Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Objective: To investigate the feasibility of magnetic anastomosis for uretero-ileal anastomosis using experimental rabbit models. Methods: Six experimental rabbits were used as the models.The lower part of the left ureter was cut with scissors，the daughter magnet (DM) was placed in the middle of the ureter，and the distal end of the ureter was ligated.After that，the ileum wall was opened，the parent magnet (PM) was inserted through it，the positions of the PM and DM were adjusted so that their ends were attracted to each other，and then ileum wall incision was sutured.The operation time，intraoperative blood loss，postoperative complications and magnet discharge time were recorded.Two weeks after operation，left ureterography was performed to obtain the specimens of the uretero-ileal anastomosis，and to observe the patency of the anastomosis.The formation of the anastomosis was observed with naked eyes and light microscope. Results: Uretero-ileal magnetic anastomosis was performed successfully in 6 experimental rabbits.The operation time was 28-39（32.50±3.94） min，and the intraoperative blood loss was less than 5 mL.The rabbits recovered well after operation，and no complications were observed.All animals survived to the end point of observation.The disconnection time of magnet after operation was 9-13(10.83±1.72) days.The gross specimen showed that the anastomosis was patent.The histological observation showed that the mucosa of the anastomosis was continuous and smooth，and the anastomosis was well formed. Conclusion: Magnetic anastomosis is feasible for uretero-ileal anastomosis with simple operation and good anastomosis formation.After further experimental verification，this technique is expected to be used in clinical practice.

Objective: To explore the correlation between traditional Chinese medicine (TCM) constitution and depressive symptom among school aged children and adolescents, so as to provide evidences for informing constitution based regulation and prevention of depressive symptom. Methods: From June to December 2024, a total of 4 729 students aged 6-14 were recruited by cluster random sampling from 10 primary schools in Baoding (Hebei Province), Heze and Liaocheng (Shandong Province). General information, TCM constitution and depressive symptom were collected. Restricted cubic spline (RCS) models were used to analyze related factors and threshold effects of depressive symptom. Binary Logistic regression was applied to examine the association between depressive symptom and TCM constitution, with subgroup analyses conducted. Results: The detection rate of depressive symptom among the included children and adolescents was 25.82%. RCS analyses indicated non linear associations between depressive symptom and age (inflection point at 10 years old), bedtime (inflection point at 22:00), and wake up time (inflection point at 6:30 ) (all P non linearity <0.01). Linear associations were observed with body mass index (BMI) and sleep duration (all P non linearity > 0.05 ). After adjusting for covariates such as age, BMI and sleep status, binary Logistic regression analyses showed that Yin deficient constitution ( OR =1.26, 95% CI =1.09-1.45) and Phlegm-dampness constitution ( OR =1.42, 95% CI =1.11-1.82) were significantly associated with depressive symptom among children and adolescents (all P <0.05). Conclusions Depressive symptom among school aged children and adolescents is primarily associated with Yin deficiency and Phlegm dampness constitutions in TCM constitution. Active attention should be paid to susceptible TCM constitution among children and adolescents. Targeted health guidance and interventions should be implemented to improve TCM constitution health status for preventing the occurrence of depressive symptom.

ObjectiveTo investigate the mechanism of ferroptosis mediated by long-chain acyl-CoA synthetase 4 （ACSL4） signalling pathway in rats with coronary heart disease with blood stasis syndrome and the intervention effect of Xuefu Zhuyutang. MethodsSPF male SD rats were randomly divided into normal group， sham-operation group， model group， trimetazidine group （5.4 mg·kg^-1）， low-， medium-， and high-dose group （3.51， 7.02，14.04 g·kg^-1） of Xuefu Zhuyutang. The coronary artery left anterior descending ligation method was used to prepare a model of coronary heart disease with blood stasis syndrome， and continuous treatment for 7 d was conducted， while the sham-operation group was only threaded and not ligated. The general macroscopic symptoms of the rats were observed， and indicators such as electrocardiogram， echocardiography， and blood rheology were detected. The pathological morphology of myocardial tissue was observed by hematoxylin-eosin （HE） staining， and the changes in mitochondria in myocardial tissue were observed by transmission electron microscopy. The level of iron deposition in myocardial tissue was observed by Prussian blue staining. The levels of 12-hydroxyeicosatetraenoic acid （12-HETE） and 15-HETE were detected in serum by enzyme-linked immunosorbent assay. A biochemical colourimetric assay was used to detect the levels of Fe²⁺， lipid peroxidation （LPO）， glutathione （GSH）， and T-GSH/glutathione disulfide （GSSG） in myocardial tissue. DCFH-DA fluorescence quantitative assay was employed to detect the levels of reactive oxygen species （ROS）. Western blot and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was adopted to detect the protein and mRNA expressions of glutathione peroxidase 4 （GPX4）， ferritin heavy chain 1 （FTH1）， ACSL4， and ly-sophosphatidylcholine acyltransferase3 （LPCAT3） in myocardial tissue. ResultsCompared with those in the normal group， the rats in the model group were poor in general macroscopic symptoms. The electrocardiogram showed widened QRS wave amplitude and increased voltage， bow-back elevation of the ST segments， elevated T waves， J-point elevation， and accelerated heart rate. Echocardiography showed a significant reduction in left ventricular ejection fraction （LVEF） and left ventricular fraction shortening （LVFS） （P<0.01）. Blood rheology showed that the viscosity of the whole blood （low， medium， and high rate of shear） was significantly increased （P<0.01）. HE staining showed an abnormal structure of myocardial tissue. There was a large area of myocardial necrosis and inflammatory cell infiltration and a large number of connective tissue between myocardial fibers. Transmission electron microscopy showed that the mitochondria were severely atrophy or swelling. The cristae were reduced or even broken， and the matrix was flocculent or even vacuolated. Prussian blue staining showed that there were a large number of iron-containing particles， and the iron deposition was obvious. The content of 12-HETE and 15-HETE in the serum was significantly increased （P<0.01）. The content of Fe²⁺， LPO， and ROS in myocardial tissue was significantly increased （P<0.01）. The content of GSH was significantly decreased （P<0.01）， and T-GSH/GSSG was decreased （P<0.01）. The protein and mRNA expressions of GPX4 and FTH1 in myocardial tissue were both significantly decreased （P<0.05， P<0.01）， while those of ACSL4 and LPCAT3 increased significantly （P<0.01）. Compared with the model group， the general macroscopic symptoms and electrocardiogram results of rats in low-， medium- and high-dose groups of Xuefu Zhuyutang were alleviated， and the differences in LVEF/LVFS ratios were all significantly increased （P<0.05， P<0.01）. The differences in whole-blood viscosity （low， medium， and high rate of shear） were all significantly decreased （P<0.01）. The results of HE staining and transmission electron microscopy showed that the morphology， structure， and mitochondria of cardiomyocytes were improved. The content of 12-HETE and 15-HETE in serum was reduced to different degrees in low-， medium-， and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）. The content of Fe²⁺， LPO， and ROS was significantly reduced in the medium- and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）， and the content of GSH and T-GSH/GSSG was significantly increased （P<0.05， P<0.01）. The protein and mRNA expressions of GPX4 and FTH1 were significantly increased to varying degrees in the medium- and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）， and ACSL4 and LPCAT3 were decreased to different degrees in the low-， medium-， and high-dose groups of Xuefu Zhuyutang （P<0.05， P<0.01）. ConclusionXuefu Zhuyutang can regulate iron metabolism and anti-lipid oxidation reaction to mediate ferroptosis through the ACSL4 signalling pathway， thus exerting a protective effect on rats with coronary heart disease with blood stasis syndrome.

OBJECTIVE: To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease. METHODS: This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used. RESULTS: During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity. CONCLUSION Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Exercise ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; Risk Factors ; United Kingdom/epidemiology* ; Incidence ; Adult

Since the beginning of the new century, advances in understanding the intricate interactions between oncology and the immune system have accelerated the rapid development of immune checkpoint inhibitors for the treatment of non-small cell lung cancer. However, resistance to immunotherapy is inevitable. Therefore, uncovering the mechanisms of immunotherapy resistance, proposing strategies to overcome resistance, and identifying future research directions are imperative. Given the limitations of space in each article, this review will explore the complex mechanisms underlying immunotherapy resistance. These mechanisms involve almost all cell types within the body, excluding foreign cancer cells. Notably, these cells serve as recipients (either inhibitory or stimulatory, or both) and producers of signals, playing different roles in various contexts. At the molecular level, these mechanisms include genetic and epigenetic abnormalities in all cells within the microenvironment, as well as the influence of a variety of protein kinase, growth factors, and cytokines with temporal and spatial heterogeneity. At the macroscopic level, host factors such as nutritional metabolism, comorbidities, and microbiota within the organs, as well as neuro-psychological regulation, influence the efficacy of immunotherapy.

Insulin is an important protein hormone that participates in multiple metabolic pathways.Biosynthetic insulin has been widely used in the treatment of type 1 and type 2 diabetes.Currently,the number of reported cases of insulin overdose both at home and abroad is gradually increasing,and insulin homicide is no longer a means of"committing murder without leaving a trace".At present,there are no systematic protocols for the identification of insulin overdose in the field of forensic medi-cine in China.This article introduces the causes,toxicological characteristics,forensic examination,labo-ratory testing methods and indicator reference of insulin overdose.Based on the identification practice and research results and referring to relevant studies on insulin overdose at home and abroad,this pa-per aims to provide recommendations and references for the formulation of forensic identification guide-lines for insulin overdose cases.

Objective:To establish an HPLC method to simultaneously determine the contents of 7 components, including Cardol triene, Cardol diene, (8'Z,11'Z,14'Z)-5-(Heptadeca-8',11',14'-trienyl)benzene-1,3-diol, Alkylresorcinol B, 5-(8'Z,11'Z-heptadecadienyl)-1,3-benzenediol, Adipostatin A, and 5-(11'Z-heptadecenyl)-resorcinol in Embelia laeta (L.) Mez. Methods:Chromatographic column was Arcus EP-C18(4.6 mm×250 mm, 5 μm); mobile phase was methanol-water (90∶10); column temperature was 25 ℃; flow rate was 1 ml/min; detection wavelength was 220 nm; the injection volume was 10 μl.Results:The 7 compounds in Embelia laeta (L.) Mez showed good linear relationships, which sample recovery rate ranges from 97.69%- 100.62%. The average contents of the 7 components from 9 origins were 3.099 9, 6.246 3, 9.942 8, 4.093 7, 2.180 3, 0.960 2, 1.855 9 mg/g. Conclusion:The established HPLC method for simultaneous determination of the contents of 7 components in Embelia laeta (L.) Mez is feasible, which can provide references for further development and utilization of Embelia laeta (L.) Mez.

Objective To compare the disease burden and evolving trends of major malignant tumors in China and globally from 1990 to 2021,and conduct predictive analysis,so as to provide a reference for formulating prevention and treatment policies for malignant tumor in China.Methods Based on the Global Burden of Disease Database 2021(GBD 2021),descriptive research methods were used to analyze the incidence and mortality of major malignant tumors in China and globally,as well as the changes in their rankings.The Joinpoint log-linear model was applied to analyze trends in age-standardized incidence rates(ASIR)and age-standardized mortality rates(ASMR)of malignant tumors in China and globally from 1990-2021.A Bayesian age-period-cohort(BAPC)model was constructed using R 4.4.0 to predict the incidence trends of malignant tumor in China and globally from 2022 to 2035.Results In 2021,there were 17.2294 million new cases of malignant tumors(excluding non-melanoma skin cancer)and 9.7763 million deaths globally,with an ASIR of 201.06/100,000 and ASMR of 115.11/100,000.In China,4.5375 million new cases and 2.7964 million deaths were reported,with ASIR and ASMR of 221.30/100,000 and 136.36/100,000,respectively.Lung cancer ranked first in both incidence and mortality of malignant tumors in China and globally.Female breast cancer had the second-highest ASIR in China.The number of incident cases and deaths from digestive system malignancies included in this study accounted for 42.0%of the total incident cases and 46.8%of the total deaths from all cancers in China,respectively.From 1990 to 2021,the average annual percentage change(AAPC)for overall ASIR of malignant tumors in China was 0.30,while ASMR declined(AAPC:-0.97).Globally,ASIR decreased slightly(AAPC:-0.10),and ASMR declined(AAPC:-0.78).The BAPC model predicted that by 2035,China's ASIR of malignant tumors may rise to 252.44/100,000,whereas the global ASIR is expected to decrease to 183.05/100,000.Conclusions China has achieved some success in cancer prevention and treatment,but still faces a heavy disease burden,with ASIR and ASMR exceeding global averages and ASIR persistently increasing.Cancer prevention and control work such as health education should be strengthened.Precise prevention and control measures should be taken for key cancer types,and preventive interventions should be focused on the elderly population.

Objective To observe the difference of bone micro-structure in different regions of proximal femur,micro-CT scanning was performed on 30 proximal femur specimens to explain the mechanism of proximal femur fracture and to provide anatomical basis for prosthesis design.Methods Totally 30 intact proximal femur specimens were obtained from 60-80 year-old cadavers.Micro-CT scanning was used to measure the trabecular thickness(Tb.Th),trabecular number(Tb.N),trabecular space(Tb.Sp),connectivity(Conn)and bone mineral density(BMD)and other parameters in 7 regions of proximal femur,including proximal pressure trabecular(PPT),distal pressure trabecular(DPT),femoral head-neck junction(FHNJ),head and neck of femoral neck(HNFN),the base of femoral neck(BPFN),intertrochanteric line(IL)and greater trochanter(GT).Results The bone mineral density of IL and GT were higher than those of BPFN,FHNJ,DPT and PPT.The trabecular thickness of GT was the largest,followed by IL,BPFN and HNFN,and the smallest was FHNJ,DPT and PPT.The trabecular space of IL was larger than that of GT,and the data of both were larger than those of other parts,among which DPT and PPT were the smallest.The trabecular number of IL and GT were the smallest,BPFN,HNFN and FHNJ were larger,and DPT was the largest.The volume fraction of IL was the smallest,BPFN and HNFN were larger,DPT and PPT were the largest.Conclusion The bone density,trabecular thickness,bone volume,and total volume of GT and IL in the proximal femur of elderly patients are all relatively large,so the reason for the high incidence of fractures is not due to weak internal bone microstructure;The bone density,trabecular thickness,and trabecular gap at the proximal and distal ends of the vertical trabecular bone are relatively small.If it is necessary to perform core decompression for prosthesis filling at this location,the design should be conducive to the mechanical conduction of the prosthesis and the regeneration of surrounding bone tissue.