[摘 要] 目的：评估放疗作为原位疫苗的联合治疗模式在晚期软组织肉瘤（STS）患者中的有效性和安全性。方法：回顾性分析2020年12月至2024年9月期间在南京大学医学院附属鼓楼医院肿瘤中心接受联合治疗模式的12例晚期STS患者的临床资料。12例患者均接受了联合治疗。放疗主要以大分割为主。靶向治疗：安罗替尼10例、阿帕替尼2例。免疫治疗以PD-1抗体为主。主要研究终点为疾病控制率（DCR），次要研究终点为客观有效率（ORR）及安全性。结果：接受联合治疗的12例STS患者中有0例CR，4例PR，7例SD，1例PD。ORR为33%，DCR为91.7%，其中靶病灶的DCR为100%。12例患者中，9例出现Ⅰ~Ⅱ级不良反应。最常发生的血液学不良反应是贫血（6例）、肝功能检查结果异常（3例）。最常发生的非血液学不良反应是尿蛋白（5例）、高血压（4例）、甲状腺功能异常（3例）、厌食（3例）、恶心呕吐（2例）；仅2例发生Ⅲ级血液毒性，有1例发生Ⅲ级气胸。结论：放疗作为原位疫苗的联合治疗模式在晚期STS患者中展现出较高的DCR，且未出现严重不良反应。该联合治疗模式具有良好的有效性与安全性。

ObjectiveTo investigate the protective effects and mechanisms of Zhenzhu Tiaozhi capsules on the kidneys in the mouse model of diabetic kidney disease. MethodsThirty male C57BL/6J mice were selected as experimental objects. The model of diabetic kidney disease was induced by intraperitoneal injection of streptozotocin （STZ） at 40 mg·kg^-1 for 5 days combined with a high-fat diet （HFD）. Fasting blood glucose （FBG） ≥ 11.1 mmol·L^-1， increased urine volume， and continuous appearance of proteinuria indicated successful modeling. Mice were grouped as follows： Blank， model， low- and high-dose （0.98 and 1.96 g·kg^-1， respectively） Zhenzhu Tiaozhi capsules， and losartan potassium （30 mg·kg^-1）， with six mice in each group. After 12 weeks of continuous gavage， urine and kidney specimens were collected， and the 24-h urinary protein and the urinary albumin-to-creatinine ratio （UACR） in mice were measured. Hematoxylin-eosin （HE） staining， periodic acid-Schiff （PAS） staining， and Masson staining were performed for observation of histopathological changes in kidneys. Immunofluorescence assay was employed to detect the positive expression of the podocyte marker protein nephrin. Oil red O staining was used to detect renal lipid deposition. Enzyme linked immunosorbent assay was employed to measure the levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in the renal tissue. Western blot was employed to determine the expression levels of sterol regulatory element-binding protein cleavage-activating protein （SCAP）， sterol regulatory element-binding protein-1c （SREBP-1c）， and NOD-like receptor protein 3 （NLRP3） in the renal tissue. ResultsCompared with the blank group， the model group showed increases in 24-h urinary protein and UACR （P<0.05）， glomeruli exhibiting capsule adhesion， collagen fiber deposition， mesangial proliferation， and inflammatory cell infiltration， elevated levels of IL-1β， IL-6， and TNF-α （P<0.05）， reduced positive expression of nephrin （P<0.05）， increased lipid deposition （P<0.05）， and up-regulated expression of SCAP， SREBP-1c， and NLRP3 （P<0.05） in the renal tissue. Compared with the model group， the treatment with losartan potassium or high-dose Zhenzhu Tiaozhi capsules for 12 weeks decreased 24-h urinary protein and UACR （P<0.05）， and the treatment with low-dose Zhenzhu Tiaozhi capsules for 12 weeks reduced the 24-h urinary protein （P<0.05）. Pathological staining results revealed that kidney damage in mice from all treatment groups was alleviated， with reduced inflammatory infiltration， collagen fiber deposition， and mesangial proliferation， and increased positive expression of nephrin in the renal tissue （P<0.05）. In addition， all the treatment groups showed reduced lipid droplets （P<0.05）， lowered levels of IL-1β， IL-6， and TNF-α （P<0.05）， and down-regulated expression of SCAP， SREBP-1c， and NLRP3 （P<0.05） in the renal tissue. ConclusionZhenzhu Tiaozhi capsules can ameliorate kidney damage in the mouse model of diabetic kidney disease by inhibiting the activation of the SCAP-SREBP-1c/NLRP3 signaling pathway， which reduces renal lipid deposition and inflammation.

ObjectiveTo investigate the protective effects and mechanisms of Zhenzhu Tiaozhi capsules on the kidneys in the mouse model of diabetic kidney disease. MethodsThirty male C57BL/6J mice were selected as experimental objects. The model of diabetic kidney disease was induced by intraperitoneal injection of streptozotocin （STZ） at 40 mg·kg^-1 for 5 days combined with a high-fat diet （HFD）. Fasting blood glucose （FBG） ≥ 11.1 mmol·L^-1， increased urine volume， and continuous appearance of proteinuria indicated successful modeling. Mice were grouped as follows： Blank， model， low- and high-dose （0.98 and 1.96 g·kg^-1， respectively） Zhenzhu Tiaozhi capsules， and losartan potassium （30 mg·kg^-1）， with six mice in each group. After 12 weeks of continuous gavage， urine and kidney specimens were collected， and the 24-h urinary protein and the urinary albumin-to-creatinine ratio （UACR） in mice were measured. Hematoxylin-eosin （HE） staining， periodic acid-Schiff （PAS） staining， and Masson staining were performed for observation of histopathological changes in kidneys. Immunofluorescence assay was employed to detect the positive expression of the podocyte marker protein nephrin. Oil red O staining was used to detect renal lipid deposition. Enzyme linked immunosorbent assay was employed to measure the levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in the renal tissue. Western blot was employed to determine the expression levels of sterol regulatory element-binding protein cleavage-activating protein （SCAP）， sterol regulatory element-binding protein-1c （SREBP-1c）， and NOD-like receptor protein 3 （NLRP3） in the renal tissue. ResultsCompared with the blank group， the model group showed increases in 24-h urinary protein and UACR （P<0.05）， glomeruli exhibiting capsule adhesion， collagen fiber deposition， mesangial proliferation， and inflammatory cell infiltration， elevated levels of IL-1β， IL-6， and TNF-α （P<0.05）， reduced positive expression of nephrin （P<0.05）， increased lipid deposition （P<0.05）， and up-regulated expression of SCAP， SREBP-1c， and NLRP3 （P<0.05） in the renal tissue. Compared with the model group， the treatment with losartan potassium or high-dose Zhenzhu Tiaozhi capsules for 12 weeks decreased 24-h urinary protein and UACR （P<0.05）， and the treatment with low-dose Zhenzhu Tiaozhi capsules for 12 weeks reduced the 24-h urinary protein （P<0.05）. Pathological staining results revealed that kidney damage in mice from all treatment groups was alleviated， with reduced inflammatory infiltration， collagen fiber deposition， and mesangial proliferation， and increased positive expression of nephrin in the renal tissue （P<0.05）. In addition， all the treatment groups showed reduced lipid droplets （P<0.05）， lowered levels of IL-1β， IL-6， and TNF-α （P<0.05）， and down-regulated expression of SCAP， SREBP-1c， and NLRP3 （P<0.05） in the renal tissue. ConclusionZhenzhu Tiaozhi capsules can ameliorate kidney damage in the mouse model of diabetic kidney disease by inhibiting the activation of the SCAP-SREBP-1c/NLRP3 signaling pathway， which reduces renal lipid deposition and inflammation.

OBJECTIVE: To observe the effects of electroacupuncture (EA) on improving motor function and regulating microglial activation based on Notch receptor 1 (Notch1)/Hes family bHLH transcription factor 1 (Hes1) pathway in mice with Parkinson's disease (PD). METHODS: Thirty-six male C57BL/6 mice were randomly divided into a control group, a model group and an EA group, 12 mice in each group. PD model was established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days in the model group and the EA group. From the 1st day of modeling, EA was applied at "Baihui" (GV20) and bilateral "Shenshu" (BL23) in the EA group, with continuous wave, in frequency of 2 Hz and current of 2 mA, 15 min a time, once a day for 14 days continuously. The behavioral performance was evaluated by gait test, pole climbing test and hanging test, the number of positive cells of tyrosine hydroxylase (TH) and the co-expression positive cells of Notch1/ionized calcium binding adaptor molecule 1 (Iba-1) in the substantia nigra of midbrain was assessed by immunofluorescence, the protein expression of TH, α-synuclein (α-syn), Notch1, Hes1, Iba-1, inducible nitric oxide synthase (iNOS), Arginase-1 (ARG1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 was detected by Western blot, the mRNA expression of Notch1 and Hes1 was detected by real-time PCR. RESULTS: Compared with the control group, in the model group, the stride frequency was accelerated (P<0.001) and the stride length was shortened (P<0.001) for the four limbs, the pole climbing test time was prolonged (P<0.01) and the grip level was reduced (P<0.01); in the substantia nigra of midbrain, the number of positive cells of TH was decreased (P<0.001), the number of co-expression positive cells of Notch1/Iba-1 was increased (P<0.001), the protein expression of α-syn, Notch1, Hes1, Iba-1, iNOS, TNF-α, IL-1βand IL-6 was increased (P<0.01, P<0.05, P<0.001), the protein expression of TH, ARG1 and IL-10 was decreased (P<0.01, P<0.001), the mRNA expression of Notch1 and Hes1 was increased (P<0.01). Compared with the model group, in the EA group, the stride frequency was decelerated (P<0.001) and the stride length was increased (P<0.05, P<0.01, P<0.001) for the four limbs, the pole climbing test time was shortened (P<0.05) and the grip level was increased (P<0.05); in the substantia nigra of midbrain, the number of positive cells of TH was increased (P<0.01), the number of co-expression positive cells of Notch1/Iba-1 was decreased (P<0.001), the protein expression of α-syn, Notch1, Hes1, Iba-1, iNOS, TNF-α, IL-6 and IL-1β was decreased (P<0.05, P<0.01), the protein expression of TH, ARG1 and IL-10 was increased (P<0.05, P<0.001, P<0.01), the mRNA expression of Notch1 and Hes1 was decreased (P<0.05). CONCLUSION EA can improve the behavioral performance and protect the dopaminergic neurons in PD mice, its mechanism may relate to the inhibition of Notch1/Hes1-mediated neuroinflammation, thus inhibiting the microglial activation.
Animals ; Electroacupuncture ; Microglia/metabolism* ; Male ; Receptor, Notch1/metabolism* ; Parkinson Disease/physiopathology* ; Transcription Factor HES-1/metabolism* ; Mice ; Mice, Inbred C57BL ; Humans ; Signal Transduction

Objective:To explore the efficacy and safety of tislelizumab combined with zanubrutinib in the treatment of refractory diffuse large B-cell lymphoma (DLBCL).Methods:A prospective observational study was conducted. A total of 10 patients with refractory DLBCL admitted to Beijing Chaoyang District Third Ring Cancer Hospital, a specialist medical consortium of Cancer Hospital Chinese Academy of Medical Sciences from November 2020 to February 2023 were prospectively collected. All the 10 refractory DLBCL patients at least received first-line systemic therapy containing rituximab; and they were given tislelizumab 200 mg, intravenous infusion, on day 1 and zanubrutinib 160 mg, orally, twice a day, day 1-day 21, with 21 days as 1 cycle; 6 patients received second-line therapy and 4 patients received ≥ third-line therapy. Subsequent regimens were added with rituximab (375 mg/m 2, intravenous infusion on day 1). The primary endpoint will be reached 12 months after enrollment if there was no disease progression or other events that were scheduled to withdraw from the study. The therapeutic efficacy was summarized at the end of the follow-up in March 2023. Kaplan-Meier method was used to make survival analysis and the adverse reactions were summed up. Results:There were 6 males and 4 females, all at stage Ⅲ-Ⅳ; and age [ M ( Q1, Q3)] was 55 years (50 years, 69 years). All 10 patients completed 90 cycles of treatment with tislelizumab and zanubrutinib, with the cycle number of 8 cycles (2 cycles, 24 cycles). The follow-up time was 19 months (11 months, 28 months); 4 cases achieved complete remission, 3 cases achieved partial remission and 1 case had the stable disease. The progression-free survival was 8.5 months (1.3 months, 27.0 months); the median remission duration time and median overall survival time were not reached. Treatment-related adverse reactions included 2 cases of neutropenia, 1 case of anemia, and 1 case of elevated alanine aminotransferase and aspartate aminotransferase, all of which were grade 1-2. Conclusions:Tislelizumab combined with zanubrutinib has good clinical efficacy and safety in the treatment of refractory DLBCL.

Objective To compare the safety and clinical efficacy of lesion removal combined with percutaneous pedicle screw fixation with classical posterior lesion removal in the treatment of lumbar brucelli spondylitis(LBS)by unilateral biportal endoscopic technique with transforaminal lumbar interbody fusion(UBE-LIF)technique.Methods The clinical data of 32 patients with LBS admitted by the Department of Spine and Orthopedics of Gansu Provincial Hospital of Traditional Chinese Medicine from January 2020 to January 2022 were retrospectively analyzed,and the clinical data of the 32 LBS patients were divided into 15 cases in the UBE-LIF group and 17 cases in the posterior group.The general data,surgery-related indexes,and postoperative pathological HE staining of the two groups were recorded and analyzed.The patients'clinical recovery was assessed according to their erythrocyte sedimentation rate(ESR)and C-reactive protein(CRP),low back pain visual analogue score(VAS),Japanese Orthopaedic Association(JOA)score,and Oswestry Dysfunction Index(ODI)preoperative,1 week after surgery,1,3,6 months and 1 year after surgery.Lumbar lordosis angle(LL)and intervertebral space height(DH)were measured by imaging before surgery and at the last follow-up,and intervertebral bone graft fusion was assessed using Suk grading criteria.Results Both groups successfully completed the operation and no serious postoperative complications occurred.There were no significant differences in gender,age,surgical segment,operation time,preoperative ESR and CRP,preoperative VAS,JOA score and ODI index,preoperative LL and DH(P＞0.05).The intraoperative blood loss,postoperative drainage,postoperative getting out of bed,and postoperative hospital stay in UBE-LIF group were significantly lower than those in the posterior group(P＜0.001).Pathological examination of diseased tissues was performed during surgery,all of which was consistent with brucellosis changes.Patients in both groups were followed up for 12-18 months,with an average of 14.8 months.The VAS,JOA score,and ODI index at all postoperative time points in the two groups were significantly improved compared with the preoperative period(P＜0.05).The difference between the two groups was significantly greater than that in the postoperative group:VAS score was lower in UBE-LIF group than in the posterior group(P＜0.01),CRP in both groups was higher than that in the preoperative group,and the elevation level was significantly lower in UBE-LIF group than in the posterior group(P＜0.001).There was no significant difference in ESR between the two groups compared with that before surgery(P＞0.05).There were no significant differences in VAS,JOA score,ODI index,CRP or ESR between the remaining time points after surgery(P＞0.05).At the last follow-up,imaging examination showed that the overall fusion rate of intervertebral bone graft in UBE-LIF group was 93.3％and 94.1％in the posterior group,without significant difference(x2=0.246,P=0.884).LL and DH were significantly improved in both groups compared with preoperative ones(P＜0.01),and the two groups did not significantly differ before and after surgery(P＞0.05).Conclusion Both surgical treatments for LBS are safe effect.Compared with posterior lesion removal bone graft fusion internal fixation,UBE-LIF technology combined with percutaneous pedicle screw internal fixation has the advantages of clear intraoperative vision,less blood loss,faster early postoperative recovery,and shorter postoperative hospital stay,and thus is a feasible surgical method for the minimally invasive treatment of LBS.

Objective:To evaluate the reliability and validity of different quantitative methods based on CT images to evaluate the proportion of shoulder glenoid defect.Methods:Four shoulder joint specimens with no trauma, osteoarthritis or deformity were used, including 2 females and 2 males; the average age of death was 58±10 years old; all the specimens were prepared with a standard method with no bone defect occurring before preparation. A glenoid bone defect model was established with each specimen being cut into four defect gradient defects of approximately 8%, 16%, 24%, and 32% in proportion in sequence. A total of 16 samples were obtained. Physical photography and CT image reconstruction were performed on the 16 samples respectively. A total of 8 quantitative methods were used to quantify bone defects, which were surface area method, superimposed circle method, Barchilon method, Pico method, Shaha method, Griffith method, Sugaya method, and Giles method. Intraclass correlation (ICC) using a consistency model was used to evaluate reliability. Paired t-test was used to evaluate validity, with the physical measurement of the specimens using the surface area method as the reference standard. Result:The consistency ICC of each quantitative method was greater than 0.9, and all had high reliability. Combining the results of all bone defect gradients and imaging images, the surface area method had the best validity, which was 0.83%±0.75%; the Barchilon method came second, which was 0.91%±0.93%; the superimposed circle method and the Pico method had good validity, which were 0.99%±0.87% and 1.27%±1.09%, respectively; the Shaha method, the Griffith method, and the Sugaya method had poor validity, which were 6.11%±1.56%, 5.06%±1.35%, and 6.02%±1.61%, respectively; the Giles method had the worst validity, which was 8.40%±3.08%. Conclusion:In clinical practice, surface area method and superimposed circle method are the most reliable to quantify the proportion of bone defect if they can be performed. Otherwise, linear measurement of Barchilon method is the favored method while PICO method is the favored method for angle measurement.

Objective To explore the safety and mid-term efficacy of autologous hamstring tendon implantation in the treatment of severe anterior vaginal wall prolapse.Methods We performed a prospective single arm clinical study.From May 2021,pelvic organ prolapse(POP)patients with severe anterior vaginal wall prolapse as the main cause who had symptoms and required surgical treatment were included.The patient was fully informed and voluntarily selected autologous hamstring tendon implantation and high sacral ligament suspension.Postoperative follow-ups were carried out on the Pelvic Organ Prolapse Quantification(POP-Q),Pelvic Floor Distress Inventory-Short Form 20(PFDI-20),postoperative satisfaction score,and Patient Global Impression of Improvement(PGI-I).Function of the lower limb on the tendon removal side,as well as postoperative complications and re-operations were recorded.Results The operation time of tendon removal was(19.7±8.3)min,the operation time of pelvic floor was(122.1±37.8)min,the median intraoperative bleeding volume was 70 ml(range,50-400 ml),and there was no intraoperative co-morbidity or postoperative fever.A total of 12 cases were followed up for(26.4±2.5)months.The measured values of Aa,Ba,and C were 3(-1-3),5(2-10),and 4(-1-10)before operation and-3(-3-3),-3(-3-3),and-6(-6-3)at 24 months after operation,respectively,with significant difference(P＜0.05).The PFDI-20 scores of the 12 patients before surgery and at 24 months after surgery were 88.0 points(range,16.7-204.2 points)and 8.3 points(range,0-32.3 points),respectively,with significant difference(Z=-2.803,P=0.005).The PGI-I questionnaire showed 11 patients with significant improvement in postoperative symptoms and 1 patient with improvement.The satisfaction scores at 6 and 24 months after surgery were(4.8±0.4)points and(4.6±0.7)points,respectively.One patient experienced vaginal prolapse at 12 months after surgery,with a Ⅲ degree prolapse of the anterior wall and vaginal vault,the recurrence rate being 8.3％(1/12).Two patients had pulmonary embolism at 9 d and 2 weeks after surgery,with Clavien-Dindo Ⅱ and Ⅲ grades,and recovered after outpatient and hospitalization treatment.One patient was found fascia exposure at the vagina,and had improvement with medication treatment.All the patients had good wound healing at the tendon removal site,with normal muscle strength and lower limb activity.No re-operation was required due to recurrence or complications of tendon surgery.Conclusions Autologous hamstring tendon implantation is safe in the treatment of severe anterior vaginal wall prolapse with satisfactory mid-term efficacy.Before surgery,it is necessary to educate patients on lower limb exercise to prevent complications of venous thrombosis.

Objective:To investigate the teaching effect of the single-circulation organ system integration course Nervous System and Disease for pediatrics 5+3 program, to guide the teaching practice of the integration course, and to promote the education and teaching reform of pediatrics.Methods:A total of 56 students of the class of 2019 in the pediatrics 5+3 program of Shanghai Jiao Tong University School of Medicine were selected as subjects, and the single-circulation organ system integration course was used for teaching. With the course of Nervous System and Disease as an example, evaluation results and questionnaires were used to assess the teaching effect of the single-circulation organ system course for pediatrics from the aspects of general information, course scores, student satisfaction, and expert supervision. SPSS 22.0 was used to perform descriptive statistics and analyses.Results:The course of Neurological System and Diseases integrated the contents of 11 related disciplines, with a mean score of (74.60±7.52) points. The scores of the students for course content, teaching mode, teaching resources, teaching effect, and the degree of overall satisfaction with the course were (4.71±0.54), (4.35±0.81), (4.50±0.69), (4.50±0.72), and (4.30±0.66), respectively. The score of expert supervision was (26.38±2.06) for teaching content and (26.52±2.03) for teaching methods, which still needed to be improved.Conclusions:The construction of the single-circulation organ system integration course provides new ideas for the curriculum reform of pediatrics; however, it is necessary to improve the construction of system and mechanism, explore the coordinated development of teachers, and strengthen deep integration and student guidance, thereby improving the teaching effect of the integrated course of pediatrics and promoting the training of medical talents in pediatrics.

Objective:To investigate the lipidomics differences of CD4+T immune cells in diabetic kidney disease(DKD)mice,and screen out the differential metabolites with biological significance.Methods:CD4(L3T4)MicroBeads immunomagnetic beads were used to isolate CD4+T immune cells from spleen of BKS.Cg-Dock7m+/+Leprdb/J mice with spontaneous DKD;the purity of CD4+T cells were identified by flow cytometry.The non-targeted lipidomics of CD4+T cells were detected by LC-MS/MS,and the differ-ential metabolites were analyzed.Results:A total of 463 metabolites were detected by LC-MS.PCA and OPLS-DA analysis showed that the metabolic components were significantly separated;twenty-four differential metabolites were screened out.KEGG and enrich-ment analysis showed that the differential metabolites involved in the disorder of glycerol phospholipid metabolism.Conclusion:Phos-pholipid metabolism of CD4+T cells is closely related to the occurrence of DKD.Phospholipid metabolism targeting DKD CD4+T cells in DKD may be a new direction of DKD treatment.