Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Objective To investigate the expression of cyclooxygenase-2(COX-2)and Ki-67 in rectal cancer tissues and their predictive value for the sensitivity to neoadjuvant chemoradiotherapy(NAC).Methods The clinical data of 87 patients receiving chemoradiotherapy before rectal cancer surgery at Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine(the Second Hospital of Nanjing)from June 2021 to September 2022 were retrospectively analyzed.In addition,40 normal rectal tissue samples were selected from the Department of Pathology of Nanjing University of Chinese Medicine(the Second Hospital of Nanjing)as control.The expression levels of COX-2 and Ki-67 in tumor and adjacent tissues of patients with rectal cancer as well as in normal rectal tissues were detected by using the immunohistochemical method.The patients were divided into chemoradiotherapy-sensitive group(n=62)and chemoradiotherapy-resistant group(n=27)according to whether they were sensitive to chemoradiotherapy.The correlation between the expression levels of COX-2,Ki-67 in tumor tissues and adjacent tissues and the sensitivity to chemoradiotherapy was analyzed.The relative factors affecting the effect of chemoradiotherapy on rectal cancer patients were analyzed by using the logistic regression model.The receiver operating characteristic(ROC)curve was drawn,and the area under the curve(AUC)was used to evaluate the predictive value of COX-2 and Ki-67 expression levels in tumor tissues of rectal cancer patients for the sensitivity to NAC.Results Among the 87 patients with rectal cancer,60 patients were sensitive to chemoradiotherapy,with a sensitivity rate of 68.97％.The positive expression rates of COX-2 and Ki-67 in tumor tissues and adjacent tissues were significantly higher than those in normal rectal tissues(x2=53.187,7.131,53.047,14.613;P＜0.05).The positive expression rates of COX-2 and Ki-67 in tumor tissues were significantly higher than those in adjacent tissues(x2=72.572,67.616;P＜0.05).The positive expression rates of COX-2 and Ki-67 in tumor tissues of patients in the chemoradiotherapy-sensitive group were significantly lower than those in the chemoradiotherapy-resistant group(x2=3.965,6.264;P＜0.05).Logistic regression analysis showed that the positive expression of COX-2 and Ki-67 in tumor tissues were factors affecting the efficacy of NAC in rectal cancer patients(P＜0.05).ROC curve analysis results showed that the sensitivity of COX-2 and Ki-67 expression and their combination for predicting sensitivity of patients to NAC was 100.00％,100.00％,and 100.00％,respectively;while the specificity was 13.33％,20.00％,and 31.67％,respectively;and the AUC was 0.567,0.600,and 0.658,respectively.Conclusion The positive expression of COX-2 and Ki-67 in tumor tissues are factors affecting the efficacy of NAC in rectal cancer patients,and the combined detection of COX-2 and Ki-67 expression has a high predictive value for the sensitivity of NAC.

ObjectiveTo assess the level of internal exposure to PCP in a community population in Shanghai， to investigate the factors affecting the level of PCP， and to analyze the correlation between the exposure and thyroid hormone levels. MethodsA total of 464 residents of a community in Shanghai were selected as the study subjects. A questionnaire survey was conducted to obtain the demographic information， dietary situation， lifestyle and behavioral habits， and disease history of the individuals， and blood samples were collected. Gas chromatography-electron trap was applied to determine the PCP levels in serum. Multicategorical logistic regression analysis was used to analyze the possible influencing factors of PCP exposure in humans. Thyroid hormone levels were used as the dependent variable and serum PCP as the independent variable. Multiple linear regression analysis was used to assess the association between PCP and thyroid hormones in the community population after controlling the confounding factors such as age， gender， literacy， annual personal income， and chronic diseases. ResultsThe detection rate of serum PCP in 464 subjects was 90.3%， and the median serum PCP level was 0.43 μg·L^-1. The differences in PCP levels among different age groups were statistically significant. There were no significant differences in PCP levels among different gender and BMI groups. The study of PCP exposure factors showed that age， frequency of using plastic products， consumption of freshwater fish， type of occupation， annual income， and consumption of tea or coffee were the potential influencing factors for PCP exposure. Among them， age， frequency of using plastic products， consumption of tea or coffee， and consumption of freshwater fish were positively associated with PCP levels， and annual personal income was negatively associated with it. The results of multiple linear regression analysis showed that among men， PCP levels were positively correlated with TSH （b=0.105， 95%CI：0.017‒0.313） and negatively correlated with FT4 （b=-0.026， 95%CI：-0.057‒0.004）， and among women， PCP levels were positively correlated with TSH （b=0.092， 95%CI：-0.211‒0.904） and FT3 （b=0.017， 95%CI：-0.058‒0.230） and negatively correlated with FT4 （b=-0.013， 95%CI：-0.011‒0.037）. ConclusionSerum PCP detection is common among community residents in Shanghai. Different demographic characteristics or behavioral habits may increase or decrease PCP exposure. PCP exposure then affects human thyroid hormone levels.

ObjectiveTo establish an High Performance Liquid Chromatography-Inductively Coupled Plasma-Mass Spectrometry （HPLC-ICP-MS） method for determination of six arsenic species in human urine，including arseniccholine （AsC）， arsenobetaine （AsB）， arsenite （As³⁺）， dimethylarsinic acid （DMA⁵⁺）， monomethylarsonic acid （MMA⁵⁺）， and arsenate （As⁵⁺）. MethodsThe pH value of mobile phase and the content of anhydrous ethanol were optimized. Ammonium carbonate （50 mmol·L^-1， containing 2% anhydrous ethanol， pH-8.5） mobile phase was selected. Cl^- interference was eliminated by He mode. The arsenic species in 10-fold diluted human urine samples were separated by an Hamilton PRP X-100 anionic column. A method for the determination of six arsenic species was established. ResultsSix arsenic species could be separated in 13 minutes. The linear correlation coefficients were above 0.999. The limits of detection were 0.10‒0.20 μg·L^-1， and the limits of quantification were 0.30‒0.50 μg·L^-1. Precision experiments showed that RSD ranged from 5.96% to 9.07% when adding concentration 0.20 μg·L^-1； from 2.48% to 6.38% when adding concentration 2.00 μg·L^-1； and from 1.41% to 2.57% when adding concentration 5.00 μg·L^-1. Accuracy test showed that the recoveries were 80%‒125%. ConclusionThe established HPLC-ICP-MS method for determination of six arsenic species in human urine is rapid， accurate and sensitive. It can be applied to the determination of arsenic species in human urine.

Adjuvants enhance the efficacy of the vaccine by regulating or enhancing the immune response to antigens,helping to reduce the amount of antigen and improve the vaccine safety.With the deepening of adjuvant researches,it has been found that the combination of two or more adjuvants can produce synergistic effects by activating multiple immune mechanisms.Highly effective vaccines are urgently needed for the group with pathogens that are difficult to remove and with low immune system function.This requirement can be met by the combination of immunologic adjuvants.In this paper,the progress of some new adjuvants and the applications of combined adjuvants were reviewed including liposomes,immunostimulating complexes,Montanides,polycationic peptide IC31,nanoemulsion and AS adjuvant systems.

Major causes of cholestasis include abnormal bile metabolism, obstructed bile flow and regurgitation, and bile duct injury and obstruction. Abnormal bile metabolism is mainly caused by gene abnormality, while obstructed bile flow is often caused by bile duct injury or occlusion due to cholangitis. Abnormal bile metabolism is the most common cause of progressive familial intrahepatic cholestasis (PFIC), while autoimmune cholangitis is the major cause of bile duct injury. Both congenital/autoimmune bile duct injury and secondary/acquired ductular reaction had relatively specific histopathological changes, and a confirmed diagnosis needs a comprehensive analysis based on clinical, pathological, imaging, immunological, and genetic examinations. This article elaborates on the research advances in the pathomorphology of autoimmune bile duct injury and PFIC and introduces the similar lesions, in order to provide a reference for the clinical diagnosis of bile duct injury and cholestatic liver diseases.

Objective To investigate the effect of early continuous veno-venous hemofiltration (CVVH) on intra-abdominal pressure (IAP) and serum interleukin-6 (IL-6) in severe acute pancreatitis (SAP) patients with abdominal compartment syndrome (ACS).Methods 41 SAP patients with ACS were selected as treatment group and treated with CVVH as well as conventional methods in ICU.The other 12 patients with the same disease were selected as the control group and were only treated with conventional methods because of economic reasons.IAP and blood level of IL-6 in the two groups were measured daily in order to investigate their changes and the correlation between the two parameters.Results The serum IL-6 level and IAP in the two groups were higher on admission day.IAP and serum IL-6 level in the treatment group were significantly decreased on the first day after treatment,and thereafter decreased rapidly.In the control group,IAP and serum IL-6 level were significantly decreased on the 3rd day after treatment.IAP and serum IL-6 level from the 1st day to the 6th day after treatment in the treatment group were significantly lower than those of the control group at the same time point (P＜0.05).There was a significant positive correlation between blood IL-6 level and IAP in SAP patients with ACS(r=0.48,P＜0.01).IL-6 difference before and after treatment was also positively correlated with the difference of IAP(R=0.39,P＜0.05).Conclusions VVH significantly decreased the IAP and the blood level of IL-6 in ACS patients of SAP.The blood level of IL-6 is significantly correlated with IAP,suggesting that IL-6 may play an important role in the pathogenesis of ACS.Therefore early CVVH may clear the cytokines such as IL-6 and lower IAP,thus to prevent multiple organ dysfunction syndrome (MODS),which should be applied in the early stage of ACS.

Immunological checkpoints are a mechanism evolved by human beings to control the intensity and duration of immunoreaction and minimize the excessive inflammatory responses and autoimmune diseases caused by overactive immune responses.Compared to radiotherapy,chemotherapy and other traditional treatments,immunotherapy has fewer side effects on normal cells,and has become an emerging technology in tumor treatments.As the focus on tumor treatment research,immunological checkpoint therapy can damage the tumor cells by breaking the immune tolerance and activating the body's own immune system,which make it a promising treatment method.In this paper,the mechanisms of immune activation,immune regulation and immune evasion were described.The action mechanism and clinical application of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor-1 (PD-1) were summarized.The application prospect of immune checkpoint inhibitors was discussed.

In recent years,cancer immunotherapy has developed rapidly due to its significant advantages compared with the traditional cancer treatment methods.Tumor immunotherapy aims at mobilizing or stimulating the body's own immune function,thereby inhibiting and killing cancer cells.With the development of nanotechnology,biological nano-carrier materials provide a new insight into the vaccine development.Nano-vaccines are therapeutic or prophylactic vaccines based on nanotechnology including exogenous antigens for inducing immune responses,vectors delivering antigens,and adjuvants for enhancing immunogenicity and accelerating and prolonging the availability of cancer vaccines.Nano-delivery vectors have good biocompatibility as well as unique physical and chemical properties.They can effectively deliver the antigens,and further activated the immune response of antigenspecific cellulars based on the activation of the body's humoral immunity by regulating the presentation pathways in the antigen-presenting cells.In this paper,the applications of nano-delivery systems in cancer vaccine research were summarized.