Identification of N7-methylguanosine-related lncRNAs for the risk stratification of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The N7-methylguanosine (m7G) modification is related to the biological processes and regulation of various diseases. This study investigated the role and predictive value of m7G-related long non-coding RNAs (lncRNAs) in HCC. Methods: HCC patients were clustered by consensus clustering, and a prognostic signature was developed using Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. The immune landscape and clinicopathological features of the distinct clusters and subgroups were investigated. Results: A total of 32 m7G-related lncRNAs were confirmed to be prognostic lncRNAs. Two molecular clusters showed significant differences in terms of their clinicopathological features, prognoses, and immune checkpoint gene (ICG) expression levels. Cluster II was associated with upregulated ICG expression and poor overall survival (OS). The Cancer Genome Atlas training cohort was then used to create an m7G-related lncRNA signature for predicting OS. The signature exhibited excellent predictive performance in the training, test, and all cohorts. The high-risk patients had worse clinical outcomes than the low-risk patients. Further study revealed that this signature was an independent prognostic indicator, and a predictive nomogram was developed based on the clinicopathological features and risk score. In addition, we discovered that this model was correlated with ICG expression and tumor immune cell infiltration. Conclusions: Our findings demonstrated that m7G-related lncRNAs are associated with the tumor immune landscape and prognosis and can serve as independent prognostic markers for HCC. These findings provide new insights into the functions of m7G-related lncRNAs in HCC.

Side effect profile of pharmacologic therapies for liver fibrosis in nonalcoholic fatty liver disease: a systematic review and network meta-analysis.

Several studies have found that antifibrosis treatment for nonalcoholic fatty liver disease (NAFLD) can cause a variety of side effects. No network meta-analysis (NMA) analyzes the adverse events of antifibrotic drugs for NAFLD. This NMA aimed to systematically compare the drug-related side effects when using different pharmacological agents for the treatment of liver fibrosis in NAFLD. PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched to select related studies published in English from the database inception until 30 June 2022. We conducted Bayesian fixed-effects NMA using data from randomized controlled trials (RCTs) to derive relative risks (RRs). The surface under the cumulative ranking (SUCRA) probabilities was used to assess ranking. A total of 26 RCTs with 19 interventions met the inclusion criteria. SUCRA analysis suggested that the lanifibranor group had the highest risk of diarrhea (SUCRA, 94), whereas the liraglutide group had the highest risk of constipation (SUCRA, 92.9). The semaglutide group showed the highest incidence of nausea (SUCRA, 81.2) and abdominal pain (SUCRA, 90.5), respectively. The cenicriviroc group showed the highest risk in the incidence of fatigue (SUCRA, 82.4). The MSDC-0602K group had the highest risk of headache (SUCRA, 76.4), whereas the obeticholic acid group had the highest risk of pruritus (SUCRA, 80.1). The risk of side effects significantly varied among different pharmacologic regimens, and evidence showed that lanifibranor, liraglutide, semaglutide, cenicriviroc, MSDC-0602K and obeticholic acid were the pharmacological interventions with the highest risk in patients with NAFLD. This study may guide clinicians and support further research.

Machine learning for lymph node metastasis prediction of in patients with gastric cancer: A systematic review and meta-analysis.

Objective: To evaluate the diagnostic performance of machine learning (ML) in predicting lymph node metastasis (LNM) in patients with gastric cancer (GC) and to identify predictors applicable to the models. Methods: PubMed, EMBASE, Web of Science, and Cochrane Library were searched from inception to March 16, 2022. The pooled c-index and accuracy were used to assess the diagnostic accuracy. Subgroup analysis was performed based on ML types. Meta-analyses were performed using random-effect models. Risk of bias assessment was conducted using PROBAST tool. Results: A total of 41 studies (56182 patients) were included, and 33 of the studies divided the participants into a training set and a test set, while the rest of the studies only had a training set. The c-index of ML for LNM prediction in training set and test set was 0.837 [95%CI (0.814, 0.859)] and 0.811 [95%CI (0.785-0.838)], respectively. The pooled accuracy was 0.781 [(95%CI (0.756-0.805)] in training set and 0.753 [95%CI (0.721-0.783)] in test set. Subgroup analysis for different ML algorithms and staging of GC showed no significant difference. In contrast, in the subgroup analysis for predictors, in the training set, the model that included radiomics had better accuracy than the model with only clinical predictors (F = 3.546, p = 0.037). Additionally, cancer size, depth of cancer invasion and histological differentiation were the three most commonly used features in models built for prediction. Conclusion: ML has shown to be of excellent diagnostic performance in predicting the LNM of GC. One of the models covering radiomics and its ML algorithms showed good accuracy for the risk of LNM in GC. However, the results revealed some methodological limitations in the development process. Future studies should focus on refining and improving existing models to improve the accuracy of LNM prediction. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022320752.

[Analysis of GALNS gene mutation in thirty-eight Chinese patients with mucopolysaccharidosis type IVA].

OBJECTIVE: Mucopolysaccharidosis (MPS) type IVA (MPS IVA) is an autosomal recessive lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) needed to degrade glycosaminoglycanes (GAGs), accumulation of GAGs in the tissue resulting in disorder of function. So far, the small number of articles about clinical study of Chinese MPS IVA were published and only one paper about gene mutation analysis was published. This study aimed to investigate the mutation spectrum and characteristic of GALNS gene in Chinese patients with MPS IVA who were diagnosed in our hospital. METHOD: Thirty-eight patients from 36 families (male 17, female 21) were diagnosed as MPS IVA by GALNS activity determination [(0.85 ± 1.33) nmol/(17 h·mg)] and clinical symptoms during 2006-2012. The average age of diagnosis was (5.7 ± 3.6) years. Mutation analysis of GALNS gene performed performed by PCR-direct DNA sequencing for 38 patients. PCR-restriction fragment length polymorphism analysis was used for validating novel mutation, and also to assess amino acid conservation for novel missense variants in five different species. PolyPhen-2 tool was used to predict the possible impact of missense mutations on the structure and function of the human GALNS protein, etc. Analysis of GALNS activity and gene mutation in amniotic fluid were performed to provide the prenatal diagnosis for some families with MPS type IVA. RESULT: (1) Thirty-eight kinds of mutation in GALNS gene were identified in 38 patients of them, 71% were missense mutations. p. M318R was a hot-spot mutation (21%) tested. Five kinds of mutation i.e., p. P163H, p.G168L, p. A324E, p. L366P and p. F452L were only found in Chinese patients with MPS IVA. Eighteen kinds of novel mutation were detected including p. E315K, p.G304D, p.R251Q, p.Y240C, p.G161E, p.N32D, p.L390P, p. D60E, p. P420S, W403C/T404S, p.L454P, for p.W405X, p. M1I, c.409_ c.420del12, c.1176_1178del3, c.1046delG, c.1188delG and IVS9-2A>C. (2) The polymorphism of novel missense variants were ruled out by the PCR-restriction fragment length polymorphism analysis and no related mutations were found in 50 normal controls. A splice site mutation IVS9-2A>C had been validated by reverse transcription PCR direct sequencing. The amino acid of mutant position of 10 kinds of missense variants are highly conserved and only p. L454 is moderately conserved position. These missense variants were predicted to cause damage to the structure and function of human GALNS protein possibly according to the PolyPhen-2 tool, so these novel missense variants may be disease-causing mutations. (3) Prenatal diagnosis was provided for 7 families and three fetuses were diagnosed as MPS IVA. CONCLUSION: The GALNS gene mutation spectrum in Chinese patients with MPS IVA is really different from that in other countries, five kinds of mutation were only found in Chinese patients with MPS IVA. The reports of hot-spot mutation in Chinese patients were also different, and should be analyzed by more data of gene mutation analysis and epidemiological study.

Beta-galactosidase deficiencies and novel GLB1 mutations in three Chinese patients with Morquio B disease or GM1 gangliosidosis.

BACKGROUND: This paper aims to report GLB1 activities and mutation analysis of three patients from the mainland of China, one with Morquio B disease and two with GM1 gangliosidosis. METHODS: GLB1 activity and GLB1 gene mutation were analyzed in the three patients who were clinically suspected of having Morquio B disease or GM1 gangliosidosis. Novel mutations were analyzed by aligning GLB1 homologs, 100 control chromosomes, and the PolyPhen-2 tool. RESULTS: The enzymatic activity of GLB1 was found to be 5.03, 4.20, and 4.50 nmol/h/mg in the three patients, respectively. Patient 1 was a compound heterozygote for p.[Arg148Cys] and p.[Tyr485Cys] mutations in the GLB1 gene. Patient 2 was a compound heterozygote for p.[Tyr270Phe] and p.[Leu337Pro] mutations. Patient 3 was a homozygote for p.[Asp448Val] mutation. Three mutations (p.[Tyr485Cys], p.[Tyr270Phe] and p.[Leu337Pro]) were novel variants and were predicted to damage GLB1 function. CONCLUSIONS: The enzymatic activity and related gene analysis of ß-galactosidase should be performed in clinically suspected individuals to confirm diagnosis. The three novel mutations, p.[Tyr485Cys], p.[Tyr270Phe], and p.[Leu337Pro], are thought to be disease-causing mutations.

[GLB1 gene mutation and clinical characteristics of a patient with mucopolysaccharidosis type IVB].

OBJECTIVE: To report the results of clinical characteristics, enzyme activity determination and mutation analysis of GLB1 gene in a Chinese patient with mucopolysaccharidosis (MPS) type IVB (Morquio B disease). METHOD: A 14-year-old Chinese boy with MPS type IVB was firstly diagnosed by blood leucocytes galactosamine-6-sulfate sulfatase (GALNS) and ß-galactosidase (GLB1) determination, who was characterized by short stature, multiplex skeletal abnormalities, difficulty in walking. PCR-sequencing analysis was applied to detect the mutations in GLB1 of the patient. RESULT: The patient was characterized by dwarfism, pectus carinatum, kyphosis, normal intelligence, and no neurologic damage of spasms, linguistic capacity and so on. The patient had normal GALNS enzyme activity and very low GLB1 enzyme activity [5.03 nmol/(h·mg) vs. normal value 118 - 413 nmol/(h·mg) ] in leukocytes. A compound heterozygous missense mutations c.442C > T(p.R148C)/c.1454A > G(p.Y485C) in GLB1 gene were detected in this patient. The mutation p.Y485C is a novel variant. With the method of gene analysis of new variant, the mutation p.Y485C was considered to be a pathogenic mutation. CONCLUSION: The MPS IVB patient showed severe multiple skeletal deformities, normal intelligence, no neurologic damage and very low GLB1 enzyme activity, who carries compound heterozygous mutations p.R148C/p.Y485C. The mutation p.Y485C in GLB1 gene may be a novel pathologic mutation of MPS type IVB.