bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Insulin-like Growth Factor–Mammalian Target of Rapamycin Signaling by MicroRNA in Childhood Adrenocortical Tumors
Authors: Doghman Mabrouka , Wakil Abeer El , Cardinaud Bruno , Thomas Emilie , Wang Jinling , Zhao Wei , Peralta-Del Valle Maria Helena C. , Figueiredo Bonald C. , Zambetti Gerard P. , Lalli Enzo
Published: May 2010

MicroRNAs (miRNAs) act at the posttranscriptional level to control gene expression in virtually every biological process, including oncogenesis. Here, we report the identification of a set of miRNAs that are differentially regulated in childhood adrenocortical tumors (ACT), including miR-99a and miR-100. Functional analysis of these miRNAs in ACT cell lines showed that they coordinately regulate expression of the insulin-like growth factor–mammalian target of rapamycin (mTOR)–raptor signaling pathway through binding sites in their 3′-untranslated regions. In these cells, the active Ser2448-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G2-M phases of the cell cycle. Pharmacologic inhibition of mTOR signaling by everolimus greatly reduces tumor cell growth in vitro and in vivo. Our results reveal a novel mechanism of regulation of mTOR signaling by miRNAs, and they lay the groundwork for clinical evaluation of drugs inhibiting the mTOR pathway for treatment of adrenocortical cancer. Cancer Res; 70(11); 4666–75. ©2010 AACR.
ADAMTS1 Contributes to the Acquisition of an Endothelial-like Phenotype in Plastic Tumor Cells
Authors: Casal Carmen , Torres-Collado Antoni Xavier , Plaza-Calonge María del Carmen , Martino-Echarri Estefanía , Ramón y Cajal Santiago , Rojo Federico , Griffioen Arjan W. , Rodríguez-Manzaneque Juan Carlos
Published: May 2010

Cancer stem cells have been hypothesized to explain tumor plasticity, including the capability to adopt distinct differentiation commitments. Among the mechanisms of tumor neovascularization, the ability of some malignant cells to mimic an endothelial phenotype has been recognized by a capacity to form matrix-enriched pseudovascular structures. In addition to the expression of genes associated with an endothelial nature, the molecular dynamism of specific microenvironments may also be critical. Here, we report the identification of the extracellular protease ADAMTS1 as a critical molecule for tumor cells to acquire endothelial-like properties. In a fibrosarcoma model, ADAMTS1 increased tumor growth rate in an angiogenesis-independent manner, influencing the tumor cells to display an exclusive endothelial-like gene signature. We documented the relevant expression of ADAMTS1 in aggressive and highly plastic melanoma and Ewing sarcoma cells. Notably, inhibiting ADAMTS1 action compromised the endothelial mimetic attributes observed in this setting. Our findings provide insights into how the tumor microenvironment can elicit endothelial mimicry by tumor cells. Cancer Res; 70(11); 4676–86. ©2010 AACR.
Telomere Loss as a Mechanism for Chromosome Instability in Human Cancer
Authors: Murnane John P.
Published: May 2010

Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (DSB) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to DSBs, so that DSBs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of DSBs, a mechanism that prevents chromosome instability resulting from DSBs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. Cancer Res; 70(11); 4255–9. ©2010 AACR.
Activation of FOXO3a Is Sufficient to Reverse Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor Chemoresistance in Human Cancer
Authors: Yang Jer-Yen , Chang Chun-Ju , Xia Weiya , Wang Yan , Wong Kwok-Kin , Engelman Jeffrey A. , Du Yi , Andreeff Michael , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: May 2010

Drug resistance is a central challenge of cancer therapy that ultimately leads to treatment failure. In this study, we characterized a mechanism of drug resistance that arises to AZD6244, an established mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor currently being evaluated in cancer clinical trials. AZD6244 enhanced the expression of transcription factor FOXO3a, which suppressed cancer cell proliferation. In AZD6244-resistant cancer cells, we observed the impaired nuclear localization of FOXO3a, reduced FOXO3a-mediated transcriptional activity, and decreased the expression of FOXO3a target gene Bim after cell treatment with AZD6244. Resistant cells could be sensitized by phosphoinositide 3-kinase (PI3K)/AKT inhibitors, which are known to enhance FOXO3a nuclear translocation. Our findings define FOXO3a as candidate marker to predict the clinical efficacy of AZD6244. Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors. Cancer Res; 70(11); 4709–18. ©2010 AACR.
Downregulation of MicroRNA-200 in EBV-Associated Gastric Carcinoma
Authors: Shinozaki Aya , Sakatani Takashi , Ushiku Tetsuo , Hino Rumi , Isogai Maya , Ishikawa Shunpei , Uozaki Hiroshi , Takada Kenzo , Fukayama Masashi
Published: May 2010

EBV-associated gastric carcinoma is a distinct gastric carcinoma subtype with characteristic morphologic features similar to those of cells that undergo epithelial-to-mesenchymal transition. The effect of microRNA abnormalities in carcinogenesis was investigated by measuring the expression of the epithelial-to-mesenchymal transition–related microRNAs, miR-200a and miR-200b, in 36 surgically resected gastric carcinomas using quantitative reverse transcription-PCR analysis. MiR-200 family expression was decreased in EBV-associated gastric carcinoma, as compared with that in EBV-negative carcinoma. Downregulation of the miR-200 family was found in gastric carcinoma cell lines infected with recombinant EBV (MKN74-EBV, MKN7-EBV, and NUGC3-EBV), accompanied by the loss of cell adhesion, reduction of E-cadherin expression, and upregulation of ZEB1 and ZEB2. E-cadherin expression was partially restored by transfection of EBV-infected cells with miR-200 family precursors. Reverse transcription-PCR analysis of primary precursors of miR-200 (pri-miR-200) revealed that the transcription of pri-miR-200 was decreased in EBV-infected cells. Transfection of MKN74 cells with BARF0, EBNA1, and LMP2A resulted in a decrease of pri-miR-200, whereas transfection with EBV-encoded small RNA (EBER) did not. These four latent genes contributed to the downregulation of the mature miR-200 family and the subsequent upregulation of ZEB1/ZEB2, resulting in the reduction of E-cadherin expression. These findings indicate that all the latency type I genes have a synergetic effect on the downregulation of the miR-200 family that leads to reduced E-cadherin expression, which is a crucial step in the carcinogenesis of EBV-associated gastric carcinoma. Cancer Res; 70(11); 4719–27. ©2010 AACR.
Notch1 Functions as a Tumor Suppressor in a Model of K-ras–Induced Pancreatic Ductal Adenocarcinoma
Authors: Hanlon Linda , Avila Jacqueline L. , Demarest Renée M. , Troutman Scott , Allen Megan , Ratti Francesca , Rustgi Anil K. , Stanger Ben Z. , Radtke Fred , Adsay Volkan , Long Fenella , Capobianco Anthony J. , Kissil Joseph L.
Published: May 2010

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated in a subset of PDACs, leading to the hypothesis that Notch1 functions as an oncogene in this setting. To determine whether Notch1 is required for K-ras–induced tumorigenesis, we used a mouse model in which an oncogenic allele of K-ras is activated and Notch1 is deleted simultaneously in the pancreas. Unexpectedly, the loss of Notch1 in this model resulted in increased tumor incidence and progression, implying that Notch1 can function as a tumor suppressor gene in PDAC. Cancer Res; 70(11); 4280–6. ©2010 AACR.
Benzyl Isothiocyanate–Mediated Inhibition of Histone Deacetylase Leads to NF-κB Turnoff in Human Pancreatic Carcinoma Cells
Authors: Batra Sanjay , Sahu Ravi P. , Kandala Prabodh K. , Srivastava Sanjay K.
Published: May 2010

NF-κB/p65 is constitutively activated in pancreatic cancers, where it plays a critical role in the transcriptional activation of multiple cell survival genes. We have previously shown the apoptosis-inducing effects of benzyl isothiocyanate (BITC) in pancreatic cancer cells. We hypothesized that inhibition of NF-κB/p65 could be the mechanism of BITC-induced apoptosis. Therefore, the effect of BITC on NF-κB/p65 was evaluated in BxPC-3, Capan-2, and normal HPDE-6 cells by Western blotting, transcriptional and DNA-binding activity, and immunohistochemistry in the xenografted tumors. Our results reveal a remarkable decrease in the phosphorylation of NF-κB/p65 at Ser536 in both BxPC-3 and Capan-2 cells by BITC treatment. The expression of NF-κB/p65 was downregulated significantly in BxPC-3 cells, whereas it remained unchanged in Capan-2 cells. BITC treatment caused a significant decrease in NF-κB transcriptional and DNA-binding activity in both BxPC-3 and Capan-2 cells. A drastic decrease was observed in the expression and reporter activity of cyclin D1 in both the cell lines. Moreover, BITC also caused a significant decrease in the expression and activity of histone deacetylase (HDAC) 1 and HDAC3 in BxPC-3 and HDAC3 in Capan-2 cells. Overexpression of HDAC1 or HDAC3 abrogated the effects of BITC. BITC treatment did not cause any change in HDAC expression in normal HPDE-6 cells. Immunohistochemical analysis of tumors from BITC-treated mice showed significantly reduced staining for NF-κB, cyclin D1, HDAC1, and HDAC3 compared with control. Our results suggest inhibition of HDAC1/HDAC3 by BITC as a plausible mechanism of NF-κB inactivation, resulting in the in vitro and in vivo growth suppression of pancreatic cancer cells. Mol Cancer Ther; 9(6); 1596–608. ©2010 AACR.
ARQ 197, a Novel and Selective Inhibitor of the Human c-Met Receptor Tyrosine Kinase with Antitumor Activity
Authors: Munshi Neru , Jeay Sébastien , Li Youzhi , Chen Chang-Rung , France Dennis S. , Ashwell Mark A. , Hill Jason , Moussa Magdi M. , Leggett David S. , Li Chiang J.
Published: May 2010

The met proto-oncogene is functionally linked with tumorigenesis and metastatic progression. Validation of the receptor tyrosine kinase c-Met as a selective anticancer target has awaited the emergence of selective c-Met inhibitors. Herein, we report ARQ 197 as the first non-ATP–competitive small molecule that selectively targets the c-Met receptor tyrosine kinase. Exposure to ARQ 197 resulted in the inhibition of proliferation of c-Met–expressing cancer cell lines as well as the induction of caspase-dependent apoptosis in cell lines with constitutive c-Met activity. These cellular responses to ARQ 197 were phenocopied by RNAi-mediated c-Met depletion and further demonstrated by the growth inhibition of human tumors following oral administration of ARQ 197 in multiple mouse xenograft efficacy studies. Cumulatively, these data suggest that ARQ 197, currently in phase II clinical trials, is a promising agent for targeting cancers in which c-Met-driven signaling is important for their survival and proliferation. Mol Cancer Ther; 9(6); 1544–53. ©2010 AACR.
Continuous Vagal Nerve Stimulation for Recurrent Laryngeal Nerve Protection in Thyroid Surgery
Authors: Jonas J.
Published: May 2010

Introduction: Newly developed vagal stimulation probes permit continuous intraoperative neuromonitoring of the recurrent laryngeal nerve during thyroid resection. Complete signal loss indicates damage of the nerve. There is no other criterion so far to warn before imminent nerve function impairment. Methods: In 100 patients, thyroid resection (188 nerves at risk, 52 thyroidectomies, 21 Dunhill resections, 12 hemithyroidectomies, 5 two-sided subtotal resections) was performed. The vagus electrode V3 was used for continuous stimulation and placed between the carotid artery and the internal jugular vein (V3 electrode; laryngeal adhesive tube electrode; Fa. inomed Medizintechnik GmbH, Teningen, Germany). The signals were recorded via the tube electrode during the complete operation. The signal parameters amplitude, latency and thresholds of nerve conductance were compared at the start of thyroid resection and after completion of thyroid preparation. The changes of these parameters were analyzed. Results: The latencies (right vagal nerve 4.39 ± 0.51 ms; left vagal nerve 6.78 ± 0.75 ms) remained unchanged during the operation. The lower threshold of nerve conduction varied from 0.5 to 2.5 mA, the upper threshold from 1.5 to 5.0 mA. There were no changes between the two measuring points in the majority of cases (lower threshold 92.1%, upper threshold 80.8%). The signal amplitude values were identical in 48% of the cases compared to values at the beginning of operation. A large change in signal amplitude was seen from –58% to +243% after resection. None of the recorded changes of these three parameters were associated with laryngoscopic visible vocal cord disorders. Complete signal loss during operation was documented in 4 cases. Vocal cord palsy was confirmed in 3 cases after operation. In the 4th case, the stimulation signal could be deviated again with diminished amplitude at the end of the operation without vocal cord pareses at laryngoscopy afterwards. Conclusions: The parameters signal amplitude, latency and stimulation threshold cannot be used as reliable warning criteria for nerve function impairment during thyroid resection. Loss of signal remains the most important criterion for the surgeon. The coupling of the signal change to operational procedure may be beneficial in difficult thyroid preparation. This gives the surgeon the possibility to react immediately in the case of signal loss.
Comparative Outcomes between Hemo- and Peritoneal Dialysis Patients with Acute Intracerebral Hemorrhage
Authors: Hsieh Cheng-Yang , Chen Chih-Hung , Wu An-Bang , Tseng Chin-Chung
Published: May 2010

Background/Aims: The optimal mode of dialysis for end-stage renal disease (ESRD) patients with spontaneous intracerebral hemorrhage (ICH) remains controversial. We compared the outcomes of ESRD patients who received continuous peritoneal dialysis (CPD) or extended hemodialysis (EHD) after ICH, and investigated the factors determining prognosis.Methods: We incorporated our ICH patients with ESRD, requiring dialysis from January 2005 to December 2009. Patients were allocated to the CPD or EHD group according to the dialysis mode after ICH. We compared the 30-day mortality rate and modified Rankin Scale (mRS) of the two groups and analyzed the factors associated with mortality. Results: There were 40 patients with 16 episodes in CPD and 27 episodes in EHD group, without significant differences in baseline demographic data. The 30-day mortality rate and mRS were not different between the two groups. The patients who died within 30 days had higher ICH scores (4 ± 1 vs. 1 ± 1, p < 0.001) and outcome scores (5 ± 2 vs. 1 ± 1, p < 0.001). Dialysis-related complications occurred more frequently in the PD group (p = 0.07), but were unrelated to mortality. Conclusion: Among ESRD patients with ICH, EHD had a similar 30-day mortality rate and 30-day mRS to those receiving CPD. The mortality was significantly related to the severity of ICH.
Kaposi Sarcoma-Associated Herpesvirus (Human Herpesvirus Type 8)-Associated Extracavitary Lymphoma: Report of a Case in an HIV-Positive Patient with Simultaneous Kaposi Sarcoma and a Review of the Literature
Authors: Zhang Hailing , Yang Xiao Yan , Hong Tao , Feldman Tatyana , Bhattacharyya Pritish K.
Published: May 2010

Background: Kaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV8), is consistently identified in 2 human immunodeficiency virus (HIV)-associated lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease. Rarely, KSHV/HHV8-positive extracavitary solid tissue lymphomas occur, often at extranodal sites, which are not associated with an effusion. These solid variants of PEL are similar morphologically, immunophenotypically, clinically and genetically to classic PEL. Case Report: Here we report a case of a 46-year-old HIV-positive patient with lymphadenopathy and Kaposi sarcoma of the skin. The lymph node biopsy shows a KSHV/HHV8-positive high-grade B-cell lymphoma with co-infection with Epstein-Barr virus, which supports the diagnosis of a solid variant of PEL. The same lymph node is also multifocally involved in Kaposi sarcoma. Conclusion: Analysis of viral infection is of primary importance to define this solid variant of PEL. The exact oncogenic mechanisms of HHV8 are not clearly defined. It is believed that it is related to a few latent viral gene products including ORF73, ORF72, and ORF71 which increase proliferation and impair apoptosis through variant regulatory processes. To the best of our knowledge, this is the first reported case of solid tissue PEL along with Kaposi sarcoma involving the same anatomic site.
Deficiency in the Serum-Derived Hyaluronan-Associated Protein-Hyaluronan Complex Enhances Airway Hyperresponsiveness in a Murine Model of Asthma
Authors: Zhu Long , Zhuo Lisheng , Kimata Koji , Yamaguchi Etsuro , Watanabe Hideto , Aronica Mark A. , Hascall Vincent C. , Baba Kenji
Published: May 2010

Background: Serum-derived hyaluronan (HA)-associated proteins (SHAPs), the heavy chains of inter-α-trypsin inhibitor, covalently bind to HA to form the SHAP-HA complex. The SHAP-HA complex is involved in the pathophysiology of inflammatory diseases, including rheumatoid arthritis. We investigated whether this complex is also involved in airway allergy. Methods: SHAP-HA-deficient (bikunin knockout, KO) mice and wild-type (WT) mice were immunized twice by intraperitoneal injection of ovalbumin (OVA) and exposed to aerosol OVA for 30 min each day for 2 weeks. Twenty-four hours after the final OVA challenge, airway responsiveness to inhaled methacholine (MCh) was measured, and analysis of bronchoalveolar lavage fluid (BALF) and lung histological studies were done. Results: Compared to WT mice, KO mice showed higher airway hyperresponsiveness to inhaled MCh and higher late-phase responses to OVA whereas the early-phase responses were similar. Cell differentials of BALF showed an increased number of macrophages and neutrophils in KO mice. Furthermore, decreased concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were found in BALF from KO mice whereas the levels of Th1 and Th2 cytokines were not different from WT mice. Immunochemical study of the lung tissues revealed stronger staining of sTNFR1 in KO than in WT mice. Conclusions: Our results suggest that in this murine asthma model, the SHAP-HA complex has an inhibitory role in the development of airway hyperresponsiveness and allergic airway inflammation which may be attributed, at least in part, to negative feedback mechanisms exerted by sTNFR1, the shedding of which from the cell surface might also be promoted by the SHAP-HA complex.
The Temporal Profile of Inflammatory Markers and Mediators in Blood after Acute Ischemic Stroke Differs Depending on Stroke Outcome
Authors: Worthmann H. , Tryc A.B. , Goldbecker A. , Ma Y.T. , Tountopoulou A. , Hahn A. , Dengler R. , Lichtinghagen R. , Weissenborn K.
Published: May 2010

Background: Early inflammation has been suggested as an important factor contributing to unfavorable prognosis after acute ischemic stroke. The present study aimed to clarify the temporal dynamics of discrete inflammatory markers/mediators for future mechanism-targeting anti-inflammatory strategies in ischemic brain damage. Methods: Blood samples of 69 patients with transient ischemic attack or ischemic stroke were taken upon admission and at time points 6, 12 and 24 h, as well as 3 and 7 days after symptom onset for analysis of monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), C-reactive protein (CRP) and the brain damage marker S100B. Clinical scores (modified Rankin Scale, National Institute of Health Stroke Scale) were assessed on day 90. Results: MCP-1, MMP-9, TIMP-1, IL-6, CRP and S100B showed significantly different time courses depending on stroke outcome. While the levels of IL-6, MCP-1 and MMP-9 increased already a few hours after symptom onset, CRP and S100B gradually rose commencing at 12–24 h. TIMP-1 demonstrated an extended plateau. By multiple linear regression analysis IL-6, MCP-1, TIMP-1 and S100B were determined to be independently related to clinical outcome scores at specific time points. Conclusions: Our data show important differences in the early time course of several potential markers for the complex network of inflammation and brain damage after ischemic stroke depending on stroke outcome. This must be considered for any therapeutical approach using anti-inflammatory treatment.
Evaluation of the Distribution and Orientation of Remineralized Enamel Crystallites in Subsurface Lesions by X-Ray Diffraction
Authors: Tanaka T. , Yagi N. , Ohta T. , Matsuo Y. , Terada H. , Kamasaka K. , To-o K. , Kometani T. , Kuriki T.
Published: May 2010

Remineralization is the process by which hydroxyapatite (HAp) is restored in enamel subsurface lesions, and transversal microradiography (TMR) has been used to analyze remineralization in terms of the recovery of mineral content. In this study, we directly detected the distribution and orientation of longitudinal HAp crystallite at the remineralized zone in enamel subsurface lesions by using an X-ray microbeam (6-µm diameter) diffraction method. This method was demonstrated and involves the simultaneous detection of wide-angle X-ray diffraction (WAXRD) and small-angle X-ray scattering (SAXS). WAXRD reflects the amount of HAp crystallites, and SAXS reflects that of voids in crystallites. The polished surface of a bovine enamel block was divided into three zones of sound, demineralized, and remineralized zones. Thin sections of approximately 150 µm thickness were then cut perpendicular to the surface, and subjected to WAXRD and SAXS following TMR. The increase in the amount of HAp crystallites and the decrease in voids in the crystallites at the remineralized zone were detected by WAXRD and SAXS, respectively, which was consistent with the result of TMR. This study indicates that both the spatial distribution and orientation of the restored HAp crystals in the remineralization process at the subsurface lesion can be simultaneously analyzed by the X-ray diffraction methods.
Effect of Different Time Intervals between Examinations on the Reproducibility of ICDAS-II for Occlusal Caries
Authors: Jablonski-Momeni A. , Ricketts D.N.J. , Weber K. , Ziomek O. , Heinzel-Gutenbrunner M. , Schipper H.M. , Stoll R. , Pieper K.
Published: May 2010

Aim: To evaluate intra- and interexaminer reproducibility of ICDAS-II on occlusal caries diagnosis when different time intervals were allowed to elapse between examinations. A subsidiary aim was to determine whether collapsing the codes would influence this reproducibility. Methods: The occlusal surfaces of 50 permanent posterior teeth were investigated by 3 trained examiners using ICDAS-II at baseline, 1 day, 1 week and 4 weeks after baseline. Results: Weighted kappa values for intra- and interexaminer reproducibility were 0.76–0.93. Conclusion: The time span did not have a major impact on assessing intra- and interexaminer reproducibility. Collapsing ICDAS-II codes had no impact on examiner reproducibility.
Genes and Their Effects on Dental Caries May Differ between Primary and Permanent Dentitions
Authors: Wang X. , Shaffer J.R. , Weyant R.J. , Cuenco K.T. , DeSensi R.S. , Crout R. , McNeil D.W. , Marazita M.L.
Published: May 2010

The importance of genetic factors in the genesis of dental caries of both primary and permanent dentitions is well established; however, the degree to which genes contribute to the development of dental caries, and whether these genes differ between primary and permanent dentitions, is largely unknown. Using family-based likelihood methods, we assessed the heritability of caries-related phenotypes for both children and adults in 2,600 participants from 740 families. We found that caries phenotypes in the primary dentition were highly heritable, with genes accounting for 54–70% of variation in caries scores. The heritability of caries scores in the permanent dentition was also substantial (35–55%, all p < 0.01), although this was lower than analogous phenotypes in the primary dentition. Assessment of the genetic correlation between primary and permanent caries scores indicated that 18% of the covariation in these traits was due to common genetic factors (p < 0.01). Therefore, dental caries in primary and permanent teeth may be partly attributable to different suites of genes or genes with differential effects. Sex and age explained much of the phenotypic variation in permanent, but not primary, dentition. Further, including pre-cavitated white-spot lesions in the phenotype definition substantially increased the heritability estimates for dental caries. In conclusion, our results show that dental caries are heritable, and suggest that genes affecting susceptibility to caries in the primary dentition may differ from those in permanent teeth. Moreover, metrics for quantifying caries that incorporate white-spot lesions may serve as better phenotypes in genetic studies of the causes of tooth decay.
Microdialysis Sampling for Investigations of Bioavailability and Bioequivalence of Topically Administered Drugs: Current State and Future Perspectives
Authors: Holmgaard R. , Nielsen J.B. , Benfeldt E.
Published: May 2010

Microdialysis (MD) in the skin is a unique technique for in vivo sampling of topically as well as systemically administered drugs at the site of action, e.g. sampling the unbound tissue concentrations in the dermis and subcutaneous tissue. MD as a research method has undergone significant development, improvement and validation during the last decade and has proved to be a versatile, safe and valuable tool for pharmacokinetic and pharmacodynamic studies. This review gives an overview of the current state and future perspectives of dermal MD sampling. Methodological issues such as choice of instrumentation, calibration and experimental procedures are discussed along with the analytical considerations necessary for successful sampling. Clinical MD studies in the skin are reviewed with emphasis on pharmacokinetic studies of topically applied drugs with or without impairment of skin barrier function by skin disease or barrier perturbation. A comparison between MD and other tissue sampling techniques reveals the advantages and limitations of the method. Subsequently, an in-depth discussion of the application of MD for the evaluation of bioavailability and bioequivalence of topical formulations is concluded by the current regulatory point of view. The future perspective includes further expansion and validation of the use of MD in the experimental and clinical setting as well as in the optimization of the method for regulatory purposes, i.e. the commercialization of bioequivalent, generic drug products.
Standardized Tape Stripping: A Practical and Reproducible Protocol to Uniformly Reduce the Stratum Corneum
Authors: Dickel H. , Goulioumis A. , Gambichler T. , Fluhr J.W. , Kamphowe J. , Altmeyer P. , Kuss O.
Published: May 2010

The basic idea of the strip patch test (SPT), a modification of the conventional patch test (PT), is to increase the bioavailability of a test substance in the deeper epidermal cell layers by defined tape stripping of the test area on the back prior to a PT. In a prospective, investigator-blinded clinical study, we evaluated the variability and the interrater agreement of our proposed SPT protocol. The relative stratum corneum (SC) reduction after tape stripping was measured on 75 subjects for variability and in a subgroup of 18 subjects for interrater agreement, by performing in vivo confocal laser scanning microscopy. We found good reproducibility with an SC reduction of 31%, with 95% of the values lying between 22 and 40%, and good interrater agreement. As a result, our SPT protocol yields a clinically adequate standardization of the SC reduction and the SPT may therefore be recommended for performance in daily clinical routine.
Long-Term Outcome of Adjunctive Celecoxib Treatment After Paclitaxel-Eluting Stent Implantation for the Complex Coronary Lesions
Authors: Chung Jin-Wook , Yang Han-Mo , Park Kyung-Woo , Lee Hae-Young , Park Jin-Shik , Kang Hyun-Jae , Cho Young-Seok , Youn Tae-Jin , Koo Bon-Kwon , Chae In-Ho , Choi Dong-Ju , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: May 2010

Background—

In the COREA-TAXUS trial (“Effect of Celecoxib On REstenosis after coronary Angioplasty with a TAXUS stent”), celecoxib reduced late luminal loss and adverse cardiac events at follow-up around 6 months. The objective of this study was to assess the long-term outcome of short-term adjunctive celecoxib treatment after paclitaxel-eluting stent implantation.

Methods and Results—

This is a 2-year clinical follow-up of the COREA-TAXUS trial, an open-label randomized controlled study. A total 274 patients were randomized to receive or not receive celecoxib (400 mg before the intervention and 200 mg twice daily for 6 months after the procedure), and 271 underwent successful paclitaxel-eluting stent implantation. All patients were given aspirin (100 mg daily indefinitely) and clopidogrel (75 mg daily for at least 6 months). Among the 271 patients, 267 (98.5%) completed the 2-year clinical follow-up. From the previous follow-up to 2 years, there was no difference in the rate of adverse cardiac events between the celecoxib and control groups (1.6% versus 4.3%,
P
=0.27). Thus, at 2 years, the rate of adverse cardiac events was consistently lower in the celecoxib group (6.9% versus 19.7%,
P
=0.002). A significant reduction in need for target lesion revascularization was observed (6.2% versus 18.2%,
P
=0.003). The efficacy benefit in the celecoxib group was not undermined by an increased risk for cardiac death or myocardial infarction at 2 years (1.5% versus 1.4%).

Conclusions—

Six-month adjunctive celecoxib treatment after paclitaxel-eluting stent implantation was associated with durable long-term efficacy up to 2 years. However, the inconclusive evidence for the long-term safety of this treatment warrants caution.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT 00292721.
Concurrent Microvascular and Infarct Remodeling After Successful Reperfusion of ST-Elevation Acute Myocardial Infarction
Authors: Sezer Murat , Aslanger Emre K. , Cimen Arif O. , Yormaz Ebru , Turkmen Cuneyt , Umman Berrin , Nisanci Yılmaz , Bugra Zehra , Adalet Kamil , Umman Sabahattin
Published: May 2010

Background—

Connection between the course of microvascular and infarct remodeling processes over time after reperfused ST-elevation acute myocardial infarction has not been fully elucidated. The aim of this study is to investigate the association of temporal changes in hemodynamics of microcirculation in the infarcted territory and infarct size (IS) after primary percutaneous coronary intervention in patients with ST-elevation acute myocardial infarction.

Methods and Results—

Thirty-five patients admitted with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention were enrolled in the study. Coronary flow reserve (CFR), index of microvascular resistance (IMR), and IS were assessed 2 days after primary percutaneous coronary intervention and at the 5-month follow-up. The predictors of the 5-month IS were the baseline values of IS (β=0.6,
P
<0.001), IMR (β=0.280,
P
=0.013), and CFR (β=−0.276,
P
=0.017). There were significant correlations between relative change in IS and relative change in measures of microvascular function (IS and CFR [
r
=−0.51,
P
=0.002]); IS and IMR ([
r
=0.55,
P
=0.001]). In multivariate model, relative changes in IMR (β=0.552,
P
=0.001) and CFR (β=−0.511,
P
=0.002) were the only predictors of relative change in IS. In patients with an improvement in IMR >33%, the mean IS decreased from 32.3±16.9% to 19.3±14% (
P
=0.001) in the follow-up. Similarly, in patients with an improvement in CFR >41%, the mean IS significantly decreased from 29.9±20% to 15.8±12.4% (
P
=0.003). But in patients with an improvement in IMR and CFR, which were below than the mean values, IS did not significantly decrease during the follow-up.

Conclusions—

Improvement in microvascular function in the infarcted territory is associated with reduction in IS after reperfused ST-elevation acute myocardial infarction. This link suggests that further investigations are warranted to determine whether therapeutic protection of microvascular integrity results in augmentation of infarct healing.
Led Astray by Punctuation The Meaning of πιορκ in Matt 5:33
Authors: Lee John A.L.
Published: May 2010

The meaning of πιορκ in Matt 5:33 remains uncertain in the NT lexicon of Bauer in English and in major commentaries. This paper traces the problem in Bauer to misreading of punctuation. A re-examination of the evidence establishes that the appropriate meaning is break one’s sworn promise, and this is seen to be the meaning Bauer intended.
James 1:2-15 and Hellenistic Psychagogy
Authors: Kloppenborg John S.
Published: May 2010

In elaborating the Jesus tradition (Q 11:9-10; 6:22-23) James expands, compresses and elaborates Q sayings in a way which reveals an array of interests in psychagogy and the care of the soul which we know also to have characterized various strains of Hellenistic philosophy of the early Roman period. The author of James displays a remarkable interest, not in such concrete ends as subsistence, debt relief, and the rewards for withstanding persecution, but rather in the psychic processes that occur between stimulus and decision and in the role that proper cognition plays in constructing the subject as perfect.
Circumpolar Arctic Tundra Vegetation Change Is Linked to Sea Ice Decline
Authors: Bhatt Uma S. , Walker Donald A. , Raynolds Martha K. , Comiso Josefino C. , Epstein Howard E. , Jia Gensuo , Gens Rudiger , Pinzon Jorge E. , Tucker Compton J. , Tweedie Craig E. , Webber Patrick J.
Published: May 2010

Linkages between diminishing Arctic sea ice and changes in Arctic terrestrial ecosystems have not been previously demonstrated. Here, the authors use a newly available Arctic Normalized Difference Vegetation Index (NDVI) dataset (a measure of vegetation photosynthetic capacity) to document coherent temporal relationships between near-coastal sea ice, summer tundra land surface temperatures, and vegetation productivity. The authors find that, during the period of satellite observations (1982–2008), sea ice within 50 km of the coast during the period of early summer ice breakup declined an average of 25% for the Arctic as a whole, with much larger changes in the East Siberian Sea to Chukchi Sea sectors (>44% decline). The changes in sea ice conditions are most directly relevant and have the strongest effect on the villages and ecosystems immediately adjacent to the coast, but the terrestrial effects of sea ice changes also extend far inland. Low-elevation (<300 m) tundra summer land temperatures, as indicated by the summer warmth index (SWI; sum of the monthly-mean temperatures above freezing, expressed as °C month−1), have increased an average of 5°C month−1 (24% increase) for the Arctic as a whole; the largest changes (+10° to 12°C month−1) have been over land along the Chukchi and Bering Seas. The land warming has been more pronounced in North America (+30%) than in Eurasia (16%). When expressed as percentage change, land areas in the High Arctic in the vicinity of the Greenland Sea, Baffin Bay, and Davis Strait have experienced the largest changes (>70%). The NDVI has increased across most of the Arctic, with some exceptions over land regions along the Bering and west Chukchi Seas. The greatest change in absolute maximum NDVI occurred over tundra in northern Alaska on the Beaufort Sea coast [+0.08 Advanced Very High Resolution Radiometer (AVHRR) NDVI units]. When expressed as percentage change, large NDVI changes (10%–15%) occurred over land in the North America High Arctic and along the Beaufort Sea. Ground observations along an 1800-km climate transect in North America support the strong correlations between satellite NDVI observations and summer land temperatures. Other new observations from near the Lewis Glacier, Baffin Island, Canada, document rapid vegetation changes along the margins of large retreating glaciers and may be partly responsible for the large NDVI changes observed in northern Canada and Greenland. The ongoing changes to plant productivity will affect many aspects of Arctic systems, including changes to active-layer depths, permafrost, biodiversity, wildlife, and human use of these regions. Ecosystems that are presently adjacent to year-round (perennial) sea ice are likely to experience the greatest changes.
Physical Climate Response to a Reduction of Anthropogenic Climate Forcing
Authors: Samanta Arindam , Anderson Bruce T. , Ganguly Sangram , Knyazikhin Yuri , Nemani Ramakrishna R. , Myneni Ranga B.
Published: May 2010

Recent research indicates that the warming of the climate system resulting from increased greenhouse gas (GHG) emissions over the next century will persist for many centuries after the cessation of these emissions, principally because of the persistence of elevated atmospheric carbon dioxide (CO2) concentrations and their attendant radiative forcing. However, it is unknown whether the responses of other components of the climate system—including those related to Greenland and Antarctic ice cover, the Atlantic thermohaline circulation, the West African monsoon, and ecosystem and human welfare—would be reversed even if atmospheric CO2 concentrations were to recover to 1990 levels. Here, using a simple set of experiments employing a current-generation numerical climate model, the authors examine the response of the physical climate system to decreasing CO2 concentrations following an initial increase. Results indicate that many characteristics of the climate system, including global temperatures, precipitation, soil moisture, and sea ice, recover as CO2 concentrations decrease. However, other components of the Earth system may still exhibit nonlinear hysteresis. In these experiments, for instance, increases in stratospheric water vapor, which initially result from increased CO2 concentrations, remain present even as CO2 concentrations recover. These results suggest that identification of additional threshold behaviors in response to human-induced global climate change should focus on subcomponents of the full Earth system, including cryosphere, biosphere, and chemistry.
A Method to Infer the Three Cartesian Wavelengths of a Mountain Wave from Three Soundings
Authors: Alexander P. , de la Torre A.
Published: May 2010

The number of atmospheric sounding techniques and the amount of missions within each of them continue to grow at the present time. The probability of having two or more profiles in a given region and time interval therefore is increasing. In the case of three close observations it would be a priori possible to infer the three Cartesian wavelengths of a mountain wave. However, the relative orientation of the three sounding paths cannot be arbitrary and must fulfill some conditions to avoid errors growing out of given bounds.
Climatology of Anomalous Propagation Radar Echoes in a Coastal Area
Authors: Mesnard Frédéric , Sauvageot Henri
Published: May 2010

Anomalous propagation (AP) of ground-based radar beam results in the detection of ground echoes beyond the horizon. One year of data gathered with an S-band meteorological radar located on the coast in southwest France is used to analyze the spatial distribution of AP ground echoes (APE). The APE distributions of duration and reflectivity in the radar-observed area are found to be strongly related to the main feature of the regional orography and topography up to the farthest distance (250 km) observed by the radar, notably the nature of the surface, the topographic orientation with respect to the radar beam direction, and the altitude. The distribution of APE in the studied area is found to be strongly anisotropic around the radar, with wide differences between land and sea. Rain accumulation equivalent to the APE is, in certain places, of the same order or higher than the real rain depth. The distribution of the ground surfaces, as calculated from a ground numerical model, compares qualitatively well with the APE radar reflectivity distribution.
Objectively Determining the Rotational Center of Tropical Cyclones in Passive Microwave Satellite Imagery
Authors: Wimmers Anthony J. , Velden Christopher S.
Published: May 2010

Precise center-fixing of tropical cyclones (TCs) is critical for operational forecasting, intensity estimation, and visualization. Current procedures are usually performed with manual input from a human analyst, using multispectral satellite imagery as the primary tools. While adequate in many cases, subjective interpretation can often lead to variance in the estimated center positions. In this paper an objective, robust algorithm is presented for resolving the rotational center of TCs: the Automated Rotational Center Hurricane Eye Retrieval (ARCHER). The algorithm finds the center of rotation using spirally oriented brightness temperature gradients in the TC banding patterns in combination with gradients along the ring-shaped edge of a possible eye. It is calibrated and validated using 85–92-GHz passive microwave imagery because of this frequency’s relative ubiquity in TC applications; however, similar versions of ARCHER are also shown to work effectively with other satellite imagery of TCs. In TC cases with estimated low to moderate vertical wind shear, the accuracy (RMSE) of the ARCHER estimated center positions is 17 km (9 km for category 1–5 hurricanes). In cases with estimated high vertical shear, the accuracy of the ARCHER estimated center positions is 31 km (21 km for category 2–5 hurricanes).
Simulations of Subtropical Cyclones in a Baroclinic Channel Model
Authors: Davis Christopher A.
Published: May 2010

The present study considers a variety of cyclone developments that occur in an idealized, baroclinic channel model featuring full condensation heating effects over an ocean with prescribed sea surface temperature variation. The geostrophic basic-state jet is specified by the tropopause shape, and horizontal shear is included by specifying the meridional variation of zonal wind on the lower boundary. The horizontal shear induces anticyclonic wave breaking of baroclinic waves. Normal mode perturbations are computed using a “fake-dry” version of the model but integrated forward using full physics.

Low-latitude moist convection is particularly strong in simulations with strong surface easterlies that destabilize the troposphere through water vapor fluxes from the ocean surface. Deep convection produces a locally elevated dynamic tropopause and an associated anticyclone. This modified zonal flow supports moist baroclinic instability. The resulting cyclones, identified as subtropical cyclones, occur in deep westerly vertical wind shear but are nearly devoid of lower-tropospheric baroclinicity initially. These systems are distinguished from baroclinically dominated secondary cyclones that also form at relatively low latitudes in the simulations.

For weak jets and strong subtropical surface easterlies, subtropical cyclone development dominates formation on the midlatitude jet. For strong westerly jets or weak horizontal shear, the situation is reversed and the midlatitude baroclinic wave can help or hinder the ultimate intensification of the subtropical cyclone. The similarity of this cross-latitude influence to the extratropical transition of tropical cyclones is noted.
Tropical Tropopause Transition Layer Cirrus as Represented by CALIPSO Lidar Observations
Authors: Virts Katrina S. , Wallace John M. , Fu Qiang , Ackerman Thomas P.
Published: May 2010

The spatial and temporal variability of cirrus cloud fraction within the tropical tropopause transition layer (TTL) is investigated based on three years of data from the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) mission, analyzed in conjunction with fields from the European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA)-Interim and temperature profiles from radiosondes launched at Manus Island, Papua New Guinea (2°S, 147°E). TTL cirrus is found to be mainly confined to the rising branch of the Hadley cell within ∼15° of the equator, with maximum cloud fraction between 14 and 15 km. The time-varying spatial pattern of cloud fraction within this belt does not resemble the pattern of cloud fraction in the layer below, as would be expected if the TTL cirrus were formed by the spreading of the anvils of convective clouds. On the contrary, within the stably stratified layer above ∼13 km, cirrus cloud fraction and temperature both appear to be modulated by the planetary-scale vertical velocity field. The time-varying spatial patterns are reminiscent of the vertical-propagating Kelvin wave response to an equatorial heat source, with the coldest, cloudiest air in the TTL centered approximately 30° of longitude to the east of the strongest heating.