Lower Prealbumin and Higher CRP Increase the Risk of Voriconazole Overexposure and Adverse Reactions.

BACKGROUND: Voriconazole (VRZ) is a commonly used antifungal drug. However, the drug has nonlinear metabolic kinetic characteristics. Many factors can affect the plasma drug concentration, thus affecting the safety and effectiveness of VRZ. OBJECTIVE: The aim of this study is to characterize the correlation between prealbumin (PA) or CRP and VRZ overexposure and adverse reactions. METHODS: Patients who received VRZ as a treatment and performed therapeutic drug monitoring (TDM) were included. Biomarkers and combined medications were analyzed to find out factors that were related to VRZ trough concentrations (Cmin) and overexposure (Cmin >5.0 mg/L). Receiver operating characteristic (ROC) curves were used to determine the cut-off levels. Patients were divided into three groups according to different PA and CRP levels. Then, the incidence rate of VRZ adverse reactions between groups was analyzed. RESULTS: A total of 123 patients were included in the study. PA was negatively correlated, while CRP was positively correlated with VRZ concentrations. Lower PA or higher CRP was related to VRZ overexposure with a cut-off level of 145.5 mg/L and 102.23 mg/L, respectively. Patients in Group 2 (PA <145.5 mg/L and CRP >102.23 mg/L) had an incidence rate of adverse reactions up to 70.27%, while the incidence rates in Group 1 (PA >145.5 mg/L and CRP <102.23 mg/L) and Group 3 (PA <145.5 mg/L and CRP <102.23 mg/L or PA >145.5 mg/L and CRP >102.23 mg/L) were 15.38% and 32.43%, respectively. CONCLUSIONS: PA and CRP were both related to VRZ concentrations and overexposure. The risk of VRZ overexposure and adverse reactions significantly increased in patients with PA <145.5 mg/L and CRP >102.23 mg/L at the same time.

Mycophenolate mofetil increases the risk of diarrhea in allogeneic hematopoietic stem cell transplantation recipients.

OBJECTIVES: Mycophenolate mofetil (MMF) was reported to be a main cause of diarrhea following organ transplantation. However, research on MMF-induced diarrhea following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently insufficient. This retrospective study examined the incidence of MMF-induced diarrhea among allo-HSCT recipients. METHODS: Recipients were divided according to the receipt of MMF and the appearance of diarrhea. The differences in clinical information, MMF usage and trough concentrations, and the occurrence of diarrhea from the first day of conditioning treatment to 100 days after transplantation were analyzed. RESULTS: In total, 32.9% of the recipients reported diarrhea. The incidence rate of diarrhea was higher in the MMF group than in the non-MMF group (40.0% vs. 16.7%). MMF-induced diarrhea usually occurred within 9 days of MMF initiation and persisted for 7.27 ± 3.54 days. The average body weight, MMF daily dose, and MMF trough concentration were higher in patients with diarrhea. CONCLUSION: MMF increased the risk of diarrhea in allo-HSCT recipients, and the risk was related to the MMF dose and trough concentration. The difference in onset time could be a basis for identifying the cause of diarrhea in allo-HSCT recipients.

Secondary light chain amyloidosis with Waldenström's macroglobulinemia and intermodal marginal zone lymphoma: A case report.

BACKGROUND: The co-existence of Waldenström's macroglobulinemia (WM) with internodal marginal zone lymphoma (INMZL) is rare and often associated with poor prognosis. CASE SUMMARY: We present a Chinese female patient who developed secondary light chain amyloidosis due to WM and INMZL and provides opinions on its systemic treatment. A 65-year-old woman was diagnosed with WM 6 years ago and received Bruton tyrosine kinase inhibitor monotherapy for two years. Her INMZL was confirmed due to left cervical lymphadenopathy. The patient presented with oedema in both lower limbs one year ago, and was diagnosed with secondary light chain amyloidosis. Treatment with the BC regimen (rituximab 375 mg/m2 monthly for 6-8 courses, and bendamustine 90 mg/m2 per day × 2, monthly for six courses) was initiated, but not tolerated due to toxic side effects. Bortezomib-based therapy was given for two months, including bortezomib, dexamethasone, and zanubrutinb. Oedema in both lower limbs was relieved and treatment efficacy was evaluated as partial remission. CONCLUSION: A detailed clinical evaluation and active identification of the aetiology are recommended to avoid missed diagnosis and misdiagnosis.

Comprehensive bioinformatics analysis confirms RBMS3 as the central candidate biological target for ovarian cancer.

Ovarian cancer (OC) is one of the most lethal malignancies in the female reproductive system. To find genes related to cancer progression targeting specific biological factors for targeted therapy, bioinformatics technology has been widely used. To screen the prognostic gene markers of OC by bioinformatics and explore their potential molecular biological mechanisms. Two data sets related to OC, GSE54388, and GSE119056, were rooted in the open comprehensive gene expression database (GEO). To correct the background of the data, standardize and screen differentially expressed genes (DEGs) using the R software limma package. The selected DEGs were enriched by Gene Ontology (GO) and through DAVID online database. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis and protein-protein interaction network (PPI-network) map were constructed by STRING online database and Cytoscape software. Combined with the TCGA database, univariate and multivariate COX regression were used to screen prognostic genes. QRT-PCR was used to verify DEGs in clinical tissue samples. Eventually, the function of RBMS3 on the viability, migration, invasion, and apoptosis of OC cells was tested through functional experiments in vitro. 352 common DEGs were screened from GSE54388 and GSE119056 data sets. Survival analysis showed that MEIS2, TSTA3, CNTN1, RBMS3, and TRA2A were considered to be connected with the prognosis of OC. We discover that the expression level of RBMS3 was positively connected with the overall survival (OS) rate of sufferers with OC. The level of RBMS3 in OC tissues was markedly lower than that in neighboring structures and the outcomes of the GEPIA database were consistent with those of the qRT-PCR experiment. Through gene transfection technology it was found that overexpression of RBMS3 in OC cells substantially suppressed the vitality, migration, and invasion of OC cells and raised the rates of apoptosis in the OC cells. In this experiment, we distinguish 5 genes that may participate in the prognosis of OC and showed the key genes and pathways related to OC. It is speculated that RBMS3, a tumor suppressor gene, can be applied as a potential biological marker for the treatment of OC, gene expression summary, and prognosis.

Abnormal Cerebral Blood Flow and Volumetric Brain Morphometry in Patients With Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is a serious breathing disorder, leading to myocardial infarction, high blood pressure, and stroke. Brain morphological changes have been widely reported in patients with OSA. The pathophysiological mechanisms of cerebral blood flow (CBF) changes associated with OSA are not clear. In this study, 20 patients with OSA and 36 healthy controls (HCs) were recruited, and then pseudo-continuous arterial spin labeling (pCASL) and voxel-based morphometry (VBM) methods were utilized to explore blood perfusion and morphological changes in the patients with OSA. Compared with the HC group, the OSA group showed increased CBF values in the right medial prefrontal cortex (mPFC), left precentral gyrus, and right insula and showed decreased CBF values in the right temporal pole (TP) and the right cerebellum_Crus2. Compared with the HC group, the patients with OSA showed decreased gray matter volume (GMV) in the right dorsal lateral prefrontal cortex (DLPFC), the right occipital pole, and the vermis. There were no significantly increased GMV brain regions found in patients with OSA. Pearson correlation analysis showed that the reduced GMV in the right DLPFC and the right occipital pole was both positively correlated with Mini-Mental State Examination (MMSE) (r = 0.755, p < 0.001; r = 0.686, p = 0.002) and Montreal Cognitive Assessment (MoCA) scores (r = 0.716, p = 0.001; r = 0.601, p = 0.008), and the reduced GMV in the right occipital pole was negatively correlated with duration of illness (r = -0.497, p = 0.036). Patients with OSA have abnormal blood perfusion metabolism and morphological changes in brain regions including the frontal lobe and the cerebellum and were closely related to abnormal behavior, psychology, and cognitive function, which play an important role in the pathophysiological mechanism of OSA.

Helicid Improves Lipopolysaccharide-Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway.

DNA methylation is reportedly associated with stress responses and depression. Treatment with antidepressants can regulate DNA methylation and, subsequently, gene expression in the hippocampus. Hence, DNA methylation is a potential target for treatment of depression. Screening of high-throughput data of a rat model of chronic unpredictable mild stress revealed relatively low expression of SH2 domain-containing 5 (SH2D5). SH2D5 can be overexpressed by treatment with helicid. Therefore, in order to further explore the role of SH2D5 in depression and whether helicid mediates the DNA methylation of SH2D5 as a potential antidepressant role, SH2D5 was overexpressed in C6 cells as a lipopolysaccharides (LPS)-induced model of depression. The expression levels of Bax, Bcl-2, Bad, and Daxx, and changes to the CytC/caspase9/caspase3 signal pathway were detected by qRT-PCR and Western blot analyses. After treatment with helicid or silencing of SH2D5, the above indices were detected. The results showed that helicid regulated the CytC/caspase9/caspase3 signaling pathway and improved the apoptosis indices of C6 cells through the overexpression of SH2D5. Interestingly, silencing of SH2D5 reversed the effects of helicid on the above indices. Then, in order to study the underlying mechanism, the cells were administered to helicid or 5-aza-2'-deoxycytidine (5-AzaD) and expression of SH2D5 was detected by qRT-PCR and Western blot analyses, while to assess the DNA methylation level of SH2D5 using bisulfite sequencing/PCR. The results showed that SH2D5 was hypermethylated with low expression in LPS-induced C6 cells, which was reversed by helicid and 5-AzaD. These results suggest that helicid may affect the CytC/caspase9/caspase3 apoptosis signaling pathway and improve the apoptosis indices by mediating DNA methylation of SH2D5.

RAB27B inhibits proliferation and promotes apoptosis of leukemic cells via 3-Hydroxy butyrate dehydrogenase 2 (BDH2).

RAB27B is a member of Ras-like small GTPases that plays a role in endocytosis, exocytosis, and vesicle trafficking. We made an attempt to study the impacts of RAB27B on the proliferation and apoptosis of acute myeloid leukemia (AML) cells. The silencing of RAB27B was induced by siRNA for the detection of proliferation, cell cycle, and apoptosis, respectively by Cell Counting Kit-8 (CCK8), flow cytometry, and TUNEL. Related markers were also evaluated by Western blot analysis. The interaction between RAB27B and BDH2 was predicted by bioinformatics analysis and determined by immunoprecipitation. The gain of function of BDH2 was also detected by these functional assays. RAB27B exhibited high levels in AML cells, and RAB27B silencing led to reduced proliferation, increased cell cycle arrest and apoptosis levels. Then, the interaction between RAB27B and BDH2 was confirmed. Moreover, the effects of RAB27B inhibition on the proliferation, cell cycle arrest, and cell apoptosis were abolished after BDH2 overexpression. RAB27B inhibits proliferation and promotes apoptosis of leukemic cells by interacting with BDH2. Targeting RAB27B might be an effective method for the treatment of AML.

Association of endocrine disrupting chemicals levels in serum, environmental risk factors, and hepatic function among 5- to 14-year-old children.

Endocrine-disrupting chemicals (EDCs) might increase the risk of childhood diseases by disrupting hormone-mediated processes that are critical for growth and development during childhood, however, the association among the exposure level of EDCs such as Nonylphenol (NP), Bisphenol A (BPA), Dimethyl phthalate (DMP) in children and environmental risk factors, as well as hepatic function has not been elaborated. This study aimed to discuss this interesting relationship among NP, BPA, DMP concentrations in serum, environmental risk factors, hepatic function of 5- to 14-year-old children in industrial zone, residential zone and suburb in northern district of Guizhou Province, China. In Zunyi city, 1006 children participated in cross-sectional health assessments from July to August 2018, and their parents completed identical questionnaires on the environmental risk factors of EDCs exposure to mothers and children. Serum NP, BPA and DMP concentrations were measured by high performance liquid chromatography (HPLC). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) were detected with automatic biochemical analyzer. The median concentrations of serum NP, BPA, and DMP in the participants were 45.85 ng/mL, 26.31 ng/mL and 31.62 ng/mL, respectively, which were higher than the environmental concentration limits of the U.S. National Environmental Protection Agency (EPA). Hair gels used during pregnancy, types of domestic drinking water, nail polish and cosmetics used by children were significantly positive correlated with serum NP concentration (P < 0.05). Gender, feeding pattern, plastic water cup used during pregnancy, hair spray and perfume use for children, duration of children birth, materials for baby bottle or cup and ways to plastic products were significantly positively correlated with serum BPA concentration (P < 0.05). Gender, perms used during pregnancy, hair spray and perfume use for children, using plastic lunch box during pregnancy, duration of children birth, exposure to pesticides, parents' occupations were significantly positively correlated with serum DMP concentrations (P < 0.05). Serum NP (ß = 0.296, P = 0.036) and DMP (ß = 0.316, P = 0.026) concentrations and TBIL level were significantly positively correlated. Serum NP concentration and the levels of IBIL (ß = 0.382, P = 0.006) are significantly positively correlated. Cosmetics used during pregnancy significantly increased AST level (ß = 2.641, P = 0.021). There was a positive correlation between the frequency of hair spray and perfume use for children and the AST (ß = 4.241, P = 0.022). NP, BPA and DMP, which were commonly detected in the serum of children aged 5-14 years old in Zunyi City, Northern Guizhou Province, China, were closely related to the environmental risk factors of exposure environment during pregnancy, infancy and school age. Exposure to NP, BPA and DMP would have negative effects on hepatic function, and these effects showed differences in gender and geographical location. Notably,The relationships were more evident in girls than in boys.

Clinical application of vancomycin population pharmacokinetics model in patients with hematological diseases and neutropenia.

To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases and neutropenia. Patients with hematological diseases and neutropenia were included in the PPK model study. Nonlinear mixed effect modeling approach (NONMEM) was used for model establishment. Monte Carlo simulation was carried out. A total of 74 patients were divided into model group and non-model group for clinical application research. The model group was given the initial dose of 1g q8h, and the non-model group was given 1g q12h as an empiric initial dosage. The follow-up dose adjustments were made according to the concentration results. This two-compartment model showed good stability and accuracy. The first trough concentration (C0 ) and the compliance rate of the first C0 were much higher in the model group than that in the non-model group (14.30 ± 4.73 µg/ml and 59.38% vs. 8.02 ± 2.61 µg/ml, 35.71%). Less patients needed dose adjustments and fewer adjustment times in the model group than those in the non-model group (12.50% and 0.13 ± 0.34 times vs. 50.00% and 0.61 ± 0.66 times). This suggested that for those patients who had a Creatinine clearance rate (CLCR) ≥ 90 ml/min/1.73 m2 , the initial dose of 1g q8h may help to reach the target C0 (10∼20 µg/ml) quickly. It also helped to reduce the times and number of patients who need dose adjustments. Our PPK model of vancomycin in patients with hematologic diseases and neutropenia can be used to shorten the time to reach the target concentration and reduce the number of dose adjustments.Clinical trial registration: Not applicable (Retrospective study).

Secondary peripheral T-cell lymphoma and acute myeloid leukemia after Burkitt lymphoma treatment: A case report.

BACKGROUND: Multiple primary cancer refers to more than one synchronous or sequential cancer in the same individual. Multiple primary cancer always presents as solid cancer or acute myeloid leukemia (AML) secondary to lymphoma. Here, we report a rare case of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment. CASE SUMMARY: A 54-year-old female patient was admitted to our hospital complaining of edema on her left lower limb. Physical examination revealed multiple superficial lymphadenectasis on her neck and pelvis. Color ultrasonography examination showed multiple uterine fibroids and a solid mass at the lower left side of the abdomen. Pathological biopsy revealed Burkitt lymphoma. After three hyper-CVAD (A + B) regimens, she achieved complete remission. Two years later, lymphadenectasis reoccurred. A relevant biopsy confirmed the diagnosis of peripheral T-cell lymphoma, which was accompanied by gastrointestinal invasion and hemocytopenia. Meanwhile, bone marrow examination revealed AML. On the second day of scheduled treatment, she developed gastrointestinal bleeding, peptic ulcers, and hemorrhagic shock and was critically ill. She was then discharged from the hospital due to financial concerns. CONCLUSION: This is the first report of secondary peripheral T-cell lymphoma and AML after Burkitt lymphoma treatment with heterochronous and synchronal multiple primary cancers.

Delivery of miR-26a Using an Exosomes-Based Nanosystem Inhibited Proliferation of Hepatocellular Carcinoma.

Background: MicroRNA (abbreviated miRNA)-based treatment holds great promise for application as clinical antitumor therapy, but good carriers for delivery of the miRNA drug are lacking. Exosomes secreted by mesenchymal stem cells (MSCs) have proved to be safe, and exogenously modified exosomes may potentially represent an excellent drug delivery vehicle. Methods: In this study, we designed a delivery nano system using single-stranded variable fragment (scFv)-modified exosomes derived from human cord blood MSCs. Genetic engineering technology was used to obtain anti-Glypican 3 (GPC3) scFv-modified exosomes, which were then loaded with miR-26a mimics through electroporation. Results: Results of electron microscopy and dynamic light scattering indicated that the diameter of the drug-carrying exosomes was about 160 nm. Furthermore, anti-GPC3 scFv-modified exosomes effectively delivered miR-26a to GPC3-positive hepatocellular carcinoma cells, thereby inhibiting cell proliferation and migration by regulating the expression of downstream target genes of miR-26a. The exosomes-based nano system displayed favorable anti-tumor effect in vivo with no obvious side effects. Conclusion: Our data provided a new perspective for the use of exosome delivery systems for miRNA-based antitumor therapy.

Development and validation of a novel survival model for acute myeloid leukemia based on autophagy-related genes.

BACKGROUND: Acute myeloid leukemia (AML) is one of the most common blood cancers, and is characterized by impaired hematopoietic function and bone marrow (BM) failure. Under normal circumstances, autophagy may suppress tumorigenesis, however under the stressful conditions of late stage tumor growth autophagy actually protects tumor cells, so inhibiting autophagy in these cases also inhibits tumor growth and promotes tumor cell death. METHODS: AML gene expression profile data and corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, from which prognostic-related genes were screened to construct a risk score model through LASSO and univariate and multivariate Cox analyses. Then the model was verified in the TCGA cohort and GEO cohorts. In addition, we also analyzed the relationship between autophagy genes and immune infiltrating cells and therapeutic drugs. RESULTS: We built a model containing 10 autophagy-related genes to predict the survival of AML patients by dividing them into high- or low-risk subgroups. The high-risk subgroup was prone to a poorer prognosis in both the training TCGA-LAML cohort and the validation GSE37642 cohort. Univariate and multivariate Cox analysis revealed that the risk score of the autophagy model can be used as an independent prognostic factor. The high-risk subgroup had not only higher fractions of CD4 naïve T cell, NK cell activated, and resting mast cells but also higher expression of immune checkpoint genes CTLA4 and CD274. Last, we screened drug sensitivity between high- and low-risk subgroups. CONCLUSION: The risk score model based on 10 autophagy-related genes can serve as an effective prognostic predictor for AML patients and may guide for patient stratification for immunotherapies and drugs.

Spectrum of gene mutations identified by targeted next-generation sequencing in Chinese leukemia patients.

BACKGROUND: Despite targeted sequencing have identified several mutations for leukemia, there is still a limit of mutation screening for Chinese leukemia. Here, we used targeted next-generation sequencing for testing the mutation patterns of Chinese leukemia patients. METHODS: We performed targeted sequencing of 504 tumor-related genes in 109 leukemia samples to identify single-nucleotide variants (SNVs) and insertions and deletions (INDELs). Pathogenic variants were assessed based on the American College of Medical Genetics and Genomics (ACMG) guidelines. The functional impact of pathogenic genes was explored through gene ontology (GO), pathway analysis, and protein-protein interaction network in silico. RESULTS: We identified a total of 4,655 SNVs and 614 INDELs in 419 genes, in which PDE4DIP, NOTCH2, FANCA, BCR, and ROS1 emerged as the highly mutated genes. Of note, we were the first to demonstrate an association of PDE4DIP mutation and leukemia. Based on ACMG guidelines, 39 pathogenic and likely pathogenic mutations in 27 genes were found. GO annotation showed that the biological process including gland development, leukocyte differentiation, respiratory system development, myeloid leukocyte differentiation, mesenchymal to epithelial transition, and so on were involved. CONCLUSION: Our study provided a map of gene mutations in Chinese patients with leukemia and gave insights into the molecular pathogenesis of leukemia.

The association between environmental endocrine disruptors and cardiovascular diseases: A systematic review and meta-analysis.

BACKGROUND: Except for known cardiovascular risk factors, long-term exposure to environmental endocrine disruptors (EEDs) - a class of exogenous chemicals, or a mixture of chemicals, that can interfere with any aspect of hormone action - has been shown to increase the risk of cardiovascular diseases (CVDs), which are still controversial. OBJECTIVE: To conduct a comprehensive systematic review and meta-analysis to estimate the association between EEDs, including nonylphenol (NP), bisphenol A (BPA), polychlorinated biphenyl (PCB), organo-chlorine pesticide (OCP) and phthalate (PAE) exposure and CVD risk. METHODS: The heterogeneity between different studies was qualitatively and quantitatively evaluated using Q test and I2 statistical magnitude, respectively. Subgroup analysis was performed using chemical homologs - a previously unused grouping method - to extract data and perform meta-analysis to assess their exposure to CVD. RESULTS: Twenty-nine literatures were enrolled with a total sample size of 88891. The results indicated that exposure to PCB138 and PCB153 were the risk factors for CVD morbidity (odds ratio (OR) = 1.35, 95% confidence interval (CI): 1.10-1.66; OR = 1.35, 95% CI: 1.13-1.62). Exposure to organo-chlorine pesticide (OCP) (OR = 1.12, 95% CI: 1.00-1.24), as well as with phthalate (PAE) (OR = 1.11, 95% CI: 1.06-1.17) and BPA (OR = 1.19, 95% CI: 1.03-1.37) were positively associated with CVD risk, respectively. BPA exposure concentration had no correlation with total cholesterol (TC), or low-density lipoprotein (LDL), but exhibited a correlation with gender, waist circumference (WC), high-density lipoprotein (HDL), age, and body mass index (BMI) (standardized mean difference (SMD)) = 1.51; 95% CI: =(1.01-2.25); SMD = 0.16; 95% CI: (0.08-0.23); SMD = -0.19; 95% CI: (-0.27-0.12); SMD = -0.78; 95% CI: (-1.42-0.14); SMD = 0.08; 95% CI: (0.00-0.16). CONCLUSIONS: EED exposure is a risk factor for CVD. Long-term exposure to EEDs can influence cardiovascular health in humans. A possible synergistic effect may exist between the homologs. The mechanism of which needs to be further explored and demonstrated by additional prospective cohort studies, results of in vitro and in vivo analyses, as well as indices affecting CVD.

[Expression Level of TGFß1 and VEGF Gene in Acute Myeloid Patients and Its Clinical Prognostic Value].

OBJECTIVE: To study the expression level of TGFß1 and VEGF gene in patients with acute myeloid leukemia (AML) and its clinical prognostic value. METHODS: Seventy-eight AML patients treated in our hospital from July 2016 to September 2018 were selected. After isolation of bone marrow mononuclear cells from the patients, the levels of TGFß1 and VEGF genes were detected by RT-PCR, and the correlation of TGFß1 with VEGF genes and clinical characteristics of AML patients was analyzed. OS and EFS of the patients were evaluated by Kaplan-Meier, and Cox risk ratio model was used to analyze the prognostic risk factors of AML patients. RESULTS: The relative expression level of TGFß1 gene in AML patients was 0.32±0.04, which was significantly lower than that in control group (P<005). The relative expression level of vascular endothelial growth factor(VEGF) gene in the patients was 2.65±0.15, which was significantly higher than that in the control group (P<0.05). The levels of TGFß1 and VEGF genes significantly correlated with leukocyte count, hemoglobin, platelet and peripheral blast levels in AML patients (P<0.05). The level of TGFß1 in AML patients with complete remission was higher than that in patients with partial remission or non-remission (P<0.05). The level of TGFß1 in AML patients with partial remission was significantly higher than that in patients with non-remission (P<0.05). The level of VEGF in AML patients with complete remission was lower than at in patients with partial remission or non-remission (P<0.05). The level of VEGF in AML patients with partial remission was significantly lower than that in patients with non-remission (P<0.05). Kaplan-Meier survival analysis showed that OS and DFS in AML patients with high expression of TGFß1 were better than those in patients with low expression of TGFß1 (P<0.05), OS and DFS in AML patients with low expression of VEGF were better than those in patients with high expression of VEGF (P<0.05). Multivariate Cox regression analysis showed that platelet, TGFß1 and VEGF gene were independent influencing factors of OS (P<0.05). Leukocyte, TGFß1 and VEGF gene were independent influencing factors of DFS (P<0.05). CONCLUSION: Decreased expression of TGFß1 and increased expression of VEGF gene in AML patients closely relate to the poor prognosis of AML patients, which can provide reference for improving clinical efficacy of AML patients.

Influence of nonylphenol exposure on basic growth, development, and thyroid tissue structure in F1 male rats.

OBJECTIVE: Environmental endocrine disruptors (EEDs) with a weak ability to mimic estrogen have been associated with thyroid dysfunction. However, little is known about the effect of nonylphenol (NP), a well-known EED, on thyroid structure. The present study evaluates whether gestational and lactational exposure to NP impacts growth and thyroid structure in F1 male rats. METHODS: A total of 60 rats were gavaged with NP (25, 50, and 100 mg/kg), estradiol (E2, 30 µg/kg/day), and corn oil alone (vehicle control) from gestational day 6 to postnatal day (PND) 21. Serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone levels were detected by automated chemiluminescence immunoassay analyzer. The NP level in the thyroid was measured using high-performance liquid chromatography. The ultrastructure of follicular epithelial cells was examined using transmission electron microscopy. Histopathology was conducted using hematoxylin and eosin staining. RESULTS: On PND 0, exposure to 50 and 100 mg/kg/day NP led to a significant decrease in the average litter size, litter weight and number of live pups per litter compared to the control group (P < 0.05). Dams exposed to NP during perinatal period demonstrated decreased serum levels of FT3 and FT4 in F1 male rats, when compared to the control group (P < 0.05). The NP level in the control group was 3.39 ± 0.08 ng/mg, while NP levels in the low, middle, and high dose groups ranged from 5.20 to 11.00 ng/mg. Exposure caused a dose-related increase in NP level in the thyroid of male pups (P < 0.01). The thicknesses of the thyroid follicular epithelium were 2.06 ± 0.37 µm in the control group and 3.97 ± 1.61 µm in the high-dose group. The thickness of the thyroid follicular epithelium increased with an increase in treatment dose in a dose-dependent manner (P < 0.05). The sizes of the thyroid follicles were 1,405.53 ± 866.62 µm2 in the control group and 317.49 ± 231.15 µm2 in the high-dose group. With increasing NP dosages, animals showed a decreased size of the thyroid follicle (P < 0.01). Thyroid follicular cells of NP-treated rats showed mildly swollen mitochondria and dilated rough endoplasmic reticulum in the cytoplasm. CONCLUSION: Nonylphenol can cross the placental barrier and accumulate in the thyroid of F1 male rats. Gestational and lactational exposure to NP in dams impacted both development and growth of pups and damaged the ultrastructure of their thyroid tissue, which may further negatively influence normal thyroid function.

microRNA-22 can regulate expression of the long non-coding RNA MEG3 in acute myeloid leukemia.

AIM: Acute myeloid leukemia (AML) is the most common blood tumor with poor prognosis. At present, the research found that the pathogenesis of AML is related to many factors, such as recurrent somatic mutations and gene expression and epigenetic changes, however, the molecular mechanism of AML is still unclear. Long non-coding RNA MEG3 is a newly found tumor suppressor and plays a very important role in the regulation of a variety of tumor formation and progression. Studies found that the MEG3 expression was significantly decreased in AML. However, to date, it is not clear the cause of its abnormal expression. Therefore, the molecular mechanism of AML is urgently needed to study the molecular mechanism of AML. METHODS: The different expression level of MEG3, TET2, miR-22-3p, miR-22-5p in AML was detected by real-time quantification PCR. MEG3, TET2, miR-22-3p, miR-22-3p expression cell pools in K562 cells was used to interfering and TET2, MEG3 TET2, relations with miR-22-3p, miR-22-5p. The effect of AML cell on proliferation was evaluated by TET2 lower expression. RESULTS: 1. The lower expression of MEG3 and TET2 in AML cell lines was detected by RT-qPCR. 2. The stable MEG3, TET2 overexpression cell pools in K562 cells was successful established. 3. After transfection, MTT assay revealed that cell growth was significantly increased in AML cell lines transfected with TET2 compared with controls. CONCLUSIONS: Our findings suggested that MEG3 is significantly down regulated in AML cell lines.

Identification of microRNAs associated with medullary thyroid carcinoma by bioinformatics analyses.

The present study aimed to investigate the microRNA (miRNA) profile in human medullary thyroid carcinoma (MTC) tissue. The GSE40807 data profile was downloaded from the Gene Expression Omnibus database. Following preprocessing, differentially expressed microRNAs (DEMs) between MTC and healthy tissues were identified. Based on the obtained DEMs, transcription factor (TF)­miRNA and miRNA­target gene regulatory association pairs were predicted. Finally, functional enrichment analysis was performed on target genes of DEMs. Fifteen upregulated and 17 downregulated DEMs were identified. In the constructed TF­miRNA regulatory network, hsa­miR­9­5p was regulated by 9 TFs and hsa­miR­1 was regulated by 8 TFs. TFs of nuclear factor of κ light polypeptide gene enhancer in B­cells 1 (NF­κB1) and v­myc avian myelocytomatosis viral oncogene homolog (MYC) regulated 4 and 3 DEMs, respectively. In the miRNA­target gene regulatory network, hsa­miR­1, hsa­miR­9­5p, hsa­miR­96­5p and hsa­miR­590­5p were most upregulated. The target genes of these 4 miRNAs were primarily enriched in the mitogen activated protein kinase (MAPK) signaling pathway. Therefore, MAPK signaling pathway may serve important roles in MTC progression. In conclusion, the DEMs hsa­miR­1 and hsa­miR­9­5p, and TFs of NF­κB1 and MYC may be used as biomarkers for the diagnosis and treatment of MTC.

TET2 and MEG3 promoter methylation is associated with acute myeloid leukemia in a Hainan population.

The promoter of MEG3, which encodes the long non-coding RNA (lncRNA) MEG3, is often hypermethylated in acute myeloid leukemia (AML). Additionally, the Tet methylcytosine dioxygenase 2 gene (TET2) is frequently inactivated, which can lead to impaired DNA methylation and promote AML development. We examined the association between TET2 and MEG3 promoter hypermethylation in Hainan patients with AML. The expression of MEG3, TET2, miR-22-3p, and miR-22-5p was assessed in bone marrow samples from AML patients and healthy controls using real-time quantitative PCR. Using Sequenom MassARRAY technology, we compared MEG3 promoter methylation in AML patients and healthy controls. MEG3 expression was lower in AML patients than in the controls (P = 0.136). Moreover, there was greater methylation of MEG3 promoter in the AML patients than the controls (P < 0.05). Methylation of the MEG3 promoter correlated negatively with TET2 expression (P < 0.05, r < 0). Likewise there was a negative correlation between TET2 activity and MEG3 promoter methylation (P < 0.05, r < 0). These results suggest that hypermethylation of the MEG3 promoter in AML may result from decreased TET2 activity. These data provide insight into the molecular mechanisms underlying AML development and progression.

[Effect of Tiam 1 on cell proliferation and migration in head and neck squamous cell carcinoma cells].

OBJECTIVE: To investigate the effect of T lymphoma invasion and metastasis 1 (Tiam 1) overexpression in head and neck squamous cell carcinoma (HNSCC) cells. METHOD: Endogenous expression of Tiam 1 in 8 head and neck squamous cell carcinoma cell (HNSCC) lines was investigated by real-time RT-PCR. A lentivirus vector containing Tiaml was transfected into UM-SCC-47 cells, a head and neck squamous cell carcinoma cell line with little endogenous Tiaml expression. Stable clone, obtained by G418 screening, were assayed by RT-PCR and Western blot to validate the gene expression efficiency. The biological behaviors of the transduced cells were determined by cell counting, MTT and in-vitro migration assay. RESULT: Tiam 1 gene was highly expressed in M2 cell line and it's low level expression was found in UM-SCC-47. Cell counting and MTT assay showed that over-expression of Tiaml significantly promoted cell proliferation (P < 0.05). The cell monolayers overexpressed Tiaml that resulted in a significant increasment of cell migration in infected head and neck squamous cell carcinoma cell lines (P < 0.05). CONCLUSION: Tiam 1 gene plays an important role in the growth and migration in head and neck squamous cell carcinoma cell lines. It may be a useful marker for metastasis of head and neck squamous cell carcinoma.