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

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 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

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.

Objective:To analyze the clinical and pathological features and gene mutations of pancreatic acinar cell carcinoma (PACC).Methods:Clinical data of 34 patients with PACC admitted to the Department of Pancreatic Surgery of the First Affiliated Hospital of Naval Medical University from December 2009 to July 2018 were retrospectively analyzed to summarize its clinical characteristics, and the expressions of α1-ACT, CaM5.2, Syn and CgA in pancreatic tumor tissues were detected by immunohistochemistry. Next-generation gene sequencing technology was used to detect gene mutations in tumor specimens.Results:Among the 34 PACC patients, 23(68%) were males and 11(32%) were females; the age ranged from 25 to 75 years, with an average age of 54 years. The first symptom was abdominal pain or distension in 21 cases (62%), skin or scleral yellow staining in 4 cases(12%), and 9 cases(26%) were found in routine physical examination. BMI was 17.6-34.0 kg/m 2, of which 3 cases (9%) were <18.5 kg/m 2, 23 cases (68%) were 18.5-24.0 kg/m 2, and 8 cases (23%) were >24.0 kg/m 2. Preoperative examination showed elevated CA19-9 in 7 cases (20.6%), elevated CEA in 3 cases (8.8%), and elevated AFP in 7 cases (20.6%). Blood amylase was 16-247 U/L, with an average of 80 U/L. Enhanced CT showed that the lesion was irregular in shape, showing inhomogeneity and slightly low density, with areas of cystic degeneration and necrosis. The tumor was located in the head of the pancreas in 14 cases (41%), the body and tail of the pancreas in 19 cases (56%), and the neck of the pancreas in 1 case (3%). The largest tumor diameter was 1.5-15.5 cm, with an average of 5.4 cm. Postoperative pathologic stage I was confirmed in 4 cases (12%), stage Ⅱ in 14 cases (41%), stage Ⅲ in 14 cases (41%) and stage Ⅳ in 2 cases (6%). Immunohistochemical results showed that both α1-ACT and CaM5.2 were positively expressed (100%). Syn was positive in 8 cases (23.5%) and CgA was positive in 6 cases (17.6%). Ki-67 index was from 9% to 70%, with an average of 41%. Gene sequencing of pancreatic tumor tissue from 6 patients showed BRCA2 mutation in 2 patients (7155C>G), K-ras mutation in 1 patient (35G>T), RET mutation in 1 patient (200G>A), and LKB1 mutation (234G>T) in 1 patient, and one double mutation of K-ras and RET (35G>A, 1 798C>T). 30 patients were followed up, and the median survival was 38.3 months. Conclusions:PACC was a rare pancreatic tumor with no specific clinical manifestations. The positive expression rates of α1-ACT and CAM5.2 in tumor tissues were 100%. BRCA2, K-ras, RET and LKB1 were common gene mutations.

Objective:To explore the medical costs and influencing factors of patients diagnosed with Brucellosis in Xinjiang Uygur Autonomous Region (Xinjiang).Methods:Information on demographics, medical visits, and costs of patients diagnosed with Brucellosis were collected between January 1,2017 and December 31,2019. The effects of different genders, age groups, clinical stages, and comorbidities on patients' health care utilization and medical costs were analyzed by nonparametric tests. The median was used to describe the outpatient and inpatient costs of patients with Brucellosis.Results:A total of 13 532 patients (8 113 outpatient and 5 419 inpatient cases) were included in the analysis. A total of 67.8% (9 176/13 532) were male, with an average age of (42.7±15.4 ) years; age between 18-44 years (46.6%, 6 304/13 532) and 45-59 years (34.2%,4 622/13 532) were the dominant groups. The mean age of inpatients [(43.3±15.7) years] was higher than that of outpatients [(42.3±15.1) years, Z=-3.85, P<0.001]. When hospitalized patients are treated,systemic symptoms were common with fever (36.9%, 1 997/5 419) and fatigue (36.6%, 1 983/5 419), and with joint/muscle pain (68.9%, 3 735/5 419) being the highest proportion of local symptoms. A total of 79.1% (4 289/5 419) of inpatients were diagnosed with acute Brucellosis. A total of 46.5% (2 519/5 419) of inpatients had complications;skeletal system complications ranked the highest. The average number of outpatient visits per outpatient was (1.6±1.4) times. The duration of hospitalization was (11.3±4.2) days, with longer days for patients in the chronic phase and with complications ( P<0.05). A total of 89.3% (4 840/5 419) of inpatients had outpatient records in the same year,and the average number of outpatient visits per patient was (3.6±2.6) times. Outpatient medical costs were dominated by laboratory and drug costs (75.1%), and inpatient costs were dominated by drug, laboratory, and other costs (74.4%). Outpatient medical expenses M( Q1, Q3) were 61(52, 497) Yuan, 61 (51, 346) Yuan and 58 (46, 318) Yuan,respectively. Inpatients' medical expenses M ( Q1, Q3) were 8 214 (6 355, 10 721) Yuan,9 095 (7 018, 12 155) Yuan and 9 492 (7 530, 12 351) Yuan, respectively. For patients, age, clinical stages,complications,and joint/muscle pain symptoms were influential factors for hospitalization costs ( P<0.001). Conclusions:The economic burden was higher for inpatients, especially those in the high age group, with chronic phases and skeletal and neurological complications. Improving patients' awareness of early treatment, standardized treatment, and reducing chronicity and complications are the main points in reducing the economic burden caused by Brucellosis diagnosis and treatment.