ObjectiveTaking the cuproptosis/oxidative stress pathway as the entry point， this study investigated the effect and mechanism of Liangyi Paste on hepatic lipid deposition in naturally aged mice fed with a high-fat diet. MethodsAfter adaptive feeding， 80 ten-week-old male C57BL/6 mice were used. Thirty of them were randomly divided into three groups （10 mice per group）： The 12-month-old control group （12MCON）， the 15-month-old control group （15MCON）， and the 15-month-old group with a high-fat diet （15MHFD）. The 12MCON and 15MCON groups were continuously fed a standard diet， while the 15MHFD group started receiving a high-fat diet at 12 months of age. Tissue samples were collected at the corresponding time points for each group. The remaining 50 mice were randomly divided into five groups （10 mice per group）： the 20-month-old control group （20MCON）， the model group， and the low-， medium-， and high-dose Liangyi Paste groups （2.91 ， 5.82 ， 11.64 g·kg^-1·d^-1， respectively）. The 20MCON group was continuously fed a standard diet， while the other groups started receiving a high-fat diet at 15 months of age. At 18 months of age， the Liangyi Paste groups were administered the corresponding doses of Liangyi Paste by gavage， while the 20MCON and model groups were given an equal volume of saline by gavage. After 8 weeks of continuous gavage （when the mice reached 20 months of age）， tissue samples were collected. Hepatic TG levels were measured using assay kits； liver histology and lipid deposition were observed via hematoxylin-eosin （HE） and oil red O staining； reactive oxygen species （ROS） were detected by enzyme-linked immunosorbent assay （ELISA）； Cu²⁺， superoxide dismutase （SOD）， and malondialdehyde （MDA） levels were measured by colorimetry； mRNA and protein expression of genes related to cuproptosis and oxidative stress pathways were analyzed by Real-time polymerase chain reaction（Real-time PCR） and Wes automated protein expression system. ResultsCompared with 12MCON， the 15MCON group showed significantly increased hepatic TG， Cu²⁺， ROS， and MDA levels （P<0.01）， decreased SOD （P<0.01）， hepatocyte swelling， and disordered arrangement. The mRNA and protein levels of ferredoxin 1 （FDX1）， dihydrolipoamide S-acetyltransferase （DLAT）， heat shock protein 70 （HSP70）， dihydrolipoamide dehydrogenase （DLD）， pyruvate dehydrogenase E1 subunit-β （PDHB）， nuclear factor erythroid 2-related factor 2 （Nrf2）， and peroxisome proliferator-activated receptor γ （PPARγ） were significantly elevated （P<0.05， P<0.01）. Compared with 15MCON group， the 15MHFD and 20MCON groups exhibited further increases in TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， and aggravated hepatocyte swelling and disorder. There were increased lipid droplets with mild vacuolization in the 15MHFD group， and no significant lipid deposition was observed in the 20MCON group. FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and protein levels were significantly increased （P<0.05， P<0.01）. Compared with 20MCON group， the model group demonstrated markedly elevated TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， severe hepatic steatosis， and upregulated expression of FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and proteins （P<0.05， P<0.01）. All abnormalities were significantly reversed after Liangyi Paste treatment. ConclusionLiangyi paste can ameliorate hepatic lipid deposition in naturally aged mice with a high-fat diet by modulating the cuproptosis/oxidative stress pathway.

Objective To analyze the clinical characteristics and risk factors of extreme thrombocytosis caused by piperacillin sodium and tazobactam sodium injection, and provide reference for medical treatment and pharmaceutical care of such patients. Methods Extreme thrombocytosis of a patient treated with piperacillin sodium and tazobactam sodium injection was found by clinical pharmacists, who participated in clinical diagnosis and treatment by analyzing of the adverse drug reaction, optimization of the medical treatment and pharmaceutical care. Results After correlation analysis, the patient's extreme thrombocytosis was likely to be an adverse reaction caused by the piperacillin sodium and tazobactam sodium injection. The medication was immediately discontinued, and antiplatelet therapy with aspirin was administered. Two weeks later, the patient's platelet count had significantly decreased compared to before. Conclusion Clinical pharmacists participated in patients’ clinical diagnosis and treatment, carried out pharmaceutical care and assisted physicians in adjusting treatment plans, which ensured the safety and effectiveness of patients' clinical drug therapy.

Immune checkpoint inhibitor-related pneumonitis(CIP)is a relatively common immune-related adverse event.The current treatment for CIP mainly relies on glucocorticoids,with 70％～80％of patients being controlled by conventional glucocorticoid therapy.However,steroid-unresponsive CIP is often se-vere and can be life-threatening.There is no standard treatment protocol for steroid-unresponsive CIP,highlighting a significant unmet clinical need.This paper reviews the diagnosis,treatment progress,and exploratory research of steroid-unresponsive CIP to provide evidence-based guidelines and directions for clinical and translational research.

Objective:To review the clinicopathological features of TFE3-rearranged renal cell carcino-ma(TFE3-RCC)with venous tumor thrombus(VT)(TFE3-VT),to explore treatment strategies and to prognostic characteristics,and to provide diagnostic and therapeutic references for TFE3-VT patients.Methods:Patients who underwent surgery at Department of Urology,Peking University Third Hospital from January 2013 to January 2024 were enrolled,including three cohorts:Pathologically confirmed TFE3-VT patients,TFE3-RCC patients without VT(TFE3-non-VT),and non-TFE3-rearranged renal cell carcinoma patients with VT(non-TFE3-VT).Clinical history,imaging data,pathological data,and follow-up records were collected.Primary and secondary endpoints were progression-free survival(PFS)and overall survival(OS),respectively.(1)Baseline characteristics were compared between the TFE3-VT and TFE3-non-VT patients.Normally distributed continuous variables were expressed as mean±SD and compared using Student's t-test;non-normally distributed variables were expressed as M(P25,P75)and analyzed with Mann-Whitney U test;categorical variables were described as frequency and percentage[n(％)]and compared by x2 test or Fisher's exact test.(2)Clinical history,radiological presenta-tions,surgical data,and histopathological features of the TFE3-VT patients were comprehensively charac-terized.(3)Survival analysis was performed for the TFE3-VT patients.Follow-up data of the TFE3-VT patients were described in detail,and their survival outcomes were compared with the TFE3-non-VT and non-TFE3-VT patients.When compared with the TFE3-non-VT counterparts,Kaplan-Meier method was used to generate PFS and OS curves among:(1)the TFE3-RCC patients across clinical stages Ⅰ-Ⅳ;(2)TFE3-VT versus TFE3-non-VT cohorts;(3)stage Ⅲ subgroups of the TFE3-VT and TFE3-non-VT patients.Intergroup survival differences were statistically evaluated using Log-rank tests.For comparisons with the non-TFE3-VT patients,a 1∶1 propensity score matching(PSM)was implemented to balance baseline characteristics between the two cohorts.Post-matching Kaplan-Meier curves were generated to compare PFS and OS between the matched groups,with Log-rank tests employed to determine statistical significance of survival disparities.All statistical analyses were conducted with R software(v 4.2.3),and two-tailed P＜0.05 was considered statistically significant.Results:The study included 45 TFE3-RCC patients:13 TFE3-VT and 32 TFE3-non-VT cases.Additionally,523 non-TFE3-VT patients were enrolled.Among the 13 TFE3-VT patients,9 were female(69.2％)and 4 male(30.8％),with a mean age of(37.9±14.4)years,mean BMI of(22.2±3.5)kg/m2,median age-adjusted Charlson comorbidity index(aCCI)of 1.0(0.0,1.0),and preoperative creatinine level of(75.3±15.9)μmol/L;tumors were located in the left kidney in 7 patients(53.8％)and right kidney in 6(46.2％);preoperative distant metastasis(M1 stage)was present in 6 patients(46.2％),while 7(53.8％)showed no metastasis;VT distribution by Mayo level comprised 7 cases(53.8％)at level 0,1 case each at levels Ⅰ and Ⅳ(7.7％respectively),and 2 cases each at levels Ⅱ and Ⅲ(15.4％respectively);surgical approaches comprised open surgery(n=2,15.4％),laparoscopic surgery(n=6,46.1％),and robot-assisted laparoscopic surgery(n=5,38.5％);mean operative time was(273±79)min,and intraoperative blood loss was(722±570)mL;mean maximum tumor diameter was(10.8±2.4)cm.All the 13 patients underwent TFE3 protein immunohistochemistry(IHC)staining,with 7 confirmed by fluorescence in situ hybridization(FISH).Tumor recurrence or metastasis occurred in 11 patients(84.6％),and 9(69.2％)patients died during follow-up.Median PFS was 4 months(1 year PFS rate:31％),and median OS was 13 months(1 year OS rate:54％).Survival analysis of 45 TFE3-RCC pa-tients revealed statistically significant differences in PFS and OS across all the clinical stages(P＜0.001).The TFE3-VT patients exhibited significantly worse PFS and OS than the TFE3-non-VT patients(P＜0.001),with persistent significance in stage Ⅲ subgroup analysis(P＜0.05).After PSM,TFE3-VT pa-tients showed significantly inferior PFS compared with non-TFE3-VT(P=0.01),though no significant difference was shown between the OS curves(P=0.11).Conclusion:TFE3-VT predominantly occurs in young females with frequent preoperative metastases.Strongly-positive staining of TFE3 protein in IHC stai-ning and red-green split signals in FISH tests are reliable diagnostic markers.TFE3-VT patients exhibit in-ferior survival compared with TFE3-non-VT patients and earlier progression than non-TFE3-VT patients.

Objective:To investigate the clinical efficacy and safety of different combination therapies with aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of facial basal cell carcinoma in the elderly.Methods:A retrospective analysis was conducted on 131 elderly patients with facial basal cell carcinoma who visited Shanghai Skin Disease Hospital from August 2020 to October 2023. According to the depth of the lesions, the patients were divided into 3 groups to receive intensive pretreatment with curettage (41 cases), CO 2 laser therapy (35 cases), and narrow-margin excision surgery without sutures (55 cases) respectively, all followed by ALA-PDT. During the follow-up period of 17.7 ± 9.0 months, the efficacy was evaluated and adverse reactions were recorded in each group. Results:The total remission rates were 100%, 100%, and 96.4% in the curettage + ALA-PDT group, CO 2 laser + ALA-PDT group, and narrow-margin excision surgery without sutures + ALA-PDT group, respectively. The patients experienced mild pain and local erythematous swelling during ALA-PDT treatment, which were temporary and fully tolerable, and no wound infections or difficulties in healing were observed. After treatment, scar formation was observed in 3 cases of basal cell carcinoma on the nose and nasolabial folds in the narrow-margin excision surgery without sutures + ALA-PDT group, but the rest of the patients retained a good facial appearance. Conclusions:In this preliminary exploration study on PDT for basal cell carcinoma of different depths, ALA-PDT combined with curettage, CO 2 laser or narrow-margin excision surgery without sutures all exhibited definite efficacy and minimal damage, providing effective treatment options for facial basal cell carcinoma in the elderly.

Objective:To analyze the reasons for the low results obtained by the determination of isosorbide dini-trate tablets content using the methods in the Chinese Pharmacopoeia and to improve the content determination method.Methods:The content of isosorbide dinitrate in 10 tablets was determined by high-performance liquid chromatography(HPLC)using a Phenomenex Luna C18 column(4.6 mm ×250 mm,5 μm)for separation,with a mobile phase of methanol-water(54∶46),a flow rate of 1.0 mL·min-1,and a UV detector set at a wavelength of 230 nm.The average content of 10 tablets was taken as the result of the content determination.Results:Isosor-bide dinitrate showed good linearity in the range of 49.22 to 1 230.5 μg·mL-1(r=0.999 96);the relative stand-ard deviation was 0.11％,the recovery rate was 96.0％,and the RSD was 1.5％(n=9).Conclusion:This method simplifies the experimental operations and steps,can eliminate the interference factors introduced by the original method,and improves the accuracy of the detection results.

Immune checkpoint inhibitor-related pneumonitis(CIP)is a relatively common immune-related adverse event.The current treatment for CIP mainly relies on glucocorticoids,with 70％～80％of patients being controlled by conventional glucocorticoid therapy.However,steroid-unresponsive CIP is often se-vere and can be life-threatening.There is no standard treatment protocol for steroid-unresponsive CIP,highlighting a significant unmet clinical need.This paper reviews the diagnosis,treatment progress,and exploratory research of steroid-unresponsive CIP to provide evidence-based guidelines and directions for clinical and translational research.

Objective:To investigate the association between the triglyceride-glucose(TyG)index and the incidence and mortality of cardiovascular disease(CVD)in a large population-based cohort.Methods:Participants aged 40-79 years without a history of CVD at baseline were drawn from the CHi-nese Electronic health Records Research in Yinzhou(CHERRY)study between January 1,2010,and May 31,2020.The TyG index was calculated using baseline triglyceride and fasting blood glucose.Cox proportional hazards models were used to assess the association between the TyG index and the composite outcome of CVD(incidence and mortality),adjusting for age,gender,education,region,smoking sta-tus,body mass index,systolic blood pressure,and total cholesterol.Hazard ratios(HR)and 95％confi-dence intervals(CI)were calculated.Nonlinear associations between the TyG index and CVD were fur-ther evaluated using restricted cubic splines,and subgroup analyses by gender and age were conducted to explore potential differences.Results:A total of 226 406 individuals were included,with a mean age of(55.0±9.7)years at baseline,46.8％of whom were men,and a median TyG index of 8.68.Over a median follow-up of 7.99 years,9 815(4.34％)participants experienced CVD incidence or mortality.After adjusting for age,gender,education,region,smoking status,body mass index,systolic blood pressure and total cholesterol,the risk of CVD increased with higher TyG index levels(P＜0.001).The risk in the highest TyG quartile(TyG＞9.10)was 42％higher than in the lowest quartile(TyG ≤8.32)(HR=1.42,95％CI:1.34-1.51).Individuals under 60 years had a higher HR for CVD compared with those aged 60 years and above(HR:1.71 vs.1.27,P＜0.05).Restricted cubic spline analysis revealed a reverse L-shaped association between the TyG index and CVD risk in the overall population(P＜0.001 for nonlinear trend),with risk increasing after the TyG index exceeded 8.67.However,the threshold varied by gender,with a lower threshold in women(8.51)than in men(8.67).Conclusion:A significant nonlinear relationship was revealed between the TyG index and CVD risk,with a threshold effect.The risk of CVD increased once the TyG index surpassed a certain threshold,with a lower threshold in women than in men.These findings suggest that cardiovascular risk prediction and interven-tions based on the TyG index should be gender-stratified,and early intervention for individuals under 60 years old might have important public health implications.

Objective:To investigate the role of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) in renal tubular epithelial-mesenchymal transition (EMT) in diabetic nephropathy (DN).Methods:Renal tissue specimens from 24 DN patients (DN group) confirmed by medical history, clinical laboratory tests, and pathological diagnosis at the Third Hospital of Hebei Medical University and 15 adjacent normal renal tissues (control group) from 2018 to 2023 were collected. Immunohistochemical staining was performed to detect the expression of EBP50, E-cadherin, and Vimentin proteins. Additionally, 10 healthy volunteers were enrolled as a normal group, and fasting blood glucose, serum creatinine, blood urea nitrogen, and 24 h urinary protein levels were compared between DN patients and the normal group.Results:Fasting blood glucose, serum creatinine, blood urea nitrogen, and 24 h urinary protein levels were significantly higher in the DN group than in the normal group (all P<0.01). Periodic acid-schiff (PAS) staining revealed significant thickening of the glomerular basement membrane, increased extracellular matrix, vacuolar degeneration of renal tubules, and elevated extracellular matrix in the renal interstitium in the DN group. Immunohistochemistry showed higher expression of EBP50 and E-cadherin proteins in the control group than in the DN group (all P<0.01), while Vimentin expression was lower in the control group ( P<0.01). Conclusions:EBP50 is involved in the EMT process of renal tubules in DN and is associated with tubular injury.

Objectives:To describe the use of antihypertensive, antidiabetic and lipid-lowering drugs, and evaluate the effects on blood pressure, blood glucose and blood lipids controls required by Chinese Guideline on the Primary Prevention of Cardiovascular Diseases (the guideline) in a community-based cohort of individuals at high risk for cardiovascular disease. To analyze the association of the uses of antihypertensive, antidiabetic and lipid-lowering drugs, and the comprehensive control of blood pressure, blood glucose and blood lipids with cardiovascular disease. Methods:From the CHinese Electronic health Records Research in Yinzhou (CHERRY), those who were at high risk for cardiovascular disease and aged 40-75 years as of January 1, 2013 in in Yinzhou District of Ningbo, Zhejiang Province were selected as study subjects. The information about their antihypertensive, antidiabetic, and lipid-lowering drug uses between 2013 and 2015 was collected, and blood pressure, blood glucose, and blood lipid measurements were conducted during the follow-up. The study constructed two kinds of comprehensive scores: the comprehensive medication score based on the guideline requirement for the treatment of hypertension, diabetes and hyperlipidemia, dividing the study participants into the compliancy group and non-compliancy group; and the comprehensive control score based on the guideline requirement for blood pressure, blood glucose, and blood lipids control, dividing the study participants into better control group, moderate control group, and poor control group. Cox proportional hazards regression model was used to analyze the association of the comprehensive medication score and comprehensive control score with cardiovascular disease. The incidence data of cardiovascular disease were collected from January 1, 2015 (baseline time) to August 31, 2020 (follow up end time).Results:A total of 79 734 participants at high risk for cardiovascular disease were included in the study, in whom 68.4%, 27.4%, and 4.2% had 1, 2, or 3 cardiometabolic conditions (hypertension, diabetes, or hyperlipidemia), respectively. In the participants with hypertension, diabetes, and hyperlipidemia from 2013 to 2015, the proportions of those who had two years of medication compliancy records were 66.0%, 67.4%, and 13.9%, respectively. In the hypertension patients, 59.2% had better blood pressure control, in the diabetes patients, 28.7% had better blood glucose control, and in the patients with hyperlipidemia, 27.4% had better blood lipid control. After a median follow-up of 5.66 years, 4 088 cardiovascular disease cases or deaths occurred. After multivariate adjustment, compared with the non-compliancy group, the compliancy group had lower risk for cardiovascular disease ( HR=0.91, 95% CI: 0.85-0.96). Compared with the better control group, the poor control group had an increased risk for cardiovascular disease ( HR=1.67, 95% CI: 1.53-1.81). In the moderate control group, the risk increased significantly in the diabetes patients ( HR=1.29, 95% CI: 1.07-1.56), while no additional risk for cardiovascular disease was observed in non-diabetes patients ( HR=1.06, 95% CI: 0.97-1.16). Conclusions:Compliancy to the medication required by the guideline is associated with lower risk for cardiovascular disease. However, it is still necessary to improve the medication compliancy in people at high risk in primary prevention, especially in the patients with hyperlipidemia, due to their low taking rate of lipid-lowering drugs. Additionally, as the requirement of the guideline becomes more stringent, the management of disease has met more challenges. Notably, diabetes patients who have not met the guideline requirement are at high risk for cardiovascular disease, to whom the disease management should be strengthened.