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 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.

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.

BACKGROUND:In recent years,epidemiological studies have shown that sleep patterns are risk factors for osteoarthritis,but the causal relationship between sleep characteristics and osteoarthritis remains unknown. OBJECTIVE:To investigate the causal relationship between seven sleep phenotypes and osteoarthritis,thereby providing a theoretical foundation for clinical prevention and intervention of osteoarthritis. METHODS:Seven sleep-related features,namely sleep duration,wake-up time,daytime napping,morning/evening preference,snoring,insomnia,and hypersomnia,were selected from published genome-wide association studies.Instrumental variables for these sleep-related features were extracted.Instrumental variables for knee osteoarthritis and hip osteoarthritis were obtained from publicly available genome-wide association studies.Causal relationships between sleep characteristics and outcome risks were evaluated using two-sample and multivariable Mendelian randomization analyses.The inverse variance weighted method was employed as the primary Mendelian randomization approach.Various methods,including weighted median,weighted mode,Mendelian randomization-Egger regression,Mendelian randomization pleiotropy-residual sum and outlier,were utilized to detect and correct for the presence of pleiotropy. RESULTS AND CONCLUSION:The results of the inverse variance-weighted method in the two-sample Mendelian randomization study revealed a detrimental causal association between the duration of sleep and the incidence risk of knee osteoarthritis[odds ratio(OR)=0.621,95%confidence interval(CI):0.470-0.822,P=0.001].Concurrently,insomnia displayed a positive causal connection with hip osteoarthritis risk(OR=2.016,95%CI:1.249-3.254,P=0.005).Sensitivity analysis affirmed the robustness of these causal relationships,and Mendelian randomization-Egger intercept analysis found no evidence of potential horizontal pleiotropy(knee osteoarthritis:P=0.468,hip osteoarthritis:P=0.551).Moreover,the results from the multivariable Mendelian randomization analysis showed that the causal association between insomnia and hip osteoarthritis lacked statistical significance(P=0.715).In contrast,sleep duration exhibited a direct negative causal relationship with the incidence risk of knee osteoarthritis(OR=0.526,95%CI:0.336-0.824,P=0.005).Reverse Mendelian randomization analysis indicated that knee osteoarthritis did not influence sleep duration(P=0.757).These findings indicate a negative correlation between sleep duration and incidence risk of knee osteoarthritis,suggesting that correcting insufficient sleep might mitigate the incidence risk of knee osteoarthritis.

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.

Knee osteoarthritis （KOA） is a common degenerative joint disease characterized primarily by the degeneration and damage of knee joint cartilage， accompanied by osteophyte formation and inflammation. In recent years， the prevalence of KOA has been increasing globally， significantly impacting the quality of life patients. However， the pathogenesis of KOA remains not fully understood， and current treatment methods are limited. Therefore， finding new therapeutic strategies is a research hotspot. Previous studies have found that the onset of KOA is related to abnormal mitochondrial regulation. Mitochondria， functioning as secondary messengers， play crucial roles in cellular respiration， reactive oxygen species （ROS） generation， and adenosine triphosphate （ATP） production through oxidative phosphorylation. Mitochondrial quality control is a pivotal mechanism for maintaining the morphology， quantity， and quality of mitochondria. The connection between mitochondrial quality control and the pathogenesis of KOA involves several factors， such as mitochondrial oxidative stress， mitophagy， imbalances in mitochondrial biogenesis， abnormal mitochondrial dynamics （fission and fusion）， and dysregulation of calcium ions. Metabolic abnormalities in the body lead to mitochondrial structural damage， which in turn contributes to the onset and progression of KOA. Traditional Chinese medicine （TCM） has made some progress in intervening in mitochondrial quality control， employing multi-faceted， multi-pathway， and multi-target strategies to treat KOA. Several studies have shown that mitochondrial quality control may be one of the therapeutic targets of TCM in treating KOA. However， there is currently a lack of comprehensive reviews summarizing the TCM interventions in mitochondrial quality control for treating KOA. This paper systematically reviewed the research progress in TCM treatment of KOA based on five aspects of mitochondrial quality control， aiming to provide a theoretical basis for the clinical prevention and treatment of KOA.

Background Tributyl phosphate (TBP) is widely used as an organophosphate flame retardant. However, there are limited studies on the toxicity of TBP to aquatic organisms at low levels of exposure. Objective To investigate the effects of TBP on early development of zebrafish (Danio rerio). Methods Zebrafish embryos were randomly divided into four groups at 2 h post-fertilisation (2 hpf), namely, the 0.01% dimethyl sulfoxide (DMSO) control group and TBP exposure groups (0.02, 0.2 and 2 μg·L⁻¹). The exposure time was from 2 hpf to 120 hpf and the hatching rate, malformation rate, heart rate and body length of zebrafish embryos at 72 hpf, the frequency of tail curling at 24-29 hpf, the locomotor ability at 96 hpf and the survival rate at 120 hpf were evaluated, respectively. The whole-body triiodothyronine (T₃) and tetraiodothyronine (T₄) levels of juvenile fish were measured by enzyme immunoassay at the end of the infection, and the expression levels of hypothalamic-pituitary-thyroid axis (HPT) and neurodevelopmental-related genes were detected by quantitative real-time PCR (q-PCR). Results The heart rates of zebrafish embryos were significantly decreased in all TBP-treated groups (P<0.001), the survival rates of the 0.02 and 2 μg·L⁻¹ TBP groups were significantly decreased (P<0.05), and the malformation rate of the 2 μg·L⁻¹ treated group was significantly increased (P<0.05), which was mainly manifested by pericardial oedema. The frequency of tail curling of zebrafish embryos in all groups reached the highest at 25 hpf, which was significantly lower (P<0.001) in all exposure groups than in the control group (P<0.001). In the locomotor behaviour experiments, the swimming speed of zebrafish larvae in the dark cycle was significantly decreased in the 0.02 and 0.2 μg·L⁻¹ TBP groups (P<0.05), and similar results were found for the light cycle in the 0.2 and 2 μg·L⁻¹ TBP groups (P<0.05). Compared with the control group, the T₃ level of zebrafish juveniles in the 0.2 μg·L⁻¹ TBP group increased significantly (P<0.05). The q-PCR results showed that the expression levels of HTP axis-related genes [thyroid hormone receptors (trα, \begin{document}$tr\beta $\end{document}), thyroglobulin (tg), and sodium/iodide co-transporter (nis)] were significantly down-regulated in the exposure groups, the expression level of transthyretin (ttr) was significantly up-regulated in the 0.02 μg·L⁻¹ TBP group, and the iodothyronine deiodinase 2 (dio2) expression level was significantly down-regulated in the 0.02 μg·L⁻¹ TBP group (P<0.05); the neurodevelopment-related gene acetylcholinesterase (ache) was significantly down-regulated in the exposure groups, and the expression levels of myelin basic protein (mbp) and Elav like neuron-specific RNA binding protein 3 (elavl3) were significantly down-regulated in the 0.02 μg·L⁻¹ TBP group (P<0.05). Conclusion TBP exposure can lead to early developmental abnormalities in zebrafish, manifested as developmental toxicity, thyroid endocrine disruption and neurotoxicity during hatching and early juvenile stages.