BACKGROUNDColon cancer is one of the major malignancies worldwide and it still remains resistant to much of the currently available chemotherapy. Downregulation of HGF/c-Met signaling pathway is an emerging therapy for cancer treatment.

METHODSIn this study, the inhibitory effects of c-Met phosphorylation were observed with SU11274 on different colon cancer cell lines in vitro.

RESULTSThe results revealed the significant inhibitory effects of SU11274 on cell proliferation and cell survival, in a time and dose-dependent manner. Furthermore, the inhibitory effects of SU11274 on different subgroups of colon cancer cells via the HGF/c-Met signaling pathway were implicated in this study.

CONCLUSIONThe results suggested the possible selective therapeutic effects of c-Met inhibitor on colon cancer.

Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Colonic Neoplasms ; drug therapy ; pathology ; Hepatocyte Growth Factor ; pharmacology ; Humans ; Indoles ; pharmacology ; Piperazines ; pharmacology ; Proto-Oncogene Proteins c-met ; antagonists & inhibitors ; physiology ; Signal Transduction ; Sulfonamides ; pharmacology

BACKGROUNDThe CKLF-like MARVEL transmembrane domain-containing family (CMTM) is a novel family of proteins linking chemokines and TM4SF. Different members exhibit diverse biological functions. In this study, the effect of intracellular CMTM2 on regulating human immunodeficiency virus type-1 (HIV-1) transcription was evaluated.

METHODSThe effects of CMTM2 on regulating full-length HIV-1 provirus and the HIV-1 long terminal repeat (LTR)-directed transcription were assessed by luciferase assay. Transcription factor assays, using the luciferase reporter plasmids of AP-1, CRE, and NF-κB were conducted to explore the signaling pathway(s) that may be regulated by CMTM2. The potential relationship between CMTM2 and the transcription factor AP-1 was further analyzed by Western blotting analyses to investigate the effect of CMTM2 on PMA-induced ERK1/2 phosphorylation.

RESULTSThe results from the current study revealed that CMTM2 acts as a negative regulator of HIV-1 transcription. CMTM2 exerted a suppressive action on both full-length HIV-1 provirus and HIV-1 LTR-directed transcription. Transcription factor assays showed that CMTM2 selectively inhibited basal AP-1 and CREB activity. Co-expression of HIV-1 Tat, a potent AP-1 and CREB activator, can not reverse CMTM2-mediated AP-1 and CREB inhibition, suggesting a potent and specific effect of CMTM2 on negatively regulating these two signaling pathways.

CONCLUSIONIntracellular CMTM2 can negatively regulate HIV-1 transcription, at least in part, by targeting the AP-1 and CREB pathways. Exploring the mechanisms further may lead to new ways to control HIV-1 replication.

Chemokines ; physiology ; Cyclic AMP Response Element-Binding Protein ; antagonists & inhibitors ; HIV Long Terminal Repeat ; HIV-1 ; genetics ; Humans ; Intracellular Space ; metabolism ; Jurkat Cells ; MARVEL Domain-Containing Proteins ; Tetradecanoylphorbol Acetate ; pharmacology ; Transcription Factor AP-1 ; antagonists & inhibitors ; Transcription, Genetic ; U937 Cells

Uterine leiomyosarcoma is an uncommon malignant neoplasm of smooth muscle origination and is associated with a poor prognosis. We report two cases of uterine leiomyosarcoma that presented with pulmonary metastases. 2-deoxy-2-(¹⁸F)fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) was performed to identify the primary carcinoma and found the focus located in the uterus. The follow-up magnetic resonance imaging (MRI) confirmed the diagnosis was uterine leiomyosarcoma.
Adult ; Female ; Fluorodeoxyglucose F18 ; Humans ; Leiomyosarcoma ; diagnosis ; Magnetic Resonance Imaging ; methods ; Middle Aged ; Positron-Emission Tomography ; methods ; Tomography, X-Ray Computed ; methods ; Uterine Neoplasms ; diagnosis

Objective To evaluate the application value of whole exome sequencing (WES) in diagnosis of NDDs (neuro-developmental disorders) children.Metheod WES was used for the diagnosis of 35 unexplained NDD children, which admitted to the outpatient and ward of Children′s hospital affiliated to Capital institute of pediatric from November 2015 to November 2016.These children′s clinical data was collected detailedly.Using bioinformatics software tools combining with patient′s phenotype, the candidate genetic/genomic variants of these patients were identified from WES data.The final pathogenicity of genetic/genomic variants was interpreted according to the guideline of the American College of Medical Genetics and Genomics (ACMG), meanwhile, the variants validation and co-separation analysis in the parents and their family members were performed by Sanger sequencing, real time-PCR and multiplex ligation-dependent probe amplification (MLPA).Results 14 pathogenic single nucleotide variants (SNVs) and three pathogenic copy number variations (CNVs) were detected in the 35 NDD children, the detection rate in this study is 48.6%.Among the 14 pathogenic SNVs, 11 of them are the definite NDD-related genes according to OMIM database (such as CHARGE syndrome, Wiedemann-Steiner syndrome, Cockayne syndrome, etc.), and six of them are de novo (6/11, 54.6%).Three pathogenic CNVs were identified from WES data, including two microduplications and one microdeletion.Meanwhile, a female child carrying a frame shift mutation in MECP2 was found and the germline mosaicism with low-frequency mutation of this site (8.4%) was confirmed by his father's sperm.Conclusions The diagnosis rate of WES in NDDs children is 48.6% in our small-sample study.In addition to pathogenic/likely pathogenic SNVs, CNVs can be detected successfully from WES data, which effectively improved the diagnosis yield in NDDs children.

OBJECTIVETo study changes in the levels of systematic and airway local oxidative stress in patients in different stages of chronic obstructive pulmonary diseases (COPD), and explore the association between oxidative stress and glucocorticoid receptor (GR) level in the peripheral blood leukocytes.

METHODSThe levels of malonaldehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in induced sputum and plasma, as well as GR levels in peripheral blood leukocytes and plasma levels of cortisol and adrenocorticotrophic hormone (ACTH), were examined in 33 patients with acute exacerbations of COPD (AECOPD, group A), 27 with stable COPD (group B), and 28 healthy volunteers (including 15 smokers as group C, and 15 nonsmokers as group D).

RESULTSMDA level in induced sputum and plasma decreased, whereas the levels of GSH, SOD and GSH-PX increased significantly in the order of groups A, B, C, and D (P<0.05). The activity of SOD in induced sputum and plasma were significantly lower in group C than in group D. No significant difference was noted in the other oxidative stress indices between groups C and D (P>0.05). The plasma levels of cortisol and ACTH showed no significant difference between the 4 groups, while the GR level in peripheral blood leukocytes increased significantly in the order of groups A, B, C and D (1565-/+719, 2069-/+488, 2739-/+926, and 4793 -/+1415 U, respectively, P<0.05). After controlling for the factor of smoking status, the plasma and sputum SOD activity were both positively correlated to GR, with the partial correlation coefficient of 0.512 and 0.564, respectively (P<0.001).

CONCLUSIONPatients in different stages of COPD, especially those with AECOPD, may sustain systematic and local oxidation and anti-oxidation imbalance. Decreased SOD activity may contribute to GR level decrement in peripheral blood leukocytes in these patients.

Aged ; Female ; Glutathione Peroxidase ; metabolism ; Humans ; Leukocytes ; metabolism ; Male ; Middle Aged ; Oxidative Stress ; Pulmonary Disease, Chronic Obstructive ; metabolism ; Receptors, Glucocorticoid ; metabolism ; Superoxide Dismutase ; metabolism

OBJECTIVETo study the selective effect to tumor cells mediated by a recombinant adenoviral vector carrying E2F-1 promoter.

METHODSThe AdEasy-1 adenoviral vector system was used in this experiment. Several recombinant adenovirus with tumor-targeting E2F-1 promoter were constructed and then the E2F-1 promoter gene was checked by PCR and sequencing. The two adenovirus expressing GFP gene which is regulated by E2F-1 promoter or CMV promoter were used to respectively transfect tumor cells and non-proliferating normal cells, then observed and analyzed the different results caused by different promoters. Vpr gene was cloned into the targeting recombinant adenovirus. The new adenovirus named rvAdE2F-1/vpr was used to transfect tumor cells SMMC-7721, LS174T and non-proliferating normal cells H292, L-02. The surviving rate of each group was registered; the level of E2F-1 protein expressed in normal and tumor cell lines were checked by Western Blot.

RESULTE2F-1 promoter can regulate the downstream gene GFP selectively expressed in LS174T and its activity in LS174T was similar with CMV promoter's; Vpr gene regulated by E2F-1 promoter can suppress the proliferation of tumor cells and no toxicity to normal cells; In all of the tumor cells, a much higher level of E2F-1 was expressed compared with normal cell lines. E2F-1 promoter's activity correlated well with E2F-1 protein levels.

CONCLUSIONSE2F-1 promoter can control a selective cell killing to cancer cells, with no effect to normal cells. The system of E2F-1 promoter is a useful method for tumor-targeting gene therapy.

Adenoviridae ; genetics ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; E2F1 Transcription Factor ; genetics ; metabolism ; Gene Products, vpr ; genetics ; physiology ; Genetic Therapy ; methods ; Genetic Vectors ; Green Fluorescent Proteins ; genetics ; metabolism ; Humans ; Neoplasms ; genetics ; pathology ; therapy ; Promoter Regions, Genetic ; genetics ; Recombinant Fusion Proteins ; genetics ; metabolism ; Transfection

BACKGROUNDColonic polyps are frequently encountered in clinics. Computed tomographic colonography (CTC), as a painless and quick detection, has high values in clinics. In this study, we evaluated the application value of computer-aided detection (CAD) in CTC detection of colonic polyps in the Chinese population.

METHODSCTC was performed with a GE 64-row multidetector computed tomography (MDCT) scanner. Data of 50 CTC patients (39 patients positive for at least one polyp of ≥ 0.5 cm in size and the other 11 patients negative by endoscopic detection) were retrospectively reviewed first without computer-aided detection (CAD) and then with CAD by four radiologists (two were experienced and another two inexperienced) blinded to colonoscopy findings. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of detected colonic polyps, as well as the areas under the ROC curves (Az value) with and without CAD were calculated.

RESULTSCAD increased the overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the colonic polyps detected by experienced and inexperienced readers. The sensitivity in detecting small polyps (5 - 9 mm) with CAD in experienced and inexperienced readers increased from 82% and 44% to 93% and 82%, respectively (P > 0.05 and P < 0.001). With the use of CAD, the overall false positive rate and false negative rate for the detection of polyps by experienced and inexperienced readers decreased in different degrees. Among 13 sessile polyps not detected by CAD, two were ≥ 1.0 cm, eleven were 5 - 9 mm in diameter, and nine were flat-shaped lesions.

CONCLUSIONSThe application of CAD in combination with CTC can increase the ability to detect colonic polyps, particularly for inexperienced readers. However, CAD is of limited value for the detection of flat polyps.

Adult ; Aged ; Colonic Polyps ; diagnosis ; diagnostic imaging ; Colonography, Computed Tomographic ; methods ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Sensitivity and Specificity ; Young Adult

OBJECTIVETo observe the impact of systolic blood pressure (SBP) on visit-to-visit blood pressure variability (BPV) in middle-aged and elderly people.

METHODSVisit-to-visit BPV was determined in 5440 workers in the Kailuan study cohort from 2006 to 2007. The subjects were ≥ 40 years-old and had no history of stroke, transient ischemic attack or myocardial infarction. Participants were divided into five groups according to different levels of SBP. Linear regression was used to analyze the related factors which might affect BPV.

RESULTSMean systolic BPV of all subjects was 10.35 mm Hg [coefficient of variation (CV 7.96%)]. The mean systolic BPV of males was 10.54 mm Hg (CV 7.90%) while the mean SBPV of females was 10.06 mm Hg (CV 7.90%). The BPV of males was significant higher than that of females (P < 0.001). CV of SBP was similar between males and females. Furthermore, higher SBP was associated with higher BPV. There were significant differences in BPV between different groups with different levels of SBP (P < 0.001). Linear regression analysis demonstrated that SBP, age, gender, high-sensitivity C-reactive protein (hsCRP) were affecting factors of BPV. Twenty mm Hg SBP increase was linked with 2.02 mm Hg BPV increase and 0.388%CV increase. Age increase of 1 year was associated with 0.044 mm Hg BPV increase and 0.029% CV increase.

CONCLUSIONSBP, age, gender and hsCRP are important factors affecting BPV in middle-aged and elderly people. Higher SBP is closely related to greater BPV in this cohort.

Adult ; Aged ; Aged, 80 and over ; Blood Pressure ; physiology ; Blood Pressure Monitoring, Ambulatory ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Regression Analysis ; Systole

OBJECTIVETo identify the disease-causing gene mutations and to reveal the relationship between the genotype and the phenotype in Chinese patients with hypertrophic cardiomyopathy (HCM).

METHODSOne hundred unrelated patients with HCM and 120 controls were enrolled in this study. The full encoding exons and flanking sequences of the cardiac myosin binding protein C gene (MYBPC3) were amplified with PCR and the products were sequenced.

RESULTSA novel missense mutation c.706T > C was identified in exon 6 of MYBPC3 gene in three HCM patients, which resulted a Serine (S) to Glycine (G) exchange at amino acid residue 236 (S236G). The clinical phenotypes of the three patients were different (2 obstructive HCM, 1 non-obstructive HCM). The 120 controls were normal in the genetic test.

CONCLUSIONSThe novel S236G mutation in MYBPC3 gene was a hot-spot mutation in Chinese patients with HCM.

Adult ; Asian Continental Ancestry Group ; genetics ; Cardiomyopathy, Hypertrophic ; genetics ; Carrier Proteins ; genetics ; Case-Control Studies ; DNA ; Female ; Genome, Human ; Humans ; Male ; Middle Aged ; Mutation ; Phenotype ; Young Adult

As a new direction of pancreatic cancer treatment, neoadjuvant therapy for pancreatic cancer has been confirmed to be able to improve the prognosis of the patients. Under multidisciplinary treatment (MDT) mode, neoadjuvant therapy combines multidisciplinary advantages to solve patients′ problems of diagnosis and treatment, provides accurate, comprehensive and individual treatments, and maximizes the clinical benefit for patients. In this article, we summarize the present problems of neoadjuvant therapy for pancreatic cancer in patient selection, treatment regimen selection, treatment response evaluation and surgical selection, and explore the direction of clinical research and neoadjuvant therapy for pancreatic cancer under MDT mode.