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 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 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 protective effect of melatonin (MT) on formaldehyde (FA) inhalation-in- duced acute lung injury (ALI) in rats and its mechanism through the regulation of nuclear factor E2-related factor 2 (Nrf2) signaling pathway． Methods : Fifty female Wistar rats were randomly divided into Control group ，FA group，FA + MT 5 mg / kg group，FA + MT 10 mg / kg group and FA + MT 20 mg / kg group，with 10 rats in each group．Except for the Control group，all other groups inhaled 3 mg / m3 FA daily for 21 d consecutively to construct the tainted model，and then treated with different MT doses for 14 d．The tainting was continued during the MT treatment．Hematoxylin-eosin (HE) staining was used to observe the histopathological changes in lung tissue，lung water content and lung coefficient were weighed and measured，glutathione ( GSH) ，superoxide dismutase (SOD) and 8-hydroxydeoxyguanosine ( 8-OHdG) levels were measured by absorbance photometric method ，and enzyme linked immunosorbent assay(ELISA) was used to measure the levels of tumor necrosis factor-alpha (TNF-α) ，in- terleukin (IL) -6，and IL-1 β concentrations，Western blot to detect the protein expression levels of Nrf2，heme ox- ygenase-1 (HO-1) ，nuclear factor-κB ( NF-κB) ，and phosphorylated nuclear factor-κB ( p-NF-κB) in lung tis- sues，and quantitative polymerase chain reaction(qPCR) to detect the Nrf2，HO-1，and Kelch-like ECH-associated protein 1 (Keap1) mRNA expression levels. Results : Compared with the control group，lung injury was obvious in rats in the FA group ; lung tissue GSH and SOD levels were reduced ，and 8-OHdG levels were elevated ( P < 0. 05) ; alveolar lavage fluid TNF-α , IL-6，and IL-1 β levels were elevated (P＜0. 05) ; Nrf 2 and HO-1 protein expression levels were reduced in the lung tissue (P＜0. 05) ，and p-NF-κB protein expression levels were was ele- vated (P＜0. 05) ; the relative mRNA expression of Nrf2 and HO-1 in lung tissue was decreased，and the relative mRNA expression of Keap1 was elevated (P＜0. 05) ．Compared with the FA group，the lung injury of rats in the MT group was improved ; the levels of GSH and SOD in the lung tissue were increased (P＜0. 05) ，and the level of 8-OHdG was decreased (P＜0. 05) ; the levels of TNF-α , IL-6，and IL-1 β in the alveolar lavage fluid were de- creased (P＜0. 05) ; and the expression levels of the Nrf2 and HO-1 proteins in the lung tissue were increased (P ＜0. 05) ．p-NF-κB protein expression level was decreased (P ＜0. 05) ; the relative mRNA expression levels of Nrf2 and HO-1 in lung tissues were increased (P＜0. 05) ，and the relative mRNA expression level of Keap1 was decreased (P＜0. 05) in lung tissues，and all of them were in a dose-dependent manner． Conclusion MT can al- leviate oxidative stress and inflammatory responses and mitigate FA exposure-induced acute lung injury by regula- ting the Nrf2 / Keap1 / HO-1 signaling pathway.

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: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.