γ-Gammaglutamyl transferase predicts all-cause mortality within three-year intervals in patients undergoing peritoneal dialysis.

OBJECTIVES: Peritoneal dialysis (PD) serves as a vital renal replacement therapy for patients with end-stage kidney disease (ESKD). γ-Gamma-glutamyl transferase (γ-GGT) is a recognized predictor of oxidative stress and mortality. This study aimed to assess the prognostic significance of γ-GGT in predicting all-cause and cardiovascular mortality among PD patients. METHODS: A retrospective study was conducted, enrolling 640 PD patients from a single center. The one-year, three-year, and five-year mortality rates for all causes and cardiovascular causes were evaluated. Kaplan-Meier survival analysis and multivariate Cox regression analysis were performed. RESULTS: Within five years of initiating PD, the observed all-cause mortality rates at one, three, and five years were 11.72%, 16.09%, and 23.44%, while cardiovascular mortality rates were 2.97%, 7.34%, and 11.09%, respectively. Lower γ-GGT levels were associated with decreased all-cause mortality during one-, three-, and five-year follow-ups, along with reduced cardiovascular mortality in the first and third years, as indicated by Kaplan-Meier analysis on median γ-GGT groupings. Multivariate Cox regression analysis showed significantly decreased hazard ratios (HRs) for one- to five-year all-cause mortality and cardiovascular mortality in the lower γ-GGT group compared to higher groups. However, when sex differences were eliminated using separate tertile groupings for males and females, only the one- and three-year all-cause mortality rates demonstrated significantly reduced hazard ratios (HRs) in the lower γ-GGT groups. CONCLUSION: This retrospective study suggests that γ-GGT levels have prognostic significance in predicting one- and three-year all-cause mortality among PD patients when accounting for sex differences.

Synthesis and anti-SARS-CoV-2 activity and mechanism research of lycorine derivatives / 药学学报

We designed and synthesized eighteen lycorine derivatives with five different structural types, and evaluated their antiviral activities on a HCoV-OC43-infected H460 cell model. Structure-activity relationships suggested that the introduction of appropriate substituents on the 6N atom of lycorine was beneficial to activity. Compound 6a gave a good activity with the half effective concentration (EC50) and selectivity index (SI) values of 2.36 μmol·L-1 and 16.52, respectively. Surface plasmon resonance (SPR) result indicated that 6a might target the non-structural protein 12 (NSP12) subunit in RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with the dissociation constant (KD) value of 1.36 μmol·L-1. Molecular docking indicated that 6a might act on nidovirus RdRp-associated nucleotidyltransferase (NiRAN) catalytic center of NSP12, distinct from the mechanism of nucleoside-like drugs such as remdesivir. This study provides scientific data for the development of lycorine derivatives into a new class of anti-SARS-CoV-2 small molecule inhibitors.

Machine-learning algorithm-based prediction of a diagnostic model based on oxidative stress-related genes involved in immune infiltration in diabetic nephropathy patients.

Diabetic nephropathy (DN) is the most prevalent microvascular consequence of diabetes and has recently risen to the position of the world's second biggest cause of end-stage renal diseases. Growing studies suggest that oxidative stress (OS) responses are connected to the advancement of DN. This study aimed to developed a novel diagnostic model based on OS-related genes. The differentially expressed oxidative stress-related genes (DE-OSRGs) experiments required two human gene expression datasets, which were given by the GEO database (GSE30528 and GSE96804, respectively). The potential diagnostic genes were identified using the SVM-RFE assays and the LASSO regression model. CIBERSORT was used to determine the compositional patterns of the 22 different kinds of immune cell fraction seen in DN. These estimates were based on the combined cohorts. DN serum samples and normal samples were both subjected to RT-PCR in order to investigate the degree to which certain genes were expressed. In this study, we were able to locate 774 DE-OSRGs in DN. The three marker genes (DUSP1, PRDX6 and S100A8) were discovered via machine learning on two different machines. The high diagnostic value was validated by ROC tests, which focused on distinguishing DN samples from normal samples. The results of the CIBERSORT study suggested that DUSP1, PRDX6, and S100A8 may be associated to the alterations that occur in the immunological microenvironment of DN patients. Besides, the results of RT-PCR indicated that the expression of DUSP1, PRDX6, and S100A8 was much lower in DN serum samples compared normal serum samples. The diagnostic value of the proposed model was likewise verified in our cohort, with an area under the curve of 9.946. Overall, DUSP1, PRDX6, and S100A8 were identified to be the three diagnostic characteristic genes of DN. It's possible that combining these genes will be effective in diagnosing DN and determining the extent of immune cell infiltration.

Serum platelet distribution width predicts cardiovascular and all-cause mortality in patients undergoing peritoneal dialysis.

BACKGROUND: Platelet distribution width (PDW) is a predictor for all-cause mortality in patients with cardiovascular diseases (CVD). This study aimed to evaluate the prognostic implication of PDW in predicting cardiovascular and all-cause mortality in patients undergoing peritoneal dialysis (PD). METHODS: In total, 762 PD patients from a single center were recruited retrospectively from 2005 to 2017 and followed up until 2021. The primary and secondary outcomes were cardiovascular and all-cause mortality, respectively. Survival analysis was conducted using Kaplan-Meier estimates and Cox regression analysis. RESULTS: During a median of 52.2 months of follow-up, 135 (17.7%) cases of CVD and 253 (33.2%) cases of all-cause mortality were reported. After multivariate adjustment, high levels of PDW were associated with an increased risk of death from CVD (HR: 1.583; 95% CI: 1.109-2.258; P = 0.011) and all-cause mortality (HR: 1.313; 95% CI: 1.006-1.758; P = 0.045). Subgroup analysis indicated a stronger association between PDW and all-cause mortality among female participants (P-value for interaction = 0.033). Higher levels of PDW predicted an increased risk of all-cause mortality in female patients (HR: 1.986; 95% CI,1.261-3.127). CONCLUSION: High levels of PDW are independently associated with cardiovascular and all-cause mortality in the PD population, and differences by sex exist in the association of PDW with all-cause mortality.

Progress of companion diagnostics in chimeric antigen receptor T-cell therapy / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved good efficacy in treatment of hematological malignancies. As a precise and individualized treatment method, CAR-T is gradually moving towards commercialization. In addition to the introduction of corresponding policies and guiding principles, the related detection protocols should also be updated and improved to maximize its effect and achieve precise individualization. This article introduces and expands the concept of "companion diagnostics" that first appeared in targeted drugs, and introduces the significances of various detection technologies and biomarkers for patient screening, safety monitoring and evaluation of efficacy and CAR-T function in the whole process of CAR-T treatment.

Long-term follow-up of humanized and murine CD19 CAR-T-cell therapy for B-cell acute lymphoblastic leukemia / 中华血液学杂志

Objective: Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods: Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results: The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions: The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.

Factors Predicting Progression to Severe COVID-19: A Competing Risk Survival Analysis of 1753 Patients in Community Isolation in Wuhan, China.

Most studies of coronavirus disease 2019 (COVID-19) progression have focused on the transfer of patients within secondary or tertiary care hospitals from regular wards to intensive care units. Little is known about the risk factors predicting the progression to severe COVID-19 among patients in community isolation, who are either asymptomatic or suffer from only mild to moderate symptoms. Using a multivariable competing risk survival analysis, we identify several important predictors of progression to severe COVID-19-rather than to recovery-among patients in the largest community isolation center in Wuhan, China from 6 February 2020 (when the center opened) to 9 March 2020 (when it closed). All patients in community isolation in Wuhan were either asymptomatic or suffered from mild to moderate COVID-19 symptoms. We performed competing risk survival analysis on time-to-event data from a cohort study of all COVID-19 patients (n = 1753) in the isolation center. The potential predictors we investigated were the routine patient data collected upon admission to the isolation center: age, sex, respiratory symptoms, gastrointestinal symptoms, general symptoms, and computed tomography (CT) scan signs. The main outcomes were time to severe COVID-19 or recovery. The factors predicting progression to severe COVID-19 were: male sex (hazard ratio (HR) = 1.29, 95% confidence interval (CI) 1.04-1.58, p = 0.018), young and old age, dyspnea (HR = 1.58, 95% CI 1.24-2.01, p < 0.001), and CT signs of ground-glass opacity (HR = 1.39, 95% CI 1.04-1.86, p = 0.024) and infiltrating shadows (HR = 1.84, 95% CI 1.22-2.78, p = 0.004). The risk of progression was found to be lower among patients with nausea or vomiting (HR = 0.53, 95% CI 0.30-0.96, p = 0.036) and headaches (HR = 0.54, 95% CI 0.29-0.99, p = 0.046). Our results suggest that several factors that can be easily measured even in resource-poor settings (dyspnea, sex, and age) can be used to identify mild COVID-19 patients who are at increased risk of disease progression. Looking for CT signs of ground-glass opacity and infiltrating shadows may be an affordable option to support triage decisions in resource-rich settings. Common and unspecific symptoms (headaches, nausea, and vomiting) are likely to have led to the identification and subsequent community isolation of COVID-19 patients who were relatively unlikely to deteriorate. Future public health and clinical guidelines should build on this evidence to improve the screening, triage, and monitoring of COVID-19 patients who are asymtomatic or suffer from mild to moderate symptoms.

Progress of chimeric antigen receptor T-cell therapy for drug resistance and relapse of hematologic malignancies / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) has made a breakthrough in the treatment of hematologic malignancies, but drug resistance and recurrence have limited its wide application. And at the 63rd annual meeting of the American Society of Hematology, a series of related reports on the mechanism and prevention strategies of drug resistance and recurrence after CAR-T therapy were carried out. These reports provide important indications for improving the clinical efficacy of CAR-T therapy and reducing relapse.

Hematological malignancies immunotherapy-related coagulopathy and laboratory tests / 中华检验医学杂志

Immunotherapy has been one of the most promising approaches in tumor-treating fields, including immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapy, etc. It has achieved major breakthroughs in the treatment of hematological and other malignancies. However, related safety management issues are becoming increasingly prominent, especially the diagnosis and treatment of coagulopathy deserves the attention of clinical and laboratory physicians. Therefore, this review summarizes immunotherapy-related coagulopathy from the perspectives of epidemiology, pathogenesis and laboratory indicators and provides guidance for early clinical identification, diagnosis and intervention.

In vivo and in vitro antiproliferative and antimetastatic effects of hemolymph of Aspongopus chinensis Dallas on breast cancer cell.

OBJECTIVE: To investigate the effects of Aspongopus（A.）chinensis hemolymph on the proliferation and metastasis of breast cancer cells. METHODS: The in vitro effects of A. chinensis hemolymph were investigated in murine (4T1) and human (HCC1937) breast cancer cell lines. Cytotoxicity, cell apoptosis, and cell migration were evaluated by using the cell counting kit-8 assay, Hoechst staining, and wound healing experiments, respectively. A syngeneic mouse model was established to evaluate the in vivo effects of the hemolymph extract on tumor growth and metastasis. Mouse body weight, tumor size, blood levels of function-related enzymes, and pathological features of the liver and kidney tissues were evaluated. RESULTS: The hemolymph of A. chinensis significantly inhibited in vitro tumor cell migration and viability while inducing apoptosis. Furthermore, it inhibited in vivo tumor growth and metastasis with a minimal effect on mouse body weight, and did not induce liver or kidney damage. CONCLUSION: Our results suggested that the A.chinensis hemolymph has antitumorigenic properties, suggesting it has potential as a novel therapeutic option for the treatment of metastatic breast cancer.

Immunological profiling of COVID-19 patients with pulmonary sequelae

Cellular immunity may be involved in organ damage and rehabilitation in patients with coronavirus disease 2019 (COVID-19). We aimed to delineate immunological features of COVID-19 patients with pulmonary sequelae (PS) one year after discharge. 50 COVID-19 survivors were recruited and classified according to radiological characteristics: 24 patients with PS and 26 patients without PS. Phenotypic and functional characteristics of immune cells were evaluated by multiparametric flow cytometry. Patients with PS had an increased proportion of natural killer (NK) cells and lower percentage of B cells compared to patients without PS. Phenotypic and functional features of T cells in patients with PS were predominated by the accumulation of CD4+ T cells secreting IL-17A, short-lived effector-like CD8+ T cells (CD27-CD62L-) and senescent T cells with excessive secretion of granzyme-B/perforin/IFN-{gamma}. NK cells were characterized by the excessive secretion of granzyme-B and perforin and the downregulation of NKP30 and NKP46; highly activated NKT and {gamma}{delta} T cells exhibited NKP30 and TIM-3 upregulation and NKB1 downregulation in patients with PS. However, immunosuppressive cells were comparable between the two groups. The interrelation of immune cells in COVID-19 was intrinsically identified, whereby T cells secreting IL-2, IL-4 and IL-17A were enriched among CD28+ and CD57-cells and cells secreting perforin/granzyme-B/IFN-{gamma}/TNF- expressed markers of terminal differentiation. CD57+NK cells, CD4+perforin+ T cells and CD8+CD27+CD62L+ T cells were identified as the independent predictors for residual lesions. Overall, our findings unveil the profound imbalance of immune landscape that may correlate with organ damage and rehabilitation in COVID-19. IMPORTANCEA considerable proportion of COVID-19 survivors have residual lung lesions, such as ground glass opacity and fiber streak shadow. To determine the relationship between host immunity and residual lung lesions, we performed an extensive analysis of immune responses in convalescent patients with COVID-19 one year after discharge. We found significant differences in immunological characteristics between patients with pulmonary sequelae and patients without pulmonary sequelae one year after discharge. Our study highlights the profound imbalance of immune landscape in the COVID-19 patients with pulmonary sequelae, characterized by the robust activation of cytotoxic T cells, NK cells and {gamma}{delta} T cells as well as the deficiencies of immunosuppressive cells. Importantly, CD57+NK cells, CD4+perforin+ T cells and CD8+CD27+CD62L+ T cells were identified as the independent predictors for residual lesions.

Model-based cellular kinetic analysis of SARS-CoV-2 infection: different immune response modes and treatment strategies

Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.

Progress in the safety of chimeric antigen receptor T cells therapy / 白血病·淋巴瘤

Chimeric antigen receptor T cells (CAR-T) therapy is progressing rapidly, and its safety has been widely concerned. At the 62nd American Society of Hematology Annual Meeting, a series of reports on the mechanism, predictive indicators and treatment strategies of major adverse reactions were carried out. These reports have certain guiding significance for comprehensively improving the safety of CAR-T therapy.

Multi-organ Proteomic Landscape of COVID-19 Autopsies

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report an in-depth multi-organ proteomic landscape of COVID-19 patient autopsy samples. By integrative analysis of proteomes of seven organs, namely lung, spleen, liver, heart, kidney, thyroid and testis, we characterized 11,394 proteins, in which 5336 were perturbed in COVID-19 patients compared to controls. Our data showed that CTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. Dysregulation of protein translation, glucose metabolism, fatty acid metabolism was detected in multiple organs. Our data suggested upon SARS-CoV-2 infection, hyperinflammation might be triggered which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart and thyroid. Evidence for testicular injuries included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. In summary, this study depicts the multi-organ proteomic landscape of COVID-19 autopsies, and uncovered dysregulated proteins and biological processes, offering novel therapeutic clues. HIGHLIGHTSO_LICharacterization of 5336 regulated proteins out of 11,394 quantified proteins in the lung, spleen, liver, kidney, heart, thyroid and testis autopsies from 19 patients died from COVID-19. C_LIO_LICTSL, rather than ACE2, was significantly upregulated in the lung from COVID-19 patients. C_LIO_LIEvidence for suppression of glucose metabolism in the spleen, liver and kidney; suppression of fatty acid metabolism in the kidney; enhanced fatty acid metabolism in the lung, spleen, liver, heart and thyroid from COVID-19 patients; enhanced protein translation initiation in the lung, liver, renal medulla and thyroid. C_LIO_LITentative model for multi-organ injuries in patients died from COVID-19: SARS-CoV-2 infection triggers hyperinflammatory which in turn induces damage of gas exchange barrier in the lung, leading to hypoxia, angiogenesis, coagulation and fibrosis in the lung, kidney, spleen, liver, heart, kidney and thyroid. C_LIO_LITesticular injuries in COVID-19 patients included reduced Leydig cells, suppressed cholesterol biosynthesis and sperm mobility. C_LI

High rate of increased level of plasma Angiotensin II and its gender difference in COVID-19: an analysis of 55 hospitalized patients with COVID-19 in a single hospital, WuHan, China

Background2019 Novel coronavirus disease (COVID-19) is turning into a pandemic globally lately. Angiotensin-converting enzyme 2 (ACE2) is identified as an important functional receptor for SARS-Cov-2. ACE2 and ACE are homologues with inverse functions in the renin-angiotensin system. ACE converts angiotensin I into a vital vasoactive peptide called angiotensin II(AngII), whereas ACE2 hydrolyzes AngII into a series of vasodilators. There were few reports illustrated the expression of AngII in COVID-19. This study aimed to demonstrate the expression of angiotensin II in COVID-19 and how it correlated to the disease. MethodsWe enrolled 55 patients with COVID-19 admitted to renmin Hospital of Wuhan University from January 21st to February 21st, 2020. Demographic data were collected upon admission. COVID-19 nuclear acid, plasma AngII, Renin and aldosterone in the lying position without sodium restriction, and other laboratory indicators were together measured by the laboratory department of our hospital. FindingsOf the 55 patients with COVID-19, 34(61.8%) had an increased level of AngII. The severity of COVID-19 and male is positively related with the level of AngII. The level of blood lymphocyte, PCT, ALT, and AST were remarkably severe with those of normal level of AngII (P < 0.05). CD4/CD8 cells ratio was significantly higher whereas CD3+CD8+ cells amount, CD3+CD8+ cells proportion, CD56+CD16+CD3- cells amount and CD19+CD3- cells amount were considerably lower than those of normal level of AngII (P < 0.05). Abnormal rates of blood lymphocyte and PCT were significantly higher in Patients with elevated AngII level. The results of binary logistic regression analysis showed that the severity of COVID-19 (OR=4.123) and CD4/CD8 ratio(OR=4.050) were the co-directional impact factor while female(OR=0.146) was inverse impact factor of elevated AngII level. InterpretationHigh rate of increased level of AngII was detected in COVID-19 patients. Patients with elevated AngII level were more likely to be critically ill with COVID-19. Considering the gender differences in ACE2 expression and no gender differences in angiotensin expression, the gender differences in AngII level might indicate less loss of ACE2 in female patients. Elevated AngII level was correlated with CD4/CD8 ratio, suggesting it might involve in immune disorder.

Does a neutropenic diet reduce adverse outcomes in patients undergoing chemotherapy?

OBJECTIVE: This study aimed to compare clinical outcomes of chemotherapy patients who received either a neutropenic diet (ND) or liberalised diet (LD) and to investigate associations between ND and infectious outcomes. METHODS: A retrospective case note audit of patients admitted to Flinders Medical Centre from 2013 to 2017 was conducted. Patients were eligible if they were aged 18 years and above, received chemotherapy and were neutropenic during admission. Demographic and clinical data were collected from medical records. Primary outcomes were occurrence of infections and fever. Secondary outcomes include hospital length of stay and infection-related mortality. RESULTS: Seventy-nine patients received ND while 75 patients received LD. The ND group had more patients with acute myeloid leukaemia (p < .001) and receiving high-toxicity chemotherapy (p = .005). Incidence of febrile neutropenia (p = .016), bacteraemia (p = .044) and number of febrile days (p = .033) was higher in the ND group. ND was not independently associated with occurrence of febrile neutropenia or infections. Subsample analysis of 20 pairs of patients matched on age, sex and cancer diagnosis found no significant differences in clinical outcomes between groups. CONCLUSION: ND was not associated with the prevention of adverse outcomes in chemotherapy patients.

Application Advance of Flow Cytometry in the CAR-T Cell Therapy--Review / 中国实验血液学杂志

Abstract　　Chimetic antigen receptor T cells (CAR-T) are a kind of novel killer cells derived from autogenous or allogeneic T cells targeting the tumor specific antigens by gene engineering transpormation. The CAR-T cells possess the advantages of high specificity, high efficiency and non-MHC restriction, thus achieving good therapeutic effects in relapsed/refractory hematological tumors and some solid tumors. The process of CAR-T cell preparation includes cell isolation and purification, activation and differentiation, gene modification, in vitro amplification, phenotypic quality control, preservation and reinfusion. In recent years, with the rapid development of flow cytometry, this technology has been widely used in all aspects of CAR-T cell therapy, including pre-treatment screening, in vitro preparation and post-transfusion monitoring, which plays an important role in its innovative optimization.

Development and current status of research on thrombosis and hemorrhagic diseases in China / 白血病·淋巴瘤

Thrombosis and hemostasis are clinical interdisciplinary subjects involving multiple specialties. Related thrombus and hemorrhagic diseases seriously endanger health. Since the founding of the People's Republic of China, the diagnosis and treatment level of thrombus and hemorrhagic diseases in China have been continuously improved, the theoretical research has been continuously deepened, and a series of fruitful results have been achieved in the basic and clinical research on platelets, coagulation factors, anticoagulant and fibrinolytic systems. This paper summarizes the current situation and future development direction of related representative work.

Recombinant Tissue Plasminogen Activator-conjugated Nanoparticles Effectively Targets Thrombolysis in a Rat Model of Middle Cerebral Artery Occlusion / 华中科技大学学报（医学）（英德文版）

The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration.The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy.We conjugated rtPA to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size,zeta potential,enzyme activity of conjugated rtPA and its storage stability at 4℃.The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP,the properties to fibrin targeting and its influences on systemic hemostasis in vivo.The results showed that rtPA-NP equivalent to 10％ of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P＜0.001).RtPA-NP did not influence the in vivo hemostasis or coagulation system.The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA.These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.

Recombinant Tissue Plasminogen Activator-conjugated Nanoparticles Effectively Targets Thrombolysis in a Rat Model of Middle Cerebral Artery Occlusion / 华中科技大学学报（医学）（英德文版）

The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration.The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy.We conjugated rtPA to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size,zeta potential,enzyme activity of conjugated rtPA and its storage stability at 4℃.The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP,the properties to fibrin targeting and its influences on systemic hemostasis in vivo.The results showed that rtPA-NP equivalent to 10％ of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P＜0.001).RtPA-NP did not influence the in vivo hemostasis or coagulation system.The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA.These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.