bluuebunny/crossref_metadata_2025 huggingface dataset:
Membrane Receptor for Thyroid Hormone: Physiologic and Pharmacologic Implications
Authors: Davis Paul J. , Davis Faith B. , Mousa Shaker A. , Luidens Mary K. , Lin Hung-Yun
Published: January 2011

Plasma membrane integrin αvβ3 is a cell surface receptor for thyroid hormone at which nongenomic actions are initiated. L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (T3) promote angiogenesis and tumor cell proliferation via the receptor. Tetraiodothyroacetic acid (tetrac), a deaminated T4derivative, blocks the nongenomic proliferative and proangiogenic actions of T4and T3. Acting at the integrin independently of T4and T3, tetrac and a novel nanoparticulate formulation of tetrac that acts exclusively at the cell surface have oncologically desirable antiproliferative actions on multiple tumor cell survival pathway genes. These agents also block the angiogenic activity of vascular growth factors. Volume and vascular support of xenografts of human pancreatic, kidney, lung, and breast cancers are downregulated by tetrac formulations. The integrin αvβ3 receptor site for thyroid hormone selectively regulates signal transduction pathways and distinguishes between unmodified tetrac and the nanoparticulate formulation. The receptor also mediates nongenomic thyroid hormone effects on plasma membrane ion transporters and on intracellular protein trafficking.
microRNAs: Master Regulators as Potential Therapeutics in Cancer
Authors: Garofalo Michela , Croce Carlo M.
Published: January 2011

It has been demonstrated that all the known processes involved in cancer, including apoptosis, proliferation, survival, and metastasis, are regulated by small regulatory noncoding RNAs consisting of approximately 19–25 nucleotides; these are named microRNAs (miRNAs). Both loss and gain of miRNA function contribute to cancer development through the upregulation and silencing, respectively, of different target genes. Experimental evidence indicates that the use of miRNA mimics or anti-microRNAs may represent a powerful therapeutic strategy to interfere with key molecular pathways involved in cancer. This review provides insights about how micro- RNAs act as oncogenes and tumor suppressor genes and how these findings, along with our increasing understanding of miRNA regulation, can be applied to optimize recent miRNA-based technologies and make them suitable for clinical applications.
Modulation of Monoamine Receptors by Adaptor Proteins and Lipid Rafts: Role in Some Effects of Centrally Acting Drugs and Therapeutic Agents
Authors: Björk Karl , Svenningsson Per
Published: January 2011

The monoamines and their cognate receptors are widespread in the central nervous system and are vital for normal brain function. Dysfunction in these systems underlies several psychiatric and neurological disease states, and consequently monoamines are targets of a host of pharmacotherapies. This review provides an overview on how monoamine receptors are regulated by adaptor proteins and lipid rafts with emphasis on interactions in nerve cells. Monoamine receptors have prominent intracellular loops that provide binding sites for adaptor proteins. Receptor function is further modulated by cholesterol and submembranous microdomains termed lipid rafts. These interactions determine several facets of G protein–coupled receptor (GPCR) function including trafficking, localization, and signaling. Possible roles of adaptor proteins and lipid rafts in disease states and in mediating actions of drugs and therapeutic agents are also discussed.
Molecular Mechanisms and Treatment Options for Muscle Wasting Diseases
Authors: Rüegg Markus A. , Glass David J.
Published: January 2011

Loss of muscle mass can be the consequence of pathological changes, as observed in muscular dystrophies; or it can be secondary to cachexia-inducing diseases that cause muscle atrophy, such as cancer, heart disease, or chronic obstructive pulmonary disease; or it can be a consequence of aging or simple disuse. Although muscular dystrophies are rare, muscle loss affects millions of people worldwide. We discuss the molecular mechanisms involved in muscular dystrophy and in muscle atrophy and present current strategies aimed at ameliorating these diseases. Finally, we discuss whether lessons learned from studying muscular dystrophies will also be helpful for halting muscle loss secondary to nondystrophic diseases and whether strategies to halt muscle atrophy have potential for the treatment of muscular dystrophies.
Large-scale phosphoproteomic analysis of membrane proteins in renal proximal and distal tubule
Authors: Feric Marina , Zhao Boyang , Hoffert Jason D. , Pisitkun Trairak , Knepper Mark A.
Published: January 2011

Recent advances in mass spectrometry (MS) have provided means for large-scale phosphoproteomic profiling of specific tissues. Here, we report results from large-scale tandem MS [liquid chromatography (LC)-MS/MS]-based phosphoproteomic profiling of biochemically isolated membranes from the renal cortex, with focus on transporters and regulatory proteins. Data sets were filtered (by target-decoy analysis) to limit false-positive identifications to <2%. A total of 7,125 unique nonphosphorylated and 743 unique phosphorylated peptides were identified. Among the phosphopeptides identified were sites on transporter proteins, i.e., solute carrier (Slc, n = 63), ATP-binding cassette (Abc, n = 4), and aquaporin (Aqp, n = 3) family proteins. Database searches reveal that a majority of the phosphorylation sites identified in transporter proteins were previously unreported. Most of the Slc family proteins are apical or basolateral transporters expressed in proximal tubule cells, including proteins known to mediate transport of glucose, amino acids, organic ions, and inorganic ions. In addition, we identified potentially important phosphorylation sites for transport proteins from distal nephron segments, including the bumetanide-sensitive Na-K-2Cl cotransporter ( Slc12a1 or NKCC2) at Ser87, Thr101, and Ser126 and the thiazide-sensitive Na-Cl cotransporter ( Slc12a3 or NCC) at Ser71 and Ser124. A subset of phosphorylation sites in regulatory proteins coincided with known functional motifs, suggesting specific regulatory roles. An online database from this study ( http://dir.nhlbi.nih.gov/papers/lkem/rcmpd/ ) provides a resource for future studies of transporter regulation.
Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility
Authors: Gabunia Khatuna , Jain Surbhi , England Ross N. , Autieri Michael V.
Published: January 2011

Vascular smooth muscle cell (VSMC) migration is an important cellular event in multiple vascular diseases, including atherosclerosis, restenosis, and transplant vasculopathy. Little is known regarding the effects of anti-inflammatory interleukins on VSMC migration. This study tested the hypothesis that an anti-inflammatory Th2 interleukin, interleukin-19 (IL-19), could decrease VSMC motility. IL-19 significantly decreased platelet-derived growth factor (PDGF)-stimulated VSMC chemotaxis in Boyden chambers and migration in scratch wound assays. IL-19 significantly decreased VSMC spreading in response to PDGF. To determine the molecular mechanism(s) for these cellular effects, we examined the effect of IL-19 on activation of proteins that regulate VSMC cytoskeletal dynamics and locomotion. IL-19 decreased PDGF-driven activation of several cytoskeletal regulatory proteins that play an important role in smooth muscle cell motility, including heat shock protein-27 (HSP27), myosin light chain (MLC), and cofilin. IL-19 decreased PDGF activation of the Rac1 and RhoA GTPases, important integrators of migratory signals. IL-19 was unable to inhibit VSMC migration nor was able to inhibit activation of cytoskeletal regulatory proteins in VSMC transduced with a constitutively active Rac1 mutant (RacV14), suggesting that IL-19 inhibits events proximal to Rac1 activation. Together, these data are the first to indicate that IL-19 can have important inhibitory effects on VSMC motility and activation of cytoskeletal regulatory proteins. This has important implications for the use of anti-inflammatory cytokines in the treatment of vascular occlusive disease.
Functional characterization and modified rescue of novel AE1 mutation R730C associated with overhydrated cation leak stomatocytosis
Authors: Stewart Andrew K. , Kedar Prabhakar S. , Shmukler Boris E. , Vandorpe David H. , Hsu Ann , Glader Bertil , Rivera Alicia , Brugnara Carlo , Alper Seth L.
Published: January 2011

We report the novel, heterozygous AE1 mutation R730C associated with dominant, overhydrated, cation leak stomatocytosis and well-compensated anemia. Parallel elevations of red blood cell cation leak and ouabain-sensitive Na+ efflux (pump activity) were apparently unaccompanied by increased erythroid cation channel-like activity, and defined ouabain-insensitive Na+ efflux pathways of nystatin-treated cells were reduced. Epitope-tagged AE1 R730C at the Xenopus laevis oocyte surface exhibited severely reduced Cl− transport insensitive to rescue by glycophorin A (GPA) coexpression or by methanethiosulfonate (MTS) treatment. AE1 mutant R730K preserved Cl− transport activity, but R730 substitution with I, E, or H inactivated Cl− transport. AE1 R730C expression substantially increased endogenous oocyte Na+-K+-ATPase-mediated 86Rb+ influx, but ouabain-insensitive flux was minimally increased and GPA-insensitive. The reduced AE1 R730C-mediated sulfate influx did not exhibit the wild-type pattern of stimulation by acidic extracellular pH (pHo) and, unexpectedly, was partially rescued by exposure to sodium 2-sulfonatoethyl methanethiosulfonate (MTSES) but not to 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) or 2-(trimethylammonium)ethyl methanethiosulfonate bromide (MTSET). AE1 R730E correspondingly exhibited acid pHo-stimulated sulfate uptake at rates exceeding those of wild-type AE1 and AE1 R730K, whereas mutants R730I and R730H were inactive and pHo insensitive. MTSES-treated oocytes expressing AE1 R730C and untreated oocytes expressing AE1 R730E also exhibited unprecedented stimulation of Cl− influx by acid pHo. Thus recombinant cation-leak stomatocytosis mutant AE1 R730C exhibits severely reduced anion transport unaccompanied by increased Rb+ and Li+ influxes. Selective rescue of acid pHo-stimulated sulfate uptake and conferral of acid pHo-stimulated Cl− influx, by AE1 R730E and MTSES-treated R730C, define residue R730 as critical to selectivity and regulation of anion transport by AE1.
Mycobacterium ulcerans infections cause progressive muscle atrophy and dysfunction, and mycolactone impairs satellite cell proliferation
Authors: Houngbédji Germain Mabèrou , Bouchard Patrice , Frenette Jérôme
Published: January 2011

Clinical observations from Buruli ulcer (BU) patients in West Africa suggest that severe Mycobacterium ulcerans infections can cause skeletal muscle contracture and atrophy leading to significant impairment in function. In the present study, male mice C57BL/6 were subcutaneously injected with M. ulcerans in proximity to the right biceps muscle, avoiding direct physical contact between the infectious agent and the skeletal muscle. The histological, morphological, and functional properties of the muscles were assessed at different times after the injection. On day 42 postinjection, the isometric tetanic force and the cross-sectional area of the myofibers were reduced by 31% and 29%, respectively, in the proximate-infected muscles relative to the control muscles. The necrotic areas of the proximate-infected muscles had spread to 7% of the total area by day 42 postinjection. However, the number of central nucleated fibers and myogenic regulatory factors (MyoD and myogenin) remained stable and low. Furthermore, Pax-7 expression did not increase significantly in mycolactone-injected muscles, indicating that the satellite cell proliferation is abrogated by the toxin. In addition, the fibrotic area increased progressively during the infection. Lastly, muscle-specific RING finger protein 1 (MuRF-1) and atrogin-1/muscle atrophy F-box protein (atrogin-1/MAFbx), two muscle-specific E3 ubiquitin ligases, were upregulated in the presence of M. ulcerans . These findings confirmed that skeletal muscle is affected in our model of subcutaneous infection with M. ulcerans and that a better understanding of muscle contractures and weakness is essential to develop a therapy to minimize loss of function and promote the autonomy of BU patients.
Interdependence of HIF-1α and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression
Authors: Basu Rajit K. , Hubchak Susan , Hayashida Tomoko , Runyan Constance E. , Schumacker Paul T. , Schnaper H. William
Published: January 2011

Increasing evidence suggests that chronic kidney disease may develop following acute kidney injury and that this may be due, in part, to hypoxia-related phenomena. Hypoxia-inducible factor (HIF) is stabilized in hypoxic conditions and regulates multiple signaling pathways that could contribute to renal fibrosis. As transforming growth factor (TGF)-β is known to mediate renal fibrosis, we proposed a profibrotic role for cross talk between the TGF-β1 and HIF-1α signaling pathways in kidney cells. Hypoxic incubation increased HIF-1α protein expression in cultured human renal tubular epithelial cells and mouse embryonic fibroblasts. TGF-β1 treatment further increased HIF-1α expression in cells treated with hypoxia and also increased HIF-1α in normoxic conditions. TGF-β1 did not increase HIF-1α mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances normoxic HIF-1α translation. TGF-β receptor (ALK5) kinase activity was required for increased HIF-1α expression in response to TGF-β1, but not to hypoxia. A dominant negative Smad3 decreased the TGF-β-stimulated reporter activity of a HIF-1α-sensitive hypoxia response element. Conversely, a dominant negative HIF-1α construct decreased Smad-binding element promoter activity in response to TGF-β. Finally, blocking HIF-1α transcription with a biochemical inhibitor, a dominant negative construct, or gene-specific knockdown decreased basal and TGF-β1-stimulated type I collagen expression, while HIF-1α overexpression increased both. Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1α and suggest a new paradigm in which HIF-1α is necessary for normoxic, TGF-β1-stimulated renal cell fibrogenesis.
Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism
Authors: Wang Xiaoxin X. , Jiang Tao , Shen Yan , Santamaria Hannah , Solis Nathaniel , Arbeeny Cynthia , Levi Moshe
Published: January 2011

Diet-induced obesity (DIO) and insulin resistance in mice are associated with proteinuria, renal mesangial expansion, accumulation of extracellular matrix proteins, and activation of oxidative stress, proinflammatory cytokines, profibrotic growth factors, and the sterol regulatory element binding proteins, SREBP-1 and SREBP-2, that mediate increases in fatty acid and cholesterol synthesis. The purpose of the present study was to determine whether treatment of DIO mice with the vitamin D receptor (VDR) agonist doxercalciferol (1α-hydroxyvitamin D2) prevents renal disease. Our results indicate that treatment of DIO mice with the VDR agonist decreases proteinuria, podocyte injury, mesangial expansion, and extracellular matrix protein accumulation. The VDR agonist also decreases macrophage infiltration, oxidative stress, proinflammatory cytokines, and profibrotic growth factors. Furthermore, the VDR agonist also prevents the activation of the renin-angiotensin-aldosterone system including the angiotensin II type 1 receptor and the mineralocorticoid receptor. An additional novel finding of our study is that activation of VDR results in decreased accumulation of neutral lipids (triglycerides and cholesterol) and expression of adipophilin in the kidney by decreasing SREBP-1 and SREBP-2 expression and target enzymes that mediate fatty acid and cholesterol synthesis and increasing expression of the farnesoid X receptor. This study therefore demonstrates multiple novel effects of VDR activation in the kidney which prevent renal manifestations of DIO in the kidney.
Gender Differences of Plaque Characteristics in Elderly Patients with Stable Angina Pectoris: An Intravascular Ultrasonic Radiofrequency Data Analysis
Authors: Nakamura Tomohiro , Ogita Manabu , Ako Junya , Momomura Shin-ichi
Published: January 2011

The purpose of this study was to evaluate the relation between gender and plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) in patients with stable angina pectoris. Preinterventional VH-IVUS image was available for analysis in 88 men and 60 women patients. Women had significantly smaller vessel volume (12.7 ± 3.9 versus 14.5 ± 4.2 mm3/mm,P=.01) and smaller plaque volume (8.4 ± 3.5 versus 9.7 ± 3.5 mm3/mm,P=.04). However, these differences were no longer significant when corrected for body surface area (BSA). In VH-IVUS analysis, women had significantly higher dense calcium when corrected for BSA in the culprit lesion (volume: 0.32 ± 0.26 versus 0.44 ± 0.40 mm3/mm/BSA,P=.03; proportion: 8.2 ± 6.1 versus 11.2 ± 7.6%,P=.009). VH-IVUS analysis of plaque components in elderly patients with stable angina showed that women had higher calcium contents compared with men.
Properties of Cartilage on Micro- and Nanolevel
Authors: Chizhik Sergei A. , Wierzcholski Krzysztof , Trushko Anastasia V. , Zhytkova Mariya A. , Miszczak Andrzej
Published: January 2011

Results of investigation of the elastic modulus for cartilage tissue using a technique of micro- and nanoindentation performed with help of an atomic force microscope are presented. SEM and AFM methods were applied to visualize a topography of surface layers of the entire cartilage and as well as its slices and thus to reveal features of the collagen fibers orientation. The technique used for a quantitative evaluation of the elastic modulus under compression against a ball microindenter (curvature radius - 350 micron) and a nanoindenter (30 nm) is described. It was shown that the cartilage behavior is highly stabile under the load if the entire composite structure of cartilage tissue is engaged into the deformation process. Tribological characteristics were investigated using the ball indenter oscillated by a tuning fork. Dependence of the friction coefficient from applied loads was obtained that revealed strong influence of an interstitial fluid on friction properties. Friction coefficient of a rat cartilage tissue as 0.08 was obtained using a developed plant prototype for tribological measurements based on the AFM construction.
Case Report: Late Complication of a Dry Socket Treatment
Authors: Alemán Navas Ramón Manuel , Martínez Mendoza María Guadalupe
Published: January 2011

Dry socket is often treated in dentistry with intra-alveolar dressings; the use of them remains controversial and has been related to some side effects such as neuritis, foreign body reactions, and myospherulosis. We present a case of an intra-alveolar dressing (zinc-oxide eugenol paste) that mimicked a trigeminal neuralgia for 3 years and caused a right maxillary chronic osteomyelitis and foreign body reaction in a zone corresponding to the alveolus of the maxillary first molar. This long-term complication was successfully managed by complete removal of the foreign body and curettage of the affected area.
Animal Models of Bacterial Keratitis
Authors: Marquart Mary E.
Published: January 2011

Bacterial keratitis is a disease of the cornea characterized by pain, redness, inflammation, and opacity. Common causes of this disease are Pseudomonas aeruginosa and Staphylococcus aureus. Animal models of keratitis have been used to elucidate both the bacterial factors and the host inflammatory response involved in the disease. Reviewed herein are animal models of bacterial keratitis and some of the key findings in the last several decades.
Confounding Effects of Hormone Replacement Therapy in Protein Biomarker Studies
Authors: Pitteri Sharon J. , Hanash Samir M.
Published: January 2011

Background: We have recently investigated effects of hormone replacement therapy (HRT) on the serum proteome, and found a high proportion of proteins with altered levels associated with oral estrogen and/or estrogen plus progesterone treatment. Given this finding, we have investigated the extent to which exposure to HRT may have a confounding effect in the assessment of circulating proteins as cancer biomarkers.

Methods: We utilize mass spectrometry data collected from the HRT serum proteome studies to estimate the overall effect of postmenopausal hormone therapy on candidate ovarian cancer biomarkers that have been previously reported.

Results: Levels of approximately half of the proteins reported as potential ovarian cancer biomarkers were found to be affected by HRT. The impact of HRT on levels of insulin-like growth factor and inhibin protein families was found to be substantial.

Conclusions: We conclude that the potential confounding effect of HRT and other types of exposures should be taken into consideration in cancer biomarker study design.

Impact: HRT significantly affects the serum proteome and should be taken into account as part of biomarker study design and data analysis. Cancer Epidemiol Biomarkers Prev; 20(1); 134–9. ©2011 AACR.
Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent
Authors: Chang Bao-Li , Spangler Elaine , Gallagher Stephen , Haiman Christopher A. , Henderson Brian , Isaacs William , Benford Marnita L. , Kidd LaCreis R. , Cooney Kathleen , Strom Sara , Ingles Sue Ann , Stern Mariana C. , Corral Roman , Joshi Amit D. , Xu Jianfeng , Giri Veda N. , Rybicki Benjamin , Neslund-Dudas Christine , Kibel Adam S. , Thompson Ian M. , Leach Robin J. , Ostrander Elaine A. , Stanford Janet L. , Witte John , Casey Graham , Eeles Rosalind , Hsing Ann W. , Chanock Stephen , Hu Jennifer J. , John Esther M. , Park Jong , Stefflova Klara , Zeigler-Johnson Charnita , Rebbeck Timothy R.
Published: January 2011

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.

Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.

Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.

Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.

Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.
Feasibility of Identifying Pancreatic Cancer Based on Serum Metabolomics
Authors: Bathe Oliver F. , Shaykhutdinov Rustem , Kopciuk Karen , Weljie Aalim M. , McKay Andrew , Sutherland Francis R. , Dixon Elijah , Dunse Nicole , Sotiropoulos Dina , Vogel Hans J.
Published: January 2011

Background: We postulated that the abundance of various metabolites in blood would facilitate the diagnosis of pancreatic and biliary lesions, which could potentially prevent unnecessary surgery.

Methods: Serum samples from patients with benign hepatobiliary disease (n = 43) and from patients with pancreatic cancer (n = 56) were examined by 1H NMR spectroscopy to quantify 58 unique metabolites. Data were analyzed by “targeted profiling” followed by supervised pattern recognition and orthogonal partial least-squares discriminant analysis (O-PLS-DA) of the most significant metabolites, which enables comparison of the whole sample spectrum between groups.

Results: The metabolomic profile of patients with pancreatic cancer was significantly different from that of patients with benign disease (AUROC, area under the ROC curve, = 0.8372). Overt diabetes mellitus (DM) was identified as a possible confounding factor in the pancreatic cancer group. Thus, diabetics were excluded from further analysis. In this more homogeneous pancreatic cancer group, compared with benign cases, serum concentrations of glutamate and glucose were most elevated on multivariate analysis. In benign cases, creatine and glutamine were most abundant. To examine the usefulness of this test, a comparison was made to age- and gender-matched controls with benign lesions that mimic cancer, controlling also for presence of jaundice and diabetes (n = 14 per group). The metabolic profile in patients with pancreatic cancer remained distinguishable from patients with benign pancreatic lesions (AUROC = 0.8308).

Conclusions: The serum metabolomic profile may be useful for distinguishing benign from malignant pancreatic lesions.

Impact: Further studies will be required to study the effects of jaundice and diabetes. A more comprehensive metabolomic profile will be evaluated using mass spectrometry. Cancer Epidemiol Biomarkers Prev; 20(1); 140–7. ©2010 AACR.
Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers
Authors: Devaney James , Stirzaker Clare , Qu Wenjia , Song Jenny Z. , Statham Aaron L. , Patterson Kate I. , Horvath Lisa G. , Tabor Bruce , Coolen Marcel W. , Hulf Toby , Kench James G. , Henshall Susan M. , Pe Benito Ruth , Haynes Anne-Maree , Mayor Regina , Peinado Miguel A. , Sutherland Robert L. , Clark Susan J.
Published: January 2011

Background: Previously, we showed that gene suppression commonly occurs across chromosome 2q14.2 in colorectal cancer, through a process of long-range epigenetic silencing (LRES), involving a combination of DNA methylation and repressive histone modifications. We now investigate whether LRES also occurs in prostate cancer across this 4-Mb region and whether differential DNA methylation of 2q14.2 genes could provide a regional panel of prostate cancer biomarkers.

Methods: We used highly sensitive DNA methylation headloop PCR assays that can detect 10 to 25 pg of methylated DNA with a specificity of at least 1:1,000, and chromatin immunoprecipitation assays to investigate regional epigenetic remodeling across 2q14.2 in prostate cancer, in a cohort of 195 primary prostate tumors and 90 matched normal controls.

Results: Prostate cancer cells exhibit concordant deacetylation and methylation of histone H3 Lysine 9 (H3K9Ac and H3K9me2, respectively), and localized DNA hypermethylation of EN1, SCTR, and INHBB and corresponding loss of H3K27me3. EN1 and SCTR were frequently methylated (65% and 53%, respectively), whereas INHBB was less frequently methylated.

Conclusions: Consistent with LRES in colorectal cancer, we found regional epigenetic remodeling across 2q14.2 in prostate cancer. Concordant methylation of EN1 and SCTR was able to differentiate cancer from normal (P < 0.0001) and improved the diagnostic specificity of GSTP1 methylation for prostate cancer detection by 26%.

Impact: For the first time we show that DNA methylation of EN1 and SCTR promoters provide potential novel biomarkers for prostate cancer detection and in combination with GSTP1 methylation can add increased specificity and sensitivity to improve diagnostic potential. Cancer Epidemiol Biomarkers Prev; 20(1); 148–59. ©2011 AACR.
Allelic Imbalance in BRCA1 and BRCA2 Gene Expression and Familial Ovarian Cancer
Authors: Shen Jie , Medico Leo , Zhao Hua
Published: January 2011

Background: Family history is the strongest risk factor for ovarian cancer. Recent evidence suggests that unidentified BRCA1/2 variations or other genetic events may contribute to familial ovarian cancers. Allelic imbalance (AI) of BRCA1/2 expression, a result of a significant decrease in the ratios between the expression from one allele of BRCA1/2 and the other allele, has been observed in breast cancer. The AI of BRCA1/2 expression could decrease the level of transcripts and thus contribute to an increased susceptibility of developing familial ovarian cancer.

Methods: To test this hypothesis, we applied a quantitative, allelic-specific, real-time PCR method to survey the levels of AI in BRCA1/2 in lymphoblastoid cell lines (LCL) from 126 familial ovarian cancer patients who are noncarriers of any known BRCA1/2 and MLH/MSH mutations and 118 cancer-free relative controls.

Results: The AI ratios of BRCA1, but not BRCA2, in the LCLs from familial ovarian cancer patients were found to be significantly increased as compared with family controls (BRCA1: 0.463 ± 0.054 vs. 0.405 ± 0.111, P = 0.0007; BRCA2: 0.325 ± 0.124 vs. 0.302 ± 0.118, P = 0.328). Using the cutoff point of 0.458 identified from the receiver operating characteristic (ROC) analysis, higher levels of AI were associated with a 4.22-fold increased risk of familial ovarian cancer (95% CI: 1.60–11.16). In further analysis, we observed that levels of AI were negatively significantly correlated with the age of familial ovarian cancer diagnosis (ρ = −0.469, P < 0.001).

Conclusion: Taken together, our data suggest that AI affecting BRCA1 may contribute to familial ovarian cancer. Cancer Epidemiol Biomarkers Prev; 20(1); 50–6. ©2011 AACR.
Infection with Hepatitis B and C Viruses and Risk of Lymphoid Malignancies in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: Franceschi Silvia , Lise Mauro , Trépo Christian , Berthillon Pascale , Chuang Shu-Chun , Nieters Alexandra , Travis Ruth C. , Vermeulen Roel , Overvad Kim , Tjønneland Anne , Olsen Anja , Bergmann Manuela M. , Boeing Heiner , Kaaks Rudolf , Becker Nikolaus , Trichopoulou Antonia , Lagiou Pagona , Bamia Christina , Palli Domenico , Sieri Sabina , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita Bas , Peeters Petra H.M. , Rodríguez Laudina , Barroso Leila Luján , Dorronsoro Miren , Sánchez María-José , Navarro Carmen , Barricarte Aurelio , Regnér Sara , Borgquist Signe , Melin Beatrice , Hallmans Göran , Khaw Kay-Tee , Wareham Nick , Rinaldi Sabina , Hainaut Pierre , Riboli Elio , Vineis Paolo
Published: January 2011

Background: Case–control studies suggested a moderate, but consistent, association of hepatitis C virus (HCV) infection with lymphoid tissue malignancies, especially non–Hodgkin lymphoma (NHL). More limited data suggested that hepatitis B virus (HBV) infection might also be associated with NHL. However, prospective studies on the topic are few.

Methods: A nested case–control study was conducted in eight countries participating in the EPIC prospective study. Seven hundred thirty-nine incident cases of NHL, 238 multiple myeloma (MM), and 46 Hodgkin lymphoma (HL) were matched with 2,028 controls. Seropositivity to anti-HCV, anti-HBc, and HBsAg was evaluated and conditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for NHL, MM, or HL, and their combination.

Results: Anti-HCV seropositivity among controls in different countries ranged from 0% to 5.3%; HBsAg from 0% to 2.7%; and anti-HBc from 1.9% to 45.9%. Similar nonsignificant associations were found with seropositivity to HBsAg for NHL (OR = 1.78; 95% CI: 0.78–4.04), MM (OR = 4.00; 95% CI: 1.00–16.0), and HL (OR = 2.00; 95% CI: 0.13–32.0). The association between HBsAg and the combination of NHL, MM, and HL (OR = 2.21; 95% CI: 1.12–4.33) was similar for cancer diagnosed less than 3 and 3 or more years after blood collection. No significant association was found between anti-HCV and NHL, MM, or HL risk, but the corresponding CIs were very broad.

Conclusions: Chronic HBV infection may increase the risk of lymphoid malignancies among healthy European volunteers.

Impact: Treatment directed at control of HBV infection should be evaluated in HBsAg-seropositive patients with lymphoid tissue malignancies. Cancer Epidemiol Biomarkers Prev; 20(1); 208–14. ©2011 AACR.
Efficacy of Exercise Interventions in Modulating Cancer-Related Fatigue among Adult Cancer Survivors: A Meta-Analysis
Authors: Brown Justin C. , Huedo-Medina Tania B. , Pescatello Linda S. , Pescatello Shannon M. , Ferrer Rebecca A. , Johnson Blair T.
Published: January 2011

Background: The purpose of this meta-analysis was to explore the efficacy of exercise as a nonpharmacologic intervention to reduce cancer-related fatigue (CRF) among adult cancer survivors. We also investigated how different components of the exercise prescription (Ex Rx), methodologic considerations, and subject characteristics modulate CRF.

Methods: A systematic search for randomized controlled trials was conducted using words related to cancer, exercise, and fatigue.

Results: In total, 44 studies with 48 interventions qualified, including 3,254 participants of varying cancer types, stages of diagnosis, treatments, and exercise interventions. Cancer survivors in exercise interventions reduced their CRF levels to a greater extent than usual care controls, d+ = 0.31 (95% CI = 0.22–0.40), an effect that appeared to generalize across several types of cancer. CRF levels improved in direct proportion to the intensity of resistance exercise (β = 0.60, P = 0.01), a pattern that was stronger in higher quality studies (β = 0.23, P < 0.05). CRF levels also reduced to a greater extent when interventions were theoretically driven (β = 0.48, P < 0.001) or cancer survivors were older (β = 0.24, P = 0.04).

Conclusions: Exercise reduced CRF especially in programs that involved moderate-intensity, resistance exercise among older cancer survivors and that were guided by theory.

Impact: Our results indicate exercise interventions for adult cancer survivors should be multi-dimensional and individualized according to health outcome and cancer type. Cancer Epidemiol Biomarkers Prev; 20(1); 123–33. ©2011 AACR.
A Role of Sphingosine Kinase 1 in Head and Neck Carcinogenesis
Authors: Shirai Keisuke , Kaneshiro Tatsuya , Wada Masayuki , Furuya Hideki , Bielawski Jacek , Hannun Yusuf A. , Obeid Lina M. , Ogretmen Besim , Kawamori Toshihiko
Published: January 2011

It is important to identify novel and effective targets for cancer prevention and therapy against head and neck squamous cell carcinoma (HNSCC), one of the most lethal cancers. Accumulating evidence suggests that the bioactive sphingolipids, such as sphingosine-1-phosphate (S1P) and its generating enzyme, sphingosine kinase 1 (SphK1) play pivotal roles in several important biological functions including promoting tumor growth and carcinogenesis. However, roles of SphK1/S1P in HNSCC development and/or progression have not been defined previously. Therefore, in this study, we first analyzed the expression of SphK1 in human HNSCC tumor samples and normal head & neck tissues (n = 78 and 17, respectively) using immunohistochemistry. The data showed that SphK1 is overexpressed in all of the HNSCC tumors tested (stages I–IV). We next investigated whether SphK1 is necessary for HNSCC development. To define the role of SphK1/S1P in HNSCC development, we utilized 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC model in wild-type mice compared with SphK1−/− knockout (KO) mice. Remarkably, we found that the genetic loss of SphK1, which reduced S1P generation, significantly prevented 4-NQO–induced HNSCC carcinogenesis, with decreased tumor incidence, multiplicity, and volume when compared with controls. Moreover, our data indicated that prevention of 4-NQO–induced HNSCC development in SphK1−/− KO mice might be associated with decreased cell proliferation, increased levels of cleaved (active) caspase 3, and downregulation of phospho (active) AKT expression. Thus, these novel data suggest that SphK1/S1P signaling may play important roles in HNSCC carcinogenesis, and that targeting SphK1/S1P might provide a novel strategy for chemoprevention and treatment against HNSCC. Cancer Prev Res; 4(3); 454–62. ©2011 AACR.
Computational Models Reduce Complexity and Accelerate Insight Into Cardiac Signaling Networks
Authors: Yang Jason H. , Saucerman Jeffrey J.
Published: January 2011

Cardiac signaling networks exhibit considerable complexity in size and connectivity. The intrinsic complexity of these networks complicates the interpretation of experimental findings. This motivates new methods for investigating the mechanisms regulating cardiac signaling networks and the consequences these networks have on cardiac physiology and disease. Next-generation experimental techniques are also generating a wealth of genomic and proteomic data that can be difficult to analyze or interpret. Computational models are poised to play a key role in addressing these challenges. Computational models have a long history in contributing to the understanding of cardiac physiology and are useful for identifying biological mechanisms, inferring multiscale consequences to cell signaling activities and reducing the complexity of large data sets. Models also integrate well with experimental studies to explain experimental observations and generate new hypotheses. Here, we review the contributions computational modeling approaches have made to the analysis of cardiac signaling networks and forecast opportunities for computational models to accelerate cardiac signaling research.
Cardiopoietic Factors
Authors: Noseda Michela , Peterkin Tessa , Simões Filipa C. , Patient Roger , Schneider Michael D.
Published: January 2011

Cardiac muscle creation during embryogenesis requires extracellular instructive signals that are regulated precisely in time and space, intersecting with intracellular genetic programs that confer or fashion the ability of the cells to respond. Unmasking the essential signals for cardiac lineage decisions has paramount importance for cardiac development and regenerative medicine, including the directed differentiation of progenitor and stem cells to a cardiac muscle fate.
Valve Configuration Determines Long-Term Results After Repair of the Bicuspid Aortic Valve
Authors: Aicher Diana , Kunihara Takashi , Abou Issa Omar , Brittner Brigitte , Gräber Stefan , Schäfers Hans-Joachim
Published: January 2011

Background—

Reconstruction of the regurgitant bicuspid aortic valve has been performed for >10 years, but there is limited information on long-term results. We analyzed our results to determine the predictors of suboptimal outcome.

Methods and Results—

Between November 1995 and December 2008, 316 patients (age, 49±14 years; male, 268) underwent reconstruction of a regurgitant bicuspid aortic valve. Intraoperative assessment included extent of fusion, root dimensions, circumferential orientation of the 2 normal commissures (>160°, ≤160°), and effective height after repair. Cusp pathology was treated by central plication (n=277), triangular resection (n=138), or pericardial patch (n=94). Root dilatation was treated by subcommissural plication (n=100), root remodeling (n=122), or valve reimplantation (n=2). All patients were followed up echocardiographically (cumulative follow-up, 1253 years; mean, 4±3.1 years). Clinical and morphological parameters were analyzed for correlation with 10-year freedom from reoperation with the Cox proportional hazards model. Hospital mortality was 0.63%; survival was 92% at 10 years. Freedom from reoperation at 5 and 10 years was 88% and 81%; freedom from valve replacement, 95% and 84%. By univariable analysis, statistically significant predictors of reoperation were age (hazard ratio [HR]=0.97), aortoventricular diameter (HR=1.24), effective height (HR=0.76), commissural orientation (HR=0.95), use of a pericardial patch (HR=7.63), no root replacement (HR=3.80), subcommissural plication (HR=2.07), and preoperative aortic regurgitation grade 3 or greater. By multivariable analysis, statistically significant predictors for reoperation were age (HR=0.96), aortoventricular diameter (HR=1.30), effective height (HR=0.74), commissural orientation (HR=0.96), and use of a pericardial patch (HR=5.16).

Conclusions—

Reconstruction of bicuspid aortic valve can be performed reproducibly with good early results. Recurrence and progression of regurgitation, however, may occur, depending primarily on anatomic features of the valve.
Dabigatran Versus Warfarin in Patients With Atrial Fibrillation
Authors: Nagarakanti Rangadham , Ezekowitz Michael D. , Oldgren Jonas , Yang Sean , Chernick Michael , Aikens Timothy H. , Flaker Greg , Brugada Josep , Kamenský Gabriel , Parekh Amit , Reilly Paul A. , Yusuf Salim , Connolly Stuart J.
Published: January 2011

Background–

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation.

Methods and Results–

Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%;
P
<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin,
P
=0.71; D150 versus warfarin,
P
=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin,
P
=0.06; D150 versus warfarin,
P
=0.99).

Conclusions–

This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion.

Clinical Trial Registration–

URL:
http://www.ClinicalTrials.gov
. Unique identifier: NCT00262600.
Angiotensin II Regulates Adrenal Vascular Tone Through Zona Glomerulosa Cell–Derived EETs and DHETs
Authors: Kopf Phillip G. , Gauthier Kathryn M. , Zhang David X. , Falck John R. , Campbell William B.
Published: January 2011

Elevated concentrations of aldosterone are associated with several cardiovascular diseases. Angiotensin II (Ang II) increases aldosterone secretion and adrenal blood flow. This concurrent increase in steroidogenesis and adrenal blood flow is not understood. We investigated the role of zona glomerulosa (ZG) cells in the regulation of vascular tone of bovine adrenal cortical arteries by Ang II. ZG cells enhanced endothelium-dependent relaxations to Ang II. The ZG cell–dependent relaxations to Ang II were unchanged by removing the endothelium-dependent response to Ang II. These ZG cell–mediated relaxations were ablated by cytochrome P450 inhibition, epoxyeicosatrienoic acid (EET) antagonism, and potassium channel blockade. Analysis of ZG cell EET production by liquid chromatography/mass spectrometry demonstrated an increase in EETs and dihydroxyeicosatrienoic acids with Ang II stimulation. These EETs and dihydroxyeicosatrienoic acids produced similar concentration-dependent relaxations of adrenal arteries, which were attenuated by EET antagonism. Whole-cell potassium currents of adrenal artery smooth muscle cells were increased by Ang II stimulation in the presence of ZG cells but decreased in the absence of ZG cells. This increase in potassium current was abolished by iberiotoxin. Similarly, 14,15-EET induced concentration-dependent increases in potassium current, which was abolished by iberiotoxin. ZG cell aldosterone release was not directly altered by EETs. These data suggest that Ang II stimulates ZG cells to release EETs and dihydroxyeicosatrienoic acids, resulting in potassium channel activation and relaxation of adrenal arteries. This provides a mechanism by which Ang II concurrently increases adrenal blood flow and steroidogenesis.
Detecting Sodium-Sensitivity in Hypertensive Patients
Authors: Castiglioni Paolo , Parati Gianfranco , Brambilla Lorenzo , Brambilla Valerio , Gualerzi Massimo , Di Rienzo Marco , Coruzzi Paolo
Published: January 2011

Sodium sensitivity is an important cardiovascular risk factor for which a diagnosis requires a time-consuming protocol, the implementation of which is often challenging for patients and physicians. Our aim was to assess the reliability of an easier approach based on data from 24-hour ambulatory blood pressure monitoring performed in hypertensive subjects during daily-life conditions and habitual diet. We enrolled 46 mild to moderate hypertensive subjects who underwent 24-hour ambulatory blood pressure monitoring during usual sodium intake. Patients were divided into 3 classes of sodium sensitivity risk on the basis of ambulatory blood pressure monitoring data: low risk if dippers and a 24-hour heart rate ≤70 bpm; high risk if nondippers and a 24-hour heart rate of >70 bpm; intermediate risk with the remaining combinations (dippers with heart rate >70 bpm or nondippers with heart rate ≤70 bpm). Then patients underwent a traditional sodium sensitivity test for the dichotomous classification as sodium sensitive or sodium resistant and for evaluating the sodium sensitivity index. Prevalence of sodium-sensitive patients and mean value of sodium sensitivity index were calculated in the 3 risk classes. The sodium sensitivity index markedly and significantly increased from the low-risk to the high-risk class, being equal to 19.9±14.4, 37.8±8.3, and 68.3±17.0 mm Hg/(mol/day) in the low-risk, intermediate-risk, and high-risk classes, respectively (M±SEM). Also, the prevalence of sodium-sensitive patients increased significantly from the low-risk class (25%) to the intermediate-risk (40%) and high-risk (70%) classes. Thus, performance of 24-hour ambulatory blood pressure monitoring in daily-life conditions and habitual diet may give useful information on the sodium sensitivity condition of hypertensive subjects in an easier manner than with the traditional sodium sensitivity test approach.