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1.  Glioma Initiating Cells Form a Differentiation Niche Via the Induction of Extracellular Matrices and Integrin αV 
PLoS ONE  2013;8(5):e59558.
Glioma initiating cells (GICs) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC maintenance/differentiation, we established GIC clones having the potential to differentiate into malignant gliomas, and subjected to DNA microarray/iTRAQ based integrated proteomics. 21,857 mRNAs and 8,471 proteins were identified and integrated into a gene/protein expression analysis chart. Gene Ontology analysis revealed that the expression of cell adhesion molecules, including integrin subfamilies, such as α2 and αV, and extracellular matrices (ECMs), such as collagen IV (COL4), laminin α2 (LAMA2), and fibronectin 1 (FN), was significantly upregulated during serum-induced GIC differentiation. This differentiation process, accompanied by the upregulation of MAPK as well as glioma specific proteins in GICs, was dramatically accelerated in these ECM (especially FN)-coated dishes. Integrin αV blocking antibody and RGD peptide significantly suppressed early events in GIC differentiation, suggesting that the coupling of ECMs to integrin αV is necessary for GIC differentiation. In addition, the expression of integrin αV and its strong ligand FN was prominently increased in glioblastomas developed from mouse intracranial GIC xenografts. Interestingly, during the initial phase of GIC differentiation, the RGD treatment significantly inhibited GIC proliferation and raised their sensitivity against anti-cancer drug temozolomide (TMZ). We also found that combination treatments of TMZ and RGD inhibit glioma progression and lead the longer survival of mouse intracranial GIC xenograft model. These results indicate that GICs induce/secrete ECMs to develop microenvironments with serum factors, namely differentiation niches that further stimulate GIC differentiation and proliferation via the integrin recognition motif RGD. A combination of RGD treatment with TMZ could have the higher inhibitory potential against the glioma recurrence that may be regulated by the GICs in the differentiation niche. This study provides a new perspective for developing therapeutic strategies against the early onset of GIC-associated glioma.
doi:10.1371/journal.pone.0059558
PMCID: PMC3660593  PMID: 23704872
2.  Risk factors for adverse reactions from contrast agents for computed tomography 
Background
Symptoms of an adverse reaction to contrast agents for computed tomography are diverse ranging, and sometimes serious. The goal of this study is to create a scoring rule to predict adverse reactions to contrast agents used in computed tomography.
Methods
This was a retrospective cohort study of all adult patients undergoing contrast enhanced CT scan for 7 years. The subjects were randomly divided into either a derivation or validation group. Baseline data and clinically relevant factors were collected from the electronic chart. Primary outcome was any acute adverse reactions to contrast media, observed for during 24 hours after administration. All potential candidate predictors were included in a forward stepwise logistic regression model. Prediction scores were assigned based on β coefficient. A receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) and incidence of acute adverse reactions at each point were obtained. The same process was performed in the validation group.
Results
36,472 patients underwent enhanced CT imaging: 20,000 patients in the derivation group and 16,472 in the validation group. A total of 409 (2.0%, 95% CI:1.9-2.3) and 347 (2.1%, 95% CI:1.9-2.3) acute adverse reactions were seen in the derivation and validation groups. Logistic regression analysis revealed that prior adverse reaction to contrast agents, urticaria, an allergic history to drugs other than contrast agents, contrast agent concentration >70%, age <50 years, and total contrast agent dose >65 g were significant predictors of an acute adverse reaction. AUC was 0.70 (95% CI:0.67-0.73) and 0.67 (95% CI:0.64-0.70) in the derivation and validation groups.
Conclusions
We suggest a prediction model consisting of six predictors for acute adverse reactions to contrast agents used in CT.
doi:10.1186/1472-6947-13-18
PMCID: PMC3562527  PMID: 23363607
3.  The optimal screening interval for gastric cancer using esophago-gastro-duodenoscopy in Japan 
BMC Gastroenterology  2012;12:144.
Background
Gastric cancer is one of the most significant diseases, and esophago-gastro-duodenoscopy (EGD) is one of screening methods for gastric cancer. This study was conducted to identify the optimal screening interval for gastric cancer using EGD in healthy adults.
Methods
A retrospective cohort study was conducted on 3,723 healthy participants without a known diagnosis of gastric cancer at baseline from January 2005 to December 2010. Participants underwent annual health screenings, including EGD, at the Center for Preventive Medicine at St Luke’s International Hospital, a community teaching hospital in Japan. Participants with cytological abnormalities underwent further examination. A generalized estimating equation (GEE) was used to analyze the longitudinal data. We decided 0.5% of incidence of gastric cancer as a cutoff point for interval.
Results
The mean age (SD) of the participants was 55 (11) years, and 1,879 (50.5%) were male. During the study period, gastric cancer was detected in 35 participants. However, the incidence varied based on their ages. In the age groups <40, 40–49, 50–59, 60–69 and ≥70 years old, the 5-year cumulative incidences (95%CI) of gastric cancer were 0% (0-0%), 0.3% (0.1-1.0%), 1.0% (0.5-1.8%), 1.4% (0.8-2.4%) and 1.9% (0.8-3.8%), respectively. The odds ratios of the incidence of gastric cancer per year, which were evaluated using GEE models for the age groups 40–49, 50–59, 60–69 and ≥70 years old, were 1.51 (95%CI: 0.91-2.49), 1.94 (95%CI: 1.31-2.86), 1.59 (95%CI: 1.23-2.06) and 1.46 (95%CI: 1.06-2.02), respectively.
Conclusions
A screening for gastric cancer using EGD may be appropriate annually for healthy people over 70 years old, every two or three years for people 60–69 years old and every four years for people 50–59 years old. People younger than 50 years old may only need repeat screenings every five years or more.
doi:10.1186/1471-230X-12-144
PMCID: PMC3503735  PMID: 23072453
4.  Bone Tenderness 
Mayo Clinic Proceedings  2010;85(9):e65.
doi:10.4065/mcp.2010.0125
PMCID: PMC2931628  PMID: 20810790

Results 1-4 (4)