BACKGROUND: Currently, lung cancer is one of the malignant tumors with a high morbidity and mortality all over the world. However, the exact mechanisms underlying lung cancer progression remain unclear. The tumor necrosis factor receptor associated factor (TRAF) family members are cytoplasmic adaptor proteins, which function as both adaptor proteins and ubiquitin ligases to regulate diverse receptor signalings, leading to the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling. The aim of this study was to investigate the expression of TRAFs in different tissues and cancer types, as well as its mRNA expression, protein expression, prognostic significance and functional enrichment analysis in non-small cell lung cancer (NSCLC), in order to provide new strategies for the diagnosis and treatment of NSCLC. METHODS: RNA sequencing data from the The Genotype-Tissue Expression database was used to analyze the expression patterns of TRAF family members in different human tissues. RNA sequencing data from the Cancer Cell Line Encyclopedia database was used to analyze the expression patterns of TRAF family members in different types of cancer cell lines. RNA sequencing data from the The Cancer Genome Atlas (TCGA) database was used to analyze the mRNA levels of TRAF family members across different types of human cancers. Immunohistochemistry (IHC) analyses from HPA database were used to analyze the TRAF protein levels in NSCLC [lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC)]. Overall survival analysis was performed by Log-rank test using original data from Kaplan-Meier Plotter database to evaluate the correlation between TRAF expressions and prognosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on the TRAF family-related genes using RNA sequencing data from the TCGA database for NSCLC. The correlation between the expression levels of TRAF family members and the tumor immune microenvironment was analyzed using the ESTIMATE algorithm based on RNA sequencing data from the TCGA database. RESULTS: The TRAF family members exhibited significant tissue-specific expression heterogeneity. TRAF2, TRAF3, TRAF6 and TRAF7 were widely expressed in most tissues, while the expressions of TRAF1, TRAF4 and TRAF5 were restricted to specific tissues. The expressions of TRAF family members were highly specific among different types of cancer cell lines. In mRNA database of LUAD and LUSC, the expressions of TRAF2, TRAF4, TRAF5 and TRAF7 were significantly upregulated; while TRAF6 did the opposite; moveover, TRAF1 and TRAF3 only displayed a significant upregulation in LUAD and LUSC, respectively. Except for TRAF3, TRAF4 and TRAF7, other TRAF proteins displayed an obviously deeper IHC staining in LUAD and LUSC tissues compared with normal tissues. Additionally, patients with higher expression levels of TRAF2, TRAF4 and TRAF7 had shorter overall survival; while patients with higher expression levels of TRAF3, TRAF5 and TRAF6 had significantly longer overall survival; however, no significant difference had been observed between TRAF1 expression and the overall survival. TRAF family members differentially regulated multiple pathways, including NF-κB, immune response, cell adhesion and RNA splicing. The expression levels of TRAF family members were closely associated with immune cell infiltration and stromal cell content in the tumor immune microenvironment, with varying positive and negative correlations among different members. CONCLUSIONS TRAF family members exhibit highly specific expression differences across different tissues and cancer types. Most TRAF proteins exhibit upregulation at both mRNA and protein levels in NSCLC, whereas, only upregulated expressions of TRAF2, TRAF4 and TRAF7 predict worse prognosis. The TRAF family members regulate processes such as inflammation, immunity, adhesion and splicing, and influence the tumor immune microenvironment.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/mortality* ; Prognosis ; Gene Expression Regulation, Neoplastic ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism*

Uncovering the risk factors of pulmonary hypertension and its mechanisms is crucial for the prevention and treatment of the disease.In the current study,we showed that experimental periodontitis,which was established by ligation of molars followed by orally smearing subgingival plaques from patients with periodontitis,exacerbated hypoxia-induced pulmonary hypertension in mice.Mechanistically,periodontitis dysregulated the pulmonary microbiota by promoting ectopic colonization and enrichment of oral bacteria in the lungs,contributing to pulmonary infiltration of interferon gamma positive(IFNγ+)T cells and aggravating the progression of pulmonary hypertension.In addition,we identified Prevotella zoogleoformans as the critical periodontitis-associated bacterium driving the exacerbation of pulmonary hypertension by periodontitis,and the exacerbation was potently ameliorated by both cervical lymph node excision and IFNγ neutralizing antibodies.Our study suggests a proof of concept that the combined prevention and treatment of periodontitis and pulmonary hypertension are necessary.

Objective:To explore the clinical and genetic characteristics of a fetus diagnosed with Congenital myasthenic syndrome type 16 (CMS16).Methods:A couple who had visited Tianjin Medical University General Hospital in February 2018 due to "adverse outcome of two pregnancies" was selected as the study subject. Clinical data was gathered. Peripheral blood and amniotic fluid samples were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. Low-depth whole-genome sequencing was carried out to detect copy number variation (CNV) in the fetus.Results:The couple′s first pregnancy had resulted in a miscarriage at 27 + 5 weeks, when ultrasound had revealed pleural effusion and polyhydramnios in the fetus. Their second pregnancy was terminated at 30 + 5 weeks due to fetal hand malformations, polyhydramnios and pleural fluid. Both couple had denied family history of genetic conditions. For their third pregnancy, no CNV abnormality was detected, whilst a compound heterozygous variants, including a maternally derived c. 3172C>T (p.R1058W) and paternal c. 1431delG (p.K477fs*89) in the SCN4A gene were detected. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 3172C>T (p.R1058W) was predicted as a likely pathogenic variant (PM1+ PM2_supporting+ PP3+ PP4), whilst the c. 1431delG (p.K477fs*89) was predicted as a pathogenic variant (PVS1+ PM2_supporting+ PP4). Conclusion:The c. 3172C>T (p.R1058W) and c. 1431delG (p.K477fs*89) compound heterozygous variants of the SCN4A gene probably underlay the CMS16 in the third fetus.

Objective:To explore the clinical and molecular basis for a Chinese pedigree affected with Complete androgen insensitivity syndrome (CAIS).Methods:A CAIS pedigree presented at Tianjin Medical University General Hospital between 2019 and 2021 was selected as the study subject. Clinical data of the proband was collected, along with peripheral blood samples from the proband and her family members. Chromosomal karyotyping, sex-determining region of the Y chromosome ( SRY) testing, and next-generation sequencing (NGS) were carried out for the proband, and candidate variant was verified by Sanger sequencing of her family members. Prenatal diagnosis was provided for the sister of the proband. This study was approved by Medical Ethics Committee of the Tianjin Medical University General Hospital (Ethics No. IRB2023-WZ-070). Results:The 18-year-old proband, who has a social gender of female, underwent laparoscopic examination, which showed no presence of uterus and ovaries. The karyotype of peripheral blood sample was 46, XY, with SRY gene detected. NGS indicated that the proband has harbored a heterozygous c. 1988C>G (p.Ser663Ter) variant of the AR gene. Sanger sequencing confirmed that her mother and sister had both harbored the same variant, whilst her father and younger sister were of the wild-type. Prenatal diagnosis revealed that her sister′s first fetus had harbored carried the same variant, which had led to termination of pregnancy. Her second fetus did not carry the variant, and a healthy boy was born. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PM2_Supporting+ PM4+ PP3_Moderate+ PP4). Conclusion:The c. 1988C>G (p.Ser663Ter) variant of the AR gene probably underlay the CAIS in the proband. The accurate diagnosis of sex development disorders will rely on the physicians′ thorough understanding of the clinical symptoms and pathogenic genes. Genetic testing and counseling can enable precise diagnosis, prenatal diagnosis, and guidance for reproduction

AIM:This study aims to examine the ependymin-related protein 1(EPDR1)expression in various tissues from wild-type C57BL/6 mice and type 2 diabetes(db/db)mice.The impact of EPDR1 on lipid accumulation in al-pha mouse liver 12(AML12)hepatocytes was also investigated.METHODS:Western blot was used to detect EPDR1 protein expression in the heart,liver,spleen,lung,kidney,gastrocnemius,brown adipose and brain tissues of C57BL/6 mice.Western blot and immunohistochemical(IHC)staining were also used to compare EPDR1 protein expression in the liver,gastrocnemius muscle,heart and kidney tissues of db/db and C57BL/6 mice.To develop an AML12 cell lipid deposi-tion model,palmitic acid(PA)+oleic acid(OA)was used,and the cells were transfected with adenovirus overexpressing EPDR1 or treated with exogenous recombinant EPDR1 protein(rEPDR1).ELISA was conducted to determine intracellu-lar triglyceride(TG)content,and oil red O staining was employed to assess the effect of EPDR1 on lipid accumulation in AML12 cells.RESULTS:Western blot and IHC staining results revealed that EPDR1 was widely expressed in various tis-sues of wild-type mice,with the liver exhibiting the highest protein expression level.However,EPDR1 expression was down-regulated in the liver,gastrocnemius muscle,heart and kidney tissues in diabetic db/db mice compared with wild-type mice.Oil red O staining revealed that overexpression of EPDR1 in AML12 liver cells or rEPDR1 treatment led to re-duced lipid accumulation.Furthermore,the TG content significantly decreased compared with the model group(P<0.05).CONCLUSION:EPDR1 is expressed in various tissues of wild-type mice,but showed diminished expression in the liver tissues of diabetic mice.Nevertheless,enhancing the expression of EPDR1 can aid in reducing lipid accumula-tion in hepatocytes.These findings provide an experimental foundation for further exploration of the role of EPDR1 in the development of fatty liver in diabetic liver tissue.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:To explore the relationship between CDKN1B expression and clinicopathological features in colorectal cancer.Methods:Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis (GEPIA) database were used to analyze the expression of CDKN1B in colorectal cancer tissues and its relationship with the prognosis of colorectal cancer. The data of 98 patients with colorectal cancer who underwent surgery from January 2020 to December 2021 at Yixing Clinical College of Yangzhou University Medical School were retrospectively analyzed, and pathological specimens were collected. Immunohistochemistry method was used to detect CDKN1B protein expression level in colorectal cancer and paracancerous normal tissues (2 cm from the tumor site) and the correlation of CDNK1B expression with clinicopathological characteristics was analyzed.Results:The results of bioinfomatics analysis and the prediction from HPA database and GEPIA database suggested that the expression level of CDKN1B in colorectal cancer was lower than that in the normal colorectal tissues; In HPA database, the 5-year overall survival rate of patients in the CDKN1B high expression (425 cases) was higher than that of those in the CDKN1B low expression (172 cases) (65% vs.51%), and the difference in the overall survival of both group was statistically significant ( P < 0.001). GEPIA database staging module analysis showed that CDKN1B gene expression level was correlated with the pathological stage of patients with colorectal cancer ( P = 0.033). Immunohistochemistry analysis showed that CDKN1B expression was localized in the nucleus and cytoplasm. The proportion of patients with CDKN1B high expression in colorectal cancer tissues was lower than that in paracancerous normal tissues [18.37% (18/98) vs. 90.82% (89/98), P < 0.01]. The proportion of CDKN1B high expression in cancer tissues of colorectal cancer patients with poor differentiation [poor differentiation vs. high-middle differentiation: 3.70% (1/27) vs. 23.94% (17/71)], lymph node metastasis [metastasis vs. non-metastasis: 6.38% (3/53) vs. 29.41% (15/45)], TNM higher stage [stage Ⅳ vs. Ⅲ vs. Ⅱ vs. Ⅰ: 5.00% (1/20) vs. 13.95% (3/33) vs. 20.59% (8/30) vs. 36.36% (6/15)] was lower (all P < 0.05), while there were no statistically significant differences in the proportion of patients with CDKMB high expression in colorectal cancer tissues among different subgroups stratified by gender, age and tumor size (all P > 0.05). Conclusions:CDKN1B is mainly expressed in the nucleus and cytoplasm, and is lowly expressed in colorectal cancer. The lower CDKN1B expression may indicate the poorer prognosis of patients. CDKN1B can be used as a marker for clinical diagnosis, treatment and prognosis evaluation of colorectal cancer.

Objective:The epidemiological and clinical characteristics of 18 cases of Japanese spotted fever (JSF) in Zigui County were analyzed in order to improve the prevention and treatment of JSF.Methods:This is a case series analysis. The epidemiological and clinical data, laboratory tests and imaging characteristics of 18 JSF cases with median age of 60 years (54, 68) identified by The People′s Hospital of Zigui from April 2021 to August 2022 were collected and analyzed retrospectively.Results:Most (17/18) of the patients were farmers and all had a field exposure history. The patient′s onset was from April to October. Spring and autumn were the seasons with the highest incidence of JSF. The first symptoms of patients were high fever, headache, and fatigue. Of the 18 cases, 15 had a rash and 12 presented an eschar and 3 had neither rash nor eschar. In addition, 10 of 18 cases experienced edema of both lower extremities, and 3 got disturbance of consciousness. Laboratory tests found that 15 patients had abnormal white blood cells and 11 patients had decreased platelets. C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase, and alpha-hydroxybutyrate dehydrogenase were elevated in all patients; 13 patients with elevated alanine aminotransferase, 14 patients with elevated aspartate transamination. Kidney damage caused by Rickettsia japonica infection showed by abnormal proteinuria in 11 of the patients. Conclusions:The most common clinical manifestations of JSF are non-specific indications such as high fever, chills, fatigue, headache. The eschar and rash, which are the main features of Rickettsia infection, are not present in all patients, resulting delay of diagnosis or misdiagnosis. Medical workers should be more alert to rickettsial infections in patients with fever of unknown origin, especially in seasons of high incidence of spotted fever. Early diagnosis and correct antibiotic treatment shall be given according to the patient′s clinical manifestations, laboratory results and imaging test to control disease progression.

The rapid spread of carbapenemase-producing Klebsiella pneumoniae(cpKP)poses seri-ous threats to public health;however,the underlying genetic basis for its dissemination is still unknown.We conducted a comprehensive genomic epidemiology analysis on 420 cpKP isolates col-lected from 70 hospitals in 24 provinces/autonomous regions/municipalities of China during 2009-2017 by short-/long-read sequencing.The results showed that most cpKP isolates were categorized into clonal group 258(CG258),in which ST11 was the dominant clone.Phylogenetic analysis revealed three major clades including the top one of Clade 3 for CG258 cpKP isolates.Additionally,carbapenemase gene analysis indicated that blaKPC was dominant in the cpKP isolates,and most blaKPC genes were located in five major incompatibility(Inc)groups of blaKPC-harboring plasmids.Importantly,three advantageous combinations of host-blaKPC-carrying plasmid(Clade 3.1+3.2-IncFⅡpHN7A8,Clade 3.1+3.2-IncFⅡpHN7A8:IncR,and Clade 3.3-IncFⅡpHN7A8:InCpA1763-KPC)were identified to confer cpKP isolates the advantages in both genotypes(strong correlation/coevolution)and phenotypes(resistance/growth/competition)to facilitate the nationwide spread of ST11/CG258 cpKP.Intriguingly,Bayesian skyline analysis illustrated that the three advanta-geous combinations might be directly associated with the strong population expansion during 2007-2008 and subsequent maintenance of the population of ST11/CG258 cpKP after 2008.We then examined drug resistance profiles of these cpKP isolates and proposed combination treatment regimens for CG258/non-CG258 cpKP infections.Thus,the findings of our systematical analysis shed light on the molecular epidemiology and genetic basis for the dissemination of ST11/CG258 cpKP in China,and much emphasis should be given to the close monitoring of advantageous cpKP-plasmid combinations.

OBJECTIVE: To explore the molecular basis for a rare case with Para-Bombay AB blood type. METHODS: Serological method was used to determine the blood type of the proband. Exons 6 and 7 of the ABO gene and the coding regions of FUT1 and FUT2 genes were analyzed by direct sequencing. RESULTS: Serological results showed that the proband was a Para-Bombay AB subtype. His genotype was determined as ABO*A1.02/B.01. The proband was also found to harbor c.551-552delAG and c.881-882delTT of the FUT1 gene. For his four children, there were three type B and one type A, though the expression of the H type was normal. CONCLUSION The double deletions in the coding region of the FUT1 gene probably underlay the Para-Bombay blood type in the proband. Carrier of single-strand deletions may have a normal ABO phenotype.
ABO Blood-Group System/genetics* ; Alleles ; Fucosyltransferases/genetics* ; Genotype ; Humans ; Male ; Phenotype ; Sequence Analysis