HDAC6 deacetylates IDH1 to promote the homeostasis of hematopoietic stem and progenitor cells.

Hematopoietic stem and progenitor cells (HSPCs) are cells mainly present in the bone marrow and capable of forming mature blood cells. However, the epigenetic mechanisms governing the homeostasis of HSPCs remain elusive. Here, we demonstrate an important role for histone deacetylase 6 (HDAC6) in regulating this process. Our data show that the percentage of HSPCs in Hdac6 knockout mice is lower than in wild-type mice due to decreased HSPC proliferation. HDAC6 interacts with isocitrate dehydrogenase 1 (IDH1) and deacetylates IDH1 at lysine 233. The deacetylation of IDH1 inhibits its catalytic activity and thereby decreases the 5-hydroxymethylcytosine level of ten-eleven translocation 2 (TET2) target genes, changing gene expression patterns to promote the proliferation of HSPCs. These findings uncover a role for HDAC6 and IDH1 in regulating the homeostasis of HSPCs and may have implications for the treatment of hematological diseases.

Positive progress for non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations: A novel targeted therapy option.

Epidermal growth factor receptor gene exon 20 insertion mutations are seen in ∼4-12% of patients with epidermal growth factor receptor-mutant non-small cell lung cancer. However, there is no targeted therapy approved for the treatment of non-small cell lung cancer patients with these rare epidermal growth factor receptor mutations. Previous studies revealed that epidermal growth factor receptor gene exon 20 insertion mutations are unique in their ability to activate epidermal growth factor receptor without the typical structural changes associated with the common epidermal growth factor receptor mutations, reducing the clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors currently approved for non-small cell lung cancer. Therefore, there is an urgent need to identify active epidermal growth factor receptor-tyrosine kinase inhibitors and other effective treatment strategies for non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. Mobocertinib is a novel irreversible epidermal growth factor receptor-tyrosine kinase inhibitor that selectively targets epidermal growth factor receptor gene exon 20 insertion mutations. Preclinical study revealed that mobocertinib inhibited the viability of epidermal growth factor receptor gene exon 20 insertion mutations-driven patient-derived xenografts and murine orthotopic tumors more potently than traditional epidermal growth factor receptor-tyrosine kinase inhibitors. In a study recently published in Cancer Discovery, Gonzalvez et al. assessed the safety, tolerability, and antitumor efficacy of mobocertinib in metastatic non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. They found that non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations can benefit from mobocertinib treatment. Additionally, the treatment-related toxicity of mobocertinib was manageable. These findings lay the foundation for the application of mobocertinib in epidermal growth factor receptor gene exon 20 insertion-mutated non-small cell lung cancer.

Polycythemia vera transforming to myelofibrosis and then biphenotype acute leukemia.

BACKGROUND: A case with 17-year detailed illness history including evolution of polycythemia vera (PV) to myelofibrosis (MF) and then biphenotype acute leukemia (BAL) was reported. Ten years of PV followed by seven years of MF and then BAL, the patient experienced a classical "complete course" of myeloproliferative neoplasm (MPN). High WBC counts as well as low Hb and platelet counts in MF phase, long disease course, older than 50 years age, and positive JAK2 were her high risk factors of transformation from MPN to leukemia. Pancytopenia in her secondary MF phase responded well to the therapy of corticosteroids, which indicated that the immune mechanism was involved in the pathogenesis of MF. Progression of PV to MF and then BAL might be related to discontinuation of interferon-alpha because of poor tolerance.

Primary cilia restrict autoinflammation by mediating PD-L1 expression.

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Longitudinal genetically detectable minimal residual disease by fluorescence in situ hybridization confers a poor prognosis in myeloma.

Background: Deeper depth of response (DpR) after induction therapy, especially gain of negative minimal residual disease (MRD), has been linked to prolonged survival in multiple myeloma (MM). However, flow-MRD examination focuses on the numbers but not on the biological characteristics of residual plasma cells (PCs). Objectives: To explore whether the genetic features of residual tumor cells affect the survival time of patients with MM. Design: A retrospective cohort study. Methods: We investigated the clonality of cytogenetic abnormalities (CAs) of the residual PCs using interphase fluorescence in situ hybridization (iFISH) in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Here, a longitudinal cohort of 269 patients with patient-paired diagnostic and post-induction iFISH results was analyzed. Results: Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those with genetically detectable MRD [median progression-free survival (mPFS): 59.7 versus 35.7 months, p < 0.001; median overall survival (mOS): 97.1 versus 68.8 months, p = 0.011]. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. Patients who maintained at a high risk during follow-up had the worst survival (mPFS: 30.5 months; mOS: 54.4 months), while those who returned to lower risk or had iFISH- at both time points had the best survival (mPFS: 62.0 months, mOS: not reached). Conclusion: These findings highlighted the prognostic value of genetic testing in residual tumor cells, which may provide a deep understanding of clonal evolution and guide clinical therapeutic strategies.

Study using fluorescence in situ hybridization (iFISH) to investigate the clonality of cytogenetic abnormalities of the residual plasma cells in multiple myeloma Gain of negative minimal residual disease (MRD) has been linked to prolonged survival in cancer treatment. However, in multiple myeloma (MM), detection of MRD-negativity (MRD-) using multiparameter flow cytometry (MFC) only reflects the quantitative characteristics of residual plasma cells (PCs), while the biological and genetic features of MRD are neglected. To address this gap, our study has employed interphase fluorescence in situ hybridization (iFISH) to evaluate the clonality of cytogenetic abnormalities (CAs) of the bone marrow residual PCs after induction therapy, in combined with MRD detection by MFC to predict the prognosis of MM patients. A total of 396 patients from the database of National Longitudinal Cohort of Hematological Diseases in China (ClinicalTrials.gov identifiers: NCT04645199) were enrolled. Persistent CAs after induction therapy were detected in about half of the patients (118/269, 43%), and patients with undetectable CAs showed significantly improved survival compared with those without genetically detectable MRD. In addition, different patterns of therapy-induced clonal evolution were observed by comparing the clonal structure of residual PCs with paired baseline samples. And therapy-induced clonal evolution exerted a significant impact on patient outcomes. These findings highlighted the importance of genetic testing of residual tumor cells after induction therapy, which may represent a reliable complementary technique for flow-MRD detection and provide a further understanding of clonal evolution.

Bibliometric analysis of nanotechnology applied in oncology from 2002 to 2011.

Innovation in the last decade has endowed nanotechnology with an assortment of tools for drug delivery system, imaging, and sensing in cancer research. These rapidly emerging tools are indicative of a burgeoning field ready to expand into medical applications. The aim of this study is to analyze the applications of nanotechnology in oncology with bibliometric methods and evaluate development in this field. Literature search was performed using PubMed search engines with MeSH terms (all)--nanotechnology, nanomedicine, nanoparticle, nanocapsules, micellar systems, and oncology or cancer or neoplasms. Within 2,543 articles from 2002 to 2011 in over 50 medical magazines from over 30 countries, we did a series analysis on these articles' countries, keywords, and authors. Our results show that articles in nanotechnology in oncology are increasing year by year, especially in recent years. Quantity and quality of the articles are becoming more and influential. In the global research, the USA is leading in this field, accounting for half above of the whole articles, followed by countries like Japan, Germany, and France and also some emerging nations like China, in the second place, and India. Subjects like nanoparticles, tumor marker, and drug delivery are the common research focus. So, with more and more scientists' interests and attention drawn to this field, it is likely to make major breakthroughs in the coming years.

[Telomere length and gene expression of shelterin in CD3(+) T cell of severe aplastic anemia patients].

OBJECTIVE: To explore the changes in telomere length and gene expression of complex shelterin (composed of 6 core components: TRF1, TRF2, POT1, TIN2, TPP1 and RAP1) in severe aplastic anemia (SAA). METHODS: Bone marrow samples were obtained from 20 SAA patients and 10 normal controls. CD3(+)T cells were sorted by immunomagnetic separation. Telomere length was tested by Southern blot and the gene expressions of TRF1, TRF2, POT1, TIN2, TPP1 and RAP1 were detected by reverse transcription-PCR(RT-PCR). RESULTS: Telomeres of CD3(+)T cells were found significantly shorter in SAA untreated ((4.4 ± 1.1) kb, n = 9) and recovering groups((5.8 ± 1.0) kb, n = 11) than control group ((9.2 ± 3.3) kb, P < 0.05). Telomere length of CD3(+)T cells shortened with TH/S decreasing (r = 0.564, P = 0.029). The mRNA expression of POT1 decreased in untreated SAA patients (0.16(0.02-0.29)) and over-expressed in recovering patients (1.17(0.82-1.86), P < 0.05). The mRNA expression of RAP1 was significantly higher in untreated patients (4.14 (1.93-6.92)) than that in recovering group (0.87 (0.30-1.73) ) and controls (0.62 (0.45-4.07) , both P < 0.05). CONCLUSION: Changes in telomere length and shelterin gene expression occur in CD3(+)T cells of SAA patients and may be correlated with disease severity.

VEXAS Syndrome-Review.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined refractory adult-onset autoinflammatory syndrome caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene in hematopoietic stem and progenitor cells, resulting in a shift in UBA1 isoform expression. Thus, patients develop a spectrum of systemic inflammatory manifestations and hematologic symptoms. To date, patients respond poorly to immune suppressive drugs, except high-dose glucocorticoids, and no treatment guidelines have been established. Given the high mortality rate, VEXAS syndrome needs to be taken seriously by physicians in all specialties. This article aims to describe the key features, pathogenesis, and clinical manifestations of VEXAS syndrome to better understand the targeted treatment and improve the prognosis of VEXAS syndrome.

Identification of Plasma Thrombopoietin Level and Its Significance in Patients with Aplastic Anemia and Myelodysplastic Syndrome.

Objective Our objective was to investigate the concentration of plasma thrombopoietin (TPO) in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS), as well as its relationship with patients' responses to recombined human TPO (rhTPO) therapy. Methods We detected the concentration of plasma TPO in 31 patients with AA, 27 patients with MDS, and 11 normal controls using enzyme-linked immunosorbent assay. Results The median concentration of plasma TPO in patients with AA, MDS, and controls was (841.08 ± 768.64), (212.41 ± 338.93), and (35.09 ± 18.21) pg/mL, respectively. The TPO concentration in patients with AA and MDS was significantly higher than that in controls ( p < 0.05). The median platelet (PLT) counts were (184 ± 34) ×10 9 /L in the control group and (24 ± 19) ×10 9 /L and (80 ± 71) ×10 9 /L in AA and MDS patients, respectively. Negative correlations were found between plasma TPO concentration and PLT counts as well as megakaryocytes in bone marrow ( p < 0.05). In AA patients treated with rhTPO, a negative correlation was observed between increased PLT counts and pretreatment TPO levels ( p < 0.05). Conclusion Plasma TPO concentration in AA and MDS was significantly higher than that in normal controls. Plasma TPO was negatively correlated with peripheral blood PLT counts and bone marrow megakaryocyte counts. The pretreatment TPO level may serve as a prognostic indicator for the therapeutic effect of rhTPO in AA patients.

Pim-2 Kinase Regulates Energy Metabolism in Multiple Myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) and is associated with poor prognosis in patients with MM. Changes in quantitative metabolism, glycolysis, and oxidative phosphorylation pathways are reportedly markers of all tumor cells. However, the relationship between Pim-2 and glycolysis in MM cells remains unclear. In the present study, we explored the relationship between Pim-2 and glycolysis. We found that Pim-2 inhibitors inhibited glycolysis and energy production in MM cells. Inhibition of Pim-2 decreased the proliferation of MM tumor cells and increased their susceptibility to apoptosis. Our data suggest that reduced Pim-2 expression inhibits the energy metabolism process in MM, thereby inhibiting tumor progression. Hence, Pim-2 is a potential metabolic target for MM treatment.

Phagocytosis checkpoints on hematopoietic stem cells in patients with myelodysplastic syndromes.

BACKGROUND: The myelodysplastic syndrome (MDS) is a high-risk hemocytopenia easily converted to acute myeloid leukemia. CD47 plays an important role in regulating phagocytosis, and its role in the pathogenesis of MDS is unclear. METHODS: CD47 and PI3K/AKT/mTOR on CD34+ CD38- cells were detected by flow cytometry. NF-κB, PI3K, AKT, PTEN, and mTOR mRNA overexpressed in CD34+ CD38- CD47+ cells were performed by real-time quantitative transcriptase-polymerase chain reaction. Phagocytic capacity of macrophages was measured with carboxyfluorescein succinimidyl ester and fluorescent microspheres. Sorted CD34+ CD38- CD47+ cells were injected into NOD-Prkdcscid Il2rgnull mice. RESULTS: The expression of CD47 on CD34+ CD38- cells of the patients in high-risk MDS based on IPSS-R/WPSS score was higher than that in low-risk MDS and controls. The signaling pathway of PI3K/AKT/mTOR is active in CD34+ CD38- CD47+ cells of MDS patients. CD47 overexpressing CD34+ CD38- cells has antiphagocytosis. CD47 overexpressing leukemia stem cell (LSC) -transplanted mice has a short survival time. The macrophages originated from MDS might elicit a pro-tumor response in MDS by inhibiting phagocytosis. CONCLUSIONS: Phagocytosis checkpoints are impaired in MDS. High expression of CD47 on CD34+CD38- cells indicates poor clinical prognosis in MDS.

[Expression and Significance of PD-1 and ICOS in Patients with Primary Immune Thrombocytopenia].

OBJECTIVE: To investigate the expression of programmed death receptor-1 (PD-1) and inducible costimulator (ICOS) on the surface of CD8+ T cells in peripheral blood of patients with primary immune thrombocytopenia (ITP), and explore the roles of PD-1 and ICOS in the occurrence and development of ITP. METHODS: A total of 28 ITP patients treated in Tianjin Medical University General Hospital from September to December 2020 were selected, including 13 patients with newly diagnosed ITP, 15 patients with chronic ITP, and 22 healthy volunteers were recruited as control group. Flow cytometry was used to detect the expression levels of PD-1 and ICOS, and evaluate their correlation with clinical indicators. RESULTS: The percentage of CD8 + T cells in ITP patients of chronic group was higher than that of the newly diagnosed group and the control group (P<0.05). The expression level of PD-1 on CD8+ T cells in ITP patients of newly diagnosed group and chronic group were significantly lower than that of the control group (P<0.05), while the expression level of ICOS were significantly higher (P<0.05). In ITP patients, PD-1 was negatively correlated with platelet count (r=-0.4942, P<0.01), but positively with ICOS (r=0.4342). PD-1 and ICOS were both negatively correlated with lymphocyte count (rPD-1=-0.4374; rICOS=-0.4492). CONCLUSION: In ITP patients, the unbalanced expression of PD-1 and ICOS may interfere with the immune homeostasis of the body, which can be used as a therapeutic target for ITP patients.

Targeting De Novo Lipogenesis and Cholesterol Biosynthesis Simultaneously is a Novel Therapeutic Option for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and serious types of cancer in the world. Currently, the treatment options for patients with HCC are limited. Lipid metabolic alterations are being recognized as a therapeutic target in the past few years. De novo lipogenesis has been frequently observed in HCC. Fatty acid synthase (FASN) is the key enzyme of de novo lipogenesis. Previous studies have indicated that loss of FASN suppresses the growth of HCC cells, but it cannot completely prevent HCC formation in vivo. Thus, other mechanisms that can support HCC tumor formation in the absence of de novo lipogenesis maybe existed. In a study recently published in Gut, Che and colleague investigated the functions of Fasn in HCC mouse model and explore the crosstalk between de novo lipogenesis and cholesterol biosynthesis-associated pathway during HCC development. These findings highlight the simultaneous inhibition of de novo lipogenesis and cholesterol biosynthesis as a novel therapeutic and prevention strategy for HCC.

Primary mediastinal large B cell lymphoma.

Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive large B cell lymphoma originating in the mediastinum, that mainly expresses B cell surface molecules, such as CD19, CD20, CD22, andCD79a. Clinically, they are characterized by rapidly increasing anterior mediastinal masses, which can cause compression of the surrounding tissues. The diagnosis of PMBCL mainly depends on the pathological features, imaging examination and clinical features. Currently, the most commonly used therapeutic regimens are R-CHOP and R-EPOCH. Radiotherapy is beneficial in some patients, but it can also lead to long-term toxicity. The research and development of novel therapies are ongoing, and some studies have achieved encouraging results, including those conducted on chimeric antigen receptor-modified T (CAR-T) cell therapy and anti-PD-1 drugs. However, randomized controlled trials with larger sample sizes are still needed. Positron emission tomography-computed tomography (PET-CT) is mainly used to assess the curative effect after treatment and to guide the subsequent treatment strategy.

The Role of T Lymphocytes in the Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell genetic mutation disease that causes defective erythrocyte membrane hemolysis. Its pathologic basis is the mutation of the PIG-A gene, whose product is necessary for the synthesis of glycosylphosphatidylinositol (GPI) anchors; the mutation of PIG-A gene results in the reduction or deletion of the GPI anchor, which leads to the deficiency of GPI-anchored proteins (GPI-APs), such as CD55 and CD59, which are complement inhibitors. The deficiency of complement inhibitors causes chronic complement-mediated intravascular hemolysis of GPI-anchor-deficient erythrocyte. PIG-A gene mutation could also be found in bone marrow hematopoietic stem cells (HSCs) of healthy people, but they have no growth advantage; only the HSCs with PIG-A gene mutation in PNH patients have this advantage and expand. Besides, HSCs from PIG-A-knockout mice do not show clonal expansion in bone marrow, so PIG-A mutation cannot explain the clonal advantage of the PNH clone and some additional factors are needed; thus, in recent years, many scholars have put forward the theories of the second hit, and immune escape theory is one of them. In this paper, we focus on how T lymphocytes are involved in immune escape hypothesis in the pathogenesis of PNH.

[Expression and Significance of IL-9 and IL-6 in Patients with BCR-ABL- MPN].

OBJECTIVE: To investigate the expression of IL-9 and IL-6 in patients with BCR-ABL- bone marrow proli- ferative tumor (MPN), and to explore its role in the occurrence and development of MPN. METHODS: A total of 71 newly diagnosis MPN patients treated in Tianjin Medical University General Hospital from 2018 to 2019 were selected, including 32 patients with polycythemia vera (PV) and 22 patients with primary thrombocytosis (ET), and 17 patients with primary myelofibrosis (PMF). Then 58 patients who retestine after treatment were selected as therapy group，and 20 healthy volunteers were recruited as control group. ELISA was used to detect the expression level of IL-6 and IL-9 in bone marrow supernatant, and the relative expression level of IL-6 and IL-9 mRNA in BMMNC was detected by real-time PCR. The proportion of Th9 cells in peripheral blood were detected by flow cytometry (FCM). The expression level of IL-6 mRNA and IL-9 mRNA of BMMNC and clinical indicators were analyzed, and the correlation between JAK2 gene mutation load and IL-9 level was further analyzed. RESULT: The level of IL-6 in bone marrow supernatant and the expression of IL-6 mRNA in BMMNC were higher in the newly diagnosed group as compared with those in the treated group and the control group (P<0.001). The expression level of IL-9 in bone marrow supernatant and the expression of IL-9 mRNA in BMMNC were lower in the newly diagnosed group as compared with those in the treated group and the control group (P<0.05). The proportion of Th9 cells in peripheral blood was lower in the newly diagnosed group as compared with that in the treated group and the control group (P<0.001). The level of IL-6 in bone marrow supernatant and the expression of IL-6 mRNA in BMMNC in JAK2+ group were higher than those in JAK2- group (P<0.05). The expression level of IL-9 in bone marrow supernatant and the expression of IL-9 mRNA in BMMNC were lower in JAK2+ group as compared with those in JAK2- group (P<0.05). The expression of IL-6 and IL-9 in the patient group showed correlation with the number of lymphocytes (IL-6: r=-0.49, P<0.01; IL-9: r=0.53, P<0.001), and also related with Hb in PV patients (IL-6: r= 0.87, P<0.001; IL-9: r=-0.54, P<0.01), and platelets in ET patients (IL-6: r=0.64, P<0.05; IL-9: r=-0.46, P<0.05). CONCLUSION: The increased expression of IL-6 in MPN and hyperfunction may promote the progression of BCR-ABL- MPN disease. The expression of IL-9 in MPN decreases, and it negatively correlates with the mutation load of JAK2 gene, which may be related with the decrease of tumor environmental antitumor immune effect.

Ginsenoside Rg3 promotes beta-amyloid peptide degradation by enhancing gene expression of neprilysin.

OBJECTIVES: It has been hypothesized that the accumulation of beta-amyloid peptide (Abeta) in the brain is a triggering event leading to the pathological cascade of Alzheimer's disease. The steady-state levels of Abeta are determined by the metabolic balance between anabolic and catabolic activity and the dysregulation of this activity leads to Alzheimer's disease. Recent evidence has shown that neprilysin (NEP) is the rate-limiting enzyme in the Abeta degradation in the brain. Ginseng, the root of Panax ginseng C.A. Meyer, is widely used as a tonic for the prevention and treatment of age-related disorders in China. We aimed to investigate the basis of this use. METHODS: In this study, we investigated the effect of ginsenoside Rg3, one of the major active components of ginseng, on the metabolism of Abeta40 and Abeta42 in SK-N-SH cells transfected with Swedish mutant beta-amyloid precursor protein (SweAPP). RESULTS: The ELISA result showed that Rg3 significantly reduced the levels of Abeta40 and Abeta42, 19.65 +/- 6.05%, 23.61 +/- 6.74%, respectively (P < 0.01). The Western blot analysis showed that Rg3 reduced the levels of Abeta40 and Abeta42 through enhancing NEP gene expression, and real-time PCR assay showed that 50 microM Rg3 could significantly enhance NEP gene expression (2.9 fold at 48 h). CONCLUSIONS: Our findings suggest that the Rg3 compound of ginseng may be useful for treating patients suffering with Alzheimer's disease.

GDF11 is increased in patients with aplastic anemia.

OBJECT: To explore the critical role of growth differentiation factor 11 (GDF11) in the pathobiology of aplastic anemia (AA). METHODS: We have examined the serum GDF11 levels for 79 AA patients and 30 healthy controls. A total of 79 AA patients, which included 29 new diagnosed (untreated) cases, 14 cases with no response, 21 partial remission (PR) cases and 15 complete remission (CR) cases after immunosuppressive therapy (IST). GDF11 serum levels were assessed by an enzyme-linked immunosorbent assay. GDF11 mRNA expression in peripheral blood mononuclear (PBMNC) was detected through real time polymerase chain reaction. The correlation between GDF11 expression and erythropoietic function was evaluated. RESULTS: The serum GDF11 levels in untreated AA patients were higher than that of the control group. The serum GDF11 levels of PR patients or CR patients after IST was decreased, compared with untreated patients, but did not recover back to the normal levels. GDF11 levels had a negative correlation with hemoglobin (Hb) levels and reticulocyte counts in AA patients. GDF11 levels did not correlate with age, sex and severity of in AA patients. CONCLUSION: Serum GDF11 levels were increased and negatively correlated with Hb levels and reticulocyte counts in AA patients. This suggests an impaired GDF11 response contributing to anemia in AA patients.

[Relationship of Peripheral Blood IL-37 Expression with T Lymphocytes Subsets and NK Cells in Patients with Primary Immune Thrombocytopenia].

OBJECTIVE: To study the correlation of IL-37 with T lymphocytes subsets and NK cells in ITP patients, and to explore its possible mechanisms involved in the pathogenesis of ITP. METHODS: Forty-five patients with newly diagnosed ITP(newly diagnosed group), 32 patients of complete remission (remission group) and 22 healthy persons(control group) were selected. The serum level of IL-37 in 3 groups was determined by enzyme linked immunosorbent assay (ELISA). The mRNA expression of IL-37, IL-17 and IL-18 in peripheral blood mononuclear cells（PBMNC） in 3 groups was measured by real-time fluorescence quantitative polymerase chain reaction (PCR). The number of IL-18Rα+CD4+ T cells and Tim-3+NK cells in the peripheral blood in 3 groups was detected by flow cytometry (FCM). RESULTS: The serum level of IL-37 in the peripheral blood of ITP patients in the newly diagnosed group was significantly higher than that in the control group and the remission group(P＜0.01) . The expression level of IL-37 in PBMNC of the ITP patients in newly diagnosed group was higher than that in the control group and the remission group(P＜0. 05). The expression level of IL-17 and IL-18 in PBMNC of the ITP patients in newly diagnosed group was higher than that in the control group and the remission group(P＜0. 01); the expression of IL-18Rα in CD4+ T cells in newly diagnosed group was significantly higher than that in both the control and the remission group(P＜0.01).The expression of Tim-3 in NK cells in ITP patients was significantly lower than that in the control group (P＜0. 01). In ITP patients, the serum IL-37 level and IL-18Rα+CD4+T cells ratio both negatively correlated with Plt count (r=-0.58, r=-0.48) moreo-ver the serum IL-37 level also negatively correlated with amount of CD4+ T cells and NK cells (r=-0.29, r=-0.28), but positively correlated with amount of CD8+ T cells (r=0.329). CONCLUSION: The IL-37 and its receptors may play an immunoregulatory role in CD4+ T cells and NK cells, the IL-37 may be a therapeutic target for ITP patients.

Histone deacetylase inhibitor valproic acid inhibits proliferation and induces apoptosis in KM3 cells via downregulating VEGF receptor.

The expression of vascular endothelial growth factor receptor 1(VEGFR-1) in human multiple myeloma KM3 cells in vitro, effects of valproic acid (VPA), as a histone deacetylase inhibitor, on cell proliferation and apoptosis and the underlying molecular mechanism were investigated. The effects of VPA on the growth of KM3 cells were studied by MTT assay. The apoptosis rate was determined with flow cytometry. The mRNA level of VEGFR was determined by RT-PCR; and immunocytochemistry was used to detect the protein level of ac-H4 and VEGFR. VPA inhibited proliferation of KM3 cells in a time- and dose-dependent manner. Treatment with VPA (4, 2, 1 and 0.5 mmol/L) for 48h, the apoptosis rates of KM3 cells were (13.27+/-3.54)%, (22.13+/-1.20)%, (24.41+/-2.23)% and(40.62+/-4.28)% respectively. The expression of VEGFR-1 in KM3 cells were decreased in VPA-treated group by the immunochemistry and RT-PCR, whereas the acetylated histone H4(ac-H4) accumulated. It suggested VPA could decrease the expression of VEGFR-1 in KM3 cells, and it might play an important role in regulating the proliferation and apoptosis of multiple myeloma cell line KM3 cells. These results provide the framework for clinical trials.