bluuebunny/crossref_metadata_2025 huggingface dataset:
Early effects of doxorubicin in perfused heart: transcriptional profiling reveals inhibition of cellular stress response genes
Authors: Tokarska-Schlattner Malgorzata , Lucchinetti Eliana , Zaugg Michael , Kay Laurence , Gratia Séverine , Guzun Rita , Saks Valdur , Schlattner Uwe
Published: January 2010

Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its clinical application is limited by the risk of severe cardiac-specific toxicity, for which an efficient treatment is missing. Underlying molecular mechanisms are not sufficiently understood so far, but nonbiased, systemic approaches can yield new clues to develop targeted therapies. Here, we applied a genome-wide transcriptome analysis to determine the early cardiac response to DXR in a model characterized earlier, that is, rat heart perfusion with 2 μM DXR, leading to only mild cardiac dysfunction. Single-gene and gene set enrichment analysis of DNA microarrays yielded robust data on cardiac transcriptional reprogramming, including novel DXR-responsive pathways. Main characteristics of transcriptional reprogramming were 1) selective upregulation of individual genes or gene sets together with widespread downregulation of gene expression; 2) repression of numerous transcripts involved in cardiac stress response and stress signaling; 3) modulation of genes with cardiac remodeling capacity; 4) upregulation of “energy-related” pathways; and 5) similarities to the transcriptional response of cancer cells. Some early responses like the induction of glycolytic and Krebs cycle genes may have compensatory function. Only minor changes in the cardiac energy status or the respiratory activity of permeabilized cardiac fibers have been observed. Other responses potentially contribute to acute and also chronic toxicity, in particular, those in stress-responsive and cardiac remodeling transcripts. We propose that a blunted response to stress and reduced “danger signaling” is a prime component of toxic DXR action and can drive cardiac cells into pathology.
Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4
Authors: Jewell Jenna L. , Oh Eunjin , Thurmond Debbie C.
Published: January 2010

Type 2 diabetes has been coined “a two-hit disease,” as it involves specific defects of glucose-stimulated insulin secretion from the pancreatic beta cells in addition to defects in peripheral tissue insulin action required for glucose uptake. Both of these processes, insulin secretion and glucose uptake, are mediated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein core complexes composed of syntaxin, SNAP-23/25, and VAMP proteins. The SNARE core complex is regulated by the Sec1/Munc18 (SM) family of proteins, which selectively bind to their cognate syntaxin isoforms with high affinity. The process of insulin secretion uses multiple Munc18-syntaxin isoform pairs, whereas insulin action in the peripheral tissues appears to use only the Munc18c-syntaxin 4 pair. Importantly, recent reports have linked obesity and Type 2 diabetes in humans with changes in protein levels and single nucleotide polymorphisms (SNPs) of Munc18 and syntaxin isoforms relevant to these exocytotic processes, although the molecular mechanisms underlying the observed phenotypes remain incomplete ( 5 , 104 , 144 ). Given the conservation of these proteins in two seemingly disparate processes and the need to design and implement novel and more effective clinical interventions, it will be vitally important to delineate the mechanisms governing these conserved SNARE-mediated exocytosis events. Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes.
Endothelin in the female vasculature: a role in aging?
Authors: Lekontseva Olga , Chakrabarti Subhadeep , Davidge Sandra T.
Published: January 2010

Cardiovascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.
Functional implications of the three-dimensional architecture of the rat renal inner medulla
Authors: Layton Anita T. , Pannabecker Thomas L. , Dantzler William H. , Layton Harold E.
Published: January 2010

A new, region-based mathematical model of the urine concentrating mechanism of the rat renal inner medulla (IM) was used to investigate the significance of transport and structural properties revealed in recent studies that employed immunohistochemical methods combined with three-dimensional computerized reconstruction. The model simulates preferential interactions among tubules and vessels by representing two concentric regions. The inner region, which represents a collecting duct (CD) cluster, contains CDs, some ascending thin limbs (ATLs), and some ascending vasa recta; the outer region, which represents the intercluster region, contains descending thin limbs, descending vasa recta, remaining ATLs, and additional ascending vasa recta. In the upper portion of the IM, the model predicts that interstitial Na+and urea concentrations (and osmolality) in the CD clusters differ significantly from those in the intercluster regions: model calculations predict that those CD clusters have higher urea concentrations than the intercluster regions, a finding that is consistent with a concentrating mechanism that depends principally on the mixing of NaCl from ATLs and urea from CDs. In the lower IM, the model predicts that limited or nearly zero water permeability in descending thin limb segments will increase concentrating effectiveness by increasing the rate of solute-free water absorption. The model predicts that high urea permeabilities in the upper portions of ATLs and increased contact areas of longest loop bends with CDs both modestly increase concentrating capability. A surprising finding is that the concentrating capability of this region-based model falls short of the capability of a model IM that has radially homogeneous interstitial fluid at each level but is otherwise analogous to the region-based model.
Role(s) of gravitational loading during developing period on the growth of rat soleus muscle fibers
Authors: Kawano Fuminori , Goto Katsumasa , Wang Xiao Dong , Terada Masahiro , Ohira Takashi , Nakai Naoya , Yoshioka Toshitada , Ohira Yoshinobu
Published: January 2010

Effects of gravitational loading or unloading on the gain of the characteristics in soleus muscle fibers were studied in rats. The tail suspension was performed in newborn rats from postnatal day 4 to month 3, and the reloading was allowed for 3 mo in some rats. Single expression of type I myosin heavy chain (MHC) was observed in ∼82% of fibers in 3-mo-old controls, but the fibers expressing multiple MHC isoforms were noted in the unloaded rats. Although 97% of fibers in 3-mo-old controls had a single neuromuscular junction at the central region of fiber, fibers with multiple nerve endplates were seen in the unloaded group. Faster contraction speed and lower maximal tension development, even after normalization with fiber size, were observed in the unloaded pure type I MHC fibers. These parameters generally returned to the age-matched control levels after reloading. It was suggested that antigravity-related tonic activity plays an important role in the gain of single neural innervation and of slow contractile properties and phenotype in soleus muscle fibers.
Time course and mechanisms of adaptations in cardiorespiratory fitness with endurance training in older and young men
Authors: Murias Juan M. , Kowalchuk John M. , Paterson Donald H.
Published: January 2010

The time-course and mechanisms of adaptation of cardiorespiratory fitness were examined in 8 older (O) (68 ± 7 yr old) and 8 young (Y) (23 ± 5 yr old) men pretraining and at 3, 6, 9, and 12 wk of training. Training was performed on a cycle ergometer three times per week for 45 min at ∼70% of maximal oxygen uptake (V̇o2 max). V̇o2 max increased within 3 wk with further increases observed posttraining in both O (+31%) and Y (+18%), ( P < 0.05). Maximal cardiac output (Q̇max, open-circuit acetylene) and stroke volume were higher in O and Y after 3 wk with further increases after 9 wk of training ( P < 0.05). Maximal arterial-venous oxygen difference (a-vO2diff) was higher at weeks 3 and 6 and posttraining compared with pretraining in O and Y ( P < 0.05). In O, ∼69% of the increase in V̇o2 max from pre- to posttraining was explained by an increased Q̇max with the remaining ∼31% explained by a widened a-vO2diff. This proportion of Q̇ and a-vO2diff contributions to the increase in V̇o2 max was consistent throughout testing in O. In Y, 56% of the pre- to posttraining increase in V̇o2 max was attributed to a greater Q̇max and 44% to a widened a-vO2diff. Early adaptations (first 3 wk) mainly relied on a widened maximal a-vO2diff (∼66%) whereas further increases in V̇o2 max were exclusively explained by a greater Q̇max. In conclusion, with short-term training O and Y significantly increased their V̇o2 max; however, the proportion of V̇o2 max increase explained by Q̇max and maximal a-vO2diff throughout training showed a different pattern by age group.
Applicability of White-Noise Techniques to Analyzing Motion Responses
Authors: van Kleef Joshua P. , Stange Gert , Ibbotson Michael R.
Published: January 2010

Motion processing in visual neurons is often understood in terms of how they integrate light stimuli in space and time. These integrative properties, known as the spatiotemporal receptive fields (STRFs), are sometimes obtained using white-noise techniques where a continuous random contrast sequence is delivered to each spatial location within the cell's field of view. In contrast, motion stimuli such as moving bars are usually presented intermittently. Here we compare the STRF prediction of a neuron's response to a moving bar with the measured response in second-order interneurons (L-neurons) of dragonfly ocelli (simple eyes). These low-latency neurons transmit sudden changes in intensity and motion information to mediate flight and gaze stabilization reflexes. A white-noise analysis is made of the responses of L-neurons to random bar stimuli delivered either every frame (densely) or intermittently (sparsely) with a temporal sequence matched to the bar motion stimulus. Linear STRFs estimated using the sparse stimulus were significantly better at predicting the responses to moving bars than the STRFs estimated using a traditional dense white-noise stimulus, even when second-order nonlinear terms were added. Our results strongly suggest that visual adaptation significantly modifies the linear STRF properties of L-neurons in dragonfly ocelli during dense white-noise stimulation. We discuss the ability to predict the responses of visual neurons to arbitrary stimuli based on white-noise analysis. We also discuss the likely functional advantages that adaptive receptive field structures provide for stabilizing attitude during hover and forward flight in dragonflies.
Prostate Cancer Risk Allele Specific for African Descent Associates with Pathologic Stage at Prostatectomy
Authors: Whitman Eric J. , Pomerantz Mark , Chen Yongmei , Chamberlin Michael M. , Furusato Bungo , Gao Chunling , Ali Amina , Ravindranath Lakshmi , Dobi Albert , Sestrehenn Isabell A. , McLeod David G. , Srivastava Shiv , Freedman Matthew , Petrovics Gyorgy
Published: January 2010

Purpose: A region on chromosome 8q24 was recently identified as a novel prostate cancer risk locus. Inherited variation in this region is associated with prostate cancer risk in the general population (21-58%), and specific alleles show a strong association in African-American men. This study was designed to evaluate associations between 8q24 risk alleles and clinical variables, such as pathologic stage, age at diagnosis, and recurrence, in a case series of African-American men.

Experimental Design: Peripheral blood DNA samples from 114 African-American men with prostate cancer, including 106 who had undergone radical prostatectomy, were genotyped for six single-nucleotide polymorphisms on three 8q24 regions. The presence of these single-nucleotide polymorphisms was compared with clinicopathologic and follow-up data after radical prostatectomy.

Results: The mean age of diagnosis and follow-up time were 57.4 (±8.9) years and 49.1 (±31.6) months, respectively. Patients carrying the Broad11934905 A risk allele, which is specific for African ancestry, were more likely to have a higher pathologic stage (pT3-4) than individuals with the wild type (odds ratio, 4.48; 95% confidence interval, 1.42-14.14; P = 0.011). A trend toward increased frequency of and shorter time to biochemical recurrence was noted in patients with this risk allele on Kaplan-Meier unadjusted survival analysis (P = 0.076).

Conclusions: The Broad11934905 polymorphism at 8q24, which is only found in people of African ancestry, is associated with an increase in non-organ-confined prostate cancer at prostatectomy. In addition, for those with this risk allele, there is a trend toward early biochemical recurrence that requires validation in larger studies. Cancer Epidemiol Biomarkers Prev; 19(1); 1–8
Sun and Solarium Exposure and Melanoma Risk: Effects of Age, Pigmentary Characteristics, and Nevi
Authors: Veierød Marit Bragelien , Adami Hans-Olov , Lund Eiliv , Armstrong Bruce Konrad , Weiderpass Elisabete
Published: January 2010

Background: Few prospective studies have analyzed solar and artificial (solarium) UV exposure and melanoma risk. We investigated these associations in a Norwegian-Swedish cohort study and addressed effect modification by age, pigmentary characteristics, and nevi.

Methods: The cohort included women ages 30 to 50 years at enrollment from 1991 to 1992. Host factors and exposure to sun and solariums in life decades were collected by questionnaire at enrollment. Relative risks (RR) with 95% confidence intervals (CI) were estimated by Poisson regression.

Results: Among 106,366 women with complete follow-up through 2005, 412 melanoma cases were diagnosed. Hair color and large, asymmetric nevi on the legs were strongly associated with melanoma risk (Ptrend < 0.001), and the RR for ≥2 nevi increased from brown/black to blond/yellow to red-haired women (RRs, 1.72, 3.30, and 4.95, respectively; Pinteraction = 0.18). Melanoma risk increased significantly with the number of sunburns and bathing vacations in the first three age decades (Ptrend ≤ 0.04) and solarium use at ages 30 to 39 and 40 to 49 years [RRs for solarium use ≥1 time/mo 1.49 (95% CI, 1.11-2.00) and 1.61 (95% CI 1.10-2.35), respectively; Ptrend ≤ 0.02]. Risk of melanoma associated with sunburns, bathing vacations, and solarium use increased with accumulating exposure across additional decades of life.

Conclusions: Melanoma risk seems to continue to increase with accumulating intermittent sun exposure and solarium use in early adulthood. Apparently, super-multiplicative joint effects of nevi and hair color identify people with red hair and multiple nevi as a very high risk group and suggest important gene-gene interactions involving MC1R in melanoma etiology. Cancer Epidemiol Biomakers Prev; 19(1);111–20
Dietary Glucosinolate Intake, Polymorphisms in Selected Biotransformation Enzymes, and Risk of Prostate Cancer
Authors: Steinbrecher Astrid , Rohrmann Sabine , Timofeeva Maria , Risch Angela , Jansen Eugène , Linseisen Jakob
Published: January 2010

A protective role of glucosinolates in prostate cancer development might be mediated by the induction of biotransformation enzymes. These enzymes, enhancing the elimination of carcinogens from the body, are known to be polymorphic. Therefore, we evaluated whether a possible association between glucosinolate intake and prostate cancer risk is modified by polymorphisms in GSTT1, GSTM1, GSTA1, GSTP1, or NOQ1 genes. A case-control study including 248 prostate cancer cases and 492 matched controls was nested in the prospective European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort. At baseline, participants provided dietary and lifestyle data and blood samples, which were used for genotyping and measurement of serum glutathione S-transferase-α concentration. Odds ratios and 95% confidence intervals were calculated by conditional logistic regression. We found an inverse association of glucosinolate intake with prostate cancer risk (adjusted odds ratio, 0.72 per 10 mg/d increment; 95% confidence interval, 0.53-0.96). Stratification by genotype showed significantly reduced risks for subjects with wild-type of NQO1 (C609T) compared with CT or TT carriers (Pinteraction = 0.04). Those with deletions in both GSTM1 and GSTT1 genes combined had a significantly reduced risk with increasing glucosinolate intake (Pinteraction = 0.01). There was no effect modification of glucosinolate intake and cancer risk by GSTA1 (G-52A) or GSTP1 (A313G) genotype, but serum glutathione S-transferase-α concentrations were inversely associated with prostate cancer. This study showed that the inverse association between glucosinolate intake and prostate cancer risk was modified by NQO1 (C609T) and GSTM1 and GSTT1 deletion polymorphisms. This information will help to further elucidate the mechanism of action of potentially protective substances in vivo. Cancer Epidemiol Biomarkers Prev; 19(1); 135–43
Genetic Variability in theMTHFRGene and Colorectal Cancer Risk Using the Colorectal Cancer Family Registry
Authors: Levine A. Joan , Figueiredo Jane C. , Lee Won , Poynter Jenny N. , Conti David , Duggan David J. , Campbell Peter T. , Newcomb Polly , Martinez Maria Elena , Hopper John L. , Le Marchand Loic , Baron John A. , Limburg Paul J. , Ulrich Cornelia M. , Haile Robert W.
Published: January 2010

Background: The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk.

Methods: We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r2 >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models.

Results: From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; Pinteraction = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (Pinteraction = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups.

Conclusion: The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk. Cancer Epidemiol Biomarkers Prev; 19(1); 89–100
ESR1/SYNE1 Polymorphism and Invasive Epithelial Ovarian Cancer Risk: An Ovarian Cancer Association Consortium Study
Authors: Doherty Jennifer A. , Rossing Mary Anne , Cushing-Haugen Kara L. , Chen Chu , Van Den Berg David J. , Wu Anna H. , Pike Malcolm C. , Ness Roberta B. , Moysich Kirsten , Chenevix-Trench Georgia , Beesley Jonathan , Webb Penelope M. , Chang-Claude Jenny , Wang-Gohrke Shan , Goodman Marc T. , Lurie Galina , Thompson Pamela J. , Carney Michael E. , Hogdall Estrid , Kjaer Susanne Kruger , Hogdall Claus , Goode Ellen L. , Cunningham Julie M. , Fridley Brooke L. , Vierkant Robert A. , Berchuck Andrew , Moorman Patricia G. , Schildkraut Joellen M. , Palmieri Rachel T. , Cramer Daniel W. , Terry Kathryn L. , Yang Hannah P. , Garcia-Closas Montserrat , Chanock Stephen , Lissowska Jolanta , Song Honglin , Pharoah Paul D.P. , Shah Mitul , Perkins Barbara , McGuire Valerie , Whittemore Alice S. , Di Cioccio Richard A. , Gentry-Maharaj Aleksandra , Menon Usha , Gayther Simon A. , Ramus Susan J. , Ziogas Argyrios , Brewster Wendy , Anton-Culver Hoda ,   The Australian Ovarian Cancer Study Management Group,   The Australian Cancer Study (Ovarian Cancer), Pearce Celeste Leigh ,   on behalf of the Ovarian Cancer Association Consortium (OCAC)
Published: January 2010

We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 244–50
Occupational Exposure to Formaldehyde, Hematotoxicity, and Leukemia-Specific Chromosome Changes in Cultured Myeloid Progenitor Cells
Authors: Zhang Luoping , Tang Xiaojiang , Rothman Nathaniel , Vermeulen Roel , Ji Zhiying , Shen Min , Qiu Chuangyi , Guo Weihong , Liu Songwang , Reiss Boris , Freeman Laura Beane , Ge Yichen , Hubbard Alan E. , Hua Ming , Blair Aaron , Galvan Noe , Ruan Xiaolin , Alter Blanche P. , Xin Kerry X. , Li Senhua , Moore Lee E. , Kim Sungkyoon , Xie Yuxuan , Hayes Richard B. , Azuma Mariko , Hauptmann Michael , Xiong Jun , Stewart Patricia , Li Laiyu , Rappaport Stephen M. , Huang Hanlin , Fraumeni Joseph F. , Smith Martyn T. , Lan Qing
Published: January 2010

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures. Cancer Epidemiol Biomarkers Prev; 19(1); 80–8.
Diabetes and Outcomes After Radical Prostatectomy: Are Results Affected by Obesity and Race? Results from the Shared Equal-Access Regional Cancer Hospital Database
Authors: Jayachandran Jayakrishnan , Aronson William J. , Terris Martha K. , Presti Joseph C. , Amling Christopher L. , Kane Christopher J. , Freedland Stephen J.
Published: January 2010

Background: Diabetes is associated with lower prostate cancer risk. The association of diabetes with prostate cancer outcomes is less clear. We examined the association between diabetes and outcomes after radical prostatectomy and tested whether associations varied by race and/or obesity.

Materials and Methods: This study is a retrospective analysis of 1,262 men treated with radical prostatectomy between 1988 and 2008 within the Shared Equal-Access Regional Cancer Hospital database. We examined the multivariate association between diabetes at surgery and adverse pathology, biochemical recurrence (BCR), and prostate-specific antigen doubling time at recurrence using logistic, proportional hazards, and linear regression, respectively. Data were examined as a whole and stratified by race and obesity.

Results: Diabetes was more prevalent among black (22% versus 15%, P < 0.001) and more obese men (P < 0.001). Diabetes was associated with higher tumor grade (odds ratio, 1.73; P = 0.002), seminal vesicle invasion (odds ratio, 1.73; P = 0.04), but not BCR (P = 0.67) or PSADT at recurrence (P = 0.12). In the secondary analysis, among white obese men, diabetes was associated with 2.5-fold increased BCR risk (P = 0.002) and a trend toward shorter PSADT, whereas among all other men (nonobese white men and black men), diabetes was associated with 23% lower recurrence risk (P = 0.09) and longer PSADT (P = 0.04).

Conclusion: In a radical prostatectomy cohort, diabetes was not associated with BCR. In the secondary analysis, diabetes was associated with more aggressive disease in obese white men and less aggressive disease for all other subsets. If externally validated, these findings suggest that among men with prostate cancer, the association between diabetes and prostate cancer aggressiveness may vary by race and obesity. Cancer Epidemiol Biomarkers Prev; 19(1); 9–17
Nutrient-Based Dietary Patterns and Laryngeal Cancer: Evidence from an Exploratory Factor Analysis
Authors: Edefonti Valeria , Bravi Francesca , Garavello Werner , La Vecchia Carlo , Parpinel Maria , Franceschi Silvia , Dal Maso Luigino , Bosetti Cristina , Boffetta Paolo , Ferraroni Monica , Decarli Adriano
Published: January 2010

Background: The issue of diet and laryngeal cancer has been rarely addressed considering the potential role of dietary patterns.

Methods: We examined this association using data from a case-control study carried out between 1992 and 2000. Cases were 460 histologically confirmed incident laryngeal cancers hospitalized in two Italian areas. Controls were 1,088 subjects hospitalized for acute nonneoplastic diseases unrelated to tobacco or alcohol consumption. Dietary habits were investigated through a 78-item food frequency questionnaire. A posteriori dietary patterns were identified through principal component factor analysis carried out on a selected set of 28 major nutrients. The internal reproducibility, robustness, and reliability of the identified patterns were evaluated. Odds ratios (OR) of laryngeal cancer and 95% confidence intervals (95% CI) were estimated using unconditional multiple logistic regression models on quartiles of factor scores.

Results: We identified five major dietary patterns named “animal products,” “starch-rich,” “vitamins and fiber,” “vegetable unsaturated fatty acids,” and “animal unsaturated fatty acids.” The vitamins and fiber dietary pattern was inversely associated with laryngeal cancer (OR, 0.35; 95% CI, 0.24-0.52 for the highest versus the lowest score quartile), whereas the animal products (OR, 2.34; 95% CI, 1.59-3.45) and the animal unsaturated fatty acids (OR, 2.07; 95% CI, 1.42-3.01) patterns were directly associated with it. There was no significant association between the vegetable unsaturated fatty acids and the starch-rich patterns and laryngeal cancer risk.

Conclusion: These findings suggest that diets rich in animal products and animal fats are directly related, and those rich in fruit and vegetables inversely related, to laryngeal cancer risk. Cancer Epidemiol Biomarkers Prev; 19(1); 18–27
Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models
Authors: Daouti Sherif , Higgins Brian , Kolinsky Kenneth , Packman Kathryn , Wang Huisheng , Rizzo Christine , Moliterni John , Huby Nicholas , Fotouhi Nader , Liu Mei , Goelzer Petra , Sandhu Harpreet K. , Li Jia Kui , Railkar Aruna , Heimbrook David , Niu Huifeng
Published: January 2010

Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non–ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC50s in plasma were 1.36 μmol/L (880 ng/mL) and 3.35 μmol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC50 (1.41 μmol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (≥90%), an average plasma drug concentration of 0.65 or 5.23 μmol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC90 values (0.64 or 4.1 μmol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen. Mol Cancer Ther; 9(1); 134–44
A Conserved Lysine in the Thyroid Hormone Receptor–α1 DNA-Binding Domain, Mutated in Hepatocellular Carcinoma, Serves as a Sensor for Transcriptional Regulation
Authors: Chan Ivan H. , Privalsky Martin L.
Published: January 2010

Nuclear receptors are hormone-regulated transcription factors that play key roles in normal physiology and development; conversely, mutant nuclear receptors are associated with a wide variety of neoplastic and endocrine disorders. Typically, these receptor mutants function as dominant negatives and can interfere with wild-type receptor activity. Dominant-negative thyroid hormone receptor (TR) mutations have been identified in over 60% of the human hepatocellular carcinomas analyzed. Most of these mutant TRs are defective for corepressor release or coactivator binding in vitro, accounting for their transcriptional defects in vivo. However, two HCC-TR mutants that function as dominant-negative receptors in cells display near-normal properties in vitro, raising questions about the molecular basis behind their transcriptional defects. We report here that a single amino acid substitution, located at the same position in the DNA-binding domain of both mutants, is responsible for their impaired transcriptional activation and dominant-negative properties. Significantly, this amino acid, K74 in TRα, is highly conserved in all known nuclear receptors and seems to function as an allosteric sensor that regulates the transcriptional activity of these receptors in response to binding to their DNA recognition sequences. We provide evidence that these two human hepatocellular carcinoma mutants have acquired dominant-negative function as a result of disruption of this allosteric sensing. Our results suggest a novel mechanism by which nuclear receptors can acquire transcriptional defects and contribute to neoplastic disease. Mol Cancer Res; 8(1); 15–23
Cytogenetic and Array-CGH Characterization of a Complex de novo Rearrangement Involving Duplication and Deletion of 9p and Clinical Findings in a 4-Month-Old Female
Authors: Hulick P.J. , Noonan K.M. , Kulkarni S. , Donovan D.J. , Listewnik M. , Ihm C. , Stoler J.M. , Weremowicz S.
Published: January 2010

Approximately 15 patients with partial trisomy 9p involving de novo duplications have been previously described. Here, we present clinical, cytogenetic, FISH and aCGH findings in a patient with a de novo complex rearrangement in the short arm of chromosome 9 involving an inverted duplication at 9p24→p21.3 and a deletion at 9pter→p24.2. FISH probes generated from BACs selected from the UCSC genome browser were utilized to verify this rearrangement. It is likely that some previously described duplications of 9p may also be products of complex chromosomal aberrations. This report in which FISH and aCGH were used to more comprehensively characterize the genomic rearrangement in a patient with clinical manifestations of 9p duplication syndrome underscores the importance of further characterizing cytogenetically detected rearrangements.
Impacts of Vaccination on Hepatitis B Viral Infections in Korea over a 25-Year Period
Authors: Park Neung Hwa , Chung Young-Hwa , Lee Hyo-Suk
Published: January 2010

Background: Hepatitis B virus (HBV) vaccination has effectively reduced the acute and chronic infection rates in recent years. Since 1983, HBV vaccination has been recommended for all neonates in Korea. Methods: This article reviews the impacts of HBV vaccination throughout the past 25 years in Korea. Before the introduction of the HBV vaccination program, approximately 8% of the general Korean population tested positive for hepatitis B virus surface antigen (HBsAg). Results: The percentage of vaccinated infants has surpassed 98.9% since 1990. The HBsAg carrier rate in the general population decreased to 3.7% in 2007. In particular, the prevalence of HBsAg decreased to 0.44% in teenagers and to 0.2% in children younger than 10 years. In addition, administration of the HBV vaccine may have reduced the risk of hepatocellular carcinoma among adults. Despite the administration of hepatitis B immunoglobulin and the HBV vaccine to children with HBsAg-positive mothers, the failure rate of HBV immunoprophylaxis was 4.2% in 2008. In Korea, there have been no reported cases of HBV surface gene variants such as G145R. Conclusions: The prevalence of HBV carriers in Korea was markedly reduced after the introduction of the universal HBV vaccination program. Korea is now classified as an area of intermediate endemicity for HBV.
Blood Inflammatory Proteins and Risk of Incident Depression in the Elderly
Authors: Forti Paola , Rietti Elisa , Pisacane Nicoletta , Olivelli Valentina , Mariani Erminia , Chiappelli Martina , Licastro Federico , Ravaglia Giovanni
Published: January 2010

Background: It is unclear whether high levels of blood inflammatory proteins are associated with the risk of developing depression in late life. Methods: Blood C-reactive protein, interleukin (IL)-6, α1-antichymotrypsin (ACT), intercellular adhesion molecule 1, and tumor necrosis factor α were measured in an elderly cohort (n = 968). Major depression diagnosed according to clinical criteria and relevant depressive symptoms measured by the Geriatric Depression Scale (score ≧10) were assessed at baseline and 4 year later. Results: Baseline IL-6 and ACT were increased in both prevalent major depression and relevant depressive symptoms. Baseline ACT was increased in incident major depression. All associations weakened below significance after adjustment for possible confounders and multiple comparisons. Conclusions: Blood inflammatory proteins do not predict the risk of developing depression in older age.
Wisconsin Card Sorting Test and Brain Perfusion Imaging in Early Dementia
Authors: Takeda Naoya , Terada Seishi , Sato Shuhei , Honda Hajime , Yoshida Hidenori , Kishimoto Yuki , Kamata Gosuke , Oshima Etsuko , Ishihara Takeshi , Kuroda Shigetoshi
Published: January 2010

Background/Aims: The presence of frontal or executive deficits in patients even at early stages of dementia is now widely recognized. We investigated the relationship between the scores of the Wisconsin card sorting test (WCST) and brain perfusion in patients with early dementia. Methods: A total of 77 subjects participated in this study. They underwent the WCST and brain single photon emission computed tomography with 99mTc-ethylcisteinate dimer. We analyzed the data using a regional cerebral blood flow (rCBF) quantification software program, 3DSRT. Results: The number of categories achieved (CA) scores of the WCST had a weakly positive correlation with regional cerebral blood flow in the bilateral precentral, bilateral callosomarginal, bilateral pericallosal, right thalamus, left central and left parietal segments. The number of perseverative errors of the Nelson type (PEN) scores had a weakly negative correlation with rCBF in the right thalamus. Conclusion: The results in this study suggest that CA scores mainly reflect the function of the precentral segments, especially the left side, and that PEN scores correlate with rCBF in the right thalamus. The results suggest that CA scores and PEN scores should be differentially estimated in the WCST.
Role of Myo-Inositol by Magnetic Resonance Spectroscopy in Early Diagnosis of Alzheimer’s Disease in APP/PS1 Transgenic Mice
Authors: Chen Shuang-Qing , Wang Pei-Jun , Ten Gao-Jun , Zhan Wei , Li Ming-Hua , Zang Feng-Chao
Published: January 2010

Background/Aims: To explore the potential value of myo-inositol (mIns), which is regarded as a biomarker for early diagnosis of Alzheimer’s disease, in APP/PS1 transgenic (tg) mice detected by 1H-MRS. Methods:1H-MRS was performed in 30 APP/PS1 tg mice and 20 wild-type (wt) littermates at 3, 5 and 8 months of age. Areas under the peak of N-acetylaspartate (NAA), mIns and creatine (Cr) in the frontal cortex and hippocampus were measured, and the NAA/Cr and mIns/Cr ratios were analyzed quantitatively. Results: Compared with the wt mice, the mIns/Cr ratio of the 3-month-old tg mice was significantly higher (p < 0.05), and pathology showed activation and proliferation of astrocytes in the frontal cortex and hippocampus. The concentration of NAA was significantly lower at 8 and 8 months of age (p < 0.05). According to the threshold of mIns/Cr that was adopted to separate the tg from the wt mice, the rate of correct predictions was 82, 94 and 95%, respectively, for 3, 5 and 8 months. Conclusion: Of the early AD metabolites as detected by 1H-MRS, mIns is the most valuable marker for assessment of AD. Quantitative analysis of mIns may provide important clues for early diagnosis of AD.
Apoptosis of Oligodendrocytes and Post-Translational Modifications of Myelin Basic Protein in Multiple Sclerosis: Possible Role for the Early Stages of Multiple Sclerosis
Authors: Artemiadis Artemios K. , Anagnostouli Maria C.
Published: January 2010

Recent studies outline apoptosis of oligodendrocytes (OLDs) as an early event prior to the formation of the demyelinated plaque and post-translational modifications (PTMs) of myelin basic protein as characteristic processes of normal-appearing white matter in multiple sclerosis (MS). We reviewed reports using the following keywords: apoptosis, PTMs, autoimmunity and multiple sclerosis in all possible combinations. Introductory basic scientific information is included for the non-experts. Given the standard and ongoing studies, we raise the hypothesis that, at least in some cases, defective apoptosis of OLDs, early in the course of the disease, and post-translationally modified molecules lead to the activation of immune responses and eventually to autoimmunity. Autoimmune reactions and epitope spreading that take place in the course of the disease might obscure the initial events and leave most investigators blind to etiopathogenesis. Our paper outlines the need for studies at the very early stages of the disease, as well as sequential ones, in order to give us a valuable hint about the clarification of the cause(s) of the different clinical subtypes of MS.
Distribution and Nerve Pathways of Neurons Supplying the Bulbourethral Gland in the Pig
Authors: Klimczuk M. , Kaleczyc J.
Published: January 2010

The present study has disclosed for the first time the distribution and peripheral nerve pathways of autonomic and primary afferent neurons projecting to the bulbourethral gland (BG) in a mammalian species, the pig (n = 5), using combined retrograde tracing and cutting the hypogastric (n = 3) or pelvic (n = 3) nerve. Neurons projecting to the right BG were found in pelvic ganglia (PG), sympathetic chain ganglia (SChG; L2–S3), the caudal mesenteric ganglion (CaMG) and dorsal root ganglia (DRG; L1–L3, S1–S3). In general, the majority (about 75%) of them were located in the ipsilateral ganglia. Results of denervation experiments suggest that the neurons located in CaMG, and lumbar SChG and DRG project through the hypogastric nerve while processes of those found in the sacral SChG and DRG travel through the pelvic nerve or pelvic branch of the pudendal nerve. Moreover, the results obtained also suggest that the ‘crossing points’ (i.e. the areas where nerve fibres reach the opposite side) for the neurons found in the contralateral CaMG are located partly at the level of this ganglion and, for a smaller number of the nerve cells, at the level of the pelvic plexus. The crossing points for the SChG and DRG neurons are probably situated at the level of sympathetic chains and, for sacral SChG neurons, at the level of the pelvic plexus. The diversity of sources of the nerve supply to the porcine BG corresponds well with the variety (as previously distinguished with immunohistochemistry) of its intrinsic nerve fibre populations.
Bacteria in the Chronic Ear
Authors: Palva T. , Kärjä J. , Palva A. , Raunio V.
Published: January 2010

Results of bacteriological analyses carried out in 480 chronic ears showed that initially, 401 ears (83.5%) were infected; the most frequent bacteria were Ps. aeruginosa and St. aureus (22.5 and 21.3%). Local preoperative treatment reduced the number of infected ears to 48.2%. Specimens from the mastoid antrum and/or cells were positive in 50% of cholesteatoma ears and 20% of chronic ostitic ears. Bacteria were cultured even in 11% in dry or culture-negative ears. Ps. aeruginosa strains were most sensitive to streptomycin (69%) and next to colistin (31%). St. aureus was best sensitive to streptomycin (90%) and chloramphenicol (72%). Against Proteus strains, streptomycin was the most effective (82%) followed next by chloramphenicol (70%). Postoperative wound infection appeared in 11 ears (2.3%) and was most often due to St. aureus. Prolonged middle ear and ear canal infection continued postoperatively in 37 ears (7.7%), the main agent being Ps. aeruginosa.
The Diagnostic Importance of the Galvanic Test in Otoneurology
Authors: Pfaltz C.R.
Published: January 2010

Bipolar, binaural stimulation of the human vestibular system causes nystagmus. This perstimulatory nystagmic reaction can even be elicited if the vestibular endorgan is destroyed but it will be considerably diminished or even abolished if the peripheral neuron is damaged. Spontaneous vestibular nystagmus of peripheral origin is always suppressed by galvanic stimulation whereas central vestibular spontaneous nystagmus will hardly change its pattern. In supratentorial vestibular lesions, located subcortically or even cortically, the liminar and supraliminar galvanic reaction may show a very characteristic pattern thus contributing valuable information with respect to the differential diagnosis of peripheral and central vestibular disorders. The most important diagnostic value of this test, if it is performed under nystagmographic control (PENG), is based on the fact, that the presence of a normal galvanic response depends entirely upon the integrity of the neuronal elements of the vestibular ganglion and upon the conductivity of the vestibular nerve. It is, therefore, at present the only diagnostic method allowing the differentiation of an endorgan lesion from a lesion of the peripheral vestibular neuron.
Das ischämische Syndrom des Innenohres
Authors: Spoendlin H.
Published: January 2010

The first prohably still reversible histopathological changes in the inner ear after interruption of the blood supply to the labyrinth are described. This acute ischemique syndrome is characterized by a swelling of the dendrites to the inner hair cells, protrusions from the surface of the stria and the spiral ligament. There is evidence that vascular spasms plays a great role in the aetiology of sudden deafness. In animal experiments spontaneous and induced spasms is regularly seen in the branches of the basilar artery. According to the experience of the ENT Department of the University of Zurich there are good changes for a recovery of the ear when the patients are treated as soon as possible with large doses of Eupaverin.
Deformations of the Temporal Bone in Head Trauma
Authors: Dürrer J. , Bušek J.
Published: January 2010

Deformations of the temporal bone due to head injury have been experimentally studied with a tensometer. Three types of oscillation waves have been ascertained: (1) the simple wave in normal elasticity of the bone tissue; (2) the widened wave in the partial loss of elasticity, and (3) the wave in fractured bone.
Peek-a-Boo Audiometry
Authors: van den Horst A.P.J.M. , Kuyper P.
Published: January 2010

For the audiological examinations of infants one needs a battery of tests. We developed an audiometric technique called Peek-a-Boo audiometry. It offers various ways to test and to condition the child. There is a good agreement between Peek-a-Boo audiograms and headphone audiograms taken at a later time.