bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of an Association between the TGFBR1*6A Variant and Colorectal Cancer Risk
Authors: Skoglund Johanna , Song Bo , Dalén Johan , Dedorson Stefan , Edler David , Hjern Fredrik , Holm Jörn , Lenander Claes , Lindforss Ulrik , Lundqvist Nils , Olivecrona Hans , Olsson Louise , Påhlman Lars , Rutegård Jörgen , Smedh Kennet , Törnqvist Anders , Houlston Richard S. , Lindblom Annika
Published: June 2007

Purpose: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies.

Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted.

Results: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A.

Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.
[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 Is a Highly Efficient Radiotherapeutic for Glucagon-Like Peptide-1 Receptor–Targeted Therapy for Insulinoma
Authors: Wicki Andreas , Wild Damian , Storch Daniel , Seemayer Christian , Gotthardt Martin , Behe Martin , Kneifel Stefan , Mihatsch Michael J. , Reubi Jean-Claude , Mäcke Helmut R. , Christofori Gerhard
Published: June 2007

Purpose: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4, an 111In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.

Experimental Design: [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic β-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated.

Results: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4. Other GLP-1R–positive organs showed ≥30 times lower dose deposition. A single injection of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation.

Conclusions: The results suggest that [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as 111In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.
AZD1152, a Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenograft Growth by Inducing Apoptosis
Authors: Wilkinson Robert W. , Odedra Rajesh , Heaton Simon P. , Wedge Stephen R. , Keen Nicholas J. , Crafter Claire , Foster John R. , Brady Madeleine C. , Bigley Alison , Brown Elaine , Byth Kate F. , Barrass Nigel C. , Mundt Kirsten E. , Foote Kevin M. , Heron Nicola M. , Jung Frederic H. , Mortlock Andrew A. , Boyle F. Thomas , Green Stephen
Published: June 2007

Purpose: In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B).

Experimental Design: The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes.

Results: AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to ≥100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment.

Conclusions: These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.
Restoration of Tissue Factor Pathway Inhibitor-2 in a Human Glioblastoma Cell Line Triggers Caspase-Mediated Pathway and Apoptosis
Authors: George Joseph , Gondi Christopher S. , Dinh Dzung H. , Gujrati Meena , Rao Jasti S.
Published: June 2007

Purpose: The induction of apoptotic pathways in cancer cells offers a novel and potentially useful approach to improve patient responses to conventional chemotherapy. Tissue factor pathway inhibitor-2 (TFPI-2) is a protease inhibitor that is abundant in the extracellular matrix and highly expressed in noninvasive cells but absent or undetectable in highly invasive human glioblastoma cells.

Experimental Design: Using a recombinant adeno-associated viral vector carrying human TFPI-2 cDNA, we stably expressed TFPI-2 in U-251 cells, a highly invasive human glioblastoma cell line. Our previous studies showed that restoration of TFPI-2 in glioblastomas effectively prevents cell proliferation, angiogenesis, and tumor invasion. In this study, we determined whether TFPI-2 restoration could induce apoptosis through the caspase-mediated signaling pathway.

Results: The results from nuclear chromatin staining, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay, and fluorescence-activated cell sorting analysis showed increased apoptosis in U-251 cells after restoration of TFPI-2. Caspase-9 and caspase-3 activity assays showed increased activity, indicating enhanced apoptosis. Immunofluorescence for cleaved caspase-9 and caspase-3 depicted increased expression and colocalization of both molecules. Western blot analysis showed increased transcriptional activities of Fas ligand, tumor necrosis factor-α, Bax, Fas-associated death domain, and tumor necrosis factor receptor 1–associated death domain as well as elevated levels of cleaved caspases and poly(ADP-ribose) polymerase. Semiquantitative reverse transcription-PCR depicted increased expression of tumor necrosis factor-α and Fas ligand and the related death domains tumor necrosis factor receptor 1–associated death domain and Fas-associated death domain.

Conclusions: Taken together, these results show that restoration of TFPI-2 activates both intrinsic and extrinsic caspase-mediated, proapoptotic signaling pathways and induces apoptosis in U-251 cells. Furthermore, our study suggests that recombinant adeno-associated viral vector–mediated gene expression offers a novel tool for cancer gene therapy.
Proteomic Analysis Identifies Oxidative Stress Induction by Adaphostin
Authors: Stockwin Luke H. , Bumke Maja A. , Yu Sherry X. , Webb Simon P. , Collins Jack R. , Hollingshead Melinda G. , Newton Dianne L.
Published: June 2007

Purpose: Activities distinct from inhibition of Bcr/abl have led to adaphostin (NSC 680410) being described as “a drug in search of a mechanism.” In this study, proteomic analysis of adaphostin-treated myeloid leukemia cell lines was used to further elucidate a mechanism of action.

Experimental Design: HL60 and K562 cells treated with adaphostin for 6, 12, or 24 h were analyzed using two-dimensional PAGE. Differentially expressed spots were excised, digested with trypsin, and analyzed by liquid chromatography–tandem mass spectrometry. The contribution of the redox-active hydroquinone group in adaphostin was also examined by carrying out proteomic analysis of HL60 cells treated with a simple hydroquinone (1,4-dihydroxybenzene) or H2O2.

Results: Analysis of adaphostin-treated cells identified 49 differentially expressed proteins, the majority being implicated in the response to oxidative stress (e.g., CALM, ERP29, GSTP1, PDIA1) or induction of apoptosis (e.g., LAMA, FLNA, TPR, GDIS). Interestingly, modulation of these proteins was almost fully prevented by inclusion of an antioxidant, N-acetylcysteine. Validation of the proteomic data confirmed GSTP1 as an adaphostin resistance gene. Subsequent analysis of HL60 cells treated with 1,4-dihydroxybenzene or H2O2 showed similar increases in intracellular peroxides and an almost identical proteomic profiles to that of adaphostin treatment. Western blotting of a panel of cell lines identified Cu/Zn superoxide dismutase (SOD) as correlating with adaphostin resistance. The role of SOD as a second adaphostin resistance gene was confirmed by demonstrating that inhibition of SOD using diethyldithiocarbamate increased adaphostin sensitivity, whereas transfection of SOD I attenuated toxicity. Importantly, treatment with 1,4-dihydroxybenzene or H2O2 replicated adaphostin-induced Bcr/abl polypeptide degradation, suggesting that kinase inhibition is a ROS-dependent phenomenon.

Conclusion: Adaphostin should be classified as a redox-active–substituted dihydroquinone.
Differential Metabolism of Gefitinib and Erlotinib by Human Cytochrome P450 Enzymes
Authors: Li Jing , Zhao Ming , He Ping , Hidalgo Manuel , Baker Sharyn D.
Published: June 2007

Purpose: To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, and to compare their effects on CYP3A activity, with the aim to better understand mechanisms underlying pharmacokinetic variability and clinical effects.

Experimental Design: Enzyme kinetics were examined by incubating gefitinib or erlotinib (1.5-50 μmol/L) with recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, and CYP1B1 (10-160 pmol/mL). Their effects on CYP3A activity were examined by comparing midazolam metabolism in the presence and absence of gefitinib or erlotinib in human liver and intestinal microsomes. Parent compounds and metabolites were monitored by high-performance liquid chromatography with a photodiode detector or tandem mass spectrometer.

Results: Both drugs were metabolized primarily by CYP3A4, CYP3A5, and CYP1A1, with respective maximum clearance (Clmax) values for metabolism of 0.41, 0.39, and 0.57 mL/min/nmol for gefitinib and 0.24, 0.21, 0.31 mL/min/nmol for erlotinib. CYP2D6 was involved in gefitinib metabolism (Clmax, 0.63 mL/min/nmol) to a large extent, whereas CYP1A2 was considerably involved in erlotinib metabolism (Clmax, 0.15 mL/min/nmol). Both drugs stimulated CYP3A-mediated midazolam disappearance and 1-hydroxymidazolam formation in liver and intestinal microsomes.

Conclusions: Gefitinib is more susceptible to CYP3A-mediated metabolism than erlotinib, which may contribute to the higher apparent oral clearance observed for gefitinib. Metabolism by hepatic and extrahepatic CYP1A may represent a determinant of pharmacokinetic variability and response for both drugs. The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.
Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer–Derived Cells and Regulates Paclitaxel IC50
Authors: Turturro Francesco , Von Burton Gary , Friday Ellen
Published: June 2007

Purpose: We studied the hyperglycemia-induced expression of thioredoxin-interacting protein (TXNIP) expression and its relevance on the cytotoxic activity of paclitaxel in mammary epithelial–derived cell lines.

Experimental Design: Nontumorigenic cells (MCF10A); tumorigenic, nonmetastatic cells (MCF-7/T47D); and tumorigenic, metastatic cells (MDA-MB-231/MDA-MB-435s) were grown either in 5 or 20 mmol/L glucose chronically. Semiquantitative reverse transcription-PCR was used to assess TXNIP RNA expression in response to glucose. Reactive oxygen species were detected by CM-H2DCFDA (5-6-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. Thioredoxin activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorption. Obtained absorbance values were used to calculate the paclitaxel IC50 in 5 or 20 mmol/L glucose using the Chou's dose-effect equation.

Results: We show that hyperglycemia by itself affects the level of TXNIP RNA in breast cancer–derived cells. TXNIP RNA level differs between nontumorigenic/nonmetastatic, tumorigenic cells (low TXNIP level), and metastatic cells (high TXNIP level). The differences in TXNIP RNA level, in reactive oxygen species level, and in thioredoxin activity are all related. We further show that hyperglycemia is a favorable condition in increasing the paclitaxel cytotoxicity by causing IC50 3-fold decrease in metastatic breast cancer–derived MDA-MB-231 cells. The increased paclitaxel cytotoxicity is associated with an additive effect on the hyperglycemia-mediated TXNIP expression more evident in conditions of hyperglycemia than normoglycemia.

Conclusions: Our study opens a new perspective on the relevance of metabolic conditions of hyperglycemia in the biology and treatment of cancer, particularly in view of the epidemic of diabetes.
Whole-Body Optical Imaging in Animal Models to Assess Cancer Development and Progression
Authors: Kaijzel Eric L. , van der Pluijm Gabri , Löwik Clemens W.G.M.
Published: June 2007

Different optical-based imaging models were used to investigate tumor progression and metastasis with particular emphasis on metastasis to bone and bone marrow. We describe how optical imaging can be used to follow important processes in tumor development and treatment response, including angiogenesis, apoptosis, and proteolysis. Finally, we discuss the translation of one optical imaging modality, near-IR fluorescence, from animal validation studies to applications in the clinic related to cancer management.
Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice
Authors: Kim Seungwon , Yazici Yasemin D. , Calzada Gabriel , Wang Zhuo-Ying , Younes Maher N. , Jasser Samar A. , El-Naggar Adel K. , Myers Jeffrey N.
Published: June 2007

Anaplastic thyroid carcinoma (ATC) remains one of the most lethal human cancers. We hypothesized that sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-β kinase, would decrease tumor growth and angiogenesis in an orthotopic model of ATC. The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined. To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice, sorafenib was given p.o. at 40 or 80 mg/kg daily. Intratumoral effects were studied using immunohistochemical analysis. The effect of sorafenib on survival of the mice was also studied. Sorafenib inhibited the in vitro proliferation of ATC cell lines. Sorafenib also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer. As result, the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved. Sorafenib exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect. The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the BRAF mutational status of thyroid tumors. Given the lack of curative options for patients with ATC, sorafenib warrants further study as a therapeutic agent against ATC. [Mol Cancer Ther 2007;6(6):1785–92]
Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure
Authors: Robey Robert W. , Shukla Suneet , Steadman Kenneth , Obrzut Tomasz , Finley Elizabeth M. , Ambudkar Suresh V. , Bates Susan E.
Published: June 2007

ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 μmol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3- to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [125I]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 μmol/L, compared with a 50% to 70% reduction by 20 μmol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC50 values for inhibition of [125I]iodoarylazidoprazosin labeling of 0.37 and 0.23 μmol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds—BIM IV, BIM V, arcyriaflavin A, and K252c—reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates. [Mol Cancer Ther 2007;6(6):1877–85]
5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells
Authors: Kiziltepe Tanyel , Hideshima Teru , Catley Laurence , Raje Noopur , Yasui Hiroshi , Shiraishi Norihiko , Okawa Yutaka , Ikeda Hiroshi , Vallet Sonia , Pozzi Samantha , Ishitsuka Kenji , Ocio Enrique M. , Chauhan Dharminder , Anderson Kenneth C.
Published: June 2007

In this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage–related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC50 of ∼0.8–3 μmol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine–induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine–induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine–induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM. [Mol Cancer Ther 2007;6(6):1718–27]
Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice
Authors: Kiguchi Kaoru , Ruffino Lynnsie , Kawamoto Toru , Franco Eugenia , Kurakata Shin-ichi , Fujiwara Kosaku , Hanai Masaharu , Rumi Mohammad , DiGiovanni John
Published: June 2007

Biliary tract cancer is still challenging to treat and manage due to its poor sensitivity to conventional therapies and the inability to prevent or detect the early tumor formation. The most well known risk factor for gallbladder cancer is the presence of chronic inflammation, usually related to gallstones. It has been suggested that cyclooxygenase-2 (COX-2) plays a variety of roles in the gastrointestinal tract, including pathogenic processes such as neoplasia. Recently, we have generated transgenic mice that overexpress rat ErbB-2 under the control of bovine keratin 5 promoter (BK5.ErbB-2 mice). Homozygous BK5.ErbB-2 mice develop adenocarcinoma of gallbladder with an ∼90% incidence. In addition to the activation of ErbB-2 and epidermal growth factor receptor, mRNA and protein levels of COX-2 were up-regulated in the gallbladder carcinomas that developed in these transgenic mice. The aim of this study was to examine the effects of a COX-2 inhibitor, CS-706, on the development of gallbladder carcinomas using the BK5.ErbB-2 mouse model. Ultrasound image analysis as well as histologic evaluation revealed a significant therapeutic effect of CS-706 on the gallbladder tumors, either as reversion to a milder phenotype or inhibition of tumor progression. The antitumor effect was associated with inhibition of prostaglandin E2 synthesis. CS-706 treatment also down-regulated the activation of ErbB-2 and epidermal growth factor receptor, resulting in decreased levels of phosphorylated Akt and COX-2 in gallbladder cancers of BK5.ErbB-2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective therapy alone or in combination with other therapeutic agents for patients with biliary tract cancer. [Mol Cancer Ther 2007;6(6):1709–17]
Breast cancer cells with acquired antiestrogen resistance are sensitized to cisplatin-induced cell death
Authors: Yde Christina Westmose , Gyrd-Hansen Mads , Lykkesfeldt Anne E. , Issinger Olaf-Georg , Stenvang Jan
Published: June 2007

Antiestrogens are currently used for treating breast cancer patients who have estrogen receptor–positive tumors. However, patients with advanced disease will eventually develop resistance to the drugs. Therefore, compounds effective on antiestrogen-resistant tumors will be of great importance for future breast cancer treatment. In this study, we have investigated the effect of the chemotherapeutic compound cisplatin using a panel of antiestrogen-resistant breast cancer cell lines established from the human breast cancer cell line MCF-7. We show that the antiestrogen-resistant cells are significantly more sensitive to cisplatin-induced cell death than antiestrogen-sensitive MCF-7 cells and we show that cisplatin induces cell death by activating both the caspase and lysosomal death pathways. The antiestrogen-resistant cell lines express lower levels of antiapoptotic Bcl-2 protein compared with parental MCF-7 cells. Our data show that Bcl-2 can protect antiestrogen-resistant breast cancer cells from cisplatin-induced cell death, indicating that the reduced expression of Bcl-2 in the antiestrogen-resistant cells plays a role in sensitizing the cells to cisplatin treatment. [Mol Cancer Ther 2007;6(6): 1869–76]
The role of integrin-linked kinase in melanoma cell migration, invasion, and tumor growth
Authors: Wong Ronald P.C. , Ng Philip , Dedhar Shoukat , Li Gang
Published: June 2007

Melanoma is a life-threatening disease with a high mortality rate due to rapid metastasis. Currently, there is no effective treatment for metastatic melanoma. Integrin-linked kinase (ILK) is a serine/threonine kinase and has its role implicated in connecting cell-extracellular matrix interaction and growth factor signaling to cell survival, cell migration, invasion, anchorage-independent growth, angiogenesis, and epithelial-mesenchymal transition. However, the functional role of ILK in melanoma progression is not completely understood. We have previously shown that strong ILK expression was significantly associated with melanoma thickness. In this study, we further elucidate the role of ILK in melanoma cell migration, invasion, anchorage-independent growth, and tumor growth in vivo by specific ILK knockdown using small interfering RNA and short hairpin RNA. We found that ILK knockdown impeded melanoma cell migration, which was associated with reduced stress fiber formation, cell spreading, and cell adhesion. Furthermore, ILK knockdown decreased the invasion ability of melanoma cells and the formation of anchorage-independent colonies in soft agar. Moreover, ILK knockdown significantly impaired the growth of melanoma xenografts in severe combined immunodeficient mice. This study highlights the importance of ILK in melanoma progression and provides an attractive target for the treatment of melanoma. [Mol Cancer Ther 2007;6(6):1692–1700]
Models Wagging the Dog: Are Circuits Constructed with Disparate Parameters?
Authors: Nowotny Thomas , Szücs Attila , Levi Rafael , Selverston Allen I.
Published: June 2007

In a recent article, Prinz, Bucher, and Marder (2004) addressed the fundamental question of whether neural systems are built with a fixed blueprint of tightly controlled parameters or in a way in which properties can vary largely from one individual to another, using a database modeling approach. Here, we examine the main conclusion that neural circuits indeed are built with largely varying parameters in the light of our own experimental and modeling observations. We critically discuss the experimental and theoretical evidence, including the general adequacy of database approaches for questions of this kind, and come to the conclusion that the last word for this fundamental question has not yet been spoken.
Multiplicative Updates for Nonnegative Quadratic Programming
Authors: Sha Fei , Lin Yuanqing , Saul Lawrence K. , Lee Daniel D.
Published: June 2007

Many problems in neural computation and statistical learning involve optimizations with nonnegativity constraints. In this article, we study convex problems in quadratic programming where the optimization is confined to an axis-aligned region in the nonnegative orthant. For these problems, we derive multiplicative updates that improve the value of the objective function at each iteration and converge monotonically to the global minimum. The updates have a simple closed form and do not involve any heuristics or free parameters that must be tuned to ensure convergence. Despite their simplicity, they differ strikingly in form from other multiplicative updates used in machine learning. We provide complete proofs of convergence for these updates and describe their application to problems in signal processing and pattern recognition.
Critical Analysis of Dimension Reduction by a Moment Closure Method in a Population Density Approach to Neural Network Modeling
Authors: Ly Cheng , Tranchina Daniel
Published: June 2007

Computational techniques within the population density function (PDF) framework have provided time-saving alternatives to classical Monte Carlo simulations of neural network activity. Efficiency of the PDF method is lost as the underlying neuron model is made more realistic and the number of state variables increases. In a detailed theoretical and computational study, we elucidate strengths and weaknesses of dimension reduction by a particular moment closure method (Cai, Tao, Shelley, & McLaughlin, 2004; Cai, Tao, Rangan, & McLaughlin, 2006) as applied to integrate-and-fire neurons that receive excitatory synaptic input only. When the unitary postsynaptic conductance event has a single-exponential time course, the evolution equation for the PDF is a partial differential integral equation in two state variables, voltage and excitatory conductance. In the moment closure method, one approximates the conditional kth centered moment of excitatory conductance given voltage by the corresponding unconditioned moment. The result is a system of k coupled partial differential equations with one state variable, voltage, and k coupled ordinary differential equations. Moment closure at k = 2 works well, and at k = 3 works even better, in the regime of high dynamically varying synaptic input rates. Both closures break down at lower synaptic input rates. Phase-plane analysis of the k = 2 problem with typical parameters proves, and reveals why, no steady-state solutions exist below a synaptic input rate that gives a firing rate of 59 s−1 in the full 2D problem. Closure at k = 3 fails for similar reasons. Low firing-rate solutions can be obtained only with parameters for the amplitude or kinetics (or both) of the unitary postsynaptic conductance event that are on the edge of the physiological range. We conclude that this dimension-reduction method gives ill-posed problems for a wide range of physiological parameters, and we suggest future directions.
Multistability in Spiking Neuron Models of Delayed Recurrent Inhibitory Loops
Authors: Ma Jianfu , Wu Jianhong
Published: June 2007

We consider the effect of the effective timing of a delayed feedback on the excitatory neuron in a recurrent inhibitory loop, when biological realities of firing and absolute refractory period are incorporated into a phenomenological spiking linear or quadratic integrate-and-fire neuron model. We show that such models are capable of generating a large number of asymptotically stable periodic solutions with predictable patterns of oscillations. We observe that the number of fixed points of the so-called phase resetting map coincides with the number of distinct periods of all stable periodic solutions rather than the number of stable patterns. We demonstrate how configurational information corresponding to these distinct periods can be explored to calculate and predict the number of stable patterns.
Analysis and Design of Associative Memories Based on Recurrent Neural Networks with Linear Saturation Activation Functions and Time-Varying Delays
Authors: Zeng Zhigang , Wang Jun
Published: June 2007

In this letter, some sufficient conditions are obtained to guarantee recurrent neural networks with linear saturation activation functions, and time-varying delays have multiequilibria located in the saturation region and the boundaries of the saturation region. These results on pattern characterization are used to analyze and design autoassociative memories, which are directly based on the parameters of the neural networks. Moreover, a formula for the numbers of spurious equilibria is also derived. Four design procedures for recurrent neural networks with linear saturation activation functions and time-varying delays are developed based on stability results. Two of these procedures allow the neural network to be capable of learning and forgetting. Finally, simulation results demonstrate the validity and characteristics of the proposed approach.
Robust Loss Functions for Boosting
Authors: Kanamori Takafumi , Takenouchi Takashi , Eguchi Shinto , Murata Noboru
Published: June 2007

Boosting is known as a gradient descent algorithm over loss functions. It is often pointed out that the typical boosting algorithm, Adaboost, is highly affected by outliers. In this letter, loss functions for robust boosting are studied. Based on the concept of robust statistics, we propose a transformation of loss functions that makes boosting algorithms robust against extreme outliers. Next, the truncation of loss functions is applied to contamination models that describe the occurrence of mislabels near decision boundaries. Numerical experiments illustrate that the proposed loss functions derived from the contamination models are useful for handling highly noisy data in comparison with other loss functions.
Individual and Cultural Differences On Status Differentiation
Authors: Matsumoto David
Published: June 2007

The concept of status differentiation is introduced along with a description of the development and initial validation of an individual-difference measure called the Status Differentiation Scale (SDS). This is followed by reports of cross-cultural differences on the SDS in three countries. Study 1 used American participants and established the scoring procedure for the SDS, its internal reliability and structural relationships, and construct validity. Study 2 used American and Japanese participants and demonstrated its internal reliability, structural relationships, and construct validity with a measure of allocentrism in both countries and predictable country differences that could not be accounted for by collectivism. Study 3 used American and South Korean participants and documented its internal reliability, structural relationships, and construct validity with a measure of values in both countries and predictable country differences that could not be accounted for by values. The concept of status differentiation, and the availability of the SDS, can have important theoretical and empirical ramifications for future studies of culture.
Interpersonal Relationship and Lay Third Parties' Side-Taking Preference
Authors: Yang Huadong , Van de Vliert Evert , Shi Kan
Published: June 2007

In two comparative studies, both conducted in China and in the Netherlands, we investigated the effect of an asymmetric relationship on lay third parties' side-taking preference in an interpersonal dispute. The first study shows that a perceived close relationship with one of the disputants motivates both Chinese and Dutch lay third parties to side with that disputant. The second study complicates the interpersonal relationship and side-taking link by taking account of contrasting information (either legitimacy or negative sanctions) about the other disputant and cultural dimensions (horizontal and vertical individualism-collectivism). The results suggest that contrasting legitimacy information has a decisive effect on lay third parties' side-taking preference, especially among Dutch lay third parties who highly value vertical individualism. In addition to legitimacy criteria, Chinese lay third parties, whether individualistic or collectivistic oriented, seem to also consider interpersonal relationship and sanction information when making their side-taking decision.
Frequent Behavioral Delay Tendencies By Adults
Authors: Ferrari Joseph R. , Díaz-Morales Juan Francisco , O'Callaghan Jean , Díaz Karem , Argumedo Doris
Published: June 2007

Adult men ( n = 582) and women ( n = 765) from six nations (Spain, Peru, Venezuela, the United Kingdom, Australia, and the United States) completed two reliable and valid measures of chronic procrastination. Because both arousal and avoidant procrastination types were significantly related across the entire sample ( r = .72, p < .001) and within each national sample, regression analyses calculated “pure” arousal and “pure” avoidant procrastinators, controlling for the scale scores of the other scale. Results indicated no significant sex or nationality differences within and between nations on self-reported arousal or avoidant procrastination. Overall, 13.5% and 14.6% of men and women self-identified as either arousal or avoidant procrastinators, respectively. These findings suggest that the tendency toward frequent delays in starting or completing tasks may be prevalent across diverse populations in spite of their distinct cultural values, norms, and practices.
Juvenile Waiver, Boot Camp, and Recidivism in a Northwestern State
Authors: Steiner Benjamin , Giacomazzi Andrew L.
Published: June 2007

The waiver of juveniles to adult criminal court, an increasing phenomenon in recent years, transfers young offenders out of the juvenile system and into the adult criminal justice system, where the range of sanctions is presumably greater. Boot camps, one such sanction, are an intermediate response that are typically designed for youthful, first-time offenders, making waived youth likely candidates for placement there. The authors examine the effectiveness of a boot camp program in terms of recidivism for juveniles waived to criminal court in a northwestern state. They compare juveniles in the boot camp program to juveniles waived to criminal court and sentenced to probation using a 2-year follow-up period.
Predictive Factors for Violent Misconduct in Close Custody
Authors: Cunningham Mark D. , Sorensen Jon R.
Published: June 2007

A retrospective review was conducted of the 2003 disciplinary records of close-custody inmates ( N = 24,514) in the Florida Department of Corrections. The frequency of various forms of violent misconduct was inversely related to the severity of this prison violence. A logistic regression analysis controlling for other factors demonstrated that younger age, shorter sentence, prison gang affiliation, prior prison violence, and prior prison term were predictive of violent institutional misconduct. Conversely, older age, longer sentence, and violent offense of conviction were associated with lower rates of violent prison infractions. Actuarial models constructed from the logistic regression analysis were modestly successful in predicting institutional misconduct (area under the curve = .717 to .738, p < .001), whether predicting all infractions or violent misconduct of varying severity.
Accuracy in Judgments of Aggressiveness
Authors: Kenny David A. , West Tessa V. , Cillessen Antonius H. N. , Coie John D. , Dodge Kenneth A. , Hubbard Julie A. , Schwartz David
Published: June 2007

Perceivers are both accurate and biased in their understanding of others. Past research has distinguished between three types of accuracy: generalized accuracy, a perceiver's accuracy about how a target interacts with others in general; perceiver accuracy, a perceiver's view of others corresponding with how the perceiver is treated by others in general; and dyadic accuracy, a perceiver's accuracy about a target when interacting with that target. Researchers have proposed that there should be more dyadic than other forms of accuracy among well-acquainted individuals because of the pragmatic utility of forecasting the behavior of interaction partners. We examined behavioral aggression among well-acquainted peers. A total of 116 9-year-old boys rated how aggressive their classmates were toward other classmates. Subsequently, 11 groups of 6 boys each interacted in play groups, during which observations of aggression were made. Analyses indicated strong generalized accuracy yet little dyadic and perceiver accuracy.
Identifying synonymous concepts in preparation for technology mining
Authors: Courseault Trumbach Cherie , Payne Dinah
Published: June 2007

In this research, the development of a `concept-clumping algorithm' designed to improve the clustering of technical concepts is demonstrated . The algorithm developed first identifies a list of technically relevant noun phrases from a cleaned extracted list and then applies a rule-based algorithm for identifying synonymous terms based on shared words in each term. An assessment of the algorithm found that the algorithm has an 89—91% precision rate, was successful in moving technically important terms higher in the term frequency list, and improved the technical specificity of term clusters.
A New Technique for Reconstruction of the Ulnar Collateral Ligament of the Thumb
Authors: Baskies Michael A. , Tuckman David , Paksima Nader , Posner Martin A.
Published: June 2007

Background

Several previous studies have described reconstructive methods for the treatment of an injury to the ulnar collateral ligament of the thumb. However, there are few biomechanical studies to date to analyze the strength of the surgical reconstruction.

Purpose

To evaluate 2 reconstruction techniques with use of a cadaveric model (1) reconstruction with the use of a free tendon graft placed in a figure-of-8 fashion through drill holes in the metacarpal and proximal phalanx of the thumb, and (2) reconstruction with the use of the Bio-Tenodesis Screw System.

Study Design

Controlled laboratory study.

Methods

Eight matched pairs of cadaveric specimens underwent removal of the proper and accessory ulnar collateral ligaments. One of the 2 reconstruction methods was performed, and specimens were mounted on a materials-testing machine. The specimens were subjected to valgus stress to failure at 30° of flexion. Failure was defined as valgus laxity of 30° at the metacarpophalangeal joint.

Results

The peak load to failure was 23.5 ± 11.4 N for the figure-of-8 reconstruction and 24.3 ± 12.3 N for the reconstruction using the Bio-Tenodesis Screw System. Comparing the 2 groups, there was no statistically significant difference in peak loads to failure (P = .88).

Conclusion

There was no statistically significant difference between the peak loads to failure of the 2 reconstructions.

Clinical Relevance

The Bio-Tenodesis Screw System may provide another viable option for surgical reconstruction of the ulnar collateral ligament of the thumb.
Numerical Stress Analysis of the Bond between a Reinforced Concrete T-Beam and FRP Sheets
Authors: Huang D. , Lyons J.
Published: June 2007

Three-dimensional non-linear elastic finite element analysis models of a concrete beam strengthened with fiber-reinforced plastic composites have been developed. The results contribute to a fundamental understanding of the stresses and strains that occur at the interface between the composite overlay and the concrete substrate. How the presence of interface cracks affects the stress state along the bond between the FRP overlay and concrete substrate is investigated. Increased composite stiffness increases the interface shear stress and the energy release rate G at the interface crack tip. The load mode that occurs in the beam is mostly Mode II or mixed Mode I/Mode II loading.
The Significance of Underfill on the IC Packages Subjected to Temperature Cyclic Loading
Authors: Tsai Hsin-Chun , Jong Wen-Ren
Published: June 2007

The melting point of Sn—Ag/Sn—Ag—Cu solders are higher than that of Sn—Pb solders by 30°C in particular. These in turn lead to significant divergences in plastic and creep behaviors. This research uses the validated finite-element analyses to study the elastic-plastic-creep behaviors of the 96.5Sn—3.5Ag, 95.5Sn—3.8Ag—0.7Cu lead-free solders, and the classical 63Sn—37Pb solder bumped wafer level chip scale package (WLCSP) on printed circuit board (PCB) assemblies subjected to four different temperature cycle tests. The behaviors of equivalent stress and equivalent total strain hysteresis loops are examined in the five key areas, which are the center, upper-right, upper-left, lower-right, and lower-left, at the outmost corner solder joint. It can be seen that: (1) for the elastic-plastic-creep behaviors to these three solder alloys, the range of the temperature loading is the most important factor to assess the reliability of the solder bumped WLCSP on PCB assemblies; (2) in the case of the same scale to the WLCSP and the WLCSP with underfill, the difference of the equivalent total strain range exceed an order of magnitude for all the three solder joints.
An Experimental Study of Water-Assisted Injection Molding of Plastic Tubes with Dimensional Transitions
Authors: Liu Shih-Jung , Lin Chia-Hung
Published: June 2007

This report was made to experimentally study water assisted injection molding of plastic tubes with dimensional transitions. Experiments were carried out on an 80-ton injection-molding machine equipped with a lab scale water injection system, which included a water pump, a pressure accumulator, a water injection pin, a water tank equipped with a temperature regulator, and a control circuit. The materials used for the experiments included an amorphous polystyrene and a semi-crystalline polypropylene. Two types of water injection pins, the orifice and the porous type, combined with two ``float-shape'' axisymmetric cavities were used to mold the plastic parts. After molding, the hollowed core ratios of molded parts were measured. Various processing variables were studied in terms of their influence on the residual wall thickness and hollowed core ratio of water assisted injection molded parts: melt temperature, mold temperature, water temperature, water pressure, water injection delay time and water hold time, and melt short shot size. The core-out geometries in water-assisted injection molded parts were also compared to those in gas-assisted injection molded products. It was found that the porous type water pin molded plastic tubes had a more uniform thickness distribution than the orifice type water pin and the ring type gas pin. Additionally, the experimental result suggests that the water injection delay time and short shot size were the principal parameters affecting the core out behavior of molded d-2d-d tubes, while the core-out geometries of the d-4d-d tubes were mainly influenced by the melt and mold temperatures, water pressure and water injection delay time, and melt short shot size.
Predictors and Consequences of Grade Retention
Authors: Guèvremont Anne , Roos Noralou P. , Brownell Marni
Published: June 2007

Data from a population-based repository in Manitoba showed that students who are male, young for grade, and in Grades 1, 2, 7, and 8 were the most likely to be retained. After controlling for key student factors including socioeconomic status, school changes, and key school characteristics including stability of the student body, retention was a strong predictor of high school withdrawal rates. The odds of student withdrawal were 3 times higher for students who have been retained once and almost 8 times higher for students who had been retained more than once. Not only do withdrawal rates suggest that retention is potentially harmful, but also Grade 3 standards test results taken in consecutive years by retained students indicate that only one in four retained students improve their score. These results generally replicate the research done in the United States.