0.048]. Individuals with 2-3 risk genotypes had a significantly higher NB risk than those with 0-1 risk genotypes (adjusted OR = 1.40, 95% CI = 1.04-1.88, P=0.027). The stratified analysis showed that the rs828867 G > A associated with decreased NB risk is remarkable among children aged >18 months (adjusted OR = 0.67, 95% CI = 0.46-0.96, P=0.029) and patients at clinical III + IV stages (adjusted OR = 0.67, 95% CI = 0.45-0.98, P=0.040). Compared with the 0-1 risk genotype, the concurrence of 2-3 risk genotypes significantly increased NB risk in the following subgroups: children aged >18 months and patients at clinical III + IV stages. GTEx analysis suggested that rs828867 G > A was significantly associated with RP11-287D1.4 and POLE4 mRNA expression. Conclusions: Overall, our results revealed that rs828867 G > A in the TET3 gene is significantly associated with predisposition to NB.

ALKBH1 rs2267755 C>T polymorphism decreases neuroblastoma risk in Chinese children.

Neuroblastoma is a highly malignant extracranial solid tumor in pediatrics. ALKBH1 as a recently discovered DNA N6-methyldeoxyadenosine (6mA) demethylase closely links to tumorigenesis. Whether the ALKBH1 polymorphism contributes to neuroblastoma risk remains unclear. In the present study, we genotyped the ALKBH1 single nucleotide polymorphisms (SNPs) in 402 neuroblastoma patients and 473 healthy controls by TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated to evaluate the strength of the association. Our result exhibited that the rs2267755 C>T (CT vs. CC, adjusted OR=0.69, 95% CI=0.50-0.94, P=0.019) is significantly associated with reduced neuroblastoma risk. And its protective effect is particularly significant in children with tumors originating from the retroperitoneal. Combined genotype analysis revealed that carriers with 1-2 protective genotypes are more susceptible to neuroblastoma than those with 3-4 protective genotypes (adjusted OR=0.71, 95% CI=0.53-0.97, P=0.028). Moreover, the rs2267755 C>T is significantly associated with messenger RNA (mRNA) expression of ALKBH1 and three of its surrounding genes, including SNWQ, ADCK1, and RPL21P10. These results suggest that the rs2267755 C>T may be a genetic variant to reduce neuroblastoma risk.

Genetic variants of m7G modification genes influence neuroblastoma susceptibility.

Objective: Neuroblastoma is a life-threatening pediatric solid tumor whose etiology remains unclear. N7-methylguanosine (m7G) is one of the most important epigenetic modifications of RNA, which plays a crucial role in tumorigenesis. The m7G-mediated genes METTL1 and WDR4 also have been reported to be dysregulated in various cancers. However, the implications of METTL1 and WDR4 in neuroblastoma have not been clarified. Methods: Given the oncogenic potential of m7G modification, we performed a case-control study to assess the association of METTL1 and WDR4 genes polymorphisms with neuroblastoma risk in a Chinese population consisting of 402 cases and 473 controls. Odds ratios (ORs) and 95 % confidence intervals (CIs) were applied to evaluate the associations between studied polymorphisms and neuroblastoma risk. The adjusted odds ratio (AOR) was adjusted for age and gender. Results: Overall, four polymorphisms were significantly associated with neuroblastoma risk, including METTL1 rs2291617 (recessive model: adjusted OR = 1.59, 95 % CI = 1.08-2.34, P = 0.019), WDR4 rs2156316 (dominant model: adjusted OR = 0.74, 95 % CI = 0.57-0.97, P = 0.028), WDR4 rs6586250 (dominant model: adjusted OR = 0.59, 95 % CI = 0.42-0.84, P = 0.004) and WDR4 rs15736 (dominant model: adjusted OR = 0.60, 95 % CI = 0.42-0.85, P = 0.004). Stratified analysis showed stronger correlations between significant polymorphisms and neuroblastoma risk among subgroups divided by age, gender, tumor origin, and clinical stage. Furthermore, expression quantitative trait loci (eQTL) analysis revealed that significant polymorphisms were associated with the expression of the adjacent genes. Conclusions: Our study indicated that four polymorphisms in m7G-mediated genes contribute to neuroblastoma susceptibility in the eastern Chinese population. However, our findings should be verified further by large-scale and well-designed studies.

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis.

BACKGROUND AND AIMS: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. METHODS: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. RESULTS: Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. CONCLUSIONS: In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.

Clinical characteristics associated with recurrent viral RNA positivity in patients within two weeks after recovering from the first SARS-CoV-2 infection.

Many studies have shown that recovered coronavirus disease 2019 (COVID-19) patients frequently exhibit recurrent viral RNA positivity (RP) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our study aimed to summarize the clinical characteristics of these patients and explore potential reasons for RP occurrence. We divided 439 participants into four groups based on the severity of illness prior to the COVID-19 recovery and age: mild-child group, moderate-child group, mild-adult group, and moderate-adult group. Laboratory data were collected and statistical analyzed using the SPSS software, version 24.0. Significant differences were observed in age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP), interleukin 6 (IL-6), and neutrophil to lymphocyte ratio (NLR) levels between the mild-adult group and the moderate-adult group (P < 0.05). Additionally, AST levels differed significantly between the mild-child group and the moderate-child group (P < 0.05). The proportion of RP patients within the four groups varied from 7.95% to 26.13% within a 2-week period. Logistic regression analysis revealed that younger age and moderate symptoms were risk factors for RP in children, while the presence of comorbidities (such as chronic heart, lung, liver, and kidney diseases), elevated IL-6 levels, and NLR were risk factors for RP in adults. We constructed two predictive models containing these relevant parameters, and the results of the receiver operating characteristic (ROC) curves indicated strong predictive utility. Our findings suggest that younger children with more severe symptoms, as well as adult patients with elevated levels of IL-6 and NLR and underlying diseases, are at higher risk of RP occurrence.

Functional TET2 gene polymorphisms increase the risk of neuroblastoma in Chinese children.

The 5-methylcytosine (m5C) is the key chemical modification in RNAs. As one of the demethylases in m5C, TET2 has been shown as a tumor suppressor. However, the impact of TET2 gene polymorphisms on neuroblastoma has not been elucidated. 402 neuroblastoma patients and 473 controls were genotyped for TET2 gene polymorphisms using the TaqMan method. The impact of TET2 gene polymorphisms on neuroblastoma susceptibility was determined using multivariate logistic regression analysis. We also adopted genotype-tissue expression database to explore the impact of TET2 gene polymorphisms on the expression of host and nearby genes. We used the R2 platform and Sangerbox tool to analyze the relationship between gene expression and neuroblastoma risk and prognosis through non-parametric testing and Kaplan-Meier analysis, respectively. We found the TET2 gene polymorphisms (rs10007915 G > C and rs7670522 A > C) and the combined 2-5 risk genotypes can significantly increase neuroblastoma risk. Stratification analysis showed that these significant associations were more prominent in certain subgroups. TET2 rs10007915 G > C and rs7670522 A > C are significantly associated with reduced expression of TET2 mRNA. Moreover, lower expression of TET2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastoma. The rs10007915 G > C and rs7670522 A > C are significantly related to the increased expression of inorganic pyrophosphatase 2 mRNA, and higher expression of PPA2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastomas. In summary, TET2 rs10007915 G > C and rs7670522 A > C significantly confer neuroblastoma susceptibility, and further research is needed to investigate the underlying mechanisms.

RTEL1 gene polymorphisms and neuroblastoma risk in Chinese children.

BACKGROUND: Neuroblastoma, a neuroendocrine tumor originating from the sympathetic ganglia, is one of the most common malignancies in childhood. RTEL1 is critical in many fundamental cellular processes, such as DNA replication, DNA damage repair, genomic integrity, and telomere stability. Single nucleotide polymorphisms (SNPs) in the RTEL1 gene have been reported to confer susceptibility to multiple cancers, but their contributing roles in neuroblastoma remain unclear. METHODS: We conducted a study on 402 neuroblastoma cases and 473 controls to assess the association between four RTEL1 SNPs (rs3761124 T>C, rs3848672 T>C, rs3208008 A>C and rs2297441 G>A) and neuroblastoma susceptibility. RESULTS: Our results show that rs3848672 T>C is significantly associated with an increased risk of neuroblastoma [CC vs. TT/TC: adjusted odds ratio (OR)=1.39, 95% confidence interval (CI)=1.02-1.90, P=0.038]. The stratified analysis further indicated that boy carriers of the rs3848672 CC genotype had a higher risk of neuroblastoma, and all carriers had an increased risk of developing neuroblastoma of mediastinum origin. Moreover, the rs2297441 AA genotype increased neuroblastoma risk in girls and predisposed children to neuroblastoma arising from retroperitoneal. CONCLUSION: Our study indicated that the rs3848672 CC and rs2297441 AA genotypes of the RTEL1 gene are significantly associated with an increased risk of neuroblastoma in Chinese children in a gender- and site-specific manner.

MIR938 rs2505901 T>C polymorphism is associated with increased neuroblastoma risk in Chinese children.

Neuroblastoma (NB) is a kind of childhood cancer that is a prevailing and deadly solid neoplasm among pediatric malignancies. The transcriptional output of MIR938 is capable of participating in the posttranscriptional modulation of gene expression, whereby it exerts its regulatory effect by modulating both the stability and translation of target mRNAs. Previous studies showed that MIR938 was associated with many cancers. Hence, functional genetic variants in the MIR938 can be attributed to NB risk. We recruited 402 neuroblastoma patients and 473 controls from the Children's Hospital of Nanjing Medical University and genotyped one MIR938 single-nucleotide polymorphism (SNP) (rs2505901 T>C). There were significant associations between the rs2505901 T>C and NB risk [CC vs. TT: adjusted odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.02-3.55, P=0.045; CC vs. TT/TC: adjusted OR = 2.02, 95% CI = 1.09-3.75, P=0.026]. This analysis of genotypes revealed that T>C increased the risk of NB. Some borderline significant different relationships were observed in the stratified analyses: age ≤ 18 months (adjusted OR = 2.95, 95% CI = 0.92-9.51, P=0.070), male sex (adjusted OR = 2.19, 95% CI = 0.95-5.08, P=0.067), and clinical stage III+IV (adjusted OR = 2.12, 95% CI = 0.98-4.56, P=0.055). The present study revealed that the MIR938 rs2505901 T>C polymorphism may be a potential risk factor for neuroblastoma in Chinese children. In the long term, conducting large and diverse sample studies from different ethnicities will indeed be crucial in determining the role of MIR938 polymorphisms in NB risk. By including individuals from various ethnic backgrounds, researchers can account for potential genetic variations that may exist between populations.

miR-100 rs1834306 a > G polymorphism decreases neuroblastoma risk in Chinese children.

BACKGROUND: Neuroblastoma is a common malignant tumor stemming from the sympathetic nervous system in children, which is often life-threatening. The genetics of neuroblastoma remains unclear. Studies have shown that miRNAs participate in the regulation of a broad spectrum of biological pathways. The abnormity in the miRNA is associated with the risk of various cancers, including neuroblastoma. However, research on the relationship of miRNA polymorphisms with neuroblastoma susceptibility is still in the initial stage. METHODS: In this research, a retrospective case-control study was conducted to explore whether miR-100 rs1834306 A > G polymorphism is associated with neuroblastoma susceptibility. We enrolled 402 cases and 473 controls for the study. The logistic regression analysis was adopted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between miR-100 rs1834306 A > G and neuroblastoma risk. RESULTS: Our results elucidated that the miR-100 rs1834306 A > G polymorphism was associated with the decreased risk of neuroblastoma (AG versus AA: adjusted OR = 0.72, 95% CI = 0.53-0.98, and P = 0.038). The subsequent stratified analysis further found that rs1834306 AG/GG genotype reduced the risk of neuroblastoma in the subgroup with tumors of the mediastinum origin (adjusted OR = 0.63, 95% CI = 0.41-0.95, and P = 0.029). CONCLUSIONS: In summary, miR-100 rs1834306 A > G polymorphism was shown to associate with decreased neuroblastoma risk in Chinese children, especially for neuroblastoma of mediastinum origin. This conclusion needs to be verified in additional large-size case-control studies.

Functional polymorphisms of the TET1 gene increase the risk of neuroblastoma in Chinese children.

Common genetic mutations are absent in neuroblastoma, one of the most common childhood tumours. As a demethylase of 5-methylcytosine (m5C) modification, TET1 plays an important role in tumourigenesis and differentiation. However, the association between TET1 gene polymorphisms and susceptibility to neuroblastoma has not been reported. Three TET1 gene polymorphisms (rs16925541 A > G, rs3998860 G > A and rs12781492 A > C) in 402 Chinese patients with neuroblastoma and 473 cancer-free controls were assessed using TaqMan. Multivariate logistic regression analysis was used to evaluate the association between TET1 gene polymorphisms and susceptibility to neuroblastoma. The GTEx database was used to analyse the impact of these polymorphisms on peripheral gene expression. The relationship between gene expression and prognosis was analysed using Kaplan-Meier analysis with the R2 platform. We found that both rs3998860 G > A and rs12781492 A > C were significantly associated with increased neuroblastoma risk. Stratified analysis further showed that rs3998860 G > A and rs12781492 A > C significantly increased neuroblastoma risk in certain subgroups. In the combined risk genotype model, 1-3 risk genotypes significantly increased risk of neuroblastoma compared with the 0 risk genotype. rs3998860 G > A and rs12781492 A > C were significantly associated with increased STOX1 mRNA expression in adrenal and whole blood, and high expression of STOX1 mRNA in adrenal and whole blood was significantly associated with worse prognosis. In summary, TET1 gene polymorphisms are significantly associated with increased neuroblastoma risk; further research is required for the potential mechanism and therapeutic prospects in neuroblastoma.

Association between GPC2 polymorphisms and neuroblastoma risk in Chinese children.

BACKGROUND: The cell surface glycoprotein glypican 2 (GPC2) has been shown to increase susceptibility to neuroblastoma, which is the most common malignancy in children. However, associations between single nucleotide polymorphism(s) of GPC2 and neuroblastoma risk remain unclarified. METHODS: We conducted a case-control study to investigate two GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) in 473 healthy controls and 402 pediatric patients with neuroblastoma. Single nucleotide polymorphism (SNP) genotyping was conducted on the samples by the TaqMan technique, and the data were subsequently analyzed by the t test, chi-squared test, and logistic regression model. In addition, we further performed stratification analysis by age, sex, tumor site of origin, or clinical stage to control confounding factors. RESULTS: According to the data of dominant models (GA/AA vs. GG: adjusted OR = 0.99, 95% CI = 0.76-1.29, p = 0.943; CT/TT vs. CC: adjusted OR = 0.91, 95% CI = 0.70-1.19, p = 0.498) or other comparisons, as well as the conjoint analysis (adjusted OR = 1.22, 95% CI = 0.93-1.59, p = 0.152), we unfortunately proved that the analysis of single or multiple loci did not support any significant association of GPC2 polymorphisms with susceptibility to neuroblastoma. CONCLUSION: GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) are unable to statistically affect neuroblastoma risk in Chinese children. Therefore, more samples, especially from patients of various ethnic backgrounds, are required to increase the sample size and verify the effect of GPC2 polymorphisms on neuroblastoma risk in the presence of ethnic factor.

Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer.

Increasing evidence suggests that long non-coding riboneucleic acids (lncRNAs), as competing endogenous RNA (ceRNA), play a key role in the initiation, invasion, and metastasis of cancer. As a new hypothesis, the lncRNA-micro RNA (miRNA)-messenger RNA (mRNA), ceRNA regulatory network has been successfully constructed in a variety of cancers. However, lncRNA, which plays a ceRNA function in endometrial cancer (EC), is still poorly understood. In this study, we downloaded EC expression profiling from The Cancer Genome Atlas database and used the R software "edgeR" package to analyze the differentially expressed genes between EC and normal endometrium samples. Then, differentially expressed (DE) lncRNAs, miRNAs and mRNAs were selected to construct a lncRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of lncRNAs in EC. Kaplan-Meier method and the log-rank test were used for survival analysis. Based on the "ceRNA hypothesis," we constructed a co-expression network of mRNA and lncRNA genes mediated by miRNA in the process of tumor genesis. Furthermore, we successfully constructed a dysregulated lncRNA-associated ceRNA network containing 96 DElncRNAs, 27 DEmiRNAs, and 74 DEmRNAs. Through Kaplan-Meier curve analysis, we found that 9 lncRNAs, 3 miRNAs, and 12 mRNAs were significantly correlated with the overall survival rate of patients among all lncRNAs, miRNAs, and mRNAs involved in ceRNA (P < .05). Our research provides a new perspective for the interaction among lncRNAs, miRNAs, and mRNA and lays the foundation for further research on the mechanism of lncRNAs in the occurrence of EC.

NSUN2 gene rs13181449 C>T polymorphism reduces neuroblastoma risk.

Neuroblastoma is the most common tumor in infants. RNA m5C modification regulates the survival, differentiation, and migration of cells affecting RNA function. However, the effects of the m5C modification methyltransferase gene NSUN2 polymorphism on neuroblastoma susceptibility have not been reported. TaqMan method was used to determine genotypes of four NSUN2 polymorphisms (rs4702373 C>T, rs13181449 C>T, rs166049 T>G, and rs8192120 A>C) in 402 patients with neuroblastoma and 473 cancer-free controls from Jiangsu province, China. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association of NSUN2 polymorphisms with neuroblastoma susceptibility. The association was also further assessed in subgroups stratified by age, sex, tumor origin, and stage. GTEx was used to analyze the effect of these polymorphisms on NSUN2 expression. We found the rs13181449 C>T was significantly associated with reduced neuroblastoma risk (CT vs. CC: adjusted OR = 0.68, 95% CI = 0.51-0.92, P = 0.012; CT/TT vs. CC: adjusted OR = 0.70, 95% CI = 0.53-0.92, P = 0.010). Compared with 0-2 protective genotypes, those with 3-4 protective genotypes could significantly reduce the neuroblastoma risk (adjusted OR = 0.68, 95% CI = 0.52 to 0.90, P = 0.006). Stratification analysis showed that the protective effect of rs13181449 polymorphism remained significant in children with age >18 months, boys, and those with early INSS stages. Moreover, children with more protective genotypes in the same subgroups also exhibited significantly reduced neuroblastoma risk. GTEx analysis showed that the rs13181449 T genotype was related with decreased NSUN2 gene expression. In conclusions, NSUN2 rs13181449 polymorphism is associated with decreased neuroblastoma risk, and the underlying mechanism in neuroblastoma needs further study.

Clinical characteristics and risks of the convalescent COVID-19 patients with re-detectable positive RNA test: a 430 patients with Omicron infected cross-sectional survey in Tianjin, China.

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV-2) Omicron variant occurred in Tianjin, China, at the beginning of 2022. In the present study, we identified risk factors that may affect positive (RP) RNA re-testing in recovered patients infected with Omicron variants during recovery in hospital. METHODS: We retrospectively analyzed the medical records of 425 patients with Omicron variant infection admitted to our medical center from January 21, 2022 to February 24, 2022, based on the recurrence of RT-PCR positive results for SARS-CoV-2 after cure and discharge. Patients were divided into re-tested positive (RP) and non-re-detectable positive patients (NRP) groups, and clinical data from both groups were analyzed to investigate the characteristics and risk factors of RP patients. RESULTS: Univariate analysis showed significant differences in age, vaccination rate and dose, partial signs and symptoms, most co-existing disorders, and levels of CRP and IL-6 between the RP and NRP groups (all P < 0.05), while multifactorial logistic regression analysis showed that vaccination status and levels of IL-6 were independent risk factors for RP patients. CONCLUSION: Our results suggested that clinicians should assess the probability of "re-positive" nucleic acid tests after discharge, taking the following indicators into account: pre-admission underlying diseases, unvaccinated status, and high levels of CRP and IL-6. Post-discharge isolation and follow-up should also be strengthened.

Novel serum proteomic biomarkers for early diagnosis and aggressive grade identification of prostate cancer.

Background: Prostate cancer (PCa) is one of the most common tumors and the second leading cause of cancer-related death in men. The discovery of novel biomarkers for PCa diagnosis in the early stage, as well as discriminating aggressive PCa from non-aggressive PCa continue to pose a challenge. The aim of this study was to identify serum proteins that were sensitive and specific enough to detect early-stage and aggressive PCa. Methods: The serum proteomic profiling of patients with PCa and benign prostatic hyperplasia (BPH) was comprehensively analyzed using data-independent acquisition mass spectrometry (DIA-MS), and the bioinformatics analysis was performed. The differentially expressed proteins (DEPs) of interest were further verified by enzyme-linked immunosorbent assay (ELISA) and immunoturbidimetry assay. Results: Statistically significant difference in abundance showed 56 DEPs between early-stage PCa and BPH and 47 DEPs between aggressive and non-aggressive PCa patients. In addition, the verification results showed that serum L-selectin concentration was significantly higher (p<0.05) in Gleason 6 PCa when compared with BPH, and the concentration of osteopontin (SPP1) and ceruloplasmin (CP) increased with higher Gleason score. Conclusions: DIA-MS has great potential in cancer-related biomarker screening. Our data demonstrated that adding SPP1 and CP to PSA improved the separation of Gleason 7 (4 + 3) or above from Gleason 7 (3 + 4) or below compared with PSA diagnosis alone. Serum SPP1 and CP could be effective biomarkers to differentiate aggressive PCa (especially Gleason 7 (4 + 3) or above) from non-aggressive disease.

Acetaminophen-induced reduction of NIMA-related kinase 7 expression exacerbates acute liver injury.

Background & Aims: Acetaminophen (APAP)-induced acute liver injury (ALI) is a global health issue characterised by an incomplete understanding of its pathogenesis and unsatisfactory therapies. NEK7 plays critical roles in both cell cycle regulation and inflammation. In the present study, we investigated the role and mechanism of NEK7 in APAP-induced ALI. Methods: In mice with NEK7 overexpression (hydrodynamic tail vein injection of NEK7 plasmids), hepatocyte-specific NEK7 knockout (cKO), and inducible NEK7 knockout (iKO), an overdose of APAP was administered to induce ALI. Liver injury was determined by an analysis of serum liver enzymes, pathological changes, inflammatory cytokines, and metabonomic profiles. In vitro, hepatocyte damage was evaluated by an analysis of cell viability, the reactive oxygen species levels, and mitochondrial function in different cell lines. Hepatocyte proliferation and the cell cycle status were determined by Ki-67 staining, EdU staining, and the cyclin levels. Results: NEK7 was markedly downregulated in APAP-induced injured liver and damaged hepatocytes. NEK7 overexpression in the liver significantly alleviated APAP-induced liver injury, as shown by the restored liver function, reduced pathological injury, and decreased inflammation and oxidative stress, which was confirmed in a hepatocyte cell line. Moreover, both NEK7 cKO and iKO mice exhibited exacerbation of APAP-induced ALI. Finally, we determined that cyclin B1-mediated cell cycle progression could mediate the protective effect of NEK7 against APAP-induced ALI. Conclusions: Reduced NEK7 contributes to APAP-induced ALI, possibly by dysregulating cyclins and disturbing cell cycle progression. Lay summary: Acetaminophen-induced acute liver injury is one of the major global health issues, owing to its high incidence, potential severity, and limited therapeutic options. Our current understanding of its pathogenesis is incomplete. Herein, we have shown that reduced NEK7 (a protein with a key role in the cell cycle) exacerbates acetaminophen-induced acute liver injury. Hence, NEK7 could be a possible therapeutic target for the prevention or treatment of this condition.

Corrigendum: Development and Validation of Novel Nomograms to Predict the Overall Survival and Cancer-Specific Survival of Cervical Cancer Patients With Lymph Node Metastasis.

[This corrects the article DOI: 10.3389/fonc.2022.857375.].

Antisense oligonucleotides rescue an intronic splicing variant in the ABCB11 gene that causes progressive familial intrahepatic cholestasis type 2.

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disorder caused by variants in the ABCB11 gene encoding the bile salt export pump (BSEP). We investigated the molecular defect in a PFIC2 infant and rescued the splicing defect with antisense oligonucleotides (ASOs). METHODS: Whole-exome sequencing (WES) revealed compound heterozygous variants in the ABCB11 gene in a PFIC2 patient. Liver biopsy was immunostained for BSEP. The splicing effect of the candidate variants was investigated by minigene assay. ASOs were designed to rescue aberrant splicing. RESULTS: A Chinese girl of two nonconsanguineous healthy parents suffered from low glutamyl transpeptidase cholestasis and showed no response to the ursodeoxycholic acid. WES revealed that the patient was compound heterozygous for two novel variants in the ABCB11 gene: c.76+29T>G and c.390-2A>G. Liver immunohistochemistry showed the absence of BSEP. The variant c.76+29T>G was confirmed to retain 42 bp in the mature mRNA. The variant c.390-2A>G was confirmed to cause exon 6 skipping. We designed two ASOs and identified one of them that efficiently induced pseudoexon exclusion. CONCLUSION: We reported two novel variants of the ABCB11 gene, c.76+29T>G and c.390-2A>G, in a PFIC2 infant, thereby expanding the genotype of PFIC2. Our findings provide evidence for ASOs as a therapeutic approach for PFIC2 patients carrying intronic variants.