The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion.

Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.

Emergency Combination of Four Drugs for Bloodstream Infection Caused by Carbapenem-Resistant Enterobacteriaceae in Severe Agranulocytosis Patients with Hematologic Malignancies after Hematopoietic Stem Cell Transplantation.

Bloodstream infection (BSI) caused by multidrug-resistant (MDR) bacteria or extensively drug-resistant (XDR) bacteria is a global threat. However, an effective treatment regimen is still controversial and inadequate due to the rapid deterioration caused by the bacteria. In immunocompromised and neutropenic patients, MDR-BSI is an emergency, which causes treatment-related mortality. In this study, four agranulocytosis patients with hematologic malignancies after HSCT receiving treatment for carbapenem-resistant Enterobacteriaceae- (CRE-) BSI were included. Conventional treatment using two to three combined antibiotics was administered in the first and second patients. Combination treatment using four drugs, polymyxin B, high-dose tigecycline, fosfomycin, and double-dose carbapenem, was administered in the third and fourth patients. None of the patients receiving conventional treatment survived. Both patients receiving combination treatment using four drugs survived. Therefore, four-drug combination therapy may be needed in CRE-BSI patients who experienced severe agranulocytosis after HSCT. The efficacy of the four-drug combination treatment for CRE-BSI patients as well as the adverse effects need to be further studied.

Macrophage regulation of graft-vs-host disease.

Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells' reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.

A Case of Acute Lymphocytic Leukaemia with t(3;13) and Central Nervous System Leukemia after Allogenic Cord Blood Transplantation.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a neoplastic cancer characterized by clonal expansion of leukemic cells in lymph organs and bone marrow. Lots of kinds of different chromosomal translocations can be found in those leukemic cells. However, the role of abnormal chromosomes and genes in leukemogenesis is not yet fully understood. Identifying new chromosomal translocations can facilitate a better understanding of pathogenesis of this disease. CASE PRESENTATION: We report a rare case of acute lymphocytic leukaemia with t(3;13)(q29, q21). The patient was diagnosed pre-B-ALL with no abnormal chromosomal or gene fusion and achieved complete remission (CR) after induction chemotherapy; 10 months later, she relapsed in the consolidation, with cytogenetics tests showing 46, XX, t(3;13)(q29, q21). Given no CR after two chemotherapy regimens, the patient received salvage cord blood transplantation. Regular intrathecal methotrexate was applied to prevent central nervous system leukemia. Good graft versus leukemia was induced by daily injection of a low dose of IL-2 2 months post-transplantation. Minimal residual disease negativity was maintained until central nervous system (CNS) leukemia was found 8 months after transplantation. A whole exome sequencing was performed. Nine driver mutation genes and seven tumor genes were found. CONCLUSIONS: We highly suspect that the relapse in the CNS after transplantation is associated with a rare chromosomal translocation.

Efficacy and Safety of Eltrombopag for Aplastic Anemia: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Eltrombopag seems to be effective in treating patients with aplastic anemia in several clinical trials. This paper aims to perform the first meta-analysis analyzing the efficacy and safety of eltrombopag for aplastic anemia. METHODS: Literatures were retrieved from PubMed, EMBASE, OVID, Web of Science, Cochrane, Wanfang, http://clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform search portal from establishment to July 2018. Using Stata statistical software version 12.0, subgroup analyses and sensitivity analyses were conducted. RESULTS: The overall hematologic response rate is 88% (95% CI 83-94%) for patients treated with eltrombopag plus immunosuppressive therapy, and 47% (95% CI 38-56%) for patients with refractory aplastic anemia using eltrombopag alone. Karyotype abnormality rates include an overall rate of 10% (95% CI 7-14%), a subtotal rate of 8% (95% CI 3-13%) for patients who are treated with eltrombopag plus immunosuppressive therapy without using antithymocyte globulin before, and a subtotal rate of 17% (95% CI 10-24%) for patients with refractory aplastic anemia treated with eltrombopag alone. CONCLUSIONS: With different treatments and in different conditions eltrombopag showed a distinctive effect for aplastic anemia. However, clone evolution and adverse events were associated with treatment.

[Effects of electroacupuncture at neiguan (PC6) on c-Jun NH2-teminal kinase signaling pathways in hypertrophic myocardial cells].

OBJECTIVE: To study the effects of electroacupuncture (EA) at Neiguan (PC6) on c-Jun NH2-terminal kinases (JNK) signaling pathways in hypertrophic myocardial cells. METHODS: Thirty female SD rats were randomly divided into three groups, i.e., the normal group, the model group, and the EA group, 10 in each group. Isoprenaline hydrochloride (ISO) injection at the daily dose of 3 mg/kg was subcutaneously injected for 14 days to establish the cardiac hypertrophy (CH) model. Rats in normal group were subcutaneously injected with an equal volume of normal saline. EA at Neiguan (PC6) was applied for rats in the EA group while modeling, once daily, for 14 successive days. The left ventricular weight index (LVWI) and heart weight index (HWI) were calculated in all rats. The content of angiotensin II (Ang II) in the cardiac muscular tissue was tested using radioimmunoassay. The protein expressions of JNK and phosphorated JNK (p-JNK) in cardiocytes were detected using Western blot. RESULTS: Compared with the normal group, LVWI and HWI, the Ang II content, and the expressions of JNK and p-JNK were significantly higher in the model group, showing statistical difference (P < 0.01). The aforesaid indices were obviously lower in the EA group than in the model group with statistical difference (P < 0.05). CONCLUSIONS: EA at PC6 could prevent and treat CH possibly correlated with regulation of JNK signaling pathways. EA might play a role possibly through regulating its upstream neuroendocrine factors.

[Effects of electroacupuncture at "Neiguan" (PC 6) on p38 MAPK signaling pathway in rats with cardiac hypertrophy].

OBJECTIVE: To discuss the mechanisms of electroacupuncture at "Neiguan" (PC 6) on p38 MAPK signaling pathway in rats with cardiac hypertrophy. METHODS: Forty SD rats were randomly divided into four groups: a normal group, a model group, a model plus p38 MAPK inhibitor group, a model plus electroacupuncture group, ten rats in each group. The model rats were established by subcutaneous injection 3 mg/(kg x d) of Isoprenaline Hydrochloride; model plus p38 MAPK inhibitor group were injected 0.3 mg/(kg x d) of specific inhibitor SB 203580; model plus electroacupuncture group was treated by electroacupuncture at "Neiguan"(PC 6) with continuous-wave, 2 Hz and 1 mA for 20 minutes, once a day for 14 days. There was no treatment in other two groups. The contents of TNF-alpha and IL-1beta in heart tissue were detected by radioimmunoassay and the p38 MAPK, p-p38 MAPK by western blot. RESULTS: Compared with normal group, the contents of TNF-alpha, IL-1beta, p38 MAPK, p-p38 MAPK were significantly increased in model group (all P < 0.01). The contents of TNFalpha, IL-1beta, p38 MAPK, p-p38 MAPK were significantly decreased in model plus p38 MAPK inhibitor group and model plus electroacupuncture group, compared with model group, all P < 0.05; compared with normal group, P < 0.05, P < 0.01; but no significant difference between model plus p38 MAPK inhibitor group and model plus electroacupuncture group (P > 0.05). CONCLUSION: Electroacupuncture at "Neiguan" (PC 6) can prevent the phosphorylation of p38 MAPK of myocardial hypertrophy, and the mechanism maybe adjust p38 MAPK signaling pathway by inhibiting the expression of TNF-alpha and IL-1beta.

Electroacupuncture at PC6 (Neiguan) Improves Extracellular Signal-Regulated Kinase Signaling Pathways Through the Regulation of Neuroendocrine Cytokines in Myocardial Hypertrophic Rats.

Electroacupuncture (EA) therapy has been widely accepted as a useful therapeutic technique with low or no risk in the clinical prevention of cardiac hypertrophy. However, the signaling transduction mechanism underlying this effect remains unclear. The current study investigates the effects of EA on the signaling pathways of myocardial hypertrophy (MH) in rats. Up to 40 3-month-old Sprague-Dawley (SD) rats were randomly divided into normal, model, PC6 (Neiguan), and LI4 (Hegu) groups, with ten rats in each group. All the rats except for the normal group received 3 mg/kg·d of isoprinosine hydrochloride (ISO) injection into the back skin. The rats in the PC6 and LI4 groups received EA for 14 days. On the 15th day, electrocardiograms were recorded, and the ultrastructure of the myocardial cells was observed. The myocardial hypertrophy indices (MHIs), electrocardiograph (ECG), ultrastructure observation, levels of plasma angiotensin II (Ang II) and endothelin (ET), as well as protein expression of extracellular signal-regulated kinase (ERK), and phosphorylation extracellular signal regulating kinase (p-ERK) in the left ventricular myocardial tissue were measured. The results indicated that EA can improve cardiac function in MH rats by modulating upstream neuroendocrine cytokines that regulate the ERK signaling pathways.