Stocktaking: May 7, 2020 Blood Research Select

1The high-fat diet delays the production of plasma lysozyme in a thrombosis-regulated protein-dependent manner
https://doi.org/10.1182/blood.2019004267https://doi.org/10.1182/blood.2019004267https://doi.org/10.1182/blood.2019004267obesity is a common risk factor for thrombosis, characterized by fibrin formation enhancement and fibrin dissolution inhibitionFibrin not only promotes thrombosis, but also drives the pathophysiology of obesityrecently, researchers have developed a plasma lysozyme production (PG) test using a filisolyse-specific fluorescent matrix that is sensitive to tissue fibrinolycel lysozyme, alpha2-antififilip lysozyme, active filisolyse activator inhibitor (PAI-1) and fibrin formation, but not sensitive to fibrin cross-linking in mouse plasmaThe plasma of mice fed a high-fat diet (HFD) had a lower PG delay and a lower PG rate than the plasma of mice fed a controlled diet (CD)While PG is damaged, HFD also increases the production of clotting enzymes (TGs)The combined effects of TG and PG abnormalities on HFD-fed mice produced normal fibrin formation dynamics, but delayed fibrin dissolutionFunctional and proteomic analysis found that the PG delay in HFD-fed mice was not due to a change in the level of filisolyse, alpha-2-antififilip lysozyme, or fibrinogenPG changes cannot be explained by PAI-1 elevation, as the active PAI-1 concentration required to inhibit PG assays is 100 times higher than the circulating concentration in miceHFD-fed mice with elevated circulating thrombosis-regulating proteins, inhibiting thrombosis or thrombosis-activated fibrous inhibitors (TAFI) can normalize PG, revealing anti-filisotic mechanisms for thrombosis and TAFI dependenceThe binding dynamics parameters of the TG/PG ratio were calculated to quantify the net transfer of HFD-fed mice to pheon supplows 2: PIM inhibits or improves the of chemotherapy prognosis in patients with IL7 reactive CD127-T-ALL and T-LBL
https://doi.org/10.1182/blood.2019003880 T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are invasive hematologic malignancies and are currently treated with high-dose chemotherapy In recent years, the research on new low toxicity treatment strategies for Patients with T-ALL/T-LBL has focused on the identification of the intracellular characteristics of tumor cells However, specific cancer-causing pathways that are not self-activated by non-cells may also provide therapeutic targets that can be studied at the level of treatment Recently researchers have found that endogenous IL7 can increase the expression of the carcinogenic kinase PIM1 in CD127-All/T-LBL, making these tumor cells sensitive to PIM inhibition in the body Using different CD127-T-ALL/T-LBL xenotransplantation models, the researchers also found that PIM1 expression was consistently upward compared to untreated tumor cells after short-term chemotherapy It is worth noting that this effect is short-lived because no elevated PIM1 levels were observed in recurrent diseases after the abolition of initial chemotherapy In addition, the researchers found that this phenomenon, at least in part, was mediated by the ability of glucocorticoids to cause IL7RA transcription upwards in T-ALL/T-LBL PDX cells, and eventually to non-cell autonomous PIM1 upwards through endogenous IL7 Finally, the researchers demonstrated in vivo that the pDX model of CD127-T-ALL improved leukemia survival in combination with chemotherapy pan-PIM inhibitors 3: MTOR activation of iacoma multicenter Castleman disease enhances https://doi.org/10.1182/blood.2019002792 iMCD is a rare and incomprehensible blood disease characterized by lymph node disease, systemic inflammation, blood cell reduction, and multiple organ dysfunction of life Interleukin 6 (IL-6) inhibition can effectively treat about 1/3 of patients The choice of IL-6 non-reactive persons is limited due to the unclear etiology, disorder cell type and signaling pathway The researchers reported three cases of mTOR activation-enhanced anti-IL-6 non-reactive, and they responded to the suppression of mTOR by siromos Recently, researchers studied mTOR signals from iMCD patients and control seroprotein groups detected pS6, p4EBP1 and p70S6K (known as mTORC1-activated effect molecules and indicators) in iMCD patients (26 cases) and healthy controls in the lymph nodes through immunohistization (IHC), and showed an increase in mTOR activation in the small bubble gap in the lymph nodes of iMCD patients compared to healthy controls In addition, IHC test pS6 also showed that iMCD's mTOR activation level was higher than Hodgkin's lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that mTOR activation in iMCD is not only a product of lymphatic hyperplasia/inflammatory lymph node disease In addition, the activation level of mTOR in iMCD is comparable to that of autoimmune lymphatic hyperplasia syndrome, a disease that is a response to the treatment of seromox caused by overactivation of mTOR Analysis of gene concentration data on serum proteomics in iMCD patients (88) and control (42 cases) showed that the mTORC1 signal was significantly enriched Finally, functional studies showed an increase in baseline mTOR pathway activation in samples of trans-concebo and T-cells in patients with iMCD remission compared to healthy controls IL-6 stimulation enhances mTOR activation in iMCD patients, and JAK1/2 inhibition can counteract this effect the of the SIRPA knock-in model of normal and malignant hematopoietic stem cells
https://doi.org/10.1182/blood.2019002194 in human-mouse allogeneic transplants, the polymorphism of signal-regulating protein alpha (SIRPA) determines its affinity with HUMAN CD47, which is critical to the implantation efficiency of human cells Recently, the researchers created a new C57BL/6 Rag2null Il2rgnull (BRG) mouse line using Sirpahuman/human, whose Sirpa gene was replaced with the human SIRPA gene for the entire (eight exons) the mice's macrophages were significantly stronger in affinity to human CD47 than SirpaNOD/NOD, and did not show detectable phagocytosis for human hematopoietic stem cells In turn, macrophages in Sirpahuman/human mice had only moderate-intensity affinity to CD47 in mice, and BRGShuman mice did not exhibit blood cell reduction in Sirpa/-mice in heterogeneous transplantation, BRGShuman mice showed a highly effective transplant, maintained human hematopoietic function, had a high level of myelin cell reconstruction, and improved the reconstruction of surrounding tissue compared to BRG in SirpaNOD/NOD (BRGSNOD) mice Compared to BRGSNOD mice, BRGShuman mice also showed significant increases in implantation and growth of human colon cancer cells with acute myeloid leukemia and subcutaneous transplantation 5 CD19 CAT-T cell combined with ilutinib to treat R/R CLL efficacy and safety https://doi.org/10.1182/blood.2019002936 https://doi.org/10.1182/blood.2019002936 previous studies have shown that patients with recurrent or refractory (R/R) chronic lymphocytic leukemia (CLL) can be treated with CD19 targeted heptid antigen receptor engineering T (CD19 CAR-T) cell immunotherapy In light of pre-clinical studies that showed that elutinib can improve the efficacy of CAR-T cell antitumor stos and reduce cytokine release syndrome (CRS), the researchers conducted a pilot study to assess the safety and feasibility of the combined application of ilutinib and CD19 CAR-T cell immunotherapy recruited 19 CLL patients The previous median treatment was 5 times, with 17 (89%) patients having high-risk cytogenetics (17p deficiency and/or complex nuclei) It is planned to start with errutinib at least 2 weeks before white blood cell extraction and continue treatment for at least another 3 months after CAR-T cell infusion The combined CD19 CAR-T cell immunotherapy of ilutinib was well tolerated; 13 (68%) patients received ilutinib treatment as planned without reducing the dose of the drug The overall 4-week remission rate was 83%, and 61% of patients received minimal residual lesions (MRD) negative bone marrow remission (IGH sequencing) The overall survival rate (OS) and non-progress survival (PFS) were 86% and 59%, respectively Compared to CLL patients treated only with CAR-T cells, CAR-T cell binding elutinib reduced the severity of CRS and reduced serum concentration of CRS-associated cytokines, although patients with both therapies had the same CAR-T cell amplification Cd19 CAT-T cells combined with Ilutinib or non-ilutinib in patients with 1-year PFS of 38% and 50%, respectively Source: MedSci Original