Triggering receptor expressed on myeloid cells 2 （TREM2） is expressed in resident non-parenchymal cells （NPCs） and is involved in various pathological processes including liver inflammation and immunoregulation. In recent years， TREM2 has attracted attention in the field of acute and chronic liver diseases， and more and more studies have shown that TREM2 is a potential target for the treatment of acute and chronic liver diseases； however， there is a lack of systematic summary for the mechanism of action of TREM2 in acute and chronic liver diseases. Therefore， this article reviews the latest research advances in the regulatory role of TREM2 in acute and chronic liver diseases， in order to provide new ideas for the clinical prevention and treatment of acute and chronic liver diseases.

Objective: To investigate the effect of neurite outgrowth inhibitor extracellular peptide residues 1-40 (NEP1-40) combined with poly (lactic-co-glycolic acid) (PLGA) and gelatin electrospun fiber membrane on facial nerve repair in rats. Methods: According to the principle of random grouping, 108 male SD rats were divided into four groups (n = 27 in each group, approved by the ethics committee), namely, the sham group, control group, PLGA group, and NEP1-40 + PLGA group. A facial nerve fracture model was established for all of the groups except for the sham group. The control group received no further treatment, the PLGA group and the NEP1-40+PLGA group were supported by PLGA membrane, and the NEP1-40+PLGA group received one immediate local injection of NEP1-40 (5 μg/μL) at a dose of 10 μL. Facial nerve function analysis, electrophysiological examination, transmission electron microscope observation, HE staining, and immunohistochemical staining of myelin marker S100β and axonal marker β3-tubulin were used to evaluate the recovery of injured facial nerves of rats at 2, 4 and 8 weeks. Results : At 8 weeks, the facial nerve function score of the NEP1-40+PLGA group was better than that of the control group and PLGA group (P < 0.001), and facial nerve function was significantly restored. Electrophysiological examination of nerve action potentials at the injured facial nerve showed that the amplitude in the NEP1-40+PLGA group was higher than that of the control group and PLGA group (P < 0.001), but there was no significant difference in latency and conduction velocity results between the groups (P > 0.05). At 2, 4, and 8 weeks, transmission electron microscopy showed that the number of myelinated nerve fibers and myelin sheath thickness in the cross-section of the injured facial nerve in the NEP1-40+PLGA group were greater than those in the other groups (P < 0.05). At 8 weeks, HE staining showed that the facial nerves in the control group had partially recovered, but the overall cell distribution was uneven and the boundary with surrounding tissues was slightly blurred. In contrast, the NEP1-40+PLGA group had a relatively uniform cell distribution and a clearer boundary with surrounding tissues. At 2, 4, and 8 weeks, the immunohistochemical results showed that in the cross-section of the injuried facial nerve, NEP1-40 increased the expression of neural markers S100 β and β3-tubulin, especially β3-tubulin, which was close to normal levels (P > 0.05) Conclusion NEP1-40 is beneficial for the generation of new myelin sheaths and axons at the site of injury, and it can promote the repair and regeneration of injured facial nerves to a certain extent, thus accelerating the recovery of injured nerve function.

OBJECTIVE: To analyze a Chinese pedigree with Hereditary coagulation factor Ⅻ (FⅫ) deficiency duo to variants of F12 gene and explore its molecular pathogenesis. METHODS: A patient who underwent laparoscopic cystectomy at the Department of Gynecology of the First Affiliated Hospital of Wenzhou Medical University in June 2012 was selected as the study subject. Coagulation factor indexes of the proband and her family members (5 individuals from three generations) were determined. All exons, flanking sequences, 5' and 3' untranslated regions of the F12 gene of the proband and her family members were analyzed by direct sequencing. Three bioinformatics software was used to analyze the conservation, pathogenicity and protein model of the variant. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No. 2012-17). RESULTS: The activated partial thromboplastin time (APTT), FⅫ activity (FⅫ:C) and FⅫ antigen (FⅫ:Ag) of the proband was 180.0 s, 1.0% and 2.1%, respectively. DNA sequencing revealed that she has harbored compound heterozygous variants of the F12 gene, namely c.712_713insT (p.Cys238Leufs *73) in exon 8 and c.1561G>A (p.Glu521Lys) in exon 13. Her mother and younger son were heterozygous for the p.Cys238Leufs*73 variant, while her older son was heterozygous for the p.Glu521Lys variant. Bioinformatic analysis suggested that Cys238 is highly conserved and p.Cys238Leufs*73 is a pathogenic variant, which eventually resulted in a truncated protein. CONCLUSION The c.712_713insT and c.1561G>A compound heterozygous variants of the F12 gene probably underlay the decreased FⅫ level in this pedigree, among which c.712_713insT (NM_000505) was unreported previously.
Adult ; Female ; Humans ; Male ; Middle Aged ; Base Sequence ; China ; Factor XII/genetics* ; Heterozygote ; Mutation ; Pedigree ; Factor XII Deficiency/genetics* ; East Asian People

OBJECTIVE: To investigate the molecular pathogenic mechanisms of a family with hereditary factor Ⅶ (FⅦ) deficiency. METHODS: A family (3 generations, 12 members) with hereditary FⅦ deficiency, in which the proband presented with menorrhagia and was admitted to the First Affiliated Hospital of Wenzhou Medical University in April 2023, was selected as the study subject. Clinical data of the family members were collected. Peripheral venous blood samples were collected from all 12 members for routine coagulation tests and genomic DNA extraction. All exons and flanking sequences of the F7 gene were amplified by PCR and analyzed by Sanger sequencing. Thrombin generation assay was performed to evaluate the coagulation potential of the proband and her parents. Multiple online bioinformatics software tools were used to analyze the conservation and pathogenicity of candidate variants identified in the proband. The pathogenicity of variant was classified according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as ACMG guidelines). Homology modeling of the variant FⅦ protein was performed using homology modeling (SWISS-MODEL). Amino acid sequence alignment between wild-type and variant FⅦ proteins was conducted using MEGA v7, and spatial conformational differences were analyzed using PyMOL to assess the potential impact of the F7 gene variants on the structure and function of the FⅦ protein. This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (Ethics No.: KY2022-R193). RESULTS: Coagulation tests showed that the proband's prothrombin time (PT) was significantly prolonged to 33.1 s, and both factor Ⅶ activity (FⅦ:C) and antigen (FⅦ:Ag) levels were reduced to 2%. Her parents, eldest sister, second sister, younger brother, and four children all showed mildly prolonged PT, with FⅦ:C and FⅦ:Ag levels approximately 50% of normal. Genetic sequencing identified compound heterozygous variants in the F7 gene of the proband: a heterozygous missense variant c.722C>A (p.Thr241Asn) in exon 7, and a heterozygous deletion variant c.1261_1261delA (p.Ile421Ser*fs75) in exon 8. Retrieval from domestic and international databases found no previous reports of the latter variant, suggesting it is novel. Familial co-segregation analysis confirmed that these variants were inherited from her father and mother, respectively. The thrombin generation assay demonstrated that the proband had a significantly decreased peak thrombin height (peak ratio: 29.5%), significantly increased thrombin lag time ratio and time-to-peak ratio (3.03 and 2.93, respectively), but only a mildly decreased endogenous thrombin potential (ETP) ratio of 90.7%. Online bioinformatics analysis indicated that threonine-241 (p.Thr241) in the FⅦ protein was not conserved, while isoleucine-421 (p.Ile421) was highly conserved. Both the p.Thr241Asn and p.Ile421Serfs*75 variant sites in the proband's F7 gene were predicted to be pathogenic. According to the ACMG guidelines, the p.Thr241Asn (PM3+PP1+PP3+PP4+PP5) and p.Ile421Ser*fs75 (PM2+PM4 +PP1+PP3+PP4) variants were both classified as "likely pathogenic". Structural analysis of the FⅦ protein indicated that the p.Ile421Ser*fs75 frameshift variant led to the substitution of Cysteine-428 by Alanine, preventing the formation of a critical disulfide bond between amino acid residues 400 and 428 present in the wild-type FVII protein. CONCLUSION The compound heterozygous variants p.Thr241Asn and p.Ile421Ser*fs75 in the F7 gene are likely the genetic etiology responsible for the reduced FⅦ levels in this hereditary FⅦ deficiency family.
Adult ; Female ; Humans ; Male ; Middle Aged ; China ; Factor VII/chemistry* ; Factor VII Deficiency/genetics* ; Heterozygote ; Mutation ; Pedigree ; East Asian People/genetics*

OBJECTIVE: To analyze the phenotype and genotype of a family with hereditary coagulation factor Ⅹ (FⅩ) deficiency and preliminarily explore its molecular pathogenesis. METHODS: A hereditary FⅩ deficiency pedigree presented at the First Affiliated Hospital of Wenzhou Medical University on August 13, 2024 was selected as the study subject. Coagulation parameters of the proband and her family members (7 individuals from 3 generations) were measured using a one-stage clotting assay. All of the 8 exons and flanking sequences of the F10 gene were amplified by PCR and directly sequenced. Bioinformatics software was used to analyze the functional impact and pathogenicity of the variant proteins, as well as the spatial conformational changes and evolutionary conservation of the mutation sites. This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (Ethics No.: KY2022-R193). RESULTS: The proband exhibited significantly abnormal prothrombin time (PT, 33.3 s), activated partial thromboplastin time (APTT, 47.7 s), and FⅩ activity (FⅩ:C, 3%), while other coagulation parameters remained normal. The plasma thromboplastin generation test (PTGT) demonstrated that the proband and her children had lower thromboplastin generation levels compared with the healthy control group, and the proband's thromboplastin generation capacity was more severely impaired. Genetic analysis revealed that the proband, her daughter, and grandson have all harbored a heterozygous missense variant c.212T>C (p.Phe71Ser) in exon 2 of the F10 gene, which was located in the β-sheet core region of the Gla domain. The variant has altered surrounding hydrogen bonds and disrupted calcium-binding sites. Additionally, the proband, her son, and granddaughter have all carried a heterozygous missense variant c.1270G>T (p.Val424Phe) in exon 8, which increased the side-chain volume, leading to steric hindrance in the catalytic domain and impaired coagulation function. Bioinformatics analysis confirmed that both p.Phe71Ser and p.Val424Phe were pathogenic variants, with Phe71 and Val424 being highly conserved residues. CONCLUSION The reduced FⅩ levels in this hereditary FⅩ-deficient family may be attributed to the heterozygous missense variants c.212T>C (p.Phe71Ser) in the exon 2 and c.1270G>T (p.Val424Phe) in the exon 8 of the F10 gene.
Humans ; Female ; Male ; Pedigree ; Adult ; Heterozygote ; Mutation ; Middle Aged ; Factor X/genetics* ; Exons ; Factor X Deficiency/genetics*

OBJECTIVE: To investigate the molecular mechanism for a family with Hereditary coagulation factor Ⅻ (FⅫ) deficiency. METHODS: The proband, a 63-year-old female, was admitted to the First Affiliated Hospital of Wenzhou Medical University in August 2024 for lumbar disc herniation. Coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (APTT), and FⅫ activity (FⅫ:C), were carried out for the proband and her family members (9 individuals from three generations) using a one-stage clotting assay. The level of FⅫ antigen (FⅫ:Ag) was determined with an Enzyme-linked immunosorbent assay (ELISA). Sanger sequencing was conducted to identify potential variants in the F12 gene. Multiple in silico tools were used to predict the conservation, hydrophobicity, and structural impact of the identified variants. Recombinant expression plasmids were constructed and transiently transfected into HEK293T cells. The recombinant FⅫ protein was analyzed using Western blotting (WB) and ELISA. This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (Ethics No.: KY2022-R193). RESULTS: The proband showed a markedly prolonged APTT (160.3 s) and significantly decreased FⅫ:C (2%) and FⅫ:Ag (5%) levels. Analysis of the F12 gene sequence revealed a 46C/T genotype in the promoter region, a heterozygous c.1457G>A (p.Cys467Tyr) missense variant in exon 12, and a heterozygous c.1561G>A (p.Glu502Lys) missense variant in exon 13. Bioinformatic analysis showed that the p.Cys467 is highly conserved across various species, and the p.Cys467Tyr variant may affect local structural stability of the FⅫ protein. The p.Cys467Tyr variant had no effect on the transcription of the F12 gene. However, the variant has significantly decreased the FⅫ:Ag levels and FⅫ protein expression in the cell culture supernatant compared to the wild-type expression vector, while in the cell lysate, it is higher than the wild-type expression vector. In other words, the p.Cys467Tyr variant has probably caused a secretion defect of FⅫ protein. CONCLUSION The 46C/T genotype, the heterozygous p.Cys467Tyr missense variant, and the heterozygous p.Glu502Lys missense variant are associated with reduced plasma FⅫ levels in this pedigree. The p.Cys467Tyr variant, which was unreported previously, did not affect the synthesis of FⅫ but may have resulted in a secretion defect.
Humans ; Female ; Middle Aged ; Mutation, Missense ; Pedigree ; HEK293 Cells ; Male ; Factor XII/genetics* ; Adult ; Factor XII Deficiency/genetics*

Objective:To summarize the clinical and imaging presentations of the pontine tegmental cap dysplasia (PTCD).Methods:The clinical, high resolution CT(HRCT) and MRI materials of 4 patients with PTCD between August 2007 to December 2024 were retrospectively analyzed. Among these, there were 2 males and 2 females, their ages ranged from 10 months to 16 years.Results:Of 4 PTCD patients, severe or profound severe hearing loss ( n=8 ears), developmental delay, hypotonia and severe facioplegia ( n=3 cases) were found. On HRCT, all of 4 cases were associated with temporal anomalies [including a narrow bony cochlear nerve canal ( n=8 ears), duplicated (each n=4 ears) or narrow ( n=1 ear) internal auditory canal, enlarged vestibular aqueduct ( n=2 ears), enlarged vestibules and dysplastic lateral semicircular canals ( n=3 ears), ossicular deformation( n=2 ears). The stenosis of the labyrinthine segments of the facial nerve canal ( n=3 ears) and facial nerve canal ectopia(n=6 ears)], atrial or ventricular septal defect (each n=1 case), thoracic or lumbar vertebral anomalies and ribs fusion ( n=3 cases). On the brain MRI, the variable flattening of the ventral pons and dysmorphism of the dorsal upper pons cap-like bulging and protruding in the fourth ventricle were shown in all cases, the vermian and cerebellar peduncles hypoplasia gave rise to a molar tooth appearance. The dysplastic ( n=3 ears), aplastic( n=5 ears) cochlear nerves and dysplastic facial nerves ( n=3 ears) were found. Conclusion:The PTCD patients usually present severe hearing loss, developmental delay, hypotonia, and facioplegia. The flattening of the ventral pons and the dorsal upper pons cap-like bulging usually with duplicated internal auditory canal and severe facial and auditory nerves dysplasia are its imaging features.

Objective:To investigate the clinicopathological features, immunophenotype and prognosis of SWI/SNF complex-deficient sinonasal carcinomas.Methods:The clinicopathological, immunohistochemical profiles of 13 SWI/SNF complex-deficient sinonasal carcinomas diagnosed at Xuanwu Hospital, Beijing, China between Januay 2019 and December 2024 were reviewed and followed up.Results:The patients′ ages ranged from 33-81 years, median 59.0 (41.5, 64.5) years, including 10 males and 3 females. Imaging findings showed space-occupying lesions in the nasal cavity and sinuses. Microscopically, tumors predominantly exhibited invasive growth in medium-to-large nests or sheets, with relatively uniform morphology, mainly basaloid and/or small cells, while one recurrent case displayed epithelioid morphology. Focal necrosis was observed in 7 cases. Immunohistochemical results showed loss of SMARCA4/BRG1 in 7 cases, loss of SMARCB1/INI1 in 6 cases, and concurrent loss of SMARCA2 in 5 cases. CKpan was expressed to varying extent in all cases, 10 cases were EMA positive, and 5 cases were partially positive for p63/p40. Among neuroendocrine markers, 10 cases showed focal expression of syn or CgA. The Ki-67 proliferation index ranged from 40% to 90%. PD-L1 staining showed combined positive score (CPS) was ≥1 in 3 SMARCB1-deficient cases (CPS ranging from 2 to 3) and CPS <1 in the other 10 cases. Among the 13 patients, 2 were lost to follow-up, 6 died (postoperative survival: 1-25 months), and 5 remained alive, with the longest survival time of 130 months (follow-up range, 8-130 months).Conclusions:SWI/SNF complex-deficient sinonasal carcinoma is a rare undifferentiated malignancy in the head and neck, characterized by distinct pathological and molecular genetic features. SMARCA4-deficient and SMARCB1-deficient carcinomas both exhibit basaloid or small cell-like morphology. Compared to SMARCB1-deficient carcinomas, SMARCA4-deficient carcinomas show reduced expression of squamous cell markers but increased expression of neuroendocrine markers. The positive PD-L1 staining is more likely present in SMARCB1-deficient carcinomas than SMARCB4-dificient ones. Co-loss of SWI/SNF and SMARCA2 correlates with poorer prognosis. Comprehensive evaluation of histopathology, immunohistochemistry, and molecular genetics is critical for accurately diagnosing this rare entity.

Objective To develop a toolkit suitable for assisting community health institutions in the early identification and inter-vention of mild cognitive impairment(MCI)among older adults.Methods A literature review was conducted to construct a draft of the identification and intervention toolkit.Tools with an expert approval rate above 70%were included after expert consultation.The final version of the toolkit was developed by integrating these tools with officially recommended tools in China.Results The expert consultation yielded an authority coefficient of 0.84.The finalized toolkit included the assessment tools of Mini-Mental State Examination,Montreal Cognitive Assessment,General Practitioner Assessment of Cognition,Cognitive Abilities Screening Instrument and Clock Drawing Test,and 18 intervention measures in-cluding pharmacological treatment,cognitive training and psychological interventions,etc.Conclusion The MCI Identification-Intervention Toolkit may serve as a reference for guiding the identification and inter-vention of MCI among older adults for community health institutions.

Objective:To investigate the association between albumin-corrected anion gap(ACAG)and short-to long-term death out-comes in patients with acute pancreatitis(AP).Methods:This retrospective study was based on the Medical Information Mart for Inten-sive Care-IV database,and the adult patients who were diagnosed with AP and were admitted to the intensive care unit were enrolled in this study.Cox regression risk analysis,receiver operating charac-teristic(ROC)curve analysis,Kaplan-Meier survival curve analy-sis,restricted cubic spline,and subgroup analysis were used to in-vestigate the value of ACAG in predicting the death outcome of AP patients.Results:A total of 444 patients were enrolled in this study,and according to the death status of the patients on day 28 after ad-mission,the patients were divided into survival group with 412 pa-tients and death group with 32 patients,with a mortality rate of 7.2%on day 28 after admission.The multivariate Cox regression analysis showed that ACAG was an independent predictive factor for all-cause mortality rate on day 28 after admission in AP patients(hazard ratio[HR]=1.18,95%CI=1.05-1.32),while it was not an in-dependent predictive factor for death outcome on days 90(HR=1.05,95%CI=0.97-1.14)and 180(HR=1.01,95%CI=0.94-1.09)and at 1 year(HR=1.02,95%CI=0.95-1.10).The ROC curve analysis showed that ACAG had an area under the ROC curve(AUC)of 0.732(95%CI=0.632-0.832)in predicting 28-day death outcome,which was better than that of AG(AUC=0.665,95%CI=0.550-0.781)and serum albumin(Alb)(AUC=0.655,95%CI=0.550-0.761)and was similar to that of Sequential Organ Failure Assessment(SOFA)score(AUC=0.745,95%CI=0.651-0.838).The ROC curve showed that the optimal cut-off value of ACAG was 21.375.Based on the cut-off value of ACAG of 21.375,the patients were divided into high-value group and normal-value group,and the Kaplan-Meier curve analysis showed that the patients with a high level of ACAG had a significantly higher mortality rate than those with normal ACAG(P<0.001).The subgroup analysis showed that the results were stable.Conclusion:ACAG can be used as an independent pre-dictive factor for all-cause mortality rate on day 28 after admission in AP patients,with a better efficacy than AG and Alb and a similar efficacy to SOFA.However,it is not significantly associated with 90-day,180-day,and 1-year death outcomes in AP patients.