OBJECTIVE: To explore the peripheral neural mechanism underlying representation along the distribution of stomach meridian induced by intestinal inflammatory reaction using diarrhea predominant-irritable bowel syndrome (IBS-D) mice. METHODS: Among 62 healthy male C57BL/6 mice of clean grade, 12 mice were randomly selected and divided into a control group and a model group, 6 mice in each group, additionally, 12 mice were randomly selected and divided into a Tianshu group, a Liangqiu group and a Zusanli group, 4 mice in each group. In the model group, citrobacter was administered orally to establish IBS-D model. In the control group and the model group, the visceral pain threshold was observed using fecal colorectal distension (fCRD) induced electromyography of external oblique muscle, the positive cell number of neutrophil in the colonic muscularis was detected by myeloperoxidase (MPO) staining, the number, location and distribution rule of Evans blue (EB) extravasation points were observed by injection of EB staining solution into the tail vein. In the Tianshu group, the Liangqiu group and the Zusanli group, fluorescent dye Dil was injected at bilateral "Tianshu" (ST25), "Liangqiu" (ST34) and "Zusanli" (ST36) respectively, to observe the dye-positive cell number in different dorsal root ganglion (DRG) segments. In the control group and the model group, the activation of satellite glial cells (SGCs) in different DRG segments was observed by immunofluorescence. RESULTS: Compared with the control group, in the model group, the area under curve of electromyography of external oblique muscle was increased at fCRD of 25, 50 and 75 μL distilled water (P<0.001, P<0.01); the MPO-positive cell number of neutrophil in the colonic muscularis was increased (P<0.01). Few EB extravasation points could be found in the control group, while there were much more EB extravasation points observed in the model group, which was specially distribution in the area of stomach meridian, from "Huaroumen" (ST24) to "Zusanli" (ST36), as well as the surface area dominated by L₂-L₅ segment of the spinal cord. The Dil-positive cells were mainly exhibited in the DRG of T₁₁, L₅ and L₄ segments in the Tianshu group, the Liangqiu group and the Zusanli group, respectively. Compared with the control group, the ratio of glial fibrillary acidic protein (GFAP)/glutamine synthetase (GS) co-expression was increased in the DRG of T₁₁, L₄ and L₅ segments in the model group (P<0.05, P<0.01). CONCLUSION The activation of SGCs within DRG of T₁₁, L₄ and L₅ segments may relate closely to the occurrence of the representation along the stomach meridian distribution in IBS-D mice.
Animals ; Male ; Mice ; Irritable Bowel Syndrome/therapy* ; Mice, Inbred C57BL ; Meridians ; Stomach/physiopathology* ; Humans ; Acupuncture Points ; Disease Models, Animal

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction. Iguratimod (IGU) is a novel conventional synthetic disease-modifying antirheumatic drugs (csDMARD) with good efficacy and safety for the treatment of active RA in China and Japan. However, the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown. We aimed to investigate the efficacy and safety of iguratimod (IGU), a combination of methotrexate (MTX) and IGU, and IGU in patients with active rheumatoid arthritis (RA) who were naïve to MTX. METHODS: This multicenter, double-blind, randomized, non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China. In total, 911 patients were randomized (1:1:1) to receive MTX monotherapy (10-15 mg weekly, n = 293), IGU monotherapy (25 mg twice daily, n = 297), or IGU + MTX (10-15 mg weekly for MTX and 25 mg twice daily for IGU, n = 305) for 52 weeks. The patients' clinical characteristics, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), disease activity score in 28 joints-C-reactive protein (DAS28-CRP) level, and disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) were assessed at baseline. The primary endpoints were the proportion of patients with ≥20% improvement according to the American College of Rheumatology (ACR20) response and changes in the van der Heijde-modified total Sharp score (vdH-mTSS) at week 52. RESULTS: The proportions of patients achieving an ACR20 response at week 52 were 77.44%, 77.05 %, and 65.87% for IGU monotherapy, IGU + MTX, and MTX monotherapy, respectively. The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20 (11.57%; 95% confidence interval [CI], 4.35-18.79%; P <0.001) and vdH-mTSS (-0.37; 95% CI, -1.22-0.47; P = 0.022). IGU monotherapy was also superior to MTX monotherapy in terms of ACR20 ( P = 0.002) but not the vdH-mTSS. The superiority of IGU + MTX over MTX monotherapy was confirmed in terms of the ACR20 (11.18%; 95% CI, 3.99-18.37%; P = 0.003), but not in the vdH-mTSS (-0.68; 95% CI, -1.46-0.11; P = 0.091). However, the difference in the incidence rates of adverse events was not statistically significant. CONCLUSIONS: IGU monotherapy/IGU + MTX showed a more favorable clinical response than did MTX monotherapy. IGU may have some clinical benefits over MTX in terms of radiographic progression, implying that IGU may be considered as an initial therapeutic option for patients with active RA. TRIAL REGISTRATION https://classic.clinicaltrials.gov/ , NCT01548001.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antirheumatic Agents/therapeutic use* ; Arthritis, Rheumatoid/drug therapy* ; Chromones/adverse effects* ; Double-Blind Method ; Drug Therapy, Combination ; Methotrexate/adverse effects* ; Treatment Outcome ; Sulfonamides

OBJECTIVES: To investigate the prognostic value of molecular minimal residual disease (Mol-MRD) monitored before and after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric acute myeloid leukemia (AML). METHODS: Clinical data of 71 pediatric AML patients who underwent HSCT between August 2016 and December 2023 were analyzed. Mol-MRD levels were dynamically monitored in MRD-positive patients, and survival outcomes were evaluated. RESULTS: No significant difference in the 3-year overall survival (OS) rate was observed between patients with pre-HSCT Mol-MRD ≥0.01% and <0.01% (77.3% ± 8.9% vs 80.4% ± 7.9%, P=0.705). However, patients with pre-HSCT Mol-MRD <1.75% had a significantly higher 3-year OS rate than those with Mol-MRD ≥1.75% (86.6% ± 5.6% vs 44.4% ± 16.6%, P=0.020). The median Mol-MRD level in long-term survivors was significantly lower than in non-survivors [0.61% (range: 0.04%-51.58%)] vs 10.60% (range: 1.90%-19.75%), P=0.035]. Concurrent flow cytometry-based MRD positivity was significantly higher in non-survivors (80% vs 24%, P=0.039). There was no significant difference in the 3-year overall survival rate between patients with Mol-MRD ≥0.01% and those with <0.01% at 30 days post-HSCT (P=0.527). For children with Mol-MRD <0.22% at 30 days post-HSCT, the 3-year overall survival rate was 80.4% ± 5.9%, showing no significant difference compared to those with molecular negativity (87.0% ± 7.0%) (P=0.523). CONCLUSIONS Patients with pre-HSCT Mol-MRD <1.75% or post-HSCT Mol-MRD <0.22% may achieve long-term survival outcomes comparable to Mol-MRD-negative cases through HSCT and targeted interventions.
Humans ; Hematopoietic Stem Cell Transplantation ; Neoplasm, Residual ; Leukemia, Myeloid, Acute/genetics* ; Child ; Male ; Female ; Child, Preschool ; Prognosis ; Adolescent ; Infant ; Transplantation, Homologous

OBJECTIVES: To evaluate the efficacy of molecular targeted agents in children with progressive pediatric low-grade gliomas (pLGG). METHODS: A retrospective analysis was conducted on pLGG patients treated with oral targeted therapies at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2021. Treatment responses and safety profiles were assessed. RESULTS: Among the 20 enrolled patients, the trametinib group (n=12, including 11 cases with BRAF fusions and 1 case with BRAF V600E mutation) demonstrated 4 partial responses (33%) and 2 minor responses (17%), with a median time to response of 3.0 months. In the vemurafenib group (n=6, all with BRAF V600E mutation), 5 patients achieved partial responses (83%), showing a median time to response of 1.0 month. Comparative analysis revealed no statistically significant difference in progression-free survival rates between the two treatment groups (P>0.05). The median duration of clinical benefit (defined as partial response + minor response + stable disease) was 11.0 months for vemurafenib and 18.0 months for trametinib. Two additional cases, one with ATM mutation treated with olaparib for 24 months and one with NF1 mutation receiving everolimus for 21 months, discontinued treatment due to sustained disease stability. No severe adverse events were observed in any treatment group. CONCLUSIONS Molecular targeted therapy demonstrates clinical efficacy with favorable tolerability in pLGG. Vemurafenib achieves high response rates and induces early tumor shrinkage in patients with BRAF V600E mutations, supporting its utility as a first-line therapy.
Humans ; Glioma/genetics* ; Male ; Female ; Child ; Child, Preschool ; Retrospective Studies ; Brain Neoplasms/genetics* ; Molecular Targeted Therapy/adverse effects* ; Adolescent ; Infant ; Proto-Oncogene Proteins B-raf/genetics* ; Pyrimidinones/therapeutic use* ; Mutation

OBJECTIVES: To investigate the effects of methylenetetrahydrofolate reductase (MTHFR) rs1801133 and γ-glutamyl hydrolase (GGH) rs11545078 gene polymorphisms on plasma concentrations and toxicity following high-dose methotrexate (MTX) therapy in children with acute lymphoblastic leukemia (ALL). METHODS: Children with ALL treated at the Xuzhou Children's Hospital of Xuzhou Medical University from January 2021 to April 2024 were selected for this study. Genotypes of MTHFR rs1801133 and GGH rs11545078 were determined using multiplex polymerase chain reaction. MTX plasma concentrations were measured by enzyme-multiplied immunoassay technique, and toxicity was graded according to the Common Terminology Criteria for Adverse Events version 5.0. The relationships between MTHFR rs1801133 and GGH rs11545078 genotypes and both MTX plasma concentrations and associated toxicities were analyzed. RESULTS: In the low-risk ALL group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 72 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05), and the GGH rs11545078 genotype was associated with increased MTX plasma concentrations at 48 hours (P<0.05). In the intermediate- to high-risk group, the MTHFR rs1801133 genotype was associated with the occurrence of reduced hemoglobin (P<0.05), and the GGH rs11545078 genotype was associated with the occurrence of thrombocytopenia (P<0.05). CONCLUSIONS Detection of MTHFR rs1801133 and GGH rs11545078 genotypes can be used to predict increased MTX plasma concentrations and the occurrence of toxic reactions in high-dose MTX treatment of ALL, enabling timely interventions to enhance safety.
Humans ; Methotrexate/toxicity* ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood* ; Male ; Female ; Child ; Child, Preschool ; gamma-Glutamyl Hydrolase/genetics* ; Antimetabolites, Antineoplastic/adverse effects* ; Infant ; Polymorphism, Genetic ; Adolescent ; Genotype ; Polymorphism, Single Nucleotide

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective To analyze the factors affecting the risk of hepatocellular carcinoma(HCC)in patients with chronic hepatitis B-associated cirrhosis(CHB-Cir)complicated by essential hypertension(EH)and explore the impact of EH on HCC risk in patients with CHB-Cir.Methods This study was conducted among the patients with CHB-Cir with or without EH received antiviral therapy in the Infectious Disease Department,Third Affiliated Hospital of Xinxiang Medical University from January,2017 to January,2024.The cases with insufficient follow-up time or missing data were excluded.The patients were subjected to propensity score matching in a 1:1 ratio to form an EH group and a non-EH group.The Kaplan-Meier method was used to compare the cumulative incidence of HCC between the two groups,and the Cox proportional hazards regression model was used to analyze the risk of HCC and the factors affecting HCC risk.Results A total of 390 CHB-Cir patients(274 male and 116 female patients)were enrolled in this study,including 195 with EH and 195 without EH.In these patients,EH was significantly correlated with the occurrence of HCC(HR=1.69,P=0.002).Multivariate analysis suggested that the male gender(HR=1.73,P=0.005),a family history of liver cancer(HR=2.23,P<0.001),elevated alpha-fetoprotein(HR=2.83,P=0.001),elevated glutathione reductase(HR=1.53,P=0.046),reduced high-density lipoprotein(HR=1.46,P=0.027),and elevated low-density lipoprotein(HR=2.29,P=0.003)were all significantly correlated with HCC occurrence,while elevated triglycerides(HR=0.37,P<0.001)was a protective factor against HCC.In the EH group,treatment with non-RASIs drugs(HR=2.77,P=0.021)and no treatment/diuretic treatment(HR=7.18,P<0.001)were significantly correlated with HCC occurrence.Conclusion Hypertension increases the risk of HCC in patients with CHB-Cir,suggesting the importance of controlling hypertension in these patients.

Objective To analyze the factors affecting the risk of hepatocellular carcinoma(HCC)in patients with chronic hepatitis B-associated cirrhosis(CHB-Cir)complicated by essential hypertension(EH)and explore the impact of EH on HCC risk in patients with CHB-Cir.Methods This study was conducted among the patients with CHB-Cir with or without EH received antiviral therapy in the Infectious Disease Department,Third Affiliated Hospital of Xinxiang Medical University from January,2017 to January,2024.The cases with insufficient follow-up time or missing data were excluded.The patients were subjected to propensity score matching in a 1:1 ratio to form an EH group and a non-EH group.The Kaplan-Meier method was used to compare the cumulative incidence of HCC between the two groups,and the Cox proportional hazards regression model was used to analyze the risk of HCC and the factors affecting HCC risk.Results A total of 390 CHB-Cir patients(274 male and 116 female patients)were enrolled in this study,including 195 with EH and 195 without EH.In these patients,EH was significantly correlated with the occurrence of HCC(HR=1.69,P=0.002).Multivariate analysis suggested that the male gender(HR=1.73,P=0.005),a family history of liver cancer(HR=2.23,P<0.001),elevated alpha-fetoprotein(HR=2.83,P=0.001),elevated glutathione reductase(HR=1.53,P=0.046),reduced high-density lipoprotein(HR=1.46,P=0.027),and elevated low-density lipoprotein(HR=2.29,P=0.003)were all significantly correlated with HCC occurrence,while elevated triglycerides(HR=0.37,P<0.001)was a protective factor against HCC.In the EH group,treatment with non-RASIs drugs(HR=2.77,P=0.021)and no treatment/diuretic treatment(HR=7.18,P<0.001)were significantly correlated with HCC occurrence.Conclusion Hypertension increases the risk of HCC in patients with CHB-Cir,suggesting the importance of controlling hypertension in these patients.

Objective:To observe the development process of the neuronal synapse in cerebral cortex and basal ganglionic eminence(GE)regions of the mice,and to clarify the differences in the development of excitatory and inhibitory synapses in different brain regions in vivo and in vitro.Methods:The female C57BL/6 mice were euthanized by cervical dislocation from the 13.5th day to the 15.5th day during the pregnancy,and the embryos were collected under the sterile conditions.The cortex and GE regions of brain tissue of the embryonic mice were gradually isolated under microscope.The primary neurons from the embryonic mice were cultured in vitro,and the cell samples were collected on the 3rd,7th,14th,and 21th days,respectively,and regarded as culture 3 d,7 d,14 d,and 21 d groups.The expression levels of postsynaptic density 95(PSD95)and Gephyrin mRNA in the primary neurons from the cortex and GE regions of the mice in various groups were detected by real-time fluorescence quantitative PCR(RT-qPCR)method.Immunofluorescence method was used to detect the expression levels of vesicular glutamate transporter 1(vGLUT1),PSD95,vesicular GABA transporter(vGAT),and Gephyrin proteins in the neurons from the cortex and GE regions of the mice in various groups.Immunofluorescence method was also used to detect the expression levels of vGLUT1 and vGAT proteins in the neurons from the cortical and GE regions in brain tissue of the embryonic mice.Results:Compared with culture 3 d group,the expression levels of PSD95 and Gephyrin mRNA in cortex and GE regions of the mice in culture 14 d and 21 d groups were significantly increased(P<0.01).Compared with cortex area,the expression level of Gephyrin mRNA in the neurons from GE region of the mice in culture 14 d group was significantly decreased(P<0.01).The microscope observation results showed that the excitatory and inhibitory synapses in the neurons from cortex and GE regions of the mice in culture 14 d group showed preliminary development,with positive expression of relevant proteins;among them,the excitatory synaptic proteins showed more distinct positive expression in the cortex neurons,and the presynaptic vGLUT1 and postsynaptic PSD95 molecules exhibited co-localization in the cell bodies and protrusions of the cortical neurons;the inhibitory presynaptic vGAT protein and postsynaptic Gephyrin protein in the neurons from GE region also exhibited co-localization in the cell bodies and protrusions,and there were more distinct expressions of the presynaptic molecule proteins than postsynaptic molecule proteins.Compared with cortex region,the levels of vGLUT1 and PSD95 proteins in the neurons from GE region of the mice in culture 14 d group were significantly decreased(P<0.01),while the levels of vGAT and gephyrin proteins were significantly increased(P<0.01).In culture 21 d group,the positive expressions of synaptic protein in the neurons from cortex and GE regions were increased,and the excitatory and inhibitory synapses further matured and enhanced.In the neurons from cortex and GE regions,rich patterns of corresponding pre-and postsynaptic expression were formed in the cell bodies and protrusions,and synapse structures showed gradual,positive development,with more apparent expression of presynaptic molecules compared wih postsynaptic proteins.Compared with cortex region,the levels of vGLUT1 and PSD95 proteins in the neurons from GE region of the mice in culture 21 d group were significantly decreased(P<0.01),and the levels of vGAT and Gephyrin proteins were significantly increased(P<0.01).Compared with cortex region,the expression level of vGLUT1 protein in the neurons from GE region in brain tissue of the embryonic mice was significantly decreased(P<0.01),while the expression level of vGAT protein was significantly increased(P<0.05).Conclusion:There are distinct differences in synaptic development between the neurons from cortex and GE regions,the excitatory synapses develope earlier in the cortical region and the inhibitory synapses develope earlier in the GE region.The region-specific development of synapses suggests that different types of neural diseases with different cell types might originate from different developmental processes.