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Scientific Reports Jul 2024METTL3 and METTL14 are traditionally posited to assemble the m6A methyltransferase complex in a stoichiometric 1:1 ratio, modulating mRNA fate via m6A modifications....
METTL3 and METTL14 are traditionally posited to assemble the m6A methyltransferase complex in a stoichiometric 1:1 ratio, modulating mRNA fate via m6A modifications. Nevertheless, recent investigations reveal inconsistent expression levels and prognostic significance of METTL3 and METTL14 across various tumor types, challenging their consistent functional engagement in neoplastic contexts. A pan-cancer analysis leveraging The Cancer Genome Atlas (TCGA) data has identified pronounced disparities in the expression patterns, functional roles, and correlations with tumor burden between METTL3 and METTL14, particularly in esophageal squamous cell carcinoma (ESCC). Knockdown experiments of METTL3 in EC109 cells markedly suppress cell proliferation both in vitro and in vivo, whereas METTL14 knockdown shows a comparatively muted effect on proliferation and does not significantly alter METTL3 protein levels. mRNA sequencing indicates that METTL3 singularly governs the expression of 1615 genes, with only 776 genes co-regulated with METTL14. Additionally, immunofluorescence co-localization studies suggest discrepancies in cellular localization between METTL3 and METTL14. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses demonstrate that METTL3 uniquely associates with the Nop56p-linked pre-rRNA complex and mRNA splicing machinery, independent of METTL14. Preliminary bioinformatics and multi-omics investigations reveal that METTL3's autonomous role in modulating tumor cell proliferation and its involvement in mRNA splicing are potentially pivotal molecular mechanisms. Our study lays both experimental and theoretical groundwork for a deeper understanding of the m6A methyltransferase complex and the development of targeted tumor therapies focusing on METTL3.
Topics: Methyltransferases; Humans; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Disease Progression; Animals; Adenosine; Mice; RNA, Messenger
PubMed: 38965238
DOI: 10.1038/s41598-024-64517-3 -
Nature Communications Jul 2024Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators....
Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.
Topics: Liver Neoplasms; Carcinoma, Hepatocellular; Hepatocyte Nuclear Factor 4; Humans; Gene Expression Regulation, Neoplastic; Epigenesis, Genetic; Cell Proliferation; Histone Demethylases; DNA Transposable Elements; Animals; Cell Line, Tumor; Mice; Histones; Gene Silencing; Male; Mice, Nude
PubMed: 38965210
DOI: 10.1038/s41467-024-49926-2 -
Techniques in Coloproctology Jul 2024Perineal hernia (PH) is a late complication of abdominoperineal resection (APR) that may compromise a patient's quality of life. The frequency and risk factors for PH...
BACKGROUND
Perineal hernia (PH) is a late complication of abdominoperineal resection (APR) that may compromise a patient's quality of life. The frequency and risk factors for PH after robotic APR adopting recent rectal cancer treatment strategies remain unclear.
METHODS
Patients who underwent robotic APR for rectal cancer between December 2011 and June 2022 were retrospectively examined. From July 2020, pelvic reinforcement procedures, such as robotic closure of the pelvic peritoneum and levator ani muscles, were performed as prophylactic procedures for PH whenever feasible. PH was diagnosed in patients with or without symptoms using computed tomography 1 year after surgery. We examined the frequency of PH, compared characteristics between patients with PH (PH+) and without PH (PH-), and identified risk factors for PH.
RESULTS
We evaluated 142 patients, including 53 PH+ (37.3%) and 89 PH- (62.6%). PH+ had a significantly higher rate of preoperative chemoradiotherapy (26.4% versus 10.1%, p = 0.017) and a significantly lower rate of undergoing pelvic reinforcement procedures (1.9% versus 14.0%, p = 0.017). PH+ had a lower rate of lateral lymph node dissection (47.2% versus 61.8%, p = 0.115) and a shorter operative time (340 min versus 394 min, p = 0.110). According to multivariate analysis, the independent risk factors for PH were preoperative chemoradiotherapy, not undergoing lateral lymph node dissection, and not undergoing a pelvic reinforcement procedure.
CONCLUSIONS
PH after robotic APR for rectal cancer is not a rare complication under the recent treatment strategies for rectal cancer, and performing prophylactic procedures for PH should be considered.
Topics: Humans; Retrospective Studies; Robotic Surgical Procedures; Male; Female; Risk Factors; Middle Aged; Perineum; Aged; Proctectomy; Rectal Neoplasms; Incidence; Postoperative Complications; Hernia; Incisional Hernia
PubMed: 38965146
DOI: 10.1007/s10151-024-02961-z -
Aging Clinical and Experimental Research Jul 2024This study aimed to compare the postoperative outcomes of < 75-year-old patients and ≥ 75-year-old patients who underwent pancreaticoduodenectomy (PD) for... (Comparative Study)
Comparative Study
OBJECTIVE
This study aimed to compare the postoperative outcomes of < 75-year-old patients and ≥ 75-year-old patients who underwent pancreaticoduodenectomy (PD) for pancreatic head and periampullary region tumors.
METHODS
Patients who underwent PD in our hospital between February 2019 and December 2023 were evaluated. Demographics, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores, American Society of Anesthesiologists (ASA) scores, comorbidities, hospital stays, complications, and clinicopathological features were analyzed. Patients were divided into < 75 years (Group A) and ≥ 75 years (Group B) groups and compared.
RESULTS
The median age of the entire cohort (n = 155) was 66 years (IQR = 16). There was a significant difference between Group A (n = 128) and Group B (n = 27) regarding the ECOG-PS and ASA scores. There was no significant difference between the groups regarding postoperative complications. The 30-day mortality rate was greater in Group B (p = 0.017). Group B had a cumulative median survival of 10 months, whereas Group A had a median survival of 28 months, with a statistically significant difference (p < 0.001). When age groups were stratified according to ECOG-PS, for ECOG-PS 2-3 Group A, survival was 15 months; for ECOG-PS 2-3 Group B, survival was eight months, and the difference was not statistically significant (p = 0.628).
CONCLUSIONS
With the increasing aging population, patient selection for PD should not be based solely on age. This study demonstrated that PD is safe for patients older than 75 years. In older patients, performance status and the optimization of comorbidities should be considered when deciding on a candidate's suitability for surgery.
Topics: Humans; Pancreaticoduodenectomy; Aged; Male; Female; Pancreatic Neoplasms; Middle Aged; Postoperative Complications; Aged, 80 and over; Age Factors; Treatment Outcome; Retrospective Studies
PubMed: 38965089
DOI: 10.1007/s40520-024-02804-9 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024Liver biopsy is an important means of clinical diagnosis and treatment of liver diseases, but it is not easily accepted by patients because of its invasiveness. The most... (Review)
Review
Liver biopsy is an important means of clinical diagnosis and treatment of liver diseases, but it is not easily accepted by patients because of its invasiveness. The most commonly employed liver biopsy approaches are percutaneous or transjugular. Endoscopic ultrasound-guided liver biopsy (EUS-LB), a newly emerging transjugular technique, has been widely studied and applied in recent years, but its application in China is less common. The EUS-LB has the advantages of high safety and comfort, simultaneous sampling of both liver lobes, and adequate sampling volume; however, it also has the disadvantages of high requirements for hardware, operators, and cost. This article reviews the clinical application of EUS-LB in accordance with pertinent research findings from recent years and discusses its advantages, disadvantages, and implementation feasibility.
Topics: Humans; Liver; Endosonography; Liver Diseases
PubMed: 38964902
DOI: 10.3760/cma.j.cn501113-20240319-00143 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024Hepatocellular carcinoma (HCC) is a common type of poorly prognosticated malignant tumor. Surgical resection is the preferred treatment method for early-stage HCC.... (Review)
Review
Hepatocellular carcinoma (HCC) is a common type of poorly prognosticated malignant tumor. Surgical resection is the preferred treatment method for early-stage HCC. However, at the time of the initial diagnosis, fewer than 30% of patients with liver cancer are suitable for radical therapy. Systemic therapy plays an important role in the treatment process of patients with intermediate- to advanced-stage HCC, as it can effectively extend patients' survival time. With an emphasis on the status and role of systemic therapy for comprehensive management of HCC, this article summarizes the latest progress at home and abroad in the past five years, including first-line combined immunotherapy for advanced-stage HCC, second-line therapy selection, perioperative systemic therapy application, and combined therapy of systemic and local. Currently, the treatment model combined with local therapy has already become a new research hotspot in the treatment of advanced-stage HCC. Nevertheless, in the future, individualized and precise systemic therapeutic strategies will need further exploration.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Immunotherapy; Combined Modality Therapy
PubMed: 38964901
DOI: 10.3760/cma.j.cn501113-20240412-00200 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024To explore the genotype-phenotype relationship of Wilson's disease (WD) and further study the mutation spectrum in the ATP7B gene. The clinical data and genetic test...
To explore the genotype-phenotype relationship of Wilson's disease (WD) and further study the mutation spectrum in the ATP7B gene. The clinical data and genetic test results of 115 cases with WD diagnosed in the First Affiliated Hospital of Zhengzhou University from 2015 to 2022 were retrospectively analyzed. The rank sum test was used for quantitative data comparison, and (2) test was used for count data comparison. Multivariate logistic regression was used to analyze the relationship between patients' genotype and phenotype. The onset of liver manifestations (hepatic type) accounted for 60.9%, neurological symptoms (cerebral type) for 13.0%, and mixed hepato-cerebral symptoms for 26.1%. Presymptomatic individuals (hepatic types) accounted for 62.9%. Next-generation sequencing- diagnosed WD cases accounted for 87.8%. Combined multiplex ligation-dependent probe amplification assay-diagnosed WD cases accounted for 89.6%. A single case with a detected pathogenic locus accounted for 10.4%. The diagnostic rate of WD by genetic testing combined with clinical data was 100%. A total of 76 ATP7B mutations were detected, and the top three mutation frequencies were c.2333G>T (p.Arg778Leu) (30.7%), c.2975C>T (p.Pro992Leu) (7.3%), and c.2621C>T (p.Ala874Val) (6.4%). The mutations were mainly distributed in exons 8, 11-13, and 15-18, accounting for more than 90% of the total mutations. Eight new mutations were found, including c.3724G>A (p.Glu1242Lys), c.3703G>C (p.Gly1235Arg), c.3593T>C (p.Val1198Ala), c.2494A>C (p.Lys832Gln), c.1517T>A (p.Ile506Lys), c.484G>T (p.Glu162Ter), c.1870-49A>G, and the missing of exons 10-21. Liver histopathology showed cellular edema, degeneration, inflammation, and necrosis, as well as a 42.8% copper staining positive rate. Genotype-phenotype analysis showed that the p.Arg778Leu mutation had higher alanine aminotransferase (ALT) levels than those carrying other mutations (=0.024), while the homozygous mutation of p.Arg778Leu was associated with cerebral-type patients (=0.027). Genetic testing plays an important role in the diagnosis of WD. p.Arg778Leu is the first high-frequency mutation in the Chinese population, and patients carrying it have higher ALT levels. The p.Arg778Leu homozygous mutation is prone to causing cerebral-type WD. This study expands the ATP7B gene mutation spectrum.
Topics: Humans; Hepatolenticular Degeneration; Copper-Transporting ATPases; Mutation; Genotype; Phenotype; Retrospective Studies; Female; Male; Cation Transport Proteins; Genetic Association Studies; Adult; Adenosine Triphosphatases; Young Adult; Adolescent; Child; Genetic Testing; Middle Aged; High-Throughput Nucleotide Sequencing
PubMed: 38964899
DOI: 10.3760/cma.j.cn501113-20240416-00208 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD)....
To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD). Inpatients with HLD confirmed at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine from January 1989 to December 2022 were selected as the research subjects. Clinical classification was performed according to the affected organs. Patients with liver disease phenotypes were classified into the liver disease group and further divided into the severe liver disease group and the ordinary liver disease group. The clinical characteristics and genetic variations were compared in each group of patients. The predictive indicators of patients with severe liver disease were analyzed by multiple regression. Statistical analysis was performed using the -test, Mann-Whitney test, or (2) test according to different data. Of the 159 HLD cases, 142 were in the liver disease group (34 in the severe liver disease group and 108 in the ordinary liver disease group), and 17 were in the encephalopathy group. The median age of onset was statistically significantly different between the liver disease group and the encephalopathy group [12.6 (7.0, 13.3) years versus 16.9 (11.0, 21.5) years, <0.01]. 156 gene mutation sites were found in 83 cases with genetic testing results, of which 54 cases carried the p.Arg778Leu gene mutation (allele frequency 46.2%). Compared with patients with other types of gene mutations (=65), patients with homozygous p.Arg778Leu mutations (=18) had lower blood ceruloplasmin and albumin levels, a higher prognostic index, Child-Pugh score, an international normalized ratio, and prothrombin time (<0.05). Hemolytic anemia, corneal K-F ring, homozygous p.Arg778Leu mutation, and multiple laboratory indexes in the severe liver disease group were statistically significantly different from those in the ordinary liver disease group (<0.05). Multivariate logistic regression analysis showed that the predictive factors for severe liver disease were homozygous p.Arg778Leu mutation, total bilirubin, and bile acids (=16.512, 1.022, 1.021, 95% : 1.204-226.425, 1.005-1.039, and 1.006-1.037, respectively, <0.05). The drawn ROC curve demonstrated a cutoff value of 0.215 3, an AUC of 0.953 2, and sensitivity and specificity of 90.91% and 92.42%, respectively. Liver disease phenotypes are common in HLD patients and have an early onset. Total bilirubin, bile acids, and the homozygous p.Arg778Leu mutation of is related to the severity of liver disease in HLD patients, which aids in predicting the occurrence and risk of severe liver disease.
Topics: Humans; Hepatolenticular Degeneration; Phenotype; Male; Female; Adolescent; Young Adult; Child; Mutation; Adult; Liver Diseases; Middle Aged
PubMed: 38964898
DOI: 10.3760/cma.j.cn501113-20230926-00122 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size. The clinical, pathological,...
To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size. The clinical, pathological, and MRI imaging data of 40 cases with HEHE confirmed pathologically from December 2009 to September 2021 were retrospectively analyzed. A paired sample -test was used for comparison between the two groups. There were 40 cases (5 solitary, 24 multifocal, 9 local fusion, and 2 diffuse fusion) and 214 lesions (163 nodules, 31 masses, and 20 fusion foci). The most common features of lesions were subcapsular growth and capsular depression. The signal intensity of lesions ≤1cm was usually uniform with whole or ring enhancement. Nodules and mass-like lesions ≥1cm on a T1-weighted image had slightly reduced signal intensity or manifested as a halo sign. Target signs on a T2-weighted image were characterized by: target or centripetal enhancement; fusion-type lesions; irregular growth and hepatic capsular retraction, with ring or target-like enhancement in the early stage of fusion and patchy irregular enhancement in the late stage; blood vessels traversing or accompanied by malformed blood vessels; focal bleeding; an increasing proportion of extrahepatic metastases and abnormal liver function with the type of classified manifestation; primarily portal vein branches traversing; and reduced overall intralesional bleeding rate (17%). Lollipop signs were presented in 19 cases, with a high expression rate in mass-type lesions (42%). The fusion lesions were expressed, but the morphological manifestation was atypical. The diffusion-weighted imaging mostly showed high signal or target-like high signal. An average apparent diffusion coefficient of lesions was (1.56±0.36) ×10(-3)mm(2)/s, which was statistically significantly different compared with that of adjacent normal liver parenchyma (=8.28, <0.001). The MRI manifestations for the HEHE classification are closely related to the morphology and size of the lesions and have certain differences and characteristics that are helpful for the diagnosis of the disease when combined with clinical and laboratory examinations.
Topics: Humans; Liver Neoplasms; Hemangioendothelioma, Epithelioid; Retrospective Studies; Magnetic Resonance Imaging; Liver; Female; Male; Middle Aged; Adult
PubMed: 38964897
DOI: 10.3760/cma.j.cn501113-20230910-00100 -
Zhonghua Gan Zang Bing Za Zhi =... Jun 2024To systematically evaluate the effect of hepatitis B virus (HBV) infection on the risk of adverse pregnancy outcomes. We searched PubMed, Embase, Web of Science, and... (Meta-Analysis)
Meta-Analysis
To systematically evaluate the effect of hepatitis B virus (HBV) infection on the risk of adverse pregnancy outcomes. We searched PubMed, Embase, Web of Science, and Cochrane databases. Two researchers independently screened the literature, extracted data, and evaluated the quality. Meta-analysis and cumulative meta-analysis were performed using R4.4.1 software. Fixed/random effects models were used to analyze heterogeneous and non-heterogeneous results. Heterogeneous modifiers were identified by subgroup analysis. Funnel plots and Peters' test were used to analyze potential publication bias. A total of 48 studies involving 92 836 HBsAg-positive pregnant women and 7 123 292 HBsAg-negative pregnant women were included. In terms of adverse pregnancy outcomes, HBV infection was significantly correlated with the occurrence of gestational diabetes mellitus [odds ratio ()=1.34, 95% confidence interval (): 1.17-1.53] and intrahepatic cholestasis (=2.48, 95%: 1.88-3.29), with statistically significant differences. In terms of adverse neonatal outcomes, HBV infection was significantly correlated with the occurrence of neonatal asphyxia (=1.49, 95%: 1.20-1.86) and preterm birth (=1.22, 95%: 1.12-1.33), with statistically significant differences. In addition, the cumulative meta-analysis demonstrated that the risk of gestational diabetes mellitus and preterm birth both tended to be stable in pregnant women with HBV infection following 2009 and 2010, respectively. The supplementary questions answered for repeated studies had limited significance. Intrahepatic cholestasis, gestational diabetes mellitus, neonatal asphyxia, and preterm birth occurrence risk can be raised with HBV infection in pregnant women.
Topics: Humans; Pregnancy; Female; Hepatitis B; Pregnancy Outcome; Pregnancy Complications, Infectious; Hepatitis B virus; Diabetes, Gestational; Premature Birth; Infant, Newborn; Cholestasis, Intrahepatic; Risk Factors
PubMed: 38964896
DOI: 10.3760/cma.j.cn501113-20240204-00080