Isocitrate dehydrogenase 1 (IDH1) R132H is the most common mutated gene in grade II-III gliomas and oligodendrogliomas. Instead of activating telomerase (a reverse transcriptase which using RNA as a template to extend telomere length), the majority of IDH1^R132H mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination (HR), which is known as alterative lengthening of telomere (ALT).The phenotype of ALT mechanism include: ALT associated promyelocytic leukemia protein (PML) bodies (APBs); extrachromosomal telomeric DNA repeats such as C- and T-loops; telomeric sister chromatid exchange (T-SCE), etc. The mechanism of ALT activation is not fully understood. Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways. Firstly, the IDH1^R132H mutation mediates RAP1 down-regulation leading to telomere dysfunction, thus ensuring persistent endogenous telomeric DNA damage, which is important for ALT activation. Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication (BIR)‑mediated ALT telomere lengthening, and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA, transcribed from telomeric DNA repeat sequences (TERRA) transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage, thereby inhibiting ALT telomere synthesis. Similarly, in ALT cells, knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation, which leads to increased replication pressure. Overexpression of RNaseH1, on the other hand, attenuates the recombination capacity of ALT telomeres, leading to telomere depletion, suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression. Secondly, the IDH1^R132H also alters the preference of the telomere damage repair pathway by down-regulating XRCC1, which inhibits the alternative non-homologous end joining (A-NHEJ) pathway at telomeres and alters cellular preference for the HR pathway to promote ALT. Finally, the IDH1^R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α ketoglutarate (α‑KG) and NADPH, so that the mutant IDH1^R132H catalyzes the hydrogenation of α‑KG to produce 2-hydroxyglutarate (2-HG)in a NADPH-dependent manner. Because 2-HG is structurally similar to α‑KG, which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α‑KG-dependent histone demethylase KDM4B, and recruits heterochromatin protein HP1α to heterochromatinize telomeres, and promote ALT phenotypes in cooperation with the inactivating of ATRX. In addition, it has been shown that APBs contain telomeric chromatin, which is essentially heterochromatin, and HP1α is directly involved in the formation of APBs. Based on these studies, this article reviews the mechanism of IDH1^R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT, which may provide references for clinical targeted therapy of IDH1^R132H mutant glioma.

AIM To study the chemical constituents from the leaves of Cyanocarya paliurus(Batalin)Iljinskaja and their α-glucosidase inhibitory activities.METHODS The 95%ethanol extract from the leaves of C.paliurus was isolated and purified by macroporous resin,silica gel,Sephadex LH-20,polyamide,C18 reversed-phase silica gel and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.Their α-glucosidase inhibitory activities were evaluated by PNPG.RESULTS Fifteen compounds were isolated and identified as cyclopaloside C(1),cyclopaloside A(2),juglanosides E(3),vaccinin A(4),ent-murin A(5),kaempferol 3-O-α-L-rhamnopyranoside(6),kaempferol-3-O-β-D-glucopyranoside(7),kaempferol-3-O-β-D-glucuronide methyl ester(8),kaempferol-3-O-β-D-glucuronide ethyl ester(9),kaempferol-3-O-β-D-glucuronide butyl ester(10),quercetin-3-O-α-L-rhamnopyranoside(11)quercetin-3-O-β-D-glucopyranoside(12),quercetin-3-O-β-D-galactopyranoside(13),quercetin-3-O-β-D-glucuronide butyl ester(14),dihydrokaempferol(15).The IC50 value of total extracts ihibited α-glucosidase was(1.83±0.04)μg/mL,and the IC50 values of compounds 1,4-5 were(29.48±1.86),(0.50±0.07),(0.71±0.07)μmol/L,respectively.CONCLUSION Compound 1 is a new tetrahydronaphthalene glycoside.Compounds 4-5,8-10 and 14 are isolated from the leaves of C.paliurus for the first time.Compounds 4-5 are relatively rare flavonoid lignans with potential inhibitory activities against α-glucosidase.

OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ₊TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45⁺ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.
Male ; Animals ; Mice ; Tripterygium ; Psoriasis/drug therapy* ; Keratinocytes ; Skin Diseases/metabolism* ; Cytokines/metabolism* ; Imiquimod/metabolism* ; Dermatitis/pathology* ; Disease Models, Animal ; Mice, Inbred BALB C ; Skin/metabolism*

Objective:To explore the relationship between BMI and levels of plasma amino acids and acylcarnitines in Chinese adults.Methods:Based on 2 182 individuals with targeted mass spectrometry metabolomic measurements from the first resurvey of the China Kadoorie Biobank, we assessed the linear and nonlinear associations between BMI and plasma levels of 20 amino acids and 40 acylcarnitines using linear regression models and restricted cubic spline models, and identified BMI-related metabolic pathways. We conducted one-sample Mendelian randomization (MR) with BMI genetic risk scores as the instrumental variable further to explore the potential causal relationships between BMI and 20 amino acids and 40 acylcarnitines, and tested for horizontal pleiotropy using the MR-Egger method.Results:Observational analyses found that BMI was associated with increased plasma levels of 3 branched-chain amino acids (isoleucine, leucine, and valine), 2 aromatic amino acids (phenylalanine and tyrosine), 3 other amino acids (cysteine, glutamate, lysine), and 7 acylcarnitines (C3, C4, C5, C10, C10:1, C14, and C16), and with decreased circulating levels of asparagine, serine, and glycine. Pathway analysis identified 7 BMI-related amino acids metabolic pathways (false discovery rate corrected all P<0.05), including branched-chain amino acids and aromatic amino acids biosynthesis, glutathione metabolism, etc. BMI showed a nonlinear relationship with leucine, valine, and threonine, and a linear relationship with other amino acids and acylcarnitines. One-sample MR analyses revealed that BMI was associated with elevated levels of tyrosine and 4 acylcarnitines [C5-DC(C6-OH), C5-M-DC, C12-DC, and C14], with tyrosine and acylcarnitine C14 positively correlated with BMI in both observational [the β values (95% CIs) were 0.057 (0.044-0.070) and 0.018 (0.005-0.032), respectively] and One-sample MR analyses [the β values (95% CIs) were 0.102 (0.035-0.169) and 0.104 (0.036-0.173), respectively]. The MR analyses of the current study satisfied the 3 core assumptions of instrumental variable. Conclusions:BMI was associated with circulating 11 amino acids and 7 acylcarnitines in Chinese adults, involving several pathways such as branched-chain amino acid and aromatic amino acid metabolism, fatty acid metabolism, and oxidative stress. There may be a causal relationship between BMI and tyrosine and acylcarnitine C14.

Objective:To understand the symptoms of diarrhea of residents in Tianjin and their willingness to vaccinate, to provide reference for health education, prevention and control of infectious diarrhea.Methods:Cross-sectional study design was adopted. From September to December 2023, a questionnaire survey was conducted among some residents as subjects in Nankai District, Beichen District, Baodi District and Binhai Area of Tianjin by multistage stratified cluster random sampling,to collect information such as sociodemographic characteristics, diarrhea symptoms and vaccination intention. According to the formula n=[ u2απ (1 - π)]/ δ2, the estimated sample size was 3 458 cases. The logistic regression model was used to analyze the factors related to the willingness of the respondents to receive diarrhea vaccination. The software SPSS 24.0 was used for statistical analysis. Results:A total of 3 808 subjects were investigated, with the male-to-female ratio as 1∶1.11 (1 806∶2 002), the age was (42.48±21.59) years old, and the education level of middle school or below accounted for 50.84% (1 936/3 808). The incidence rate of diarrhea was 18.28% (696/3 808), and 48.84% (1 860/3 808) were willing to be vaccinated with diarrhea vaccine. The results of multivariate logistic regression analysis showed that the age was 15-59 years old and ≥60 years old (a OR=2.31, 95% CI:1.80-2.96; a OR=1.66, 95% CI:1.38-2.00), lived in Binhai Area (a OR=2.09, 95% CI:1.62-2.71), and those who knew that community health service centers can provide the vaccination (a OR=1.61,95% CI:1.34-1.92), those who walked from the address to the community health service center were less than 15 minutes (a OR=1.54, 95% CI:1.28-1.85), those who often travel or on business (a OR=1.36, 95% CI:1.07-1.73), and those who actively obtained health care information related to diarrhea prevention when going abroad (a OR=1.69,95% CI:1.43-1.98) were more willing to be vaccinated against diarrhea. Conclusions:The incidence of diarrhea symptoms of residents was slightly higher in Tianjin, but they were less willing to be vaccinated against diarrhea. People who often go outside and go abroad were more willing to be vaccinated against diarrhea. It is suggested that the popular science propaganda and health education of diarrhea vaccine should be effectively carried out by using network platform in community.

Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.

Objective To analyze the risk factors of gastrointestinal bleeding in patients with type A aortic dissection(TAAD)after Sun's operation.Methods The clinical data of 87 patients who underwent TAAD Sun's operation in our hospital from March 2021 to June 2022 were retrospectively analyzed.They were divided into the bleeding group and the non-bleeding group according to whether there was gastrointestinal bleeding after operation.The clinical data of patients in the two groups was compared and analyzed.The binary Logistic regression analysis was used to analyze the risk factors of gastrointestinal bleeding.The clinical predictor of postoperative gastrointestinal bleeding was analyzed by receiver operating characteristic(ROC)curve.Results In this study,there were 40 cases of postoperative gastrointestinal bleeding(the bleeding group)and 47 cases of non-bleeding(the non-bleeding group).Compared with the non-bleeding group,the bleeding group had a shorter onset time,a higher proportion of patients with hypertension history,a higher preoperative creatinine abnormality rate,more intraoperative blood loss,longer postoperative mechanical ventilation time,higher postoperative infection rate,and higher poor prognosis rate,with statistically significant differences(P<0.05).There was no statistically significant difference in the gender,age,gastrointestinal diseases history,smoking history,preoperative platelets,preoperative international normalized ratio(INR),preoperative alanine aminotransferase(ALT),preoperative aspartate aminotransferase(AST),preoperative γ-glutamyl transpeptidase(GGT),preoperative dissection involving abdominal aorta,operation time,intraoperative cardiopulmonary bypass time,intraoperative circulatory arrest time,intraoperative aortic occlusion time or intraoperative blood transfusion rate.Logistic regression analysis showed that hypertension history(OR=2.468,95%CI:0.862 to 7.067,P=0.037),preoperative creatinine>105 μmol/L(OR=3.970,95%CI:1.352 to 11.659,P=0.011),long postoperative mechanical ventilation time(OR=1.015,95%CI:0.094 to 1.018,P=0.041)and postoperative infection(OR=3.435,95%CI:0.991 to 11.900,P=0.012)were the independent risk factors for postoperative gastrointestinal bleeding in TAAD patients.ROC curve showed that the postoperative mechanical ventilation time exceeding 64 hours were the clinical predictor of postoperative gastrointestinal bleeding in TAAD patients.Conclusion The prognosis of TAAD patients with postoperative gastrointestinal bleeding after Sun's operation is poor.Hypertension history,preoperative acute renal insufficiency,long postoperative mechanical ventilation time and postoperative infection are closely related to postoperative gastrointestinal bleeding in TAAD patients after operation,which should be paid more attention to,and corresponding evaluation,early identification and early intervention should be made to improve the prognosis of patients.

Cases of human infection with H7 subtype avian influenza virus(AIV)combined with five NA subtypes(N2,N3,N4,N7,and N9)have been reported.This study was aimed at establishing a method for simultaneous detection and dif-ferential diagnosis of H7 and five NA subtypes of AIV.Seven pairs of specific primers were designed according to the conserved sequences of the HA gene of H7 subtype AIV,the NA gene of five NA AIV subtypes,and the M gene of all AIV subtypes.A high-throughput GeXP typing method was established for simultaneous detection of the H7 subtype and the five NA subtypes of AIV by using GeXP multiple gene expression and capillary electrophoresis analysis technology.The specificity and sensitivity of the method were determined,and clinical samples were tested.The specificity results indicated that this method was able to simultaneously detect seven target genes in a single tube;each pair of specific primers was able to detect the corresponding AIV subtype,and the universal detection primers were able to detect all subtypes of AIV,with no cross-reaction with other common avian disease pathogens.Sensitivity results demonstrated that this method was able to simultaneously detect seven target genes with a threshold detection limit was 100 copies/μL.The detection results for 150 clinical samples were consistent with those of viral isolation and identification.The high-throughput GeXP method for simultaneous differential diagnosis of the H7 subtype and five subtypes of AIV established in this study has advantages of high specificity,high sensitivity,rapidity,and simplicity,thus providing a new detection method for the effective prevention and control of AIV.

Objective:To investigate the clinical features,gene mutation profile,efficacy and prognostic factors of primary extranodal diffuse large B-cell lymphoma(EN-DLBCL).Methods:A retrospective analysis was performed for 382 patients with primary EN-DLBCL with complete clinical data who were treated in West China Hospital from January 2013 to January 2023,and their clinical characteristics,gene mutation profile,efficacy and prognostic factors were analyzed.Results:The median age of the 382 patients with EN-DLBCL was 56 (18-89 )years old.The male-to-female ratio was 1.12∶1,and the most common primary sites were gastrointestinal tract (31.7％),Wechsler ring (19. 1％)and breast gland (7.1％).A total of 51 gene mutations were fund,and the most common frequencies of gene mutations were TP53 (32.5％),MYD88 (32.5％),and CD79B (30.0％).The median follow-up was 63 months,and the 5-year progression-free survival (PFS)rate was 74.5％ and the 5-year overall survival (OS)rate was 89.6％. The adverse factors on PFS were as follows:>1 extranodal sites involvement (P<0.001),P53≥50％(P<0.001),hyper double expression(hDEL)of C-myc>50％/Bcl-2>70％(P<0.001).The adverse factors affecting the OS of patients were as follows:>1 extranodal sites involvement (P<0.001),P53≥50％(P<0.001),hDEL(P<0.001). Chemotherapy combined with local radiotherapy could improve PFS (P=0.041)and OS (P=0.003),while R-CHOP+X (molecule agents as BTKi、HDACi、Lenalidomide)failed to show a significant difference in PFS (P=0.075)and OS (P=0.767 ).Among the 40 patients who underwent next-generation sequencing at high risk,there was no significant in PFS (P=0.849)and OS (P=0.500)of patients with positive MYD88 and/or CD79B mutations (MCD subtype)treated with BTKi and patients with negative MYD88 and CD79B mutations.Conclusion:Primary EN-DLBCL can involve multiple organs or tissue sites.TP53,MYD88,and CD79B are the most common gene mutations.The efficacy of BTKi in patients with positive MCD subtypes at intermediate and high risk is not inferior to that in MCD-negative control patients.

OBJECTIVE: To compare the clinical therapeutic effect between electroacupuncture at "four points of sacral region" and transurethral Erbium laser in treatment of moderate to severe stress urinary incontinence after radical prostatectomy. METHODS: A total of 68 patients of moderate to severe stress urinary incontinence after radical prostatectomy were divided into an electroacupuncture group (34 cases) and an Erbium laser group (34 cases, 3 cases dropped off) according to the settings. In the electroacupuncture group, electroacupuncture was applied at "four points of sacral region", i.e. points of 0.5 cun beside bilateral sacrococcygeal joints and bilateral Huiyang (BL 35), with continuous wave, 2 Hz in frequency, 60 min each time, once every other day, 3 times a week, 12 times as one course of treatment. In the Erbium laser group, transurethral Erbium laser technology was given, once every 4 weeks as one course of treatment. Both groups were treated for 5 courses. The scores of the International Consultation on Incontinence questionnaire-short form (ICI-Q-SF) and the incontinence quality of life questionnaire (I-QOL) were observed before treatment, after each course of treatment and in follow-up after 1 and 2 months of treatment completion, respectively, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: Compared with those before treatment, the ICI-Q-SF scores were decreased while the I-QOL scores were increased after 5 courses of treatment and in follow-up after 1, 2 months of treatment completion in the two groups (P<0.01). The ICI-Q-SF score in follow-up after 2 months of treatment completion were higher than that after 5 courses of treatment in the Erbium laser group (P<0.05). After 3, 4, 5 courses of treatment and in follow-up after 1 and 2 months of treatment completion, the ICI-Q-SF scores in the electroacupuncture group were lower than those in the Erbium laser group (P<0.05, P<0.01); after 2, 3, 4, 5 courses of treatment and in follow-up after 1 and 2 months of treatment completion, the I-QOL scores in the electroacupuncture group were higher than those in the Erbium laser group (P<0.01). The change ranges of ICI-Q-SF score and I-QOL score between before treatment and after each course of treatment in the electroacupuncture group were lager than those in the Erbium laser group (P<0.01, P<0.05). The total effective rate was 61.8% (21/34) in the electroacupuncture group, which was superior to 19.4 (6/31) in the Erbium laser group (P<0.01). CONCLUSION Both electroacupuncture at "four points of sacral region" and transurethral Erbium laser can improve the clinical symptoms and the quality of life in patients of moderate to severe stress urinary incontinence after radical prostatectomy. The short-term efficacy and long-term efficacy of electroacupuncture are superior to the Erbium laser technology.
Male ; Humans ; Quality of Life ; Urinary Incontinence, Stress/therapy* ; Sacrococcygeal Region ; Electroacupuncture ; Erbium ; Prostatectomy/adverse effects*