bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Noxa Sensitizes Human Colorectal Cancer Cells Expressing Mcl-1 to the Small-Molecule Bcl-2/Bcl-xL Inhibitor, ABT-737
Authors: Okumura Kenji , Huang Shengbing , Sinicrope Frank A.
Published: December 2008

Purpose: The intrinsic drug resistance of colorectal cancers is related in part to overexpression of prosurvival Bcl-2 family proteins. We determined the effects of ABT-737, a small-molecule inhibitor of Bcl-2/Bcl-xL but not Mcl-1, on apoptosis induction alone and in combination with CPT-11 and explored mechanisms underlying their cooperativity.

Experimental Design: Human colorectal carcinoma cell lines (HCT116 wild-type and Bax-/-, HT-29, and RKO) were incubated with ABT-737 alone and combined with CPT-11 or bortezomib, and cell viability, caspase cleavage, and Annexin V labeling were measured. In drug-treated cell lines, protein-protein interactions were analyzed by immunoprecipitation. Lentiviral short hairpin RNA was used to knockdown Noxa expression.

Results: ABT-737 induced apoptosis in a dose-dependent manner and its coadministration with the topoisomerase I inhibitor, CPT-11, resulted in a synergistic cytotoxic effect. Apoptosis induction by the drug combination was associated with enhanced caspase-8, caspase-9, and caspase-3 activation and poly(ADP-ribose) polymerase cleavage that were completely abrogated in Bax knockout cells. ABT-737 unsequestered the BH3-only protein Bim from its complex with Bcl-xL or Bcl-2 and disrupted the interaction of Bcl-xL with Bak. CPT-11 treatment up-regulated Noxa expression, as did bortezomib, and enhanced Noxa/Mcl-1 complexes. CPT-11 also disrupted the Mcl-1/Bak interaction. Knockdown of Noxa using short hairpin RNA lentiviral constructs was shown to significantly attenuate the cytotoxic effect of CPT-11 or bortezomib combined with ABT-737 and inhibited caspase-3 cleavage.

Conclusions: Induction of Noxa by CPT-11 or bortezomib can sensitize colorectal cancer cells expressing Mcl-1 to ABT-737. Up-regulation of Noxa may therefore represent an important strategy to enhance the therapeutic efficacy of ABT-737 against colorectal cancer and other solid tumors.
αvβ3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers
Authors: Belleri Mirella , Ribatti Domenico , Savio Monica , Stivala Lucia Anna , Forti Luca , Tanghetti Elena , Alessi Patrizia , Coltrini Daniela , Bugatti Antonella , Mitola Stefania , Nicoli Stefania , Vannini Vanio , Presta Marco
Published: December 2008

Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stereoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated. Recently, trans-resveratrol has been shown to interact with the β3 integrin subunit, raising the possibility that inhibition of endothelial αvβ3 integrin function may concur to its angiosuppressive activity. To get novel insights about the antiangiogenic activity of resveratrol, we compared cis- and trans-resveratrol stereoisomers for their effect on the angiogenesis process and endothelial αvβ3 integrin function. trans-Resveratrol inhibits endothelial cell proliferation and the repair of mechanically wounded endothelial cell monolayers. Also, it prevents endothelial cell sprouting in fibrin gel, collagen gel invasion, and morphogenesis on Matrigel. In vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, trans-resveratrol, but not cis-resveratrol, inhibits αvβ3 integrin-dependent endothelial cell adhesion and the recruitment of enhanced green fluorescent protein-tagged β3 integrin in focal adhesion contacts. In conclusion, stereoisomery affects the antiangiogenic activity of resveratrol, the trans isomer being significantly more potent than the cis isoform. The different antiangiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect αvβ3 integrin function. This may have profound implications for the design of synthetic antiangiogenic/angiopreventive phytoalexin derivatives. [Mol Cancer Ther 2008;7(12):3761–70]
A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors
Authors: Lam Elaine T. , O'Bryant Cindy L. , Basche Michele , Gustafson Daniel L. , Serkova Natalie , Baron Anna , Holden Scott N. , Dancey Janet , Eckhardt S. Gail , Gore Lia
Published: December 2008

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluorodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1-14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8-21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3-24 months). [18F]fluorodeoxyglucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies. [Mol Cancer Ther 2008;7(12):3685–94]
Challenge and promise: roles for Livin in progression and therapy of cancer
Authors: Wang Ling , Zhang Qi , Liu Bin , Han Mei , Shan Baoen
Published: December 2008

Livin is a member of the inhibitors of apoptosis protein gene family, which is highly expressed in a variety of human neoplasms. Several studies have shown that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential, and sensitizes tumor cells to chemotherapeutic drugs. Furthermore, emerging data reveal that Livin fragments cleavaged by caspases restored paradoxical proapoptotic activity during the apoptotic process, suggesting that Livin cleavage will become a highly potent proapoptotic agent in the future. In this article, we review the current understanding of the versatile roles of Livin in the apoptotic cascade and exploit the promising approach to interfere with Livin as a novel strategy for cancer therapy. [Mol Cancer Ther 2008;7(11):3661–9]
ESE-1/EGR-1 pathway plays a role in tolfenamic acid-induced apoptosis in colorectal cancer cells
Authors: Lee Seong-Ho , Bahn Jae Hoon , Choi Chang Kyoung , Whitlock Nichelle C. , English Anthony E. , Safe Stephen , Baek Seung Joon
Published: December 2008

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to prevent colorectal tumorigenesis. Although antitumor effects of NSAIDs are mainly due to inhibition of cyclooxygenase activity, there is increasing evidence that cyclooxygenase-independent mechanisms may also play an important role. The early growth response-1 (EGR-1) gene is a member of the immediate-early gene family and has been identified as a tumor suppressor gene. Tolfenamic acid is a NSAID that exhibits anticancer activity in a pancreatic cancer model. In the present study, we investigated the anticancer activity of tolfenamic acid in human colorectal cancer cells. Tolfenamic acid treatment inhibited cell growth and induced apoptosis as measured by caspase activity and bioelectric impedance. Tolfenamic acid induced EGR-1 expression at the transcription level, and analysis of the EGR-1 promoter showed that a putative ETS-binding site, located at −400 and −394 bp, was required for activation by tolfenamic acid. The electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed that this sequence specifically bound to the ETS family protein epithelial-specific ETS-1 (ESE-1) transcription factor. Tolfenamic acid also facilitated translocation of endogenous and exogenous ESE-1 to the nucleus in colorectal cancer cells, and gene silencing using ESE-1 small interfering RNA attenuated tolfenamic acid-induced EGR-1 expression and apoptosis. Overexpression of EGR-1 increased apoptosis and decreased bioelectrical impedance, and silencing of endogenous EGR-1 prevented tolfenamic acid-induced apoptosis. These results show that activation of ESE-1 via enhanced nuclear translocation mediates tolfenamic acid-induced EGR-1 expression, which plays a critical role in the activation of apoptosis. [Mol Cancer Ther 2008;7(12):3739–50]
Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death
Authors: Little Joy L. , Wheeler Frances B. , Koumenis Constantinos , Kridel Steven J.
Published: December 2008

Fatty acid synthase (FASN) is the terminal enzyme responsible for fatty acid synthesis and is up-regulated in tumors of various origins to facilitate their growth and progression. Because of several reports linking the FASN and proteasome pathways, we asked whether FASN inhibitors could combine with bortezomib, the Food and Drug Administration-approved proteasome inhibitor, to amplify cell death. Indeed, bortezomib treatment augmented suboptimal FASN inhibitor concentrations to reduce clonogenic survival, which was paralleled by an increase in apoptotic markers. Interestingly, FASN inhibitors induced accumulation of ubiquinated proteins and enhanced the effects of bortezomib treatment. In turn, bortezomib increased fatty acid synthesis, suggesting crosstalk between the pathways. We hypothesized that cell death resulting from crosstalk perturbation was mediated by increased unfolded protein response (UPR) signaling. Indeed, disruption of crosstalk activated and saturated the adaptation arm of UPR signaling, including eIF2α phosphorylation, activating transcription factor 4 expression, and X-box-binding protein 1 splicing. Furthermore, although single agents did not activate the alarm phase of the UPR, crosstalk interruption resulted in activated c-Jun NH2-terminal kinase and C/EBP homologous protein-dependent cell death. Combined, the data support the concept that the UPR balance between adaptive to stress signaling can be exploited to mediate increased cell death and suggests novel applications of FASN inhibitors for clinical use. [Mol Cancer Ther 2008;7(12):3816–24]
Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells
Authors: Shen Lijun , Au Wing-Yan , Wong Kai-Yau , Shimizu Norio , Tsuchiyama Junjiro , Kwong Yok-Lam , Liang Raymond H. , Srivastava Gopesh
Published: December 2008

The proteasome inhibitor bortezomib (PS-341/Velcade) is used for the treatment of relapsed and refractory multiple myeloma and mantle-cell lymphoma. We recently reported its therapeutic potential against natural killer (NK)-cell neoplasms. Here, we investigated the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cells. NK lymphoma cell lines (SNK-6 and NK-YS) and primary cultures of NK lymphomas treated with bortezomib were examined for alterations in cell viability, apoptosis, cellular senescence, and cell cycle status. Bortezomib primarily induced mitochondrial apoptosis in NK-YS cells and in primary lymphoma cells at the same concentration as reported in myeloma cells. Unexpectedly, SNK-6 cells required a significantly higher median inhibitory concentration of bortezomib (23 nmol/L) than NK-YS and primary lymphoma cells (6-13 nmol/L). Apoptosis was limited in SNK-6 cells due to the extensively delayed turnover of Bcl-2 family members. These cells were killed by bortezomib, albeit at higher pharmacologic concentrations, via mitotic catastrophe—a mitotic cell death associated with M-phase arrest, cyclin B1 accumulation, and increased CDC2/CDK1 activity. Our results suggest that, in addition to cell death by apoptosis at lower bortezomib concentrations, NK lymphoma cells resistant to bortezomib-induced apoptosis can be killed via mitotic catastrophe, an alternative cell death mechanism, at higher pharmacologic concentrations of bortezomib. Hence, activating mitotic catastrophe by bortezomib may provide a novel therapeutic approach for treating apoptosis-resistant NK-cell malignancies and other cancers. [Mol Cancer Ther 2008;7(12):3807–15]
Combination of antiangiogenesis with chemotherapy for more effective cancer treatment
Authors: Ma Jie , Waxman David J.
Published: December 2008

Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. However, the survival benefits of antiangiogenic drugs have thus far been rather modest, stimulating interest in developing more effective ways to combine antiangiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between antiangiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Antiangiogenic drugs such as the anti-vascular endothelial growth factor antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of coadministered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of coadministered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where antiangiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase antitumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of antiangiogenic therapies and to identify responsive patients. New targets for antiangiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs. [Mol Cancer Ther 2008;07(12):3670–84]
UBE1L causes lung cancer growth suppression by targeting cyclin D1
Authors: Feng Qing , Sekula David , Guo Yongli , Liu Xi , Black Candice C. , Galimberti Fabrizio , Shah Sumit J. , Sempere Lorenzo F. , Memoli Vincent , Andersen Jesper B. , Hassel Bret A. , Dragnev Konstantin , Dmitrovsky Ethan
Published: December 2008

UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed. [Mol Cancer Ther 2008;7(12):3780–8]
Overexpression of the dual specificity phosphatase, Cdc25C, confers sensitivity on tumor cells to doxorubicin-induced cell death
Authors: Varmeh Shohreh , Manfredi James J.
Published: December 2008

Cdc25C is a dual-specificity phosphatase that is involved in induction of mitosis by removal of the inhibitory phosphates from cyclin-dependent kinase 1/cyclin B. In this study, adenovirus-mediated overexpression of Cdc25C sensitizes U2OS tumor cells to doxorubicin-induced apoptosis. U2OS cells that stably overexpress Cdc25C are also sensitized to doxorubicin-induced cell death. These cells show reduced phosphorylation of cyclin-dependent kinase 1 on Tyr15 and impaired up-regulation of p21 in response to treatment with doxorubicin. In contrast to doxorubicin, overexpression of Cdc25C does not confer sensitivity to apoptosis on treatment with 5-fluorouracil or hydroxyurea. This sensitization of tumor cells to doxorubicin-induced cell death by overexpression of Cdc25C is not p53 dependent. Intriguingly, nontransformed MCF10A cells are not sensitized to doxorubicin treatment by overexpression of Cdc25C nor does the lack of Cdc25C affect cell cycle progression or the G2 arrest caused by doxorubicin. These results support the idea that a combination of overexpressing Cdc25C with treatment with conventional genotoxic agents should be given serious considerations as a novel therapeutic strategy. [Mol Cancer Ther 2008;7(12):3789–99]
Menin Promotes the Wnt Signaling Pathway in Pancreatic Endocrine Cells
Authors: Chen Gao , A Jingbo , Wang Min , Farley Steven , Lee Lung-Yi , Lee Lung-Ching , Sawicki Mark P.
Published: December 2008

Menin is a tumor suppressor protein mutated in patients with multiple endocrine neoplasia type 1. We show that menin is essential for canonical Wnt/β-catenin signaling in cultured rodent islet tumor cells. In these cells, overexpression of menin significantly enhances TCF gene assay reporter activity in response to β-catenin activation. Contrastingly, inhibition of menin expression with Men1 siRNA decreases TCF reporter gene activity. Likewise, multiple endocrine neoplasia type 1 disease associated missense mutations of menin abrogate the ability to increase TCF reporter gene activity. We show that menin physically interacts with proteins involved in the canonical Wnt signaling pathway, including β-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2). Menin overexpression increases expression of the Wnt/β-catenin downstream target gene Axin2, which is associated with increased H3K4 trimethylation of the Axin2 gene promoter. Moreover, inhibition of menin expression by siRNA abrogates H3K4 trimethylation and Axin2 gene expression. Based on these studies, we hypothesized that Wnt signaling could inhibit islet cell proliferation because loss of menin function is thought to increase endocrine tumor cell proliferation. TGP61 rodent islet tumor cells treated with a glycogen synthase kinase 3β inhibitor that increases Wnt pathway signaling had decreased cell proliferation compared with vehicle-treated cells. Collectively, these data suggest that menin has an essential role in Wnt/β-catenin signaling through a mechanism that eventually affects histone trimethylation of the downstream target gene Axin2, and activation of Wnt/β-catenin signaling inhibits islet tumor cell proliferation. (Mol Cancer Res 2008;6(12):1894–907)
EWS-Fli1 Up-Regulates Expression of the Aurora A and Aurora B Kinases
Authors: Wakahara Kazuhiko , Ohno Takatoshi , Kimura Masashi , Masuda Takahiro , Nozawa Satoshi , Dohjima Taikoh , Yamamoto Takatoshi , Nagano Akihito , Kawai Gou , Matsuhashi Aya , Saitoh Mitsuru , Takigami Iori , Okano Yukio , Shimizu Katsuji
Published: December 2008

EWS-Fli1, a fusion gene resulting from the chromosomal translocation t(11;22, q24;q12), encodes a transcriptional activator, promotes cellular transformation, and is often found in Ewing sarcoma and primitive neuroectodermal tumor. The Aurora A and Aurora B kinases belong to a highly conserved family of serine/threonine protein kinases, are tightly regulated during the cell cycle, and are overexpressed in many carcinomas. Because the relationship between the Aurora A and/or Aurora B genes and the EWS-Fli1 fusion gene is unknown, we investigated the regulatory mechanism(s) by which Aurora kinases are controlled. Knockdown of EWS-Fli1 by small interfering RNA reduced mRNA levels not only of EWS-Fli1 but also of Aurora A and Aurora B. Luciferase assay using Aurora A and Aurora B promoters showed up-regulated activities compared with those of an empty vector. Experiments with deletion and point mutants showed positive regulatory Ets-binding sites located −84 and −71 bp upstream of the transcription initiation sites in Aurora A and Aurora B, respectively. Moreover, chromatin immunoprecipitation assay revealed that EWS-Fli1 gene products interact with both the Aurora A and Aurora B promoters. These results strongly suggest that the mitotic kinases Aurora A and Aurora B are regulated by EWS-Fli1 fusion protein in Ewing sarcoma cells. (Mol Cancer Res 2008;6(12):1937–45)
Influence of Exogenous Tissue Factor on Estrogen Receptorα Expression in Breast Cancer Cells: Involvement of β1-Integrin, PAR2, and Mitogen-Activated Protein Kinase Activation
Authors: Collier Mary E.W. , Li Chao , Ettelaie Camille
Published: December 2008

Increased expression of tissue factor (TF) has been associated with invasive forms of breast cancer. Conversely, the loss of estrogen receptor α (ERα) is associated with increased cell invasiveness. We have examined the influence of exogenous truncated recombinant TF (rTF) on ERα expression and cell invasiveness and investigated the mechanism of rTF signaling. The influence of rTF on ERα expression in MCF-7 and T47D cell lines was investigated using reverse transcription-PCR and ELISA. Cell invasion was measured using Boyden chamber-based invasion assays. Additionally, the interaction of fluorescein-labeled rTF with the surface of MCF-7 cells and particularly with β1-integrin was examined. Treatment of cells with rTF resulted in the down-regulation of ERα mRNA and protein over 24 h, which required β1-integrin and involved the mitogen-activated protein kinase pathway but did not require PAR2 activation. The addition of rTF reduced estradiol-mediated cell proliferation as well as increased cell invasiveness requiring both PAR2 and β1-integrin activation. Fluorescein-labeled rTF was shown to bind to the surface of MCF-7 cells within 5 min and peaked at 15 min. The bound rTF colocalized with cellular β1-integrin and was disrupted in the presence of excess unlabeled rTF and an anti-β1 polyclonal antibody. Finally, affinity purification of β1-integrin using rTF-conjugated agarose showed a requirement for the presence of divalent cations but not factor VIIa. The results indicate that rTF is capable of down-regulating ERα expression in breast cancer cells, resulting in decreases in estrogen-mediated cell proliferation and increased invasiveness. Furthermore, the mechanisms by which rTF induces these changes involve both PAR2 and β1-integrin. (Mol Cancer Res 2008;6(12):1807–18)
The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting
Authors: Wykosky Jill , Debinski Waldemar
Published: December 2008

The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among these are EphA2 and ephrinA1, which are involved in the development and maintenance of many different types of solid tumors. The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment. These variables affect the expression of the EphA2 and ephrinA1 proteins, the pathways through which they induce signaling, and the functional consequences of that signaling on the behavior of tumor cells and tumor-associated cells. This review will specifically focus on the roles that EphA2 and ephrinA1 play in the different cell types that contribute to the malignancy of solid tumors, with emphasis on the opportunities for therapeutic targeting. (Mol Cancer Res 2008;6(12):1795–806)
Disparate Effects of Roscovitine on Renal Tubular Epithelial Cell Apoptosis and Senescence: Implications for Autosomal Dominant Polycystic Kidney Disease
Authors: Park Jin-Young , Park See-Hyoung , Weiss Robert H.
Published: December 2008

Background/Aims: Control of apoptosis in autosomal dominant polycystic kidney disease (ADPKD) and in at least some cancers is likely regulated by the endogenous cyclin kinase inhibitor p21, levels of this protein being decreased in ADPKD and increased in many malignancies. The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD. We asked how a single agent can be efficacious in both PKD and cancer. Methods: Renal tubular epithelial cells were incubated at diverse roscovitine concentrations; apoptosis and senescence were measured. Subsequently, levels of pro- and antiapoptotic proteins were evaluated. Results: Renal tubular epithelial cells exposed to ‘low’ concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21, and these cells became senescent. Conversely, cells exposed to ‘high’ levels of roscovitine became apoptotic. The mechanism of antiapoptosis and senescence with ‘low’-dose roscovitine involves augmentation of the antiapoptotic proteins. Conclusions: Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD, and suggest that further study of this agent should focus on assessment of dose response. Furthermore, our discovery of senescence induced by a PKD effective drug suggests a new area of therapeutic investigation in this disease.
Sexual Dimorphism in the Parietal Substrate Associated with Visuospatial Cognition Independent of General Intelligence
Authors: Hänggi Jürgen , Buchmann Andreas , Mondadori Christian R. A. , Henke Katharina , Jäncke Lutz , Hock Christoph
Published: December 2008

Sex differences in visuospatial cognition (VSC) with male advantage are frequently reported in the literature. There is evidence for sexual dimorphisms in the human brain, one of which postulates more gray matter (GM) in females and more white matter (WM) in males relative to total intracranial volume. We investigated the neuroanatomy of VSC independent of general intelligence (g) in sex-separated populations, homogenous in age, education, memory performance, a memory- and brain morphology-related gene, and g. VSC and g were assessed with the Wechsler adult intelligence scale. The influence of g on VSC was removed using a hierarchical factor analysis and the Schmid–Leiman solution. Structural high-resolution magnetic resonance images were acquired and analyzed with voxel-based morphometry. As hypothesized, the clusters of positive correlations between local volumes and VSC performance independent of g were found mainly in parietal areas, but also in pre- and postcentral regions, predominantly in the WM in males, whereas in females these correlations were located in parietal and superior temporal areas, predominantly in the GM. Our results suggest that VSC depends more strongly on parietal WM structures in males and on parietal GM structures in females. This sex difference might have to do with the increased axonal and decreased somatodendritic tissue in males relative to females. Whether such sex-specific implementations of the VSC network can be explained genetically as suggested in investigations into the Turner syndrome or as a result of structural neural plasticity upon different experience and usage remains to be shown.
Top–Down Enhancement and Suppression of Activity in Category-selective Extrastriate Cortex from an Act of Reflective Attention
Authors: Johnson Matthew R. , Johnson Marcia K.
Published: December 2008

Recent research has demonstrated top–down attentional modulation of activity in extrastriate category-selective visual areas while stimuli are in view (perceptual attention) and after they are removed from view (reflective attention). Perceptual attention is capable of both enhancing and suppressing activity in category-selective areas relative to a passive viewing baseline. In this study, we demonstrate that a brief, simple act of reflective attention (“refreshing”) is also capable of both enhancing and suppressing activity in some scene-selective areas (the parahippocampal place area [PPA]) but not others (refreshing resulted in enhancement but not in suppression in the middle occipital gyrus [MOG]). This suggests that different category-selective extrastriate areas preferring the same class of stimuli may contribute differentially to reflective processing of one's internal representations of such stimuli.
The Frequency and Characteristics of Lake-Effect Precipitation Events Associated with the New York State Finger Lakes
Authors: Laird Neil , Sobash Ryan , Hodas Natasha
Published: December 2008

This study presents a climatological analysis of the frequency and characteristics of lake-effect precipitation events that were initiated or enhanced by lakes within the New York State (NYS) Finger Lakes region for the 11 winters (October–March) from 1995/96 through 2005/06. Weather Surveillance Radar-1988 Doppler (WSR-88D) data from Binghamton, New York, were used to identify 125 lake-effect events. Events occurred as 1) a well-defined, isolated precipitation band over and downwind of a lake, 2) an enhancement of mesoscale lake-effect precipitation originating from Lake Ontario and extending southward over an individual Finger Lake, 3) a quasi-stationary mesoscale precipitation band positioned over a lake embedded within extensive regional precipitation from a synoptic weather system, or 4) a transition from one type to another. Results show that lake-effect precipitation routinely develops over lakes that are considerably smaller than lakes previously discussed as being associated with lake-effect precipitation, such as the Great Lakes. Lake-effect events occurred during each month (October–March) across the 11 winters studied and were identified in association with each of the six easternmost Finger Lakes examined in this study. The frequency of NYS Finger Lakes lake-effect events determined in the current investigation paired with subsequent analyses of the environmental conditions leading to these events will allow for 1) comparative analyses of necessary conditions for lake-effect development across a range of lake sizes (e.g., NYS Finger Lakes, Lake Champlain, Great Salt Lake, and Great Lakes) and 2) an informative examination of the connection between mesoscale processes and climate variability.
What Controls the Transition from Shallow to Deep Convection?
Authors: Wu Chien-Ming , Stevens Bjorn , Arakawa Akio
Published: December 2008

In this study, a 2D cloud-system-resolving model (CSRM) is used to assess the control mechanism for the transition from shallow to deep convection in the diurnal cycle over land. By comparing with a 3D CSRM under conditions taken from the Large-Scale Biosphere–Atmosphere field study (in the Amazon), the authors show that the 2D CSRM reproduces the main features evident in previous 3D simulations reasonably well. To extract the essence of the transition from shallow to deep convection, the observed case is idealized to isolate two control parameters, the free troposphere stability and the relative humidity. The emergence of a distinct transition between shallow and deep convection shows that the convective transition is an intrinsic property of the system. A transition time is defined to evaluate the key mechanism of the transition. The authors show that the transition coincides with the time when the lapse rate of the virtual potential temperature of the clouds becomes larger than that of the environment, suggesting that the transition happens when shallow clouds become, on average, buoyant. This suggests that, given the opportunity, convection prefers to be shallow.
A Test of the Simulation of Tropical Convective Cloudiness by a Cloud-Resolving Model
Authors: Lopez Mario A. , Hartmann Dennis L. , Blossey Peter N. , Wood Robert , Bretherton Christopher S. , Kubar Terence L.
Published: December 2008

A methodology is described for testing the simulation of tropical convective clouds by models through comparison with observations of clouds and precipitation from earth-orbiting satellites. Clouds are divided into categories that represent convective cores: moderately thick anvil clouds and thin high clouds. Fractional abundances of these clouds are computed as a function of rain rate. A three-dimensional model is forced with steady forcing characteristics of tropical Pacific convective regions, and the model clouds are compared with satellite observations for the same regions. The model produces a good simulation of the relationship between the precipitation rate and optically thick cold clouds that represent convective cores. The observations show large abundances of anvil cloud with a strong dependence on rain rate, but the model produces too little anvil cloud by a factor of about 4 and with a very weak dependence on the rain rate. The observations also show probability density functions for outgoing longwave radiation (OLR) and albedo with maxima that correspond to extended upper-level cold clouds, whereas the model does not. The sensitivity of the anvil cloud simulation to model parameters is explored using a two-dimensional model. Both cloud physical parameters and mean wind shear effects are investigated. The simulation of anvil cloud can be improved while maintaining a good simulation of optically thick cloud by adjusting the cloud physics parameters in the model to produce more ice cloud and less liquid water cloud.
Regional and Global Impacts of Land Cover Change and Sea Surface Temperature Anomalies
Authors: Findell Kirsten L. , Pitman Andrew J. , England Matthew H. , Pegion Philip J.
Published: December 2008

The atmospheric and land components of the Geophysical Fluid Dynamics Laboratory’s (GFDL’s) Climate Model version 2.1 (CM2.1) is used with climatological sea surface temperatures (SSTs) to investigate the relative climatic impacts of historical anthropogenic land cover change (LCC) and realistic SST anomalies. The SST forcing anomalies used are analogous to signals induced by El Niño–Southern Oscillation (ENSO), the North Atlantic Oscillation (NAO), and the background global warming trend. Coherent areas of LCC are represented throughout much of central and eastern Europe, northern India, southeastern China, and on either side of the ridge of the Appalachian Mountains in North America. Smaller areas of change are present in various tropical regions. The land cover changes in the model are almost exclusively a conversion of forests to grasslands.

Model results show that, at the global scale, the physical impacts of LCC on temperature and rainfall are less important than large-scale SST anomalies, particularly those due to ENSO. However, in the regions where the land surface has been altered, the impact of LCC can be equally or more important than the SST forcing patterns in determining the seasonal cycle of the surface water and energy balance. Thus, this work provides a context for the impacts of LCC on climate: namely, strong regional-scale impacts that can significantly change globally averaged fields but that rarely propagate beyond the disturbed regions. This suggests that proper representation of land cover conditions is essential in the design of climate model experiments, particularly if results are to be used for regional-scale assessments of climate change impacts.
Social Support and Physical Activity in Type 2 Diabetes A Social-Ecologic Approach
Authors: Gleeson-Kreig JoAnn
Published: December 2008

Purpose This study utilized social-ecology to describe sources of social-environmental support for physical activity perceived by people with type 2 diabetes, and examined the relationship between support and physical activity.

Methods Multidimensional support and physical activity were measured in 58 people with diabetes. Descriptive and correlational statistics were used.

Results Support from the media scored highest, followed by the health care team, personal support, workplace, family and friends, and lowest for the community. Physical activity was related to personal, media, and community support.

Conclusions Using a social-ecological approach, health care professionals must focus on enhancing support from media sources, strengthening community context, and bolstering personal self-management. Professionals must also critically examine patient-provider interactions to motivate lifestyle change.
Healthy Changes™ for Living with Diabetes
Authors: Klug Cindy , Toobert Deborah J. , Fogerty Michaela
Published: December 2008

Purpose This article addresses the gap between research and practice by describing the feasibility and outcomes of an evidence- based diabetes self-management health education program. The Healthy Changes™ program used a peer-led group format to promote physical activity and healthful eating practices, using culturally relevant materials and measures.

Methods Older adults (mean age = 69.2 years; SD = 10.7) with type 2 diabetes (N = 243) were recruited from 9 communities to participate in the Healthy Changes™ program. Components included goal setting, problem solving, group support, and interactive lectures from experts. Measures of eating patterns, physical activity, body weight, community resources, self-rated health, and self-efficacy were administered at baseline, and at 4, 8, and 12 months.

Results Participants attended on average 13 weekly sessions, and showed improvements in health behaviors, supportive resources, and self-efficacy at 4, 8, and 12 months.

Conclusions The Healthy Changes™ program can be successfully translated into community settings and led by trained peer leaders, yielding health improvements similar to those reported in efficacy trials. Trained peer leaders are key to effective program implementation. Peer-led groups enhance goal attainment by giving participants a venue to discuss obstacles and strategize solutions.
Living with Diabetes
Authors: Olshansky Ellen , Sacco Diane , Fitzgerald Kathryn , Zickmund Susan , Hess Rachel , Bryce Cindy , McTigue Kathleen , Fischer Gary
Published: December 2008

Purpose The purpose of this qualitative study was to explore perceptions of people with diabetes about their experience of living with and managing their diabetes.

Methods This study was part of a larger study of patients with diabetes who used a novel computer portal system for access to information about diabetes and to their health care providers for enhanced communication. The research method used for this portion of the study was grounded theory methodology, a particular kind of qualitative research method.

Results A central theme generated from the data was “normalizing an identity as a person with diabetes.” The participants described themselves as diabetic; they took on an identity in which having diabetes was central. They struggled with how to become “a person with diabetes” rather than a “diabetic person.”

Conclusions For people who are diagnosed with diabetes, there is a struggle to become a person with diabetes rather than a diabetic person and to manage the lifestyle changes that are mandated by this role/identity. One way of dealing or coping with this new identity is to begin to “normalize” these lifestyle changes—to view them as healthy living for all people, those with and without diabetes. This will then have implications for interventions—encouraging healthy lifestyles among people with diabetes rather than emphasizing that people with diabetes are “different from” the general population.
My house was on Torchwood!
Authors: Mills Brett
Published: December 2008

Using life writing, this article examines my responses to seeing my house on television — during an episode of Torchwood filmed around Cardiff. The article explores the intersections between personal history, ideas of home and televisual representation. It focuses on the ways in which personal knowledge affects readings of programmes; the relationships between tourists and residents; the emotive nature of responses to representations; and television's role as a recorder of locations. In doing so, the article attempts to bring together the personal and emotive nature of culture with ideas of identity, the media's role in society, and cultural and social change.
Literary tourism
Authors: Earl Benjamin
Published: December 2008

Tourism and cultural geography have often made much of how visitors use and appropriate tourist sites as a means of cultural identity and distinction. This article looks at how, in a globalized world where access to such once high-cultural geographic sites becomes more democratized, certain tourist groups have to resort to alternative strategies in order to maintain their high-cultural requirements for the touristic experience. The article presents an account of how one particular tourist party utilized the cultural value of authorship to legitimate and authenticate their experience. Drawing on Bourdieu, Benjamin and Althusser, this article examines how a series of lectures by authors is commissioned by the group leader to create a sense of aura, distinction and uniqueness around the geographical tourist sites themselves.
Hosea 1—3 in Twentieth-Century Scholarship
Authors: Kelle Brad E.
Published: December 2008

Throughout the twentieth century, critical scholarship on the book of Hosea has focused overwhelmingly on the marriage metaphor in Hosea 1—3. Scholars often saw these chapters as establishing the primary interpretive issues for the message of the prophet and the book as a whole, although a lack of consensus concerning even the most basic exegetical issues remains. Newer studies have rightly pushed beyond this isolation of Hosea 1—3. This article surveys the major trends of the modern interpretation of these chapters, with particular attention to the second half of the twentieth century. From the early 1900s to the 1980s, critical works focused primarily on the biographical reconstruction of the prophet and his family life, as well as related historical and form-critical concerns. From the 1930s forward, such study was particularly concerned to read Hosea 1—3 against the background of a purported sexualized Baal cult in eighth-century Israel. Beginning in the 1980s, feminist-critical readings of Hosea 1—3 came to occupy a prominent position. In subsequent years, these concerns have been complemented by an emerging emphasis on metaphor theory, as well as newer kinds of literary, book-oriented, and socio-historical analyses. A follow-up article will treat recent scholarship on Hosea 4—14.
Rebuilding Organizational Capacity in Turnaround Schools
Authors: Murphy Joseph , Meyers Coby V.
Published: December 2008

In this article, we provide a grounded narrative of capacity building in the turnaround equation by exploring the turnaround literature outside of education and applying it to troubled schools. Our analysis is based upon reviews of: (1) 14 comprehensive, historical volumes that examine the turnaround phenomenon; (2) 16 book-length analyses of turnaround in a single organization or a specific industry; (3) articles attending to theory building in this emerging area of scholarship; and (4) a plethora of empirical studies examining turnaround in a variety of different (non-educational) contexts. We organize findings on capacity building in turnarounds into the following broad categories: (1) rallying and mobilizing people (motivating people, building, morale, and communicating openly); (2) growing people (empowering people, building teams, and developing people); and (3) creating a productive culture. We close by teasing out important lessons from the turnaround literature in the non-education sector to capacity building in troubled schools.
Budget Monitoring and Control in South African Township Schools
Authors: Mestry Raj , Naidoo Gans
Published: December 2008

This article investigates budget monitoring and control in township schools in South Africa. The enactment of the Schools Act 1996 revolutionized school financial management in South Africa, making it part of the drive for democratic school governance. School governing bodies had to be established, whose responsibility it became to manage finances at school. Schools were allowed to raise funds over and above the departmental allocations, which to township schools were increased in order to redress past imbalances. However, most of these school governors lacked the necessary financial knowledge, skills and competencies required to effectively manage large sums of cash, and as a result many schools experienced financial difficulty. This study investigated the way in which a group of township schools in South Africa monitor and control their budgets. The findings revealed that the level of education plays a significant role in the way in which budget monitoring and control is perceived. It was concluded that, if applied conscientiously, the schools can remain liquid in terms of cash flow and operate within the confines of the approved budget.
Leadership at the Top
Authors: Williams Allan P.O.
Published: December 2008

A UK business school was researched to record its history and to account for its development. The data collection and interpretation were influenced by the flexible and iterative nature of the methodology. Theories and concepts used to make sense of the findings include: open systems, force fields, and power. The focus is on strategic leadership, and two visual models are developed to identify the critical environmental and organizational variables that deans have to contend with in modifying the school/environmental fit. Three critical roles for deans are highlighted: determining the priorities to be followed in relation to an ongoing range of strategic dilemmas; supervising relationships with external stakeholders; managing culture change. The potential value of interspersing academic deans with those from business is identified.
Exploring Aspiring Principals' Perceptions of Principalship
Authors: Trnavčevič Anita , Roncelli Vaupot Silva
Published: December 2008

A lot is expected of Slovenian principals, yet very little is known about aspiring principals' own expectations of principalship. Currently there is no Slovenian study of aspiring principals, although they represent the majority of those enrolled on the `certification programme' of the National School for Leadership in Education. The purpose of this article is to explore: (1) what aspiring principals perceive as principalship and how they define it; (2) what participants perceive as significant influences on principalship; (3) the tensions that aspiring principals might perceive and anticipate as a part of principalship; and (4) the metaphors used for principalship. Data indicate that participants discuss principalship from a managerial position in which the main tasks revolve around the `smooth work of an organization'. Principals' personalities play pivotal role in successful principalship, while the legal context, legislation and national policies `dictate' schools' work. Power is concentrated with principals, which the metaphors nicely reflect. Principals are seen to be paternalistic and hierarchical.