bluuebunny/crossref_metadata_2025 huggingface dataset:
Female sex and estrogen receptor-β attenuate cardiac remodeling and apoptosis in pressure overload
Authors: Fliegner Daniela , Schubert Carola , Penkalla Adam , Witt Henning , Kararigas George , Dworatzek Elke , Staub Eike , Martus Peter , Noppinger Patricia Ruiz , Kintscher Ulrich , Gustafsson Jan-Åke , Regitz-Zagrosek Vera
Published: April 2010

We investigated sex differences and the role of estrogen receptor-β (ERβ) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ERβ knockout (ERβ−/−) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery. Left ventricular (LV) samples were analyzed by microarray profiling, real-time RT-PCR, and histology. After 9 wk, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. ERβ deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that WT male hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than WT female hearts. ERβ−/− mice exhibited a different transcriptional response. ERβ−/−/TAC mice of both sexes exhibited induction of proapoptotic genes with a stronger expression in ERβ−/− males. Cardiac fibrosis was more pronounced in male WT/TAC than in female mice. This difference was abolished in ERβ−/− mice. The number of apoptotic nuclei was increased in both sexes of ERβ−/−/TAC mice, most prominent in males. Female sex offers protection against ventricular chamber dilation in the TAC model. Both female sex and ERβ attenuate the development of fibrosis and apoptosis, thus slowing the progression to heart failure.
Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice
Authors: Zhang Hongyu , Schin MaryLee , Saha Jharna , Burke Kathleen , Holzman Lawrence B. , Filipiak Wanda , Saunders Thomas , Xiang Minghui , Heilig Charles W. , Brosius Frank C.
Published: April 2010

Increased expression of the facilitative glucose transporter, GLUT1, leads to glomerulopathy that resembles diabetic nephropathy, whereas prevention of enhanced GLUT1 expression retards nephropathy. While many of the GLUT1-mediated effects are likely due to mesangial cell effects, we hypothesized that increased GLUT1 expression in podocytes also contributes to the progression of diabetic nephropathy. Therefore, we generated two podocyte-specific GLUT1 transgenic mouse lines (driven by a podocin promoter) on a db/m C57BLKS background. Progeny of the two founders were used to generate diabetic db/db and control db/m littermate mice. Immunoblots of glomerular lysates showed that transgenic mice had a 3.5-fold ( line 1) and 2.1-fold ( line 2) increase in GLUT1 content compared with wild-type mice. Both lines showed similar increases in fasting blood glucose and body weights at 24 wk of age compared with wild-type mice. Mesangial index (percent PAS-positive material in the mesangial tuft) increased 88% ( line 1) and 75% ( line 2) in the wild-type diabetic mice but only 48% ( line 1) and 39% ( line 2) in the diabetic transgenic mice ( P < 0.05, transgenic vs. wild-type mice). This reduction in mesangial expansion was accompanied by a reduction in fibronectin accumulation, and vascular endothelial growth factor (VEGF) levels increased only half as much in the transgenic diabetic mice as in wild-type diabetic mice. Levels of nephrin, neph1, CD2AP, podocin, and GLUT4 were not significantly different in transgenic compared with wild-type mice. Taken together, increased podocyte GLUT1 expression in diabetic mice does not contribute to early diabetic nephropathy; surprisingly, it protects against mesangial expansion and fibronectin accumulation possibly by blunting podocyte VEGF increases.
The ANG-(1–7)/ACE2/mas axis in the regulation of nephron function
Authors: Ferrario Carlos M. , Varagic Jasmina
Published: April 2010

The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1–7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1–7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease.
Evidence that actomyosin cross bridges contribute to “passive” tension in detrusor smooth muscle
Authors: Ratz Paul H. , Speich John E.
Published: April 2010

Contraction of detrusor smooth muscle (DSM) at short muscle lengths generates a stiffness component we termed adjustable passive stiffness (APS) that is retained in tissues incubated in a Ca2+-free solution, shifts the DSM length-passive tension curve up and to the left, and is softened by muscle strain and release (strain softened). In the present study, we tested the hypothesis that APS is due to slowly cycling actomyosin cross bridges. APS and active tension produced by the stimulus, KCl, displayed similar length dependencies with identical optimum length values. The myosin II inhibitor blebbistatin relaxed active tension maintained during a KCl-induced contraction and the passive tension maintained during stress-relaxation induced by muscle stretch in a Ca2+-free solution. Passive tension was attributed to tension maintaining rather than tension developing cross bridges because tension did not recover after a rapid 10% stretch and release as it did during a KCl-induced contraction. APS generated by a KCl-induced contraction in intact tissues was preserved in tissues permeabilized with Triton X-100. Blebbistatin and the actin polymerization inhibitor latrunculin-B reduced the degree of APS generated by a KCl-induced contraction. The degree of APS generated by KCl was inhibited to a greater degree than was the peak KCl-induced tension by rhoA kinase and cyclooxygenase inhibitors. These data support the hypothesis that APS is due to slowly cycling actomyosin cross bridges and suggest that cross bridges may play a novel role in DSM that uniquely serves to ensure proper contractile function over an extreme working length range.
Molecular structure of tail tendon fibers in TIEG1 knockout mice using synchrotron diffraction technology
Authors: Gumez Laurie , Bensamoun Sabine F. , Doucet Jean , Haddad Oualid , Hawse John R. , Subramaniam Malayannan , Spelsberg Thomas C. , Pichon Chantal
Published: April 2010

The purpose of this study was to characterize the effect of TIEG1 on the molecular structure of collagen within tail tendon fibers using 3-mo-old female C57BL/6 wild-type (WT) and TIEG1 KO mice. Synchrotron X-ray microdiffraction experiments were carried out on single tendon fibers extracted from the WT and TIEG1 KO dorsal tail tendon. The fibers were scanned in the radial direction, and X-ray patterns were obtained. From these patterns, the meridional direction was analyzed through X-ray intensity profile. In addition, collagen content was investigated using hydroxyproline assays, and qualitative real-time PCR experiments were performed on RNA isolated from fibroblasts to examine specific gene expression changes. The results showed different X-ray diffraction patterns between WT and TIEG1 KO tendon fibers, indicating a disorganization of the collagen structure for the TIEG1 KO compared with WT mice. Furthermore, the analyses of the X-ray intensity profiles exhibited a higher (23 Å) period of collagen for the TIEG1 KO compared with the WT mice. The results of the hydroxyproline assays revealed a significant decrease in the TIEG1 KO compared with WT mice, leading to a decrease in the total amount of collagen present within the TIEG1 KO tendons. Moreover, qualitative real-time PCR results showed differences in the expression profiles of specific genes known to play important roles in tendon fiber development. These data further elucidate the role of TIEG1 on tendon structure and could explain the previous defects in the structure-function relationship found for TIEG1 KO tendon fibers.
Dynamic cerebral autoregulation during and after handgrip exercise in humans
Authors: Ogoh Shigehiko , Sato Kohei , Akimoto Toshinari , Oue Anna , Hirasawa Ai , Sadamoto Tomoko
Published: April 2010

The purpose of the present study was to examine the effect of static exercise on dynamic cerebral autoregulation (CA). In nine healthy subjects at rest before, during, and after static handgrip exercise at 30% maximum voluntary contraction, the response to an acute drop in mean arterial blood pressure and middle cerebral artery mean blood velocity was examined. Acute hypotension was induced nonpharmacologically via rapid release of bilateral thigh occlusion cuffs. Subjects were instructed to avoid executing a Valsalva maneuver during handgrip. To quantify dynamic CA, the rate of regulation (RoR) was calculated from the change in cerebral vascular conductance index during the transient fall in blood pressure. There was no significant difference in RoR between rest (mean ± SE; 0.278 ± 0.052/s), exercise (0.333 ± 0.053/s), and recovery (0.305 ± 0.059/s) conditions ( P = 0.747). In addition, there was no significant difference in the rate of absolute cerebral vasodilatory response to acute hypotension between three conditions ( P = 0.737). This finding indicates that static exercise and related elevations in blood pressure do not alter dynamic CA.
Neural Substrates of Graphomotor Sequence Learning: A Combined fMRI and Kinematic Study
Authors: Swett Bruce A. , Contreras-Vidal Jose L. , Birn Rasmus , Braun Allen
Published: April 2010

The goal of this study was to characterize the dynamics and functional connectivity of brain networks associated with fast (short-term) learning of handwriting using functional magnetic resonance imaging. Participants ( n = 12) performed a graphomotor sequence learning task (naïve subjects learning to draw simple, 3-stroke Chinese word characters), which focused the learning process on the kinematic aspects of sequence learning instead of on the production of the line segments. Learning of the graphomotor sequence was demonstrated by a progressive improvement in movement smoothness as assessed by normalized jerk scores. Examination of the patterns of regional neural activity and functional connectivity during sequence learning demonstrated that cortical regions, which may support visuomotor mapping components of the task, were active prior to subcortical areas that may play a role in encoding and refining the novel sequences. Importantly, differences in the time course of recruitment of basal ganglia and cerebellar networks suggest distinct but integrated roles in the encoding and refining of the handwritten sequences. This implies multiple kinematic representations of graphomotor trajectories may be encoded at various spatiotemporal scales.
Insect Hygroreceptor Responses to Continuous Changes in Humidity and Air Pressure
Authors: Tichy H. , Kallina W.
Published: April 2010

The most favored model of humidity transduction views the cuticular wall of insect hygroreceptive sensilla as a hygromechanical transducer. Hygroscopic swelling or shrinking alters the geometry of the wall, deforming the dendritic membranes of the moist and dry cells. The small size the sensilla and their position surrounded by elevated structures creates technical difficulties to mechanically stimulate them by direct contact. The present study investigated hygroreceptors on the antennae of the cockroach and the stick insect. Accurately controlled, homogeneous mechanical input was delivered by modulating air pressure. Both the moist and dry cells responded not only to changes in air pressure but also in the opposite direction, as observed during changes in air humidity. The moist cell's excitatory response to increasing humidity and increasing air pressure implies that swelling of the hygroscopic cuticle compresses the dendrites, and the dry cell's excitatory response to decreasing humidity and decreasing air pressure implies that shrinking of the hygroscopic cuticle expands the dendrites. The moist and dry cells of the stick insect are more sensitive to pressure changes than those of the cockroach, but the responses to air pressure are generally weaker than to humidity. Therefore the hygroreceptive sensilla differ in their physical properties and constitutions. Furthermore, the mechanical parameters associated with homogeneous changes in air pressure on the sensillum surface can only partially account for the responses of the moist and dry cells of both species to humidity stimulation.
Response Sensitivity of Barrel Neuron Subpopulations to Simulated Thalamic Input
Authors: Pesavento Michael J. , Rittenhouse Cynthia D. , Pinto David J.
Published: April 2010

Our goal is to examine the relationship between neuron- and network-level processing in the context of a well-studied cortical function, the processing of thalamic input by whisker-barrel circuits in rodent neocortex. Here we focus on neuron-level processing and investigate the responses of excitatory and inhibitory barrel neurons to simulated thalamic inputs applied using the dynamic clamp method in brain slices. Simulated inputs are modeled after real thalamic inputs recorded in vivo in response to brief whisker deflections. Our results suggest that inhibitory neurons require more input to reach firing threshold, but then fire earlier, with less variability, and respond to a broader range of inputs than do excitatory neurons. Differences in the responses of barrel neuron subtypes depend on their intrinsic membrane properties. Neurons with a low input resistance require more input to reach threshold but then fire earlier than neurons with a higher input resistance, regardless of the neuron's classification. Our results also suggest that the response properties of excitatory versus inhibitory barrel neurons are consistent with the response sensitivities of the ensemble barrel network. The short response latency of inhibitory neurons may serve to suppress ensemble barrel responses to asynchronous thalamic input. Correspondingly, whereas neurons acting as part of the barrel circuit in vivo are highly selective for temporally correlated thalamic input, excitatory barrel neurons acting alone in vitro are less so. These data suggest that network-level processing of thalamic input in barrel cortex depends on neuron-level processing of the same input by excitatory and inhibitory barrel neurons.
fMRI-Adaptation and Category Selectivity in Human Ventral Temporal Cortex: Regional Differences Across Time Scales
Authors: Weiner Kevin S. , Sayres Rory , Vinberg Joakim , Grill-Spector Kalanit
Published: April 2010

Repeating object images produces stimulus-specific repetition suppression referred to as functional magnetic resonance imaging-adaptation (fMRI-A) in ventral temporal cortex (VTC). However, the effects of stimulus repetition on functional selectivity are largely unknown. We investigated the effects of short-lagged (SL, immediate) and long-lagged (LL, many intervening stimuli) repetitions on category selectivity in VTC using high-resolution fMRI. We asked whether repetition produces scaling or sharpening of fMRI responses both within category-selective regions as well as in the distributed response pattern across VTC. Results illustrate that repetition effects across time scales vary quantitatively along an anterior-posterior axis and qualitatively along a lateral-medial axis. In lateral VTC, both SL and LL repetitions produce proportional fMRI-A with no change in either selectivity or distributed responses as predicted by a scaling model. Further, there is larger fMRI-A in anterior subregions irrespective of category selectivity. Medial VTC exhibits similar scaling effects during SL repetitions. However, for LL repetitions, both the selectivity and distributed pattern of responses vary with category in medial VTC as predicted by a sharpening model. Specifically, there is larger fMRI-A for nonpreferred categories compared with the preferred category, and category selectivity does not predict fMRI-A across the pattern of distributed response. Finally, simulations indicate that different neural mechanisms likely underlie fMRI-A in medial compared to lateral VTC. These results have important implications for future fMRI-A experiments because they suggest that fMRI-A does not reflect a universal neural mechanism and that results of fMRI-A experiments will likely be paradigm independent in lateral VTC but paradigm dependent in medial VTC.
LeishmaniaInterferes with Host Cell Signaling to Devise a Survival Strategy
Authors: Bhardwaj Suvercha , Srivastava Neetu , Sudan Raki , Saha Bhaskar
Published: April 2010

The protozoan parasiteLeishmania spp.exists as extracellular promastigotes in its vector whereas it resides and replicates as amastigotes within the macrophages of its mammalian host. As a survival strategy,Leishmaniamodulates macrophage functions directly or indirectly. The direct interference includes prevention of oxidative burst and the effector functions that lead to its elimination. The indirect effects include the antigen presentation and modulation of T cell functions in such a way that the effector T cells help the parasite survive by macrophage deactivation. Most of these direct and indirect effects are regulated by host cell receptor signaling that occurs through cycles of phosphorylation and dephosphorylation in cascades of kinases and phosphatases. This review highlights howLeishmaniaselectively manipulates the different signaling pathways to ensure its survival.
Temperature Control in Spark Plasma Sintering: An FEM Approach
Authors: Molénat G. , Durand L. , Galy J. , Couret A.
Published: April 2010

Powder consolidation assisted by pulsed current and uniaxial pressure, namely, Spark Plasma Sintering (SPS), is increasingly popular. One limitation however lies in the difficulty of controlling the sample temperature during compaction. The aim of this work is to present a computational method for the assembly temperature based on the finite elements method (FEM). Computed temperatures have been compared with experimental data for three different dies filled with three materials with different electrical conductivities (TiAl, SiC, ). The results obtained are encouraging: the difference between computed and experimental values is less than 5%. This allows thinking about this FEM approach as a predictive tool for selecting the right control temperatures in the SPS machine.
High-Fat Diet-Induced Neuropathy of Prediabetes and Obesity: Effect of PMI-5011, an Ethanolic Extract ofArtemisia dracunculusL.
Authors: Watcho Pierre , Stavniichuk Roman , Ribnicky David M. , Raskin Ilya , Obrosova Irina G.
Published: April 2010

Artemisiaspecies are a rich source of herbal remedies with antioxidant and anti-inflammatory properties. We evaluated PMI-5011, an ethanolic extract ofArtemisia dracunculusL., on neuropathy in high-sfat diet-fed mice, a model of prediabetes and obesity developing oxidative stress and proinflammatory changes in peripheral nervous system. C57Bl6/J mice fed high-fat diet for 16 weeks developed obesity, moderate nonfasting hyperglycemia, nerve conduction deficit, thermal and mechanical hypoalgesia, and tactile allodynia. They displayed 12/15-lipoxygenase overexpression, 12(S)-hydroxyeicosatetraenoic acid accumulation, and nitrosative stress in peripheral nerve and spinal cord. PMI-5011 (500 mgkg-1d-1, 7 weeks) normalized glycemia, alleviated nerve conduction slowing and sensory neuropathy, and reduced 12/15-lipoxygenase upregulation and nitrated protein expression in peripheral nervous system. PMI-5011, a safe and nontoxic botanical extract, may find use in treatment of neuropathic changes at the earliest stage of disease.
Percutaneous Liver Biopsy after Living Donor Liver Transplantation Resulting in Fulminant Hepatic Failure: The First Reported Case of Hepatic Compartment Syndrome
Authors: Nissen Nicholas N. , Geller Stephen A. , Klein Andrew , Colquhoun Steve , Yamini David , Tran Tram T. , Weinberg Benjamin , Winn Julie , Poordad Fred
Published: April 2010

A 28-year-old female who underwent live donor liver transplantation 3 years prior presented after percutaneous liver biopsy with abdominal and shoulder pain, nausea, vomiting, and elevated liver enzymes. Computed tomography (CT) showed an intrahepatic and subcapsular hematoma. There was a progressive increase in liver enzymes, bilirubin, and INR and a decline in hemoglobin. Subsequent CT imaging revealed flattening of the portal vein consistent with compression by the enlarging hematoma. Liver failure ensued and the patient required urgent retransplantation. The explant demonstrated ischemic necrosis of greater than 90% of the liver parenchyma. We report this case of “Hepatic Compartment Syndrome” leading to fulminant hepatic failure.
Targeting TLR/IL-1R Signalling in Human Diseases
Authors: Loiarro Maria , Ruggiero Vito , Sette Claudio
Published: April 2010

The members of Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily play a fundamental role in the immune response. These receptors detect microbial components and trigger complex signalling pathways that result in increased expression of multiple inflammatory genes. On the other hand, an aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases, raising the interest in the development of therapeutic strategies for the control of their function. In this review, we illustrate the structural and functional features of TLR/IL-1R proteins and discuss some recent advances in the approaches undertaken to develop anti-inflammatory therapeutic drugs. In particular, we will focus on inhibitors, such as decoy peptides and synthetic mimetics, that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R superfamily. Given their central role in innate and adaptive immune responses, it is foreseen that pharmaceutical modulation of TLR/IL-1R signalling pathways by these drugs might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.
Progress on Antiangiogenic Therapy for Patients with Malignant Glioma
Authors: Ahluwalia Manmeet S. , Gladson Candece L.
Published: April 2010

Glioblastoma (GBM) is the most common primary brain tumor occurring in America. Despite recent advances in therapeutics, the prognosis for patients with newly diagnosed GBM remains dismal. As these tumors characteristically show evidence of angiogenesis (neovascularization) there has been great interest in developing anti-angiogenic therapeutic strategies for the treatment of patients with this disease and some anti-angiogenic agents have now been used for the treatment of patients with malignant glioma tumors. Although the results of these clinical trials are promising in that they indicate an initial therapeutic response, the anti-angiogenic therapies tested to date have not changed the overall survival of patients with malignant glioma tumors. This is due, in large part, to the development of resistance to these therapies. Ongoing research into key features of the neovasculature in malignant glioma tumors, as well as the general angiogenesis process, is suggesting additional molecules that may be targeted and an improved response when both the neovasculature and the tumor cells are targeted. Prevention of the development of resistance may require the development of anti-angiogenic strategies that induce apoptosis or cell death of the neovasculature, as well as an improved understanding of the potential roles of circulating endothelial progenitor cells and vascular co-option by tumor cells, in the development of resistance.
The Bright and the Dark Sides of DNA Repair in Stem Cells
Authors: Frosina Guido
Published: April 2010

DNA repair is a double-edged sword in stem cells. It protects normal stem cells in both embryonic and adult tissues from genetic damage, thus allowing perpetuation of intact genomes into new tissues. Fast and efficient DNA repair mechanisms have evolved in normal stem and progenitor cells. Upon differentiation, a certain degree of somatic mutations becomes more acceptable and, consequently, DNA repair dims. DNA repair turns into a problem when stem cells transform and become cancerous. Transformed stem cells drive growth of a number of tumours (e.g., high grade gliomas) and being particularly resistant to chemo- and radiotherapeutic agents often cause relapses. The contribution of DNA repair to resistance of these tumour-driving cells is the subject of intense research, in order to find novel agents that may sensitize them to chemotherapy and radiotherapy.
Pseudo‐Steady‐State Productivity Formula for a Partially Penetrating Vertical Well in a Box‐Shaped Reservoir
Authors: Lu Jing , Tiab Djebbar
Published: April 2010

For a bounded reservoir with no flow boundaries, the pseudo‐steady‐state flow regime is common at long‐producing times. Taking a partially penetrating well as a uniform line sink in three dimensional space, by the orthogonal decomposition of Dirac function and using Green′s function to three‐dimensional Laplace equation with homogeneous Neumann boundary condition, this paper presents step‐by‐step derivations of a pseudo‐steady‐state productivity formula for a partially penetrating vertical well arbitrarily located in a closed anisotropic box‐shaped drainage volume. A formula for calculating pseudo skin factor due to partial penetration is derived in detailed steps. A convenient expression is presented for calculating the shape factor of an isotropic rectangle reservoir with a single fully penetrating vertical well, for arbitrary aspect ratio of the rectangle, and for arbitrary position of the well within the rectangle.
Mechanical and Electrophysiological Properties of the Sarcolemma of Muscle Fibers in Two Murine Models of Muscle Dystrophy: Col6a1−/−and Mdx
Authors: Canato M. , Dal Maschio M. , Sbrana F. , Raiteri R. , Reggiani C. , Vassanelli S. , Megighian A.
Published: April 2010

This study aimed to analyse the sarcolemma of Col6a1−/−fibers in comparison with wild type and mdx fibers, taken as positive control in view of the known structural and functional alterations of their membranes. Structural and mechanical properties were studied in single muscle fibers prepared from FDB muscle using atomic force microscopy (AFM) and conventional electrophysiological techniques to measure ionic conductance and capacitance. While the sarcolemma topography was preserved in both types of dystrophic fibers, membrane elasticity was significantly reduced in Col6a1−/−and increased in mdx fibers. In the membrane of Col6a1−/−fibers ionic conductance was increased likely due to an increased leakage, whereas capacitance was reduced, and the action potential (ap) depolarization rate was reduced. The picture emerging from experiments on fibers in culture was consistent with that obtained on intact freshly dissected muscle. Mdx fibers in culture showed a reduction of both membrane conductance and capacitance. In contrast, in mdx intact FDB muscle resting conductance was increased while resting potential and ap depolarization rate were reduced, likely indicating the presence of a consistent population of severely altered fibers which disappear during the culture preparation.
Genetics of Endometrial Cancers
Authors: Okuda Tsuyoshi , Sekizawa Akihiko , Purwosunu Yuditiya , Nagatsuka Masaaki , Morioka Miki , Hayashi Masaki , Okai Takashi
Published: April 2010

Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen‐dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non‐endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A β‐catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non‐endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non‐endometrioid carcinomas.
Effects of Calcium and Vitamin D on MLH1 and MSH2 Expression in Rectal Mucosa of Sporadic Colorectal Adenoma Patients
Authors: Sidelnikov Eduard , Bostick Roberd M. , Flanders W. Dana , Long Qi , Fedirko Veronika , Shaukat Aasma , Daniel Carrie R. , Rutherford Robin E.
Published: April 2010

To further clarify and develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans and develop modifiable biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination, on key DNA mismatch repair proteins in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Colorectal crypt overall expression and distribution of MSH2 and MLH1 proteins in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, MSH2 expression along the full lengths of crypts increased by 61% (P = 0.11) and 30% (P = 0.36) in the vitamin D and calcium groups, respectively, relative to the placebo group. The estimated calcium and vitamin D treatment effects were more pronounced in the upper 40% of crypts (differentiation zone) in which MSH2 expression increased by 169% (P = 0.04) and 107% (P = 0.13) in the vitamin D and calcium groups, respectively. These findings suggest that higher calcium and vitamin D intakes may result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients and that the strongest effects may be vitamin D related and in the differentiation zone of the colorectal crypt. Cancer Epidemiol Biomarkers Prev; 19(4); 1022–32. ©2010 AACR.
Mammographic Density Change with 1 Year of Aerobic Exercise among Postmenopausal Women: A Randomized Controlled Trial
Authors: Woolcott Christy G. , Courneya Kerry S. , Boyd Norman F. , Yaffe Martin J. , Terry Tim , McTiernan Anne , Brant Rollin , Ballard-Barbash Rachel , Irwin Melinda L. , Jones Charlotte A. , Brar Sony , Campbell Kristin L. , McNeely Margaret L. , Karvinen Kristina H. , Friedenreich Christine M.
Published: April 2010

Background: The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial examined the influence of aerobic exercise on biological factors that are associated with breast cancer risk. Mammographic density, a secondary outcome, is reported here.

Methods: The ALPHA Trial was a parallel group randomized controlled trial conducted between May 2003 and July 2007. Postmenopausal, sedentary women ages 50 to 74 years (n = 320) were evenly randomized to aerobic exercise (45 minutes, 5 days per week) or control (usual life-style) for 1 year. Dense fibroglandular tissue and nondense fatty tissue were measured from mammograms at baseline and 1 year using computer-assisted thresholding software for area measurements and a new technique that relies on the calibration of mammography units with a tissue-equivalent phantom for volumetric measurements.

Results: Nondense volume decreased in the exercise group relative to the control group (difference between groups = −38.5 cm3; 95% confidence interval, −61.6 to 15.4; P = 0.001). Changes in total body fat accounted for this decrease. Changes in dense area and dense volume, measures that have previously been associated with breast cancer risk, were not significantly different between the groups (P ≥ 0.26).

Conclusions: Achieving changes in mammographic measures may require more exercise or a study population with higher baseline levels of sex hormones or a wider range of mammographic density. The data from this study, however, suggest that the protective effect of exercise on breast cancer risk may operate through a mechanism other than mammographic density. Cancer Epidemiol Biomarkers Prev; 19(4); 1112–21. ©2010 AACR.
Temporal Trends in Geographic Disparities in Small-Area Breast Cancer Incidence and Mortality, 1988 to 2005
Authors: Schootman Mario , Lian Min , Deshpande Anjali D. , Baker Elizabeth A. , Pruitt Sandi L. , Aft Rebecca , Jeffe Donna B.
Published: April 2010

Background: A goal of Healthy People 2010 was to reduce health disparities. We determined the extent of reductions in geographic disparities in five breast cancer screening indicators.

Methods: We examined the extent of reductions in geographic disparities in five breast cancer screening indicators using data about women ages 40 years and older from 200 counties in the 1988 to 2005 Surveillance, Epidemiology, and End Results Program database. County-level trends in five breast cancer indicators (in situ, stage I, lymph node–positive, locally advanced, and mortality) were summarized using the estimated annual percentage change. Observed county rates were smoothed using hierarchical Bayesian spatiotemporal methods to calculate measures of absolute and relative geographic disparity and their changes over time.

Results: For in situ breast cancer, absolute disparity increased 93.7% during 1988 to 2005. Relative disparity declined 61.5% during the entire study period. Absolute and relative disparity for stage I breast cancer declined 18.5% and 41.4%, respectively. Absolute disparity for lymph node–positive breast cancer declined 37.9% during the study period, whereas relative disparity declined 17.6%. Absolute disparity for locally advanced breast cancer declined 66.5%, whereas relative disparity declined 17.8% during the study period. Absolute disparity in breast cancer mortality declined 60.5%, whereas relative disparity declined 19.8%.

Conclusions: Absolute and relative geographic disparities narrowed over time for all breast cancer indicators except for in situ breast cancer.

Impact: Progress has been made toward reducing geographic disparities in breast cancer outcomes, particularly in advanced-stage breast cancer incidence and mortality rates, although disparities remain. Cancer Epidemiol Biomarkers Prev; 19(4); 1122–31. ©2010 AACR.
Tobacco Smoke Exposure in Nonsmoking Hospitality Workers before and after a State Smoking Ban
Authors: Jensen Joni A. , Schillo Barbara A. , Moilanen Molly M. , Lindgren Bruce R. , Murphy Sharon , Carmella Steven , Hecht Stephen S. , Hatsukami Dorothy K.
Published: April 2010

Secondhand smoke exposure is estimated to account for 3,000 cancer deaths per year. Although several countries and states in the United States have passed comprehensive smoke-free laws to protect all employees, a significant number of workers are still not protected. The purpose of this study was to determine the effects of passing a comprehensive smoking ban that included bars and restaurants on biomarkers of nicotine and carcinogen exposure. The urines of nonsmoking employees (n = 24) of bars and restaurants that allowed smoking before the smoke-free law were analyzed before and after the law was passed in Minnesota. The results showed significant reductions in both total cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (free plus glucuronidated) after the ban was instituted. These results provide further support for the importance of protecting employees working in all venues. Cancer Epidemiol Biomarkers Prev; 19(4); 1016–21. ©2010 AACR.
Analgesic Use and Sex Steroid Hormone Concentrations in Postmenopausal Women
Authors: Gates Margaret A. , Tworoger Shelley S. , Eliassen A. Heather , Missmer Stacey A. , Hankinson Susan E.
Published: April 2010

Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all Ptrend ≥ 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (Ptrend = 0.04) and estrone sulfate (Ptrend = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (Ptrend = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (Ptrend = 0.001), free estradiol (Ptrend = 0.01), estrone sulfate (Ptrend = 0.03), and the ratio of estradiol to testosterone (Ptrend = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users. Cancer Epidemiol Biomarkers Prev; 19(4); 1033–41. ©2010 AACR.
Assessing the Amount of Unscheduled Screening (“Contamination”) in the Control Arm of the UK “Age” Trial
Authors: Kingston Nicola , Thomas Iyamide , Johns Louise , Moss Sue ,   the Trial Management Group
Published: April 2010

The UK Age Trial of mammographic screening from age 40 has reported a nonsignificant 17% reduction in breast cancer mortality calculated on an “intention to treat” basis. High levels of ad hoc screening in the control arm could potentially have diluted the estimated effect.

Objectives: To estimate the level of unscheduled mammography in the control arm of the UK Age Trial.

Methods: Data were obtained from questionnaires sent to a random sample of 3,706 women at five centers in the control arm of this trial. Questions included in the Office for National Statistics Omnibus Surveys about the timing of and reasons for any breast screening provided comparable data. The overall response rate was 58.8%.

Results: Overall, 24.9% (95% confidence interval, 23.0-26.8) of Age Trial controls responding reported ever having had a mammogram, 18.2% reported a mammogram for symptomatic reasons, and 8.4% reported unscheduled mammography. Overall, 4.0% and 1.8% of women reported symptomatic and unscheduled mammography, respectively, within the previous 12 months. Results from the Omnibus surveys were similar, 14.2% of women reported previous mammography for symptomatic reasons or follow-up after breast cancer and 6.8% reported unscheduled mammography.

Conclusions: The level of contamination due to mammographic screening in the control arm of the Age Trial was low and will have had a minimal effect on the estimated reduction in mortality from breast cancer.

Impact: Estimating the extent of screening in the control arm in randomized trials of screening is important to inform interpretation of the results. Cancer Epidemiol Biomarkers Prev; 19(4); 1132–6. ©2010 AACR.
Assessment of Automated Image Analysis of Breast Cancer Tissue Microarrays for Epidemiologic Studies
Authors: Bolton Kelly L. , Garcia-Closas Montserrat , Pfeiffer Ruth M. , Duggan Máire A. , Howat William J. , Hewitt Stephen M. , Yang Xiaohong R. , Cornelison Robert , Anzick Sarah L. , Meltzer Paul , Davis Sean , Lenz Petra , Figueroa Jonine D. , Pharoah Paul D.P. , Sherman Mark E.
Published: April 2010

Background: A major challenge in studies of etiologic heterogeneity in breast cancer has been the limited throughput, accuracy, and reproducibility of measuring tissue markers. Computerized image analysis systems may help address these concerns, but published reports of their use are limited. We assessed agreement between automated and pathologist scores of a diverse set of immunohistochemical assays done on breast cancer tissue microarrays (TMA).

Methods: TMAs of 440 breast cancers previously stained for estrogen receptor (ER)-α, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), ER-β, and aromatase were independently scored by two pathologists and three automated systems (TMALab II, TMAx, and Ariol). Agreement between automated and pathologist scores of negative/positive was measured using the area under the receiver operating characteristics curve (AUC) and weighted κ statistics for categorical scores. We also investigated the correlation between immunohistochemical scores and mRNA expression levels.

Results: Agreement between pathologist and automated negative/positive and categorical scores was excellent for ER-α and PR (AUC range = 0.98-0.99; κ range = 0.86-0.91). Lower levels of agreement were seen for ER-β categorical scores (AUC = 0.99-1.0; κ = 0.80-0.86) and both negative/positive and categorical scores for aromatase (AUC = 0.85-0.96; κ = 0.41-0.67) and HER2 (AUC = 0.94-0.97; κ = 0.53-0.72). For ER-α and PR, there was a strong correlation between mRNA levels and automated (ρ = 0.67-0.74) and pathologist immunohistochemical scores (ρ = 0.67-0.77). HER2 mRNA levels were more strongly correlated with pathologist (ρ = 0.63) than automated immunohistochemical scores (ρ = 0.41-0.49).

Conclusions: Automated analysis of immunohistochemical markers is a promising approach for scoring large numbers of breast cancer tissues in epidemiologic investigations. This would facilitate studies of etiologic heterogeneity, which ultimately may allow improved risk prediction and better prevention approaches. Cancer Epidemiol Biomarkers Prev; 19(4); 992–9. ©2010 AACR.
Longitudinal Predictors of Nonadherence to Maintenance of Mammography
Authors: Gierisch Jennifer M. , Earp Jo Anne , Brewer Noel T. , Rimer Barbara K.
Published: April 2010

Background: Regular adherence to screening mammography, also known as maintenance of mammography, reduces breast cancer morbidity and mortality. However, mammography maintenance is uncommon and little is know about why women do not maintain regular screening schedules. We investigated longitudinal predictors of women not maintaining adherence.

Methods: Participants were insured women enrolled in an intervention trial who had screening mammograms 8 to 9 months before study enrollment (n = 1,493). Data were collected from 2003 to 2008. We used discrete event history analysis to model nonadherence to mammography maintenance over three successive annual screening intervals (+ 2 months).

Results: Most (54%) women did not maintain screening adherence over 3 years. Women who did not maintain adherence were more likely to be ages 40 to 49 years, rate their health fair or poor, be less satisfied with their last mammography experiences, report one or more barriers to getting mammograms, be less than completely confident about getting their next mammograms (lower self-efficacy), or have weaker behavioral intentions. The odds of not maintaining adherence decreased over time.

Discussion: Although great strides have been achieved in increasing the proportion of women who have received mammograms, most women still are not maintaining regular mammography use over time. Our findings provide insights into targets for future mammography maintenance interventions. Cancer Epidemiol Biomarkers Prev; 19(4); 1103–11. ©2010 AACR.
Long-term Variation in Serum 25-Hydroxyvitamin D Concentration among Participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Hofmann Jonathan N. , Yu Kai , Horst Ronald L. , Hayes Richard B. , Purdue Mark P.
Published: April 2010

Molecular epidemiologic studies of vitamin D and risk of cancer and other health outcomes usually involve a single measurement of the biomarker 25-hydroxyvitamin D [25(OH)D] in serum or plasma. However, the extent to which 25(OH)D concentration at a single time point is representative of an individual's long-term vitamin D status is unclear. To address this question, we evaluated within-person variability in 25(OH)D concentrations across serum samples collected at three time points over a 5-year period among 29 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Blood collection took place year-round, although samples for a given participant were collected in the same month each year. The within-person coefficient of variation and intraclass correlation coefficient were calculated using variance components estimated from random effects models. Spearman rank correlation coefficients were calculated to evaluate agreement between measurements at different collection times (baseline, +1 year, +5 years). The within-subject coefficient of variation was 14.9% [95% confidence interval (CI), 12.4-18.1%] and the intraclass correlation coefficient was 0.71 (95% CI, 0.63-0.88). Spearman rank correlation coefficients comparing baseline to +1 year, +1 year to +5 years, and baseline to +5 years were 0.65 (95% CI, 0.37-0.82), 0.61 (0.29-0.81), and 0.53 (0.17-0.77), respectively. Slightly stronger correlations were observed after restricting to non-Hispanic Caucasian subjects. These findings suggest that serum 25(OH)D concentration at a single time point may be a useful biomarker of long-term vitamin D status in population-based studies of various diseases. Cancer Epidemiol Biomarkers Prev; 19(4); 927–31. ©2010 AACR.