bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ataxia Telangiectasia–Mutated Target Site Ser18 Is Required for p53-Mediated Tumor Suppression
Authors: Armata Heather L. , Garlick David S. , Sluss Hayla K. 
Published: December 2007

Abstract
The p53 tumor suppressor is phosphorylated at multiple sites within its NH2-terminal region. One of these phosphorylation sites (mouse Ser18 and human Ser15) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) protein kinases. Studies of p53S18A mice (with a germ-line mutation that replaces Ser18 with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser18 is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser18 was not required for p53-dependent tumor suppression. Here we report that the survival of p53S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser18 on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]
Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown
Authors: Lin Fan-Ru , Kuo Hui-Kai , Ying Hsia-Yuan , Yang Fu-Hung , Lin Kuo-I 
Published: December 2007

Abstract
B lymphocyte–induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1–dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells. [Cancer Res 2007;67(24):11914–23]
Induction of hsp70-Mediated Th17 Autoimmunity Can Be Exploited as Immunotherapy for Metastatic Prostate Cancer
Authors: Kottke Timothy , Sanchez-Perez Luis , Diaz Rosa Maria , Thompson Jill , Chong Heung , Harrington Kevin , Calderwood Stuart K. , Pulido Jose , Georgopoulos Nick , Selby Peter , Melcher Alan , Vile Richard 
Published: December 2007

AbstractA close connectivity between autoimmune and tumor rejection responses is known to exist in the case of melanoma immunotherapy. However, relatively little is known about self-antigens on other types of normal cells, their relation to the development of autoimmune disease, and their possible coexistence as potential tumor rejection antigens on associated tumors. In the current study, we induced inflammatory killing of normal prostate tissue in situ using a fusogenic membrane glycoprotein along with the immune adjuvant hsp70. We show here that, in the prostate, hsp70 induces interleukin (IL)-6, which triggers a CD4- and CD8-dependent progressive autoimmune reactivity, associated with IL-17 expression. This autoimmune response was also able to induce the rejection of established prostate tumors, but not other histologic types of tumors, growing elsewhere in the animal. These data show that the intimate connectivity between autoimmune and tumor rejection responses extends beyond the classic melanoma paradigm and may be clinically valuable for the treatment of established metastatic disease of the prostate. [Cancer Res 2007;67(24):11970–9]
Lack of Mutagenicity of Acrolein-Induced DNA Adducts in Mouse and Human Cells
Authors: Kim Sang-in , Pfeifer Gerd P. , Besaratinia Ahmad 
Published: December 2007

Abstract
Acrolein is an endogenous metabolite and a ubiquitous environmental pollutant. Recently, it has been suggested that acrolein is a major etiologic agent for tobacco smoking–related lung cancer. Despite the known DNA-damaging effects of acrolein, its mutagenicity to mammalian cells remains uncertain. We have investigated acrolein-induced DNA damage in relation to mutagenesis, with special focus on DNA repair, in mouse and human cells. We mapped the formation of acrolein-induced DNA adducts and the kinetics of repair of the induced lesions in the cII transgene, the mutational target, in acrolein-treated transgenic mouse fibroblasts. Acrolein-DNA adducts were formed preferentially at specific nucleotide positions, mainly at G:C base pairs, along the cII transgene. The induced acrolein-DNA adducts were moderately resistant to DNA repair. Quantification of cII mutant frequency in acrolein-treated cells, however, revealed that acrolein was not mutagenic to these cells at doses sufficient to produce DNA adducts. Determination of supF mutant frequency in DNA repair–proficient and DNA repair–deficient human fibroblasts transfected with acrolein-treated plasmids confirmed a lack of acrolein mutagenicity. Because CpG methylation may intensify acrolein-DNA adduction, we examined whether the extent of CpG methylation in the supF gene can determine acrolein-induced mutagenesis in human cells. Enhancement of acrolein-DNA adduction by methylating CpGs in the supF sequence did not elicit a mutagenic response in human fibroblasts, however. We conclude that acrolein is not mutagenic to mouse and human fibroblasts, regardless of DNA repair capacity or methylation status of CpGs, possibly because of a highly accurate replication bypass of the induced lesions. [Cancer Res 2007;67(24):11640–7]
Green Tea Polyphenols Reverse Cooperation between c-Rel and CK2 that Induces the Aryl Hydrocarbon Receptor, Slug, and an Invasive Phenotype
Authors: Belguise Karine , Guo Shangqin , Yang Shi , Rogers Adrianne E. , Seldin David C. , Sherr David H. , Sonenshein Gail E. 
Published: December 2007

Abstract
Exposure to and bioaccumulation of lipophilic environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs), has been implicated in breast cancer. Treatment of female rats with the prototypic xenobiotic PAH 7,12-dimethylbenz(a)anthracene (DMBA) induces mammary tumors with an invasive phenotype. Here, we show that green tea prevents or reverses loss of the epithelial marker E-cadherin on the surface of DMBA-induced in situ cancers. To investigate the mechanism(s) leading to a less invasive phenotype, the effects of the green tea polyphenol epigallocatechin-3 gallate (EGCG) on mammary tumor cells were assessed. EGCG reversed epithelial to mesenchymal transition (EMT) in DMBA-treated NF-κB c-Rel–driven mammary tumor cells and reduced levels of c-Rel and the protein kinase CK2. Ectopic coexpression of c-Rel and CK2α in untransformed mammary epithelial cells was sufficient to induce a mesenchymal gene profile. Mammary tumors and cell lines derived from MMTV-c-Rel × CK2α bitransgenic mice displayed a highly invasive phenotype. Coexpression of c-Rel and CK2, or DMBA exposure induced the aryl hydrocarbon receptor (AhR) and putative target gene product Slug, an EMT master regulator, which could be reversed by EGCG treatment. Thus, activation of c-Rel and CK2 and downstream targets AhR and Slug by DMBA induces EMT; EGCG can inhibit this signaling. [Cancer Res 2007;67(24):11742–50]
Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor EDG2
Authors: Horak Christine E. , Mendoza Arnulfo , Vega-Valle Eleazar , Albaugh Mary , Graff-Cherry Cari , McDermott William G. , Hua Emily , Merino Maria J. , Steinberg Seth M. , Khanna Chand , Steeg Patricia S. 
Published: December 2007

Abstract
Nm23-H1 transcriptionally down-regulates expression of the lysophosphatidic acid receptor EDG2 and this down-regulation is critical for Nm23-H1–mediated motility suppression in vitro. We investigated the effect of altered EDG2 expression on Nm23-H1–mediated metastasis suppression in vivo. Clonal MDA-MB-435–derived tumor cell lines transfected with Nm23-H1 together with either a vector control or EDG2 had similar anchorage-dependent and anchorage-independent growth rates in vitro. However, a 45- and 300-fold inhibition of motility and invasion (P &lt; 0.0001), respectively, was observed in Nm23-H1/vector lines, whereas coexpression of EDG2 restored activity to levels observed in the parental line. Using fluorescently labeled cells and ex vivo microscopy, the capacity of these cells to adhere, arrest, extravasate, and survive in the murine lung over a 24-h time course was measured. Only 5% of Nm23-H1/vector–transfected cells were retained in the murine lung 6 h following tail vein injection; coexpression of EDG2 enhanced retention 8- to 13-fold (P &lt; 0.01). In a spontaneous metastasis assay, the primary tumor size of Nm23-H1/vector and Nm23-H1/EDG2 clones was not significantly different. However, restoration of EDG2 expression augmented the incidence of pulmonary metastasis from 51.9% to 90.4% (P = 2.4 × 10−5), comparable with parental MDA-MB-435 cells. To determine the relevance of this model system to human breast cancer, a cohort of breast carcinomas was stained for Nm23-H1 and EDG2 and a statistically significant inverse correlation between these two proteins was revealed (r = −0.73; P = 0.004). The data indicate that Nm23-H1 down-regulation of EDG2 is functionally important to suppression of tumor metastasis. [Cancer Res 2007;67(24):11751–9]
Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas
Authors: Ishikawa Nobuhisa , Takano Atsushi , Yasui Wataru , Inai Kouki , Nishimura Hitoshi , Ito Hiroyuki , Miyagi Yohei , Nakayama Haruhiko , Fujita Masahiro , Hosokawa Masao , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke , Daigo Yataro 
Published: December 2007

Abstract
Gene expression profile analyses of non–small cell lung carcinomas (NSCLC) and esophageal squamous cell carcinomas (ESCC) revealed that lymphocyte antigen 6 complex locus K (LY6K) was specifically expressed in testis and transactivated in a majority of NSCLCs and ESCCs. Immunohistochemical staining using 406 NSCLC and 265 ESCC specimens confirmed that LY6K overexpression was associated with poor prognosis for patients with NSCLC (P = 0.0003), as well as ESCC (P = 0.0278), and multivariate analysis confirmed its independent prognostic value for NSCLC (P = 0.0035). We established an ELISA to measure serum LY6K and found that the proportion of the serum LY6K-positive cases was 38 of 112 (33.9%) NSCLC and 26 of 81 (32.1%) ESCC, whereas only 3 of 74 (4.1%) healthy volunteers were falsely diagnosed. In most cases, there was no correlation between serum LY6K and conventional tumor markers of carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA 21-1) values. A combined ELISA for both LY6K and CEA classified 64.7% of lung adenocarcinoma patients as positive, and the use of both LY6K and CYFRA 21-1 increased sensitivity in the detection of lung squamous cell carcinomas and ESCCs up to 70.4% and 52.5%, respectively, whereas the false positive rate was 6.8% to 9.5%. In addition, knocked down of LY6K expression with small interfering RNAs resulted in growth suppression of the lung and esophageal cancer cells. Our data imply that a cancer-testis antigen, LY6K, should be useful as a new type of tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment. [Cancer Res 2007;67(24):11536–46]
A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor-α Signaling
Authors: Gaither Alex , Porter Dale , Yao Yao , Borawski Jason , Yang Guang , Donovan Jerry , Sage David , Slisz Joanna , Tran Mary , Straub Christopher , Ramsey Tim , Iourgenko Vadim , Huang Alan , Chen Yan , Schlegel Robert , Labow Mark , Fawell Stephen , Sellers William R. , Zawel Leigh 
Published: December 2007

Abstract
Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor α (TNFα) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFα signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFα induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFα-mediated apoptosis. [Cancer Res 2007;67(24):11493–8]
PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer
Authors: Carpinelli Patrizia , Ceruti Roberta , Giorgini Maria Laura , Cappella Paolo , Gianellini Laura , Croci Valter , Degrassi Anna , Texido Gemma , Rocchetti Maurizio , Vianello Paola , Rusconi Luisa , Storici Paola , Zugnoni Paola , Arrigoni Claudio , Soncini Chiara , Alli Cristina , Patton Veronica , Marsiglio Aurelio , Ballinari Dario , Pesenti Enrico , Fancelli Daniele , Moll Jürgen 
Published: December 2007

Abstract
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition–related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status–dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser10 is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers. [Mol Cancer Ther 2007;6(12):3158–68]
The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells
Authors: Krol Janna , Francis Richard E. , Albergaria André , Sunters Andrew , Polychronis Andreas , Coombes R. Charles , Lam Eric W.-F. 
Published: December 2007

Abstract
Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G0-G1 phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. [Mol Cancer Ther 2007;6(12):3169–79]
Alternative Modernities: A Cultural Genealogy of Japan's Modernization
Authors: Brown Richard 
Published: December 2007

Traditional and largely rural patterns of relationships seem to persist in Japan despite economic and political modernization. Infused within modern technology, ideology, and apparently modern organizational forms, one discerns the persistent, if not determining, influence of native values and social patterns. Following a genealogical approach, inspired by Nietzsche and Foucault, this paper goes beyond the opposition between universalist and multiculturalist models of modernization, in order to identify certain indigenous principles of social organization manifest in both "traditional" and "modern" social formations of Japan. The persistence of these basic principles, such as the 'frame orientation," and the emphasis on
wa
(harmony, peace), is traced through the historical process of Japan's modernization in various realms of social life — the economy, political life, and popular culture. e analysis recent structural shifts in Japanese society, while still affirming the principles of Japan's "alternative modernity," also implies that major changes in its basic organizing principles might be under way.
Self-rated competency in activities predicts functioning and participation one year after traumatic brain injury
Authors: Sveen Unni , Mongs Malin , Røe Cecilie , Sandvik Leiv , Bautz-Holter Erik 
Published: December 2007

Objective: To investigate whether the Patient Competency Rating Scale at three months predicts global functioning and participation one year after traumatic brain injury. Design: Prospective cohort study with follow-up at 3 and 12 months post injury. The Patient Competency Rating Scale was analysed in a logistic regression model with the outcomes Community Integration Questionnaire, Glasgow Outcome Scale Extended and return to work/study. Setting: The neurosurgical department of a trauma referral centre in a metropolitan hospital. Subjects: A cohort of 70 patients with acute traumatic brain injury, ranging from mild to severe injury. Main measures: The Patient Competency Rating Scale, assessing competency in activities, was applied as a predictor. Outcomes describing community participation at 12 months were the Community Integration Questionnaire and return to work/study. Global functioning was evaluated by the Glasgow Outcome Scale Extended. Results: Factor analysis of the Patient Competency Rating Scale items yielded three domains: activities demanding cognition, interpersonal/emotional skills, and activities of daily living (ADL) competency. The first two of these domains significantly predicted return to work/study and community integration, whilst global functioning at one year was predicted by interpersonal/emotional competency. Conclusions: The Patient Competency Rating Scale at three months predicted functioning and participation one year after traumatic brain injury. This indicates that rehabilitation interventions should focus on cognitive and interpersonal competency in order to enhance participation after traumatic brain injury.
Influence of aspirin on the clinical outcomes of 103 anti-phospholipid antibodies-positive patients
Authors: Hereng T. , Lambert M. , Hachulla E. , Samor M. , Dubucquoi S. , Caron C. , Launay D. , Morell-Dubois S. , Queyrel V. , Hatron P.-Y. 
Published: December 2007

One hundred and three consecutive asymptomatic anti-phospholipid (aPL) antibody-positive carriers, taking aspirin ( n = 75) or not ( n = 28), were studied retrospectively to determine whether aspirin could provide primary prevention of anti-phospholipid syndrome (APS) symptoms. All patients positive for anti-cardiolipin antibodies (aCL; >25 UGPL or UMPL) and/or lupus anti-coagulant were followed for a mean of 64 ± 24.7 months. Among aPL-positive patients, 37 had systemic lupus erythematosus (SLE), 20 had prolonged activated partial thromboplastin times, 19 had other connective tissue diseases, 16 had autoimmune thrombocytopenia (AIT), 11 had diverse diseases. Nineteen patients experienced thrombotic event(s) during follow-up. Clinical features, biological parameters and hydroxychloroquine use were comparable for the two groups, but thrombotic events differed (log-rank test; P = 0.02). Four of the 10 SLE patients not taking aspirin developed thrombosis compared with 3/27 SLE patients taking aspirin (log-rank test; P = 0.03). Anti-phospholipid -positive patients with AIT developed fewer thromboses while taking aspirin (log-rank test; P = 0.01). In conclusion, aPL-positive SLE and AIT patients should take aspirin to prevent APS manifestations. Prospective therapeutic trials are needed to confirm aspirin's prophylactic role in such patients. Lupus (2008) 17, 11—15.
Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature
Authors: Erre G.L. , Pardini S. , Faedda R. , Passiu G. 
Published: December 2007

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by a hypercoagulable state related to persistently elevated levels of antiphospholipid antibodies (aPL). Current treatment for APS is only partially effective and new therapies are strongly needed. We report on a case of a 50 years old man with APS who suffered from recurrent thromboembolic episodes despite conventional anticoagulant treatment. Eight years after the first thrombotic manifestation he was diagnosed with a large B cell non-Hodgkin lymphoma. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) plus rituximab was started with partial clinical remission of lymphoma and normalization of aPL levels with a three years follow-up period free of thrombotic episodes. A review of the literature revealed that only 12 case reports on the use of rituximab in patients with primary, secondary and catastrophic APS have been published. Current knowledge clearly suggests the need for clinical trials to evaluate the effect of rituximab in the treatment of resistant APS. Lupus (2008) 17, 50—55.