Publications by authors named "Ling-Ling Hsieh"

90 Publications

Evaluation of use, comprehensibility and clarity of over-the-counter medicine labels: Consumers' perspectives and needs in Taiwan.

Health Soc Care Community 2020 Oct 9. Epub 2020 Oct 9.

Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.

An estimate of one third of preventable medication errors occurred annually due to patients' misunderstanding of use instructions. To safeguard consumers' over-the-counter (OTC) medicine use and to develop future initiatives, this study evaluated the use, comprehensibility and clarity of the information labels on OTC packages from consumers' perspectives in Taiwan. This cross-sectional study was conducted at 29 community pharmacies; 50 pharmacy clerkship students helped participant enrolment from June to September 2017. Participants (n = 470) were 20 years old or above, Mandarin speaking, and with specific OTC purchases. A face-to-face survey was administered to investigate the degree to which participants read the package labels and their comprehension of correct medicine use. An 11-item survey was used to measure participants' specific OTC purchases (3 items), the use (2 items), comprehensibility (1 item) and clarity (2 items) of OTC package labels, in addition to the sociodemographic information (3 items). Participants were also solicited to provide opinions regarding package label redesign. Descriptive statistics and logistic regressions were applied for analyses. Findings show that most (84.0%) participants read instruction labels before use, with indications (79.4%), drug names (64.5%) and dosage and administration (59.8%) being the top reads. Only 30.0% of the participants fully understood how to take the medicines correctly. Younger (OR = 1.033, p < .001) and female participants (OR = 1.965, p = .014) with a higher level of education (OR = 1.940, p = .034) tended to read package label information prior to purchase or use. Younger participants (OR = 1.030, p < .001) and those who read OTC medicine labels before use (OR = 2.317, p = .004) were more likely to correctly understand medicine use. The findings indicate that older, male adults with a lower level of education should be targeted to ensure their correct understanding of OTC labels. Pharmacists should recite pertinent label information and, concomitantly, ensure consumers' understanding when providing medicine counselling.
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http://dx.doi.org/10.1111/hsc.13190DOI Listing
October 2020

Evaluating BRCA mutation risk predictive models in a Chinese cohort in Taiwan.

Sci Rep 2019 07 15;9(1):10229. Epub 2019 Jul 15.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Accurate estimation of carrier probabilities of cancer susceptibility gene mutations is an important part of pre-test genetic counselling. Many predictive models are available but their applicability in the Asian population is uncertain. We evaluated the performance of five BRCA mutation risk predictive models in a Chinese cohort of 647 women, who underwent germline DNA sequencing of a cancer susceptibility gene panel. Using areas under the curve (AUCs) on receiver operating characteristics (ROC) curves as performance measures, the models did comparably well as in western cohorts (BOADICEA 0.75, BRCAPRO 0.73, Penn II 0.69, Myriad 0.68). For unaffected women with family history of breast or ovarian cancer (n = 144), BOADICEA, BRCAPRO, and Tyrer-Cuzick models had excellent performance (AUC 0.93, 0.92, and 0.92, respectively). For women with both personal and family history of breast or ovarian cancer (n = 241), all models performed fairly well (BOADICEA 0.79, BRCAPRO 0.79, Penn II 0.75, Myriad 0.70). For women with personal history of breast or ovarian cancer but no family history (n = 262), most models did poorly. Between the two well-performed models, BOADICEA underestimated mutation risks while BRCAPRO overestimated mutation risks (expected/observed ratio 0.67 and 2.34, respectively). Among 424 women with personal history of breast cancer and available tumor ER/PR/HER2 data, the predictive models performed better for women with triple negative breast cancer (AUC 0.74 to 0.80) than for women with luminal or HER2 overexpressed breast cancer (AUC 0.63 to 0.69). However, incorporating ER/PR/HER2 status into the BOADICEA model calculation did not improve its predictive accuracy.
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http://dx.doi.org/10.1038/s41598-019-46707-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629692PMC
July 2019

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21.

Cancer Med 2018 08 9;7(8):3988-4003. Epub 2018 Jul 9.

Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small-molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase-3/7-activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1-CDK1 and cyclin A-CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent-G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1-mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.
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http://dx.doi.org/10.1002/cam4.1658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089189PMC
August 2018

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

Mol Genet Genomic Med 2018 Apr 17. Epub 2018 Apr 17.

School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.

Background: DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1, APEX1, MUTYH, OGG1, NUDT1, XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome.

Methods: From Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DNA repair SNPs and CRC were calculated using a weighted Cox proportional hazard regression model.

Results: Heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51-5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10-6.55) were significantly associated with an increased risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. However, the variant CG+GG genotype of MUTYH rs3219489 was associated with a decreased risk of CRC (HR = 0.49, 95% CI = 0.26-0.91) compared with the homozygous CC wild-type counterparts.

Conclusion: Our findings revealed that polymorphisms of DNA repair genes that include NUDT1, ERCC2, and MUTYH are associated with CRC in patients with Lynch syndrome in Chinese population. Further studies with large sample size are needed to confirm our findings.
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http://dx.doi.org/10.1002/mgg3.402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081223PMC
April 2018

Polymer gel dosimeters for pretreatment radiotherapy verification using the three-dimensional gamma evaluation and pass rate maps.

Phys Med 2017 May 24;37:75-81. Epub 2017 Apr 24.

3D Printing Medical Research Center, China Medical University Hospital, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan, ROC. Electronic address:

Polymer gel dosimeters (PGDs) have been widely studied for use in the pretreatment verification of clinical radiation therapy. However, the readability of PGDs in three-dimensional (3D) dosimetry remain unclear. In this study, the pretreatment verifications of clinical radiation therapy were performed using an N-isopropyl-acrylamide (NIPAM) PGD, and the results were used to evaluate the performance of the NIPAM PGD on 3D dose measurement. A gel phantom was used to measure the dose distribution of a clinical case of intensity-modulated radiation therapy. Magnetic resonance imaging scans were performed for dose readouts. The measured dose volumes were compared with the planned dose volume. The relative volume histograms showed that relative volumes with a negative percent dose difference decreased as time elapsed. Furthermore, the histograms revealed few changes after 24h postirradiation. For the 3%/3mm and 2%/2mm criteria, the pass rates of the 12- and 24-h dose volumes were higher than 95%, respectively. This study thus concludes that the pass rate map can be used to evaluate the dose-temporal readability of PGDs and that the NIPAM PGD can be used for clinical pretreatment verifications.
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http://dx.doi.org/10.1016/j.ejmp.2017.04.018DOI Listing
May 2017

Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy.

Int J Clin Oncol 2017 Jun 2;22(3):484-493. Epub 2017 Jan 2.

Department of Industrial Management, National Taiwan University of Science and Technology, 43, Sec. 4, Keelung Road, Taipei, 106, Taiwan.

Background: This study examined the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and survival of patients with colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy in Taiwan.

Methods: We genotyped MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) for 498 CRC patients treated with 5-FU-based chemotherapy after receiving surgery. Survival analyses on MTHFR polymorphisms were performed using log-rank test and Kaplan-Meier curve. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MTHFR genotypes and survival.

Results: Overall survival (OS) was significantly longer in CRC patients with MTHFR 677 CT+TT genotypes compared with those with 677 CC genotype (HR 0.77; 95% CI 0.60-0.98). Although the MTHFR A1298C polymorphism was not associated with OS in CRC, this polymorphism was associated with significantly shorter OS in rectal cancer. Among rectal cancer patients, OS was shorter for patients with AC+CC genotypes than for those with the AA genotype (HR 1.95; 95% CI 1.35-2.83). In haplotype analysis, better OS was found for colon cancer patients carrying the MTHFR 677T-1298A haplotype (HR 0.73; 95% CI 0.55-0.97), but worse survival was linked to rectal cancer patients carrying the MTHFR 677C-1298C haplotype (HR 1.53; 95% CI 1.08-2.18).

Conclusions: Our findings suggest that MTHFR genotypes provide prognostic information for CRC patients treated with 5-FU-based chemotherapy.
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http://dx.doi.org/10.1007/s10147-016-1080-zDOI Listing
June 2017

DNA Methylation Identifies Loci Distinguishing Hereditary Nonpolyposis Colorectal Cancer Without Germ-Line MLH1/MSH2 Mutation from Sporadic Colorectal Cancer.

Clin Transl Gastroenterol 2016 Dec 15;7(12):e208. Epub 2016 Dec 15.

National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.

Objectives: Roughly half of hereditary nonpolyposis colorectal cancer (HNPCC) cases are Lynch syndrome and exhibit germ-line mutations in DNA mismatch repair (MMR) genes; the other half are familial colorectal cancer (CRC) type X (FCCTX) and are MMR proficient. About 70% of Lynch syndrome tumors have germ-line MLH1 or MSH2 mutations. The clinical presentation, histopathological features, and carcinogenesis of FCCTX resemble those of sporadic MMR-proficient colorectal tumors. It is of interest to obtain biomarkers that distinguish FCCTX from sporadic microsatellite stable (MSS) CRC, to develop preventive strategies.

Methods: The tumors and adjacent normal tissues of 40 patients with HNPCC were assayed using the Illumina Infinium HumanMethylation27 (HM27) BeadChip to assess the DNA methylation level at about 27,000 loci. The germ-line mutation status of MLH1 and MSH2 and the microsatellite instability status in these patients were obtained. Genome-wide DNA methylation measurements of three groups of patients with general CRC were downloaded from public domain databases. Probes with DNA methylation levels that differed significantly between patients with sporadic MSS CRC and FCCTX were examined, to explore their potential as biomarkers.

Results: We found that MSS HNPCC tumors were overwhelmingly hypomethylated compared with those from patient groups with other types of CRC, including germ-line MLH1/MSH2-mutated HNPCC and sporadic MSS CRC. Five gene-marker panels that exhibited a sensitivity of 100% and a specificity higher than 90% in both discovery and validation cohorts were proposed to distinguish MSS HNPCC tumors from sporadic MSS CRC.

Conclusions: Our results warrant further investigation and validation. The loci identified here may become useful biomarkers for distinguishing between FCCTX and sporadic MSS CRC tumors.
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http://dx.doi.org/10.1038/ctg.2016.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288582PMC
December 2016

TP53 Polymorphisms and Colorectal Cancer Risk in Patients with Lynch Syndrome in Taiwan: A Retrospective Cohort Study.

PLoS One 2016 1;11(12):e0167354. Epub 2016 Dec 1.

School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.

Background And Aim: TP53 encodes p53, which has a crucial role in modulating genes that regulate defense against cancer development. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk.

Methods: We identified 260 MLH1 and MSH2 germline mutation carriers from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association of TP53 polymorphisms with CRC development.

Results: The carriers of the variant C allele of rs1042522 were associated with a decreased CRC risk (GC genotype: HR = 0.35, 95% CI = 0.14-0.86; CC genotype: HR = 0.28, 95% CI = 0.13-0.57). In addition, the dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15-0.67). The CRC risk was decreased in carriers with the CT and TT genotypes of rs12947788 (HR = 0.20, 95% CI = 0.08-0.46 and HR = 0.25, 95% CI = 0.09-0.65, respectively). Moreover, the dominant model of rs12947788 was significantly associated with a decreased CRC risk (HR = 0.21, 95% CI = 0.09-0.46). A haplotype analysis indicated that compared with the most common GC haplotype, the CT haplotype was associated with a decreased CRC risk (HR = 0.26, 95% CI = 0.11-0.59). However, no significant interaction was observed between TP53 polymorphisms and lifestyle factors.

Conclusion: The study results revealed that the rs1042522 genotype with the C allele and the rs12947788 genotype with the T allele in TP53 were associated with a decreased CRC risk in patients with Lynch syndrome in Taiwan.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167354PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131981PMC
July 2017

Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells.

PLoS One 2016 18;11(8):e0161299. Epub 2016 Aug 18.

Department of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Background: Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity.

Methods: We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit.

Results: MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors.

Conclusions: These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161299PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990200PMC
July 2017

A Comprehensive Evaluation of NIPAM Polymer Gel Dosimeters on Three Orthogonal Planes and Temporal Stability Analysis.

PLoS One 2016 18;11(5):e0155797. Epub 2016 May 18.

3D Printing Medical Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Polymer gel dosimeters have been proven useful for dose evaluation in radiotherapy treatments. Previous studies have demonstrated that using a polymer gel dosimeter requires a 24 h reaction time to stabilize and further evaluate the measured dose distribution in two-dimensional dosimetry. In this study, the short-term stability within 24 h and feasibility of N-isopropylacrylamide (NIPAM) polymer gel dosimeters for use in three-dimensional dosimetry were evaluated using magnetic resonance imaging (MRI). NIPAM gels were used to measure the dose volume in a clinical case of intensity-modulated radiation therapy (IMRT). For dose readouts, MR images of irradiated NIPAM gel phantoms were acquired at 2, 5, 12, and 24 h after dose delivery. The mean standard errors of dose conversion from using dose calibration curves (DRC) were calculated. The measured dose volumes at the four time points were compared with those calculated using a treatment planning system (TPS). The mean standard errors of the dose conversion from using the DRCs were lower than 1 Gy. Mean pass rates of 2, 5, 12, and 24 h axial dose maps calculated using gamma evaluation with 3% dose difference and 3 mm distance-to-agreement criteria were 83.5% ± 0.9%, 85.9% ± 0.6%, 98.7% ± 0.3%, and 98.5% ± 0.9%, respectively. Compared with the dose volume histogram of the TPS, the absolute mean relative volume differences of the 2, 5, 12, and 24 h measured dose volumes were lower than 1% for the irradiated region with an absorbed dose higher than 2.8 Gy. It was concluded that a 12 h reaction time was sufficient to acquire accurate dose volume using the NIPAM gels with MR readouts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871428PMC
July 2017

Association between polymorphisms of APE1 and OGG1 and risk of colorectal cancer in Taiwan.

World J Gastroenterol 2016 Mar;22(12):3372-80

Ching-Yu Lai, Chih-Ching Yeh, School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei 11031, Taiwan.

Aim: To evaluate the effects of OGG1 (Ser326Cys, 11657A/G, and Arg154His) and APE1 (Asp148Glu, and T-656G) polymorphisms on colorectal cancer (CRC) risk.

Methods: We enrolled 727 cases newly diagnosed with colorectal adenocarcinoma and 736 age- and sex-matched healthy controls from a medical center in Taiwan. Genomic DNA isolated from the buffy coat was used for genotyping through polymerase chain reaction. Unconditional logistic regressions were used for calculating ORs and 95%CIs to determine the association between the genetic polymorphisms and CRC risk. Haplotype frequencies were estimated using PHASE software. Moreover, stratification analyses on the basis of sex, age at diagnosis, and tumor subsite and stage were performed.

Results: The CRC risk was higher in patients with the OGG1 326Ser/Cys + Cys/Cys genotype (OR = 1.38, 95%CI: 1.03-1.85, P = 0.030), particularly high in patients with stage III + IV cancer (OR = 1.48, 95%CI: 1.03-2.13) compared with patients with the Ser/Ser genotype. In addition, OGG1 11657G allele carriers had a 41% reduced CRC risk among stage 0-II patients (OR = 0.59, 95%CI: 0.35-0.98). The CRC risk was significantly higher among females with the APE1 Glu allele (OR = 1.41, 95%CI: 1.02-1.96). The APE1 148Glu/-656G haplotype was also associated with a significant CRC risk in females (OR = 1.36, 95%CI: 1.03-1.78).

Conclusion: OGG1 and APE1 polymorphisms are associated with stage- and sex-specific risk of CRC in the Taiwanese population.
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http://dx.doi.org/10.3748/wjg.v22.i12.3372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806195PMC
March 2016

Bone Marrow Stromal Antigen 2 Is a Novel Plasma Biomarker and Prognosticator for Colorectal Carcinoma: A Secretome-Based Verification Study.

Dis Markers 2015 1;2015:874054. Epub 2015 Oct 1.

Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.

Background: The cancer cell secretome has been recognized as a valuable reservoir for identifying novel serum/plasma biomarkers for different cancers, including colorectal cancer (CRC). This study aimed to verify four CRC cell-secreted proteins (tumor-associated calcium signal transducer 2/trophoblast cell surface antigen 2 (TACSTD2/TROP2), tetraspanin-6 (TSPAN6), bone marrow stromal antigen 2 (BST2), and tumor necrosis factor receptor superfamily member 16 (NGFR)) as potential plasma CRC biomarkers.

Methods: The study population comprises 152 CRC patients and 152 controls. Target protein levels in plasma and tissue samples were assessed by ELISA and immunohistochemistry, respectively.

Results: Among the four candidate proteins examined by ELISA in a small sample set, only BST2 showed significantly elevated plasma levels in CRC patients versus controls. Immunohistochemical analysis revealed the overexpression of BST2 in CRC tissues, and higher BST2 expression levels correlated with poorer 5-year survival (46.47% versus 65.57%; p = 0.044). Further verification confirmed the elevated plasma BST2 levels in CRC patients (2.35 ± 0.13 ng/mL) versus controls (1.04 ± 0.03 ng/mL) (p < 0.01), with an area under the ROC curve (AUC) being 0.858 comparable to that of CEA (0.867).

Conclusion: BST2, a membrane protein selectively detected in CRC cell secretome, may be a novel plasma biomarker and prognosticator for CRC.
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http://dx.doi.org/10.1155/2015/874054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606116PMC
July 2016

Nephrotoxic Polypharmacy and Risk of Contrast Medium-Induced Nephropathy in Hospitalized Patients Undergoing Contrast-Enhanced CT.

AJR Am J Roentgenol 2015 Oct;205(4):703-8

4 Department of Radiology, College of Medicine, National Taiwan University, Department of Medical Imaging, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei 100, Taiwan.

Objective: For unknown reasons, there is discordance among previous reports with regard to the association of contrast medium (CM) with nephropathy and the incidence of nephropathy after contrast-enhanced CT. This study aimed to determine the frequency of and possible factors related to CM-induced nephropathy in hospitalized patients, with an emphasis on detailing coprescriptions with nephrotoxic potential.

Materials And Methods: Of 1378 inpatients who underwent CT, 208 (15.1%) met the inclusion criteria: receipt of IV iodinated CM and baseline serum creatinine level obtained within 45 days before and within 2 weeks after CT. Patient demographics, clinical characteristics, comorbidity, nephrotoxic comedications (nine classes of drugs), and type of CM administered were retrospectively reviewed. Relationships between CM-induced nephropathy (serum creatinine level increase ≥ 25% or ≥ 0.5 mg/dL after CT) and risk factors were assessed by stepwise multivariate logistic regression.

Results: The cohort of 208 subjects had a high number of comorbidities (mean [± SD], 5.8 ± 3.5 diagnoses) and a high rate of receiving nephrotoxic comedications (45.2%). CM-induced nephropathy was detected in 27 (13.0%) patients. Concurrent use of four nephrotoxic agents (odds ratio [OR], 26.250; 95% CI, 3.673-233.993) was the most influential factor associated with CM-induced nephropathy; other predictors included preexisting renal disease (OR, 8.218; 95% CI, 1.622-42.357), baseline serum creatinine level less than 0.7 or greater than or equal to 1.3 mg/dL (OR, 3.463; 95% CI, 1.341-9.025), and hemoglobin level less than 9.3 g/dL (OR, 3.141; 95% CI, 1.087-8.946).

Conclusion: Among the known risk factors, such as preexisting renal disease, high serum creatinine level, and low hemoglobin level, a statistically significant association was identified between CM-induced nephropathy and concurrent receipt of four nephrotoxic medications. Relevant preventive measures are warranted for individuals at risk, especially hospitalized patients receiving multiple nephrotoxic medications who require contrast-enhanced CT.
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http://dx.doi.org/10.2214/AJR.15.14329DOI Listing
October 2015

Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome.

PLoS One 2015 8;10(6):e0130018. Epub 2015 Jun 8.

School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan; Department of Public Health, China Medical University, Taichung, Taiwan.

Background And Aim: Lynch syndrome, caused by germline mutations in mismatch repair genes, is a predisposing factor for colorectal cancer (CRC). This retrospective cohort study investigated the risk factors associated with the development of CRC in patients with MLH1 and MSH2 germline mutations.

Methods: In total, 301 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between the risk factors and CRC development. A robust sandwich covariance estimation model was used to evaluate family dependence.

Results: Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09-2.34); however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41-0.88). The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16-2.55) and 0.54 (95% CI = 0.34-0.83) among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07-2.27) than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06-6.58) compared with those with blood group type O.

Conclusion: The present study revealed that Hakka ethnicity, manual occupation, and blood group type B were associated with an increased CRC risk, whereas regular physical activity was associated with a decreased CRC risk in MLH1 and MSH2 germline mutation carriers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130018PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460082PMC
April 2016

Culture supernatants of different colon cancer cell lines induce specific phenotype switching and functional alteration of THP-1 cells.

Cell Immunol 2014 Jul 11;290(1):107-15. Epub 2014 Jun 11.

Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung & Chang Gung University, College of Medicine, Keelung, Taiwan. Electronic address:

We developed an in vitro model to evaluate the effect of products secreted from different colorectal cancer (CRC) cell lines on specific phenotypic switching and functional alterations in THP-1 cells. We co-cultured the human monocytic cell line, THP-1, or phorbol-12-myristate-13-acetate (PMA)-treated THP-1 cells, (THP-1p), with supernatants from either the HT-29 (Dukes' B), HCT-15 (Dukes' C), or Colo205 (Dukes' D) cell lines, and assessed the cells for macrophage differentiation. The surface marker and cytokine profiles suggested that secreted CRC factors differentiated THP-1 cells into a "mixed" M1/M2 phenotype, although HT-29 and Colo205 supernatants induced THP-1p cells into predominantly M1-like macrophages and M2-like macrophages, respectively. Further, all three CRC supernatants enhanced the phagocytic capacity and migration of THP-1 and THP-1p cells, altering their phenotype to a more M2-kind. Therefore, different CRC cell lines induced specific phenotype switching and functional polarization of THP-1 cells.
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http://dx.doi.org/10.1016/j.cellimm.2014.05.015DOI Listing
July 2014

Tumor site- and stage-specific associations between allelic variants of glutathione S-transferase and DNA-repair genes and overall survival in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy.

PLoS One 2013 23;8(7):e69039. Epub 2013 Jul 23.

Department of Public Health, College of Public Health, China Medical University, Taichung City, Taiwan.

Introduction: Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST) and DNA-repair genes and overall survival (OS) in CRC patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy.

Material And Methods: We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis.

Results: The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR  =1.38, 95% CI  =1.02-1.87), and rectal cancer patients had the poorest survival among them (HR  =1.87, 95% CI  =1.18-2.95). A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR  =1.69, 95% CI  =1.06-2.71), compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR  =2.60, 95% CI  =1.19-5.71) and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR  =2.77, 95% CI  =1.25-6.17).

Conclusion: The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site- and/or stage-dependent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720885PMC
March 2014

Associations between genetic polymorphisms of epidermal growth factor receptor (EGFR) and survival of colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy.

Ann Surg Oncol 2013 Dec 26;20 Suppl 3:S599-606. Epub 2013 Jun 26.

Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.

Purpose: This retrospective cohort study investigated the association between epidermal growth factor receptor (EGFR) polymorphisms and clinical outcomes in colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU)-based chemotherapy.

Methods: We genotyped 3 EGFR polymorphisms including R497K, G-216T, and the (CA)n repeat, among 499 histologically confirmed CRC patients who had received 5-FU-based chemotherapy after surgery between 1995 and 2001. Survival analyses of EGFR polymorphisms were performed by the log rank test and Kaplan-Meier curves. We used the Cox proportional hazard model to evaluate the association between EGFR genotypes and clinical outcomes. Stratification analysis by gender, tumor stage, and subsite were also carried out.

Results: CRC patients with the EGFR (CA)n L/L genotype compared to those with the S/S+S/L genotype had a significantly better overall survival (L, ≥ 20 repeats; S, <20 repeats) (hazard ratio (HR) 0.74; 95 % confidence interval (CI) 0.57-0.95), particularly for patients who were male (HR 0.63; 95 % CI 0.44-0.90), who had stage IV disease (HR 0.70; 95 % CI 0.49-0.99), and who had rectal cancer (HR 0.62; 95 % CI 0.42-0.92). Better survival was prominent among patients with the combined genotypes of EGFR (CA)n L/L, G-216T G/G, and R497K K/K (HR 0.51; 95 % CI 0.30-0.87), compared to those with the most common genotypes of the EGFR (CA)n S allele, G-216T G/G, and R497K R allele.

Conclusions: EGFR polymorphisms can serve as prognostic predictors for CRC patients receiving 5-FU-based chemotherapy.
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http://dx.doi.org/10.1245/s10434-013-3069-4DOI Listing
December 2013

Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations.

PLoS One 2013 14;8(6):e65578. Epub 2013 Jun 14.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.

Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15-2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06-2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient's response to radiotherapy/chemo-radiotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683038PMC
January 2014

Association analysis of ACE and ACTN3 in elite Caucasian and East Asian swimmers.

Med Sci Sports Exerc 2013 May;45(5):892-900

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Purpose: Polymorphic variation in the angiotensin-converting enzyme (ACE) and α-actinin-3 (ACTN3) genes has been reported to be associated with endurance and/or power-related human performance. Our aim was to investigate whether polymorphisms in ACE and ACTN3 are associated with elite swimmer status in Caucasian and East Asian populations.

Methods: ACE I/D and ACTN3 R577X genotyping was carried out for 200 elite Caucasian swimmers from European, Commonwealth, Russian, and American cohorts (short and middle distance, ≤400 m, n = 130; long distance, >400 m, n = 70) and 326 elite Japanese and Taiwanese swimmers (short distance, ≤100 m, n = 166; middle distance, 200-400 m, n = 160). Genetic associations were evaluated by logistic regression and other tests accommodating multiple testing adjustment.

Results: ACE I/D was associated with swimmer status in Caucasians, with the D allele being overrepresented in short-and-middle-distance swimmers under both additive and I-allele-dominant models (permutation test P = 0.003 and P = 0.0005, respectively). ACE I/D was also associated with swimmer status in East Asians. In this group, however, the I allele was overrepresented in the short-distance swimmer group (permutation test P = 0.041 and P = 0.0098 under the additive and the D-allele-dominant models, respectively). ACTN3 R577X was not significantly associated with swimmer status in either Caucasians or East Asians.

Conclusions: ACE I/D associations were observed in these elite swimmer cohorts, with different risk alleles responsible for the associations in swimmers of different ethnicities. The functional ACTN3 R577X polymorphism did not show any significant association with elite swimmer status, despite numerous previous reports of associations with "power/sprint" performance in other sports.
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http://dx.doi.org/10.1249/MSS.0b013e31827c501fDOI Listing
May 2013

The mitochondrial DNA Northeast Asia CZD haplogroup is associated with good disease-free survival among male oral squamous cell carcinoma patients.

PLoS One 2012 21;7(11):e49684. Epub 2012 Nov 21.

Graduate Institute of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan.

Reprogramming of energy metabolism in cancer cells has been directly/indirectly linked to mitochondria and mitochondrial functional defects and these changes seem to contribute to the development and progression of cancer. Studies have indicated that mitochondrial DNA haplogroups are associated with risk in relation to various diseases including cancer. However, few studies have examined the effect of haplogroups on cancer prognosis outcome. In order to explore the role of haplogroups on oral squamous cell carcinoma (OSCC) prognosis, the mitochondrial genomes of 300 male OSCC patients were comprehensively analyzed by direct sequencing. They were then haplotyped and grouped into four major geographic haplogroups, namely the East Asia AN, Southeast Asia RBF, East Asia MGE and Northeast Asia CZD groups. The Kaplan-Meier plot analysis indicated that individuals who were members of the CZD haplogroup showed a significant association with better disease-free survival (DFS) than the other three haplogroups and this phenomenon still existed after adjusting for tumor stage, differentiation and age at diagnosis (hazard ratio=0.55; 95% CI=0.36-0.84). In addition, an interaction between membership of the RBF haplogroup and radiotherapy/chemo-radiotherapy in DFS was also identified. The results strongly support the hypothesis that an individual's haplogroup, by defining their genomic background, plays an important role in tumor behavior and mitochondrially-targeted anticancer drugs are promising future therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049684PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504154PMC
May 2013

Low-dose zoledronic acid reduces spinal cord metastasis in pulmonary adenocarcinoma with neuroendocrine differentiation.

Anticancer Drugs 2012 Oct;23(9):970-8

Department of Internal Medicine, Division of Hemato-oncology, Chang Gung Memorial Hospital, College of Medicine, Keelung & Chang Gung University, Keelung, Taiwan.

Zoledronic acid (ZOL), a nitrogen-containing compound, is effective in the treatment of skeletal disorders, but its long-term use in high doses gives rise to complications such as osteonecrosis. We aimed to investigate the effect of low-dose ZOL on the expression of the neural cell adhesion molecule (NCAM), which may be correlated with tumor growth and spinal cord metastasis in lung adenocarcinoma with neuroendocrine differentiation. First, we used the small hairpin RNA technique to directly knock down NCAM expression in cells of a murine lung adenocarcinoma line, line 1 cells, and found that the tumor cells generated showed lower invasive capacity, slower tumor growth, and lesser tendency for spinal cord metastasis than control cells. Further, ZOL decreased NCAM expression and invasiveness in line 1 tumor cells in vitro. Line 1/lacZ cells, a stable clone tagged with the lacZ gene, were introduced into mice, followed by ZOL treatment (1 μg/kg/weekly). Low-dose ZOL significantly reduced spinal cord metastasis probably through reduced NCAM expression in vivo. These findings indicated that NCAM is involved in tumor growth and spinal cord metastasis of lung adenocarcinoma with neuroendocrine differentiation. Treatment with low-dose ZOL can reduce NCAM expression that may contribute toward reduced spinal cord metastasis, suggesting that NCAM is an alternative therapeutic target and that the low-dose ZOL treatment protocol is a reasonable approach for its treatment.
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http://dx.doi.org/10.1097/CAD.0b013e328355f0ecDOI Listing
October 2012

A novel thin NIPAM gel cassette dosimeter for photon-beam radiotherapy.

PLoS One 2012 12;7(3):e31836. Epub 2012 Mar 12.

Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Beitun District, Taichung City, Taiwan, Republic of China.

The response of thin polymer gel cassettes (called NIPAM gels) to ionizing radiation was investigated in this study. The NIPAM gels were prepared from gelatin, N-isopropyl acrylamide, tetrakis (hydroxymethyl) phosphoniumchloride, and N,N'-methylene-bis-acrylamide. Gel cassettes were irradiated in a phantom using a linear accelerator, and the polymerization morphology of irradiated NIPAM gel was characterized using scanning electron microscopy. The dose-response sensitivity of the NIPAM gels was evaluated using the differences in optical densities. The optical densities were obtained using a computer-controlled CCD camera that was connected to a planar illumination source for acquisition of optical transmission images. The central axis depth dose profiles of the phantom were extracted, and a comparison with ionization chamber measurements demonstrated similarities in profiles. The sensitivity, linearity of the response, accuracy, and reproducibility of the polymer gel cassettes were acceptable. However, the profiles of the half-blocked field irradiation showed no significant dispersion in the visible region. This study also extensively investigated the spatial stability of the NIPAM gel. The results showed that the gel cassette response remains stable for up to three months after irradiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031836PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299645PMC
August 2012

Relationships between serum HER2 ECD, TIMP-1 and clinical outcomes in Taiwanese breast cancer.

World J Surg Oncol 2012 Feb 17;10:42. Epub 2012 Feb 17.

Graduate Institute of Clinical Medical Sciences,Chang Gung University, Tao-Yuan, Taiwan.

Background: Serum levels of the extracellular domain of HER2/neu (HER2 ECD) have been demonstrated to be associated with clinical outcomes. A disintegrin and metalloproteinase-10, a sheddase of HER2/neu, can drive cancer progression and its activity is inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1). However, elevated TIMP-1 expression has been associated with a poor prognosis of breast cancer. Therefore, this study was performed to explore the relationships between serum HER2 ECD, TIMP-1 and clinical outcomes.

Methods: One hundred and eighty-five female breast cancer patients, who received curative mastectomy without neo-adjuvant chemotherapy at Chang-Gung Memorial Hospital, were recruited with informed consent for this study. Pre-operative serum levels of HER2 ECD and TIMP-1 were measured using an enzyme-linked immunosorbent assay.

Results: Twenty-three cases (12.4%) were classified HER2 ECD positive. HER2 ECD positivity was significantly associated with age, lymph node involvement, histological grade, estrogen receptor status, progesterone receptor status, tissue HER2/neu overexpression, and disease-free survival (DFS). In an age, stage, ER and HER2/neu status matched subgroup (N = 41), the serum level of TIMP-1 was significantly associated with HER2 ECD positivity and DFS.

Conclusions: A high serum TIMP-1 was significantly associated with HER2 ECD positivity and a poorer DFS among Taiwanese primary breast cancer patients with HER2 overexpression.
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http://dx.doi.org/10.1186/1477-7819-10-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312842PMC
February 2012

Cyclin D1 overexpression and poor clinical outcomes in Taiwanese oral cavity squamous cell carcinoma.

World J Surg Oncol 2012 Feb 16;10:40. Epub 2012 Feb 16.

Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.

Background: Cyclin D1 gene regulates cell cycle and plays an important role in the tumorigenesis of human cancers. The association between cyclin D1, clinicopathologic parameters and prognosis in oral cavity squamous cell carcinoma (OSCC) is inconclusive.

Methods: A total of 264 male OSCCs were examined for cyclin D1 protein expression using immunohistochemistry (IHC). The expression levels of cyclin D1 were defined as overexpression when more than 10% of tumor cells displayed nuclear staining with moderate to strong intensity.

Results: Overexpression of cyclin D1 was found in 97 (36.7%) OSCCs. Cyclin D1 protein overexpression was significantly associated with lymph node metastasis (P = 0.002), tumor cell differentiation (P = 0.031) and tumor stage (P = 0.051), but not associated with age onset, cigarette smoking, alcohol drinking, or areca quid chewing. Overexpression of cyclin D1 was also significantly associated with poor clinical outcomes in terms of disease-free survival (DFS, P = 0.002) and overall survival (OS, P < 0.001). The effects of cyclin D1 protein overexpression on DFS (hazard ratio (HR) = 1.540; 95% confidence interval (CI), 1.068 - 2.222) and OS (HR = 1.702; 95% CI, 1.168 - 2.480) were still existed after adjusting for clinicopathological parameters (such as age, primary tumor status, tumor cell differentiation, and lymph node metastasis) using logistic multivariate analysis.

Conclusion: Cyclin D1 protein worked as an independent prognostic factor and can be as a biomarker for the aggressiveness of OSCC.
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http://dx.doi.org/10.1186/1477-7819-10-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312822PMC
February 2012

ACE I/D, ACTN3 R577X, PPARD T294C and PPARGC1A Gly482Ser polymorphisms and physical fitness in Taiwanese late adolescent girls.

J Physiol Sci 2012 Mar 14;62(2):115-21. Epub 2012 Jan 14.

Graduate Institute of Biomedical Sciences, Chang Gung University, Tao-Yuan, Taiwan.

Physical performance of youth is influenced by various factors, including body composition, biological maturity status, level of habitual physical activity, and muscular strength. Muscular strength has been largely attributed to genetic effects. To exclude possible confounding effects from various acquired factors, this study examined the relationships between polymorphisms of the angiotensin-converting enzyme (ACE), α-actinin-3 (ACTN3), peroxisome proliferator-activated receptor delta (PPARD), and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A) genes and performance as measured by six fitness tests (handgrip strength of dominant hand, 30- and 60-s sit-ups, standing long jump, 60-m dash, and 800-m run) in 170 sedentary adolescent girls with the adjustment of anthropometric characteristics. We found that subjects with the ACE DD genotype were significantly heavier than those with I allele, while those with the ACTN3 RR genotype had higher fat-free mass percentage (FFM%) than those with the XX genotype. In addition, those with the PPARD TT genotype were significantly taller, heavier, and had a greater FFM than those with the CC genotype. Subjects with the ACE DD, ACTN3 RR and PPARD TC genotype had better performance in handgrip strength, 30- and 60-s sit-up tests, and standing long jump, respectively, when individual gene was analyzed independently after adjusting anthropometric characteristics. In the gene combination analysis, subjects with ACE DD, ACTN3 RR and PPARD TT genotype had significantly greater performance in handgrip strength. Overall, the results indicate that the genes studied have a modest influence on individual performance as assessed by specific fitness and strength tests in female late adolescents.
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http://dx.doi.org/10.1007/s12576-011-0189-0DOI Listing
March 2012

Appropriateness of ambulatory prescriptions in Taiwan: translating claims data into initiatives.

Int J Clin Pharm 2012 Feb 3;34(1):72-80. Epub 2011 Dec 3.

Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan, ROC.

Background: Appropriate prescribing is fundamental to successful pharmacotherapy. The status of current ambulatory medication practices in medicine and pharmacy would be better understood through an analysis of community pharmacy prescription claims.

Objective: The aims of the study were to investigate patterns of the types of prescriptions claimed by community pharmacies, undetected prescription errors by community pharmacists, and associated factors of prescription errors.

Setting: A population-based claims database of prescriptions dispensed by community pharmacies in Taiwan.

Methods: Ambulatory prescriptions were randomly sampled and reassessed for prescribing appropriateness by medical center pharmacists using explicit criteria. Demographics of patients, physicians, care facilities, and prescription/dispensing details were assessed and used to identify associated factors for prescription errors using descriptive analyses as well as logistic regression.

Main Outcome Measures: Erroneous prescriptions prescribed by physicians, and dispensed and claimed through community pharmacies.

Results: The study included analyses of 3065 prescriptions dispensed in community pharmacies resulting from 1003 patient visits, mostly to physician or dental clinics (99.5%). Prescribing characteristics, patterns, and examples of prescription errors are described. Prescription errors were identified in 18.3% (n = 560) of prescriptions and 34.9% (n = 350) of patient visits. Potential prescribing errors included errors of omission (25.5%), errors of commission (53.4%), and others (21.1%). The top three errors were incorrect dosage (27.5%), missing indication (23.6%), and insufficient or unavailable drug information (18.9%). Drugs most frequently associated with prescription errors included antihistamines, hormones, and gastrointestinal agents. Prescription were also higher in the central and eastern regions of Taiwan. Pediatricians accounted for a disproportionate number of prescription errors.

Conclusion: Prescription errors are prevalent in ambulatory care in Taiwan, and differential practice standards exist between community and hospital services. This disparity needs to be reconciled by pertinent initiatives to enhance community-hospital and pharmacist-general practitioner communication and interprofessional educational efforts to improve medication use and safety.
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http://dx.doi.org/10.1007/s11096-011-9589-8DOI Listing
February 2012

Identification of secretory gelsolin as a plasma biomarker associated with distant organ metastasis of colorectal cancer.

J Mol Med (Berl) 2012 Feb 14;90(2):187-200. Epub 2011 Oct 14.

Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China.

Colorectal cancer (CRC) is one of the most common cancers worldwide. More than half of all CRC patients will develop metastases, which represents the major cause of death for CRC patients. CRC metastases confined in other organs are potentially resectable, and patients who receive curative resections appear to have better outcomes. Thus, the early detection of metastasis in CRC patients could improve their survival rate after curative surgery. Here, we report the use of Cy-dye labeling combined with multi-dimensional fractionation and mass spectrometry as a proteomics-based approach for identifying CRC metastasis-associated biomarker(s) in plasma samples collected from three CRC patients upon diagnosis of their primary and metastatic tumors. Among the eight identified proteins, we used Western blot analysis and an in-house-developed ELISA to validate the increased plasma levels of one, secretory (plasma) gelsolin, in >80% of CRC patients with distal metastases in a larger sample cohort (32 patients). We also found a significant increase of secretory gelsolin in plasma samples of stage IV versus stages I-III CRC patients before treatment. Furthermore, immunohistochemistry showed that secretory gelsolin was highly overexpressed in CRC tissue specimens compared to adjacent normal tissues, and a cell model study showed that secretory gelsolin may help regulate CRC cell migration.
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http://dx.doi.org/10.1007/s00109-011-0817-4DOI Listing
February 2012

Comparison between two different methods of immobilizing NGF in poly(DL-lactic acid-co-glycolic acid) conduit for peripheral nerve regeneration by EDC/NHS/MES and genipin.

J Biomed Mater Res A 2011 Dec 27;99(4):576-85. Epub 2011 Sep 27.

Department of Chemical Engineering, National Chung Hsing University, Taichung, Taiwan, Republic of China.

For surface modification and nerve regeneration, chitosan, followed by nerve growth factor (NGF), was immobilized onto the interior surface of poly (lactic acit-co-glycolic) conduits, using EDC/NHS/MES system (EDCs) and genipin (GP). Four new conduits were, therefore, obtained and named by immobilizing order-EDCs/EDCs, GP/EDCs, EDCs/GP, and GP/GP groups. The immobilized methods used were evaluated and compared, respectively. The researchers found that the EDCs- and GP-cross-linked chitosan displayed higher hydrophilic than pure poly (DL-lactic acid-co-glycolic acid) (PLGA) in water contact angle experiment, which meant the cell compatibility was improved by the modification. Scanning electron microscopic observations revealed that the GP-cross-linking of chitosan greatly improved cell compatibility while cultured rat PC12 cells were flatter and more spindle-shaped than EDCs-cross-linked chitosan. The results concerning the GP-cross-linked chitosan revealed significant proliferation of the seeded cells relative to pure PLGA films, as determined by counting cells and MTT assay. The NGF was released from the modified conduits in two separate periods--an initial burst in 5 days and then slow release from day 10 to day 40. The GP/EDCs group had the highest NGF value among all groups after the 5th day. Finally, the controlled-release conduits were used to bridge a 10 mm rat sciatic nerve defect. Six weeks following implantation, morphological analysis revealed the highest numbers of myelinated axons in the midconduit and distal regenerated nerve in GP/EDCs group. Therefore, the results confirm that GP/EDCs groups with good cell compatibility and effective release of NGF can considerably improve peripheral nerve regeneration.
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http://dx.doi.org/10.1002/jbm.a.33157DOI Listing
December 2011

Relationship between epidermal growth factor receptor gene copy number and protein expression in oral cavity squamous cell carcinoma.

Oral Oncol 2012 Jan 9;48(1):67-72. Epub 2011 Aug 9.

Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients.
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http://dx.doi.org/10.1016/j.oraloncology.2011.06.511DOI Listing
January 2012

Clinical significance of preoperative squamous cell carcinoma antigen in oral-cavity squamous cell carcinoma.

Laryngoscope 2011 May;121(5):971-7

Department of Otolaryngology, Chang Gung Memorial Hospital and Chang Gung University, Taiwan, ROC.

Objectives/hypothesis: Previous studies have demonstrated a relationship between elevated serum squamous cell carcinoma (SCC) antigen (SCC-Ag) levels and shorter survival in cancer patients. Few studies, however, have investigated the role of serum SCC-Ag levels in oral SCC (OSCC). This study was conducted to analyze the relationship between preoperative SCC-Ag levels, clinicopathologic factors, and prognosis in OSCC patients.

Study Design: Retrospective case-control study.

Methods: Seventy-nine OSCC patients from Chang Gung Memorial Hospital were retrospectively recruited between April 2008 and March 2010. Serum SCC-Ag levels were measured preoperatively.

Results: An SCC-Ag level of ≥2.0 ng/mL was significantly associated with the pathologic tumor status (P < .001), pathologic nodal status (P = .037), lymph node extracapsular spread (P = .016), and tumor depth (>10 mm vs. ≤10 mm, P < .001). It was not significantly associated with histologic differentiation (P = 1.000). A univariate analysis revealed that positivity for SCC-Ag was associated with disease-free survival (DFS) (P = .034) and overall survival (OS) (P < .001). In SCC-Ag-positive patients, the distant metastatic rate was higher than in the SCC-Ag-negative patients (P = .053).

Conclusions: This study demonstrated that preoperative SCC-Ag is a good marker of pathologic lymph node metastasis, an advanced tumor stage, and a higher rate of distant metastasis. The preoperative SCC-Ag level is a potential prognostic indicator in DFS and OS, but studies with a longer follow-up period are needed to confirm these results.
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http://dx.doi.org/10.1002/lary.21721DOI Listing
May 2011
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