Neonatal diabetes mellitus （NDM） is a rare monogenic disorder primarily caused by insufficient insulin secretion resulting from mutations in the KCNJ11 and ABCC8 genes. Sulfonylureas， represented by glibenclamide， have become the standard therapy for this type of NDM by precisely closing the mutated ATP-sensitive potassium channels in pancreatic β cells， thereby restoring insulin secretion. Clinical studies confirm that sulfonylureas enable over 90% of patients to successfully transition from insulin to oral treatment， achieving long-term stable glycemic control and improving neurological outcomes to a certain extent. In terms of safety， severe hypoglycemia induced by sulfonylureas is relatively rare and gastrointestinal reactions are mild； moreover， sulfonylureas show good long-term tolerability， and have no adverse effects on child growth and development. In the future， by further refining the full-chain management pathway of “rapid genetic diagnosis-early intervention-specialized dosage forms-long-term follow-up”， the clinical application of sulfonylureas is expected to provide NDM patients with an optimized treatment regimen and maximize their health benefits.

The occurrence and development of type 2 diabetes mellitus(T2DM)are closely as-sociated with defects in insulin secretion.Synaptosomal-associated protein 25(SNAP25),as a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)complex,directly mediates the fusion of insulin secretion granules with the cell membrane and regu-lates the dynamic balance of insulin secretion stimulated by glucose.The expression defect of SNAP25 in patients with T2DM and model animals directly leads to vesicle fusion disorder,constituting the core pathological link of insulin secretion disorder and exacerbating the deterioration of β-cell func-tion.SNAP25 may serve as a key hub for multi-target synergistic intervention,and its genetic poly-morphism and the plasticity of its regulatory network offer novel strategies for precision therapy.This article innovatively integrated multidimensional regulatory mechanisms,including calcium channel ac-tivity,G-protein-coupled signaling and epigenetic modifications,to systematically analyze the spatio-temporal-specific regulatory network of SNAP25 in insulin secretion,providing a theoretical basis for T2DM therapeutic strategies targeting vesicle fusion.

Objective:To explore the molecular mechanism by which interferon regulatory factor 1 (IRF1) affects hepatic ischemia-reperfusion injury (HIRI) by regulating the polarization of Kupffer cells.Methods:Twelve male healthy C57BL/6 wild-type mice weighing 20-25 g and aged 6-8 weeks were divided into a sham operation group ( n=6) and a HIRI group ( n=6); Twelve male healthy C57BL/6 IRF1 gene knockout (IRF1 -/-) mice weighing 20-25 g and aged 6-8 weeks were divided into a sham operation IRF1 -/- group ( n=6) and a HIRI IRF1 -/- group ( n=6). The levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) in mice were measured, and hematoxylin-eosin (HE) staining of liver tissues was performed for Suzuki scoring to evaluate liver injury. Fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to evaluate the mRNA levels of IRF1 and tumor necrosis factor α (TNFα) in liver tissues. Flow cytometry and qRT-PCR were used to detect the proportion and functional changes of M1/M2-type Kupffer cells in liver tissues. IRF1 was overexpressed or knocked down in the mononuclear macrophage cell line ANA1, and a co-culture and hypoxia-reoxygenation system with the hepatocyte cell line AML12 was established. Flow cytometry was used to detect the apoptosis of AML12 cells. Results:At 12 hours after hepatic ischemia-reperfusion in wild-type mice, the liver tissue injury was the most severe. Compared with the sham operation group, the levels of serum ALT [(8 073±83) U/L vs. (81±19) U/L, q=13.59] and AST [(11 170±2 890) U/L vs. (412±210) U/L, q=13.77] in the HIRI group were significantly higher, and the differences were statistically significant (both P<0.001). The Suzuki score reached 5-6 points. At 12 hours after hepatic ischemia-reperfusion in IRF1 gene knockout mice, the liver tissue injury was not obvious. There were no significant differences in the levels of serum ALT [668 (514, 2 344) U/L vs. 254 (147, 285) U/L, q=2.52, P=0.348] and AST [1 936 (1 262, 2 003) U/L vs. 628 (423, 759) U/L, q=1.22, P=0.824] between the HIRI IRF1 -/- group and the sham operation IRF1 -/- group. Compared with the HIRI group, the ratio of M1/M2-type Kupffer cells in the liver of the HIRI IRF1 -/- group decreased [(0.958±0.090) vs. (2.788±0.258), q=2.06, P<0.0001], and the mRNA expression of TNFα decreased [(4.363±0.393) vs. (12.900±5.504), q=5.59, P=0.018], and the differences between the two groups were statistically significant. In the co-culture and hypoxia-reoxygenation experiment using ANA1 cells overexpressing IRF1 and AML12 cells, the proportion of AML12 hepatocytes in late apoptosis was higher than that in the control group [(14.05±4.25) vs. (3.15±1.16), t=2.85, P=0.047], and the difference was statistically significant. In contrast, when the expression of IRF1 was knocked down, the proportion of apoptotic AML12 cells decreased [(9.26±3.04) vs. (13.36±4.64), t=2.15, P=0.098], but the difference was not statistically significant. Conclusion:The IRF1 protein can regulate the polarization of Kupffer cells into M1-type macrophages, promote the inflammatory injury of the liver tissue after ischemia-reperfusion, and increase the apoptosis of hepatocytes.

Objective:To investigate the clinical manifestations, long-term survival, and prognosis of childhood T-cell acute lymphoblastic leukemia (T-ALL).Methods:Case summary.The clinical data of 43 T-ALL children who were diagnosed and treated in Children′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2010 to December 2021 were retrospectively analyzed.They were stratified for treatment according to the CCCG-ALL regimen, and the correlation of prognosis with the condition at initial diagnosis, early treatment response, and induced remission was analyzed.The Kaplan-Meier survival curve was used to analyze the survival rate, and the survival rates were compared between groups by the Log-rank test.The multivariate Cox regression model was used to analyze the impact of multiple factors on the long-term survival of children.Results:T-ALL patients accounted for 9.5% (43/451) of the total number of acute lymphoblastic leukemia patients admitted to the hospital at the same period.The median onset age of the 43 T-ALL patients was 7 years (1-13 years).Of the 43 patients included, 14 patients (32.6%) had concomitant mediastinal widening, 8 patients (18.6%) had concomitant giant mediastinal masses, and 4 patients (9.3%) had early precursor T-cell acute lymphoblastic leukemia (ETP-ALL) at initial diagnosis.These 43 children were treated according to the CCCG-ALL intermediate- and high-risk group regimen.Among them, 33 children (76.7%) achieved sustained remission, 5 children died, and 5 children had a relapse.As of September 30, 2024, the median follow-up time was 62 months (1-170 months), the 10-year event-free survival rate was (80.2±6.4)%, and the 10-year overall survival rate was (86.6±5.8)%.The median relapse time and 10-year cumulative relapse rate of the 5 relapsed children were 28 months (7-58 months) and (13.7±5.8)%, respectively.The relationship of prognosis with clinical characteristics at initial diagnosis and induced remission in 43 T-ALL children was analyzed.The results showed that patients aged ≥10 years, with a grade-1 non-central nervous system at initial diagnosis, ETP-ALL, abnormal chromosome number and structure, non-M1 status of bone marrow and minimal residual disease (MRD)≥ 1% on day 19 of induction treatment, and MRD ≥ 0.01% on day 46 to 55 of induction treatment had poorer long-term survival(all P<0.05).The multivariate analysis showed that age ≥10 years, ETP-ALL, and abnormal chromosome number and structure were risk factors of poor prognosis ( P=0.045, 0.030, 0.021). Conclusions:The CCCG-ALL regimen has a good overall therapeutic effect in children with T-ALL.Age ≥10 years, abnormal chromosome number and structure, ETP-ALL, grade-1 non-central nervous system at initial diagnosis, and early remission are risk factors of poor prognosis.Treatment after relapse in children with T-ALL is difficult.

Objective:To explore the molecular mechanism by which interferon regulatory factor 1 (IRF1) affects hepatic ischemia-reperfusion injury (HIRI) by regulating the polarization of Kupffer cells.Methods:Twelve male healthy C57BL/6 wild-type mice weighing 20-25 g and aged 6-8 weeks were divided into a sham operation group ( n=6) and a HIRI group ( n=6); Twelve male healthy C57BL/6 IRF1 gene knockout (IRF1 -/-) mice weighing 20-25 g and aged 6-8 weeks were divided into a sham operation IRF1 -/- group ( n=6) and a HIRI IRF1 -/- group ( n=6). The levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) in mice were measured, and hematoxylin-eosin (HE) staining of liver tissues was performed for Suzuki scoring to evaluate liver injury. Fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to evaluate the mRNA levels of IRF1 and tumor necrosis factor α (TNFα) in liver tissues. Flow cytometry and qRT-PCR were used to detect the proportion and functional changes of M1/M2-type Kupffer cells in liver tissues. IRF1 was overexpressed or knocked down in the mononuclear macrophage cell line ANA1, and a co-culture and hypoxia-reoxygenation system with the hepatocyte cell line AML12 was established. Flow cytometry was used to detect the apoptosis of AML12 cells. Results:At 12 hours after hepatic ischemia-reperfusion in wild-type mice, the liver tissue injury was the most severe. Compared with the sham operation group, the levels of serum ALT [(8 073±83) U/L vs. (81±19) U/L, q=13.59] and AST [(11 170±2 890) U/L vs. (412±210) U/L, q=13.77] in the HIRI group were significantly higher, and the differences were statistically significant (both P<0.001). The Suzuki score reached 5-6 points. At 12 hours after hepatic ischemia-reperfusion in IRF1 gene knockout mice, the liver tissue injury was not obvious. There were no significant differences in the levels of serum ALT [668 (514, 2 344) U/L vs. 254 (147, 285) U/L, q=2.52, P=0.348] and AST [1 936 (1 262, 2 003) U/L vs. 628 (423, 759) U/L, q=1.22, P=0.824] between the HIRI IRF1 -/- group and the sham operation IRF1 -/- group. Compared with the HIRI group, the ratio of M1/M2-type Kupffer cells in the liver of the HIRI IRF1 -/- group decreased [(0.958±0.090) vs. (2.788±0.258), q=2.06, P<0.0001], and the mRNA expression of TNFα decreased [(4.363±0.393) vs. (12.900±5.504), q=5.59, P=0.018], and the differences between the two groups were statistically significant. In the co-culture and hypoxia-reoxygenation experiment using ANA1 cells overexpressing IRF1 and AML12 cells, the proportion of AML12 hepatocytes in late apoptosis was higher than that in the control group [(14.05±4.25) vs. (3.15±1.16), t=2.85, P=0.047], and the difference was statistically significant. In contrast, when the expression of IRF1 was knocked down, the proportion of apoptotic AML12 cells decreased [(9.26±3.04) vs. (13.36±4.64), t=2.15, P=0.098], but the difference was not statistically significant. Conclusion:The IRF1 protein can regulate the polarization of Kupffer cells into M1-type macrophages, promote the inflammatory injury of the liver tissue after ischemia-reperfusion, and increase the apoptosis of hepatocytes.

Objective:To investigate the clinical manifestations, long-term survival, and prognosis of childhood T-cell acute lymphoblastic leukemia (T-ALL).Methods:Case summary.The clinical data of 43 T-ALL children who were diagnosed and treated in Children′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2010 to December 2021 were retrospectively analyzed.They were stratified for treatment according to the CCCG-ALL regimen, and the correlation of prognosis with the condition at initial diagnosis, early treatment response, and induced remission was analyzed.The Kaplan-Meier survival curve was used to analyze the survival rate, and the survival rates were compared between groups by the Log-rank test.The multivariate Cox regression model was used to analyze the impact of multiple factors on the long-term survival of children.Results:T-ALL patients accounted for 9.5% (43/451) of the total number of acute lymphoblastic leukemia patients admitted to the hospital at the same period.The median onset age of the 43 T-ALL patients was 7 years (1-13 years).Of the 43 patients included, 14 patients (32.6%) had concomitant mediastinal widening, 8 patients (18.6%) had concomitant giant mediastinal masses, and 4 patients (9.3%) had early precursor T-cell acute lymphoblastic leukemia (ETP-ALL) at initial diagnosis.These 43 children were treated according to the CCCG-ALL intermediate- and high-risk group regimen.Among them, 33 children (76.7%) achieved sustained remission, 5 children died, and 5 children had a relapse.As of September 30, 2024, the median follow-up time was 62 months (1-170 months), the 10-year event-free survival rate was (80.2±6.4)%, and the 10-year overall survival rate was (86.6±5.8)%.The median relapse time and 10-year cumulative relapse rate of the 5 relapsed children were 28 months (7-58 months) and (13.7±5.8)%, respectively.The relationship of prognosis with clinical characteristics at initial diagnosis and induced remission in 43 T-ALL children was analyzed.The results showed that patients aged ≥10 years, with a grade-1 non-central nervous system at initial diagnosis, ETP-ALL, abnormal chromosome number and structure, non-M1 status of bone marrow and minimal residual disease (MRD)≥ 1% on day 19 of induction treatment, and MRD ≥ 0.01% on day 46 to 55 of induction treatment had poorer long-term survival(all P<0.05).The multivariate analysis showed that age ≥10 years, ETP-ALL, and abnormal chromosome number and structure were risk factors of poor prognosis ( P=0.045, 0.030, 0.021). Conclusions:The CCCG-ALL regimen has a good overall therapeutic effect in children with T-ALL.Age ≥10 years, abnormal chromosome number and structure, ETP-ALL, grade-1 non-central nervous system at initial diagnosis, and early remission are risk factors of poor prognosis.Treatment after relapse in children with T-ALL is difficult.

Objective To investigate the correlations of serum Apelin-13 and fatty acid binding protein 4 (FABP4) levels with metabolic and bone metabolic indicators in postmenopausal women with different bone mass. Methods A total of 145 postmenopausal women were selected as subjects and divided into three groups based on bone mineral density (BMD) test results: normal bone mass group(49 cases), osteopenia (ON) group(51 cases), and osteoporosis (OP) group(45 cases). Serum Apelin-13, FABP4 levels, bone metabolic indicators, and biochemical indicators were measured and compared among the three groups. Spearman correlation analysis was used to analyze the correlations of Apelin-13, FABP4, and other indicators with BMD. Multivariate Logistic regression analysis was performed to analyze the risk factors for OP, and the receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of serum Apelin-13 for postmenopausal osteoporosis (PMOP). Results The serum Apelin-13 level in the OP group was lower than that in the ON group and the normal bone mass group (P < 0.05). No significant difference in serum FABP4 levels was found among the three groups (P>0.05). The levels of serum parathyroid hormone (PTH), alkaline phosphatase (ALP), type Ⅰ procollagen amino-terminal propeptide (PⅠNP), type Ⅰ collagen cross-linked C-terminal peptide (CTXⅠ), and bone-specific alkaline phosphatase (BALP) in the OP group were higher than those in the ON group and the normal bone mass group (P < 0.05). Lumbar post-menopause BMD was positively correlated with serum Apelin-13 levels (P < 0.05), but had no correlation with serum FABP4 levels (P>0.05). Lumbar BMD was negatively correlated with serum PTH, ALP, PⅠNP, CTXⅠ, BALP, and age (P < 0.05), but positively correlated with body weight, body mass index, T-score, fasting insulin, and insulin resistance index (P < 0.05). Multivariate Logistic regression analysis showed that serum Apelin-13, PTH, ALP, PⅠNP, CTXⅠ, and BALP levels were independent factors influencing the occurrence of OP in postmenopausal women (P < 0.05). ROC curve results showed that the optimal cut-off value of serum Apelin-13 for predicting PMOP was 18.51 pg/mL, with an area under the curve of 0.716, a sensitivity of 70.0%, and a specificity of 64.4%. Conclusion Apelin-13 is lowly expressed in the serum of PMOP patients, and its expression level is closely related to lumbar BMD, which may serve as an early screening indicator and potential therapeutic target for PMOP.

Objective:To assess the clinical efficacy and safety of image-guided γ-ray stereotactic body radiation therapy(IG γ-SBRT)in treating advanced pancreatic cancer.Methods:A total of fifty-six patients with advanced pancreatic cancer admitted to Senior Department of Oncology Medicine of the Fifth Medical Center of Chinese PLA General Hospital(Department of Oncology of the Sixth Medical Center)from February 2017 to September 2020 were selected.All patients were treated with IG γ-SBRT,and the 50%-60%of isodose curve covered the planned target volume(PTV).The peripheral dose of each time was 3.0-4.5 Gy,and there were 10-11 times of treatment.The therapeutic effect was observed and was evaluated by follow-up.The visual analog scale(VAS)score was adopted to assess the situation of the pain of patients before and 3 months after treatment,and the adverse reaction of them.Results:In the 56 patients,52 cases occurred epigastric pain with VAS ranging from 3 to 10 points,among which 32 patients accompanied by symptoms such as lower back pain and abdominal distension.After 3 months of treatment,the results of reexamination and follow-up indicated that there were 48 patients whose VAS scores decreased 3 scores and above 3 scores on the basis of original scores,and the efficiency of treating pain was 92.3%.In addition,the VAS scores of 3 patients decreased 1-2 scores on the basis of original scores,which ratio was 5.85%of the total number of people.All 56 patients were reexamined at the 3rd month after treatment,and 13 cases of them obtained complete response(CR),and 37 cases obtained partial response(PR),and 1 case obtained progressive disease(PD),and 5 cases obtained stable disease(SD),and the objectively response rate(ORR)was 89.3%,and the locally control rate was 98.2%.In addition,median progression-free survival(PFS)was 6.5 months,and 1-year survival rate was 62.5%(35/56),and 2-year survival rate was 23.2%(13/56).The adverse reactions of 56 patients were the adverse reactions of digestive system and blood system,among which 47 patients occurred upper digestive tract reaction,and the incidence of adverse reactions was 83.9%(47/56).A total of 43 patients occurred myelosuppression,and the incidence of myelosuppression was 76.8%(43/56).Conclusion:IG γ-SBRT can effectively relieve the symptoms of metastatic pancreatic cancer,and improve the effectiveness of treatment,the local control rate and survival rate.The tolerance of adverse reaction of that is favorable,and the safety of that is higher.

Purpose To investigate the features of conventional and contrast-enhanced ultrasound (CEUS) imaging in renal epithelioid angiomyolipoma (EAML). Materials and Methods We retrospectively analyzed the conventional ultrasound and CEUS images of the 30 patients with renal EAML who were confirmed by pathology in the General Hospital of the PLA from November 2010 to October 2022. The location,size,classfication,echo,boundary,shape,growth pattern and whether color Doppler ultrasound detects blood flow signals were observed by conventional ultrasound. CEUS was used to analyze the wash-in pattern,enhancement direction,peak enhancement intensity,the uniformity after enhancement,wash-out pattern and pseudocapsule sign,respectively. Results A total of 30 patients (n=30 lesions) were enrolled. The maximal diameter of the lesions varied from 1.4 to 12.6 cm. 17 cases occurred in the right kidney and 13 cases in the left kidney. On grayscale ultrasound,28 cases showed solid type,2 were cystic solid;18 cases demonstrated hypoechoic,10 were hyperechoic;the solid component in the cystic solid lesion was isoechoic in 1 case and hyperechoic in 1 case;24 cases displayed well-defined and 19 cases appeared regular shape;22 cases were presented exophytic growth. Color Doppler ultrasound detected blood flow in 24 cases. Of all 30 patients with EAML,CEUS was performed in 13 cases,6 lesions with simultaneous wash-in;10 cases with centripetal enhancement;9 cases with hyper-enhancement;10 cases with homogeneous enhancement;5 lesions with simultaneous wash-out;9 cases with pseudocapsule sign. Conclusion The ultrasonographic appearance of EAML has a tendency to be hypoechoic with exophytic growth and clear boundary on conventional ultrasound images,and centripetal enhancement,homogeneous hyperenhancement and presence of pseudocapsule on CEUS images. All these findings are contributed to the diagnosis of EAML.

Purpose To investigate the features of conventional and contrast-enhanced ultrasound (CEUS) imaging in renal epithelioid angiomyolipoma (EAML). Materials and Methods We retrospectively analyzed the conventional ultrasound and CEUS images of the 30 patients with renal EAML who were confirmed by pathology in the General Hospital of the PLA from November 2010 to October 2022. The location,size,classfication,echo,boundary,shape,growth pattern and whether color Doppler ultrasound detects blood flow signals were observed by conventional ultrasound. CEUS was used to analyze the wash-in pattern,enhancement direction,peak enhancement intensity,the uniformity after enhancement,wash-out pattern and pseudocapsule sign,respectively. Results A total of 30 patients (n=30 lesions) were enrolled. The maximal diameter of the lesions varied from 1.4 to 12.6 cm. 17 cases occurred in the right kidney and 13 cases in the left kidney. On grayscale ultrasound,28 cases showed solid type,2 were cystic solid;18 cases demonstrated hypoechoic,10 were hyperechoic;the solid component in the cystic solid lesion was isoechoic in 1 case and hyperechoic in 1 case;24 cases displayed well-defined and 19 cases appeared regular shape;22 cases were presented exophytic growth. Color Doppler ultrasound detected blood flow in 24 cases. Of all 30 patients with EAML,CEUS was performed in 13 cases,6 lesions with simultaneous wash-in;10 cases with centripetal enhancement;9 cases with hyper-enhancement;10 cases with homogeneous enhancement;5 lesions with simultaneous wash-out;9 cases with pseudocapsule sign. Conclusion The ultrasonographic appearance of EAML has a tendency to be hypoechoic with exophytic growth and clear boundary on conventional ultrasound images,and centripetal enhancement,homogeneous hyperenhancement and presence of pseudocapsule on CEUS images. All these findings are contributed to the diagnosis of EAML.