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:Seed cells are seeded on three-dimensional scaffold materials,and three-dimensional culture in bioreactors is a common in vitro tissue engineering culture method,but the changes in cell proliferation and metabolic patterns in bioengineered blood vessel construction are still unclear. OBJECTIVE:To explore the metabolic changes of cells such as oxygen consumption and their causes during the whole process of biological vascular tissue construction by in vitro bioreactor. METHODS:The self-built vascular bioreactor system was used as the platform;bovine vascular smooth muscle cells were used as the seed cells,and a conventional CO2 incubator provided the external gas environment for the cultivation process.Seed cells were seeded on a tubular porous polyglycolic acid scaffold material for three-dimensional culture,and the whole process included a one-week resting period and a seven-week pulsating tensile stress stimulation loading period.A non-invasive monitoring system was built,and the optical dissolved oxygen patch method was used to monitor the changes of dissolved oxygen in the culture solution in the reactor,and the glucose consumption and lactic acid production were measured by regular sampling.CCK-8 assay was used to determine the proliferation of smooth muscle cells on polyglycolic acid three-dimensional scaffold materials.Nicotinamide adenine dinucleotide oxidation state and reduction state ratio(NAD+/NADH)was utilized to understand cell proliferation and metabolism in the early stage of culture.RT-qPCR and western blot assay were applied to detect the expression of proliferation-related genes(Ki67)and glycolysis-related genes(GLUT-1,LDHA). RESULTS AND CONCLUSION:(1)The dissolved oxygen level in the culture solution was(4.314±0.380)mg/L from the cell injection to the end of the resting period(the first week),and gradually stabilized at(1.960±0.866)mg/L after the tensile stress stimulation(the last seven weeks);the two had significant changes(P<0.05).(2)The ratio of glucose consumption to lactic acid production in the cell culture medium YL/G increased rapidly after the cells were injected,and the highest value was above 1 on the fifth day,and then slow down to 0.5(The mean value of YL/G in the resting period was 0.89 and the mean value in the pressurized period was 0.57,P<0.05).(3)CCK-8 assay results showed that A450 value gradually increased after the cells were injected,and reached the highest value on the fifth day,reaching 3.17,and then slowly decreased.At the same time,it was found that Ki67 mRNA was up-regulated on the third day of culture,and then declined.The expression level of Ki67 protein was higher from the third day to the fifth day.(4)The detection of NAD+/NADH showed that the increase was obvious from the fifth to the seventh day after the injection of cells,and the expression of glycolysis-related genes(GLUT-1 and LDHA)was up-regulated and changed synchronously,and the relative expression was higher in the first five days.(5)The results showed that the tissue-engineered blood vessels were constructed using the vascular bioreactor and the smooth muscle cells in the early stage mainly proliferated and exhibited a metabolic feature of low oxygen consumption.The metabolic characteristics of high oxygen consumption were observed during the pulsatile tensile stress stimulation stage.

Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.
Animals ; Haplorhini ; Axons ; Motor Neurons ; Interneurons ; Macaca ; Dependovirus/genetics* ; Genetic Vectors

Objective To analyze the clinical efficacy of transcatheter tricuspid valve replacement (TTVR) in cardiac implantable electronic lead-related tricuspid regurgitation (TR). Methods The patients with severe TR who underwent LuX-Valve TTVR in 9 Chinese medical centers from June 2020 to August 2021 were retrospectively enrolled. They were divided into a cardiac implantable electronic device (CIED) group and a non-CIED group based on whether they had pre-existing CIED implantation. Success of the procedure was defined as safe implantation of the LuX-Valve and complete withdrawal of the delivery system. Prognostic improvement was defined as a decrease of TR grade to≤2+ and an improvement of cardiac function by≥2 grades. Surgical success and postoperative prognosis were compared between the two groups. Results A total of 190 patients were collected, including 50 males and 140 females with a mean age of 66.2±7.8 years. There were 29 patients in the CIED group, and 161 patients in the non-CIED group. In the CIED group, 28 patients were implanted with a permanent pacemaker and 1 patient with a cardioverter-defibrillator. Preoperative New York Heart Association (NYHA) cardiac function class, TR degree, left ventricular ejection fraction, tricuspid annular plane systolic excusion, and cardiac risk scores were comparable between the two groups (P>0.05). Postoperative TR was reduced to≤2+ in all patients, and there was no statistical difference in the incidence of perivalvular leakage between the two groups (P=0.270). Postoperative CT of CIED patients showed the valve was in place, and the lead was not extruded, twisted, or deflected. The in-hospital mortality of the two groups were 10.3% and 1.9%, respectively, and the difference was statistically significant (P=0.047). In addition, there was no statistical difference between the two groups in terms of postoperative improvement of cardiac function and mortality in the 1- and 2-year follow-up. Conclusion TTVR is feasible, safe, and effective in patients with CIED implantation, and the pre-existing lead has no significant effect on the clinical efficacy.

Objective:To investigate mevalonic acid(MEV)on reversing the antitumor effects of fluvastatin sodium(FS)on tongue squamous cell carcinoma(TSCC)cells.Methods:TSCC HSC-4 cells were treated with different concentrations of FS and MEV re-spectively or in combination.Cell counting kit-8,flow cytometry,wound healing,immunofluorescence and western blotting assays were conducted to examine cell proliferation,apoptosis and migration capacities,as well as the expression levels of Ras homolog family member A(RHOA),tissue factor(TF)and B-cell lymphoma-2-associated X(BAX)proteins,respectively.Results:FS inhibited HSC-4 cell proliferation and migration,decreased the expression of RHOA and TF,and increased BAX expression.MEV reversed the above antitumor effects of FS and promoted intracellular RHOA and TF expression.Conclusion:MEV reverses the antitumor effects of FS on HSC-4 cells in vitro.

Bone is a dynamic tissue undergoing continuous regeneration and reconstruction， and its metabolic activities are mainly regulated by bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. In addition， a variety of cells such as adipocytes， inflammatory cells， endothelial cells， and nerve cells can affect bone metabolism by changing the bone marrow microenvironment. The incidence of bone metabolic diseases caused by bone metabolism disorders is increasing with aging of the population. At present， the clinical treatment of bone metabolic diseases has the disadvantages of long cycle， high cost and many side effects. Therefore， there is an urgent need for safe and effective prevention and treatment drugs. Corylin is an isoflavonoid extracted from Psoraleae Fructus， which has a variety of pharmacological effects such as anti-inflammatory， anti-oxidation， anti-tumor， anti-atherosclerosis， attenuating obesity and improving insulin resistance. Studies have shown that corylin not only exerts osteoprotective effects by promoting osteoblast differentiation and inhibiting osteoclast differentiation， but also plays a positive role in bone metabolism by regulating lipid metabolism， inflammatory response， angiogenesis and anti-aging. The current review overviews the effects and mechanisms of corylin on regulating bone metabolism directly or indirectly， hoping to open up a new perspective for the prevention and treatment of osteoporosis， fracture， osteoarthritis and other related diseases.

ObjectiveTo elucidate the principles and methods of the Bayesian probabilistic linkage model， and to demonstrate the effect of applying the model in linking birth and death data. MethodsThrough the Shanghai birth and death registration system， data of 199 025 infants born in 2017 and 1 512 infants who died in 2017 and 2018 were collected. After cleaning the data， the data were divided into monthly blocks and fully linked. The Jaro-Winkler algorithm and Euclidean distance were employed to measure the similarity of fields for matching. A Bayesian probabilistic linkage model was constructed and the linking effect was evaluated using a confusion matrix. ResultsUsing the Bayesian probabilistic linkage model， the birth and death data of infants were effectively linked， revealing that 36.71% of infants who died in Shanghai were born outside the city， and the probability of infant death was 2.6‰. The confusion matrix of the test set showed a recall rate of 0.86， precision of 0.76， and an F-score of 0.81. ConclusionThe practical application of Bayesian probabilistic linkage demonstrates a good model performance， enabling the establishment of birth-death cohorts that more accurately reflect the true levels of infant mortality. Utilizing this technique to integrate data from different departments can effectively improve research efficiency in the field of public health.

Immunotherapy has changed the treatment landscape of advanced non-small cell lung cancer(NSCLC),showing great potential in the treatment of untreated and relapsed or refractory(R/R)patients.However,numerous issues that need further exploration remain with the wide application of immunotherapy.They include the exploration of biomarkers for efficacy prediction,the optimization of immunotherapy modalities,immune-related adverse effects,and the management of special populations.This review summarizes the progress of the research on immunotherapy for advanced NSCLC and discusses its challenges and future directions.

ObjectiveTo explore the characteristics and major factors influencing mental health literacy (MHL) among non-graduating middle school and high school students in Taizhou, Zhejiang Province, and to provide a reference for the promotion of mental health literacy among adolescents. MethodsFrom September to October 2023, a stratified random cluster sampling method was used to conduct a questionnaire survey among students from three classes each in non-graduating grades in four middle schools and four high schools in Taizhou, Zhejiang Province. The survey included basic demographic information, a Structured Mental Health Literacy Questionnaire (MHLQ), and other psychological scales [Educational Stress Scale for Adolescents (ESSA), Perceived Choice Single Scale (PC), Child Depression Inventory (CDI), Generalized Anxiety Disorder (GAD), The University of California at Los Angeles 3-item Loneliness Scale (UCLA-3) and Multidimensional Scale of Perceived Social Support (MSPSS)]. t-tests, chi-square tests, analysis of variance (ANOVA), and multiple linear regressions were applied for the statistical analysis of the data. ResultsThe mental health literacy average score of 2 094 students was (82.3±15.8) points, with a mean of (4.1±0.8) points. The dimension of belief in mental health rights had the highest score. There were significant differences in the mental health literacy score across different dimensions for students with different household registration, economic levels, academic performance, and father’s education level (P<0.001). Multiple linear regression analysis indicated that rural household registration, lower paternal education level, greater academic pressure, a weaker sense of control over one’s behavior, less social support, and symptoms of loneliness, depression, or anxiety were associated with poorer mental health literacy among the students. ConclusionThe mental health literacy of middle school and high school students in Taizhou is generally good, but there are differences among students with different characteristics. Targeted interventions should be carried out for students from rural areas, with poorer mental health, and less low social support to improve the overall mental health literacy of adolescents.

Objective:To evaluate the efficacy of neoadjuvant chemoimmunotherapy (NACI) combined with transoral robotic surgery (TORS) in the treatment of locally advanced oropharyngeal squamous cell carcinoma (OPSCC).Methods:This was a retrospective study of 15 patients with locally advanced OPSCC who underwent TORS after neoadjuvant therapy (NAT) at the Department of Otolaryngology-Head and Neck Surgery of Sun Yat-sen Memorial Hospital of Sun Yat-sen University from April 2019 to February 2023. There were 12 males and 3 females, aged 31 to 74 years. Twelve cases were tonsil cancer, and 3 cases were tongue base cancer. There were 11 cases in stage Ⅲ and 4 cases in stage Ⅳ. Two patients received neoadjuvant chemotherapy and 13 patients received NACI, with 2 to 3 cycles, and all patients underwent TORS after multidisciplinary team consultation. The clinicopathological characteristics, surgical outcomes, and oncological results were summarized.Results:All surgeries were successfully completed with negative surgical margins, and no case was required conversion surgery. All patients were fed via nasogastric tubes postoperatively, with a median gastric tube stay of 7 days (range: 2-60 days). No tracheotomy was applied. There were no major complications such as postoperative bleeding. Pathological complete response (pCR) was found in 10 cases (76.9%) among the 13 patients with NACI. The follow-up time was 21 months (range: 10-47 months), and there was no death or distant metastasis. One patient with rT0N3M0 tonsil cancer had local recurrence 5 months after surgery. The 2-year overall survival and 2-year disease-free survival were respectively 100.0% and 93.3% in the 15 patients.Conclusion:NACI combined with TORS provides a safe, effective and minimally invasive treatment for patients with locally advanced oropharyngeal squamous cell carcinoma.