Most patients with pancreatic cancer are already in the locally advanced or metastatic stage at initial diagnosis. While systemic chemotherapy provides clinical benefits for those with mid-to-late-stage pancreatic cancer, its efficacy is often limited by patient tolerance. In response to the dual clinical demands of robust antitumor activity and high targeting specificity, antibody-drug conjugate (ADC) has emerged as a promising solution. By conjugating highly selective monoclonal antibodies with potent cytotoxic small-molecule drugs, ADC achieves precise tumor-targeting while minimizing damage to healthy tissues, which thereby improves treatment tolerance. However, due to the complex pathological features of pancreatic cancer, no ADC has yet been approved for clinical use for this disease. A comprehensive evaluation of factors including ADC-specific targets, payload selection, antibody-drug linkage strategies, drug delivery mechanisms, tissue distribution variability, and tumor heterogeneity will be crucial to advancing the clinical translation of ADC for pancreatic cancer treatment.

Background Non-optimal temperatures pose significant threats to public health. Analyzing the association between temperature exposure and the number of emergency cases of acute alcohol intoxication can provide evidence for optimizing emergency resource allocation and response strategies. Objective To analyze the overall impact and lag effects of non-optimal temperatures on the number of 120 emergency calls for acute alcohol intoxication in Wuxi, and to assess the attributable risk, in order to provide empirical evidence for formulating climate-adaptive public health strategies. Methods Call records of acute alcohol intoxication from Wuxi's 120 emergency service, concurrent air pollutant data, and meteorological data (including daily mean temperature) were collected from January 1, 2014 to December 31, 2020. Distributed lag nonlinear modeling was used for time-series analysis, with cross-basis functions to capture the nonlinear relationship and lag effects between temperature and emergency volume. Confounding factors such as long-term trends, humidity, pollutants [ultimately including ozone (O₃) and fine particulate matter (PM_2.5)], day of the week, and holidays were controlled. The maximum lag period was set to 14 days. Single-day lag and cumulative lag effects of extreme temperatures were analyzed, followed by sensitivity analysis. Effects were quantified using relative risk (RR) and 95% confidence intervals (95%CI), and attributable fractions and numbers for different temperature ranges were calculated. Results A total of 10705 emergency cases of acute alcohol intoxication were included during the study period, with males accounting for 89.5% and individuals aged 18–50 years accounting for 83.4%. A non-linear "U-shaped" association was observed between daily mean temperature and the number of emergency calls, with an optimal temperature of 13.3 ℃. The effect of the extreme low temperature (1.88 ℃) was statistically significant from lag1 to lag3 after exposure (P<0.05), with the maximum effect at lag1 (RR=1.063, 95%CI: 1.002, 1.129). The extreme high temperature (32.3 ℃) showed an immediate effect, with maximum effect at lag0 (RR=1.374, 95%CI: 1.248, 1.512). The cumulative effect analysis showed that the risk associated with high temperature was the highest at lag0–3 (RR=2.000, 95%CI: 1.667, 2.399), while the risk associated with low temperature was the highest at lag0–14 (RR=1.462, 95%CI: 1.042, 2.051). The attribution analysis indicated that the mild heat (>24.7–30.8 ℃) and heat (>30.8–33.5 ℃) contributed the largest numbers of attributable cases, with 591 cases (95%CI: 56, 1032) and 190 cases (95%CI: 51, 309), respectively. The corresponding attributable fractions were 5.81% (95%CI: 0.80%, 9.94%) and 1.87% (95%CI: 0.49%, 2.96%), respectively. Conclusion Both extreme high and low temperatures significantly increase the number of 120 emergency calls for acute alcohol intoxication in Wuxi. High temperature exhibit an acute effect, while low temperature show a delayed effect. Mild heat have a significant impact on the emergency burden. It is recommended that emergency departments optimize resource allocation according to climatic characteristics and strengthen emergency responses during extreme weather to reduce alcohol-related health burden.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Objective:To investigate the clinical characteristics of first-episode and recurrent acute hypertriglyceridemic pancreatitis (HTGP).Methods:The retrospective cohort study was con-ducted. The clinical data of 313 patients with HTGP admitted to 26 medical centers in China in the Chinese Acute Pancreatitis Clinical Research Group (CAPCTG)-PERFORM database from November 2020 to December 2021 were collected. There were 219 males and 94 females, aged 38(32,44)years. Of the 313 patients, 193 patients with first-episode HTGP were allocated into the first-episode group and 120 patients with recurrent HTGP were allocated into the recurrent group. Observation indica-tors: (1) propensity score matching and comparison of general data of patients between the two groups after matching; (2) comparison of severity and prognosis in the course of disease within 14 days between the two groups; (3) the association between recurrent HTGP and the risk of persistent organ failure (POF); (4) follow-up. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Wilcoxon rank sum test. Count data were expressed as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the Wilcoxon rank sum test. The Kaplan-Meier method was used to plot the cumulative recurrence rate curve and Log-Rank test was used for survival analysis. The Logistic regression model was used for multivariate analysis, and continuous variables were converted into categorical variables according to the mean value or common criteria. Propensity score matching was performed by 1∶1 nearest neighbor matching method, with caliper value of 0.02. Paired t test or Wilcoxon rank sum test and McNemar′s test were used for comparison between matched groups. Results:(1) Propensity score matching and comparison of general data of patients between the two groups after matching. Of the 313 patients,208 cases were successfully matched, including 104 cases in the first-episode group and 104 cases in the recurrent group. After propensity score matching, there was no significant difference in demographic characteristics, severity of illness scores and laboratory test between the two groups ( P>0.05). The elimination of gender, acute physiology and chornic health evaluation (APACHE) Ⅱ score, computed tomography severity index score, systemic inflammatory response syndrome score, sequential organ failure assessment score, apolipoprotein E, C-reactive protein, creatinine, lactic acid dehydrogenase, procal-citonin confounding bias ensured comparability between the two groups. (2) Comparison of severity and prognosis in the course of disease within 14 days between the two groups. There were signifi-cant differences in POF and local complications between the first-episode group and the recurrent group ( P<0.05). (3) The association between recurrent HTGP and the risk of POF. Results of uncor-rected univariate analysis showed that there was no association between recurrent HTGP and the risk of POF ( odds ratio=0.78, 95% confidence interval as 0.46-1.30, P>0.05). Results of multivariate analysis after adjusting for covariates such as gender, age, APACHE Ⅱ score, C-reactive protein, triglyceride and total cholesterol showed that compared with first-episode HTGP, recurrent HTGP was associated with a higher risk of POF ( odds ratio=2.22, 95% confidence interval as 1.05-4.71, P<0.05). Results of subgroup analysis showed that age<40 years was associated with an increased risk of POF ( odds ratio=3.31, 95% confidence interval as 1.09-10.08, P<0.05). (4) Follow-up. Twelve of the 313 patients died during hospitalization, including 9 cases in the first-episode group and 3 cases in the recurrent group. The rest of 301 surviving patients, including 184 cases in the first-episode group and 117 cases in the recurrent group, were followed up for 19.2(15.5, 21.9)months. Results of follow-up showed that for 184 survived patients of the first-episode group, 164 cases were followed up and 24 cases experienced recurrence, for 117 survived patients of the recurrent group,29 cases experienced recurrence, showing a significant difference between the two groups ( χ2=4.67, P<0.05). Conclusion:Compared with first-episode HTGP, patients with recurrent HTGP are more prone to POF and local complications, and are more prone to recurrence after discharge. The risk of POF in recurrent HTGP patients is 2.22 times that of those with first-episode, and the risk is higher in patients with age <40 years.

Objective:To evaluate the effect of ultrasound-guided adductor canal block with bupivacaine liposome on analgesia in elderly patients undergoing total knee arthroplasty.Methods:This was a prospective study. Sixty American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ patients, regardless of gender, aged 65-83 yr, weighing 50-80 kg, scheduled for elective unilateral total knee arthroplasty under subarachnoid anesthesia from April 2023 to January 2024 in Zhengzhou Orthopaedic Hospital, were divided into 2 groups ( n=30 each) using a random number table method: bupivacaine liposome group (LB group) and ropivacaine group (R group). Ultrasound-guided adductor canal block was performed at 30 min before subarachnoid anesthesia, bupivacaine liposome diluent 20 ml (133 mg) was injected in LB group, and 0.5% ropivacaine 20 ml was injected in R group. Patient-controlled intravenous analgesia was performed after operation, and tramadol was used for rescue analgesia when the visual analogue scale (VAS) score ≥3. VAS scores at rest and during activity were recorded at 8, 12, 24, 48 and 72 h after surgery. The time to the first pressing analgesia pump and rescue analgesia were recorded within 72 h after surgery. The quadriceps muscle strength was measured at 1 day before surgery and 12, 24, 48 and 72 h after surgery. The knee joint range of motion was assessed at 1 day before surgery and 24, 48 and 72 h after surgery. Patient′s satisfaction with analgesia was recorded at 72 h after surgery. The adverse reactions within 72 h after surgery were also recorded. Results:Compared with R group, VAS scores at rest and during activity were significantly decreased at 12, 24, 48 and 72 h after surgery, the time to the first pressing analgesia pump was prolonged, the rate of rescue analgesia after surgery was decreased, the score for the patient′s satisfaction with analgesia was increased, the knee joint range of motion was increased ( P<0.05), and no significant change was found in the quadriceps muscle strength and incidence of adverse reactions in LB group ( P>0.05). Conclusions:Ultrasound-guided adductor canal block with bupivacaine liposome provides better analgesia than ropivacaine in elderly patients undergoing total knee arthroplasty.

Objective To investigate whether modification with IL-21 and CCL19 enhances killing and tumor-infiltrating efficiency of NKP30 CAR-T cells in lung cancer.Methods The modified IL-21-CCL19 NKP30 CAR-T cells expressing IL-21 and CCL19 fusion gene was constructed based on NKP30 CAR-T cells and stimulated with CD3CD28 antibodies and IL-2.The immunophenotype and migration of the cells in the presence of IL-21 were investigated using flow cytometry and migration experiments.Lactate dehydrogenase(LDH)release and sphere formation assays were used to assess the killing and infiltration capabilities of CAR-T cells,and the secretion levels of IFN-γ,IL-21 and CCL19 were determined with enzyme-linked immunospot assay(ELISPOT)and ELISA.A zebrafish model bearing HCG-27 cell xenograft was established by microinjection of the tumor cells into the yolk sac followed 24 h later by injection of the immune cells at the same site,and the fluorescence signals were captured using a fluorescent microscopy.Results The NKP30 ligand B7H6,which was almost undetectable in normal tissues and blood cells,was highly expressed(over 90%)in lung cancer cells.Compared with NKP30 CAR-T cells and conventional T cells,IL-21-CCL19 NKP30 CAR-T cells exhibited stronger proliferative and migration capabilities with the formation of central memory T cells.The reduced expressions of CTLA4 and PD1 in the constructed cells resulted in enhanced killing efficiency against lung cancer cells accompanied by significantly increased production of IFN-γ,IL-21 and CCL19.In the zebrafish models,CAR-T cells exhibited stronger cytotoxicity and proliferative abilities than typical T cells,but these differences were not statistically significant between the two CAR-T cells.Conclusion Modification of NKP30 CAR-T cells with IL-21 and CCL19 facilitates their access into solid tumors for more effective tumor cell killing while producing a large number of memory T cells.

Objective To investigate whether modification with IL-21 and CCL19 enhances killing and tumor-infiltrating efficiency of NKP30 CAR-T cells in lung cancer.Methods The modified IL-21-CCL19 NKP30 CAR-T cells expressing IL-21 and CCL19 fusion gene was constructed based on NKP30 CAR-T cells and stimulated with CD3CD28 antibodies and IL-2.The immunophenotype and migration of the cells in the presence of IL-21 were investigated using flow cytometry and migration experiments.Lactate dehydrogenase(LDH)release and sphere formation assays were used to assess the killing and infiltration capabilities of CAR-T cells,and the secretion levels of IFN-γ,IL-21 and CCL19 were determined with enzyme-linked immunospot assay(ELISPOT)and ELISA.A zebrafish model bearing HCG-27 cell xenograft was established by microinjection of the tumor cells into the yolk sac followed 24 h later by injection of the immune cells at the same site,and the fluorescence signals were captured using a fluorescent microscopy.Results The NKP30 ligand B7H6,which was almost undetectable in normal tissues and blood cells,was highly expressed(over 90%)in lung cancer cells.Compared with NKP30 CAR-T cells and conventional T cells,IL-21-CCL19 NKP30 CAR-T cells exhibited stronger proliferative and migration capabilities with the formation of central memory T cells.The reduced expressions of CTLA4 and PD1 in the constructed cells resulted in enhanced killing efficiency against lung cancer cells accompanied by significantly increased production of IFN-γ,IL-21 and CCL19.In the zebrafish models,CAR-T cells exhibited stronger cytotoxicity and proliferative abilities than typical T cells,but these differences were not statistically significant between the two CAR-T cells.Conclusion Modification of NKP30 CAR-T cells with IL-21 and CCL19 facilitates their access into solid tumors for more effective tumor cell killing while producing a large number of memory T cells.

Objective:To observe the therapeutic effect of vibrating the abdomen on anorexia model rats,as well as its effects on cholecystokinin octapeptide(CCK-8)and motilin(MTL)in the peripheral blood. Methods:Forty young rats were randomly divided into a normal group(n=10)and a modeling group(n=30).Rats in the normal group were fed common feed.The anorexia model was established by the etiological simulation method in the modeling group,and these rats were further randomly divided into a drug group,a vibrating abdomen group,and a model group 3 weeks after the anorexia model was induced,with 10 rats in each group.The drug group was given Jian Wei Xiao Shi Pian by intragastric administration at a dose of 0.72 g/(kg·bw)(0.72 g drug was dissolved in 10 mL purified water).The normal group and the model group were given purified water once a day in the morning.The vibrating abdomen group was treated with vibrating the abdomen once a day for 21 times.The body mass,food intake,serum CCK-8,MTL,gastrin(GAS),neurotensin(NT)levels,and the intestinal propulsion rate of rats in each group were measured. Results:Compared with the model group,the body mass,food intake,serum MTL and GAS levels,and the small intestine propulsion rate increased significantly,and the serum CCK-8 and NT levels,the gastric residual rate decreased significantly in the vibrating abdomen group and the drug group(P<0.05).There were no significant differences between the vibrating abdomen group and the drug group(P>0.05). Conclusion:Vibrating the abdomen increases the food intake and body mass of anorexia model rats,reduces the residue of gastric contents,improves the small intestine propulsion rate,and therefore has a good therapeutic effect on anorexia.The mechanism may be related to inhibiting the secretion of CCK-8 and NT in plasma and promoting the release of MTL and GAS in serum.

Objective To investigate the effects of high-definition transcranial direct current stimulation(HD-tDCS)on the modulation of the H-reflex and M-wave during ankle dorsiflexion-plantar flexion fatigue tasks to provide direction for the application of HD-tDCS in mitigating neuromuscular fatigue.Methods Twenty healthy young male participants were recruited and randomly assigned to either the real stimulation or sham stimulation group,with 10 participants in each group.The intervention consisted of a 5-day single-blind HD-tDCS application(duration:20 min;intensity:2 mA;target:Cz).Baseline measurements of the H-reflex and M-wave under resting conditions,M-wave during maximal voluntary isometric contraction(MVIC)of the dorsiflexor muscle,and MVIC torque of the dorsiflexor and plantar flexor muscles were obtained.An ankle dorsiflexion fatigue task was performed to determine the time to achieve fatigue for the task.The same fatigue task was repeated and evaluated one day after the intervention.A repeated-measures two-factor(stimulation condition x pre/post fatigue)analysis of variance(ANOVA)was used to analyze the effects of independent variables on the mechanical properties of the muscles and α-motoneuron conduction characteristics.Results After fatigue,voluntary activation(VA),maximal H-reflex(Hmax),maximal M-wave(Mmax),and dorsiflexor and plantar flexor MVIC torques in both groups were significantly reduced compared with pre-fatigue levels(P＜0.05).However,compared to the real stimulation group,the sham stimulation group showed a more significant decline in VA and plantar flexor MVIC torque(P＜0.05).Conclusions A continuous 5-day HD-tDCS intervention can effectively increase α-motoneuron activity at the spinal segment.It can also exert an inhibitory effect on reducing information transmission capacity at the peripheral neuromuscular junction under the ankle dorsi-plantarflexion fatigue task.