bluuebunny/crossref_metadata_2025 huggingface dataset:
Phage Display–Derived Human Monoclonal Antibodies Isolated by Binding to the Surface of Live Primary Breast Cancer Cells Recognize GRP78
Authors: Jakobsen Charlotte G. , Rasmussen Nicolaj , Laenkholm Anne-Vibeke , Ditzel Henrik J.
Published: October 2007

Clinical trials using monoclonal antibodies (mAb) against cell-surface markers have yielded encouraging therapeutic results in several cancer types. Generally, however, anticancer antibodies are only efficient against a subpopulation of cancers, and there is a strong need for identification of novel targets and human antibodies against them. We have isolated single-chain human mAbs from a large naïve antibody phage display library by panning on a single-cell suspension of freshly isolated live cancer cells from a human breast cancer specimen, and these antibodies were shown to specifically recognize cancer-associated cell-surface proteins. One of the isolated human antibody fragments, Ab39, recognizes a cell-surface antigen expressed on a subpopulation of cancer cell lines of different origins. Immunohistochemical analysis of a large panel of cancerous and normal tissues showed that Ab39 bound strongly to several cancers, including 45% breast carcinomas, 35% lung cancers, and 86% melanomas, but showed no or weak binding to normal tissues. A yeast two-hybrid screen of a large human testis cDNA library identified the glucose-regulated protein of 78 kDa (GRP78) as the antigen recognized by Ab39. The interaction was confirmed by colocalization studies and antibody competition experiments that also mapped the epitope recognized by Ab39 to the COOH terminus of GRP78. The expression of GRP78 on the surface of cancer cells, but not normal cells, makes it an attractive target for cancer therapies including mAb-based immunotherapy. Our results suggest that the human antibody Ab39 may be a useful starting point for further genetic optimization that could render it a useful diagnostic and therapeutic reagent for a variety of cancers. [Cancer Res 2007;67(20):9507–17]
Human Bone Marrow–Derived Mesenchymal Stem Cells Do Not Undergo Transformation after Long-termIn vitroCulture and Do Not Exhibit Telomere Maintenance Mechanisms
Authors: Bernardo Maria Ester , Zaffaroni Nadia , Novara Francesca , Cometa Angela Maria , Avanzini Maria Antonietta , Moretta Antonia , Montagna Daniela , Maccario Rita , Villa Raffaella , Daidone Maria Grazia , Zuffardi Orsetta , Locatelli Franco
Published: October 2007

Significant improvement in the understanding of mesenchymal stem cell (MSC) biology has opened the way to their clinical use. However, concerns regarding the possibility that MSCs undergo malignant transformation have been raised. We investigated the susceptibility to transformation of human bone marrow (BM)–derived MSCs at different in vitro culture time points. MSCs were isolated from BM of 10 healthy donors and propagated in vitro until reaching either senescence or passage (P) 25. MSCs in the senescence phase were closely monitored for 8 to 12 weeks before interrupting the cultures. The genetic characterization of MSCs was investigated through array-comparative genomic hybridization (array-CGH), conventional karyotyping, and subtelomeric fluorescent in situ hybridization analysis both before and after prolonged culture. MSCs were tested for the expression of telomerase activity, human telomerase reverse transcriptase (hTERT) transcripts, and alternative lengthening of telomere (ALT) mechanism at different passages. A huge variability in terms of proliferative capacity and MSCs life span was noted between donors. In eight of 10 donors, MSCs displayed a progressive decrease in proliferative capacity until reaching senescence. In the remaining two MSC samples, the cultures were interrupted at P25 to pursue data analysis. Array-CGH and cytogenetic analyses showed that MSCs expanded in vitro did not show chromosomal abnormalities. Telomerase activity and hTERT transcripts were not expressed in any of the examined cultures and telomeres shortened during the culture period. ALT was not evidenced in the MSCs tested. BM-derived MSCs can be safely expanded in vitro and are not susceptible to malignant transformation, thus rendering these cells suitable for cell therapy approaches. [Cancer Res 2007;67(19):9142–9]
Targeted Repression of Bone Morphogenetic Protein 7, a Novel Target of the p53 Family, Triggers Proliferative Defect in p53-Deficient Breast Cancer Cells
Authors: Yan Wensheng , Chen Xinbin
Published: October 2007

p53 tumor suppressor and its family members, p63 and p73, are known to play a role in the survival of cells exposed to stress signals. As a transcription factor, the p53 family proteins induce a plethora of target genes that mediate their functions in the cell cycle, apoptosis, and other biological activities. However, the mechanism by which the p53 family proteins regulate their cell survival functions is still not clear. Here, we showed that bone morphogenetic protein 7 (BMP7) is a novel target gene regulated by the p53 family and mediates the cell survival function of the basal physiologically relevant level of p53. Specifically, we found that knockdown of BMP7 markedly inhibits the proliferation of p53-deficient, but not p21-knockdown, breast cancer cells compared with the ones with wild-type p53. In addition, we found that inhibitor of differentiation or DNA binding 2 (Id2), a transcription factor implicated for cell survival, is regulated by the BMP7 and p53 pathways. Interestingly, whereas a functional BMP7 or p53 pathway is sufficient to maintain the basal level of Id2 expression, loss of both pathways abrogates Id2 expression. Furthermore, we showed that overexpression of Id2 can restore p53-deficient cells to survive in the absence of BMP7. As a result, we identified a previously unrecognized role for BMP7 in the maintenance of cell survival for p53-deficient cells, at least in part, through Id2. Together, we hypothesize that breast cancer patients with mutant p53 might benefit from targeted repression of BMP7 expression and/or targeted inhibition of the BMP7 pathway. [Cancer Res 2007;67(19):9117–24]
Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells
Authors: Khodarev Nikolai N. , Minn Andy J. , Efimova Elena V. , Darga Thomas E. , Labay Edwardine , Beckett Michael , Mauceri Helena J. , Roizman Bernard , Weichselbaum Ralph R.
Published: October 2007

Elsewhere, we reported that multiple serial in vivo passage of a squamous cell carcinoma cells (SCC61) concurrent with ionizing radiation (IR) treatment resulted in the selection of radioresistant tumor (nu61) that overexpresses the signal transducer and activator of transcription 1 (Stat1)/IFN-dependent pathway. Here, we report that (a) the Stat1 pathway is induced by IR, (b) constitutive overexpression of Stat1 is linked with failure to transmit a cytotoxic signal by radiation or IFNs, (c) selection of parental cell line SCC61 against IFN-α and IFN-γ leads to the same IR- and IFN-resistant phenotype as was obtained by IR selection, and (d) suppression of Stat1 by short hairpin RNA renders the IR-resistant nu61 cells radiosensitive to IR. We propose a model that transient induction of Stat1 by IFN, IR, or other stress signals activates cytotoxic genes and cytotoxic response. Constitutive overexpression of Stat1 on the other hand leads to the suppression of the cytotoxic response and induces prosurvival genes that, at high levels of Stat1, render the cells resistant to IR or other inducers of cell death. [Cancer Res 2007;67(19):9214–20]
Depletion of Peripheral Macrophages and Brain Microglia Increases Brain Tumor Titers of Oncolytic Viruses
Authors: Fulci Giulia , Dmitrieva Nina , Gianni Davide , Fontana Elisabeth J. , Pan Xiaogang , Lu Yanhui , Kaufman Claire S. , Kaur Balveen , Lawler Sean E. , Lee Robert J. , Marsh Clay B. , Brat Daniel J. , van Rooijen Nico , Rachamimov Anat Stemmer , Hochberg Fred H. , Weissleder Ralph , Martuza Robert L. , Chiocca E. Antonio
Published: October 2007

Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163+ macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68+ cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68+ cells from brain slices, and intratumoral viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163+ and brain-resident CD68+ cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68+ and CD163+ cells following treatment with OV in a patient with glioblastoma. [Cancer Res 2007;67(19):9398–406]
Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma
Authors: Chesler Louis , Goldenberg David D. , Seales Isha T. , Satchi-Fainaro Ronit , Grimmer Matt , Collins Rodney , Struett Chris , Nguyen Kim N. , Kim Grace , Tihan Tarik , Bao Yun , Brekken Rolf A. , Bergers Gabriele , Folkman Judah , Weiss William A.
Published: October 2007

Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, α-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer–TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor–microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435–42]
FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer
Authors: Akhoondi Shahab , Sun Dahui , von der Lehr Natalie , Apostolidou Sophia , Klotz Kathleen , Maljukova Alena , Cepeda Diana , Fiegl Heidi , Dofou Dimitra , Marth Christian , Mueller-Holzner Elisabeth , Corcoran Martin , Dagnell Markus , Nejad Sepideh Zabihi , Nayer Babak Noori , Zali Mohammad Reza , Hansson Johan , Egyhazi Susanne , Petersson Fredrik , Sangfelt Per , Nordgren Hans , Grander Dan , Reed Steven I. , Widschwendter Martin , Sangfelt Olle , Spruck Charles
Published: October 2007

The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skp1-Cdc53/Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin E1, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼6%. The highest mutation frequencies were found in tumors of the bile duct (cholangiocarcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational “hotspots,” which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer. [Cancer Res 2007;67(19):9006–12]
A CDKN2A Mutation in Familial Melanoma that Abrogates Binding of p16INK4a to CDK4 but not CDK6
Authors: Jones Rebecca , Ruas Margarida , Gregory Fiona , Moulin Stephanie , Delia Domenico , Manoukian Siranoush , Rowe Janice , Brookes Sharon , Peters Gordon
Published: October 2007

The CDKN2A locus encodes two distinct proteins, p16INK4a and p14ARF, both of which are implicated in replicative senescence and tumor suppression in different contexts. Here, we describe the characterization of a novel strain of human diploid fibroblasts (designated Milan HDFs) from an individual who is homozygous for the R24P mutation in p16INK4a. As this mutation occurs in the first exon of INK4a (exon 1α), it has no effect on the primary sequence of p14ARF. Based on both in vitro and in vivo analyses, the R24P variant is specifically defective for binding to CDK4 but remains able to associate with CDK6. Nevertheless, Milan HDFs behave as if they are p16INK4a deficient, in terms of sensitivity to spontaneous and oncogene-induced senescence, and the R24P variant has little effect on proliferation when ectopically expressed in normal fibroblasts. It can, however, impair the proliferation of U20S cells, presumably because they express more CDK6 than primary fibroblasts. These observations suggest that CDK4 and CDK6 are not functionally redundant and underscore the importance of CDK4 in the development of melanoma. [Cancer Res 2007;67(19):9134–41]
In vivo Significance of the G2 Restriction Point
Authors: Foijer Floris , Delzenne-Goette Elly , Dekker Marleen , te Riele Hein
Published: October 2007

Loss of activity of the retinoblastoma pathway is a common event in human cancer. Mouse models have revealed that tumorigenesis by loss of Rb was accelerated by concomitant loss of the cell cycle inhibitor p27KIP1. This has been attributed to reduced apoptosis and weakening of the G1 checkpoint. However, the role of p27KIP1 in a recently identified G2 restriction point may offer an alternative explanation for this synergy. Here, we have investigated the significance of the G2 restriction point in Rb-deficient pituitaries. We show that Rb loss in the pituitary gland activated the G2 restriction point, as evidenced by the appearance of cyclin B1–p27KIP1 complexes. Somewhat unexpectedly, these complexes remained present in Rb-deficient tumors. These results indicate that the G2 restriction point does operate in vivo. However, in the pituitary gland, this mechanism seems to retard rather than to prevent tumor growth. [Cancer Res 2007;67(19):9244–7]
Loss of the Mitochondrial Bioenergetic Capacity Underlies the Glucose Avidity of Carcinomas
Authors: López-Ríos Fernando , Sánchez-Aragó María , García-García Elena , Ortega Álvaro D. , Berrendero José R. , Pozo-Rodríguez Francisco , López-Encuentra Ángel , Ballestín Claudio , Cuezva José M.
Published: October 2007

The down-regulation of the catalytic subunit of the mitochondrial H+-ATP synthase (β-F1-ATPase) is a hallmark of most human carcinomas. This characteristic of the cancer cell provides a proteomic signature of cellular bioenergetics that can predict the prognosis of colon, lung, and breast cancer patients. Here we show that the in vivo tumor glucose uptake of lung carcinomas, as assessed by positron emission tomography in 110 patients using 2-deoxy-2-[18F]fluoro-d-glucose as probe, inversely correlates with the bioenergetic signature determined by immunohistochemical analysis in tumor surgical specimens. Further, we show that inhibition of the activity of oxidative phosphorylation by incubation of cancer cells with oligomycin triggers a rapid increase in their rates of aerobic glycolysis. Moreover, we show that the cellular expression level of the β-F1-ATPase protein of mitochondrial oxidative phosphorylation inversely correlates (P < 0.001) with the rates of aerobic glycolysis in cancer cells. The results highlight the relevance of the alteration of the bioenergetic function of mitochondria for glucose capture and consumption by aerobic glycolysis in carcinomas. [Cancer Res 2007;67(19):9013–7]
Glutathione Transferase π Plays a Critical Role in the Development of Lung Carcinogenesis following Exposure to Tobacco-Related Carcinogens and Urethane
Authors: Ritchie Kenneth J. , Henderson Colin J. , Wang Xiu Jun , Vassieva Olga , Carrie Dianne , Farmer Peter B. , Gaskell Margaret , Park Kevin , Wolf C. Roland
Published: October 2007

Human cancer is controlled by a complex interaction between genetic and environmental factors. Such environmental factors are well defined for smoking-induced lung cancer; however, the roles of specific genes have still to be elucidated. Glutathione transferase π (GSTP) catalyzes the detoxification of electrophilic diol epoxides produced by the metabolism of polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP), a common constituent of tobacco smoke. Activity-altering polymorphisms in Gstp have therefore been speculated to be potential risk modifiers in lung cancer development. To clearly establish a role for GSTP in lung tumorigenesis, we investigated whether deletion of the murine Gstp genes (Gstp1 and Gstp2) alters susceptibility to chemically induced lung tumors following exposure to BaP, 3-methylcholanthrene (3-MC), and urethane. Gstp-null mice were found to have substantially increased numbers of adenomas relative to wild-type mice following exposure to all three compounds (8.3-, 4.3-, and 8.7-fold increase for BaP, 3-MC, and urethane, respectively). In Gstp-null mice, the capacity of pulmonary cytosol to catalyze conjugation of the BaP diol epoxide was significantly reduced. Concomitant with this, a significant increase in the level of BaP DNA adducts was measured in the lungs of null animals; however, no increase in DNA adducts was measured in the case of 3-MC exposure, suggesting that an alternative protective pathway exists. Indeed, significant differences in pulmonary gene expression profiles were also noted between wild-type and null mice. This is the first report to establish a clear correlation between Gstp status and lung cancer in vivo. [Cancer Res 2007;67(19):9248–57]
Pediatric KIT–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors
Authors: Janeway Katherine A. , Liegl Bernadette , Harlow Amy , Le Claudia , Perez-Atayde Antonio , Kozakewich Harry , Corless Christopher L. , Heinrich Michael C. , Fletcher Jonathan A.
Published: October 2007

Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor α (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT–wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT–wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT–wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT–wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT–wild-type GIST. [Cancer Res 2007;67(19):9084–8]
The Ajuba LIM Domain Protein Is a Corepressor for SNAG Domain–Mediated Repression and Participates in Nucleocytoplasmic Shuttling
Authors: Ayyanathan Kasirajan , Peng Hongzhuang , Hou Zhaoyuan , Fredericks William J. , Goyal Rakesh K. , Langer Ellen M. , Longmore Gregory D. , Rauscher Frank J.
Published: October 2007

The SNAG repression domain is comprised of a highly conserved 21–amino acid sequence, is named for its presence in the Snail/growth factor independence-1 class of zinc finger transcription factors, and is present in a variety of proto-oncogenic transcription factors and developmental regulators. The prototype SNAG domain containing oncogene, growth factor independence-1, is responsible for the development of T cell thymomas. The SNAIL proteins also encode the SNAG domain and play key roles in epithelial mesenchymal differentiation events during development and metastasis. Significantly, these oncogenic functions require a functional SNAG domain. The molecular mechanisms of SNAG domain–mediated transcriptional repression are largely unknown. Using a yeast two-hybrid strategy, we identified Ajuba, a multiple LIM domain protein that can function as a corepressor for the SNAG domain. Ajuba interacts with the SNAG domain in vitro and in vivo, colocalizes with it, and enhances SNAG-mediated transcriptional repression. Ajuba shuttles between the cytoplasm and the nucleus and may form a novel intracellular signaling system. Using an integrated reporter gene combined with chromatin immunoprecipitation, we observed rapid, SNAG-dependent assembly of a multiprotein complex that included Ajuba, SNAG, and histone modifications consistent with the repressed state. Thus, SNAG domain proteins may bind Ajuba, trapping it in the nucleus where it functions as an adapter or molecular scaffold for the assembly of macromolecular repression complexes at target promoters. [Cancer Res 2007;67(19):9097–106]
Targeting the Cytoplasmic and Nuclear Functions of Signal Transducers and Activators of Transcription 3 for Cancer Therapy
Authors: Germain Doris , Frank David A.
Published: October 2007

Signal transducers and activators of transcription (STAT) are a highly conserved family of transcription factors that are activated by phosphorylation in the cytoplasm, after which they translocate to the nucleus to regulate gene expression. Among the seven STATs, STAT3 is of particular interest due to its constitutive phosphorylation in a large proportion of human cancers and its ability to induce neoplastic transformation. Inhibition of STAT3 can reverse tumor growth in experimental systems while having few effects in normal cells. These findings have implicated STAT3 as a potentially important target for therapeutic intervention. In addition to its well-described role as a transcription factor, STAT3 has been found recently to have important effects in the cytoplasm. Collectively, these functions of STAT3 directly contribute to tumorigenesis, invasion, and metastasis. Given the potential importance of STAT3 as a target for cancer therapy, molecules have been developed that can block STAT3 function at a variety of steps. These drugs show promise as anticancer agents in model systems of a variety of common human cancers. Thus, elucidating the functions of STAT3 and developing agents to inhibit this protein remain important scientific and clinical challenges.
Hypoxia Inducible Factor-1–Independent Pathways in Tumor Angiogenesis
Authors: Mizukami Yusuke , Kohgo Yutaka , Chung Daniel C.
Published: October 2007

Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.
The Proangiogenic Phenotype of Tumor-Derived Endothelial Cells is Reverted by the Overexpression of Platelet-Activating Factor Acetylhydrolase
Authors: Doublier Sophie , Ceretto Monica , Lupia Enrico , Bravo Stefania , Bussolati Benedetta , Camussi Giovanni
Published: October 2007

Purpose: We previously reported that human tumor-derived endothelial cells (TEC) have an angiogenic phenotype related to the autocrine production of several angiogenic factors. The purpose of the present study was to evaluate whether an enhanced synthesis of platelet-activating factor (PAF) might contribute to the proangiogenic characteristics of TEC and whether its inactivation might inhibit angiogenesis.

Experimental Design: To address the potential role of PAF in the proangiogenic characteristics of TEC, we engineered TEC to stably overexpress human plasma PAF-acetylhydrolase (PAF-AH), the major PAF-inactivating enzyme, and we evaluated in vitro and in vivo angiogenesis.

Results: TECs were able to synthesize a significantly enhanced amount of PAF compared with normal human microvascular endothelial cells when stimulated with thrombin, vascular endothelial growth factor, or soluble CD154. Transfection of TEC with PAF-AH (TEC-PAF-AH) significantly inhibited apoptosis resistance and spontaneous motility of TEC. In addition, PAF and vascular endothelial growth factor stimulation enhanced the motility and adhesion of TEC but not of TEC-PAF-AH. In vitro, TEC-PAF-AH lost the characteristic ability of TEC to form vessel-like structures when plated on Matrigel. Finally, when cells were injected s.c. within Matrigel in severe combined immunodeficiency mice or coimplanted with a renal carcinoma cell line, the overexpression of PAF-AH induced a significant reduction of functional vessel formation.

Conclusions: These results suggest that inactivation of PAF, produced by TEC, by the overexpression of plasma PAF-AH affects survival, migration, and the angiogenic response of TEC both in vitro and in vivo.
Characterization of a Putative Ovarian Oncogene, Elongation Factor 1α, Isolated by Panning a Synthetic Phage Display Single-Chain Variable Fragment Library with Cultured Human Ovarian Cancer Cells
Authors: Sharma Sameer , Tammela Jonathan , Wang Xinhui , Arnouk Hilal , Driscoll Deborah , Mhawech-Fauceglia Paulette , Lele Shashikant , Kazim A. Latif , Odunsi Kunle
Published: October 2007

Purpose: In an effort to identify cell surface targets and single short-chain antibody (scFv) for ovarian cancer therapy, we used a phage display approach to isolate an antibody with high reactivity against ovarian cancer.

Experimental Design: A phage scFv library was subjected to panning against human SK-OV-3 ovarian cancer cells. A clone with high reactivity was selected and tested in immunoperoxidase staining on a panel of normal tissues and ovarian carcinoma. Using immunoprecipitation, a differentially expressed band was analyzed by mass spectrometry. The antigen subclass was characterized with reverse transcription-PCR on cDNA library of normal tissues, and 91 ovarian cancer specimens, and correlated with clinicohistopathologic characteristics.

Results: Ninety-six individual scFv clones were screened in ELISA following panning. scFv F7 revealed high reactivity with ovarian cancer cell lines and showed intense staining of 15 fresh ovarian cancer specimens and no staining of a panel of normal tissues. A 40-kDa protein was identified to be translation elongation factor 1α1 (EEF1A1; P < 0.05). The expression of EEF1A2, a highly homologous and functionally similar oncogene, was found to be restricted only to the normal tissues of the heart, brain, and skeletal muscle. Aberrant EEF1A2 mRNA expression was found in 21 of 91 (23%) of ovarian cancer specimens and significantly correlated with increased likelihood of recurrence (P = 0.021).

Conclusions: scFv F7 may represent an ovarian cancer–specific antibody against translation EEF1A family of translational factors. We propose that EEF1A2 may be a useful target for therapy of human ovarian cancer.
Phosphorylation of Estrogen Receptor-α at Ser167 Is Indicative of Longer Disease-Free and Overall Survival in Breast Cancer Patients
Authors: Jiang Jie , Sarwar Naveed , Peston David , Kulinskaya Elena , Shousha Sami , Coombes R. Charles , Ali Simak
Published: October 2007

Purpose: Ser167 was first identified as a major phosphorylation site of the estrogen receptor -α (ER) positive in the MCF7 breast cancer cell line. Subsequent studies have shown that Ser167 phosphorylation is important in the regulation of ER activity and have identified p90RSK and AKT as protein kinases that phosphorylate Ser167. The purpose of this study was to determine the importance of Ser167 phosphorylation in breast cancer progression.

Experimental Design: Immunohistochemical staining of primary breast cancer biopsies (n = 290) was carried out using antibodies specific for ER phosphorylated at Ser167 and for phosphorylated p44/p42 mitogen-activated protein kinase (MAPK), phosphorylated p90RSK, and phosphorylated AKT.

Results: In ER-positive breast cancer patients, Ser167 phosphorylation was associated with low tumor grade (P = 0.011), lymph node negativity (P = 0.034), and relapse-free (P = 0.006) and overall (P = 0.023) survival. Further, Ser167 phosphorylation was strongly associated with phosphorylated p90RSK (P < 0.001), previously shown to phosphorylate Ser167 in vitro, as well as being associated with phosphorylated MAPK (P < 0.0005). The activities of both kinases also seemed to be indicative of better prognosis. There was, however, no association between HER2 positivity and Ser167 phosphorylation nor were the activities of MAPK or p90RSK associated with HER2 status, suggesting that other cell surface receptors may be important in regulating these activities in breast cancer.

Conclusions: These findings show that phosphorylation at Ser167 of ER predicts for likelihood of response of ER-positive breast cancer patients to endocrine therapies.
Smad3 Is Overexpressed in Advanced Human Prostate Cancer and Necessary for Progressive Growth of Prostate Cancer Cells in Nude Mice
Authors: Lu Shan , Lee Juwon , Revelo Monica , Wang Xiaohong , Lu Shan , Dong Zhongyun
Published: October 2007

Purpose: The purpose of this study was to investigate the potential role of Smad3, a key mediator of transforming growth factor-β signaling, in progression of prostate cancer.

Experimental Design: Expression of Smad proteins was determined in human prostate cancer tissue array and cell lines. Growth and metastasis of cells overexpressing dominant-negative Smad3 (Smad3D) were studied to determine its role in tumor progression in mice. Cell growth, apoptosis, and expression of angiogenic molecules in tumor lesions were studied to determine potential pathways that Smad3 promotes tumor progression.

Results: Smad3 was overexpressed in human prostate cancer, which correlated with Gleason score and expression of proliferating cell nuclear antigen. Androgen-independent PC-3MM2 and DU145 cells expressed much higher levels of Smad3 than did androgen-dependent LNCaP, 22Rv1, and LAPC-4 cells. Overexpression of Smad3D in PC-3MM2 cells (PC-3MM2-Smad3D) had minimal direct effects on cell growth but attenuated effects of transforming growth factor-β1 on gene expression and cell growth. Overexpression of Smad3D did not significantly alter tumor incidence but reduced tumor growth rate and metastasis incidence. Most cells in the control tumors, but not PC-3MM2-Smad3D tumors, were positively stained by an antibody to proliferating cell nuclear antigen. Microvessels and expression of angiogenic molecule interleukin-8 were significantly reduced in tumors from PC-3MM2-Smad3D cells. PC-3MM2-Smad3D tumors also expressed lower levels of vascular endothelial growth factor and platelet-derived growth factor.

Conclusions: These data suggest that Smad3, through regulating angiogenic molecule expression in tumor cells, is critical for progression of human prostate cancer.
Comparative Study of the Legal Framework of Securities Disclosure Requirements in Kuwait and the U.S.
Authors: Al-Zumai Fahad
Published: October 2007

This paper examines the regulatory framework of disclosure in Kuwait in comparison with the situation in the United States of America. It covers the theoretical arguments for and against mandatory disclosure and then engages in a regulatory analysis of the rules governing disclosure in Kuwait and the U.S.

The main areas that are explored in this paper include,

inter alia

, the disclosure of interest; periodic and real time disclosures; and rumours and duties to disclose in both jurisdictions. Afterward, anti-fraud provisions and their role in enhancing the disclosure framework are discussed and the investigation concludes that the absence of an anti-fraud provision in securities regulation in Kuwait is undermining the efficiency of the regulatory framework of disclosure in the country. Finally, the paper concludes that regulatory reform is needed in Kuwait to fill in the gaps in the current structure and in particular the current available remedies. The scope of disclosure should also be expanded to capture all major sensitive information that needs to be disclosed to the public and the shareholders.
Islamic Insurance: National Features and Legal Regulation
Authors: Bekkin Renat
Published: October 2007

The present paper studies Islamic insurance (

takaful

) as opposed to conventional one. The first part of the paper covers, among other things, such issues as the nature and historic roots of Islamic insurance and early forms of Islamic insurance and it narrates the disputes among Muslim scholars concerning the compatibility of insurance with Islamic Shariah. The second part deals with the history and emergence of Islamic insurance in the modern financial market, as well as the practice of Islamic insurance in different countries. The third part discusses the feasibility of Islamic insurance in Russia in the current legal framework. The paper contains a comprehensive glossary of related terms.
Have Gun Will Shoot?
Authors: Phillips Scott , Maume Michael O.
Published: October 2007

The weapon instrumentality hypothesis suggests that guns contribute to the escalation and lethality of violence. But the relationship between guns and violence might be spurious if the aggressor's violent tendencies or the aggressor's situation-specific intent to harm is the common cause of the presence/use of a gun and the violent outcome. To examine such rival explanations, we draw on interviews with 100 men imprisoned for an aggravated assault or homicide that stemmed from an interpersonal conflict. Each respondent described a matched pair of conflicts: the violent conflict that led to incarceration and a similar nonviolent conflict from the same time period. The matched pair design allows us to control for both potential sources of spuriousness: violent tendencies and situation-specific intent to harm. The results suggest that guns contribute to the violent escalation of conflict, but the impact of guns attenuates substantially after accounting for situation-specific intent to harm.
The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women
Authors: Lasiuk G.C. , Hegadoren K.M.
Published: October 2007

Lifetime prevalence rates of depression are higher in women than men. Because this gender disparity appears after the onset of puberty and declines after menopause, gonadal hormones may play a role in women's increased vulnerability to dysphoric states. Estrogens have powerful effects beyond their role in reproduction. Fluctuations in estrogen occur naturally throughout the reproductive years and can be associated with disruptions in mood. Treatment for depression with exogenous estrogen has produced equivocal results. To shed light on the complex interactions among estrogens, serotonin, and mood, we briefly examine (a) central serotonin systems and their relationship to mood and mood disorders, (b) nonreproductive effects of estrogens on those systems, (c) potential points of intersection between serotonin systems and estrogens, and (d) research into the use of exogenous estrogen in depression in women. In conclusion, we reiterate the call for carefully controlled research into the etiology and treatment of depression in women.
Massage Therapy: Is Its Evidence-Base Getting Stronger
Authors: Ernst E. , Pittler M.H. , Wider B. , Boddy K.
Published: October 2007

The aim of this article is to evaluate trends in the development of the evidence-base for the effectiveness of massage therapy. For this purpose, a comparison of two systematic reviews was conducted. The first related to the evidence-base in 2000, the second to 2005. Both employed the same methodology and criteria for evaluation. The results indicate that, in several areas, the evidence has become more solid and, for anxiety and back pain, it has become more positive. For a host of other indications, the evidence seems encouraging, but more studies are required to test the effectiveness of massage therapy as well as its use for specific conditions.
Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia
Authors: Théberge Jean , Williamson Kate E. , Aoyama Naoko , Drost Dick J. , Manchanda Rahul , Malla Ashok K. , Northcott Sandra , Menon Ravi S. , Neufeld Richard W. J. , Rajakumar Nagalingam , Pavlosky William , Densmore Maria , Schaefer Betsy , Williamson Peter C.
Published: October 2007

Background

Progressive volumetric changes in the brains of people with schizophrenia have been attributed to a number of factors.

Aims

To determine whether glutamatergic changes in patients with schizophrenia correlated with grey-matter losses during the first years of illness.

Method

Left anterior cingulate and thalamic glutamatergic metabolite levels and grey-matter volumes were examined in 16 patients with first-episode schizophrenia before and after 10 months and 30 months of antipsychotic treatment and in 16 healthy participants on two occasions 30 months apart.

Results

Higher than normal glutamine levels were found in the anterior cingulate and thalamus of never-treated patients. Thalamic levels of glutamine were significantly reduced after 30 months. Limited grey-matter reductions were seen in patients at 10 months followed by widespread grey-matter loss at 30 months. Parietal and temporal lobe grey-matter loss was correlated with thalamic glutamine loss.

Conclusions

Elevated glutamine levels in never-treated patients followed by decreased thalamic glutamine and grey-matter loss in connected regions could indicate either neurodegeneration or a plastic response to reduced subcortical activity.
Chocolate craving when depressed: a personality marker
Authors: Parker Gordon , Crawford Joanna
Published: October 2007

We examined links between chocolate craving in people who are depressed and both personality style and atypical depressive symptoms, with a web-based questionnaire completed by nearly 3000 individuals reporting clinical depression. Chocolate was craved by half of the respondents (more so by women), judged as beneficial for depression, anxiety and irritability, and associated specifically with personality facets encompassed by the higher-order construct of neuroticism. The simple question of depression-associated chocolate craving appeared an efficient discriminator of DSM – IV atypical depression symptoms.
Sexual Violence at the Border
Authors: Fassin Éric
Published: October 2007

Translated by James Swenson

éric fassin is a professeur agrégé at the École Normale Supérieure (Paris), a sociologist at IRIS (CNRS/EHESS), the author of L'inversion de la question homosexuelle (Éditions Amsterdam, 2005) and (with Clarisse Fabre) of Liberté, égalité, sexualités (Éditions 10/18, 2004), and editor (with Didier Fassin) of De la question sociale à la question raciale? (La Découverte, 2006).

james swenson teaches at Rutgers University, where he is chair of the French department. He has also translated essays by Étienne Balibar and Jacques Rancière and is currently working on a series of essays concerning the relation between the Enlightenment and Romanticism.
Girls Will Be Boys: Gender, Envy, and the Freudian Social Contract
Authors: Stewart-Steinberg Suzanne
Published: October 2007

suzanne stewart-steinberg is Associate Professor of Italian Studies and Comparative Literature at Brown University. She is author of Sublime Surrender: Male Masochism at the Fin de Siècle (Cornell University Press, 1998) and The Pinocchio Effect: On Making Italians (1860-1920) (Chicago University Press, 2007).
Photo-Elastimetric Researches on Mechanical Engineering Problems
Authors: Coker E. G. , Dewrance John
Published: October 2007

In a former Graduates' Lecture delivered in 1913* the Lecturer described the general principles of Photo-Elasticity, and some applications to Engineering. The present Lecture was therefore devoted to a consideration of some developments of the subject which have taken place since, and attention was mainly directed to improvements in apparatus for photo-elastic investigation and to the results obtained by this method of research when applied to elucidate the action of cutting tools.

A prime necessity in all such work is a beam of polarized light of large cross-section and considerable purity, and the scarcity of Iceland spar for Nicol's prisms of sufficiently large size has led to the use of other forms of polarizers, of which a very convenient one was described, consisting of a thin slice of Iceland spar suitably mounted between glass wedges, and provided with converging and diverging lens systems, whereby a beam of large cross-section and of great purity is obtained.
Calculation of the Specific Surface of a Powder
Authors: Heywood Harold
Published: October 2007

The advantage of expressing the fineness of a powder by means of the specific surface is the facility with which this factor may be correlated with external factors in an investigation on the production or use of fine powders. A method of calculating the specific surface of a powder has been devised, which can be applied to practically all powders irrespective of the material from which they are produced.

The dimension of a single particle having the same shape and density as the particles constituting a powder, and having the same specific surface as the average for the powder, can be calculated from the grading analysis. The shape of an irregular particle can be defined numerically by two parameters. These shape factors are combined with the above dimensional factor and the density of the material to obtain an expression from which the specific surface of the powder can be calculated.
Diesel Traction
Authors: Lomonossoff G. V.
Published: October 2007

The author points out the difficulty in designing steam locomotives of high overall efficiency, no matter to what type they may belong, and shows that the efficiency of Diesel locomotives is considerably higher, while they also possess certain other advantages, particularly in bringing about a reduction in permanent way maintenance costs.

Early Diesel locomotives are described and an account is given of the collaboration between the German and Russian railways, to investigate various types of transmission, and of the transportable locomotive laboratory which was built for carrying out the necessary tests.

The economic aspect of railway operation is carefully analysed, and the results of extended trials in Russia of steam, Diesel-electric, and Diesel geared locomotives are given and compared with the latest available figures for operating costs in this country, and with figures for sparsely populated regions in Asia.

The author, while not advocating wholesale adoption of Diesel locomotives everywhere, arrives at the conclusion that they have a definite sphere of usefulness, particularly in regions where water is scarce or of bad quality. He also emphasizes the necessity for standardized types of Diesel locomotives, and suggests that owing to the inherent drawbacks in the transmissions both of the Diesel-electric and Diesel geared types, there may be a future for the Diesel locomotive with direct drive with an enlarged engine, provided that, by research and experimental work, the difficulties previously encountered with direct drive can be removed.

The author also notes that from the point of view of fuel consumption and simplicity the speed of the Diesel engine and the number of cylinders should not exceed certain limits.