Yunfeng Cheng

IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders

Frequent mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in gliomas and acute myeloid leukemia (AML). Our aim is to assess whether IDH mutations were presented in Chinese patients with various hematological disorders. In this study, we screened the IDH1 and IDH2 mutations in a cohort of 456 Chinese patients with various hematological malignancies and disorders. We found three missense (p.R132C, p.R132G, and p.I99M; occurred in five patients) and one silent mutation (c.315C>T; occurred in two patients) in the IDH1 gene and two missense mutations (p.R140Q and p.R172K; occurred in four AML patients) and one silent mutation (c.435G>A) in the IDH2 gene. Except for one non-Hodgkin lymphoma (NHL) patient harboring IDH1 mutation p.R132C, all IDH1 and IDH2 missense mutations were observed in patients with AML. Intriguingly, the IDH2 mutation p.R140Q and novel IDH1 mutation p.I99M co-occurred in a 75-year-old patient with AML developed from myelodysplastic syndromes (MDS). The frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. Our results supported the recent findings that IDH gene mutations were common in AML. Conversely, IDH mutations were rather rare in Chinese patients with other types of hematological disorders.

Targeting roles of inflammatory microenvironment in lung cancer and metastasis.

Inflammatory cells and mediators are essential components in tumor microenvironment and play decisive roles in the initiation, proliferation, survival, promotion, invasion, or metastasis of lung cancer. Clinical and epidemiologic studies suggested a strong association between inflammation and lung cancer and an influence of immune surveillances and tumor responses to chemotherapeutic drugs, although roles of inflammation in lung cancer remain unclear. The present review outlined roles of inflammation in lung cancer, with particular focus on inflammatory components, types, biomarkers, or principal mechanisms by which the inflammation contributes to the development of lung cancer. The cancer-associated inflammatory cells (CICs) should be furthermore defined and include cancer-specific and interacted cells with inflammatory or inflammation-like characteristics, e.g., innate or adaptive immune cells and cancer tissue cells. We also discuss targeting potentials of inflammation in the prevention and treatment of lung cancer. The diversity of cancer-related inflammatory microenvironment is instrumental to design novel therapeutic approaches for lung cancer.

Detection of single cell heterogeneity in cancer

Single cell heterogeneity has already been highlighted in cancer classification, diagnosis, and treatment. Recent advanced technologies have gained more ability to reveal the heterogeneity on single cell level. In this review, we listed various detection targets applied in single cell study, including tumor tissue cells, circulating tumor cells (CTCs), disseminated tumor cells (DTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), and cancer stem cells (CSCs). We further discussed and compared detection methods using these detection targets in different fields to reveal single cell heterogeneity in cancer. We focused not only on the methods that have already been established and validated, but also on newly developed methods. In morphology and phenotype, the methods mainly included cell imaging and immune-staining. In genomics and proteomics, the main methods were single cell sequencing and single cell western blotting. Collectively, from using these methods, we can have a better understanding of the single cell variation, as well as what kind of variation it is and how the variation works. Our observations imply that study on single cell heterogeneity in cancer is an important step to precision medicine. The development of technologies in detection of single cell heterogeneity will be sure to improve the diagnosis and treatment in cancer.

High-dose dexamethasone modulates serum cytokine profile in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder which is characterized by decreased platelet count. Serum cytokines play an important role in the pathogenesis of ITP by initiating and perpetuating various cellular and humoral autoimmune processes. To investigate a broad spectrum of cytokines in ITP patients and the effects of high-dose dexamethasone (HD-DXM) regimen on serum cytokines profile, a multiplex cytokine assay was used to measure the serum levels of 20 circulating cytokines simultaneously in 22 patients before and after oral administration of 40mg/day DXM for 4 consecutive days. A cohort of 10 healthy individuals was served as control. Serum levels of interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, growth-related oncogene (GRO), interferen (IFN)-γ and tumor necrosis factor (TNF)-α were significantly decreased in pre-treatment patients, compared with healthy controls (p<0.05). After HD-DXM treatment, IL-4, IL-5, IL-6, IL-12p70, IL-13, GRO, IFN-γ and TNF-α were significantly increased in remission patients as compared with patients before treatment (p<0.05). However, there was no significant difference (except TNF-α) between remission patients and healthy controls (p>0.05). All these cytokines decreased again in relapse patients. Our findings suggest that measuring cytokine levels might help in the clinical assessment of ITP, and the HD-DXM therapy could correct the derangement of serum cytokines.

Aberrant Frequency of IL-10-Producing B Cells and Its Association with Treg/Th17 in Adult Primary Immune Thrombocytopenia Patients

Background. Regulatory B cells (Breg) are a distinct B cell subset with immunoregulatory properties. Pivotal to Breg function is interleukin-10. This study was to investigate the role of IL-10-producing B cell (B10) and its association with Treg and Th17 subsets in immune thrombocytopenia (ITP) patients. Methods. Peripheral blood mononuclear cells from ITP patients and controls were stimulated with PMA, ionomycin, and Brefeldin A. The frequencies of CD19+IL-10+ B cells, CD3+CD4+IL-17+ Th17 cells, and CD4+CD25hiFoxp3+ Treg cells were analyzed by flow cytometry. The mRNA expression of Foxp3 and RORγt was detected by real-time quantitative PCR. Results. The number of B10 cells was elevated in ITP patients. After first-line therapies, it remained at high level in patients who achieved complete or partial response but decreased in those who acquired no response. There was a positive correlation between B10 cells and Tregs in ITP both before and after therapies. The ratio of Treg/Th17 decreased in ITP, and it strongly correlated with B10 cells. Conclusions. The frequency of B10 cells is elevated in ITP and it correlates with both the Tregs counts and the Treg/Th17 ratio. B10 cells to regulate functional T cell subsets might be impaired in patients with ITP.

Roles of tumor heterogeneity in the development of drug resistance: A call for precision therapy

The drug resistance limits the optimal efficacy of drugs during target therapies for lung cancer and requires the development of precision medicine to identify and develop new highly selective drugs and more precise tailoring of medicine to the target population. Lung cancer heterogeneity as a potential cause of drug resistance to targeted therapy may foster tumor evolution and adaptation and fade personalized-medicine strategies. The present review elucidates the influence of tumor heterogeneity on drug efficacy and resistance, and discusses potential strategies to combat heterogeneity for cancer treatment. There is an urgent need to discover and develop disease- and biology-specific biomarkers for monitoring the existence and occurrence of lung cancer heterogeneity, testing targeted drugs in clinical trials, and implementing precision medicine for patients. Better understanding of lung cancer heterogeneity will strengthen therapeutic strategies and apply precision medicine to cure the disease.

Pyrroloquinoline Quinone Induces Cancer Cell Apoptosis via Mitochondrial-Dependent Pathway and Down-Regulating Cellular Bcl-2 Protein Expression

Pyrroloquinoline quinone (PQQ) has been reported as a promising agent that might contribute to tumor cell apoptosis and death, yet little is known on its mechanisms. In current study, the effect of PQQ on cell proliferation and mitochondrial-dependent apoptosis were examined in 3 solid tumor cell lines (A549, Neuro-2A and HCC-LM3). PQQ treatment at low to medium dosage exhibited potent anti-tumor activity on A549 and Neuro-2A cells, while had comparably minimal impact on the viabilities of 2 human normal cell lines (HRPTEpiC and HUVEC). The apoptosis of the 3 tumor cell lines induced by PQQ were increased in a concentration-dependent manner, which might be attributed to the accumulation of intracellular reactive oxygen species (ROS), decline in ATP levels and dissipation of mitochondrial membrane potential (MMP), in conjunction with down-regulation of Bcl-2 protein expression, up-regulation of activated caspase-3, and disturbed phosphorylated MAPK protein levels. PQQ induced tumor cells apoptosis was significantly alleviated by pan-caspase inhibitor Z-VAD-FMK. The present work highlights the potential capability of PQQ as an anti-tumor agent with low toxicity towards normal cells through activating mitochondrial-dependent apoptosis pathways, and warrants its development for cancer therapy.

Abnormal platelet kinetics are detected before the occurrence of thrombocytopaenia in HBV-related liver disease

Thrombocytopaenia is a frequent feature in patients with HBV‐related liver disease. Its underlying mechanism is not fully understood. Multiple factors might contribute to the development of thrombocytopaenia. In this study, we investigated the reticulated platelets (RP), glycocalicin (GC), serum thrombopoietin (TPO) and platelet glycoprotein (GP) in different stages of the disease.

Intraoperative platelet transfusion is associated with increased postoperative sternal wound infections among type A aortic dissection patients after total arch replacement

Blood transfusion and its impact upon clinical outcomes of cardiac surgery have been extensively discussed, especially in the post‐aprotinin era. This study compared clinical outcomes and perioperative blood utilisation among acute type A aortic dissection (AAD) patients with or without intraoperative platelet transfusion during total arch replacement, thus intending to investigate prognostic value of platelet transfusion during major aortic surgeries.

Upregulation of innate immune responses in a T cell/histiocyte-rich large B cell lymphoma patient with significant autoimmune disorders mimicking systemic lupus erythematosus.

Dear Editor, A 57-year-old woman presented to our facility in September 2010 for progressive anemia. She had a history of rheumatoid arthritis (RA) for over 10 years. Computed tomography revealed lymphadenopathy in lower cervical, mediastinal, retroperitoneal, and pelvic regions. Biopsy of left supraclavicular lymph nodes indicated T cell/histiocyte-rich large B cell lymphoma (THRLBCL). Laboratory findings suggested autoimmune hemolytic anemia (hemoglobin 4.3 g/dl; reticulocyte count 13.5 %; lactate dehydrogenase 630 U/L; direct antiglobulin test positive for IgG), hypocomplementemia (C3 0.57 g/L; C4 0.10 g/L), hypothyroidism (thyrotropin 11.84 μIU/mL), and urine λ paraprotein. Multiple autoantibodies were found positive, including antinuclear antibody (homogeneous, 1:1,000), anticardiolipin antibody (36.5 EU/ml), anti-dsDNA antibody (322 IU/ml), anti-SSA antibody, anti-TPO antibody (13.0 IU/ml), antithyroglobulin antibody (>4,000 IU/ml), and rheumatic factor (125 IU/ml). Partial remission was achieved after 3 cycles of R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and additional methylprednisolone, and her hemoglobin level bounced back to 11.9 g/dl. But severe neutropenia developed, and the patient died of respiratory failure due to invasive fungal infection 4 months after diagnosis. Tumors of lymphoid tissues are closely interweaving with autoimmune disorders. Patients with systemic lupus erythematosus (SLE), Sjögren’s syndrome, and RA are argued to possess higher risk of lymphoid malignancies, especially tumors that derive from mucosal-associated lymphoid tissue [1, 2]. THRLBCL is characterized by a limited number of scattered, large, and atypical B cells embedded in a background of abundant T cells and frequently histiocytes. THRLBCL accounts for <10 % of all DLBCL, and it is often refractory to standard chemotherapeutic regimens [3, 4]. But autoimmunity related to this particular entity has seldom been described before. Using Quantibody human cytokine array 1 (Ray Biotech, Inc. Norcross GA) with plasma samples cryopreserved at −80 °C taken on admission and after 1 cycle of R-CHOP regimen, an analysis of 20 inflammationassociated cytokines was performed and listed in Table 1. We found that IL-6, IL-8, IL-12p70, CCL5, GRO, MIP-1a, MIP1b, and VEGF were significantly elevated, while IL-2, TNF-α, GM-CSF, and MMP downregulated. This aberrant cytokine profile was alleviated after chemotherapy and additional corticosteroids. THRLBCL, sharing certain morphological features similar to nodular lymphocyte-predominant Hodgkin’s lymphoma, was argued to have a strong immunological background. Gene expression signature study indicated a crucial role for interferon-γ and innate immune responses in THRLBCL. Interpreted as manifestation of significant downregulation of host immune response, the overexpression of CCL8, IDO, and VSIG4 also revealed a highly activating state of macrophages in THRLBCL tumor microenvironment [5]. Meanwhile, the general immune status in this scenario had not been welldescribed. Though our patient showed autoimmunity affecting multiple systems, which from clinical perspective quite mimicked SLE, her cytokine profile told a different story. Other than the serum cytokine pattern predominantly concerning upregulation of IFN-γ, TNF-α, IL-4, and IL-10 among SLE B. Wu :Y. Cheng (*) Department of Hematology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China e-mail: yfcheng@fudan.edu.cn