bluuebunny/crossref_metadata_2025 huggingface dataset:
Birth Characteristics, Maternal Reproductive History, and the Risk of Infant Leukemia: A Report from the Children's Oncology Group
Authors: Spector Logan G. , Davies Stella M. , Robison Leslie L. , Hilden Joanne M. , Roesler Michelle , Ross Julie A.
Published: January 2007

Leukemias with MLL gene rearrangements predominate in infants (<1 year of age), but not in older children, and may have a distinct etiology. High birth weight, higher birth order, and prior fetal loss have, with varying consistency, been associated with infant leukemia, but no studies have reported results with respect to MLL status. Here, we report for the first time such an analysis. During 1999 to 2003, mothers of 240 incident cases (113 MLL+, 80 MLL−, and 47 indeterminate) and 255 random digit dialed controls completed a telephone interview. Odds ratios and 95% confidence intervals for quartile of birth weight, birth order, gestational age, maternal age at delivery, prior fetal loss, pre-pregnancy body mass index, and weight gain during pregnancy were obtained using unconditional logistic regression; P for linear trend was obtained by modeling continuous variables. There was a borderline significant linear trend of increasing birth weight with MLL+ (P = 0.06), but not MLL− (P = 0.93), infant leukemia. Increasing birth order showed a significant inverse linear trend, independent of birth weight, with MLL+ (P = 0.01), but not MLL− (P = 0.18), infant leukemia. Other variables of interest were not notably associated with infant leukemia regardless of MLL status. This investigation further supports the contention that molecularly defined subtypes of infant leukemia have separate etiologies. (Cancer Epidemiol Biomarkers Prev 2007;16(1):128–34)
Effect of the Women's Health Initiative Study Publication on Hormone Replacement Therapy Use among Women Who Have Undergone BRCA1/2 Testing
Authors: Dorval Michel , Vallée Marie-Hélène , Plante Marie , Chiquette Jocelyne , Gaudet Michel ,   the Interdisciplinary Health Research International Team on Breast Cancer Susceptibility, Simard Jacques ,   the Interdisciplinary Health Research International Team on Breast Cancer Susceptibility
Published: January 2007

Background: Since the publication, in July 2002, of the Women's Health Initiative (WHI) study, use of hormone replacement therapy (HRT) has decreased substantially in the general population. However, little is known about the effect of WHI study results on HRT use among women at high risk of breast cancer. The purpose of this study is to compare HRT use, prepublication versus postpublication of the WHI study, among women tested for BRCA1/2 mutations.

Methods: Participants were >35 years of age and had received their result of genetic testing (delivered within the interdisciplinary research program Interdisciplinary Health Research International Team on Breast Cancer Susceptibility), no later than February 28, 2005. HRT use was reported in self-administered questionnaires, 1 year after result disclosure. Women returning their questionnaire before July 17, 2002 were classified as pre-WHI, whereas those returning it after October 15, 2002 comprised the post-WHI group.

Results: Four hundred fifty-seven women (199 and 258 in the pre-WIH and post-WHI groups, respectively) were included in this analysis. Globally, there was no difference in HRT use between prepublication and postpublication of the WHI study (8% and 11%, respectively; prevalence ratio, 0.74; 95% confidence interval, 0.43-1.28). However, noncarriers of the familial mutation were less likely to use HRT after publication of the WHI study results (9%) than before (21%; P = 0.03).

Conclusions: Overall, HRT use among women tested for BRCA1/2 mutations is relatively low and apparently uninfluenced by the WHI study findings. However, the HRT use reduction among noncarriers is similar to that of women in the general population and consistent with the Canadian Cancer Society's recent HRT use recommendations. (Cancer Epidemiol Biomarkers Prev 2007;16(1):157–60)
Genetic Polymorphisms in Folate Metabolism and the Risk of Stomach Cancer
Authors: Zhang Fang Fang , Terry Mary Beth , Hou Lifang , Chen Jinbo , Lissowska Jolanta , Yeager Meredith , Zatonski Witold , Chanock Stephen , Morabia Alfredo , Chow Wong-Ho
Published: January 2007

Folate deficiency has been implicated in the etiology of stomach cancer through abnormal DNA methylation and disrupted DNA synthesis and repair. Enzyme-coding genes involved in folate metabolism are often polymorphic. In a population-based study of 305 cases and 427 controls in Warsaw, Poland, we evaluated the risk of stomach cancer in relation to polymorphisms in folate-metabolizing genes, including MTHFR (Ex5+79C>T and Ex8−62A>C), MTR (Ex26−20A>G), and MTRR (Ex2−64A>G, Ex5+123C>T, Ex15+572C>T, Ex15−405A>T, Ex9−85C>T, Ex15−526G>A, and Ex14+14C>T). Polymorphisms in the MTHFR gene were not associated with stomach cancer risk. No notable effect was found for polymorphisms in MTR or MTRR either, although MTR Ex26−20 A>G and MTRR Ex5+123C>T polymorphisms were associated with a borderline increased risk of stomach cancer (MTR Ex26−20A>G, AG/GG versus AA: odds ratio, 1.35; 95% confidence interval, 0.96-1.90; MTRR Ex5+123C>T, CT/TT versus CC: odds ratio, 1.30; 95% confidence interval, 0.93-1.82). We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption. Our study did not identify strong genetic determinants in the folate metabolism pathway for stomach cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):115–21)
Physical Activity and Breast Cancer Risk: The European Prospective Investigation into Cancer and Nutrition
Authors: Lahmann Petra H. , Friedenreich Christine , Schuit A. Jantine , Salvini Simonetta , Allen Naomi E. , Key Tim J. , Khaw Kay-Tee , Bingham Sheila , Peeters Petra H.M. , Monninkhof Evelyn , Bueno-de-Mesquita H. Bas , Wirfält Elisabet , Manjer Jonas , Gonzales Carlos A. , Ardanaz Eva , Amiano Pilar , Quirós José R. , Navarro Carmen , Martinez Carmen , Berrino Franco , Palli Domenico , Tumino Rosario , Panico Salvatore , Vineis Paolo , Trichopoulou Antonia , Bamia Christina , Trichopoulos Dimitrios , Boeing Heiner , Schulz Mandy , Linseisen Jakob , Chang-Claude Jenny , Chapelon Francoise Clavel , Fournier Agnès , Boutron-Ruault Marie-Christine , Tjønneland Anne , Føns Johnson Nina , Overvad Kim , Kaaks Rudolf , Riboli Elio
Published: January 2007

There is convincing evidence for a decreased risk of breast cancer with increased physical activity. Uncertainties remain, however, about the role of different types of physical activity on breast cancer risk and the potential effect modification for these associations. We used data from 218,169 premenopausal and postmenopausal women from nine European countries, ages 20 to 80 years at study entry into the European Prospective Investigation into Cancer and Nutrition. Hazard ratios (HR) from multivariate Cox regression models were calculated using metabolic equivalent value–based physical activity variables categorized in quartiles, adjusted for age, study center, education, body mass index, smoking, alcohol use, age at menarche, age at first pregnancy, parity, current oral contraceptive use, and hormone replacement therapy use. The physical activity assessment included recreational, household, and occupational activities. A total physical activity index was estimated based on cross-tabulation of these separate types of activity. During 6.4 years of follow-up, 3,423 incident invasive breast cancers were identified. Overall, increasing total physical activity was associated with a reduction in breast cancer risk among postmenopausal women (Ptrend = 0.06). Specifically, household activity was associated with a significantly reduced risk in postmenopausal (HR, 0.81; 95% confidence interval, 0.70-0.93, highest versus the lowest quartile; Ptrend = 0.001) and premenopausal (HR, 0.71; 95% confidence interval, 0.55-0.90, highest versus lowest quartile; Ptrend = 0.003) women. Occupational activity and recreational activity were not significantly related to breast cancer risk in both premenopausal and postmenopausal women. This study provides additional evidence for a protective effect of physical activity on breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):36–42)
Obesity Is Negatively Associated with Prostate-Specific Antigen in U.S. Men, 2001-2004
Authors: Werny David M. , Thompson Trevor , Saraiya Mona , Freedman David , Kottiri Benny J. , German Robert R. , Wener Mark
Published: January 2007

Background: Recent studies have shown a negative association between body mass index (BMI) and prostate-specific antigen (PSA), a commonly used serum marker for the detection and diagnosis of prostate cancer. We have examined the association between several anthropometric measures and PSA in a nationally representative sample of men.

Methods: We analyzed data from the 2001-2004 National Health and Nutrition Examination Survey. Participants in this study were men ages ≥40 years without previously diagnosed prostate cancer who had PSA measured. Height, weight, waist circumference, BMI, triceps skinfold, subscapular skinfold, and calculated total body water were examined categorically by quintiles using multiple linear regression models. All tests of significance were two sided.

Results: Among white men, we report a trend for decreasing PSA with increasing weight, BMI, waist circumference, triceps skinfold thickness, and calculated total body water. Among Mexican American men, we found a trend for decreasing PSA with increasing BMI, and among black men we found a trend for decreasing PSA with increasing triceps thickness. None of the interaction terms between race/ethnicity and any of the anthropometric measures were statistically significant. Controlling for age and race/ethnicity in the multiple linear regression model, we found moderate declines in PSA with a 1 SD increase in BMI [5.9% decrease (95% confidence interval, −9.0% to −2.8%) in geometric mean PSA per 5.2-unit increase], weight [5.9% decline (−8.8% to −2.8%) per 17.7-kg increase], waist circumference [6.6% decline (−9.4% to −3.6%) per 13.4-cm increase], triceps skinfold [5.4% decline (−8.9% to −1.8%) per 6.4-mm increase], and calculated total body water [5.7% decline (−8.9% to −2.4%) per 6.5-liter increase].

Conclusion: Our population-based, nationally representative results expand the validity of previous studies on obesity and PSA. Higher weight, BMI, waist circumference, triceps skinfold, and total body water are associated with moderately lower PSA values. A prospective study is needed to verify whether this association affects the accuracy of the PSA test in obese men. (Cancer Epidemiol Biomarkers Prev 2007;16(1):70–6)
Hypermethylation of theBreast Cancer–Associated Gene 1Promoter Does Not Predict Cytologic Atypia or Correlate with Surrogate End Points of Breast Cancer Risk
Authors: Bean Gregory R. , Ibarra Drendall Catherine , Goldenberg Vanessa K. , Baker Joseph C. , Troch Michelle M. , Paisie Carolyn , Wilke Lee G. , Yee Lisa , Marcom Paul K. , Kimler Bruce F. , Fabian Carol J. , Zalles Carola M. , Broadwater Gloria , Scott Victoria , Seewaldt Victoria L.
Published: January 2007

Mutation of the breast cancer–associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide −150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood ≤10: 18%, 2 of 11), hyperplastic (Masood 11-13: 15%, 6 of 41), and atypical cytology (Masood 14-17: 22%, 4 of 18; P = 0.79). BRCA1 promoter hypermethylation was not associated with (a) family history of breast or ovarian cancer or (b) calculated Gail or BRCAPRO risk score. BRCA1 promoter hypermethylation was associated with (a) age (P = 0.028) and (b) the combined frequency of promoter hypermethylation of the retinoic acid receptor-β2 (RARB) gene, estrogen receptor-α (ESR1) gene, and p16 (INK4A) gene (P = 0.003). These observations show that BRCA1 promoter hypermethylation (a) is not associated with breast cancer risk as measured by mathematical risk models and (b) does not predict mammary atypia in RPFNA cytologic samples obtained from high-risk women. (Cancer Epidemiol Biomarkers Prev 2007;16(1):50–6)
Early Detection of Head and Neck Cancer: Development of a Novel Screening Tool Using Multiplexed Immunobead-Based Biomarker Profiling
Authors: Linkov Faina , Lisovich Alex , Yurkovetsky Zoya , Marrangoni Adele , Velikokhatnaya Lyudmila , Nolen Brian , Winans Matthew , Bigbee William , Siegfried Jill , Lokshin Anna , Ferris Robert L.
Published: January 2007

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease that has been linked to altered immune, inflammatory, and angiogenesis responses. A better understanding of these aberrant responses might improve early detection and prognosis of SCCHN and provide novel therapeutic targets. Previous studies examined the role of multiplexed serum biomarkers in small cohorts or SCCHN sera. We hypothesized that an expanded panel comprised of multiple cytokines, chemokines, growth factors, and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. Thus, we evaluated a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple serum biomarkers. Concentrations of 60 cytokines, growth factors, and tumor antigens were measured in the sera of 116 SCCHN patients before treatment (active disease group), 103 patients who were successfully treated (no evidence of disease group), and 117 smoker controls without evidence of cancer. The multimarker panel offering the highest diagnostic power was comprised of 25 biomarkers, including epidermal growth factor, epidermal growth factor receptor, interleukin (IL)-8, tissue plasminogen activator inhibitor-1, α-fetoprotein, matrix metalloproteinase-2, matrix metalloproteinase-3, IFN-α, IFN-γ, IFN-inducible protein-10, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-1α, IL-7, IL-17, IL-1 receptor-α, IL-2 receptor, granulocyte colony-stimulating factor, mesothelin, insulin-like growth factor binding protein 1, E-selectin, cytokeratin-19, vascular cell adhesion molecule, and cancer antigen-125. Statistical analysis using an ADE algorithm resulted in a sensitivity of 84.5%, specificity of 98%, and 92% of patients in the active disease group correctly classified from a cross-validation serum set. The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(1):102–7)
Papillary Thyroid Cancer and Polymorphic Variants in TSHR- and RET-Related Genes: a Nested Case-Control Study within a Cohort of U.S. Radiologic Technologists
Authors: Lönn Stefan , Bhatti Parveen , Alexander Bruce H. , Pineda Marbin A. , Doody Michele M. , Struewing Jeffery P. , Sigurdson Alice J.
Published: January 2007

Several variants in the TSHR and RET signaling pathways genes have been reported to be related to cancer risk. We hypothesized that polymorphic variants in these genes are associated with the risk of papillary thyroid cancer. A nested case-control study was conducted within the U.S. Radiologic Technologists cohort. Eligible validated papillary thyroid cancer cases (n = 167) and frequency-matched (by sex and birth year) controls (n = 491) donated blood for analysis. There were no statistically significant associations between papillary thyroid cancer and 10 selected polymorphic variants in analyses of men and women combined. A borderline significant increasing risk was found for RET G691S (Ptrend = 0.05) and was especially pronounced among young women. For women under 38 years (the median age at diagnosis), the odds ratios were 2.1 (95% confidence interval, 1.2-3.7) for those heterozygous for the RET G691S polymorphism and 3.7 (95% confidence interval, 1.1-11.8) for those who were homozygous (Ptrend = 0.001). Our data provide limited evidence that TSHR- and RET-related genes are related to papillary thyroid cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):174–7)
Incessant Ovulation, Mucin 1 Immunity, and Risk for Ovarian Cancer
Authors: Terry Kathryn L. , Titus-Ernstoff Linda , McKolanis John R. , Welch William R. , Finn Olivera J. , Cramer Daniel W.
Published: January 2007

Background: Risk for ovarian cancer correlates directly with “ovulatory years or cycles” estimated from time not pregnant, breast-feeding, or using oral contraceptives. Recently, we reported that several factors known to reduce ovarian cancer risk may operate by inducing antibodies against mucin 1 (MUC1), a glycoprotein overexpressed in ovarian cancer. Conversely, other events might increase risk by interfering with the development of protective immunity. In this study, we examined whether the total number of ovulatory cycles decreases the likelihood of anti-MUC1 antibodies and provides an immune basis for the association between “incessant ovulation” and ovarian cancer risk.

Methods: From 1998 to 2003, we enrolled 668 epithelial ovarian cancer cases and 721 controls residing in eastern Massachusetts or New Hampshire, collected information on menstrual and reproductive events, and obtained blood samples from controls to measure anti-MUC1 antibodies. Using logistic regression, we calculated odds ratios to evaluate the influence of reproductive factors, including the estimated lifetime number of ovulatory cycles on ovarian cancer risk and on the presence of MUC1 antibodies in controls.

Results: Overall, we observed that early age at first birth, cycle lengths ≥30 days, and oral contraceptive use increased the likelihood of having anti-MUC1 antibodies. Estimated ovulatory cycles were correlated positively with ovarian cancer risk and inversely with the presence of anti-MUC1 antibodies among controls ages 46 to 60 years.

Conclusions: These data suggest that suppression of MUC1-specific immunity should be considered as an additional explanation for the observation that ovarian cancer risk increases with the lifetime number of ovulatory cycles. (Cancer Epidemiol Biomarkers Prev 2007;16(1):30–5)
Circulating Insulin and C-Peptide Levels and Risk of Breast Cancer among Predominately Premenopausal Women
Authors: Eliassen A. Heather , Tworoger Shelley S. , Mantzoros Christos S. , Pollak Michael N. , Hankinson Susan E.
Published: January 2007

Insulin and insulin resistance have been hypothesized to increase the risk of breast cancer as insulin increases breast cell proliferation and inhibits sex hormone binding globulin. Although insulin is directly related to body weight, adiposity is inversely associated with breast cancer risk in premenopausal women but directly related to risk in postmenopausal women. To explore the association between insulin and c-peptide levels and breast cancer risk, we conducted a nested case-control study of predominantly premenopausal women within the Nurses' Health Study II cohort. From 1996 to 1999, blood samples were collected from 29,611 participants. A total of 317 cases were diagnosed after blood collection and before June 2003 and matched to 634 controls; 75% of these women were premenopausal at blood collection. Logistic regression models, controlling for breast cancer risk factors, were used to calculate relative risks (RR) and 95% confidence intervals (95% CI). Among women with fasting blood samples (n = 211 cases), insulin was suggestively inversely associated with breast cancer risk (highest versus lowest quartile: RR, 0.5; 95% CI, 0.3-1.0; Ptrend = 0.06). Among all women, c-peptide was not associated with breast cancer risk (highest versus lowest quartile: RR, 1.1; 95% CI, 0.7-1.7; Ptrend = 0.79); results were similar among fasting samples. These associations did not differ by age, body mass index, or waist-to-hip ratio. Overall, higher levels of insulin and c-peptide were not associated with a higher risk of breast cancer among predominantly premenopausal women. (Cancer Epidemiol Biomarkers Prev 2007;16(1):161–4)
Viral Determinants of Human Papillomavirus Persistence following Loop Electrical Excision Procedure Treatment for Cervical Intraepithelial Neoplasia Grade 2 or 3
Authors: Kreimer Aimée R. , Katki Hormuzd A. , Schiffman Mark , Wheeler Cosette M. , Castle Philip E. ,   for the ASCUS-LSIL Triage Study Group
Published: January 2007

Background: Persistent infection with carcinogenic human papillomavirus (HPV) causes cervical precancer (cervical intraepithelial neoplasia grade 2+) which, in the United States, is commonly treated using the loop electrical excision procedure (LEEP). Data from Atypical Squamous Cells of Undetermined Significance–Low-Grade Squamous Intraepithelial Lesion Triage Study were used to evaluate HPV persistence and reappearance after LEEP.

Methods: Cervical specimens, collected before LEEP and at 6-month study visits, were tested by L1-PCR for detection of ≥27 HPV types. HPV persistence, defined as the same HPV type being present before and 6 months after LEEP, was evaluated by: (a) genotype, (b) carcinogenicity, and (c) phylogenetic species. HPV infections that cleared post-LEEP (the complement of persistence) were followed for reappearance of the same type.

Results: HPV infections (n = 1,130) were detected among 481 women who underwent LEEP. Overall, 20.4% [95% confidence interval (95% CI), 18.2-22.9%] of infections persisted. Assessment of heterogeneity within the three categorizations of HPV showed that phylogenetic species best fit the data. Persistence was significantly greater by HPV types in the α3 species [all are noncarcinogenic; 40.9% (95% CI, 31.8-50.4%)] compared with HPV types in the α9 (HPV16 and related types) and α7 species (HPV18 and related types; 17.6% and 17.9%, respectively; P < 0.001 for both). HPV reappeared in 7.8% (95% CI, 6.1-9.9%) of infections that cleared after LEEP. Infections in the α3 species (22.6%) were the most likely to reappear compared with HPV types in the α9 (7.5%) and α7 (6.8%) species.

Conclusions: Patterns of HPV persistence and reappearance following LEEP were better explained by phylogenetic rather than standard classifications. HPV types likely to persist after LEEP as well as those likely to repopulate the cervical/vaginal epithelium were those in the α3 species, which are in effect not treated, but are not associated with cervical cancer and are unlikely to cause disease. (Cancer Epidemiol Biomarkers Prev 2007;16(1):11–6)
Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation
Authors: Marrocco Deborah L. , Tilley Wayne D. , Bianco-Miotto Tina , Evdokiou Andreas , Scher Howard I. , Rifkind Richard A. , Marks Paul A. , Richon Victoria M. , Butler Lisa M.
Published: January 2007

Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA; vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (≥5 μmol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death, indicating that suppression of androgen signaling was required for synergy. At the subeffective concentrations, these agents had no effect, alone or in combination, on proliferation or death of AR-negative PC-3 prostate cancer cells. Our findings indicate that SAHA is effective in targeting the AR signaling axis and that androgen deprivation sensitizes prostate cancer cells to SAHA. Consequently, combinatorial treatments that target different components of the AR pathway may afford a more effective strategy to control the growth of prostate cancer cells. [Mol Cancer Ther 2007;6(1):51–60]
Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase
Authors: Holder Sheldon , Zemskova Marina , Zhang Chao , Tabrizizad Maryam , Bremer Ryan , Neidigh Jonathan W. , Lilly Michael B.
Published: January 2007

The pim-1 kinase is a true oncogene that has been implicated in the development of leukemias, lymphomas, and prostate cancer, and is the target of drug development programs. We have used experimental approaches to identify a selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to foster basic and translational studies of the enzyme. We used an ELISA-based kinase assay to screen a diversity library of potential kinase inhibitors. The flavonol quercetagetin (3,3′,4′,5,6,7-hydroxyflavone) was identified as a moderately potent, ATP-competitive inhibitor (IC50, 0.34 μmol/L). Resolution of the crystal structure of PIM1 in complex with quercetagetin or two other flavonoids revealed a spectrum of binding poses and hydrogen-bonding patterns in spite of strong similarity of the ligands. Quercetagetin was a highly selective inhibitor of PIM1 compared with PIM2 and seven other serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in intact RWPE2 prostate cancer cells in a dose-dependent manner (ED50, 5.5 μmol/L). RWPE2 cells treated with quercetagetin showed pronounced growth inhibition at inhibitor concentrations that blocked PIM1 kinase activity. Furthermore, the ability of quercetagetin to inhibit the growth of other prostate epithelial cell lines varied in proportion to their levels of PIM1 protein. Quercetagetin can function as a moderately potent and selective, cell-permeable inhibitor of the pim-1 kinase, and may be useful for proof-of-concept studies to support the development of clinically useful PIM1 inhibitors. [Mol Cancer Ther 2007;6(1):163–72]
Accounting for Linkage Disequilibrium among Markers in Linkage Analysis: Impact of Haplotype Frequency Estimation and Molecular Haplotypes for a Gene in a Candidate Region for Alzheimer’s Disease
Authors: Sieh Weiva , Yu Chang-En , Bird Thomas D. , Schellenberg Gerard D. , Wijsman Ellen M.
Published: January 2007

Objectives: Linkage disequilibrium (LD) between closely spaced SNPs can be accommodated in linkage analysis by specifying the multi-SNP haplotype frequencies, if known. Phased haplotypes in candidate regions can provide gold standard haplotype frequency estimates, and may be of inherent interest as markers. We evaluated the effects of different methods of haplotype frequency estimation, and the use of marker phase information, on linkage analysis of a multi-SNP cluster in a candidate region for Alzheimer’s disease (AD). Methods: We performed parametric linkage analysis of a five-SNP cluster in extended pedigrees to compare the use of: (1) haplotype frequencies estimated by molecular phase determination, maximum likelihood estimation, or by assuming linkage equilibrium (LE); (2) AD families or controls as the frequency source; and (3) unphased or molecularly phased SNP data. Results: There was moderate to strong pairwise LD among the five SNPs. Falsely assuming LE substantially inflated the LOD score, but the method of haplotype frequency estimation and particular sample used made little difference provided that LD was accommodated. Use of phased haplotypes produced a modest increase in the LOD score over unphased SNPs. Conclusions: Ignoring LD between markers can lead to substantially inflated evidence for linkage in LOD score analysis of extended pedigrees with missing data. Use of marker phase information in linkage analysis may be important in disease studies where the costs of family recruitment and phenotyping greatly exceed the costs of phase determination.
Functional Magnetic Resonance Imaging Is More Reliable than Somatosensory Evoked Potential or Mapping for the Detection of the Primary Motor Cortex in Proximity to a Tumor
Authors: Shinoura N. , Yamada R. , Suzuki Y. , Kodama T. , Sekiguchi K. , Takahashi M. , Yagi K.
Published: January 2007

The accurate localization of the primary motor cortex (M1) is critical for the preservation of motor function during resection of brain tumors in and around the M1. The goal of the present study was to determine which technique provided the most accurate localization of M1. The accuracy of preoperative functional magnetic resonance imaging (fMRI), intraoperative somatosensory evoked potential (SEP) and cortical mapping for the localization of M1 was determined in 17 patients with brain tumors in and around the M1. Because localization of the M1 is typically symmetrical in the cerebral hemispheres, the M1 on the affected side was localized by determination of the M1 location on the unaffected side using fMRI with patient hand clenching. The location of M1 was successfully determined by SEP in 5 of 11 cases. In the remainder of cases, the sulcus at which phase reversal occurred during SEP was shifted 1 or 2 gyri rostral to the central sulcus. The location of M1 was successfully determined by brain mapping in 9 of 15 cases. In the remainder of cases, stimulation failed to elicit a motor response. Finally, the location of M1 was successfully determined by fMRI in 16 of 17 cases. These data indicate that fMRI was more reliable than SEP or brain mapping for the detection of M1 in proximity to a tumor.
Neuropsychological Effects of Bilateral Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease
Authors: Bordini Brett J. , Garg Ankur , Gallagher Catherine L. , Bell Brian , Garell P. Charles
Published: January 2007

Objective: Although a relatively new technique, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of advanced cases of Parkinson’s disease (PD) shows considerable promise. While the benefits of the STN stimulation for the treatment of motor symptoms of PD are well established, some studies have reported negative neuropsychological outcomes, especially in elderly patients. The objective of the present study was to investigate the neuropsychological effects of bilateral STN-DBS in a small sample of elderly patients with PD. Methods: Six patients with PD (mean age 73.0 ± 10.45 years) were assessed both before and approximately 6 months after DBS surgery in six neuropsychological domains. These domains included orientation, estimated IQ, attention/working memory, language, memory, and visual-spatial functioning. Additionally, depressive symptoms were assessed using the Geriatric Depression Scale. Daily doses of antiparkinsonian medications, in levodopa equivalents, were also compared pre- and postoperatively. Results: Antiparkinsonian medications were reduced postoperatively by a mean of 65%, from a mean levodopa equivalent dosage of 987 mg/day to 346 mg/day. Category fluency, a word generation task within the language domain, was the only test in which participants demonstrated a statistically significant decline in performance. Participants demonstrated a mean score decrease of 41% (p < 0.05) in category fluency. Conclusions: The pathophysiology of the observed deficit remains ill defined. However, despite a small sample size, the study provides further evidence that bilateral STN-DBS in PD patients can be associated with negative neuropsychological outcome in word fluency, especially in elderly patients. Implications regarding patient selection for bilateral STN-DBS and recommendations for future research are further discussed.
Petrous Bone Langerhans Cell Histiocytosis Treated with Radiosurgery
Authors: del Río Laura , Lassaletta Luis , Martínez Roberto , Sarriá María Josefa , Gavilán Javier
Published: January 2007

Langerhans cell histiocytosis (LCH) is a rare disease that may show as a solitary or multifocal lesion of bone, soft tissue or viscera. Involvement of the temporal bone has been described in 15–61% of patients with LCH, usually in association with multisystemic involvement. We report the case of a 30-year-old man presenting with vertigo and fluctuating hearing loss caused by monosystemic LCH of the left petrous bone. The patient was treated with radiosurgery (covering dose 10 Gy at 85% isodose, maximum dose 11.76 Gy). Two years after treatment, no evidence of recurrent disease was found in the CT scan or MRI. We discuss the treatment of temporal bone LCH, traditionally based on surgery, low-dose radiation therapy and intralesional steroids. To our knowledge, this is the first reported case of LCH of the petrous bone successfully treated with radiosurgery. This approach may be interesting in cases of LCH located on nonaccessible areas of the temporal bone.
Indoxyl Sulfate and Atherosclerotic Risk Factors in Hemodialysis Patients
Authors: Taki Kentaro , Tsuruta Yoshinari , Niwa Toshimitsu
Published: January 2007

Background: Indoxyl sulfate is a uremic toxin that accelerates the progression of chronic kidney disease (CKD). Serum levels of indoxyl sulfate are increased in dialysis patients. It was reported that indoxyl sulfate plays a role in endothelial dysfunction in uremic patients, and stimulates proliferation of rat vascular smooth muscle cells (VSMC). We examined associations between indoxyl sulfate and several markers related to atherosclerosis. Methods: The association between indoxyl sulfate and atherosclerotic risk factors was studied in 224 hemodialysis (HD) patients (123 male, 101 female). Serum levels of indoxyl sulfate were measured by using high-performance liquid chromatography (HPLC). Results: There were significant differences in serum levels of creatinine, calcium × phosphate and pentosidine between high- and lowindoxyl sulfate level groups. Indoxyl sulfate showed significant positive correlations with pentosidine, creatinine, and protein catabolic rate, and a significant negative correlation with high-density lipoprotein (HDL) cholesterol. Further, pentosidine, creatinine, and HDL-cholesterol were independently associated with indoxyl sulfate by multiple linear regression analysis. Conclusion: In addition to creatinine, pentosidine and HDL-cholesterol, the risk factors of atherosclerosis, were associated with indoxyl sulfate in HD patients. Indoxyl sulfate may be involved in the pathogenesis of atherosclerosis.
Clinical and Neuropsychological Features Associated with Structural Imaging Patterns in Patients with Mild Cognitive Impairment
Authors: Rossi Roberta , Geroldi Cristina , Bresciani Lorena , Testa Cristina , Binetti Giuliano , Zanetti Orazio , Frisoni Giovanni B.
Published: January 2007

Aim: To describe the clinical and neuropsychological features of mild cognitive impairment (MCI) patients with medial temporal atrophy (MTA), white matter hyperintensities (WMH), both, and neither and to assess whether the rate of progression differs among groups. Methods: Ninety-five MCI patients were divided into 4 groups based on the presence of MTA and WMH: 29 were MTA– WMH–, 11 MTA– WMH+, 23 MTA+ WMH–, and 32 MTA+ WMH+. MCI patients were compared with 30 normal subjects. MTA and WMH were assessed with MR-based visual rating scales. Subjects underwent an extensive clinical and neuropsychological investigation. Fifty-six underwent follow-up evaluation. Results: MTA– WMH– had relatively good neuropsychological performance, little vascular and physical comorbidity. MTA– WMH+ performed poorly only on executive neuropsychological tests. MTA+ WMH– patients had poor neuropsychological performances (mainly on memory tests), high physical and vascular comorbidity. MTA+ WMH+ were impaired in neuropsychological performances, had a high number of physical diseases and severe vascular comorbidity. On follow-up, 25% of MTA+ WMH– and 32% of MTA+ WMH+ and none in MTA– WMH– and in MTA– WMH+ converted to dementia (p = 0.05, log rank test). Conclusion: Structural neuroimaging can identify subgroups of MCI patients with specific clinical and neuropsychological features.
Phosphate Salivary Secretion in Hemodialysis Patients: Implications for the Treatment of Hyperphosphatemia
Authors: Savica Vincenzo , Calò Lorenzo A. , Caldarera Renato , Cavaleri Adelaide , Granata Antonio , Santoro Domenico , Savica Rodolfo , Muraca Ugo , Mallamace Agostino , Bellinghieri Guido
Published: January 2007

Background/Aims: Hyperphosphatemia is recognized as contributing to the increased risk of cardiac death in end-stage renal disease (ESRD) and hemodialysis (HD) patients. Currently available pharmacologic treatment for hyperphosphatemia is based on phosphate binders but, despite treatment, only half of the patients fall within the range for serum phosphorus of the K/DOQI guidelines. Therefore, there is a need to identify other therapeutic approaches in order to reduce serum phosphate. Salivary fluid contains phosphate which, if related to the daily salivary secretion (1,000–1,880 ml), may raise interest in order to identify further additive approaches to phosphorus removal in uremic patients, while data about salivary phosphate secretion in ESRD patients are controversial. Methods: This study evaluates salivary phosphate secretion in 68 HD patients compared with 30 healthy subjects. Saxon’s test confirmed normal salivary function in patients and controls. Salivary calcium and serum phosphate, calcium and PTH were also measured. Results: HD patients had significantly higher salivary phosphorus levels compared with healthy controls: 30.35 (26.5–34.6) vs. 12.1 (10.58–14.73) mg/dl (p < 0.0001), and this significantly correlated (p < 0.0001) with serum phosphorus. Multiple regression analysis confirmed serum phosphorus as the only predictor (p < 0.0001) of salivary phosphorus. Conclusions: Given the functional secretive similarity between salivary glands and the kidneys, this increased salivary phosphate secretion might be interpreted as being compensatory in the presence of renal failure. Absorption of the increased salivary phosphate secretion, however, may worsen hyperphosphatemia; therefore, the binding of salivary phosphate might be considered as a further therapeutic approach to hyperphosphatemia in ESRD.
Utility of Behavioral versus Cognitive Measures in Differentiating between Subtypes of Frontotemporal Lobar Degeneration and Alzheimer’s Disease
Authors: Heidler-Gary Jennifer , Gottesman Rebecca , Newhart Melissa , Chang Shannon , Ken Lynda , Hillis Argye E.
Published: January 2007

We hypothesized that a modified version of the Frontal Behavioral Inventory (FBI-mod), along with a few cognitive tests, would be clinically useful in distinguishing between clinically defined Alzheimer’s disease (AD) and subtypes of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (dysexecutive type), progressive nonfluent aphasia, and semantic dementia. We studied 80 patients who were diagnosed with AD (n = 30) or FTLD (n = 50), on the basis of a comprehensive neuropsychological battery, imaging, neurological examination, and history. We found significant between-group differences on the FBI-mod, two subtests of the Rey Auditory Verbal Learning Test (verbal learning and delayed recall), and the Trail Making Test Part B (one measure of ‘executive functioning’). AD was characterized by relatively severe impairment in verbal learning, delayed recall, and executive functioning, with relatively normal scores on the FBI-mod. Frontotemporal dementia was characterized by relatively severe impairment on the FBI-mod and executive functioning in the absence of severe impairment in verbal learning and recall. Progressive nonfluent aphasia was characterized by severe impairment in executive functioning with relatively normal scores on verbal learning and recall and FBI-mod. Finally, semantic dementia was characterized by relatively severe deficits in delayed recall, but relatively normal performance on new learning, executive functioning, and on FBI-mod. Discriminant function analysis confirmed that the FBI-mod, in conjunction with the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B categorized the majority of patients as subtypes of FTLD or AD in the same way as a full neuropsychological battery, neurological examination, complete history, and imaging. These tests may be useful for efficient clinical diagnosis, although progressive nonfluent aphasia and semantic dementia are likely to be best distinguished by language tests not included in standard neuropsychological test batteries.
Role of Oxidative Stress in the Pathogenesis of Abdominal Aortic Aneurysms
Authors: McCormick Michael L. , Gavrila Dan , Weintraub Neal L.
Published: January 2007

The role of inflammation in the pathogenesis of abdominal aortic aneurysms (AAA) is well established. The inflammatory process leads to protease-mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMC), which are the predominant matrix synthesizing cells of the vascular wall. These processes act in concert to progressively weaken the aortic wall, resulting in dilatation and aneurysm formation. Oxidative stress is invariably increased in, and contributes importantly to, the pathophysiology of inflammation. Moreover, reactive oxygen species (ROS) play a key role in regulation of matrix metalloproteinases and induction of SMC apoptosis. ROS may also contribute to the pathogenesis of hypertension, a risk factor for AAA. Emerging evidence suggests that ROS and reactive nitrogen species (RNS) are associated with AAA formation in animal models and in humans. Although experimental data are limited, several studies suggest that modulation of ROS production or activity may suppress AAA formation and improve experimental outcome in rodent models. Although a number of enzymes can produce injurious ROS in the vasculature, increasing evidence points toward a role for NADPH oxidase as a source of oxidative stress in the pathogenesis of AAA.
Ca
2+
and Inositol 1,4,5-Trisphosphate–Mediated Signaling Across the Myoendothelial Junction
Authors: Isakson Brant E. , Ramos Susan I. , Duling Brian R.
Published: January 2007

Second messenger signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is poorly understood, but intracellular Ca
2+
concentrations ([Ca
2+
]
i
) in the 2 cells are coordinated, possibly through gap junctions at the myoendothelial junction. To study heterocellular calcium signaling, we used a vascular cell coculture model composed of monolayers of ECs and VSMCs. Stimulation of either cell type leads to an increase in [Ca
2+
]
i
in the stimulated cell and a secondary increase in [Ca
2+
]
i
in the other cell type that was blocked by gap junction inhibitors. To determine which second messengers are involved, we initially depleted Ca
2+
stores in the endoplasmic reticulum Ca
2+
with thapsigargin in ECs or VSMCs, but this had no effect on heterocellular calcium signaling. Alternatively, we loaded ECs or VSMCs with 1,2-bis(2-aminophenoxy)ethane-
N
,
N
,
N
′,
N
′-tetraacetic acid (BAPTA) to buffer changes in [Ca
2+
]
i
. BAPTA loading of ECs inhibited agonist-induced increases in intracellular calcium concentration ([Ca
2+
]
i
), in both ECs and VSMCs. In contrast, BAPTA loading of the VSMCs blunted the VSMC response but did not alter the secondary increase in EC [Ca
2+
]
i
. Xestospongin C (an inositol 1,4,5-trisphosphate receptor inhibitor) had no effect on the secondary Ca
2+
response, but when xestospongin C or thapsigargin was loaded into ECs and BAPTA into VSMCs, intercellular Ca
2+
signaling was completely blocked. We conclude that 1,4,5-trisphosphate and Ca
2+
originating in the VSMCs induces the secondary increase in EC [Ca
2+
]
i
but stimulation of the ECs generates a Ca
2+
dependent response in the VSMCs.
High-Mobility Group Box 1 Activates Integrin-Dependent Homing of Endothelial Progenitor Cells
Authors: Chavakis Emmanouil , Hain Andreas , Vinci Maria , Carmona Guillaume , Bianchi Marco E. , Vajkoczy Peter , Zeiher Andreas M. , Chavakis Triantafyllos , Dimmeler Stefanie
Published: January 2007

Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE (receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against β
1
and β
2
integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to β
2
integrins or RAGE. HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent a link between HMGB1 and integrin functions of EPCs and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing.