Acute myelogenous leukemia (AML) cells are organized in a hierarchical fashion, with only the most primitive rare population (leukemia stem cell, LSC) of AML cells capable of maintaining the leukemic clone. A broad range of studies has indicated that AML results from mutations at the level of the stem cells of AML cells. The changes of cellular and molecular features in these malignant stem cells determine the features of leukemic clone and give rise to different subtypes of AML. LSCs share some similar characteristics with normal hematopoietic stem cells (HSC) including the ability to self-renew, and also have the potential of limited differentiation. LSCs, also have some features that are not found in normal HSC. LSCs have unique phenotype such as CD90-, CD117- and CD123+. Tumor-suppressor protein-death associated protein kinase and interferon regulatory factor 1 were overexpressed in LSCs, but not in normal HSC. Due to a predominantly G0 cell-cycle status, LSCs may not be responsive to conventional chemotherapeutic agents, compared with leukemia blasts. It is proposed that surviving LSCs are a major contributing factor to leukemic relapse. Although LSC population is likely to be drug-resistant, quiescent LSCs are preferentially susceptible to apoptosis induction while sparing normal HSC, with the appropriate stimulus such as proteasome inhibitor MG-132. This article reviewed the data emerging from the study of LSCs, and elucidated the distinct cellular and molecular characteristics of the LSC population, which may shed new light on AML therapy and leukemogenesis study.
Cell Count ; Cell Cycle ; Humans ; Leukemia, Myeloid, Acute ; pathology ; Neoplastic Stem Cells ; cytology ; Oligonucleotide Array Sequence Analysis

Background: IMpower 133 trial first confirmed the efficacy and safety of adding atezolizumab or placebo to first-line treatment with chemotherapy in patients with extensive-stage small-cell lung cancer(SCLC).While,overprice limited its broad use in clinical.The aim of this study was to evaluate the cost-effectiveness of atezolizumab plus chemotherapy in treatment of extensive SCLC as first line in China.Methods: A Markov model was established by extracting data from the IMpower 133 trial with untreated extensive SCLC patients.Utility values were obtained from published studies,and the costs were acquired from real world and literature.Additionally,sensitivity analyses based on a willingness-to-pay(WTP)threshold were performed to identify the uncertain parameters of Markov model.Results: Total costs of atezolizumab group were $48,129,while cost of chemotherapy alone was just $12,920 in placebo group.The quality-adjusted life-years(QALYs)in atezolizumab group was just 0.072 higher than that in placebo group(0.858 QALYs vs.0.786 QALYs).The cost-effectiveness ratio between atezolizumab combination with chemotherapy and chemotherapy alone was$489,013/QAL Y in China.The net benefit of placebo group was significantly higher than atezolizumab group.One-way sensitivity analyses highlighted that utilities of the progression-free survival(PFS)and progression disease state in placebo group were the most influential parameter.Conclusions: Atezolizumab combination therapy was not more cost-effective than chemotherapy alone at a WTP threshold of $25,929/QALY in China.

OBJECTIVETo screen serum biomarkers for minimal residual disease (MRD) monitoring according to differential peptidomics profile in the serum from the patients with acute leukemia (AL) and healthy controls.

METHODSSerum polypeptides from 90 AL patients, 60 healthy controls and 20 patients with benign hematological disorders were enriched by copper chelate magnetic beads, and the peptidomics profile was obtained by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) analysis. And the intensities of differential peptides were calculated to assess MRD level.

RESULTSThe diagnostic models by using support vector machine (SVM) algorithm according to differential peptides between AL patients and healthy controls with P<0.01 by t-test were established. The sensitivity and specificity of distinguishing AL patients from healthy controls were 98% and 99%, respectively. The model obtained a sensitivity of 98% and a specificity of 96% for distinguishing newly-diagnosed AL patients from AL patients with hematological complete remission (AL-HCR). Then a sensitivity of 92% and a specificity of 93% were obtained for distinguishing patients with AL-CR from AL patients with molecular complete remission (AL- MR). The intensity of peptide with m/z (mass-to-charge ratio) 4468 was significantly higher in newly- diagnosed AL patients compared to healthy controls, and gradually decreased with the increase of remission degree, and it was not found increase in patients with benign hematological disorders.

CONCLUSIONThe SVM diagnostic model established by differential serum peptide profile could be used to discriminate AL patients with different stages of remission and to evaluate the treatment efficacy. The peptide of m/z 4468 could be used for MRD assessment, and continuous monitoring of its expression level will play an important role in the individual treatment and recurrence prediction.

Acute Disease ; Adolescent ; Adult ; Aged ; Biomarkers, Tumor ; blood ; Case-Control Studies ; Female ; Humans ; Leukemia ; blood ; diagnosis ; pathology ; Male ; Middle Aged ; Neoplasm, Residual ; blood ; diagnosis ; Peptides ; Protein Interaction Mapping ; Sensitivity and Specificity ; Young Adult

This study was aimed to analyze the different proteomes between human acute leukemia (AL) cells and normal white blood cells by proteomic technology in order to lay the basis for diagnosing AL and understanding the mechanism of leukemogenesis. The proteins from AL cells of 40 AL patients identified by FAB classification and proteins from normal lymphocytes and granulocytes of 20 normal volunteers were separated by two-dimensional electrophoresis (2-DE), and the differentially expressed proteins between the two groups were identified by both matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and electronspray ionization (ESI)-MS/MS. The results showed that among the differentially expressed proteins between AL cells and normal lymphocytes and granulocytes, some proteins involved in the process of malignant transformation (such as Op18, NM23-H1), cell proliferation (such as PCNA) and apoptosis inhibition (such as tumor necrosis factor inhibitor protein) were found to be up regulated in AL cells. However, some proteins involved in differentiation and physiological functions of normal cells were down regulated in AL cells. It is concluded that there are many events involved in the process of leukemogenesis, expression of some proteins relating to the malignant transformation, cell proliferation and apoptosis inhibition are up-regulated in AL cells. The proteome analysis may provide a new approach to explaining the molecular mechanism underlying the pathogenesis of AL.
Adolescent ; Adult ; Bone Marrow Cells ; chemistry ; pathology ; Female ; Humans ; Leukocytes ; chemistry ; Male ; Middle Aged ; Neoplasm Proteins ; analysis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; metabolism ; pathology ; Proteome ; analysis

OBJECTIVETo explore the molecular mechanisms of apoptotic NB4 cells induced by the histone deacetylase inhibitor, sodium butyrate(SB).

METHODSSB was exposed to NB4 cells at a final concentration of 1.0 mmol/L. The untreated and treated cells were analysed with FACS and 2-dimensional electrophoresis (2-DE) at 0, 12, 24, 48 and 72 h. The changed protein spots were identified with MALDI-TOF-MS and ESI-TOF-MS/MS.

RESULTSSB induced apoptosis of NB4 cells. Twenty-one changed proteins involving apoptotic signal transduction, immunological regulation, transcriptional control, cellular metabolism, molecular transport and so on were identified. Thirteen of them had been reported to be related to apoptosis.

CONCLUSIONSB can induce apoptosis and many functional protein changes in tumor cells. These results pave the way to further explore the anti-tumor mechanism of SB.

Apoptosis ; drug effects ; genetics ; Butyrates ; pharmacology ; Cell Line, Tumor ; Flow Cytometry ; Humans ; Proteomics

OBJECTIVETo find a kind of quick and effective haemostasis to decrease the mortality of severe bleeding.

METHODS18 severe bleeding patients with different cause received recombinant activated factor VIIa (rFVIIa) were analyzed retrospectively.

RESULTSOf total 18 cases with severe bleeding, 13 cases cured, 3 cases were effective, 2 cases ineffective. The total clinical effective rate is 88.89%. After using rFVIIa, the PT, APTT and fibrinogen level of 6 DIC patients returned to normal within 12 hours; 13 patients whose the amount of bleeding can be evaluated stopped bleeding quickly. The fastest onset time was 10 min.

CONCLUSIONrFVIIa can stanch severe bleeding for a variety of reasons rapidly and effectively, including coagulopathy, thrombocytopenia, and obstetric hemorrhage. Application of rFVIIa may decrease mortality, when conventional treatment is not valid.

Adult ; Aged ; Aged, 80 and over ; Blood Coagulation Disorders ; drug therapy ; Factor VIIa ; therapeutic use ; Female ; Hemorrhage ; drug therapy ; Humans ; Male ; Middle Aged ; Recombinant Proteins ; therapeutic use ; Retrospective Studies ; Treatment Outcome ; Young Adult

Diabetes mellitus (DM) is characterized by hyperglycemia and disturbances of carbohydrate and fat metabolism resulted from an absolute or relative deficiency of insulin and insulin resistance. Recent studies indicate that oxidative stress may have a central role in the pathogenesis of type 2 diabetes. Currently, the diagnosis of body oxidative stress level mainly depends on the detection of oxidative stress markers including reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipid peroxide in clinical and experimental studies with methods combining physical and chemical means. The mechanism underlying oxidative stress-induced diabetes mainly may be through two ways. Firstly oxidative stress damages the normal function of islet β cells, through the destruction of mitochondrial structure and inducing apoptosis, activation of nuclear transcription factor kappa B (NF-κB) signaling pathway, causing cell inflammatory response, and reducing insulin synthesis and secretion by inhibiting pancreatic and duodenal homeobox 1 (PDX-1) nuclear cytoplasm translocation as well as inhibiting energy metabolism; Secondly, oxidative stress induces insulin resistance by interfering physiological activities related to insulin signaling including phosphorylation of insulin receptor (InsR) and insulin receptor substrate (IRS), the activation of phosphatidylinositol 3-kinase (PI3K) and the translocation of glucose transporter 4 (GLUT4), as well as injuring the cytoskeleton. Studying the role of oxidative stress in the pathogenesis of diabetes not only helps to reveal the pathogenesis of diabetes, but also provides a theoretical basis for the prevention and treatment of diabetes.
Apoptosis ; Diabetes Mellitus, Type 2 ; physiopathology ; Humans ; Insulin ; physiology ; Insulin Resistance ; Mitochondria ; pathology ; NF-kappa B ; metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases ; metabolism ; Phosphorylation ; Reactive Oxygen Species ; metabolism ; Signal Transduction

Seven compounds were isolated from the leaves of Panax japonicus var. major by chromatographic methods including silica gel, Sephadex LH-20, ODS and semi-preparative HPLC. Their structures were elucidated by their physical and chemical properties and spectral data analysis as 5, 7-dihydroxy-8-methoxyl flavone (1), ginsenoside Rs2 (2), quinquenoside R1 (3), ginsenoside Rs1 (4), notoginsenoside Fe (5), ginsenoside Rd2 (6) and gypenosiden IX (7). Among them, compound 1 was obtained from the Panax genus for the first time, and compounds 2-7 were isolated from this plant for the first time.
Chromatography, High Pressure Liquid ; Flavones ; analysis ; chemistry ; isolation & purification ; Ginsenosides ; analysis ; chemistry ; isolation & purification ; Magnetic Resonance Spectroscopy ; Panax ; chemistry ; Plant Leaves ; chemistry ; Spectrometry, Mass, Electrospray Ionization

Objective To investigate the correlation between NRAMP1 gene polymorphisms and susceptibility to tuberculosis ( TB) in Tibetan people in Qinghai. Methods A case-control study was con-ducted in this study, involving 99 Tibetan patients with TB and 89 healthy Tibetans. The single nucleotide polymorphisms of NRAMP1 gene at rs17235409 and rs3731865 sites were detected by using TaqMan probe method. Gene cloning and sequencing typing were performed to analyze the single nucleotide polymorphisms of NRAMP1 gene at the rs17235416 site. SPASS20. 0 software was used to statistically analyze the correla-tion between NRAMP1 gene polymorphisms and susceptibility to TB in Tibetan people. Results No signifi-cant difference in the genotype frequencies of rs3731865 and rs17235409 was found between the two groups (χ2=0. 852, P=0. 356;χ2=0. 279, P=0. 597). The genotype frequencies of TGTG/TGTG and TGTG/del+del/del at the rs17235416 site were 70. 7% ( 70/99 ) and 29. 3% ( 29/99 ) in patients with TB and 86. 5% (77/89) and 13. 5% (12/89) in healthy subjects. There were significant differences in the geno-type frequencies of TGTG/TGTG and TGTG/del+del/del between the two groups (χ2=6. 870, P=0. 009). The genotypes of TGTG/del and del/del at rs17235416 were risk factors for TB ( OR=0. 376; 95%CI:0. 178-1. 794 as compared with the TGTG/TGTG genotype in Tibetan people in Qinghai. Conclusion This study suggested that the NRAMP1 gene polymorphisms at rs3731865 and rs1723409 sites had no correlation with the susceptibility to TB in Tibetans in Qinghai. However, the NRAMP1 gene polymorphisms at rs17235416 site were correlated with the susceptibility to TB. The TGTG/del alleles at the rs17235416 site might be the risk factors for tuberculosis in Tibetans in Qinghai.

Apoptosis ; B7-H1 Antigen/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cost-Benefit Analysis ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Ligands ; Lung Neoplasms/genetics*