bluuebunny/crossref_metadata_2025 huggingface dataset:
Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against Hepatocyte Growth Factor/c-Met–Dependent Human Tumors
Authors: Burgess Teresa , Coxon Angela , Meyer Susanne , Sun Jan , Rex Karen , Tsuruda Trace , Chen Qing , Ho Shu-Yin , Li Luke , Kaufman Stephen , McDorman Kevin , Cattley Russell C. , Sun Jilin , Elliott Gary , Zhang Ke , Feng Xiao , Jia Xiao-Chi , Green Larry , Radinsky Robert , Kendall Richard
Published: February 2006

c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the β-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the β-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors. (Cancer Res 2006; 66(3): 1721-9)
Mammographic Density and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Authors: Mitchell Gillian , Antoniou Antonis C. , Warren Ruth , Peock Susan , Brown Judith , Davies Russell , Mattison Jenny , Cook Margaret , Warsi Iqbal , Evans D. Gareth , Eccles Diana , Douglas Fiona , Paterson Joan , Hodgson Shirley , Izatt Louise , Cole Trevor , Burgess Lucy ,   EMBRACE collaborators, Eeles Ros , Easton Douglas F.
Published: February 2006

High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (Ptrend = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of ≥50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers. (Cancer Res 2006; 66(3): 1866-72)
Mutations in the PI3K/PTEN/TSC2 Pathway Contribute to Mammalian Target of Rapamycin Activity and Increased Translation under Hypoxic Conditions
Authors: Kaper Fiona , Dornhoefer Nadja , Giaccia Amato J.
Published: February 2006

Decreased oxygen causes a rapid inhibition of mRNA translation. An important regulatory mechanism of translational repression under hypoxic conditions involves inhibition of the mammalian target of rapamycin (mTOR). mTOR is a target of the phosphatase and tensin homologue detected on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase/AKT/TSC2 pathway, a pathway that is frequently mutated in human cancers. Although hypoxia has been shown to inhibit mTOR activity, we show here that the hypoxia-induced inhibition of mTOR activity is attenuated in cells lacking TSC2 or PTEN, resulting in a higher translation rate even under hypoxic conditions. Comparison of mTOR inhibition by hypoxia alone or in combination with rapamycin showed that prolonged exposure to hypoxia was required to fully inhibit mTOR activity even in wild-type cells. Increased mTOR activity and protein synthesis did not translate into enhanced cell proliferation rates. However, lack of TSC2 resulted in a survival advantage when cells were exposed to hypoxia. Protection against hypoxia-induced cell death due to TSC2 deficiency is rapamycin-resistant, suggesting that TSC2 affects an apoptotic pathway. Tumors derived from TSC2 wild-type cells exhibited a growth delay compared with TSC2-deficient tumors, indicating that enhanced mTOR activity is advantageous in the initial phase of tumor growth. Therefore, failure to inhibit mTOR under oxygen-limiting conditions can be affected by upstream activating mutations and increases the survival and growth of hypoxic tumor cells. (Cancer Res 2006; 66(3): 1561-9)
Resistance of Cancers to Immunologic Cytotoxicity and Adoptive Immunotherapy via X-Linked Inhibitor of Apoptosis Protein Expression and Coexisting Defects in Mitochondrial Death Signaling
Authors: Ravi Rajani , Fuchs Ephraim J. , Jain Ajay , Pham Vui , Yoshimura Kiyoshi , Prouser Traci , Jalla Sanju , Zhou Xianzheng , Garrett-Mayer Elizabeth , Kaufmann Scott H. , Schulick Richard D. , Pardoll Drew M. , Bedi Atul
Published: February 2006

The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-γ, and Apo2 ligand/tumor necrosis factor–related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell–mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-xL, or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-γ/Apo2L/TRAIL– or granzyme B–induced apoptosis, lymphocyte-mediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity. (Cancer Res 2006; 66(3): 1730-9)
Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-d-Glucose
Authors: Andringa Kelly K. , Coleman Mitchell C. , Aykin-Burns Nukhet , Hitchler Michael J. , Walsh Susan A. , Domann Frederick E. , Spitz Douglas R.
Published: February 2006

It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-d-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-d-glucose, and total glutathione content as well as the expression of the first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)] were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-d-glucose exposure using l-buthionine-[S,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-d-glucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steady-state levels of pro-oxidants as assayed using an oxidation-sensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-d-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-d-glucose–mediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-d-glucose–induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress. (Cancer Res 2006; 66(3): 1605-10)
Discovering Clinical Biomarkers of Ionizing Radiation Exposure with Serum Proteomic Analysis
Authors: Ménard Cynthia , Johann Donald , Lowenthal Mark , Muanza Thierry , Sproull Mary , Ross Sally , Gulley James , Petricoin Emanuel , Coleman C. Norman , Whiteley Gordon , Liotta Lance , Camphausen Kevin
Published: February 2006

In this study, we sought to explore the merit of proteomic profiling strategies in patients with cancer before and during radiotherapy in an effort to discover clinical biomarkers of radiation exposure. Patients with a diagnosis of cancer provided informed consent for enrollment on a study permitting the collection of serum immediately before and during a course of radiation therapy. High-resolution surface-enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry (MS) was used to generate high-throughput proteomic profiles of unfractionated serum samples using an immobilized metal ion-affinity chromatography nickel-affinity chip surface. Resultant proteomic profiles were analyzed for unique biomarker signatures using supervised classification techniques. MS-based protein identification was then done on pooled sera in an effort to begin to identify specific protein fragments that are altered with radiation exposure. Sixty-eight patients with a wide range of diagnoses and radiation treatment plans provided serum samples both before and during ionizing radiation exposure. Computer-based analyses of the SELDI protein spectra could distinguish unexposed from radiation-exposed patient samples with 91% to 100% sensitivity and 97% to 100% specificity using various classifier models. The method also showed an ability to distinguish high from low dose-volume levels of exposure with a sensitivity of 83% to 100% and specificity of 91% to 100%. Using direct identity techniques of albumin-bound peptides, known to underpin the SELDI-TOF fingerprints, 23 protein fragments/peptides were uniquely detected in the radiation exposure group, including an interleukin-6 precursor protein. The composition of proteins in serum seems to change with ionizing radiation exposure. Proteomic analysis for the discovery of clinical biomarkers of radiation exposure warrants further study. (Cancer Res 2006; 66(3): 1844-50)
The Immunomodulatory Benzodiazepine Bz-423 Inhibits B-Cell Proliferation by Targeting c-Myc Protein for Rapid and Specific Degradation
Authors: Sundberg Thomas B. , Ney Gina M. , Subramanian Chitra , Opipari Anthony W. , Glick Gary D.
Published: February 2006

Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F1Fo-ATPase. Bz-423 inhibits F1Fo-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful. (Cancer Res 2006; 66(3): 1775-82)
Syrian Hamster as a Permissive Immunocompetent Animal Model for the Study of Oncolytic Adenovirus Vectors
Authors: Thomas Maria A. , Spencer Jacqueline F. , La Regina Marie C. , Dhar Debanjan , Tollefson Ann E. , Toth Karoly , Wold William S.M.
Published: February 2006

Oncolytic adenoviruses represent an innovative approach to cancer therapy. These vectors are typically evaluated in immunodeficient mice with human xenograft tumors. However, in addition to being immunodeficient, this model is limited because normal and cancerous mouse tissues are poorly permissive for human adenovirus replication. This prompted us to search for a model that more accurately reflects the use of oncolytic adenoviruses in cancer patients. To this end, we developed a novel Syrian hamster model that is both immunocompetent and replication-permissive. We found that human adenovirus replicates well in Syrian hamster cell lines and confirmed replication in the lungs. Oncolytic adenovirus injection showed efficacy in three different hamster tumor models. Furthermore, i.t. oncolytic adenovirus injection resulted in suppression of primary and metastatic lesions, i.t. replication and necrosis, vector entrance into the bloodstream, replication in the liver and lungs, and anti-adenovirus antibody induction. Our findings show that the Syrian hamster is a promising immunocompetent model that is permissive to human adenovirus replication in tumors as well as normal tissues. Therefore, the Syrian hamster model may become a valuable tool for the field of oncolytic adenovirus vectors in which vector safety and efficacy can be evaluated. (Cancer Res 2006; 66(3): 1270-6)
Urogenital Carcinogenesis in Female CD1 Mice Induced by In utero Arsenic Exposure Is Exacerbated by Postnatal Diethylstilbestrol Treatment
Authors: Waalkes Michael P. , Liu Jie , Ward Jerrold M. , Powell Douglas A. , Diwan Bhalchandra A.
Published: February 2006

Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 μg/pup/d) or tamoxifen (10 μg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-α (ER-α) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-α expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers. (Cancer Res 2006; 66(3): 1337-45)
Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas
Authors: McChesney Patricia A. , Aiyar Sarah E. , Lee Ok-Jae , Zaika Alexander , Moskaluk Christopher , Li Rong , El-Rifai Wa'el
Published: February 2006

Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs. Immunohistochemical analysis of UGC tissue arrays that contained 70 tumor samples showed moderate-strong staining for COBRA1 in 60 (84%) tumors. Interestingly, the tumor samples showed absent-weak staining for TFF1 in 45 (65%) of the tumors. Simultaneous loss of TFF1 expression and overexpression of COBRA1 was observed in 42 of 70 (60%) tumors. Using small interfering RNA technology with gastric cancer cells, we have shown that COBRA1 inhibition leads to increased TFF1 promoter activity and gene expression. Promoter analysis of TFF1 indicated that regulation of TFF1 by COBRA1 is estrogen independent in contrast to breast cancer. Moreover, COBRA1 regulation of TFF1 in gastric cancer cells was independent of NELF-E. Using several truncated mutants and site mutants of the TFF1 promoter, we have shown that COBRA1 can negatively regulate the activator protein-1 (AP-1) complex at the TFF1 promoter and thus down-regulate TFF1 expression in gastric cancer cell lines. Electrophoretic mobility shift assay showed that COBRA1 attenuates AP-1 binding to DNA. Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia. (Cancer Res 2006; 66(3): 1346-53)
Rapid Alteration of MicroRNA Levels by Histone Deacetylase Inhibition
Authors: Scott Gary K. , Mattie Michael D. , Berger Crystal E. , Benz Stephen C. , Benz Christopher C.
Published: February 2006

Improved understanding of the molecular mechanisms by which small-molecule inhibitors of histone deacetylases (HDAC) induce programs, such as cellular differentiation and apoptosis, would undoubtedly assist their clinical development as anticancer agents. As modulators of gene transcript levels, HDAC inhibitors (HDACi) typically affect only 5% to 10% of actively transcribed genes with approximately as many mRNA transcripts being up-regulated as down-regulated. Using microRNA (miRNA) array analysis, we report rapid alteration of miRNA levels in response to the potent hydroxamic acid HDACi LAQ824 in the breast cancer cell line SKBr3. Within 5 hours of exposure to a proapoptotic dose of LAQ824, significant changes were measured in 40% of the >60 different miRNA species expressed in SKBr3 cells with 22 miRNA species down-regulated and 5 miRNAs up-regulated. To explore a potential functional link between HDACi induced mRNA up-regulation and miRNA down-regulation, antisense experiments were done against miR-27a and miR-27b, both abundantly expressed and down-regulated in SKBr3 cells by LAQ824. Correlating a set of genes previously determined by cDNA array analysis to be rapidly up-regulated by LAQ824 in SKBr3 with a database of potential 3′ untranslated region miRNA binding elements, two genes containing putative miR-27 anchor elements were identified as transcriptionally up-regulated following miR-27 antisense transfection, ZBTB10/RINZF, a Sp1 repressor, and RYBP/DEDAF, an apoptotic facilitator. These findings emphasize the importance of post-transcriptional mRNA regulation by HDACi in addition to their established effects on promoter-driven gene expression. (Cancer Res 2006; 66(3): 1277-81)
Targeting Heat Shock Response to Sensitize Cancer Cells to Proteasome and Hsp90 Inhibitors
Authors: Zaarur Nava , Gabai Vladimir L. , Porco John A. , Calderwood Stuart , Sherman Michael Y.
Published: February 2006

Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment. (Cancer Res 2006; 66(3): 1783-91)
Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas
Authors: Hendrix Neali D. , Wu Rong , Kuick Rork , Schwartz Donald R. , Fearon Eric R. , Cho Kathleen R.
Published: February 2006

Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize β-catenin and the ability of β-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the β-catenin protein or inactivating mutations in key negative regulators of β-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with β-catenin dysregulation compared with OEAs lacking Wnt/β-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased >6-fold in primary OEAs with Wnt/β-catenin pathway defects compared with OEAs lacking such defects. Evidence that β-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA–mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a β-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/β-catenin pathway defects. (Cancer Res 2006; 66(3): 1354-62)
Der Stellenwert der Chemotherapie in der Therapie des Endometriumkarzinoms
Authors: Fehr Mathias K. , Streich Matthias S.
Published: February 2006

Das Endometriumkarzinom ist ein heterogener Tumor, wobei klinisch, histologisch und pathogenetisch das klassische, endometrioide Karzinom (Typ 1) mit guter Prognose vom aggressiven histologischen Typ 2 mit ernster Prognose und früher Metastasierung unterschieden werden muss. Die beim Endometriumkarzinom aktivsten Substanzen sind Anthrazykline, Platinsalze und Taxane. Kombinationen sind in den meisten Studien bezüglich Ansprechrate der Monotherapie überlegen. In den letzten Jahren konnte einerseits gezeigt werden, dass eine intensive Chemotherapie in der metastasierten Situation das İberleben verlängern kann, andererseits, dass eine adjuvant durchgeführte Chemotherapie ein hohes Rezidivrisiko zu senken vermag.
Sudden Sensorineural Hearing Loss: Evidence from Taiwan
Authors: Wu Chuan-Song , Lin Herng-Ching , Chao Pin-Zhir
Published: February 2006

Objective:This study uses 5-year population data to determine the incidence rate of sudden sensorineural hearing loss (SSNHL) in Taiwan, taking into consideration the age and gender of patients, as well as seasonal variations. Study Design:A retrospective cross-sectional study. Method: The data used is from the Taiwan National Health Insurance Research Database covering the period from 1998 to 2002. A total of 9,267 sample patients were identified from the database by a principal diagnosis of unspecified sudden hearing loss (ICD-9-CM code 3882). The autoregressive integrated moving average (ARIMA) method was also carried out in order to identify any variations in the monthly incidence rates of SSNHL. Results:We find that for the period under examination, gender-specific incidence rates per 100,000 of the population were 8.85 for males, and 7.79 for females, and that there was an increase in age-specific SSNHL incidence with age. The ARIMA test for seasonality was found to be significant for the whole sample. Of all the seasons in Taiwan, the highest SSNHL incidence rates were found in autumn. Conclusions: Our finding of significant variations in the monthly incidence of SSNHL provides valuable information for otolaryngologists and public health officials, creating an awareness of periods of a potential increased risk of SSNHL.
Identification of a Novel Mutation in the Myosin VIIA Motor Domain in a Family with Autosomal Dominant Hearing Loss (DFNA11)
Authors: Di Leva Francesca , D’Adamo Pio , Cubellis Maria Vittoria , D’Eustacchio Angela , Errichiello Monica , Saulino Claudio , Auletta Gennaro , Giannini Pasquale , Donaudy Francesca , Ciccodicola Alfredo , Gasparini Paolo , Franzè Annamaria , Marciano Elio
Published: February 2006

We ascertained a large Italian family with an autosomal dominant form of non-syndromic sensorineural hearing loss with vestibular involvement. A genome-wide scan found linkage to locus DFNA11. Sequencing of the MYO7A gene in the linked region identified a new missense mutation resulting in an Ala230Val change in the motor domain of the myosin VIIA. Myosin VIIA has already been implicated in several forms of deafness, but this is the third mutation causing a dominant form of deafness, located in the myosin VIIA motor domain in a region never involved in hearing loss until now. A modelled protein structure of myosin VII motor domain provides evidence for a significant functional effect of this missense mutation.
An Evaluation of ECG Leads Used to Assess QT Prolongation
Authors: Sadanaga Tsuneaki , Sadanaga Fumiko , Yao Hiroshi , Fujishima Masatoshi
Published: February 2006

Aims: The aim of the present study is to elucidate the optimal lead to be selected for the evaluation of drug-induced QT prolongation. Methods and Results: We assessed the validity of each electrocardiography (ECG) lead for the evaluation of QT intervals in 688 patients receiving psychotropic drugs. Abnormal QTc prolongation was observed in 96 (14%) patients using the longest ECG lead. Prevalence of QTc prolongation was larger when using leads I, III, aVR, aVL, aVF, V1, and V6 (>18%), and smaller when using lead V2 (10%). In the remaining 4 ECG leads, the overall accuracy to predict QTc prolongation was higher when using lead V3 (94%) compared with lead II (89%) or lead V5 (90%). Sensitivity to predict QTc prolongation was higher when using lead V4 (81%) compared with lead II (66%) or lead V2 (63%). Conclusion: When a single lead was used for the evaluation of QT prolongation, the results were not always similar to those using the lead which demonstrated the longest QT interval, and if only one lead is to be chosen, lead V3 or V4 should be selected.
The Power of Pharmacological Sciences: The Example of Proton Pump Inhibitors
Authors: Spector Reynold , Vesell Elliot S.
Published: February 2006

Critics have questioned the foundational principles of pharmacological sciences and modern drug therapy; they also claim that drug therapy is often too expensive or of uncertain value. Contemporaneously, alternative medicine has bloomed. Yet the US government began to pay for drug therapy under Medicare in 2006, an explicit recognition of the value of modern drug therapy. To clarify this confusion, we review the philosophical and scientific foundations of pharmacology, drug discovery and development, the attendant strategies and successful results. We also review and answer the major attacks on the philosophical and scientific foundations of modern pharmacology and drug therapy. Finally, we define the characteristics of an ideal drug. As an example of the principles and strategies of modern pharmacological sciences and their successful application, we focus on the discovery and development of proton pump inhibitors (PPIs) of stomach acid production. This class of drugs approaches the ideal and exemplifies successful application of modern pharmacological principles to drug discovery and development. Moreover, the use of PPIs as a pharmacological tool allowed the resolution of important scientific questions, e.g., the role of stomach acid in peptic diseases of the stomach, duodenum and esophagus.
Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Non-Valvular Atrial Fibrillation
Authors: Diener Hans-Christoph
Published: February 2006

Background: To show results of a prespecified pooled analysis of the studies SPORTIF III (open-label) and SPORTIF V (double-blind), to assess the homogeneity of the results and to explore subgroup analyses and adverse events. Methods and Results: 7,329 patients with atrial fibrillation (AF) and ≧1 additional stroke risk factor were randomized to warfarin (international normalized ratio 2.0–3.0) or ximelagatran (36 mg twice daily). Over 11,346 patient-years (mean 18.5 months/patient), 184 patients developed primary events of stroke and systemic embolism (ximelagatran 1.62 vs. warfarin 1.65%/year; p = 0.94). Heterogeneity between trials with respect to the primary event rate (study-by-treatment interaction p = 0.026) was found. This could not be explained statistically by baseline patient characteristics or by treatment (except perhaps by the better anticoagulation with warfarin in SPORTIF V) and was not evident for secondary end-points. There was no conclusive difference in major bleeding rates (ximelagatran 1.88 vs. warfarin 2.46%/year; p = 0.054), but combined minor plus major bleeding was lower with ximelagatran (31.7 vs. 38.7%/year; p < 0.0001). Elevation of liver enzymes occurred more frequently in patients taking ximelagatran (6.1% vs. warfarin 0.8%; p < 0.0001) and was reversible except in rare cases. Conclusions: Fixed-dose oral ximelagatran without coagulation monitoring prevented stroke and systemic embolism as effectively as warfarin in patients with AF. Differences in the results of the two trials might relate to consistency of warfarin anticoagulation, different degree of blinding in the two trials, other concomitant therapies or chance. Further investigation is required to explore the long-term safety profile of ximelagatran.
G-Protein-Coupled Receptor (GPCR)-142 Does Not Contribute to Relaxin-3 Binding in the Mouse Brain: Further Support that Relaxin-3 Is the Physiological Ligand for GPCR135
Authors: Sutton Steven W. , Bonaventure Pascal , Kuei Chester , Nepomuceno Diane , Wu Jiejun , Zhu Jessica , Lovenberg Timothy W. , Liu Changlu
Published: February 2006

Relaxin-3 is a recently discovered member of the insulin/relaxin superfamily that has been shown to be the endogenous ligand for G-protein-coupled receptor (GPCR)135 (SALPR). In addition, relaxin-3 has demonstrated affinity and functional agonism for GPCR142 (GPR100) and LGR7 receptors in vitro. Recent evidence suggests GPCR142 is the insulin-like peptide 5 (INSL5) receptor and LGR7 is the actual relaxin receptor. We have recently described a chimeric R3/I5 peptide that selectively activates GPCR135 and GPCR142, but lacks affinity for LGR7. GPCR142 is a pseudogene in the rat, which allowed the use of [125I]-R3/I5 to show GPCR135-like binding sites in the rat central nervous system by autoradiography. However, mouse GPCR142 is a viable gene. In the present study we explore whether GPCR142 is expressed in the mouse brain and whether it is likely to contribute to or interfere with the pharmacological evaluation of relaxin-3 ligands. Competition binding studies confirmed mINSL5 and [125I]-mINSL5 bind to mGPCR142 with high affinity. However, no detectable specific [125I]-mINSL5 binding sites were detected throughout the mouse brain and unlabelled INSL5 did not displace [125I]-R3/I5 binding sites, indicating an absence of detectable GPCR142 binding sites. Consistent with these findings, neither GPCR142 nor INSL5 mRNA were detectable in mouse brain by in situ hybridization. Overall, the distribution of GPCR135 mRNA overlapped with the distribution of GPCR135 binding sites shown by autoradiography using [125I]-R3/I5. GPCR135 mRNA and GPCR135 receptor binding sites are most prominent in the mouse amygdala and hypothalamus. These data suggest that relaxin-3/GPCR135 is the receptor ligand pair with physiological relevance in mouse brain.
Evaluation of Serotypes of Streptococcus pneumoniae Isolated from Otitis Media Patients by Multiplex Polymerase Chain Reaction
Authors: Billal Dewan S. , Hotomi Muneki , Tasnim Sayeeda , Fujihara Keiji , Yamanaka Noboru
Published: February 2006

The increasing difficulty in the management of pneumococcal acute otitis media in parallel with increases in antimicrobial-resistant strains has led to much interest in pneumococcal capsular types for the adoption of effective prevention by vaccines. This study shows that multiplex polymerase chain reaction is a valuable and expeditious method for the capsular typing of pneumococci. The multiplex polymerase chain reaction method accurately detects the majority of serotypes and serogroups frequently isolated from pediatric patients with acute otitis media, allowing the characterization of the colonization patterns for further implications of pneumococcal vaccines.
Observations of the 11 June Dryline during IHOP_2002—A Null Case for Convection Initiation
Authors: Cai Huaqing , Lee Wen-Chau , Weckwerth Tammy M. , Flamant Cyrille , Murphey Hanne V.
Published: February 2006

The detailed analysis of the three-dimensional structure of a dryline observed over the Oklahoma panhandle during the International H2O Project (IHOP_2002) on 11 June 2002 is presented. High-resolution observations obtained from the National Center for Atmospheric Research Electra Doppler Radar (ELDORA), S-band dual-polarization Doppler radar (S-Pol), water vapor differential absorption lidar (DIAL) Lidar pour l'Etude des Interactions Aérosols Nuages Dynamique Rayonnement et du Cycle de l'Eau (LEANDRE II; translated as Lidar for the Study of Aerosol–Cloud–Dynamics–Radiation Interactions and of the Water Cycle) as well as Learjet dropsondes are used to reveal the evolution of the dryline structure during late afternoon hours when the dryline was retreating to the northwest. The dryline reflectivity shows significant variability in the along-line direction. Dry air was observed to overrun the moist air in vertical cross sections similar to a density current. The updrafts associated with the dryline were 2–3 m s−1 and were able to initiate boundary-layer-based clouds along the dryline. The formation of this dryline was caused by high equivalent potential temperature air pushing northwestward toward a stationary front in the warm sector.

Middle-level clouds with radar reflectivity greater than 18 dBZe near the dryline were detected by ELDORA. A roll boundary, which was associated with larger convergence and moisture content, was evident in the S-Pol data. It is found that the instability parameters most favorable for convection initiation were actually associated with the roll boundary, not the dryline. A storm was initiated near the roll boundary probably as a result of the combination of the favorable instability parameters and stronger upward forcing. It is noted that both the 11 June 2002 dryline and the roll boundary presented in this paper would not be identified if the special datasets from IHOP_2002 were not available.

Although all model runs [fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5), Meso Eta, and Rapid Update Cycle (RUC)] suggested deep convection over the Oklahoma panhandle and several cloud lines were observed near the dryline, the dryline itself did not initiate any storms. The reasons why the dryline failed to produce any storm inside the IHOP_2002 intensive observation region are discussed. Both synoptic-scale and mesoscale conditions that were detrimental to convection initiation in this case are investigated in great detail.
The Dryline on 22 May 2002 during IHOP_2002: Convective-Scale Measurements at the Profiling Site
Authors: Demoz Belay , Flamant Cyrille , Weckwerth Tammy , Whiteman David , Evans Keith , Fabry Frédéric , Di Girolamo Paolo , Miller David , Geerts Bart , Brown William , Schwemmer Geary , Gentry Bruce , Feltz Wayne , Wang Zhien
Published: February 2006

A detailed analysis of the structure of a double dryline observed over the Oklahoma panhandle during the first International H2O Project (IHOP_2002) convective initiation (CI) mission on 22 May 2002 is presented. A unique and unprecedented set of high temporal and spatial resolution measurements of water vapor mixing ratio, wind, and boundary layer structure parameters were acquired using the National Aeronautics and Space Administration (NASA) scanning Raman lidar (SRL), the Goddard Lidar Observatory for Winds (GLOW), and the Holographic Airborne Rotating Lidar Instrument Experiment (HARLIE), respectively. These measurements are combined with the vertical velocity measurements derived from the National Center for Atmospheric Research (NCAR) Multiple Antenna Profiler Radar (MAPR) and radar structure function from the high-resolution University of Massachusetts frequency-modulated continuous-wave (FMCW) radar to reveal the evolution and structure of the late afternoon double-dryline boundary layer. The eastern dryline advanced and then retreated over the Homestead profiling site in the Oklahoma panhandle, providing conditions ripe for a detailed observation of the small-scale variability within the boundary layer and the dryline. In situ aircraft data, dropsonde and radiosonde data, along with NCAR S-band dual-polarization Doppler radar (S-Pol) measurements, are also used to provide the larger-scale picture of the double-dryline environment.

Moisture and temperature jumps of about 3 g kg−1 and 1–2 K, respectively, were observed across the eastern radar fine line (dryline), more than the moisture jumps (1–2 g kg−1) observed across the western radar fine line (secondary dryline). Most updraft plumes observed were located on the moist side of the eastern dryline with vertical velocities exceeding 3 m s−1 and variable horizontal widths of 2–5 km, although some were as wide as 7–8 km. These updrafts were up to 1.5 g kg−1 moister than the surrounding environment.

Although models suggested deep convection over the Oklahoma panhandle and several cloud lines were observed near the dryline, the dryline itself did not initiate any storms over the intensive observation region (IOR). Possible reasons for this lack of convection are discussed. Strong capping inversion and moisture detrainment between the lifting condensation level and the level of free convection related to an overriding drier air, together with the relatively small near-surface moisture values (less than 10 g kg−1), were detrimental to CI in this case.
The Spatial Variability of Moisture in the Boundary Layer and Its Effect on Convection Initiation: Project-Long Characterization
Authors: Fabry Frédéric
Published: February 2006

An attempt was made to statistically gauge the importance of moisture variability on convection initiation by analyzing data collected by radar, surface stations, soundings, and airborne in situ sensors over the 7 weeks of the International H2O Project (IHOP_2002). Based on radar refractivity data, the spatial structure of humidity near the surface proved to be very anisotropic, crosswind variability being typically twice as large as along-wind variability, in part as a result of the west-to-east climatological gradient in moisture across the Oklahoma panhandle. Variability in humidity was largest from the afternoon to sunset and smallest a few hours before and after sunrise. At the surface, variograms of refractivity increase almost linearly with scale in the crosswind direction, suggesting that the field of moisture shows little in terms of local maxima and minima. Higher in the boundary layer, moisture variability increases at small scales because of the entrainment of dry capping stable layer air as the daytime boundary layer grows, and the rate of that dry-air entrainment could be used to calculate surface moisture variability.

The effect of the observed variability in moisture and temperature in the upper boundary layer on convective inhibition was quantified and contrasted with the effect expected from boundary layer updrafts. At synoptic scales and at the upper end of the mesoscale, the location of convection initiation is most sensitive to the variability in temperature. At smaller scales, storm development becomes extremely sensitive to the strength of updrafts; however, those same updrafts also magnify the effect of moisture and temperature variability, as a result of which the effect of small-scale moisture variability cannot be ignored. Some of the consequences of these findings on the representativeness of radiosonde measurements in the boundary layer and instrumentation needs for convection initiation forecasting are surveyed.
Finescale Vertical Structure of a Cold Front as Revealed by an Airborne Doppler Radar
Authors: Geerts Bart , Damiani Rick , Haimov Samuel
Published: February 2006

In the afternoon of 24 May 2002, a well-defined and frontogenetic cold front moved through the Texas panhandle. Detailed observations from a series of platforms were collected near the triple point between this cold front and a dryline boundary.

This paper primarily uses reflectivity and Doppler velocity data from an airborne 95-GHz radar, as well as flight-level thermodynamic data, to describe the vertical structure of the cold front as it intersected with the dryline. The prefrontal convective boundary layer was weakly capped, weakly sheared, and about 2.5 times deeper than the cold-frontal density current.

The radar data depict the cold front as a fine example of an atmospheric density current at unprecedented detail (∼40 m). The echo structure and dual-Doppler-inferred airflow in the vertical plane reveal typical features such as a nose, a head, a rear-inflow current, and a broad current of rising prefrontal air that feeds the accelerating front-to-rear current over the head. The 2D cross-frontal structure, including the frontal slope, is highly variable in time or alongfront distance. Along this slope horizontal vorticity, averaging ∼0.05 s−1, is generated baroclinically, and the associated strong cross-front shear triggers Kelvin–Helmholtz (KH) billows at the density interface. Some KH billows occupy much of the depth of the density current, possibly even temporarily cutting off the head from its trailing body.