Research Progress on the Role of Tumor-Associated Macrophages in Multiple Myeloma --Review / 中国实验血液学杂志

Bone marrow microenvironment is a highly complex environment surrounding tumor, which plays an important role in the survival, proliferation, drug resistance and migration of multiple myeloma (MM) cells. As an important cellular component in tumor microenvironment, tumor-associated macrophages(TAM) has attracted attention due to its key role in tumor progression and drug resistance. Targeting TAM has shown potential therapeutic value in cancer treatment. In order to clarify the role of macrophages in MM progression, it is necessary to understand the differentiation of TAM and its characteristics of promoting MM. This paper reviews the research progress on how TAM is programmed in MM and the mechanism of TAM promoting tumor development and drug resistance.

The Distribution and Significance of Activated T Cells and Lymphocyte Subsets in Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To investigate the distribution of bone marrow lymphocyte subsets in patients with myelodysplastic syndrome(MDS),the proportion of activated T cells with immunophenotype CD3+HLA-DR+ in the lymphocytes and its clinical significance, and to understand the effects of different types of MDS, different immunophenotypes, and different expression levels of WT1 on the proportion of lymphocyte subsets and activated T cells.@*METHODS@#The immunophenotypes of 96 MDS patients, the subsets of bone marrow lymphocytes and activated T cells were detected by flow cytometry. The relative expression of WT1 was detected by real-time fluorescent quantitative PCR, and the first induced remission rate (CR1) was calculated, the differences of lymphocyte subsets and activated T cells in MDS patients with different immunophenotype, different WT1 expression, and different course of disease were analyzed.@*RESULTS@#The percentage of CD4+T lymphocyte in MDS-EB-2, IPSS high-risk, CD34+ cells >10%, and patients with CD34+CD7+ cell population and WT1 gene overexpression at intial diagnosis decreased significantly (P<0.05), and the percentage of NK cells and activated T cells increased significantly (P<0.05), but there was no significant difference in the ratio of B lymphocytes. Compared with the normal control group, the percentage of NK cells and activated T cells in IPSS-intermediate-2 group was significantly higher(P<0.05), but there was no significant difference in the percentage of CD3+T, CD4+T lymphocytes. The percentage of CD4+T cells in patients with complete remission after the first chemotherapy was significantly higher than in patients with incomplete remission(P<0.05), and the percentage of NK cells and activated T cells was significantly lower than that in patients with incomplete remission (P<0.05).@*CONCLUSION@#In MDS patients, the proportion of CD3+T and CD4+T lymphocytes decreased, and the proportion of activated T cells increased, indicating that the differentiation type of MDS is more primitive and the prognosis is worse.

NRAS Gene Expression and Its Clinical Significance in Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the mutation rate and distribution of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in the patients with acute myeloid leukemia.@*METHODS@#The genomic DNA of bone marrow was screened by polymerase chain reaction (PCR) and sequencing for NRAS mutations. At the same time, the mutations of ASXL1, DNMT3A, TET2, CEBPA, FLT3, IDH2, NPM1 and c-KIT genes were also detected to analyze the relation with NRAS mutations.@*RESULTS@#A total of 11 NRAS mutations were found in 108 patients with initial acute myeloid leukemia and the mutation rate was 10.2%, including 6 cases of G12D, 3 cases of G13D, and 2 cases of G61K. In the mutation group, the peripheral blood leukocyte count was higher (P＜0.05), more likely to occur in the M subtype, and the M subtype was mutually exclusive (P＜0.05). Moreover, the mutant group was more likely to express CD13 than the non-mutation group (P＜0.05), while no statistic difference was found in age, gender, hemoglobin level, platelet count, lactate dehydrogenase level, bone marrow blast, cytogenetics, complete remission rate and overall survival (P＞0.05).@*CONCLUSIONS@#The mutation of NRAS gene has no effect on the prognosis of AML patients.

LY294002 Enhaces Chemosensitivity of K562 Cells to Daunorubicin / 中国实验血液学杂志

OBJECTIVE@#To investigate the proliferation inhibition and pro-apoptosis effect of LY294002 (PI3K/AKT inhibtor) combined with daunorubicin (DNR) on the chronic myeloid leurenia cell line K562 and its possible mechanisms.@*METHODS@#The effect of LY294002 and DNR on the proliferation of K562 cells in different treating time and concentration were measured by MTT assay. The cell cycle was determined by flow cytometry, the mRNA and protein expression of SKP2 , P27, BCL-2 and BAX were determined by RT-PCR and Western blot.@*RESULTS@#LY294002 and DNR were able to inhibit the growth of K562 cells and promote apoptosis in time- and concentration-dependent manner (P＜0.05), both the cell proliferation-inhibiting rate and apoptosis rate in combination therapy group were higher than that in DNR-monotherapy group (P＜0.05). After K562 cells treated by LY294002 combined DNR for 36 h, the cells were statistically significantly reduced in G/M phase (P＜0.05), as compared with control group and DNR group. Compared with DNR group, the cell level of G/G phase rased (P＜0.05) and cell level of S phase decreased (P＞0.05). Compared with DNR group, the expresson of SKP2 and BCL-2 mRNA decreased, and the expression of P27 mRNA increased in the combination therapy group (P＜0.05). The expression of BAX mRNA was not significantly different between different groups. The same result was found in the protein expression.@*CONCLUSION@#LY294002 has the sensibilizative effect on DNR chemotherapy, which may be relative with blocking the cell cycle and inducing cell apoptosis.

Methylation Status and mRNA Expression of DKK-3 and WIF-1 in Acute Myeloid Leukemia Patients / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the promoter methylation status, mRNA expression and clinical significance of DKK-3 and WIF-1 genes in patients with acute myeloid leukemia(AML).</p><p><b>METHODS</b>Methylation specific polymerase chain reaction (MS-PCR) mothod was carried out to detect DKK-3 and WIF-1 gene promoter methylation status in bone marrow specimen from 56 patients with AML and 20 patients with iron deficiency anaemia(IDA) as control; then the real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect mRNA expression of DKK-3, WIF-1 gene and β -catenin in the above-mentioned specinens, and their relationship with the clinical features and survival time was analyzed.</p><p><b>RESULTS</b>The promoter methylation rate of DKK-3 and WIF-1 gene in AML patients were significantly higher than that in control group(χ=15.330,P<0.001; χ=17.371,P<0.001). There was no relationship between DKK-3 and WIF-1 gene promoter methylation rate and AML patient's sex, age, clinical typing. The relative expression of DKK-3 and WIF-1 gene mRNA in AML group were 0.840±0.320 and 0.792±0.313, which were lower than those in control group (1.134±0.392 and 1.047±0.334) respectively, the difference was statistically significant (t=3.415,P=0.000; t=3.070, P=0.003). The relative expression of β-catenin mRNA in AML bone marrow specimens in AML group was 0.756±0.304, which was higher than that in control group(0.342±0.105), the difference was statistically significant (t=5.943, P=0.001). The expression of DKK-3 and WIF-1 gene mRNA negatively correlated with β-catenin mRNA(r=-0.543; r=-0.562). Kaplan Meier survival curve analysis showed that overall survival time in AML patients with DKK-3 gene methylation was shorter than that in the AML patients with DKK-3 gene unmethylation(χ=3.957, P=0.042). Futhermore, the orerall survival time in AML patients with WIF-1 gene methylation was also shorter than that in AML patients with WIF-1 gene unmethylation (χ=4.520, P=0.029).</p><p><b>CONCLUSION</b>Wnt/β-catenin signaling pathway is abnormally activated in AML patients, the DKK-3 and WIF-1 gene promoter methylation may be involved in Wnt pathways activation and the pathogenesis of AML.</p>

Effect of piglitazone and metformin on retinol-binding protein-4 and adiponectin in patients with type 2 diabetes mellitus complicated with non-alcohol fatty acid liver diseases / 中国医学科学院学报

<p><b>OBJECTIVE</b>To compare the effects of piglitazone and metformin on retinol-binding protein-4 (RBP-4) and adiponcetin (APN) in patients with type 2 diabetes mellitus (T2DM) complicated with Non alcohol fatty acid liver disease (NAFLD).</p><p><b>METHODS</b>Totally 60 T2DM patients complicated with NAFLD were equally and randomly divided into pioglitazone group and metform group. The levels of biochemical indicators including body mass index (BMI), glucose hemoglobin A1C (GHbA1C), insulin resistance (HOMA-IR), fasting blood glucose (FBG), fasting insulin (FIns), and serum triglycerides (TG) as well as serum RBP-4 and APN level were measured pre-treatment and 12 weeks after treatments.</p><p><b>RESULTS</b>After 12 weeks of treaments, BMI, FBG, HOMA-IR, GHbA1C, FIns, and TG decreased (all P<0.05) in both piglitazone group and metform group. APN increased (all P<0.05) in both groups. RBP-4 decreased (P<0.05) in piglitazone group. Compare with the metform group, the levels of RBP-4, FIns ,and HOMA-IR decreased and BMI increased in piglitazone group (P<0.05).</p><p><b>CONCLUSION</b>Piglitazone is superior to metoform in decreasing RBP-4 level and HOMA-IR in patients with T2DM complicated with NAFLD.</p>

Genetic analysis and prenatal diagnosis for non-syndromic hearing impairment / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect genetic mutations underlying non-syndromic hearing impairment (NSHI) and establish a method for prenatal diagnosis.</p><p><b>METHODS</b>Sixty six NSHI patients were included in this study. DNA was extracted from peripheral blood. Genetic mutations were detected by gene chip analysis and direct sequencing of GJB2 gene. For 7 pregnant women at high risk, prenatal genetic diagnosis was provided.</p><p><b>RESULTS</b>Fourteen cases (21.21%) were found to have GJB2 mutations by both methods (homozygous 235delC mutation in 3 cases, homozygous 176del16 mutation in 2 cases, 235delC and 299delAT compound heterozygous mutation in 2 cases, 299delAT and 176del16 compound heterozygous mutation in 1 case, c.339T > G and 313del12bp compound heterozygous mutation 1 case, and 235delC heterozygous mutation in 5 cases). 13 (19.70%) had SLC26A4 mutations (IVS7-2 A >G homozygous mutation in 2 cases, IVS7-2 A > G homozygous mutation in 2 cases, IVS7-2 A > G and 2168A > G compound heterozygous mutation in 3 cases, 2168A>G heterozygous mutation in 3 cases, and IVS7-2 heterozygous mutation in 3 cases); and 3 had mtDNA12S rRNA mutation (1555A > G mutation in 2 cases, 1494C > T mutation in 1 case). Prenatal diagnosis suggested that 3 fetuses have carried a heterozygous mutation. Two fetuses were detected as normal and confirmed to have normal hearing after birth. Two fetuses were found to have carried compound mutations of GJB2.</p><p><b>CONCLUSION</b>Gene chip combined with GJB2 gene analysis is an accurate and effective method for the diagnosis of NSHI. The results can facilitate accurate prenatal diagnosis.</p>

Suppressor of cytokine signaling 1 protects rat pancreatic islets from cytokine-induced apoptosis through Janus kinase/signal transducers and activators of transcription pathway / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling pathway involved in negative feedback loops. Although SOCS1 is an important intracellular suppressor of apoptosis in a variety of cell types, its role in cytokine-induced pancreatic β-cell apoptosis remains unclear. The present study investigated potential effects of SOCS1 on the cytokine-induced pancreatic β-cell apoptosis.</p><p><b>METHODS</b>After successfully transfected with SOCS1/pEGFP-C1 or pEGFP-C1 plasmids to overexpress SOCS1, RINm5F (rat insulinoma cell line) cells were exposed to cytokines, interferon (IFN)-γ alone, IFN-γ+interleukin (IL)-1β, IFN-β+IL-1β+tumor necrosis factor (TNF)-α respectively. Pancreatic β-cell apoptosis was assessed by using MTT, FACS, and caspase-3 activity assays. Protein phosphorylation of Janus kinase 2 (JAK2) and signal transducers and activators of transcription 1 (STAT1) were verified by Western blotting and mRNA expression of inducible nitric oxide synthase (iNOS), NF-κB and Fas were analyzed by RT-PCR.</p><p><b>RESULTS</b>Overexpression of SOCS1 in RINm5F cells was shown to attenuate IFN-γ alone, IFN-γ+IL-1β and IFN-γ+TNF-α+IL-1β mediated apoptosis. Phosphorylation of JAK2 and STAT1 significantly decreased in RINm5F cells which overexpressed SOCS1 protein. Overexpression of SOCS1 significantly suppressed cytokine-induced iNOS mRNA levels.</p><p><b>CONCLUSION</b>Overexpression of SOCS1 protects pancreatic islets from cytokine-induced cell apoptosis via the JAK2/STAT1 pathway.</p>

Body temperature control in patients with refractory septic shock: too much may be harmful / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The lowering of body temperature is a common, almost reflexive step in the daily care of septic shock patient. However, the effect of different magnitudes of fever control on the outcome of refractory septic patients with a very poor outcome is controversial and has yet to be explored.</p><p><b>METHODS</b>This prospective trial examined sixty-five refractory septic shock patients with a core temperature higher than 38.5°C. Patients were randomly assigned to a group achieving a "low temperature" range (LT group: 36.0 - 37.5°C) or to a group achieving a "high temperature" range (HT group: 37.5 - 38.3°C) by physical methods including a water-flow cooling blanket and ice packs. A target core temperature was achieved in 1 - 2 hours post-treatment, and maintained for 72 hours. Averaged values of core temperature as well as hemodynamic, respiratory, and laboratory variables were analyzed at baseline and during the first 72 hours after fever control.</p><p><b>RESULTS</b>Thirty-four (52.31%) patients were assigned to the LT group and thirty-one (47.69%) patients were assigned to the HT group. The mean core temperature was significantly lower in the LT group than in the HT group (36.61 vs. 37.85°C, respectively; P < 0.0001). The average heart rate (HR) (75.5 vs. 91.9 beats/min, respectively; P < 0.0001) and the mean cardiac output (CO) (5.35 vs. 6.45 L/min, respectively; P = 0.002) were also statistically significant lower in the LT group than in the HT group. The averaged serum lactate level was significantly higher in the LT group compared to the HT group (5.59 vs. 2.82 mmol/L, respectively; P = 0.008). Fibrinogen and activated partial thromboplatin time were also different between the two groups. The 28 days mortality was significantly higher in the LT group than in the HT group (61.8 vs. 25.8%, respectively; P = 0.003). A Cox-regression model analysis showed that mean core temperature during the 72 h period was an independent predictor of 28 days mortality (odds ratio (OR) = 0.42, 95%CI 0.25, 0.6; P = 0.001).</p><p><b>CONCLUSION</b>Controlling fever to a lower range (36.0 - 37.5°C) may be harmful to patients with refractory septic shock by worsening tissue perfusion, compared to controlling it within a higher range (37.5 - 38.3°C). An understanding of the mechanisms responsible for these observations requires further investigation.</p>

Correlation of epidermal growth factor receptor overexpression with increased epidermal growth factor receptor gene copy number in esophageal squamous cell carcinomas / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies in China and epidermal growth factor receptor (EGFR) is widely distributed in human epithelial cell membrane. The aim of this study was to investigate the protein overexpression and gene copy number of EGFR in ESCC, and help to identify patients who may benefit from EGFR targeted therapies.</p><p><b>METHODS</b>Immunohistochemistry (IHC) was performed to analyze the expression of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 cases of normal esophageal tissue. Fluorescence in situ hybridization (FISH) was performed to analyze the gene copy number in 80 cases of ESCC, eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue.</p><p><b>RESULTS</b>The IHC-positive rates of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 normal esophageal tissues were 97% (102/105), 44% (7/16), and 18% (2/11) respectively. The difference in the expression of EGFR among different esophageal tissue groups had statistically significance (P < 0.05). Among the 105 cases of ESCC, overexpression of EGFR was found in 90 cases (86%), of which 55 cases scored 3+ for EGFR staining and 35 cases scored 2+. In ESCC, the expression of EGFR was significantly correlated with depth of invasion and TNM stage (P < 0.05), but not with other parameters. The FISH-positive rates of EGFR in 80 cases of ESCC, the eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue were 31.3% (25/80), 0 (0/8) and 0 (0/8) respectively. In ESCC, EGFR gene amplification was found in 17 (21%) cases, high polysomy in 8 (10%) cases, disomy in 34 cases, low trisomy in 17 cases, and high trisomy in four cases. EGFR FISH-positive was significantly correlated with depth of invasion and lymph node metastasis (P < 0.05). EGFR FISH-positive was significantly associated with overexpression of EGFR.</p><p><b>CONCLUSION</b>Protein overexpression and/or increased gene copy number of EGFR is common in ESCC, and EGFR targeted therapy may be appropriate for ESCC patients.</p>

Changes of regulatory T cells and T helper cells in peripheral blood and their roles in the severity evaluation in children with asthma / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the changes of CD4+CD25+Foxp3+ regulatory T cells (Treg) and T helper cells (Th1/Th2) in peripheral blood and their roles in the severity evaluation in children with asthma.</p><p><b>METHODS</b>One hundred and fifty children with asthma were classified into acute attack (94 cases) and remission (56 cases) groups according to their clinical features, and the acute attack children were subdivided into mild asthma (54 cases) and severe asthma (40 cases) groups. Fifty healthy children were enrolled as a control group. The levels of CD4+CD25+Foxp3+ Treg, CD4+IFN-γ+ Th1 and CD4+IL-4+ Th2 in peripheral blood were measured by flow cytometer.</p><p><b>RESULTS</b>The mean levels of CD4+CD25+Foxp3+ Treg and the ratio of Th1/Th2 in asthmatic children were lower than those in the control group (P<0.01). The Treg levels and the ratio of Th1/Th2 in the acute attack group were lower than those in the remission group and in the control group (P<0.01). The Treg levels in the severe asthma group were lower than those in the mild asthma group (P<0.01). There was a remarkably negative correlation between Treg levels and the asthma severity (r=-0.737, P<0.01), and the Th1/Th2 ratio was also negatively correlated with the asthma severity (r=-0.615, P<0.01). The Treg levels were positively correlated with the Th1/Th2 ratio (r=0.856, P<0.01).</p><p><b>CONCLUSIONS</b>The Treg levels decrease remarkably and Th subsets imbalance occurs in children with asthma. This suggests that Treg and Th immunity play important roles in the pathogenesis of asthma. The Treg levels and the ratio of Th1/Th2 in peripheral blood may be useful in the evaluation of severity in children with asthma.</p>

Gene expression profile of human skeletal muscle and adipose tissue of Chinese Han patients with type 2 diabetes mellitus / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To study the differential patterns of gene expression in skeletal muscle and adipose tissue between type 2 diabetes mellitus (T2DM) patients and healthy subjects using DNA microarray analysis.</p><p><b>METHODS</b>T2DM patiens were divided into female group, young male group and old male group. DNA microarray analysis and quantitative real-time PCR were carried out to analyze the relation between gene expressions and T2DM.</p><p><b>RESULTS</b>The mRNA expression of 298, 578, and 350 genes was changed in the skeletal muscle of diabetes mellitus patients compared with control subjects. The 1320, 1143, and 2847 genes were modified in adipose tissue of the three groups. Among the genes surveyed, the change of 25 and 39 gene transcripts in skeletal muscle and adipose tissue was > or = 2 folds. These differentially expressed genes were classified into 15 categories according to their functions.</p><p><b>CONCLUSION</b>New genes are found and T2DM can be prevented or cured.</p>

Application of bolt-like casting post in posterior fixed partial denture / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To study the manipulation procedure and application of a new post-core system in posterior fixed partial dentures.</p><p><b>METHODS</b>Abutment tooth canals were firstly prepared according to respective canal directions and then complete crown preparation was made following standard procedures. The impression of prepared abutment teeth was taken with silicone and specially made syringe. The fixed partial denture and bolt-like post were fabricated respectively and lastly the two parts were glued together in patient after try-in.</p><p><b>RESULTS</b>All the fixed partial denture with the new post-core system did not get loose and there was no abutment tooth fractured after 23 months in use.</p><p><b>CONCLUSIONS</b>This new post-core system could improve retention of the posterior fixed partial denture if the inter-occlusion distance of the abutment tooth was shorter than 3 mm.</p>

Research development of Mendelian inherited diabetes / 中国医学科学院学报

Diabetes mellitus is a chronic syndrome of abnormal metabolism, determined by interaction of multifactorial genetic and environmental factors. Some specific types of diabetes, such as MODY, Leprechaunism, lipoatrophic diabetes, and Rabson-Mendenhall syndrome, are monogenic forms of diabetes and are inherited as a Mendelian pattern. The article reviews the research development of these Mendelian inherited diabetes will be reviewed.