Efficacy and risk of donor-derived CAR-T treatment of relapsed B-cell acute lymphoblastic leukemia after hematopoietic stem cell transplantation.

The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is approximately 30%. Patients experiencing a relapse after allogeneic HSCT frequently encounter difficulties in obtaining autologous CAR-T products. We conducted a study involving 14 patients who received donor-derived CAR-T therapy for relapsed B-ALL following HSCT between August 2019 and May 2023 in our center. The results revealed a CR/CRi rate of 78.6% (11/14), a GVHD rate of 21.4% (3/14), and a 1-year overall survival (OS) rate of 56%. Decreased bone marrow donor cell chimerism in 9 patients recovered after CAR-T therapy. The main causes of death were disease progression and infection. Further analysis showed that GVHD (HR 7.224, 95% CI 1.42-36.82, P = 0.017) and platelet recovery at 30 days (HR 6.807, 95% CI 1.61-28.83, P = 0.009) are significantly associated with OS after CAR-T therapy. Based on the findings, we conclude that donor-derived CAR-T cells are effective in treating relapsed B-ALL patients following HSCT. Additionally, GVHD and poor platelet recovery impact OS, but further verification with a larger sample size is needed.

The predictive value of T-cell chimerism for disease relapse after allogeneic hematopoietic stem cell transplantation.

Introduction: Chimerism is closely correlated with disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, chimerism rate is dynamic changes, and the sensitivity of different chimerism requires further research. Methods: To investigate the predictive value of distinct chimerism for relapse, we measured bone marrow (BM), peripheral blood (PB), and T-cell (isolated from BM) chimerism in 178 patients after allo-HSCT. Results: Receiver operating characteristic (ROC) curve showed that T-cell chimerism was more suitable to predict relapse after allo-HSCT compared with PB and BM chimerism. The cutoff value of T-cell chimerism for predicting relapse was 99.45%. Leukemia and myelodysplastic syndrome (MDS) relapse patients' T-cell chimerism was a gradual decline from 2 months to 9 months after allo-HSCT. Higher risk of relapse and death within 1 year after allo-HSCT. The T-cell chimerism rates in remission and relapse patients were 99.43% and 94.28% at 3 months after allo-HSCT (P = 0.009), 99.31% and 95.27% at 6 months after allo-HSCT (P = 0.013), and 99.26% and 91.32% at 9 months after allo-HSCT (P = 0.024), respectively. There was a significant difference (P = 0.036) for T-cell chimerism between early relapse (relapse within 9 months after allo-HSCT) and late relapse (relapse after 9 months after allo-HSCT) at 2 months after allo-HSCT. Every 1% increase in T-cell chimerism, the hazard ratio for disease relapse was 0.967 (95% CI: 0.948-0.987, P<0.001). Discussion: We recommend constant monitoring T-cell chimerism at 2, 3, 6, and 9 months after allo-HSCT to predict relapse.

The Extensive Regulation of MicroRNA in Immune Thrombocytopenia.

MicroRNA (miRNA) is a small, single-stranded, non-coding RNA molecule that plays a variety of key roles in different biological processes through post-transcriptional regulation of gene expression. MiRNA has been proved to be a variety of cellular processes involved in development, differentiation, signal transduction, and is an important regulator of immune and autoimmune diseases. Therefore, it may act as potent modulators of the immune system and play an important role in the development of several autoimmune diseases. Immune thrombocytopenia (ITP) is an autoimmune systemic disease characterized by a low platelet count. Several studies suggest that like other autoimmune disorders, miRNAs are deeply involved in the pathogenesis of ITP, interacting with the function of innate and adaptive immune responses. In this review, we discuss emerging knowledge about the function of miRNAs in ITP and describe miRNAs in terms of their role in the immune system and autoimmune response. These findings suggest that miRNA may be a useful therapeutic target for ITP by regulating the immune system. In the future, we need to have a more comprehensive understanding of miRNAs and how they regulate the immune system of patients with ITP.

Hypoglycemic activity of puerarin through modulation of oxidative stress and mitochondrial function via AMPK.

Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in HepG2 cells was assayed along with the qPCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program LibDock of Discovery Studio 2018 software. The results showed that puerarin improved HepG2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.

Efficacy and safety of basic fibroblast growth factor in the treatment of burns: Protocol for a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: To systematically evaluate the efficacy and safety of basic fibroblast growth factor (bFGF) in the treatment of burns and to provide evidence-based medical information for clinicians to choose the appropriate treatment measures for burns. METHODS: Seven databases, including PubMed, the Cochrane Library, Embase, the Chinese Biomedical Literature Database, the Wanfang Database, the China National Knowledge Infrastructure Internet, and the Chongqing Chongqing Weipu Chinese Science and Technology Journal Full-text Database (VIP), were searched by computer. Randomized controlled trials on bFGF in the treatment of burns were collected, and the search was conducted by using a combination of subject terms (MeSH) and free words. The search time limit was from the establishment of each database until January 2019. Two researchers independently screened the literature and extracted the data. According to the evaluation criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions version 5.3.0, they conducted a rigorous bias risk assessment for the included studies, and Stata 12.0 software was used for meta-analysis. RESULTS: System evaluation and meta-analysis were carried out strictly in accordance with the requirements of the Cochrane Handbook for Systematic Reviews of Interventions version 5.3.0 on meta-analysis and provided a high-quality evaluation of the efficacy and safety of bFGF in the treatment of burns. CONCLUSION: This study provided conclusions from evidence-based medicine and a scientific basis for the efficacy and safety of bFGF in the clinical treatment of burns. ETHICS AND DISSEMINATION: This study was not a clinical trial and therefore did not require ethical approval. The results of this study will be published in an SCI academic journal related to this study in the form of a public publication. PROSPERO REGISTRATION NUMBER: CRD42019124778.

Cyclophosphamide for the treatment of acute lymphoblastic leukemia: A protocol for systematic review.

BACKGROUND: Previous clinical trials have reported that cyclophosphamide can be used for the treatment of acute lymphoblastic leukemia (ALL). However, its efficacy is still unclear. In this systematic review study, we aim to evaluate its efficacy and safety for ALL. METHODS: The following 9 databases will be searched from their inception to the present: Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), and four Chinese databases. The randomized controlled trials or case control studies of cyclophosphamide that assess the clinical efficacy and safety in patients with ALL are included. The methodological quality of all eligible included studies will be assessed by the Cochrane risk of bias tool.The primary outcome measurement will be all-cause mortality at the period of treatment and follow-up. The secondary outcome measurements will include the health-related quality of life (HRQL), postinduction complete remission (CR) rate, event-free survival (EFS), relapse rate, and adverse events. Two authors will independently select eligible studies, exact data, and assess the methodological quality of included studies. RevMan 5.3 software will be used to synthesize the data. Reporting bias will be evaluated by the funnel plots, Begg, and Egger tests. RESULTS: This systematic review will evaluate the clinical efficacy and safety of cyclophosphamide for ALL. DISSEMINATION AND ETHICS: The findings of this review will summarize the present evidence of cyclophosphamide for ALL, and may provide guidance for clinical practice of cyclophosphamide for ALL. Its results will be published through peer-reviewed journals. This study does not need ethic approval, because it will not involve the individual data. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018119333.

Puerarin Mitigates Diabetic Hepatic Steatosis and Fibrosis by Inhibiting TGF-ß Signaling Pathway Activation in Type 2 Diabetic Rats.

Lipid metabolism disorder and inflammation are essential promoters in pathogenesis of liver injury in type 2 diabetes. Puerarin (PUR) has been reported to exert beneficial effects on many diabetic cardiovascular diseases and chemical-induced liver injuries, but its effects on diabetic liver injury and its mechanism are still unclear. The current study was designed to explore the therapeutic effect and mechanism of PUR on liver injury in a type 2 diabetic rat model induced by a high-fat diet combined with low-dose streptozotocin. The diabetic rats were treated with or without PUR (100 mg/kg/day) by gavaging for 8 weeks, and biochemical and histological changes in liver were examined. Results showed that treatment with PUR significantly attenuated hepatic steatosis by regulating blood glucose and ameliorating lipid metabolism disorder. Liver fibrosis was relieved by PUR treatment. PUR inhibited oxidative stress and inflammation which was associated with inactivation of NF-κB signaling, thereby blocking the upregulation of proinflammatory cytokines (IL-1ß, TNF-α) and chemokine (MCP-1). This protection of PUR on diabetic liver injury is possibly related with inhibition on TGF-ß/Smad signaling. In conclusion, the present study provides evidence that PUR attenuated type 2 diabetic liver injury by inhibiting NF-κB-driven liver inflammation and the TGF-ß/Smad signaling pathway.

Salvianolic Acid A Protects Against Diabetic Nephropathy through Ameliorating Glomerular Endothelial Dysfunction via Inhibiting AGE-RAGE Signaling.

BACKGROUND/AIMS: Glomerular endothelium dysfunction leads to the progression of renal architectonic and functional abnormalities in early-stage diabetic nephropathy (DN). Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) are proved to play important roles in diabetic nephropathy. This study investigated the role of Salvianolic acid A (SalA) on early-stage DN and its possible underlying mechanism. METHODS: In vitro AGEs formation and breaking rate were measured to illustrate the effect of SalA on AGEs. Type 2 diabetic nephropathy rats were induced by high-fat diet and low-dose streptozocin (STZ). After eight-week treatment with SalA 1 mg/kg/day, 24h-urine protein, creatinine clearance was tested and renal structural injury was assessed by PAS and PASM staining. Primary glomerular endothelial cell permeability was evaluated after exposed to AGEs. AGEs-induced RhoA/ROCK and subsequently activated disarrange of cytoskeleton were assessed by western blot and immunofluorescence. RESULTS: Biochemical assay and histological examination demonstrated that SalA markedly reduced endothelium loss and glomerular hyperfiltration, suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced urinary albumin and ameliorated renal function. Further investigation suggested that SalA exerted its renoprotective effects through inhibiting AGE-RAGE signaling. It not only inhibited formation of AGEs and increased its breaking in vitro, but also reduced AGEs accumulation in vivo and downregulated RAGE expression. SalA restored glomerular endothelial permeability through suppressing AGEs-induced rearrangement of actin cytoskeleton via AGE-RAGE-RhoA/ ROCK pathway. Moreover, SalA attenuated oxidative stress induced by AGEs, subsequently alleviated inflammation and restored the disturbed autophagy in glomerular endothelial cell and diabetic rats via AGE-RAGE-Nox4 axis. CONCLUSION: Our study indicated that SalA restored glomerular endothelial function and alleviated renal structural deterioration through inhibiting AGE-RAGE, thus effectively ameliorated early-stage diabetic nephropathy. SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.

Salvianolic acid A ameliorates AGEs-induced glomerular endothelial dysfunction and protects against diabetic nephropathy / 中国药理学与毒理学杂志

OBJECTIVE Diabetic nephropathy (DN) has been one of the most common complications of diabetes and the leading cause of end-stage renal disease. Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities. Salvi?anolic acid A (SalA) has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy. The present study was designed to investigate the effects of SalAon glomerular endothelial dysfunctionand diabetic nephropathy. METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products (AGEs). AGEs-induced changes of RhoA/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunoflu?orescence. The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin (35 mg·kg- 1, ip). Renal function and architectonic changes were evaluated by biochemical assay and PAS staining. RESULTS SalA 3μMameliorated AGEs- induced glomerular endothelial permeability (P<0.05) and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-RhoA/ROCK pathway. SalA 1 mg · kg- 1 markedly reduced endothelium loss (P<0.01) and glomerular hyperfiltration (P<0.05) in diabetic kidney. Subsequently,SalA 1 mg·kg-1 suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen (BUN), serum creatinine (Scr) and serum n-acetyl-β-d-glucosaminidase (NAG). AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg-1. CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability, and effec?tively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway. Thus, SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.