bluuebunny/crossref_metadata_2025 huggingface dataset:
Recreational Physical Activity Modifies the Association Between a Common GH1 Polymorphism and Colorectal Cancer Risk
Authors: Khoury-Shakour Sana , Gruber Stephen B. , Lejbkowicz Flavio , Rennert Hedy S. , Raskin Leon , Pinchev Mila , Rennert Gad
Published: December 2008

Growth hormone may be associated with the development of colorectal cancer directly and/or indirectly via increased serum level of insulin-like growth factor (IGF-I). Regular physical activity can decrease insulin resistance and modulates IGF-I production. A common polymorphism in the GH1 gene, rs2665802, was previously shown to be associated with lower IGF-I levels and decreased colorectal cancer (CRC) risk. We investigated the association of this polymorphism and physical activity with colorectal cancer risk in a case-control study.

Methods: The analysis includes 3,041 (1,402 cases and 1,639 controls) participants in the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study in Northern Israel. Analysis was carried out separately in two sets. The first set included 1,248 subjects (625 cases, 623 controls), and the second validation set consisted of 1,793 subjects (777 cases, 1,016 controls).

Results: No association was found between the studied polymorphism and CRC risk. However, evaluation of gene environment interactions revealed an interaction between leisure time physical activity and the GH1 polymorphism, which was consistent in both sets (Pinteraction = 0.005). The genotype AA was associated with decreased risk of CRC among individuals who did not engage in any such activity (odds ratio, 0.76; 95% confidence interval, 0.52-0.98), whereas the same genotype was marginally associated with increased risk among individuals who reported physical activity (odds ratio, 1.38; 95% confidence interval, 0.98-1.94).

Conclusions: We found that the A allele of the rs2665802 polymorphism is associated with reduced risk of CRC only among physically inactive individuals, indicating an interaction between physical activity and the growth hormone/IGF-I system. A replication of the observed findings and further investigation of the underlying mechanism is warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3314–8)
Green Tea, Soy, and Mammographic Density in Singapore Chinese Women
Authors: Wu Anna H. , Ursin Giske , Koh Woon-Puay , Wang Renwei , Yuan Jian-Min , Khoo Kei-Siong , Yu Mimi C.
Published: December 2008

There is increasing evidence from observational studies that breast cancer risk is inversely associated with soy and green tea consumption. We investigated the effects of these two dietary agents on mammographic density, a well-established biomarker for breast cancer risk, in a cross-sectional analysis of mammograms and validated food frequency questionnaires from 3,315 Chinese women in Singapore. Percent mammographic density (PMD) was assessed using a reproducible computer-assisted method. We used generalized linear models to estimate PMD by intake of soy, green tea, and black tea while adjusting for potential confounders. Daily green tea drinkers showed statistically significantly lower PMD (19.5%) than non-tea drinkers (21.7%; P = 0.002) after adjusting for relevant covariates. This difference in PMD between daily green tea drinkers and non-tea drinkers remained statistically significant after adjustment for soy (P = 0.002); the effect was more apparent among lower soy consumers (Q1-Q3; 21.9% versus 19.4%; P = 0.002) than in higher (Q4) consumers (20.9% versus 19.5%; P = 0.32). Black tea intake was unrelated to PMD. Only among postmenopausal women who reported very high soy intake (Q4) compared with those with less soy intake was there any association noted between PMD and soy intake (18.9% versus 20.5%; P = 0.035). Following adjustment for green tea intake, the association between soy and PMD was no longer statistically significant (P = 0.52). Our findings suggest that both regular green tea and high soy intake may have beneficial effects on the breast; the effect of green tea on PMD may be stronger than the effect of soy. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3358–65)
A Liquid Chromatography-Mass Spectrometry Method for the Simultaneous Measurement of 15 Urinary Estrogens and Estrogen Metabolites: Assay Reproducibility and Interindividual Variability
Authors: Falk Roni T. , Xu Xia , Keefer Larry , Veenstra Timothy D. , Ziegler Regina G.
Published: December 2008

Background: Accurate, reproducible, and sensitive measurements of endogenous estrogen exposure and individual patterns of estrogen metabolism are needed for etiologic studies of breast cancer. We have developed a high-performance liquid chromatography-tandem mass spectrometry method to quantitate simultaneously 15 urinary estrogens and estrogen metabolites (EM): estrone; estradiol; 3 catechol estrogens; 5 estrogens in the 16α pathway, including estriol; and 5 methoxy estrogens.

Methods: Overnight urines were obtained from 45 participants. For the reproducibility study, two blinded, randomized aliquots from 5 follicular and 5 luteal premenopausal women, 5 naturally postmenopausal women, and 5 men were assayed in each of four batches. Assay coefficients of variation and intraclass correlation coefficients were calculated with ANOVA models. Data from the additional 25 participants were added to compare EM levels by menstrual/sex group and assess interindividual variability.

Results: For each EM, overall coefficients of variation were ≤10%. Intraclass correlation coefficients for each menstrual/sex group were generally ≥98%. Although geometric mean EM concentrations differed among the four groups, rankings were similar, with estriol, 2-hydroxyestrone, estrone, estradiol, and 16-ketoestradiol accounting for 60% to 75% of total urinary EM. Within each group, interindividual differences in absolute concentrations were consistently high; the range was 10- to 100-fold for nearly all EM.

Conclusion: Our high-performance liquid chromatography-tandem mass spectrometry method for measuring 15 urinary EM is highly reproducible, and the range of EM concentrations in each menstrual/sex group is quite large relative to assay variability. Whether these patterns persist in blood and target tissues awaits further development and application of this method. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3411–8)
Polymorphisms in Mitochondrial Genes and Prostate Cancer Risk
Authors: Wang Liang , McDonnell Shannon K. , Hebbring Scott J. , Cunningham Julie M. , St Sauver Jennifer , Cerhan James R. , Isaya Grazia , Schaid Daniel J. , Thibodeau Stephen N.
Published: December 2008

The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and implicated in many diseases, including cancer. To evaluate whether mitochondria-related genes are associated with increased risk for prostate cancer, we genotyped 24 single-nucleotide polymorphisms (SNP) within the mitochondrial genome and 376 tagSNPs localized to 78 nuclear-encoded mitochondrial genes. The tagSNPs were selected to achieve ≥80% coverage based on linkage disequilibrium. We compared allele and haplotype frequencies in ∼1,000 prostate cancer cases with ∼500 population controls. An association with prostate cancer was not detected for any of the SNPs within the mitochondrial genome individually or for 10 mitochondrial common haplotypes when evaluated using a global score statistic. For the nuclear-encoded genes, none of the tagSNPs were significantly associated with prostate cancer after adjusting for multiple testing. Nonetheless, we evaluated unadjusted P values by comparing our results with those from the Cancer Genetic Markers of Susceptibility (CGEMS) phase I data set. Seven tagSNPs had unadjusted P ≤ 0.05 in both our data and in CGEMS (two SNPs were identical and five were in strong linkage disequilibrium with CGEMS SNPs). These seven SNPs (rs17184211, rs4147684, rs4233367, rs2070902, rs3829037, rs7830235, and rs1203213) are located in genes MTRR, NDUFA9, NDUFS2, NDUFB9, and COX7A2, respectively. Five of the seven SNPs were further included in the CGEMS phase II study; however, none of the findings for these were replicated. Overall, these results suggest that polymorphisms in the mitochondrial genome and those in the nuclear-encoded mitochondrial genes evaluated are not substantial risk factors for prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3558–66)
Methylation Array Analysis of Preoperative and Postoperative Saliva DNA in Oral Cancer Patients
Authors: Viet Chi T. , Schmidt Brian L.
Published: December 2008

Purpose: To perform methylation array analysis of 807 cancer-associated genes using tissue and saliva of oral squamous cell carcinoma (OSCC) patients with the objective of identifying highly methylated gene loci that hold diagnostic and predictive value as a biomarker.

Experimental Design: We did the methylation array on DNA extracted from preoperative saliva, postoperative saliva, and tissue of 13 patients with OSCC, and saliva of 10 normal subjects. We identified sites that were highly methylated in the tissue and preoperative saliva samples but not methylated in the postoperative saliva samples or in normal subjects.

Results: High quality DNA was obtained and the methylation array was successfully run on all samples. We identified significant differences in methylation patterns between the preoperative and postoperative saliva from cancer patients. We established a gene classifier consisting of 41 gene loci from 34 genes that showed methylation in preoperative saliva and tissue but were not methylated in postoperative saliva or normal subjects. Gene panels of 4 to 10 genes were constructed from genes in the classifier. The panels had a sensitivity of 62% to 77% and a specificity of 83% to 100% for OSCC.

Conclusions: We report methylation array analysis of 807 cancer-associated genes in the saliva of oral cancer patients before and after oral cancer resection. Our methylation biomarker approach shows the proof of principle that methylation array analysis of saliva can produce a set of cancer-related genes that are specific and can be used as a composite biomarker for the early detection of oral cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3603–11)
Effect of Insulin-Like Growth Factor Gene Polymorphisms Alone or In Interaction with Diabetes on the Risk of Pancreatic Cancer
Authors: Suzuki Hideo , Li Yanan , Dong Xiaoqun , Hassan Manal M. , Abbruzzese James L. , Li Donghui
Published: December 2008

Insulin-like growth factors (IGF) have been associated with risk of common human cancers, but the association between IGFs and pancreatic cancer risk is unclear. To determine whether genetic variations of IGF modify pancreatic cancer risk, we compared the frequency of six single nucleotide polymorphisms of IGF1 and IGF2 in a large-scale case control study. Single nucleotide polymorphisms were investigated using the TaqMan method in 892 patients with pancreatic ductal adenocarcinoma and 783 healthy controls who were recruited from The University of Texas M. D. Anderson Cancer Center from 2000 to 2007. Cases and controls were frequency matched by age (±5 years), race, and sex. Risk factor information was collected using direct interviews. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional multivariate logistic regression models. A haplotype of IGF1 gene containing the 3′-UTR Ex4 -177 G>C G allele had a significantly lower frequency in cases (0.027) than in controls (0.041; P = 0.039). A statistically significant joint effect of the IGF1 3′-UTR Ex4 -177 G>C C allele and diabetes on pancreatic cancer risk was observed. The OR (95% CI) were 1.07 (0.81-1.42), 2.12 (1.53-2.93), and 5.69 (2.63-12.3) for individuals who had the CC/CG genotype alone, diabetes alone, or both factors, respectively, compared with subjects without either of the two factors with adjustment for other risk factors. The IGF2 3′-UTR Ex4 -233C>T TT genotype was significantly associated with a reduced risk of pancreatic cancer (OR = 0.07; 95% CI = 0.01-0.57; P = 0.013). The polymorphic variants of the IGF genes may serve as a susceptibility factor for pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3467–73)
Triple-Negative Breast Cancer and Obesity in a Rural Appalachian Population
Authors: Vona-Davis Linda , Rose David P. , Hazard Hannah , Howard-McNatt Marissa , Adkins Farrell , Partin Jessica , Hobbs Gerald
Published: December 2008

Background: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States.

Methods: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status. Body mass index was calculated and a value of ≥30 was considered indicative of obesity.

Results: Triple-negative tumors occurred in 117 (18.9%) of the 620 patients, most often in association with invasive ductal carcinomas. Patients with triple-negative tumors were younger than those with other receptor types, 44.5% and 26.7%, respectively, being diagnosed at age <50 years (P = 0.0004). The triple-negative tumors were larger (P = 0.0003), most notably in the younger women, but small tumors (<2.0 cm) were more often accompanied by lymph node metastases. Obesity was present in 49.6% of those with triple-negative tumors but in only 35.8% of those with non-triple-negative tumors (P = 0.0098). Lymph node metastases were more frequently associated with T2 tumors in obese patients (P = 0.032) regardless of their receptor status.

Conclusions: Triple-negative breast cancers within a White, socioeconomically deprived, population occurred in younger women, with later stage at diagnosis, and in association with obesity, which itself has been associated with a poor prognosis in breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3319–24)
Human Papillomavirus-16 Modifies the Association between Fruit Consumption and Head and Neck Squamous Cell Carcinoma
Authors: Meyer Mara S. , Applebaum Katie M. , Furniss C. Sloane , Peters Edward S. , Luckett Brian G. , Smith Judith F. , Bryan Janine , McClean Michael D. , Marsit Carmen , Kelsey Karl T.
Published: December 2008

Human papillomavirus-16 (HPV-16) is a risk factor for head and neck squamous cell carcinoma (HNSCC). HPV-positive cancers have distinct disease cofactors and improved survival following treatment. There is conflicting evidence of a protective association of fruit consumption with HNSCC. As HPV-related disease is clinically distinct, we investigated whether the association between fruit consumption and HNSCC risk was modified by exposure to HPV-16. We studied 270 cases and 493 controls with fruit intake information and known HPV-16 antibody status. Cases were identified at nine Boston-area medical facilities between 1999 and 2003. Controls were randomly selected from the greater population and frequency matched to cases by age, gender, and town of residence. Controlling for age, gender, race, smoking, alcohol, total energy intake, body mass index, and education, the seronegative individuals had a significantly lower risk of HNSCC with increasing total fruit consumption [odds ratio (OR)tertile 2, 0.60; 95% confidence interval (95% CI), 0.38-0.95; ORtertile 3, 0.57; 95% CI, 0.35-0.95] and specifically increasing citrus fruit consumption (ORtertile 2, 0.61; 95% CI, 0.39-0.97; ORtertile 3, 0.59; 95% CI, 0.37-0.96). However, among the seropositive, risk increased with greater fruit consumption (ORtertile 2, 2.27; 95% CI, 0.92-5.58; ORtertile 3, 1.40; 95% CI, 0.55-3.59) and citrus fruit consumption (ORtertile 2, 3.35; 95% CI, 1.36, 8.24; ORtertile 3, 3.15; 95% CI, 1.23-8.08). This interaction was statistically significant (P < 0.05), showing that fruit consumption was associated with a reduced HNSCC risk among HPV-16-seronegative individuals but an increased HNSCC risk among the HPV-16-seropositive individuals. These findings suggest that dietary factors dramatically alter the pattern of occurrence of HPV-associated HNSCC and show that viral-related disease is clinically and etiologically distinct. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3419–26)
Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Authors: Stevens Victoria L. , Bierut Laura J. , Talbot Jeffrey T. , Wang Jen C. , Sun Juzhong , Hinrichs Anthony L. , Thun Michael J. , Goate Alison , Calle Eugenia E.
Published: December 2008

Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the α5 nicotinic receptor in heavy smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3517–25)
Missense Polymorphisms in Matrix Metalloproteinase Genes and Skin Cancer Risk
Authors: Nan Hongmei , Niu Tianhua , Hunter David J. , Han Jiali
Published: December 2008

Matrix metalloproteinases (MMP) degrade various components of the extracellular matrix, and their overexpression has been implicated in tumor progression. Nonsynonymous single nucleotide polymorphisms (SNPs) lead to amino acid substitutions that can alter the function of the encoded protein. We evaluated the associations of six nonsynonymous SNPs in the MMP3, MMP8, and MMP9 genes with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 normal controls. We observed that the MMP9 Arg668Gln polymorphism was significantly associated with a decreased risk of SCC. Compared with the Arg/Arg group, the multivariate odds ratio was 0.67 (95% confidence interval, 0.47-0.97) for the Arg/Gln group and 0.21 (95% confidence interval, 0.05-0.97) for the Gln/Gln group (Ptrend = 0.004). We did not observe any association of this SNP with the risks of melanoma and basal cell carcinoma. No associations were found for other SNPs with skin cancer risk. This study provides evidence for the contribution of the MMP9 Arg668Gln to SCC development. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3551–7)
No Association between Common Chemokine and Chemokine Receptor Gene Variants and Prostate Cancer Risk
Authors: Petersen Desiree C. , Severi Gianluca , Hoang Hoa N. , Padilla Emma J.D. , Southey Melissa C. , English Dallas R. , Hopper John L. , Giles Graham G. , Hayes Vanessa M.
Published: December 2008

There is growing evidence that inflammation and infection play important roles in the etiology of prostate cancer. As the chemokine network is directly involved in inflammation and infectious diseases, we tested for an association between six common putative functional variants and prostate cancer risk using an Australian case-control study. We measured CCL5 −403G>A, CXCL12 +801G>A, CCR2V64I (G>A), CCR5Δ32, CX3CR1V249I (G>A), and CX3CR1T280M (C>T) for 815 cases and 738 controls. Of these, only CXCL12 +801G>A has previously been tested and found to be associated with prostate cancer risk. We found no significant associations with prostate cancer risk (all P > 0.4). All per allele odds ratios ranged from 0.96 (95% confidence intervals, 0.80-1.16) to 1.06 (95% confidence intervals, 0.90-1.23). This suggests that these common chemokine and chemokine receptor variants do not play a major, if any, role in susceptibility to prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3615–7)
Delphinidin Attenuates Neoplastic Transformation in JB6 Cl41 Mouse Epidermal Cells by Blocking Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling
Authors: Kang Nam Joo , Lee Ki Won , Kwon Jung Yeon , Hwang Mun Kyung , Rogozin Evgeny A. , Heo Yong-Seok , Bode Ann M. , Lee Hyong Joo , Dong Zigang
Published: December 2008

Recent studies suggest that anthocyanidins play a pivotal role in the chemopreventive effects of fruits and vegetables. However, the underlying molecular mechanisms and cellular targets remain unknown. Neoplastic transformation of cells and inflammation are considered to be major events contributing to carcinogenesis. Here, we report that delphinidin, a major dietary anthocyanidin, inhibits tumor promoter–induced transformation and cyclooxygenase-2 (COX-2) expression in JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells by directly targeting Raf and mitogen-activated protein kinase kinase (MEK). Delphinidin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced neoplastic transformation and COX-2 expression at both the protein and transcriptional levels. The activation of activator protein-1 and nuclear factor-κB induced by TPA was dose dependently inhibited by delphinidin treatment. Delphinidin strongly suppressed Raf1 and MEK1 kinase activities and subsequently attenuated TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase (ERK), p90RSK, and MSK. Although delphinidin suppressed ERK and c-Jun NH2-terminal kinase activities, it was more effective at inhibiting Raf1 or MEK1 activities. Pull-down and competition assays revealed that delphinidin binds with Raf1 or MEK1 noncompetitively with ATP. Delphinidin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor and H-Ras, both of which are involved in the activation of Raf/MEK/ERK signaling. Together, these findings suggested that the targeted inhibition of Raf1 and MEK activities and COX-2 expression by delphinidin contribute to the chemopreventive potential of fruits and vegetables.
Identification of Mucin Depleted Foci in the Human Colon
Authors: Femia Angelo Pietro , Giannini Augusto , Fazi Marilena , Tarquini Elena , Salvadori Maddalena , Roncucci Luca , Tonelli Francesco , Dolara Piero , Caderni Giovanna
Published: December 2008

Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the β-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm2) and at a much lower density in CRC patients (average of 0.0006 lesions/cm2). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.
A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy
Authors: Kim Woo-Young , Chang Dong Jo , Hennessy Bryan , Kang Hae Jin , Yoo Jakyung , Han Seung-Ho , Kim Yoo-Shin , Park Hyun-Ju , Geo Seung-Yong , Mills Gordon , Kim Kyu-Won , Hong Waun Ki , Suh Young-Ger , Lee Ho-Young
Published: December 2008

The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat shock protein-90 and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues (SH-02, SH-03, SH-09, SH-14, and SH-15) and compared them with the parent compound and each other for structural and biochemical features; solubility; and antiproliferative effects on normal, premalignant, and malignant human bronchial epithelial (HBE) and non–small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1α as potently as did deguelin. Reverse-phase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including heat shock protein-90 clients and proteins involved in the phosphoinositide 3-kinase/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson's disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 μmol/L) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).
Colorectal Polyps: A Clinical, Endoscopic and Pathologic Study in Iranian Children
Authors: Haghi Ashtiani Mohammad Taghi , Monajemzadeh Maryam , Motamed Farzaneh , Moradi Tabriz Hedieh , Mahjoub Fatemeh , Karamian Hamid , Najafi Sani Mehri , Khatami Gholam Reza , Khodadad Ahmad , Farahmand Fatemeh , Fallahi Gholam Hossein
Published: December 2008

Objective: To study the clinical presentation, histology and colonoscopic features of lower gastrointestinal polyps in Iranian children. Material and Methods: Medical reports of children with colorectal polyps were retrospectively reviewed from 1996 to 2005 at the Children’s Medical Center Hospital, Iran. A total of 563 cases were studied. Data related to age, sex, family history, signs and symptoms, the size, location, polyp types and associated lesions were collected and analyzed. Results: The mean age of children was 5.66 ± 2.88 years (range 2 months to 17 years), with a male-to-female ratio of 1.61:1.0. The highest incidence was between ages 2 and 10 years (85.1%). Rectal bleeding was the presenting symptom in 78.5% cases. The polyps were solitary in 94% of cases. A majority of polyps (86.3%) were juvenile and 86.7% located in the rectosigmoid area. Three percent of cases had a positive family history. One case of Turcot syndrome was also identified. Conclusion: Juvenile polyps remain the most common polyps in Iranian children. Although the presence of a solitary polyp in the rectosigmoid colon is more prevalent, in a significant number of cases they are multiple and located in proximal parts. Polyps must be removed even when asymptomatic because of their probable neoplastic potential.
Giant Sigmoid Diverticulum: A Case Report
Authors: Mohammad Ali I. , Ben-Nakhi Abdel-Mohsen , Khoursheed Mousa
Published: December 2008

Objectives: To report an unusual presentation of a giant sigmoid diverticulum in the colon. Clinical Presentation and Intervention: The patient presented with an abdominal mass, altered bowel habits, and increasing weight. The provisional diagnosis was made by barium enema and CT scan. The patient underwent laparotomy, revealing a perforated giant sigmoid diverticulum that was excised using Hartmann’s procedure. The perforation could have been precipitated by the barium enema study. The histopathology of the resected specimen revealed giant sigmoid diverticulum with no evidence of malignancy. Conclusion: CT scan was adequate for diagnosis of the suspected giant sigmoid diverticulum. Surgical intervention was successfully used to excise the diverticulum.
Determination of Adrenergic and Imidazoline Receptor Involvement in Augmentation of Morphine and Oxycodone Analgesia by Clonidine and BMS182874
Authors: Gulati Anil , Bhalla Shaifali , Matwyshyn George , Zhang Zhong , Andurkar Shridhar V.
Published: December 2008

Background: Numerous agents have been demonstrated to potentiate morphine analgesia, including clonidine (α2-adrenergic and I1-imidazoline receptor agonist) and BMS182874 (endothelin-A, ETA, receptor antagonist). ET has been shown to affect pharmacological actions of clonidine. The present study was conducted to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the augmentation of morphine and oxycodone analgesia by clonidine and BMS182874. Methods: Analgesic tail flick latencies were measured in rats at various time intervals, and were converted to AUC₀→360 min. Results: It was found that clonidine produced mild analgesia, while BMS182874 did not have any analgesic effect. Clonidine (p = 0.015) and BMS182874 (p = 0.009) enhanced the analgesic action of morphine and oxycodone. Clonidine- or BMS182874-induced increases in the analgesic effect of morphine were not inhibited by idazoxan (I1-imidazoline receptor antagonist), while increases in the analgesic effect of oxycodone were blocked by idazoxan. Yohimbine (α2-adrenergic receptor antagonist) blocked the clonidine-induced potentiation of analgesic effect of morphine (p = 0.036) and oxycodone (p = 0.0167), while yohimbine did not affect BMS182874-induced potentiation of the analgesic effect of morphine or oxycodone. Conclusions: This is the first report showing that clonidine and BMS182874 augment oxycodone analgesia. Results suggest that α2-adrenergic receptors are involved in clonidine-induced, but not in the BMS182874-induced, potentiation of the analgesic effects of morphine or oxycodone, and that I1-imidazoline receptors are involved in the potentiation of oxycodone analgesia, but not morphine analgesia, by clonidine and BMS182874.
Breast Cancer Resistance Protein and P-Glycoprotein Expression in Patients with Newly Diagnosed and Therapy-Refractory Ulcerative Colitis Compared with Healthy Controls
Authors: Gutmann Heike , Hruz Petr , Zimmermann Christian , Straumann Alexander , Terracciano Luigi , Hammann Felix , Lehmann Frank , Beglinger Christoph , Drewe Juergen
Published: December 2008

Aims: Efflux transporters such as breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (Pgp; MDR1/ABCB1) are protecting the enterocytes from potentially toxic compounds. Both transporters have been reported to be downregulated in patients with active ulcerative colitis (UC). The aim of this study was to evaluate transporter expression in both unaffected and inflamed mucosa of patients with active UC, in drug-naïve and treated patients with UC and compare the results with transporter expression in healthy subjects. Methods: Transporter expression was determined with real-time RT-PCR (TaqMan) in inflamed and unaffected mucosa of newly diagnosed (n = 12) and therapy-refractory (n = 11) patients with UC. Expression levels were compared with UC patients in remission (n = 11) and control subjects (n = 26). BCRP and Pgp expression was evaluated by immunohistochemistry. Results: Compared with unaffected mucosa, BCRP expression was significantly reduced in inflamed mucosa of newly diagnosed drug-naïve patients with UC (expression reduced to 30%) as well as in patients not responding to treatment (reduced to 25%) with either 5-aminosalicylates (n = 7) or prednisone (n = 4). Unaffected mucosa of UC patients showed comparable transporter expression to unaffected mucosa of control subjects. MDR1 expression depicts a similar pattern. Protein staining for Pgp and BCRP was significantly reduced in the inflamed mucosa of patients with active UC. Conclusions: Expression of both efflux transporters BCRP and MDR1 is reduced, but only in inflamed tissue of patients with active UC. Transporter expression in unaffected mucosa of patients with active UC is comparable to healthy controls. The data suggest that the inflammatory process is responsible for the reduced levels. A major role in the pathogenesis of UC is unlikely.
Bedside Algorithms for Managing Desaturation in Ventilated Preterm Infants: A Randomised Crossover Trial
Authors: Wilkinson Dominic J. , Andersen Chad C.
Published: December 2008

Background: Desaturation episodes occur commonly in ventilated preterm infants. It is not clear how best to reduce the frequency and duration of desaturation. Objective: To study the management of desaturation episodes using two bedside algorithms. Methods: Using a randomised crossover design, over two 8-hour periods, episodes were managed with either titration of inspired oxygen (FiO2) alone or adjustment to ventilator pressures with smaller changes to FiO2. Functional oxygen saturation and heart rate were downloaded from the bedside monitor. Ventilator parameters were captured simultaneously. The primary outcome was the proportion of time in the target saturation band. A cumulative measure of desaturation and oversaturation was also developed to compare groups. Results: 33 studies were performed in 23 ventilated infants <32 weeks’ gestation. Infants spent 51% of the time with saturations in the target band. There were more changes in ventilator pressure when the second algorithm was in use. There was no difference in the proportion of time within the saturation target, in the frequency and duration of desaturation episodes, or in the desaturation/oversaturation index between the two algorithms. Conclusions: Further study is required to determine the best way to manage desaturation in ventilated preterm infants.
A Critique of Clinical Guidelines for Detection of Individuals with Chronic Kidney Disease
Authors: Connolly John O. , Woolfson Robin G.
Published: December 2008

Chronic kidney disease (CKD) and its association with cardiovascular mortality is increasingly regarded as a global public health problem. International efforts to combat this ‘epidemic’ have led to fundamental changes not only in the way we measure renal function but also how we classify and manage CKD. Clinical guidelines have established the use of estimated glomerular filtration rate (eGFR) and Kidney Disease Outcomes Quality Initiative classification of kidney disease as the cornerstones of CKD detection. The introduction of these guidelines in routine practice has had considerable impact on the large number of patients newly labelled with a chronic disease. However, it is far from clear that these patients with low GFR have intrinsic kidney disease and the vast majority will not develop end-stage renal failure. Furthermore, there is a lack of evidence that identification of low GFR can usefully be used to screen populations either for metabolic complications of kidney disease or cardiovascular risk.
An Unusual Cause of Low-Flow, Low-Gradient Severe Aortic Stenosis: Left-to-Right Shunt due to Atrial Septal Defect
Authors: Ennezat Pierre Vladimir , Juthier Francis , Vincentelli André , Pibarot Philippe , Maréchaux Sylvestre
Published: December 2008

Paradoxical low-flow, low-gradient severe aortic valve stenosis (AVS) may occur despite preserved left-ventricular (LV) ejection fraction in older females with marked LV concentric remodeling and small LV cavity size or in patients with coexisting severe mitral regurgitation. This report illustrates the case of a paradoxical low-flow, low-gradient severe AVS despite preserved LV function related to an ostium secundum atrial septal defect (ASD) in a patient presenting with congestive heart failure. Left-to-right shunt ASD that lowers forward LV stroke volume translating into lower transvalvular gradients is an underrecognized cause of paradoxical low-flow, low-gradient severe AVS. In addition, if not detected before open-heart surgery, ASD may result in cardiopulmonary bypass life-threatening complications.
Absence of Pathognomonic or Inflammatory Patterns in Cardiac Biopsies From Patients With Brugada Syndrome
Authors: Zumhagen Sven , Spieker Tilmann , Rolinck Julia , Baba Hideo A. , Breithardt Günter , Böcker Werner , Eckardt Lars , Paul Matthias , Wichter Thomas , Schulze-Bahr Eric
Published: December 2008

Background—

Brugada syndrome (BrS) is characterized by the presence of coved ST-segment elevations in the right precordial leads (so-called type I ECG) and additional clinical features. Caused by cardiac ion channel gene mutations, BrS may be associated with ventricular and atrial conduction disturbances as well as ventricular fibrillation. Recent studies have discussed whether BrS is merely a primary electric disorder or whether inflammatory or other histopathologic abnormalities in the right ventricle (RV) underlie the ECG phenotype.

Methods and Results—

We retrospectively analyzed BrS biopsy samples from 21 unrelated patients for histopathologic abnormalities (hypertrophy, fibrosis, inflammation, fatty tissue) together with the patients’ clinical, genetic, and imaging data. Eleven patients (52%) had normal RV imaging (by angiography, echocardiography, or cardiac MRI). Results of myocardial biopsies were normal in 3 patients (14%) and revealed mostly moderate abnormalities in the others. Four patients (19%) had predominant fatty tissue in the RV myocardium. Using immunohistochemistry and conventional tissue staining, we could not detect inflammatory tissue changes, an observation compatible with the clinical absence of signs for myocarditis.

Conclusions—

Imaging and histopathologic evaluation may detect moderate but uncharacteristic cardiac abnormalities in patients with BrS. None of the patients had arrhythmogenic RV cardiomyopathy or overt myocarditis. Only in a small subset did predominant histopathologic abnormalities in the biopsy samples of the RV outflow tract occur that could provide a link to the ECG phenotype. A variety of mechanisms, including genetic and structural RV alterations, may underlie the Brugada ECG phenotype.
Novel Contact Force Sensor Incorporated in Irrigated Radiofrequency Ablation Catheter Predicts Lesion Size and Incidence of Steam Pop and Thrombus
Authors: Yokoyama Katsuaki , Nakagawa Hiroshi , Shah Dipen C. , Lambert Hendrik , Leo Giovanni , Aeby Nicolas , Ikeda Atsushi , Pitha Jan V. , Sharma Tushar , Lazzara Ralph , Jackman Warren M.
Published: December 2008

Background—

An open-irrigated radiofrequency (RF) ablation catheter was developed to measure contact force (CF). Three optical fibers measure microdeformation of the catheter tip. The purpose of this study was to (1) validate the accuracy of CF sensor (CFS) (bench test); and (2) determine the relationship between CF and tissue temperatures, lesion size, steam pop, and thrombus during RF ablation using a canine thigh muscle preparation.

Methods and Results—

CFS measurements (total 1409) from 2 catheters in 3 angles (perpendicular, parallel, and 45�) were compared with a certified balance (range, 0 to 50 g). CFS measurements correlated highly (
R
2
≥0.988; mean error, ≤1.0 g). In 10 anesthetized dogs, a skin cradle over the thigh muscle was superfused with heparinized blood at 37�C. A 7F catheter with 3.5-mm saline-irrigated electrode and CFS (Endosense) was held perpendicular to the muscle at CF of 2, 10, 20, 30, and 40 g. RF was delivered (n=100) for 60 seconds at 30 or 50 W (irrigation 17 or 30 mL/min). Tissue temperature (3 and 7 mm depths), lesion size, thrombus, and steam pop increased significantly with increasing CF at each RF power. Lesion size was greater with applications of lower power (30 W) and greater CF (30 to 40 g) than at high power (50 W) with lower CF (2 to 10 g).

Conclusions—

This novel ablation catheter, which accurately measures CF, confirmed CF is a major determinant of RF lesion size. Steam pop and thrombus incidence also increases with CF. CFS in an open-irrigated ablation catheter that may optimize the selection of RF power and application time to maximize lesion formation and reduce the risk of steam pop and thrombus.
A Study of Functional Anatomy of Aortic-Mitral Valve Coupling Using 3D Matrix Transesophageal Echocardiography
Authors: Veronesi Federico , Corsi Cristiana , Sugeng Lissa , Mor-Avi Victor , Caiani Enrico G. , Weinert Lynn , Lamberti Claudio , Lang Roberto M.
Published: December 2008

Background—

Mitral and aortic valves are known to be coupled via fibrous tissue connecting the two annuli. Previous studies evaluating this coupling have been limited to experimental animals using invasive techniques. The new matrix array transesophageal transducer provides high-resolution real-time 3D images of both valves simultaneously. We sought to develop and test a technique for quantitative assessment of mitral and aortic valve dynamics and coupling.

Methods and Results—

Matrix array transesophageal (Philips iE33) imaging was performed in 24 patients with normal valves who underwent clinically indicated transesophageal echocardiography. Custom software was used to detect and track the mitral and aortic annuli in 3D space throughout the cardiac cycle, allowing automated measurement of changes in mitral and aortic valve morphology. Mitral annulus surface area and aortic annulus projected area changed reciprocally over time. Mitral annulus surface area was 8.0�2.1 cm
2
at end-diastole and decreased to 7.7�2.1 cm
2
in systole, reaching its maximum (10.0�2.2 cm
2
) at mitral valve opening. Aortic annulus projected area was 4.1�1.2 cm
2
at end-diastole, then increased during isovolumic contraction reaching its maximum (4.8�1.3 cm
2
) in the first third of systole and its minimum (3.6�1.0 cm
2
) during isovolumic relaxation. The angle between the mitral and aortic annuli was maximum (136�13�) at end-diastole and decreased to its minimum value (129�11�) during systole.

Conclusions—

This is the first study to report quantitative 3D assessment of the mitral and aortic valve dynamics from matrix array transesophageal images and describe the mitral-aortic coupling in a beating human heart. This ability may have impact on patient evaluation for valvular surgical interventions and prosthesis design.
Texture Segmentation by Genetic Programming
Authors: Song Andy , Ciesielski Vic
Published: December 2008

This paper describes a texture segmentation method using genetic programming (GP), which is one of the most powerful evolutionary computation algorithms. By choosing an appropriate representation texture, classifiers can be evolved without computing texture features. Due to the absence of time-consuming feature extraction, the evolved classifiers enable the development of the proposed texture segmentation algorithm. This GP based method can achieve a segmentation speed that is significantly higher than that of conventional methods. This method does not require a human expert to manually construct models for texture feature extraction. In an analysis of the evolved classifiers, it can be seen that these GP classifiers are not arbitrary. Certain textural regularities are captured by these classifiers to discriminate different textures. GP has been shown in this study as a feasible and a powerful approach for texture classification and segmentation, which are generally considered as complex vision tasks.
Model Representation of Local Air Quality Characteristics
Authors: Mueller Stephen F.
Published: December 2008

Daily (24 h) and hourly air quality data at several sites are used to examine the performance of the fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5)–Community Multiscale Air Quality Model (CMAQ) system over a 3-month period in 2003. A coarse (36 km) model grid was expected to provide relatively poor performance for ozone and comparatively better performance for fine particles, especially the more regional sulfate and carbonaceous aerosols. However, results were different from this expectation. Modeling showed significant skill for ozone at several locations but very little skill for particulate species. Modeling did poorly identifying surface wind directions associated with the highest and lowest pollutant exposures at most sites, although results varied widely by location. Model skill appeared to be better for ozone when spatial–temporal (S–T) patterns were examined, due in part to the ability of the model to reproduce much of the temporal variance associated with the diurnal photochemical cycle. At some sites the modeling even performed well in replicating the directional variability of hourly ozone despite relatively low spatial resolution. MM5–CMAQ spatial (directional) representation of 24-h-average particulate data was not good in most cases, but model skill improved somewhat when hourly data were examined. Modeling exhibited skill for sulfate at only one of nine sites using 24-h data averaged by daily resultant wind direction, at two of six sites when hourly data were averaged by direction, and at four of six sites when the combined spatial and temporal variance of sulfate was examined. Results were generally poorer for total carbon aerosol mass and total mass of particulate matter with diameter of less than 2.5 μm (PM2.5). The primary result of this study is that an S–T analysis of pollutant patterns reveals model performance insights that cannot be realized by only examining model error statistics as is typically done for regulatory applications. Use of this S–T analysis technique is recommended for better understanding model performance during longer simulation periods, especially when using grids of finer spatial resolution for applications supporting local air quality management studies. Of course, using this approach will require measuring semicontinuous fine particle data at more sites and for longer periods.
Development of a Coupled Regional Model and Its Application to the Study of Interactions between the West African Monsoon and the Eastern Tropical Atlantic Ocean
Authors: Hagos Samson M. , Cook Kerry H.
Published: December 2008

A regional ocean–atmosphere coupled model is developed for climate variability and change studies. The model allows dynamic and thermodynamic interactions between the atmospheric boundary layer and an ocean mixed layer with spatially and seasonally varying depth prescribed from observations. The model reproduces the West African monsoon circulation as well as aspects of observed seasonal SST variations in the tropical Atlantic. The model is used to identify various mechanisms that couple the West African monsoon circulation with eastern Atlantic SSTs. By reducing wind speeds and suppressing evaporation, the northward migration of the ITCZ off the west coast of Africa contributes to the modeled spring SST increases. During this period, the westerly monsoon flow is expanded farther westward and moisture transport on to the continent is enhanced. Near the end of the summer, upwelling associated with this enhanced westerly flow as well as the solar cycle lead to the seasonal cooling of the SSTs. Over the Gulf of Guinea, the acceleration of the southerly West African monsoon surface winds contributes to cooling of the Gulf of Guinea between April and July by increasing the entrainment of cool underlying water and enhancing evaporation.