A novel costimulatory molecule gene-modified leukemia cell-derived exosome enhances the anti-leukemia efficacy of DC vaccine in mouse models.

Objectives: Leukemia cell-derived exosomes (LEXs), carrying leukemia cell-specific antigens, can serve as a source of antigen for dendritic cell (DC) vaccine loading. However, LEX-targeted DC-based vaccines have demonstrated limited antitumor immune effects in clinical trials, attributed to the low immunogenicity of LEXs and the scant levels of costimulatory molecules on DCs. The costimulatory molecules CD80 and CD86, which are crucial to DC function, play a significant role in enhancing immune efficacy.

Mesenchymal stem cell-derived exosomes can alleviate GVHD and preserve the GVL effect in allogeneic stem cell transplantation animal models.

Background: Mesenchymal stem cells (MSCs) can alleviate graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). MSCs-derived exosomes (MEXs) can mirror the biological function of their parent cells. Whether MEXs can alleviate GVHD like their parent cells or not is unclear.

Endothelial-derived small extracellular vesicles support B-cell acute lymphoblastic leukemia development.

Purpose: The bone marrow niche plays an important role in leukemia development. However, the contributions of different niche components to leukemia development and their underlying mechanisms remain largely unclear.

Method: Cre/LoxP-based conditional knockout technology was used to delete VPS33B or ANGPTL2 gene in niche cells.

A novel costimulatory molecule gene-modified leukemia cell-derived exosome-targeted CD4 T cell vaccine efficiently enhances anti-leukemia immunity.

Previous studies demonstrated that CD4 T cells can uptake tumor antigen-pulsed dendritic cell-derived exosomes (DEXO), which harbor tumor antigen peptide/pMHC I complex and costimulatory molecules and show potent effects on inducing antitumor immunity. However, in preliminary study, CD4 T cells targeted by leukemia cell-derived exosomes (LEXs) did not show the expected effects in inducing effective anti-leukemia immunity, indicating that LEX is poorly immunogenetic largely due to an inadequate costimulatory capacity. Therefore, LEX-based anti-leukemia vaccines need to be optimized.

P2X1 enhances leukemogenesis through PBX3-BCAT1 pathways.

How bone marrow niches regulate leukemogenic activities of leukemia-initiating cells (LICs) is unclear. The present study revealed that the metabolic niche component, ATP, efficiently induced ion influx in LICs through its ligand-gated ion channel, P2X1. P2X1 deletion impaired LIC self-renewal capacities and resulted in an approximately 8-fold decrease in functional LIC numbers in a murine acute myeloid leukemia (AML) model without affecting normal hematopoiesis.

Distinct roles but cooperative effect of TLR3/9 agonists and PD-1 blockade in converting the immunotolerant microenvironment of irreversible electroporation-ablated tumors.

Irreversible electroporation (IRE) is a new cancer ablation technology, but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated. We developed a mouse model bearing large primary (300 mm) and medium distant (100 mm) EG7 lymphomas engineered to express ovalbumin (OVA) as a nominal tumor antigen. We established experimental protocols including IRE alone and IRE combined with Toll-like receptor (TLR)3/9 agonists (poly I:C/CpG) (IRE + pIC/CpG), PD-1 blockade (IRE + PD-1 blockade), or both (IRE + Combo) to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment (TME).

Construction of lncRNA-related ceRNA regulatory network in diabetic subdermal endothelial cells.

Long non-coding RNAs (lncRNAs) were considered to be involved in vascular complications in diabetes mellitus, but still only limited knowledge in this regard has been obtained. Herein, we further explored the roles of lncRNAs and mRNAs in diabetic vasculopathy (DV) through conducting bioinformatics analysis using data set downloaded from GEO database. The differentially expressed lncRNAs and mRNAs were identified by edge package.

Effect of the infusion ration between frozen plasma and plasma substitutes on the prognosis of adult patients with major burn in shock stage.

Objectives: In recent years, it has been reported that the anti-shock effect of plasma substitutes in adult patients with major burn in shock stage is not good. However, due to the shortage of clinical frozen plasma supply, it is impossible to guarantee that frozen plasma is used as colloidal solution for anti-shock treatment. The purpose of this study is to explore the effect of the infusion ration between frozen plasma and plasma substitutes on the prognosis of adult patients with major burn in shock stage.

Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models.

How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remains largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferentially localized to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7.

Enhanced immunogenicity of leukemia-derived exosomes via transfection with lentiviral vectors encoding costimulatory molecules.

Background: Tumor cell-derived exosomes (TEXs) have been widely used to induce antitumor immune responses in animal models and clinical trials. Similarly, leukemia cell-derived exosomes (LEXs) can induce antileukemia immune responses in animal models. However, the antileukemia immunity induced by LEXs is less effective, which may be due to an inadequate costimulatory capacity.

MCL-1 or BCL-xL-dependent resistance to the BCL-2 antagonist (ABT-199) can be overcome by specific inhibitor as single agents and in combination with ABT-199 in acute myeloid leukemia cells.

Aberrant over-expression of BCL-2 family proteins (BCL-2, BCL-xL, MCL-1) are associated with hematological malignancies. Antagonists of BCL-2 family proteins include BCL-2-selective inhibitor ABT-199, MCL-1-selective inhibitor A-1210477, BCL-xL-selective inhibitor A-1155463. In this study, we evaluated their potential inhibitory effectiveness.

IL-10 gene-modified dendritic cells-induced type 1 T regulatory cells inhibit graft-versus-host disease while preserving graft-versus-leukemia effect.

To explore the role of type 1 regulatory T (Tr1) cells in allogeneic bone marrow transplantation (allo-BMT), we generated Tr1 cells from naïve CD4 T cells in donor mice that were subjected to stimulation of recipient interleukin (IL)-10 gene-modified dendritic cells (DCs). In animal models, the severity of graft-versus-host disease (GVHD) in the group co-infused with DC-induced Tr1 cells was markedly milder than that in the groups without infusion of Tr1 cells. Moreover, the co-infusion Tr1 cells significantly prolonged the leukemia-free survival in tumor-bearing mice.

Knockdown of the Hippo transducer YAP reduces proliferation and promotes apoptosis in the Jurkat leukemia cell.

Leukemia and lymphoma are common hematological malignancies in children and young adults, which pose a tremendous threat to the survival of these young patients worldwide, despite availability of various effective treatments. The Hippo pathway is a novel‑signaling pathway that regulates organ size, cell proliferation, apoptosis and tumorigenesis. The chief component of this pathway is the transducer yes‑associated protein (YAP) which is over‑expressed in numerous categories of tumors.

Enhancement of Anti-Leukemia Immunity by Leukemia-Derived Exosomes Via Downregulation of TGF-β1 Expression.

Background/aims: Minimal residual leukemia cells (MRLs) are difficult to eradicate through traditional treatment and therefore remain to be a major threat to the long-term survival of leukemia patients. Tumor-derived exosomes (TEXs), which carry tumor associated antigens (TAA), may be a potential cell-free tumor vaccine for the specific eradication of MRLs. However, TEXs are intended to be less immunogenic due to exosomal TGF-β1.

Interleukin-10 Gene-Modified Dendritic Cell-Induced Type 1 Regulatory T Cells Induce Transplant-Tolerance and Impede Graft Versus Host Disease After Allogeneic Stem Cell Transplantation.

Background/aims: Tr1 cells can induce peripheral tolerance to self- and foreign antigens, and have been developed as a therapeutic tool for the induction of tolerance to transplanted tissue. We explored the feasibility of generating Tr1 cells by using IL-10 gene-modified recipient DCs (DCLV-IL-10) to stimulate donor naive CD4+ T cells. We also investigated some biological properties of Tr1 cells.

TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model.

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX) can enhance the efficacy of DC-based vaccines.

CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling.

Background: CD274 (programmed death ligand 1, also known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Increasing evidence indicates that functional monoclonal antibodies of CD274 may potently enhance the antitumor effect in many cancers. However, the role of CD274 in leukemia-initiating cells (LICs) remains largely unknown.

Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis.

Certain secretory proteins are known to be critical for maintaining the stemness of stem cells through autocrine signaling. However, the processes underlying the biogenesis, maturation, and secretion of these proteins remain largely unknown. Here we demonstrate that many secretory proteins produced by hematopoietic stem cells (HSCs) undergo exosomal maturation and release that is controlled by vacuolar protein sorting protein 33b (VPS33B).

Mucosal fluid evaporation is not the method of heat dissipation from fourth-degree laryngopharyngeal burns.

This study was designed to explore whether mucosal fluid evaporation represents a method of heat dissipation from thermal air inhalation injury and to assess laryngopharyngeal tissue damage according to heat quantity changes of dry air and vapour. Fifteen adult male beagles were divided into five groups to inhale heated air or vapour for 10 min as follows: control group (ordinary air), group I (91-110 °C heated air), group II (148-175 °C heated air), group III (209-227 °C heated air), and group IV (96 °C saturated vapour). The heat quantity changes of the dry air and vapour were calculated via thermodynamic formulas.

Heat dissipation by blood circulation and airway tissue heat absorption in a canine model of inhalational thermal injury.

Objective: This study aimed to further explore heat dissipation by blood circulation and airway tissue heat absorption in an inhalational thermal injury model.

Methods: Twelve adult male Beagle dogs were divided into four groups to inhale heated air for 10min: the control group, group I (100.5°C), group II (161.

Comparison of human coagulation factor VIII expression directed by cytomegalovirus and mammary gland-specific promoters in HC11 cells and transgenic mice.

Hemophilia A is an inherited X-linked recessive bleeding disorder caused by coagulant factor VIII (FVIII) deficiency. The conventional treatment involves the administration of recombinant human FVIII (rhFVIII) preparations. In this study, the mammary gland 'bioreactor' is designed to specifically and efficiently express a foreign protein hFVIII in the mammary glands of transgenic mice.

Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats.

In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats.

[Effect of different transplantations with bone-marrow derived mesenchymal stem cells on diabetic foot ulcers in rats].

Objective: To assess the therapeutic effect of treating diabetic foot ulcers (DFUs) in rats by subcutaneously transplanting around the wounds and intramuscularly into the leg with bone marrow derived mesenchymal stem cells (BM-MSCs).

Methods: BM-MSCs from male Wistar rats were cultured by the whole bone marrow adherence method until the third generation. The BM-MSCs were labeled by 4,6-diamino-2-phenylindole (DAPI) in vitro.

[Effect of intramuscular bone marrow-derived mesenchymal stem cell transplantation in the leg for treatment of diabetic foot ulcers in rats].

Objective: To assess the therapeutic effect of intramuscular transplantation of bone-marrow derived mesenchymal stem cells (BM-MSCs) in the leg for treatment of diabetic foot ulcers (DFUs) in rats.

Methods: Thirty-six male Wistar rats were randomly allocated into 3 equal groups, namely group A with DFUs on the bilateral hindlimb dorsum pedis and intramuscular transplantation of 4,6-diamino-2-phenylindole (DAPI)-labeled third-passage BM-MSCs from male Wistar rats into the leg, group B with nondiabetic foot ulcers, and group C with DFUs but without BM-MSC transplantation. On days 2, 5, 8 and 11 posttransplantation, the rate of wound healing was evaluated, the labeled BM-MSCs in the wound tissues were traced on frozen sections, and the thickness of granulation tissues was measured with HE staining.