bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution Single Nucleotide Polymorphism Array Analysis of Epithelial Ovarian Cancer Reveals Numerous Microdeletions and Amplifications
Authors: Gorringe Kylie L. , Jacobs Sharoni , Thompson Ella R. , Sridhar Anita , Qiu Wen , Choong David Y.H. , Campbell Ian G.
Published: August 2007

Purpose: Genetic changes in sporadic ovarian cancer are relatively poorly characterized compared with other tumor types. We have evaluated the use of high-resolution whole genome arrays for the genetic profiling of epithelial ovarian cancer.

Experimental Design: We have evaluated 31 primary ovarian cancers and matched normal DNA for loss of heterozygosity and copy number alterations using 500K single nucleotide polymorphism arrays.

Results: In addition to identifying the expected large-scale genomic copy number changes, >380 small regions of copy number gain or loss (<500 kb) were identified among the 31 tumors, including 33 regions of high-level gain (>5 copies) and 27 homozygous deletions. The existence of such a high frequency of small regions exhibiting copy number alterations had not been previously suspected because earlier genomic array platforms lacked comparable resolution. Interestingly, many of these regions harbor known cancer genes. For example, one tumor harbored a 350-kb high-level amplification centered on FGFR1 and three tumors showed regions of homozygous loss 109 to 216 kb in size involving the RB1 tumor suppressor gene only.

Conclusions: These data suggest that novel cancer genes may be located within the other identified small regions of copy number alteration. Analysis of the number of copy number breakpoints and the distribution of the small regions of copy number change indicate high levels of structural chromosomal genetic instability in ovarian cancer.
The Cancer/Testis Antigen Melanoma-Associated Antigen-A3/A6 Is a Novel Target of Fibroblast Growth Factor Receptor 2-IIIb through Histone H3 Modifications in Thyroid Cancer
Authors: Kondo Tetsuo , Zhu Xuegong , Asa Sylvia L. , Ezzat Shereen
Published: August 2007

Purpose: Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase. We reported recently that FGF receptor 2 (FGFR2) is down-regulated through extensive DNA promoter methylation in thyroid cancer. Reexpression of the FGFR2-IIIb isoform impedes signaling upstream of the BRAF/mitogen-activated protein kinase pathway to interrupt tumor progression. In this analysis, we examined a novel target of FGFR2-IIIb signaling, melanoma-associated antigen-A3 and A6 (MAGE-A3/6).

Experimental Design: cDNA microarray analysis was done on human WRO thyroid cancer cells transfected with FGFR2-IIIb or empty vector. Identified gene target was confirmed by reverse transcription-PCR and Western blotting. Gene regulation was examined by treatment of WRO cells with the methylation inhibitor 5′-azacytidine followed by methylation-specific PCR and reverse transcription-PCR and by chromatin immunoprecipitation.

Results: Gene expression profiling identified the cancer/testis antigen MAGE-A3/6 as a novel target of FGFR2-IIIb signaling. MAGE-A3/6 regulation was mediated through DNA methylation and chromatin modifications. In particular, FGF7/FGFR2-IIIb activation resulted in histone 3 methylation and deacetylation associated with the MAGE-A3/6 promoter to down-regulate gene expression.

Conclusions: These data unmask a complex repertoire of epigenetically controlled signals that govern FGFR2-IIIb and MAGE-A3/6 expression. Our findings provide insights into the interrelationship between novel tumor markers that may also represent overlapping therapeutic targets.
Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma
Authors: Herberger Beata , Puhalla Harald , Lehnert Martina , Wrba Fritz , Novak Sabine , Brandstetter Anita , Gruenberger Birgit , Gruenberger Thomas , Pirker Robert , Filipits Martin
Published: August 2007

Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors.

Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors.

Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01).

Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.
Interleukin-12: Biological Properties and Clinical Application
Authors: Del Vecchio Michele , Bajetta Emilio , Canova Stefania , Lotze Michael T. , Wesa Amy , Parmiani Giorgio , Anichini Andrea
Published: August 2007

Interleukin-12 (IL-12) is a heterodimeric protein, first recovered from EBV-transformed B cell lines. It is a multifunctional cytokine, the properties of which bridge innate and adaptive immunity, acting as a key regulator of cell-mediated immune responses through the induction of T helper 1 differentiation. By promoting IFN-γ production, proliferation, and cytolytic activity of natural killer and T cells, IL-12 induces cellular immunity. In addition, IL-12 induces an antiangiogenic program mediated by IFN-γ–inducible genes and by lymphocyte-endothelial cell cross-talk. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In contrast with the significant antitumor and antimetastatic activity of IL-12, documented in several preclinical studies, clinical trials with IL-12, used as a single agent, or as a vaccine adjuvant, have shown limited efficacy in most instances. More effective application of this cytokine, and of newly identified IL-12 family members (IL-23 and IL-27), should be evaluated as therapeutic agents with considerable potential in cancer patients.
Alteration of dihydropyrimidine dehydrogenase expression by IFN-α affects the antiproliferative effects of 5-fluorouracil in human hepatocellular carcinoma cells
Authors: Oie Shinji , Ono Mayumi , Fukushima Hiroto , Hosoi Fumihito , Yano Hirohisa , Maruyama Yuichiro , Kojiro Masamichi , Terada Tadafumi , Hirano Kazuyuki , Kuwano Michihiko , Yamada Yuji
Published: August 2007

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU) and its activity is closely associated with cellular sensitivity to 5-FU. This study examines the role of DPD in the antiproliferative effects of 5-FU combined with IFN-α on hepatocellular carcinoma (HCC) cells in culture and asks whether IFN-α could affect DPD expression. The combined action of IFN-α and 5-FU on three HCC lines was quantified by a combination index method. Coadministration of IFN-α and 5-FU showed synergistic effects against HAK-1A and KYN-2 but antagonistic effects against KYN-3. The cellular expression levels of DPD mRNA and protein were markedly up-regulated in KYN-3 cells by IFN-α but were down-regulated in HAK-1A and KYN-2. The expression of thymidylate synthase mRNA and protein was down-regulated by IFN-α in all three cell lines. Coadministration of a selective DPD inhibitor, 5-chloro-2,4-dihydroxypyridine (CDHP), enhanced the antiproliferative effect of 5-FU and IFN-α on KYN-3 ∼4-fold. However, the synergistic effects of 5-FU and IFN-α on HAK-1A and KYN-2 were not affected by CDHP. The antiproliferative effect of 5-FU could thus be modulated by IFN-α, possibly through DPD expression, in HCC cells. Inhibition of DPD activity by CDHP may enhance the efficacy of IFN-α and 5-FU combination therapy in patients with HCC showing resistance to this therapy. [Mol Cancer Ther 2007;6(8):2310–8]
The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death
Authors: Polischouk Anya G. , Holgersson Åsa , Zong Dali , Stenerlöw Bo , Karlsson Hanna L. , Möller Lennart , Viktorsson Kristina , Lewensohn Rolf
Published: August 2007

Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non–small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycin-induced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJ–mediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303–9]
Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein
Authors: Ng Angela Ping Ping , Nin Dawn Sijin , Fong Jek Howe , Venkataraman Divya , Chen Chien-Shing , Khan Matiullah
Published: August 2007

We have recently reported that PML-RAR–induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation–based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G2-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR–induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells. [Mol Cancer Ther 2007;6(8):2240–8]
Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth
Authors: Hao Honglin , Muniz-Medina Vanessa M. , Mehta Heena , Thomas Nancy E. , Khazak Vladimir , Der Channing J. , Shields Janiel M.
Published: August 2007

Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH2-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas. [Mol Cancer Ther 2007;6(8):2220–9]
CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling
Authors: Evelyn Chris R. , Wade Susan M. , Wang Qin , Wu Mei , Iñiguez-Lluhí Jorge A. , Merajver Sofia D. , Neubig Richard R.
Published: August 2007

Lysophosphatidic acid receptors stimulate a Gα12/13/RhoA-dependent gene transcription program involving the serum response factor (SRF) and its coactivator and oncogene, megakaryoblastic leukemia 1 (MKL1). Inhibitors of this pathway could serve as useful biological probes and potential cancer therapeutic agents. Through a transcription-based high-throughput serum response element-luciferase screening assay, we identified two small-molecule inhibitors of this pathway. Mechanistic studies on the more potent CCG-1423 show that it acts downstream of Rho because it blocks SRE.L-driven transcription stimulated by Gα12Q231L, Gα13Q226L, RhoA-G14V, and RhoC-G14V. The ability of CCG-1423 to block transcription activated by MKL1, but not that induced by SRF-VP16 or GAL4-VP16, suggests a mechanism targeting MKL/SRF-dependent transcriptional activation that does not involve alterations in DNA binding. Consistent with its role as a Rho/SRF pathway inhibitor, CCG-1423 displays activity in several in vitro cancer cell functional assays. CCG-1423 potently (<1 μmol/L) inhibits lysophosphatidic acid–induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho. Similarly, CCG-1423 selectively stimulates apoptosis of the metastasis-prone, RhoC-overexpressing melanoma cell line (A375M2) compared with the parental cell line (A375). CCG-1423 inhibited Rho-dependent invasion by PC-3 prostate cancer cells, whereas it did not affect the Gαi-dependent invasion by the SKOV-3 ovarian cancer cell line. Thus, based on its profile, CCG-1423 is a promising lead compound for the development of novel pharmacologic tools to disrupt transcriptional responses of the Rho pathway in cancer. [Mol Cancer Ther 2007;6(8):2249–60]
Anticancer medicines in development: assessment of bioactivity profiles within the National Cancer Institute anticancer screening data
Authors: Covell David G. , Huang Ruili , Wallqvist Anders
Published: August 2007

We present an analysis of current anticancer compounds that are in phase I, II, or III clinical trials and their structural analogues that have been screened in the National Cancer Institute (NCI) anticancer screening program. Bioactivity profiles, measured across the NCI 60 cell lines, were examined for a correspondence between the type of cancer proposed for clinical testing and selective sensitivity to appropriately matched tumor subpanels in the NCI screen. These results find strongest support for using the NCI anticancer screen to select analogue compounds with selective sensitivity to the leukemia, colon, central nervous system, melanoma, and ovarian panels, but not for renal, prostate, and breast panels. These results are extended to applications of two-dimensional structural features to further refine compound selections based on tumor panel sensitivity obtained from tumor screening results. [Mol Cancer Ther 2007;6(8):2261–70]
Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo
Authors: Hagos Ghenet K. , Carroll Robert E. , Kouznetsova Tatiana , Li Qian , Toader Violeta , Fernandez Patricia A. , Swanson Steven M. , Thatcher Gregory R.J.
Published: August 2007

Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G2-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. [Mol Cancer Ther 2007;6(8):2230–9]
Bevacizumab plus 5-fluorouracil induce growth suppression in the CWR-22 and CWR-22R prostate cancer xenografts
Authors: Hung Huynh
Published: August 2007

Prostate cancer is the most common malignancy in men. Although patients with metastatic prostate cancer can benefit from androgen ablation, most of them will die of prostate cancer progression to an androgen-refractory state. In the present study, the effects of docetaxel, bevacizumab, 5-fluorouracil (5-FU), bevacizumab plus docetaxel, and bevacizumab plus 5-FU on the growth of human CWR-22 (androgen-dependent) and CWR-22R (androgen-independent) prostate carcinoma xenografts were investigated. We report that i.p. administration of 10 mg/kg docetaxel at 1-week interval, 5 mg/kg/ bevacizumab once every 2 weeks, or 12.5 mg/kg 5-FU, bevacizumab/docetaxel, or bevacizumab/5-FU weekly to severe combined immunodeficient mice bearing prostate cancer xenografts (12 mice per treatment group) for 21 days resulted in 22.5 ± 8%, 23 ± 7%, 31 ± 8%, 22 ± 6%, and 81 ± 5% growth inhibition, respectively. Greatest growth suppression was observed in bevacizumab/5-FU treatment. Bevacizumab/5-FU–induced growth suppression was associated with reduction in microvessel density, inhibition of cell proliferation; up-regulation of phosphatase and tensin homologue, p21Cip1/Waf1, p16INK4a, and p27Kip1; hypophosphorylation of retinoblastoma protein; and inhibition of Akt/mammalian target of rapamycin pathway. Our data indicate that bevacizumab/5-FU effectively inhibits angiogenesis and cell cycle progression and suggest that bevacizumab/5-FU may represent an alternative treatment for patients with prostate cancer. [Mol Cancer Ther 2007;6(8):2149–57]
Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts
Authors: Smith Neil R. , James Neil H. , Oakley Ian , Wainwright Anna , Copley Clive , Kendrew Jane , Womersley Lynsey M. , Jürgensmeier Juliane M. , Wedge Stephen R. , Barry Simon T.
Published: August 2007

The vascular endothelial growth factor-A (VEGF-A) signaling pathway, a key stimulant of solid tumor vascularization, is primarily dependent on the activation of the endothelial cell surface receptor VEGF receptor-2 (VEGFR-2). AZD2171 is an oral, highly potent small-molecule inhibitor of VEGFR tyrosine kinase activity that inhibits angiogenesis and the growth of human tumor xenografts in vivo. Here, we show pharmacodynamic changes in VEGFR-2 phosphorylation induced by AZD2171. In mouse lung tissue, a single dose of AZD2171 at 6 mg/kg inhibited VEGF-A–stimulated VEGFR-2 phosphorylation by 87% at 2 h with significant inhibition (≥60%) maintained to 24 h. To examine inhibition of VEGFR-2 phosphorylation in tumor vasculature by immunohistochemistry, a comprehensive assessment of antibodies to various phosphorylation sites on the receptor was undertaken. Antibodies to the phosphotyrosine epitopes pY1175/1173 and pY1214/1212 were found suitable for this application. Calu-6 human lung tumor xenografts, from mice receiving AZD2171 or vehicle treatment (p.o., once daily), were examined by immunohistochemistry. A significant reduction in tumor vessel staining of phosphorylated VEGFR-2 (pVEGFR-2) was evident within 28 h of AZD2171 treatment (6 mg/kg). This effect preceded a significant reduction in tumor microvessel density, which was detectable following 52 h of AZD2171 treatment. These data show that AZD2171 is a potent inhibitor of VEGFR-2 activation in vivo and suggest that AZD2171 delivers therapeutic benefit in Calu-6 tumors by targeting vessels dependent on VEGFR-2 signaling for survival. In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation. [Mol Cancer Ther 2007;6(8):2198–208]
Age-Dependent Differences in Human Brain Activity Using a Face- and Location-Matching Task: An fMRI Study
Authors: Leinsinger G. , Born C. , Meindl T. , Bokde A.L.W. , Britsch S. , Lopez-Bayo P. , Teipel S.J. , Möller H.-J. , Hampel H. , Reiser M.F.
Published: August 2007

Purpose: To evaluate the differences of cortical activation patterns in young and elderly healthy subjects for object and spatial visual processing using a face- and location-matching task. Materials and Methods: We performed a face- and a location-matching task in 15 young (mean age: 28 ± 9 years) and 19 elderly (mean age: 71 ± 6 years) subjects. Each experiment consisted of 7 blocks alternating between activation and control condition. For face matching, the subjects had to indicate whether two displayed faces were identical or different. For location matching, the subjects had to press a button whenever two objects had an identical position. For control condition, we used a perception task with abstract images. Functional imaging was performed on a 1.5-tesla scanner using an EPI sequence. Results: In the face-matching task, the young subjects showed bilateral (right > left) activation in the occipito-temporal pathway (occipital gyrus, inferior and middle temporal gyrus). Predominantly right hemispheric activations were found in the fusiform gyrus, the right dorsolateral prefrontal cortex (inferior and middle frontal gyrus) and the superior parietal gyrus. In the elderly subjects, the activated areas in the right fronto-lateral cortex increased. An additional activated area could be found in the medial frontal gyrus (right > left). In the location-matching task, young subjects presented increased bilateral (right > left) activation in the superior parietal lobe and precuneus compared with face matching. The activations in the occipito-temporal pathway, in the right fronto-lateral cortex and the fusiform gyrus were similar to the activations found in the face-matching task. In the elderly subjects, we detected similar activation patterns compared to the young subjects with additional activations in the medial frontal gyrus. Conclusion: Activation patterns for object-based and spatial visual processing were established in the young and elderly healthy subjects. Differences between the elderly and young subjects could be evaluated, especially by using a face-matching task.
Reduction of Phosphorylated Tau during Memantine Treatment of Alzheimer’s Disease
Authors: Degerman Gunnarsson M. , Kilander L. , Basun H. , Lannfelt L.
Published: August 2007

Background: Memantine is a moderate affinity N-methyl-D-aspartate receptor antagonist approved for treatment of Alzheimer’s disease (AD). In AD, tau is abnormally hyperphosphorylated. However, no significant changes of phosphorylated tau levels in CSF are found at follow-up in studies with AD patients. It has been shown in vitro that memantine reverse induced abnormal hyperphosphorylation of tau in hippocampal neurons of rats. Methods: Eleven AD patients were examined with cognitive tests and interviews of relatives. CSF analyses were performed before starting treatment with memantine as well as after 1 year. Results: A statistically significant reduction of CSF phosphorylated tau at the 1-year follow-up was seen, from median 126 (interquartile range 107–153) to 108 (88–133) ng/l (p = 0.018). No statistically significant differences of total tau or Aβ42 were found. Conclusion: The results may reflect effects of memantine on a key pathological feature in AD in line with previous in vitro findings.
Everolimus and Mycophenolate Mofetil Sensitize Human Pancreatic Cancer Cells to Gemcitabine in vitro: A Novel Adjunct to Standard Chemotherapy?
Authors: Tuncyurek P. , Mayer J.M. , Klug F. , Dillmann S. , Henne-Bruns D. , Keller F. , Stracke S.
Published: August 2007

Background/Aims: Gemcitabine improves survival in pancreatic adenocarcinoma. A variety of drugs have been tested to potentiate gemcitabine treatment for pancreatic cancer cells. Two major immunosuppressive drugs, mycophenolate mofetil (MMF) and everolimus (RAD001) have been shown to exert an anti-tumoral effect, but their ability to sensitize human pancreatic cell lines during gemcitabine treatment remains unclear. We examined the effects of everolimus and MMF on gemcitabine-treated MiaPaCa and Panc-1 cell lines. Methods: MiaPaCa and Panc-1 human pancreatic tumor cell lines were subjected to everolimus (0.001–1 µg/ml) or MMF (0.1–100 µg/ml) treatment in combination with gemcitabine (1–106 nM). Western blot analysis was performed for Panc-1 cells in the presence or absence of TGF-β1 and different treatments: 0.1–100 µg/ml MMF and 0.1–100 µg/ml everolimus. The antiproliferative effect of the treatment was assessed by BrdU test. The results were evaluated by two-way analysis of variance followed by post-hoc tests, and nonlinear regression analysis for dose-response rates. Results: As expected, standard treatment doses of gemcitabine decreased proliferation dose-dependently. Everolimus increased the actual EC50 response to gemcitabine treatment (1–103 nM) to as much as 83.1 and 82.1% in MiaPaCa and Panc-1 cell lines, respectively. Likewise, concomitant administration with MMF altered the EC50 of gemcitabine treatment in MiaPaCa cell lines to values between 76.8 and 85.2% for doses of ≧1 µg/ml. Even the minor dose of MMF (0.1 µg/ml) increased the antiproliferative effect of gemcitabine by 43.5% for MiaPaCa and 42.4% for Panc-1 cells. In addition, treatment of Panc-1 cells with MMF (0.1–100 µg/ml) dose-dependently inhibited TGF-β1-induced collagen expression. Conclusion: We found an overadditive antiproliferative effect of both MMF and everolimus in gemcitabine-treated MiaPaCa and Panc-1 cells in vitro, and an additional inhibitory effect of MMF on TGF-β1-induced collagen type I expression. Interestingly, both the sensitizing effect of pancreatic cancer cells to gemcitabine treatment and the inhibition of collagen type I expression could be achieved by clinically feasible doses of everolimus and MMF. The use of these drugs is promising as a novel adjunct to standard chemotherapy.
Radiation dosimetry and biodistribution of the beta-amyloid plaque imaging tracer 11C-BTA-1 in humans
Authors: Thees S. , Neumaier B. , Deisenhofer S. , von Arnim C. A. F. , Reske S. N. , Mottaghy F. M. , Glatting G.
Published: August 2007

Aim: [N-methyl-11C]2-(4'-(methylaminophenyl)-benzothiazole (11C-BTA-1) is a thioflavin-T derivative that has been one of the promising PET tracers for imaging of amyloid plaque distribution in the Alzheimer patients brain in vivo. The biodistribution and dosimetry of this tracer in humans is presented and compared to the results of a previous dosimetry and biodistribution study of another thioflavin-T derivative [N-methyl-11C]2-hydroxy-(4'-(methylaminophenyl)- benzothiazole (11C-OH-BTA-1) in baboons. Methods: Five subjects underwent 2D dynamic PET imaging. Source organs were segmented using a semiautomatic algorithm based on clustering. Residence times for each source organ were determined by analytical integration of an exponential fit of the time activity curves. Finally organ doses were estimated using the software OLINDA/EXM. Results: The administration of 286 ± 93 MBq 11C-BTA-1 was well tolerated by all subjects. Effective radiation dose was 4.3 μSv/MBq, range 3.6–5.0 μSv/MBq. In four of the five subjects the liver, in one of the subjects the gallbladder was the critical organ. Conclusion: The radiation burden of a single dose of 300 MBq 11C-BTA-1 is within the accepted limits for research purpose. In contrast to the previous non-human primate study revealing the gallbladder as the critical organ for 11C-6-OH-BTA-1, we found the liver as the critical organ in humans using 11C-BTA-1. Possible explanations may be (1) a reduced bile concentration of 11C-BTA-1 due to the absent OH-group or (2) a different hepatic metabolism of thioflavin derivatives in human and baboon.
Procedure guideline for thyroid scintigraphy (version 3)
Authors: Dressler J. , W. Eschner , Leisner B. , Reiners C. , Schicha H. , Dietlein M.
Published: August 2007

The version 3 of the procedure guideline for thyroid scintigraphy is an update of the procedure guideline previously published in 2003. The interpretation of the scintigraphy requires the knowledge of the patients' history, the palpation of the neck, the laboratory parameters and of the sonography. The interpretation of the technetium-99m uptake requires the knowledge of the TSH-level. As a consequence of the improved alimentary iodine supply the 99mTc-uptake has decreased; 100 000 counts per scintigraphy should be acquired. For this, an imaging time of 10 minutes is generally needed using a high resolution collimator for thyroid imaging.
Vortex Dipoles for Surface Quasigeostrophic Models
Authors: Muraki David J. , Snyder Chris
Published: August 2007

A new class of exact vortex dipole solutions is derived for surface quasigeostrophic (sQG) models. The solutions extend the two-dimensional barotropic modon to fully three-dimensional, continuously stratified flow and are a simple model of localized jets on the tropopause. In addition to the basic sQG dipole, dipole structures exist for a layer of uniform potential vorticity between two rigid boundaries and for a dipole in the presence of uniform background vertical shear and horizontal potential temperature gradient. In the former case, the solution approaches the barotropic Lamb dipole in the limit of a layer that is shallow relative to the Rossby depth based on the dipole’s radius. In the latter case, dipoles that are bounded in the far field must propagate counter to the phase speed of the linear edge waves associated with the surface temperature gradient.
On the Growth of Layers of Nonprecipitating Cumulus Convection
Authors: Stevens Bjorn
Published: August 2007

A prototype problem of a nonprecipitating convective layer growing into a layer of uniform stratification and exponentially decreasing humidity is introduced to study the mechanism by which the cumulus-topped boundary layer grows. The problem naturally admits the surface buoyancy flux, outer layer stratification, and moisture scale as governing parameters. Large-eddy simulations show that many of the well-known properties of the cumulus-topped boundary layer (including a well-mixed subcloud layer, a cloud-base transition layer, a conditionally unstable cloud layer, and an inversion layer) emerge naturally in the simulations. The simulations also quantify the differences between nonprecipitating moist convection and its dry counterpart. Whereas dry penetrative convective layers grow proportionally to the square root of time (diffusively) the cumulus layers grow proportionally to time (ballistically). The associated downward transport of warm, dry air results in a significant decrease in the surface Bowen ratio. The linear-in-time growth of the cloud layer is shown to result from the transport and subsequent evaporation of liquid water into the inversion layer. This process acts as a sink of buoyancy, which acts to imbue the free troposphere with the properties of the cloud layer. A simple model, based on this mechanism, and formulated in terms of an effective dry buoyancy flux (which is constrained by the subcloud layer’s similarity to a dry convective layer), is shown to provide good predictions of the growth of the layer across a wide range of governing parameters.
PIV Measurements in the Atmospheric Boundary Layer within and above a Mature Corn Canopy. Part I: Statistics and Energy Flux
Authors: van Hout R. , Zhu W. , Luznik L. , Katz J. , Kleissl J. , Parlange M. B.
Published: August 2007

Particle image velocimetry (PIV) measurements just within and above a mature corn canopy have been performed to clarify the small-scale spatial structure of the turbulence. The smallest resolved scales are about 15 times the Kolmogorov length scale (η ≈ 0.4 mm), the Taylor microscales are about 100η, and the Taylor scale Reynolds numbers range between Rλ = 2000 and 3000. The vertical profiles of mean flow and turbulence parameters match those found in previous studies. Frequency spectra, obtained using the data as time series, are combined with instantaneous spatial spectra to resolve more than five orders of magnitude of length scales. They display an inertial range spanning three decades. However, the small-scale turbulence in the dissipation range exhibits anisotropy at all measurement heights, in spite of apparent agreement with conditions for reaching local isotropy, following a high-Reynolds-number wind tunnel study. Directly calculated subgrid-scale (SGS) energy flux, determined by spatially filtering the PIV data, increases significantly with decreasing filter size, providing support for the existence of a spectral shortcut that bypasses the cascading process and injects energy directly into small scales. The highest measured SGS flux is about 40% of the estimated energy cascading rate as determined from a −5/3 fit to the spectra. Terms appearing in the turbulent kinetic energy budget that can be calculated from the PIV data are in agreement with previous results. Evidence of a very strong correlation between dissipation rate and out-of-plane component of the vorticity is demonstrated by a striking similarity between their time series.
PIV Measurements in the Atmospheric Boundary Layer within and above a Mature Corn Canopy. Part II: Quadrant-Hole Analysis
Authors: Zhu W. , van Hout R. , Katz J.
Published: August 2007

Quadrant-hole (Q-H) analysis is applied to PIV data acquired just within and above a mature corn canopy. The Reynolds shear stresses, transverse components of vorticity, as well as turbulence production and cascading part of dissipation rates are conditionally sampled in each quadrant, based on stress and vorticity magnitudes. The stresses are representative of large-scale events, while the vorticity is dominated by small-scale shear. Dissipation rates (cascading energy fluxes) are evaluated by fitting −5/3 slope lines to the conditionally sampled and averaged spatial energy spectra, while the Reynolds stresses, vorticity, and production rates are calculated directly from the spatial distributions of two velocity components. The results demonstrate that sweep (quadrant 4) and ejection (quadrant 2) events are the dominant contributors to the Reynolds shear stress, consistent with previous observations. The analysis also shows a strong correlation between magnitudes of dissipation rate and vorticity. The dissipation rates and vorticity magnitudes are higher in quadrants 1 and 4, that is, when the horizontal component of the fluctuating velocity is positive, peaking in quadrant 1. Both are weakly correlated with the Reynolds stresses except for rare quadrant 1 events. However, the more frequently occurring quadrant 4 events are the largest contributors to the dissipation rate. The production rate inherently increases with increasing stress magnitude, but lacks correlation with vorticity. Quadrants 2 and 4 contribute the most to production. However, the contribution of quadrant 1 events to negative production should not be ignored above canopy. The results show a strong disconnection between small-scale- and large-scale-dominated phenomena.
Sensitivity of the Latitude of the Surface Westerlies to Surface Friction
Authors: Chen Gang , Held Isaac M. , Robinson Walter A.
Published: August 2007

The sensitivity to surface friction of the latitude of the surface westerlies and the associated eddy-driven midlatitude jet is studied in an idealized dry GCM. The westerlies move poleward as the friction is reduced in strength. An increase in the eastward phase speed of midlatitude eddies is implicated as playing a central role in this shift.

This shift in latitude is mainly determined by changes in the friction on the zonal mean flow rather than the friction on the eddies. If the friction on the zonal mean is reduced instantaneously, the response reveals two distinctive adjustment time scales. In the fast adjustment over the first 10–20 days, there is an increase in the barotropic component of zonal winds and a substantial decrease in the eddy kinetic energy; the shift in the surface westerlies and jet latitude occurs in a slower adjustment. The space–time eddy momentum flux spectra suggest that the key to the shift is a poleward movement in the subtropical critical latitude associated with the faster eastward phase speeds in the dominant midlatitude eddies. The view is supported by simulating the upper-tropospheric dynamics in a stochastically stirred nonlinear shallow water model.
An Idealized Two-Dimensional Framework to Study the West African Monsoon. Part II: Large-Scale Advection and the Diurnal Cycle
Authors: Peyrillé Philippe , Lafore Jean-Philippe
Published: August 2007

The idealized 2D model developed in Part I of this study is used to study the West African monsoon sensitivity to large-scale forcing. Using ECWMF reanalyses, a large-scale forcing is introduced in the 2D model in terms of temperature and humidity advection.

A coherent structure of cooling–moistening near the surface and drying–warming in the 2–4-km layer is found in the Saharan heat low region. The effect of the advective forcing is to block the monsoon propagation by strengthening the northerly flux and by an increase of convective inhibition. The heat low thus appears to play a key role in the monsoon northward penetration through its temperature and humidity budget. Ultimately, warmer low levels and/or more moist midlevels in the heat low favor a more northerly position of the ITCZ.

A detailed view of the continental diurnal cycle is also presented. Potential temperature and humidity budgets are performed in the deep convective and heat low area. The moistening process to sustain deep convection is made through nocturnal advection at low levels and daytime turbulence that redistributes humidity vertically. The same mechanism occurs in the heat low except that the vertical transfers by turbulence help maintain the dryness of the low levels. A possible mechanism of interaction between the deep convective zone and the Saharan heat low is also proposed that involves gravity waves in the upper troposphere.
PBL State Estimation with Surface Observations, a Column Model, and an Ensemble Filter
Authors: Hacker Joshua P. , Rostkier-Edelstein Dorita
Published: August 2007

Following recent results showing the potential for using surface observations of temperature, water vapor mixing ratio, and winds to determine PBL profiles, this paper reports on experiments with real observations. A 1D column model with soil, surface-layer, and PBL parameterization schemes that are the same as in the Weather Research and Forecasting model is used to estimate PBL profiles with an ensemble filter. Surface observations over the southern Great Plains are assimilated during the spring and early summer period of 2003. To strictly quantify the utility of the observations for determining PBL profiles in the ensemble filter framework, only climatological information is provided for initialization and forcing. The analysis skill, measured against rawinsondes for an independent verification, is compared against climatology to quantify the influence of the observations. Sensitivity to changing parameterization schemes, and to prescribed values of observation error variance, is examined. Temporal propagation of skillful analyses is also assessed, separating the effects of good prior state estimates from the impact of assimilation at night when covariance is weak. Results show that accurate profiles of temperature, mixing ratio, and winds are estimated with the column model and ensemble filter assimilating only surface observations. Results are largely insensitive to choice of parameterization scheme and specified observation error variance. The effects of using different parameterization schemes within the column model depend on whether assimilation is included, showing the importance of evaluating models within assimilation systems. At night, skillful estimates are possible because the influence of the observations from the previous day is temporally propagated, and atmospheric dynamics in the residual layer operate on slow time scales. It is expected that these profiles will have applications for nowcasting and secondary models (e.g., plume dispersion models) that rely on accurate specification of PBL structure.
A Comparison of Two Coastal Barrier Jet Events along the Southeast Alaskan Coast during the SARJET Field Experiment
Authors: Olson Joseph B. , Colle Brian A. , Bond Nicholas A. , Winstead Nathaniel
Published: August 2007

The Southeastern Alaskan Regional Jets experiment investigated the structures and physical processes of barrier jets along the coastal Fairweather Mountains near Juneau, Alaska, from 24 September to 21 October 2004. This paper compares in situ aircraft data and high-resolution simulations from the first intensive observation period (IOP1), which featured a nearly terrain-parallel barrier jet (classical jet) with another coastal jet event (IOP7) that was influenced by offshore-directed gap flows at the coast (hybrid jet). IOP1 featured southerly onshore flow preceding a landfalling trough, which was blocked by the coastal terrain and accelerated down the pressure gradient to produce a 5–10 m s−1 wind enhancement in the alongshore direction in the lowest 1 km MSL. In contrast, IOP7 featured higher surface pressure and colder low-level temperatures to the east (inland) of the study area than did IOP1, which resulted in offshore-directed coastal gap flow exiting Cross Sound below ∼500 m that turned anticyclonically and merged with the ambient flow. Unlike the classical jet (IOP1), IOP7 had a surface warm anomaly adjacent to the steep coastal terrain, while a cold anomaly existed farther offshore within the gap outflow. Above the shallow gap flow (>500 m MSL), there were more classical barrier jet characteristics. High-resolution fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5) simulations were performed to compare the structures and underlying dynamics between the two cases. Model trajectories show that coastal winds for IOP1 originated offshore, while much of the coastal flow in IOP7 had gap flow origins near the surface and offshore origins above the gap outflow. A model momentum budget suggests that the vertical mixing of southerly momentum from aloft forced the gap outflow in IOP7 to turn anticyclonically more rapidly than an inertial circle. A simulation of IOP7 with the Cross Sound gap removed (filled in) produced a coastal jet with similar maximum wind speeds to the control but resulted in a reduction in the width of the coastal jet by about 40%.
Followership
Authors: Baker Susan D.
Published: August 2007

This article presents the theoretical foundation of followership. The words follower and followership are increasingly used in discussions of leadership and organizations, and many think that the field of followership began in 1988 with Kelley's “In Praise of Followers.” Followership research began in 1955, and literature in the social sciences discussed followers and followership for decades prior. By examining why leadership rather than followership is emphasized; discussing antecedents, early theory, and research about followership; and identifying common themes found in the literature, this article provides the foundation that has been missing in contemporary discussion of the followership construct.
When Does a Corporate Social Responsibility Initiative Provide a First-Mover Advantage?
Authors: Tetrault Sirsly Carol-Ann , Lamertz Kai
Published: August 2007

Theory and research on corporate social responsibility (CSR) have been concerned primarily with identifying stakeholders, categorizing types of CSR initiatives, and linking corporate social performance to firm performance. In this conceptual article, the authors assess strategic CSR initiatives, inquiring into the conditions that might give rise to a sustainable competitive advantage in social performance. In what circumstances does a firm's CSR initiative create a first-mover advantage, and when should a firm prefer an early- or late-adopter position? Using the resource-based view and the asymmetries approach of first-mover advantages, the authors propose that for a CSR initiative to lead to a sustainable first-mover advantage, it must be central to the firm's mission, provide firm-specific benefits, and be made visible to external audiences. These strategic attributes generate internal sustainability and must be complemented to ensure external defensibility by a firm's ability to assess its environment, manage its stakeholders, and deal with social issues.