bluuebunny/crossref_metadata_2025 huggingface dataset:
High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment
Authors: Ruta Leah-Anne M. , Dickinson Hayley , Thomas Merlin C. , Denton Kate M. , Anderson Warwick P. , Kett Michelle M.
Published: March 2010

The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the “first hit” and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 ± 1, 103 ± 1, and 102 ± 2 mmHg). On a high-salt diet, MAP increased 9.1 ± 1.9 mmHg in HET1K mice ( P < 0.05) and 5.4 ± 0.9 mmHg in HET2K mice ( P < 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype.
Colon Mucinous Adenocarcinoma in Childhood: A Case Report with Emphasis on Image Findings
Authors: Muccillo Antonio , Marchiori Edson , Penna Cláudia Renata , Guimarães Regina Rodrigues , Zanetti Gláucia , Abdalla Guilherme , Ventura Nina , Constantino Carolina Lamas , Pereira Mariana Leite , Brandão Viviane , Martins Pedro , Canellas Rodrigo , Varella de Oliveira Romulo
Published: March 2010

Colorectal cancer is extremely rare in children. We report a case of a 12-year-old boy who presented with a five-month history of weight loss and anorexia, associated with vomiting episodes, dizziness, fatigue, and dyspnea. On physical examination, a palpable abdominal mass was noticed on the right hypochondrium and flank. An imaging study was performed, which showed a solid mass on the right colon. The patient underwent incisional surgical biopsy, and subsequent histopathologic analysis revealed a colon mucinous adenocarcinoma.
Inhaled Anesthetics Promote Albumin Dimerization through Reciprocal Exchange of Subdomains
Authors: Pieters Benjamin J. , Fibuch Eugene E. , Eklund Joshua D. , Seidler Norbert W.
Published: March 2010

Inhaled anesthetics affect protein-protein interaction, but the mechanisms underlying these effects are still poorly understood. We examined the impact of sevoflurane and isoflurane on the dimerization of human serum albumin (HSA), a protein with anesthetic binding sites that are well characterized. Intrinsic fluorescence emission was analyzed for spectral shifting and self-quenching, and control first derivatives (spectral responses to changes in HSA concentration) were compared against those obtained from samples treated with sevoflurane or isoflurane. Sevoflurane increased dimer-dependent self-quenching and both decreased oligomer-dependent spectral shifting, suggesting that inhaled anesthetics promoted HSA dimerization. Size exclusion chromatography and polarization data were consistent with these observations. The data support the proposed model of a reciprocal exchange of subdomains to form an HSA dimer. The open-ended exchange of subdomains, which we propose occuring in HSA oligomers, was inhibited by sevoflurane and isoflurane.
Identification of Candidate Genes Potentially Relevant to Chamber-Specific Remodeling in Postnatal Ventricular Myocardium
Authors: Torrado Mario , Iglesias Raquel , Nespereira Beatriz , Mikhailov Alexander T.
Published: March 2010

Molecular predisposition of postnatal ventricular myocardium to chamber-dependent (concentric or eccentric) remodeling remains largely elusive. To this end, we compared gene expression in the left (LV) versus right ventricle (RV) in newborn piglets, using a differential display reverse transcription-PCR (DDRT-PCR) technique. Out of more than 5600 DDRT-PCR bands, a total of 153 bands were identified as being differentially displayed. Of these, 96 bands were enriched in the LV, whereas the remaining 57 bands were predominant in the RV. The transcripts, displaying over twofold LV-RV expression differences, were sequenced and identified by BLAST comparison to known mRNA sequences. Among the genes, whose expression was not previously recognized as being chamber-dependent, we identified a small cohort of key regulators of muscle cell growth/proliferation (MAP3K7IP2, MSTN, PHB2, APOBEC3F) and gene expression (PTPLAD1, JMJD1C, CEP290), which may be relevant to the chamber-dependent predisposition of ventricular myocardium to respond differentially to pressure (LV) and volume (RV) overloads after birth. In addition, our data demonstrate chamber-dependent alterations in expression of as yet uncharacterized novel genes, which may also be suitable candidates for association studies in animal models of LV/RV hypertrophy.
Evolution of Structural-Phase States in TiNi Surface Layers Synthesized by Electron Beam Treatment
Authors: Meisner L. L. , Lotkov A. I. , Mironov Yu. P. , Neyman A. A.
Published: March 2010

The paper presents the results of X-ray diffraction analysis of nonequilibrium structural and elastic stress states in TiNi surface layers irradiated by low-energy electron beams. It is found that a surface layer with a mixed (2D columnar and 3D equiaxial) submicrocrystalline structure is formed on the irradiated side of the TiNi specimens, and the volume fractions of the two structure types depend on the beam energy parameters and number of pulses. The B2 phase synthesized in the layer is characterized by lattice microstrain due to stresses of the first and second kinds (εI≈±1%,εII=0.25%), and the layer as such is an internal stress concentrator for underlying layers of the material. In the intermediate layer beneath the stress concentrator, relaxation of irradiation-induced internal stress takes place. It is shown that the main mechanism of the relaxation is partialB2→B19′martensite transformation. TheB19′martensite phase in the intermediate layer decreases the microstrain in the conjugate B2 phase. The thickness of the layer in which the relaxation processes develop through theB2→B19′martensite transformation is 10–15μm.
Adult T-Cell Leukemia/Lymphoma with CLL-Like Morphology—A Case Report
Authors: Tageja Nishant , Mohammad Mobayed , Bentley Gail , Bishop Carter
Published: March 2010

Adult T-cell Leukemia/Lymphoma (ATL) is rarely seen in the U.S. and Europe, usually limited to African Americans from the southeastern U.S. and immigrants from HTLV-1 endemic areas. Reaching an accurate and timely diagnosis of ATL in such nonendemic areas can be challenging, owing to limited exposure, diverse manifestations, and varying cell morphology. We present a case of chronic adult T-cell leukemia (ATL) with Chronic Lymphocytic Leukemia- (CLL-) like morphology that remained untreated for ten years and then developed treatment refractory acute ATL crisis.
Modelling of Heat Transfer Phenomena for Vertical and Horizontal Configurations of In-Pool Condensers and Comparison with Experimental Findings
Authors: Papini Davide , Cammi Antonio
Published: March 2010

Decay Heat Removal (DHR) is a fundamental safety function which is often accomplished in the advanced LWRs relying on natural phenomena. A typical passive DHR system is the two-phase flow, natural circulation, closed loop system, where heat is removed by means of a steam generator or heat exchanger, a condenser, and a pool. Different condenser tube arrangements have been developed for applications to the next generation NPPs. The two most used configurations, namely, horizontal and vertical tube condensers, are thoroughly investigated in this paper. Several thermal-hydraulic features were explored, being the analysis mainly devoted to the description of the best-estimate correlations and models for heat transfer coefficient prediction. In spite of a more critical behaviour concerning thermal expansion issues, vertical tube condensers offer remarkably better thermal-hydraulic performances. An experimental validation of the vertical tube correlations is provided by PERSEO facility (SIET labs, Piacenza), showing a fairly good agreement.
Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome
Authors: Morrone Kerry , Wang Yanhua , Huizing Marjan , Sutton Elie , White James G. , Gahl William A. , Moody Karen
Published: March 2010

Background.Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in theCHS1/LYSTgene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in theCHS1gene: c.3622C>T(p.Q1208X) and c.11002G>T(p.E3668X).Conclusions.Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in theCHS1gene, the first mutation analysis published of an African-American child with Chediak-Higashi Syndrome. These two mutations predict a severe phenotype and thus identification of these mutations has an important clinical significance in CHS.
A Better Immune Reaction to Erbb-2 Tumors Is Elicited in Mice by DNA Vaccines Encoding Rat/Human Chimeric Proteins
Authors: Quaglino Elena , Mastini Cristina , Amici Augusto , Marchini Cristina , Iezzi Manuela , Lanzardo Stefania , De Giovanni Carla , Montani Maura , Lollini Pier-Luigi , Masucci Giuseppe , Forni Guido , Cavallo Federica
Published: March 2010

The Erbb-2 (neu in rat and Her-2 in humans) tyrosine kinase receptor is an oncoantigen (i.e., a tumor-associated molecule directly involved in cancer progression). Because oncoantigens are self-tolerated molecules, to trigger a response circumventing tolerance, we generated two plasmids (RHuT and HuRT) coding for chimeric neu-Her-2 extracellular and transmembrane proteins that are expressed on the cell membrane of the transfected cells and recognized by monoclonal antibodies reacting against neu and Her-2. RHuT encodes a protein in which the 410 NH2-terminal residues are from the neu extracellular domain and the remaining residues from Her-2. Almost symmetrically, HuRT encodes for a protein in which the 390 NH2-terminal residues are from Her-2 and the remainder from neu. The ability of RHuT and HuRT to elicit a protective response to neu and Her-2 in wild-type mice and in transgenic mice tolerant to neu and Her-2 proteins was compared with that of plasmids coding for the fully rat or fully human extracellular and transmembrane domains of the Erbb-2 receptor. In most cases, RHuT and HuRT elicited a stronger response, although this chimeric benefit is markedly modulated by the location of the heterologous moiety in the protein coded by the plasmid, the immune tolerance of the responding mouse, and the kind of Erbb-2 orthologue on the targeted tumor. Cancer Res; 70(7); 2604–12
Downregulation of Human DAB2IP Gene Expression in Prostate Cancer Cells Results in Resistance to Ionizing Radiation
Authors: Kong Zhaolu , Xie Daxing , Boike Thomas , Raghavan Pavithra , Burma Sandeep , Chen David J. , Habib Amyn A. , Chakraborty Arup , Hsieh Jer-Tsong , Saha Debabrata
Published: March 2010

DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase–activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90% of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60% of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G2-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G2-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens. Cancer Res; 70(7); 2829–39
Y-Box Binding Protein-1 Induces the Expression of CD44 and CD49f Leading to Enhanced Self-Renewal, Mammosphere Growth, and Drug Resistance
Authors: To Karen , Fotovati Abbas , Reipas Kristen M. , Law Jennifer H. , Hu Kaiji , Wang Jing , Astanehe Arezoo , Davies Alastair H. , Lee Lawrence , Stratford Anna L. , Raouf Afshin , Johnson Pauline , Berquin Isabelle M. , Royer Hans-Dieter , Eaves Connie J. , Dunn Sandra E.
Published: March 2010

Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1–transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1S102D enhances self-renewal, primary and secondary mammosphere growth, and soft-agar colony growth, which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here, we show that paclitaxel induces P-YB-1S102 expression, nuclear localization of activated YB-1, and CD44 expression. The overexpression of WT YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44High/CD24Low cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f. Cancer Res; 70(7); 2840–51
MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression
Authors: Chen Xueqin , Gong Jing , Zeng Hao , Chen Ni , Huang Rui , Huang Ying , Nie Ling , Xu Miao , Xia Juan , Zhao Fang , Meng Wentong , Zhou Qiao
Published: March 2010

The putative tumor suppressor miR145 is transcriptionally regulated by TP53 and is downregulated in many tumors; however, its role in prostate cancer is unknown. On the other hand, BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is overexpressed in various tumors, including prostate cancer, and may transcriptionally repress the apoptosis-inducing factor (AIF) gene. Although BNIP3 transcription is controlled by hypoxia-inducible factor 1α (also elevated in prostate cancer), we postulated the posttranscriptional regulation of BNIP3 by miR145 through bioinformatics analysis, and herein we experimentally showed that miR145 negatively regulated BNIP3 by targeting its 3′-untranslated region. Artificial overexpression of miR145 by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly downregulated BNIP3, together with the upregulation of AIF, reduced cell growth, and increased cell death. Artificial overexpression of wild-type TP53 in PC-3 cells (which lack TP53 protein) and DU145 cells (in which mutated nonfunctioning TP53 is expressed) significantly upregulated miR145 expression with consequent effects on BNIP3 and cell behavior as with miR145 overexpression. Analysis of prostate cancer (n = 134) and benign prostate (n = 83) tissue sample showed significantly decreased miR145 and increased BNIP3 expression in prostate cancer (P < 0.001), particularly in those with tumor progression, and both molecular changes were associated with unfavorable outcome. Abnormalities of the miR145-BNIP3 pair as part of TP53-miR145-BNIP3-AIF network may play a major role in prostate cancer pathogenesis and progression. Cancer Res; 70(7); 2728–38
The Immunosuppressive Surface Ligand CD200 Augments the Metastatic Capacity of Squamous Cell Carcinoma
Authors: Stumpfova Magda , Ratner Desirée , Desciak Edward B. , Eliezri Yehuda D. , Owens David M.
Published: March 2010

CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200+ SCC cells may depend on their ability to interact with CD200R+ immune cells. The predominant population of CD200R+ stromal cells was CD11b+Gr-1+ myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200+ SCC keratinocytes to directly engage and modulate CD200R+ myeloid-derived suppressor cells is essential to metastatic survival. Cancer Res; 70(7); 2962–72
Aberrant DNA Methylation Links Cancer Susceptibility Locus 15q25.1 to Apoptotic Regulation and Lung Cancer
Authors: Paliwal Anupam , Vaissière Thomas , Krais Annette , Cuenin Cyrille , Cros Marie-Pierre , Zaridze David , Moukeria Anush , Boffetta Paolo , Hainaut Pierre , Brennan Paul , Herceg Zdenko
Published: March 2010

Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene cluster at the lung cancer susceptibility locus 15q25.1. In this study, we show that the CHRNα3 gene encoding the nAChRα3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRNβ4 and CHRNα5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNα3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNα3 promoter and gene reactivation. Restoring CHRNα3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA–mediated depletion of nAChRα3 in CHRNα3-expressing lung cancer cells elicited a dramatic Ca2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNα3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNα3 gene in human cancer. In defining a mechanism of epigenetic control of nAChR expression in nonneuronal tissues, our findings offer a functional link between susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs to be theranostic targets for cancer detection and chemoprevention. Cancer Res; 70(7); 2779–88
Reciprocal Regulation of Activating and Inhibitory Fcγ Receptors by TLR7/8 Activation: Implications for Tumor Immunotherapy
Authors: Butchar Jonathan P. , Mehta Payal , Justiniano Steven E. , Guenterberg Kristan D. , Kondadasula Sri-Vidya , Mo Xiaokui , Chemudupati Mahesh , Kanneganti Thirumala-Devi , Amer Amal , Muthusamy Natarajan , Jarjoura David , Marsh Clay B. , Carson William E. , Byrd John C. , Tridandapani Susheela
Published: March 2010

Purpose: Activation of Toll-like receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors. Here, we wished to test the effect of TLR7/8 activation on monocyte Fcγ receptor (FcγR) function, as they are critical mediators of antibody therapy.

Experimental Design: The effect of the TLR7/8 agonist R-848 on cytokine production and antibody-dependent cellular cytotoxicity by human peripheral blood monocytes was tested. Affymetrix microarrays were done to examine genomewide transcriptional responses of monocytes to R-848 and Western blots were done to measure protein levels of FcγR. Murine bone marrow–derived macrophages from WT and knockout mice were examined to determine the downstream pathway involved with regulating FcγR expression. The efficacy of R-848 as an adjuvant for antibody therapy was tested using a CT26-HER2/neu solid tumor model.

Results: Overnight incubation with R-848 increased FcγR-mediated cytokine production and antibody-dependent cellular cytotoxicity in human peripheral blood monocytes. Expression of FcγRI, FcγRIIa, and the common γ-subunit was increased. Surprisingly, expression of the inhibitory FcγRIIb was almost completely abolished. In bone marrow–derived macrophage, this required TLR7 and MyD88, as R-848 did not increase expression of the γ-subunit in TLR7−/− nor MyD88−/− cells. In a mouse solid tumor model, R-848 treatment superadditively enhanced the effects of antitumor antibody.

Conclusions: These results show an as-yet-undiscovered regulatory and functional link between the TLR7/8 and FcγR pathways. This suggests that TLR7/8 agonists may be especially beneficial during antibody therapy. Clin Cancer Res; 16(7); 2065–75. ©2010 AACR.
Cyclooxygenase-2 Genetic Variants Are Associated with Survival in Unresectable Locally Advanced Non–Small Cell Lung Cancer
Authors: Bi Nan , Yang Ming , Zhang Li , Chen Xiabin , Ji Wei , Ou Guangfei , Lin Dongxin , Wang Luhua
Published: March 2010

Purpose: Cyclooxygenase-2 (COX-2) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated COX-2 expression has been reported to be correlated with reduced survival after radiotherapy. This study examined whether genetic variations in the COX-2 gene are associated with different survival in inoperable locally advanced non–small cell lung cancer (NSCLC) treated with chemoradiotherapy or radiotherapy alone.

Experimental Design: One hundred and thirty-six patients with inoperable stage IIIA-B NSCLC receiving thoracic irradiation between 2004 and 2007 were recruited in this study. Five functional COX-2 polymorphisms were genotyped using DNA from blood lymphocytes. Kaplan-Meier methods were used to compare survival by different genotypes. Cox proportional hazards models were used to identify independently significant variables.

Results: During the median 22.4 months of follow-up, the favorable COX-2 −1195GA and GG genotypes were significantly correlated with better overall survival (20.2 months versus 15.7 months; P = 0.006; hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.39-0.86) and with longer progress-free survival (11.9 months versus 9.5 months; P = 0.034) compared with the −1195AA genotype. No significant associations were found among other COX-2 polymorphisms and clinical outcomes. In the multivariate Cox proportional hazards model, COX-2 −1195G/A polymorphism was independently associated with overall survival after adjusting the clinicopathologic factors (P = 0.008; HR, 0.58; 95% CI, 0.39-0.87).

Conclusion: COX-2 −1195G/A polymorphism is a potential predictive marker of survival in locally advanced NSCLC patients treated with chemoradiotherapy or radiotherapy alone. Clin Cancer Res; 16(8); 2383–90. ©2010 AACR.
Neuropeptide Y Y5 Receptor Promotes Cell Growth through Extracellular Signal-Regulated Kinase Signaling and Cyclic AMP Inhibition in a Human Breast Cancer Cell Line
Authors: Sheriff Sulaiman , Ali Marwan , Yahya Ayesha , Haider Khawaja H. , Balasubramaniam Ambikaipakan , Amlal Hassane
Published: March 2010

Overexpression of neuropeptide Y (NPY) and its receptor system has been reported in various types of cancers. NPY Y5 receptor (Y5R) has been implicated in cell growth and angiogenesis. However, the role of Y5R in breast cancer is unknown. To identify the role of Y5R in breast cancer, we screened several breast cancer cell lines to examine the expression of Y5R and its function in breast cancer. All screened cell lines express both Y1 receptor and Y5R except BT-549, which expresses mainly Y5R. Binding studies showed that NPY, Y5R-selective agonist peptide, and Y5R-selective antagonist (CGP71683A) displaced 125I-PYY binding in BT-549 cell membranes in a dose-dependent manner. The displacement studies revealed the presence of two binding sites in Y5R with IC50 values of 29 pmol/L and 531 nmol/L. NPY inhibited forskolin-stimulated cyclic AMP accumulation with an IC50 value of 52 pmol/L. NPY treatment of BT-549 cells induced extracellular signal-regulated kinase phosphorylation but did not alter intracellular calcium. Y5R activation stimulates BT-549 cell growth, which is inhibited by CGP71683A, pertussis toxin, and extracellular signal-regulated kinase blockade. CGP71683A alone induced cell death in a time- and dose-dependent manner in Y5R-expressing cells. The stimulation of MDA MB-231 cell migration by NPY is inhibited by CGP71683A. Together, our results suggest that Y5R plays an important role in cancer cell growth and migration and could be a novel therapeutic target for breast cancer. Mol Cancer Res; 8(4); 604–14. ©2010 AACR.
HuR Knockdown Changes the Oncogenic Potential of Oral Cancer Cells
Authors: Kakuguchi Wataru , Kitamura Tetsuya , Kuroshima Takeshi , Ishikawa Makoto , Kitagawa Yoshimasa , Totsuka Yasunori , Shindoh Masanobu , Higashino Fumihiro
Published: March 2010

HuR binds to AU-rich element–containing mRNA to protect them from rapid degradation. Here, we show that knockdown of HuR changes the oncogenic properties of oral cancer cells. Oral squamous cell carcinoma cell lines, HSC-3 and Ca9.22, which express HuR protein and cytoplasmic AU-rich element mRNA more abundantly than normal cells, were subjected to HuR knockdown. In the HuR-knockdown cancer cells, the cytoplasmic expression of c-fos, c-myc, and COX-2 mRNAs was inhibited compared with those in cells that had been transfected with a control small interfering RNA, and the half-lives of these mRNAs were shorter than those of their counterparts in the control cells. HuR-knockdown cells failed to make colonies in soft agar, suggesting that the cells had lost their ability for anchorage-independent cell growth. Additionally, the motile and invasive activities of the cells decreased remarkably by HuR knockdown. Furthermore, the expression of cell cycle–related proteins, such as cyclin A, cyclin B1, cyclin D1, and cyclin-dependent kinase 1, was reduced in HuR-knockdown cancer cells, and HuR bound to cdk1 mRNA to stabilize it. These findings suggest that HuR knockdown changes the features of oral cancer cells, at least in part, by affecting their cell cycle and shows potential as an effective therapeutic approach. Mol Cancer Res; 8(4); 520–8. ©2010 AACR.
Interleukin-1R–Associated Kinase 2 Is a Novel Modulator of the Transforming Growth Factor β Signaling Cascade
Authors: Mullenders Jasper , Fabius Armida W.M. , van Dongen Miranda M.W. , Kuiken Hendrik J. , Beijersbergen Roderick L. , Bernards René
Published: March 2010

The transforming growth factor β (TGFβ) pathway orchestrates an extensive transcriptional program that is important for many processes in the cell. For example, TGFβ regulates cell cycle, migration, and epithelial-to-mesenchymal transition. The TGFβ pathway has a dual role in cancer: it is involved in early-stage tumor suppression but also contributes to tumor progression by promoting invasion. To identify the novel genes involved in TGFβ pathway signaling, we have performed a functional genetic loss-of-function screen. We screened a small interfering RNA library targeting 700 kinases and kinase-related genes in a TGFβ-responsive reporter assay. Several genes were identified that upon knockdown could repress the reporter signal; among these are the two cellular receptors for TGFβ. In addition to these two known components of the TGFβ pathway, several genes were identified that were previously not linked to the TGFβ signaling. Knockdown of one of these genes, the IRAK2 kinase, resulted not only in an impaired TGFβ target gene response but also in a reduction of the nuclear accumulation and phosphorylation of SMAD2. In addition, suppression of interleukin-1R–associated kinase 2 expression led to a partial override of a TGFβ-induced cell cycle arrest. Our data show that interleukin-1R–associated kinase 2 is a novel and critical component of TGFβ signaling. Mol Cancer Res; 8(4); 592–603. ©2010 AACR.
Resveratrol Suppresses Colitis and Colon Cancer Associated with Colitis
Authors: Cui Xiangli , Jin Yu , Hofseth Anne B. , Pena Edsel , Habiger Joshua , Chumanevich Alexander , Poudyal Deepak , Nagarkatti Mitzi , Nagarkatti Prakash S. , Singh Udai P. , Hofseth Lorne J.
Published: March 2010

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3+ T cells that express tumor necrosis factor-α and IFN-γ. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser15) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS–treated mice had 2.4 ± 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 ± 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis. Cancer Prev Res; 3(4); 549–59. ©2010 AACR.
Interphase Cytogenetics of Sputum Cells for the Early Detection of Lung Carcinogenesis
Authors: Prindiville Sheila A. , Ried Thomas
Published: March 2010

This perspective on Varella-Garcia et al. (beginning on p. 447 in this issue of the journal) examines the role of interphase fluorescence in situ hybridization for the early detection of lung cancer. This work is an important step toward identifying and validating a molecular marker in sputum samples for lung cancer early detection and highlights the value of establishing cohort studies with biorepositories of samples collected from participants followed over time for disease development. Cancer Prev Res; 3(4); 416–9. ©2010 AACR.
Lung Cancer Biomarkers: FISHing in the Sputum for Risk Assessment and Early Detection
Authors: Gomperts Brigitte N. , Spira Avrum , Elashoff David E. , Dubinett Steven M.
Published: March 2010

This perspective on Varella-Garcia et al. (beginning on p. 447 in this issue of the journal) discusses the role of sputum-based biomarkers in the risk assessment and early detection of lung cancer. The importance of the detection of sputum epithelial chromosomal aneusomy by fluorescence in situ hybridization (FISH) as a potential risk or early-detection biomarker is discussed in the context of other biomarkers and models in lung carcinogenesis. The presently reported findings on FISH in sputum cells are an important contribution worthy of further investigation in defined clinical settings. Cancer Prev Res; 3(4); 420–3. ©2010 AACR.
Frontal Sinus Cerebrospinal Fluid Leaks: Repair in 15 Patients Using an Endoscopic Surgical Approach
Authors: Shi Jian-Bo , Chen Feng-Hong , Fu Qing-Ling , Xu Rui , Wen Wei-Ping , Hou Wei-Jian , Guo Jie-Bo , Zhang Xiang-Min , Xu Geng
Published: March 2010

Objectives: To clarify the utility of a safe and effective endoscopic procedure for closing frontal sinus cerebrospinal fluid (CSF) leaks. Methods: A retrospective review of all 15 patients seen at our hospital from 2002 to 2008 whose CSF leak originated within the frontal sinus or frontal recess. A transnasal endoscopic or combined transfrontal endoscopic approach was used to repair the CSF leak. Results and Surgical Outcomes: Four defects originated in the frontal recess and 11 involved the posterior wall of the frontal sinus. Nine patients were repaired by a direct endoscopic approach and 4 patients were repaired after widening the frontal recess endoscopically. Two patients were repaired using the combined transfrontal and transnasal approach. The leak was stopped in 14 cases (93%) after the first operation. One patient (7%) required a second repair 1 month after initial surgery and has remained well after 27 months. Complications included a frontal lobe abscess and a frontal sinus obstructive mucocele. These 2 patients were successfully treated without further complications. Patient follow-up ranged from 4 to 44 months (mean 30 months). Conclusions: Most frontal CSF leaks can be successfully closed by an endoscopic surgical approach.
Significant Expression of Interleukin 15 in Rat Experimental Severe Acute Pancreatitis
Authors: Kamei K. , Yasuda T. , Ueda T. , Qiang F. , Shiozaki H. , Ohyanagi H. , Takeyama Y.
Published: March 2010

Purpose: In severe acute pancreatitis (SAP), multiple organ dysfunction syndrome is a contributor to high mortality. We recently demonstrated that the serum interleukin (IL)-15 level is a predictor of the complications and mortality in clinical SAP. The aim was to investigate the role of IL-15 in experimental SAP. Materials and Methods: SAP was induced by retrograde injection of 3 and 20% sodium deoxycholate (DCA) into biliopancreatic ducts in rats (DCA pancreatitis). Expressions of IL-15 were evaluated by Western blotting and immunohistochemical staining. Recombinant IL-15 protein was administered intraperitoneally, and the effects were investigated. Results: Western blotting revealed the expressions of IL-15 in the pancreas, liver, lung and intestine in 3% DCA pancreatitis. Immunohistochemical staining showed the expression of IL-15 in the cytoplasm of each organ. In 3% DCA pancreatitis, administration of recombinant IL-15 protein attenuated the elevation of serum alanine aminotransferase (ALT) levels and improved the morphological change of the lung 18 h after the induction of SAP. Moreover, in 20% DCA pancreatitis, IL-15 improved the elevation of serum amylase and ALT levels 6 h after the induction. Conclusions: These results suggest that IL-15 is related to organ dysfunction during SAP, and that IL-15 functions as a protective factor against the organ injuries.
Incorporating Covariates into Multipoint Association Mapping in the Case-Parent Design
Authors: Chiu Yen-Feng , Liang Kung-Yee , Pan Wen-Harn
Published: March 2010

Background/Aims: To improve the efficiency of disease locus localization in association mapping using case-parent designs and to assess or account for the main covariate effects and gene-covariate interaction effects, while localizing the disease locus. Methods: The present study extends a multipoint fine-mapping approach to incorporate covariates into the association mapping of case-parent designs through parametric and non-parametric modeling. This approach is based on the expected preferential-allele-transmission statistics for transmission from either parent to an affected child. Results: Simulation studies indicate that the efficiency in estimating the disease locus increases considerably when incorporating a covariate associated with the disease. This is especially true when the genetic effect of the disease locus is small. The proposed approach was applied to a young-onset hypertension data sample. The relative efficiency of estimating the locus of young-onset hypertension increases 110-fold after incorporating triglyceride into the association mapping while localizing the disease variant in the lipoprotein lipase gene in the non-parametric model. By incorporating the information of SNP variants into the fine-mapping, the proposed method further assesses the gene-gene interactions between the SNP and the disease locus. Conclusion: With the incorporation of covariates, the proposed method cannot only improve efficiency in estimating disease loci, but can also elucidate the etiology of a complex disease.
5-Year Prospective Follow-Up of Artisan Phakic Intraocular Lenses for the Correction of Myopia, Hyperopia and Astigmatism
Authors: Qasem Qasim , Kirwan Caitriona , O’Keefe Michael
Published: March 2010

Aim: To determine the efficacy and safety of Artisan phakic intraocular lenses (IOLs) for refractive error correction. Methods: A prospective study was conducted on patients undergoing Artisan phakic IOL implantation for myopia, hyperopia or astigmatism from 2002 to 2008. Visual acuity, manifest refractive spherical equivalent (MRSE), endothelial cell counts and higher order aberrations were recorded pre- and postoperatively. Results: One hundred and fifty-one (84 patients) myopic (mean MRSE –11.2 ± 4.1 D) and 14 (7 patients) hyperopic eyes (mean MRSE 7.1 ± 1.3 D) were treated. Twenty eyes (11 patients) had toric IOLs to correct astigmatism (mean MRSE –9.05 ± 6.13 D, mean astigmatism 4.06 ± 1.26 D). Three months postoperatively, mean MRSE in 37.6% of eyes was within ±0.5 D, 61.8% within ±1.0 D and 91.4% within ±2.0 D. 18.5% underwent keratorefractive surgery to correct residual refractive error. A 1.56-fold increase occurred in 4th order spherical aberration. Endothelial cell loss was 1.45% at 1 year and negligible at 5 years. Fifty-four eyes (29.2%) gained one or more lines of best corrected visual acuity and no eye lost a line. Conclusion: Artisan phakic IOLs are safe and effective for refractive error correction.
When Do Levodopa Motor Fluctuations First Appear in Parkinson’s Disease?
Authors: Stocchi Fabrizio , Jenner Peter , Obeso Jose A.
Published: March 2010

Although levodopa provides therapeutic benefit over the entire course of Parkinson’s disease, most patients eventually notice a decline in the duration of benefit from each dose, a phenomenon termed ‘wearing-off’ or ‘end of dose’ deterioration. This is an important indicator that the patient is entering a more complex phase of the disease. Wearing-off has been classically associated with the later stages of Parkinson’s disease, but it is becoming apparent that patients with early disease, presenting as well controlled, may already be experiencing fluctuations in their response to levodopa. However, neither the pathophysiology nor the clinical relevance of the early emergence of wearing-off has been properly explored. We now review the preclinical and clinical evidence that suggests that even patients who are apparently still in the honeymoon phase of drug treatment may have early fluctuations in their motor response to dopaminergic therapy. It is important that early wearing-off is recognized as it has important consequences for the long-term outcome and for the medication regimens to be used.
Long-Term Outcome of Alcohol Septal Ablation in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: ten Cate Folkert J. , Soliman Osama I.I. , Michels Michelle , Theuns Dominic A.M.J. , de Jong Peter L. , Geleijnse Marcel L. , Serruys Patrick W.
Published: March 2010

Background—

The impact of alcohol septal ablation (ASA)-induced scar is not known. This study sought to examine the long-term outcome of ASA among patients with obstructive hypertrophic cardiomyopathy.

Methods and Results—

Ninety-one consecutive patients (aged 54±15 years) with obstructive hypertrophic cardiomyopathy underwent ASA. Primary study end point was a composite of cardiac death and aborted sudden cardiac death including appropriate cardioverter-defibrillator discharges for fast ventricular tachycardia/ventricular fibrillation. Secondary end points were noncardiac death and other nonfatal complications. Outcomes of ASA patients were compared with 40 patients with hypertrophic cardiomyopathy who underwent septal myectomy. During 5.4±2.5 years, primary and/or secondary end points were seen in 35 (38%) ASA patients of whom 19 (21%) patients met the primary end point. The 1-, 5-, and 8-year survival-free from the primary end point was 96%, 86%, and 67%, respectively in ASA patients versus 100%, 96%, and 96%, respectively in myectomy patients during 6.6±2.7 years (log-rank,
P
=0.01). ASA patients had a ≈5-fold increase in the estimated annual primary end point rate (4.4% versus 0.9%) compared with myectomy patients. In a multivariable model including a propensity score, ASA was an independent predictor of the primary end point (unadjusted hazard ratio, 5.2; 95% CI, 1.2 to 22.1;
P
=0.02 and propensity score-adjusted hazard ratio, 6.1; 95% CI, 1.4 to 27.1;
P
=0.02).

Conclusions—

This study shows that ASA has potentially unwanted long-term effects. This poses special precaution, given the fact that ASA is practiced worldwide at increasing rate. We recommend myectomy as the preferred intervention in patients with obstructive hypertrophic cardiomyopathy.
Impact of a Single Intracoronary Administration of Adiponectin on Myocardial Ischemia/Reperfusion Injury in a Pig Model
Authors: Kondo Kazuhisa , Shibata Rei , Unno Kazumasa , Shimano Masayuki , Ishii Masakazu , Kito Tetsutaro , Shintani Satoshi , Walsh Kenneth , Ouchi Noriyuki , Murohara Toyoaki
Published: March 2010

Background—

Adiponectin plays a protective role in the development of obesity-linked disorders. We demonstrated that adiponectin exerts beneficial actions on acute ischemic injury in mice hearts. However, the effects of adiponectin treatment in large animals and its feasibility in clinical practice have not been investigated. This study investigated the effects of intracoronary administration of adiponectin on myocardial ischemia-reperfusion (I/R) injury in pigs.

Methods and Results—

The left anterior descending coronary artery was occluded in pigs for 45 minutes and then reperfused for 24 hours. Recombinant adiponectin protein was given as a bolus intracoronary injection during ischemia. Cardiac functional parameters were measured by a manometer-tipped catheter. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling staining. Tumor necrosis factor-α and interleukin-10 transcripts were analyzed by real-time polymerase chain reaction. Serum levels of derivatives of reactive oxygen metabolites and biological antioxidant potential were measured. Adiponectin protein was determined by immunohistochemical and Western blot analyses. Intracoronary administration of adiponectin protein led to a reduction in myocardial infarct size and improvement of left ventricular function in pigs after I/R. Injected adiponectin protein accumulated in the I/R-injured heart. Adiponectin treatment resulted in decreased tumor necrosis factor-α and increased interleukin-10 mRNA levels in the myocardium after I/R. Adiponectin-treated pigs had reduced apoptotic activity in the I/R-injured heart and showed increased biological antioxidant potential levels and decreased derivatives of reactive oxygen metabolite levels in the blood stream after I/R.

Conclusions—

These data suggest that adiponectin protects against I/R injury in a preclinical pig model through its ability to suppress inflammation, apoptosis, and oxidative stress. Administration of intracoronary adiponectin could be a useful adjunctive therapy for acute myocardial infarction.
Predictors of Long-Term Adverse Outcomes in Patients With Congenital Coronary Artery Fistulae
Authors: Valente Anne Marie , Lock James E. , Gauvreau Kimberlee , Rodriguez-Huertas Elizabeth , Joyce Caitlyn , Armsby Laurie , Bacha Emile A. , Landzberg Michael J.
Published: March 2010

Background—

Significant morbidities, including angina, symptomatic heart failure, and myocardial infarction, have been reported after coronary artery fistula (CAF) closure; however, predictors that may be associated with adverse outcomes have not been established. The goal of this investigation is to describe the long-term outcomes witnessed in patients with either treated or untreated CAF at our institution and to investigate whether certain features predicted adverse outcomes.

Methods and Results—

The records and angiograms of patients with CAF who underwent a diagnostic cardiac catheterization at Children’s Hospital Boston from 1959 through 2008 were reviewed. Of 76 patients identified, 20% were associated with additional congenital heart disease. Forty-four underwent transcatheter closure, 20 underwent surgical repair, and no intervention was performed in the remaining 12 subjects. Three patients who had initially undergone surgical closure had a second intervention, 1 underwent repeat surgery, and 2 underwent transcatheter closure. One patient who had undergone transcatheter closure underwent a second transcatheter closure for residual fistula. Major complications, including myocardial infarction, angina with coronary thrombosis, and symptomatic cardiomyopathy, occurred in 11 (15%) patients. The sole angiographic feature that was predictive of adverse outcome was drainage of the CAF into the coronary sinus (
P
<0.001). Clinical predictors associated with adverse outcomes included older age at diagnosis (
P
<0.001), tobacco use (
P
=0.006), diabetes (
P
=0.05), systemic hypertension (
P
<0.001), and hyperlipidemia (
P
<0.001).

Conclusions—

Long-term complications of CAF closure may include coronary thrombosis, myocardial infarction, and cardiomyopathy. CAF that drain into the coronary sinus are at particularly high-risk of long-term morbidities after closure, and strategies including long-term anticoagulation should be considered.