ObjectiveTo investigate the effect of Semaphorin 3A （Sema3A） on the progression of pathological cardiac hypertrophy. MethodsWild-type C57BL 6J mice， Sema3A global overexpressing （Sema3A/Cre-ER^TM） mice， and their littermate controls （Cre-ER^TM） were used， with 6 mice per group. A pressure-overload induced cardiac hypertrophy model was established via transverse aortic constriction （TAC）， with a sham-operated group （Sham） as the control. Cardiac hypertrophy was assessed by gross morphology， heart weight/body weight ratio （HW/BW）， heart weight/tibia length ratio （HW/HL）， and heart weight/lung weight ratio （HW/PW）. Cardiac function was evaluated by measuring ejection fraction （EF） and fractional shortening （FS） via echocardiography. In heart tissues， the mRNA level of atrial natriuretic peptide （ANP） and Sema3A were detected by RT-qPCR， Sema3A protein level was detected by western blot， morphological structure was detected by hematoxylin and eosin （HE） staining， level of fibrosis was detected by Masson’s trichrome staining， and angiogenesis was detected by immunohistochemical detection of CD31. For in vitro experiments， rat H9C2 cardiomyocytes were treated with angiotensin Ⅱ （Ang Ⅱ） to induce hypertrophy， with PBS-treated cells as the control. After 48 hours， the mRNA expression of ANP， B-type natriuretic peptide （BNP） and Sema3A were measured by RT-qPCR， and Sema3A protein level was assessed by western blot. ResultsAt the animal level， compared with the sham group， mice subjected to TAC showed significantly increased mRNA levels of ANP in cardiac tissue， as well as markedly elevated mRNA and protein levels of Sema3A （all P<0.05）. Compared with the Cre-ER^TM + TAC group， the Sema3A/Cre-ER^TM + TAC group exhibited more pronounced cardiac hypertrophy， greater ventricular wall thickening， higher HW/BW， HW/HL， and HW/PW ratios， more significant reductions in EF and FS， more severe cardiac fibrosis， and a significant decrease in cardiac CD31 expression levels （all P<0.05）. At the cellular level， compared with the control group， H9C2 cells treated with Ang Ⅱ displayed significantly increased mRNA levels of ANP and BNP， along with markedly elevated mRNA and protein levels of Sema3A （all P<0.05）. ConclusionSema3A promotes the progression of pressure overload-induced cardiac hypertrophy by inhibiting angiogenesis.

ObjectiveTo investigate the intervention effect of Tengli Kangliu prescription （TKP） on the carcinogenesis of colorectal adenoma （CRA） induced by azoxymethane （AOM）/dextran sulphate sodium salt （DSS） in C57BL/6 mice and decipher the potential mechanism through regulating the signal transducer and activator of transcription 3 （STAT3） pathway to target M2-type macrophages. MethodsA total of 55 male C57BL/6 mice were randomized into a blank group （n=10）， a model group （n=15）， a celecoxib （0.02 g·kg^-1·d^-1） group （n=15）， a TKP （42.43 g·kg^-1·d^-1） group （n=15）. The mice in the model， TKP， and celecoxib groups were modeled for CRA lesions through the AOM/DSS three-cycle protocol. The intervention in each group began one week after free access to DSS and lasted for 12 weeks， and the blank group received 20 mL·kg^-1·d^-1 normal saline through gavage. Throughout the study period， changes in body mass and survival rate were recorded， alongside measurements of colorectal length and spleen mass. Histological changes of the colonic tissue were observed by HE staining. Immunohistochemical （IHC） staining was performed to detect the positive expression of CD68 and CD11c in the colorectal tissue. Western blot was employed to assess the protein levels of STAT3， phosphorylated （p）-STAT3， B-cell lymphoma 2 （Bcl-2）， and Bcl-2-associated X protein （Bax） in the intestinal tissue. Real-time quantitative PCR was employed to analyze the mRNA levels of arginase 1 （Arg1）， CD206， and vascular endothelial growth factor （VEGF）. Enzyme-linked Immunosorbent assay（ELISA） was employed to measure the serum concentrations of Th2-type cytokines interleukin （IL）-4， IL-6， and IL-13 in mice. ResultsCompared with the blank group， the model group exhibited symptoms including diarrhea， hematochezia， and body mass loss， accompanied by shortened colon length， mucosal damage， and multiple tumors. In addition， the model group showcased up-regulated protein levels of STAT3， p-STAT3， and Bcl-2， down-regulated protein level of Bax， increased positive expression of CD68 and CD11c， and up-regulated mRNA levels of Arg1， CD206， and VEGF in the colon tissue， together with elevated serum levels of IL-4， IL-13， and IL-6 （P<0.05）. Compared with the model group， the above-mentioned indicators were partially reversed in both TKP group and celecoxib group， with superior effects observed in the TKP group （P<0.05）. ConclusionTKP significantly improves the survival quality of the mouse model of AOM/DSS-induced CRA by reducing intestinal inflammation and decreasing colorectal tumor number and size. It may delay the progression of AOM/DSS-induced colorectal tumor-like lesions by inhibiting activation of the STAT3/p-STAT3 signaling pathway in the intestinal tissue， targeting regulation of M2-type macrophages， and improving the tumor microenvironment， thereby suppressing CRA carcinogenesis.

OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of adult AML patients with NUP98::HOXA9 fusion gene. METHODS: From May 2017 to October 2023， among 2 113 AML patients who visited the Hematology Department of our hospital, patients with NUP98 rearrangements were screened. The clinical characteristics, chromosome karyotypes, immunophenotypes, gene mutations, treatment efficacy and prognosis of the patients with NUP98::HOXA9 positive were analyzed. RESULTS: Among the 2 113 AML patients, there were 18 cases with NUP98 rearrangement, including 14 NUP98::HOXA9 positive cases, with a detection rate of 0.66% (14/2 113). The median age of the NUP98::HOXA9 positive patients was 42.5 (23-64) years old. The most common chromosome karyotype was t(7; 11)(p15; p15). The immunophenotypes of all patients expressed CD13, CD33, CD117 and CD38, and most patients expressed CD34 and cMPO, while only a few expressed HLA-DR. Second-generation sequencing (NGS) was performed to detect genetic mutations associated with leukemia in all 14 patients, and the genes exhibiting a high frequency of mutation were WT1 (10/14), TET2 (7/14), and FLT3-ITD (6/14). Additionally, mutations were also observed in KRAS/NRAS, IDH1, and KIT. Of the 13 patients who received treatment, 9 achieved complete remission (CR), and all 3 patients who received azacytidine(AZA)+ venetoclax (VEN) regimen achieved CR after the first course of treatment. Within this cohort, 6 patients were classified as relapsed/refractory (6/13). 4 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), of which two achieved long-term survival. The median follow-up time was 12 (2.1-65.0) months, while the median overall survival (OS) and relapse-free survival (RFS) were recorded as 11.4 months and 9.6 months, respectively. CONCLUSION The most common type of NUP98 rearrangement in adults AML patients is NUP98::HOXA9 , which is often accompanied by somatic mutations in WT1, TET2, and FLT3-ITD. These patients are prone to relapse, have short survival time, and generally face poor prognoses. Hopefully, utilization of the AZA+VEN regimen is anticipated to enhance the rate of induced remission in the patients, and some patients may prolong their survival through allo-HSCT. However, more effective treatment methods are still needed to improve the overall prognosis of these patients.
Humans ; Adult ; Leukemia, Myeloid, Acute/genetics* ; Middle Aged ; Prognosis ; Nuclear Pore Complex Proteins/genetics* ; Oncogene Proteins, Fusion/genetics* ; Mutation ; Male ; Female ; Young Adult ; Homeodomain Proteins/genetics*

Objective:This multicenter retrospective study aimed to analyze the clinicopathological features of duodenal adenocarcinoma (DA) and identify prognostic factors for postoperative survival.Methods:Demographic characteristics, clinicopathological features, treatment outcomes and survival of DA patients undergoing surgical treatment at 18 Chinese medical centers from January 2012 to December 2023 were retrospectively analyzed.Results:Among the 2 056 DA patients included, 46.8% (963) had extra-ampullary DA (EA-DA), and 53.2% (1 093) had peri-ampullary DA (PA-DA). The 1-, 3-, and 5-year overall survival (OS) rates for patients who underwent radical surgery were 93.2%, 71.0%, and 57.2%, respectively. The median overall survival was 76 months, and the median progression-free survival (PFS) was 65 months. No differences in survival were observed between the laparotomy group and minimally invasive surgery (MIS) group either before or after propensity score matching (OS: 76 vs. 75 months before PSM, P=0.986; OS: 75 vs. 75 months after PSM, P=0.602). Furthermore, there were no significant differences between-group in operation time and postoperative complications ( P＞0.05). The MIS group experienced less intraoperative blood loss and shorter hospital stays. The multivariate Cox regression analysis revealed that advanced age ( HR=1.43,95% CI:1.18-1.73), elevated carbohydrate antigen 19-9 levels ( HR=1.24,95% CI:1.02-1.51), perineural invasion ( HR=1.44,95% CI:1.14-1.81), vascular invasion ( HR=1.35,95% CI:1.07-1.71), advanced T stage (T3-4 vs. T1-2: HR=1.86,95% CI:1.49-2.31), regional lymph node metastasis ( HR=1.93,95% CI:1.58-2.36), preoperative biliary drainage ( HR=1.26,95% CI:1.04-1.53), intraoperative blood loss ( HR=1.34,95% CI:1.11-1.62), clinically significant postoperative pancreatic fistulas ( HR=1.53,95% CI:1.12-2.09), and postoperative hemorrhage ( HR=1.62,95% CI:1.14-2.29) were independent risk factors for poor prognosis after surgery (all P＜0.05). Conclusions:Radical surgery is associated with favorable overall survival among DA patients, and no difference in survival is observed between EA-DA and PA-DA patients. MIS is a reliable alternative for DA treatment.

Objective To construct a model combining with traditional Chinese medicine(TCM)syndrome for predicting the risk of disease progression in patients with idiopathic membranous nephropathy(IMN)by machine learning methods,thus to quantitatively evaluating the value of TCM syndrome in the prediction of the risk of disease progression in IMN.Methods Monofactor analysis,recursive feature elimination(RFE)and multivariate binary Logistic regression analysis were used to screen the independent related factors affecting the risk of disease progression of IMN,and then a risk prediction model was constructed.A total of 102 patients with IMN were randomly assigned to the training set and the test set in a ratio of 65∶35,and then the comparison was conducted in the performance indicators of accuracy,sensitivity,specificity,F1 value,and area under the receiver operating characteristic(ROC)area under the curve(AUC)of the risk prediction model with or without the inclusion of the TCM syndrome information.Results Before the inclusion of TCM syndrome information,12 clinical characteristic variables for patients with MN were obtained after monofactor analysis combined with RFE screening,and they were age,hemoglobin quantification,urinary occult blood,24-hour urine protein quantification,urine protein-creatinine ratio,estimated glomerular filtration rate(eGFR),creatinine,uric acid,alanine transaminase,anti-phospholipase A2 receptor antibody(PLA2R-Ab),total cholesterol,and low-density lipoprotein cholesterd.A risk cholesterol prediction model containing the above variables was constructed.The multivariate binary Logistic regression analysis showed that the differences of the clinical variables mentioned above between the training-set group and test-set group were statistically significant,and the risk prediction model presented good sensitivity and predictability.Monofactor analysis combined with RFE screening was performed again after the inclusion of TCM syndrome information,and then 14 variables were obtained,which included blood stasis syndrome and dampness obstruction syndrome.The sensitivity and specificity of the model with the inclusion of the TCM syndrome information were significantly improved when compared with those without the inclusion of TCM syndrome information.Conclusion The results of the study initially indicate that TCM syndrome can be used as an important supplementary variable for predicting the risk of disease progression in IMN,and will provide a reference for intelligent diagnosis through the integration of traditional Chinese and western medicine information,and will supply the guidance for the treatment of IMN with TCM.

GPR126, also known as ADGRG6, is one of the most deeply studied aGPCRs. Initially, GPR126 was thought to be a receptor associated with muscle development and was primarily expressed in the muscular and skeletal systems. With the deepening of research, it was found that GPR126 is expressed in multiple mammalian tissues and organs, and is involved in many biological processes such as embryonic development, nervous system development, and extracellular matrix interactions. Compared with other aGPCRs proteins, GPR126 has a longer N-terminal domain, which can bind to ligands one-to-one and one-to-many. Its N-terminus contains five domains, a CUB (complement C1r/C1s, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a SEA (Sperm protein, Enterokinase, and Agrin) domain, a hormone binding (HormR) domain, and a conserved GAIN domain. The GAIN domain has a self-shearing function, which is essential for the maturation, stability, transport and function of aGPCRs. Different SEA domains constitute different GPR126 isomers, which can regulate the activation and closure of downstream signaling pathways through conformational changes. GPR126 has a typical aGPCRs seven-transmembrane helical structure, which can be coupled to Gs and Gi, causing cAMP to up- or down-regulation, mediating transmembrane signaling and participating in the regulation of cell proliferation, differentiation and migration. GPR126 is activated in a tethered-stalk peptide agonism or orthosteric agonism, which is mainly manifested by self-proteolysis or conformational changes in the GAIN domain, which mediates the rapid activation or closure of downstream pathways by tethered agonists. In addition to the tethered short stem peptide activation mode, GPR126 also has another allosteric agonism or tunable agonism mode, which is specifically expressed as the GAIN domain does not have self-shearing function in the physiological state, NTF and CTF always maintain the binding state, and the NTF binds to the ligand to cause conformational changes of the receptor, which somehow transmits signals to the GAIN domain in a spatial structure. The GAIN domain can cause the 7TM domain to produce an activated or inhibited signal for signal transduction, For example, type IV collagen interacts with the CUB and PTX domains of GPR126 to activate GPR126 downstream signal transduction. GPR126 has homology of 51.6%-86.9% among different species, with 10 conserved regions between different species, which can be traced back to the oldest metazoans as well as unicellular animals.In terms of diseases, GPR126 dysfunction involves the pathological process of bone, myelin, embryo and other related diseases, and is also closely related to the occurrence and development of malignant tumors such as breast cancer and colon cancer. However, the biological function of GPR126 in various diseases and its potential as a therapeutic target still needs further research. This paper focuses on the structure, interspecies differences and conservatism, signal transduction and biological functions of GPR126, which provides ideas and references for future research on GPR126.

Objective To evaluate the changes in postoperative plasma β-endorphin(β-EP)levels in patients who had received perioperative electroacupuncture(EA)treatment in 10 randomized controlled trials(RCTs)and examine the impact of EA on postoperative pain.Methods This meta-analysis evaluated the changes in plasma β-EP levels and visual analog scale(VAS)12,24 and 48 hours after surgery in patients receiving perioperative EA.It also assessed the changes in plasma serotonin(5-hydroxytryptamine,5-HT)and prostaglandin E2(PGE2)levels at 24 hours postsurgery.A comprehensive search was conducted in the China National Knowledge Infrastructure(CNKI),Wanfang,Chongqing VIP database,Chinese Biomedical Database(CBM),Web of Science,and PubMed databases.RCTs on perioperative EA and β-EP published from the inception of the websites up to July 25,2023,were retrieved.Effect size aggregation,literature quality assessment,and bias analysis were performed using RevMan 5.3 software,and sensitivity analysis was conducted via R 4.3.1.Results A total of 10 RCTs involving 706 patients were included.EA in conjunction with conventional anesthesia significantly increased plasma β-EP levels at 12 hours postsurgery[standard mean difference(SMD)=2.79,95%CI(1.85,3.72),Z=5.81,P＜0.00001],24hours postsurgery[SMD=1.87,95%CI(0.9,2.83),Z=3.79,P=0.0001],and 48 hours postsurgery[SMD=2.02,95%CI(1.49,2.54),Z=7.50,P＜0.00001].EA reduced plasma PGE2 levels at 24 hours postsurgery and plasma 5-HT levels at 24 hours postsurgery,and the VAS at 12,24 and 48 hours after surgery also decreased.Conclusion These findings suggest that perioperative EA markedly elevates plasma β-EP levels,reduces pain-inducing factors in plasma,and effectively alleviates acute postoperative pain.

Objective:To explore the efficacy of non-invasive prenatal testing (NIPT) of fetal free DNA in maternal peripheral blood in fetuses with increased nuchal translucency (NT).Methods:A retrospective analysis was conducted on 1 184 singleton pregnant women that underwent chromosomal microarray analysis (CMA) at Nanjing Drum Tower Hospital, Nanjing University Medical School from June 2014 to December 2022 due to fetal increased NT (≥3.0 mm). These subjects were categorized based on whether the increased NT was accompanied by other high-risk factors into isolated increased NT without advanced maternal age (further subdivided into 3.0 mm≤NT<3.5 mm, 3.5 mm≤NT<4.0 mm, and NT≥4.0 mm subgroups), isolated increased NT with advanced maternal age, increased NT with nasal bone abnormalities, increased NT with other soft markers, and increased NT with structural abnormalities groups. Assuming the sensitivity and specificity of NIPT and expanded NIPT at this center were both 100%, genomic abnormalities outside the detection range of NIPT or expanded NIPT were termed as residual risk of NIPT or expanded NIPT. Chi-square test and Bonferroni correction were used to compare the residual risks of NIPT and expanded NIPT among the three subgroups of isolated increased NT without advanced maternal age group. Results:(1) In the group of isolated increased NT without advanced maternal age: For the 3.0 mm≤NT<3.5 mm subgroup (329 cases), 19 abnormalities were detected by CMA [12 cases of chromosome aneuploidy, seven cases of pathogenic copy number variation (pCNV)], with residual risks of NIPT and expanded NIPT both at 2.1% (7/329). For the 3.5 mm≤NT<4.0 mm subgroup (173 cases), 29 abnormalities were detected by CMA (17 cases of chromosome aneuploidy, nine cases of pCNV, three cases of chromosome unbalanced translocation), with residual risks of NIPT at 8.1% (14/173) and expanded NIPT at 7.5% (13/173). For the NT≥4.0 mm subgroup (270 cases), CMA detected abnormalities in 70 cases (50 cases of chromosome aneuploidy, 16 cases of pCNV, three cases of unbalanced translocations, and one case of sex chromosome abnormality combined with pCNV). The residual risk of NIPT was 12.2% (33/270), and the residual risk of expanded NIPT was 7.0% (19/270). The residual risks of NIPT and expanded NIPT in the 3.0 mm≤NT<3.5 mm subgroup were lower than those in the 3.5 mm≤NT<4.0 mm and NT≥4.0 mm subgroups (Bonferroni correction, all P<0.017). (2) In the group of 92 cases with isolated increased NT and advanced maternal age, CMA detected abnormalities in 36 cases (29 cases of chromosome aneuploidy, five cases of pCNV, one case of trisomy 21 combined with sex chromosome abnormality, and one case of trisomy 18 combined with sex chromosome abnormality). The residual risk of NIPT was 7.6% (7/92), and that of expanded NIPT was 5.4% (5/92). (3) In the group of 49 cases with increased NT combined with nasal bone abnormalities, CMA detected abnormalities in 24 cases (23 cases of chromosome aneuploidy and one case of pCNV). The residual risks of NIPT and expanded NIPT were both 2.0% (1/49). (4) In the group of 26 cases with increased NT combined with other soft markers, CMA detected abnormalities in nine cases (six cases of chromosome aneuploidy, one case of pCNV, and two cases of chromosome unbalanced translocations). The residual risks of NIPT and expanded NIPT were both 11.5% (3/26). (5) In the group of 245 cases with increased NT combined with structural abnormalities, CMA detected abnormalities in 121 cases (107 cases of chromosome aneuploidy, seven cases of pCNV, four cases of chromosome unbalanced translocations, one case of trisomy 21 combined with trisomy 20, and two cases of trisomy 18 combined with sex chromosome abnormalities). The residual risk of NIPT was 16.7% (41/245), and that of expanded NIPT was 4.1% (10/245). Conclusions:For isolated NT≥3.5 mm or NT≥3.0 mm combined with other high-risk factors, chorionic villus sampling in early pregnancy can be recommended, advancing the timing of prenatal diagnosis from the second trimester to the first trimester. For fetuses with isolated 3.0 mm≤NT<3.5 mm, the 2.1% residual risk of chromosomal abnormalities should be fully informed during counseling, even if the risk of NIPT is low.

Objective:This multicenter retrospective study aimed to analyze the clinicopathological features of duodenal adenocarcinoma (DA) and identify prognostic factors for postoperative survival.Methods:Demographic characteristics, clinicopathological features, treatment outcomes and survival of DA patients undergoing surgical treatment at 18 Chinese medical centers from January 2012 to December 2023 were retrospectively analyzed.Results:Among the 2 056 DA patients included, 46.8% (963) had extra-ampullary DA (EA-DA), and 53.2% (1 093) had peri-ampullary DA (PA-DA). The 1-, 3-, and 5-year overall survival (OS) rates for patients who underwent radical surgery were 93.2%, 71.0%, and 57.2%, respectively. The median overall survival was 76 months, and the median progression-free survival (PFS) was 65 months. No differences in survival were observed between the laparotomy group and minimally invasive surgery (MIS) group either before or after propensity score matching (OS: 76 vs. 75 months before PSM, P=0.986; OS: 75 vs. 75 months after PSM, P=0.602). Furthermore, there were no significant differences between-group in operation time and postoperative complications ( P＞0.05). The MIS group experienced less intraoperative blood loss and shorter hospital stays. The multivariate Cox regression analysis revealed that advanced age ( HR=1.43,95% CI:1.18-1.73), elevated carbohydrate antigen 19-9 levels ( HR=1.24,95% CI:1.02-1.51), perineural invasion ( HR=1.44,95% CI:1.14-1.81), vascular invasion ( HR=1.35,95% CI:1.07-1.71), advanced T stage (T3-4 vs. T1-2: HR=1.86,95% CI:1.49-2.31), regional lymph node metastasis ( HR=1.93,95% CI:1.58-2.36), preoperative biliary drainage ( HR=1.26,95% CI:1.04-1.53), intraoperative blood loss ( HR=1.34,95% CI:1.11-1.62), clinically significant postoperative pancreatic fistulas ( HR=1.53,95% CI:1.12-2.09), and postoperative hemorrhage ( HR=1.62,95% CI:1.14-2.29) were independent risk factors for poor prognosis after surgery (all P＜0.05). Conclusions:Radical surgery is associated with favorable overall survival among DA patients, and no difference in survival is observed between EA-DA and PA-DA patients. MIS is a reliable alternative for DA treatment.