bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Common 8q24 Variant in Prostate and Breast Cancer from a Large Nested Case-Control Study
Authors: Schumacher Fredrick R. , Feigelson Heather Spencer , Cox David G. , Haiman Christopher A. , Albanes Demetrius , Buring Julie , Calle Eugenia E. , Chanock Stephen J. , Colditz Graham A. , Diver W. Ryan , Dunning Alison M. , Freedman Matthew L. , Gaziano John M. , Giovannucci Edward , Hankinson Sue E. , Hayes Richard B. , Henderson Brian E. , Hoover Robert N. , Kaaks Rudolf , Key Timothy , Kolonel Laurence N. , Kraft Peter , Le Marchand Loic , Ma Jing , Pike Malcolm C. , Riboli Elio , Stampfer Meir J. , Stram Daniel O. , Thomas Gilles , Thun Michael J. , Travis Ruth , Virtamo Jarmo , Andriole Gerald , Gelmann Edward , Willett Walter C. , Hunter David J. 
Published: April 2007

Abstract
Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 × 10−13). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 × 10−13). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an ORAC = 1.34 (99% confidence intervals, 1.19–1.50) and carriers with two copies of the minor allele had an ORAA = 1.86 (99% confidence intervals, 1.30–2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result. [Cancer Res 2007;67(7):2951–6]
PRL-3 Down-regulates PTEN Expression and Signals through PI3K to Promote Epithelial-Mesenchymal Transition
Authors: Wang Haihe , Quah Samantha Yiling , Dong Jing Ming , Manser Edward , Tang Jing Ping , Zeng Qi 
Published: April 2007

Abstract
PRL-3 is a metastasis-associated phosphatase. We and others have shown that its overexpression increases cell motility and invasiveness. These phenotypic changes are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development and oncogenesis. The EMT is a complex process that converts epithelia into migratory mesenchymal cells. We here attempt to unravel the underlying mechanistic basis of these phenomena. HeLa cells transiently expressing EGFP-PRL-3 (HeLa-PRL-3) exhibit reduced levels of paxillin. Similarly, Chinese hamster ovary cells stably expressing myc-PRL-3 (CHO-PRL-3) also show marked reductions in paxillin, phosphorylated paxillin-Tyr31, and vinculin at focal adhesion complexes and notable reductions in the levels of RhoA-GTP, Rac1-GTP, and filamentous-actin filaments. DLD-1 human colorectal cancer cells engineered to express EGFP-PRL-3 (DLD-1-PRL-3) underwent changes consistent with EMT. In these cells, PRL-3 activates Akt and inactivates glycogen synthase kinase-3β as assessed by phosphospecific antibodies. PRL-3 up-regulates mesenchymal markers fibronectin and Snail and down-regulates epithelial markers E-cadherin, γ-catenin (plakoglobin), and integrin β3, which are major effectors in the EMT pathway. The changes in these EMT characteristics brought about by PRL-3 can be abrogated by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, implying that PRL-3 acts upstream of PI3K and could play an initiating role to trigger the EMT switch during cancer metastasis. In addition, PRL-3 can down-regulate phosphatase and tensin homologue deleted on chromosome 10, which is an important antagonist of PI3K, further reinforcing PI3K/Akt function in PRL-3–triggered EMT. Catalytically inactive PRL-3 (C104S) was impaired in the above PRL-3–mediated events, indicating that these properties require phosphatase activity. Targeting PRL-3 may thus be a useful strategy to impede cancer cell invasion and metastasis. [Cancer Res 2007;67(7):2922–6]
Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer
Authors: Kanehira Mitsugu , Katagiri Toyomasa , Shimo Arata , Takata Ryo , Shuin Taro , Miki Tsuneharu , Fujioka Tomoaki , Nakamura Yusuke 
Published: April 2007

Abstract
To disclose the molecular mechanism of bladder cancer, the second most common genitourinary tumor, we had previously done genome-wide expression profile analysis of 26 bladder cancers by means of cDNA microarray representing 27,648 genes. Among genes that were significantly up-regulated in the majority of bladder cancers, we here report identification of M-phase phosphoprotein 1 (MPHOSPH1) as a candidate molecule for drug development for bladder cancer. Northern blot analyses using mRNAs of normal human organs and cancer cell lines indicated this molecule to be a novel cancer-testis antigen. Introduction of MPHOSPH1 into NIH3T3 cells significantly enhanced cell growth at in vitro and in vivo conditions. We subsequently found an interaction between MPHOSPH1 and protein regulator of cytokinesis 1 (PRC1), which was also up-regulated in bladder cancer cells. Immunocytochemical analysis revealed colocalization of endogenous MPHOSPH1 and PRC1 proteins in bladder cancer cells. Interestingly, knockdown of either MPHOSPH1 or PRC1 expression with specific small interfering RNAs caused a significant increase of multinuclear cells and subsequent cell death of bladder cancer cells. Our results imply that the MPHOSPH1/PRC1 complex is likely to play a crucial role in bladder carcinogenesis and that inhibition of the MPHOSPH1/PRC1 expression or their interaction should be novel therapeutic targets for bladder cancers. [Cancer Res 2007;67(7):3276–85]
Active Induction of Tumor-Specific IgE Antibodies by Oral Mimotope Vaccination
Authors: Riemer Angelika B. , Untersmayr Eva , Knittelfelder Regina , Duschl Albert , Pehamberger Hubert , Zielinski Christoph C. , Scheiner Otto , Jensen-Jarolim Erika 
Published: April 2007

AbstractA role of IgE antibodies in cancer surveillance has been implicated for a long time. Studies dealing with IgE antibodies directly targeted to tumor antigens have shown marked anticancer effects mediated by this antibody class. Thus, the basic function of IgE antibodies may be to control tumor growth. Thus far, cancer-specific IgE has only been applied passively. Consequently, the aim of this study was to establish an active vaccination protocol to induce tumor antigen–specific IgE antibodies, and to evaluate functional properties. We previously generated epitope mimics, so-called mimotopes, for the epitope recognized by the anti-HER-2 antibody trastuzumab. Upon i.p. immunizations, IgG antibodies with trastuzumab-like properties could be elicited. In the present study, we immunized BALB/c mice via the oral route with these trastuzumab mimotopes, under simultaneous neutralization and suppression of gastric acid. As shown in preceding experiments, this feeding regimen effectively induces Th2 immune responses. Oral immunizations with trastuzumab mimotopes under hypoacidic conditions indeed resulted in the formation of IgE antibodies towards the HER-2 antigen. Moreover, anti-HER-2 IgE-sensitized effector cells mediated SK-BR-3 target cell lysis in an antibody-dependent cytotoxicity assay. We conclude that directed and epitope-specific induction of IgE against tumor antigens is feasible with an oral mimotope vaccination regimen, and that these antibodies mediate anticancer effects. [Cancer Res 2007;67(7):3406–11]
Positron Emission Tomography of Herpes Simplex Virus 1 Oncolysis
Authors: Kuruppu Darshini , Brownell Anna-Liisa , Zhu Aijun , Yu Meixiang , Wang Xukui , Kulu Yakup , Fuchs Bryan C. , Kawasaki Hiroshi , Tanabe Kenneth K. 
Published: April 2007

Abstract
Viral oncolysis, the destruction of cancer cells by replicating viruses, is under clinical investigation for cancer therapy. Lytic viral replication in cancer cells both destroys the cells and liberates progeny virion to infect adjacent cancer cells. The safety and efficacy of this approach are dependent on selective and robust viral replication in cancer cells rather than in normal cells. Methods to detect and quantify viral replication in tissues have relied on organ sampling for molecular analyses. Preclinical and clinical studies of viral oncolysis will benefit significantly from development of a noninvasive method to repetitively measure viral replication. We have shown that positron emission tomography (PET) allows for in vivo detection of herpes simplex virus (HSV)-1 replication in tumor cells using 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG) as the substrate for HSV thymidine kinase (HSV-TK). As expected, phosphorylated [18F]FHBG is initially trapped within HSV-1–infected tumor cells and is detectable as early as 2 h following virus administration. MicroPET images reveal that [18F]FHBG accumulation in HSV-1–infected tumors peaks at 6 h. However, despite progressive accumulation of HSV-1 titers and HSV-TK protein in the tumor as viral oncolysis proceeds, tumor cell degradation resulting from viral oncolysis increases over time, which limits intracellular retention of [18F]FHBG. These observations have important consequences with regard to strategies to use [18F]FHBG PET for monitoring sites of HSV-TK expression during viral oncolysis. [Cancer Res 2007;67(7):3295–300]
The Regulation of AMPK β1, TSC2, and PTEN Expression by p53: Stress, Cell and Tissue Specificity, and the Role of These Gene Products in Modulating the IGF-1-AKT-mTOR Pathways
Authors: Feng Zhaohui , Hu Wenwei , de Stanchina Elisa , Teresky Angelika K. , Jin Shengkan , Lowe Scott , Levine Arnold J. 
Published: April 2007

Abstract
The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the β1 and β2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal–specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways. [Cancer Res 2007;67(7):3043–53]
Inhibition of Angiogenesis and Invasion by 3,3′-Diindolylmethane Is Mediated by the Nuclear Factor–κB Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer
Authors: Kong Dejuan , Li Yiwei , Wang Zhiwei , Banerjee Sanjeev , Sarkar Fazlul H. 
Published: April 2007

Abstract
Progression of prostate cancer is believed to be dependent on angiogenesis induced by tumor cells. 3,3′-Diindolylmethane (DIM) has been shown to repress neovascularization in a Matrigel plug assay and inhibit cell proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells. However, the molecular mechanism, by which DIM inhibits angiogenesis and invasion, has not been fully elucidated. Therefore, we sought to explore the molecular mechanism by which DIM inhibits angiogenesis and invasion, specifically by investigating the role of angiogenic factors secreted by prostate cancer cells which control all steps of angiogenesis. We found that BioResponse DIM (B-DIM), a formulated DIM with higher bioavailability, inhibited angiogenesis and invasion by reducing the bioavailability of vascular endothelial growth factor (VEGF) via repressing extracellular matrix–degrading proteases, such as matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA), in human prostate cancer cells and reduced vascularity (angiogenesis) in vivo using Matrigel plug assay. We also found that B-DIM treatment inhibited DNA binding activity of nuclear factor-κB (NF-κB), which is known to mediate the expression of many NF-κB downstream target genes, including VEGF, IL-8, uPA, and MMP-9, all of which are involved in angiogenesis, invasion, and metastasis. Our data suggest that inhibition of NF-κB DNA binding activity by B-DIM contributes to the regulated bioavailability of VEGF by MMP-9 and uPA and, in turn, inhibits invasion and angiogenesis, which could be mechanistically linked with the antitumor activity of B-DIM as observed previously by our laboratory in a prostate cancer animal model. [Cancer Res 2007;67(7):3310–9]^
High HSP90 Expression Is Associated with Decreased Survival in Breast Cancer
Authors: Pick Elah , Kluger Yuval , Giltnane Jennifer M. , Moeder Christopher , Camp Robert L. , Rimm David L. , Kluger Harriet M. 
Published: April 2007

Abstract
The heat shock protein HSP90 chaperones proteins implicated in breast cancer progression, including Her2/neu. HSP90-targeting agents are in clinical trials for breast cancer. HSP90 expression is high in breast cancer cell lines, yet no large studies have been conducted on expression in human tumors and the association with clinical/pathologic variables. Tissue microarrays containing 10 cell lines and primary specimens from 655 patients with 10-year follow-up were assessed using our automated quantitative analysis (AQUA) method; we used cytokeratin to define pixels as breast cancer (tumor mask) within the array spot and measured HSP90 expression within the mask using Cy5-conjugated antibodies. We similarly assessed estrogen receptor, progesterone receptor, and Her2/neu expression. HSP90 expression was more variable in human tumors than in cell lines (P &lt; 0.0001). High HSP90 expression was associated with decreased survival (P = 0.0024). On multivariable analysis, high HSP90 expression remained an independent prognostic marker. High HSP90 expression was associated with high Her2/neu and estrogen receptor, large tumors, high nuclear grade, and lymph node involvement. Although HSP90 levels were high in all our cell lines, expression in tumors was more variable. High HSP90 expression in primary breast cancer defines a population of patients with decreased survival. Evaluation of HSP90 expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted treatment. Prospective studies are needed to confirm the prognostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors. [Cancer Res 2007;67(7):2932–7]
Systematic Urokinase-Activated Anthrax Toxin Therapy Produces Regressions of Subcutaneous Human Non–Small Cell Lung Tumor in Athymic Nude Mice
Authors: Su Yunpeng , Ortiz Janelle , Liu Shihui , Bugge Thomas H. , Singh Ravibhushan , Leppla Stephen H. , Frankel Arthur E. 
Published: April 2007

AbstractThe novel recombinant anthrax toxin, PrAgU2/FP59, composed of the urokinase-activated protective antigen and a fusion protein of Pseudomonas exotoxin and lethal factor was tested for anti–lung cancer efficacy in an in vivo human tumor model. Male athymic nude mice (age 4–6 weeks) were inoculated s.c. with 10 million H1299 non–small cell lung cancer (NSCLC) cells in the left flank. When tumor volumes reached 200 mm3 (6–8 days), i.p. injection of 100 μL saline or different ratios and doses of PrAgU2/FP59 in 100 μL saline were given every 3 days for four doses and an additional dose at day 29. Animals were monitored twice daily and tumor measurements were made by calipers. The maximum tolerated doses of PrAgU2/FP59 differed dependent on the ratios of PrAgU2 to FP59 over the range of 3:1 to 25:1, respectively. At tolerated doses, tumor regressions were seen in all animals. Complete histologic remission lasting 60 days occurred in 30% of animals. PrAgU2/FP59 showed dramatic anti-NSCLC efficacy and warrants further clinical development for therapy of patients with advanced NSCLC. [Cancer Res 2007;67(7):3329–36]
Tumor-Released Microvesicles as Vehicles of Immunosuppression
Authors: Valenti Roberta , Huber Veronica , Iero Manuela , Filipazzi Paola , Parmiani Giorgio , Rivoltini Licia 
Published: April 2007

AbstractTumor-released microvesicles, or exosomes, which are abundant in the body fluids of patients with cancer, are likely to be involved in tumor progression. We recently showed that microvesicles released by human melanoma and colorectal carcinoma cells can promote the differentiation of monocytes to myeloid-derived suppressor cells which support tumoral growth and immune escape. These findings underscore an important role for these extracellular organelles in remodeling tumor-stromal interactions to promote malignancy. [Cancer Res 2007;67(7):2912–5]
Septic Arthritis of the Knee after Anterior Cruciate Ligament Surgery
Authors: Schulz Arndt P. , Götze Sebastian , Schmidt Hergo G. K. , Jürgens Christian , Faschingbauer Maximilian 
Published: March 2007

Background Septic arthritis is a rare complication after anterior cruciate ligament surgery. All case series reported so far have been retrospective, and case numbers of septic arthritis have ranged from 4 to 11. Hypothesis A stage-adapted treatment regimen for septic arthritis after anterior cruciate ligament surgery can provide reliable results. Study Design Case series; Level of evidence, 4. Methods From June 1993 to May 2003, 24 patients met the inclusion criteria for this study. The average age at trauma was 32.5 years. Treatment protocol was based on the grade of infection. Options included transarthroscopic treatment for Gaechter grades 1 and 2 infections or medial and lateral arthrotomy for grades 3 and 4 infections. Graft retention was decided based on clinical findings. The setting was a specialized trauma hospital. Follow-up included International Knee Documentation Committee forms, radiographs, and the Tegner and Lysholm scores at a mean of 66 months (range, 11-142) after treatment. Results In all cases, treatment of infection was successful; overall, a mean of 2.2 operations were required. In 7 cases, it was possible to salvage the graft. The Tegner activity level before the knee injury was 6.1 points. At follow-up, the average score was 3.8 points. The postoperative subjective International Knee Documentation Committee score averaged 64. The mean Lysholm score was 65.6. On clinical examination, a mean extension deficit of 3° and a mean maximum flexion of 120° were found. In the single-legged hop test, a mean capacity of 63% compared with the uninjured side was measured. Conclusion The described treatment regimen gives reliable results for this complication. There were no recurrences of septic arthritis or bone infection. Early infection can be managed arthroscopically with satisfactory results regarding the treatment of infection. In advanced or chronic infection, a more radical approach seems favorable. Results in these cases are overall only fair compared with patients with an uncomplicated anterior cruciate ligament reconstruction.
An Analysis of Soft Tissue Allograft Anterior Cruciate Ligament Reconstruction in a Rabbit Model
Authors: Soon Michael Y. H. , Hassan Afizah , Hui James H. P. , Goh James C. H. , Lee E.H. 
Published: March 2007

Background Soft tissue allografts are essential for revision and multiple ligament surgeries in the knee, where donor-site morbidity is an issue. However, the use of allografts is associated with a higher failure rate of osteointegration. Mesenchymal stem cells (MSCs) are investigated as potential agents to enhance bone tunnel and tendon healing. Purpose This study was conducted to analyze the effect of coating allografts with MSCs on the quality and rate of osteointegration at the allograft tendon and bone interface, and the biomechanical properties of these enhanced anterior cruciate ligament (ACL) grafts compared with controls. Study Design Descriptive laboratory study. Methods Bilateral ACL reconstructions using Achilles tendon allografts were performed in 36 rabbits. On 1 limb, the graft was coated with autogenous MSCs in a fibrin glue carrier, while the contralateral limb served as a control with no MSCs. The reconstructions were assessed histologically and biomechanically at 2, 4, and 8 weeks. Results At 8 weeks, histologic analysis of the controls revealed the development of mature scar tissue resembling Sharpey fibers spanning the tendon-bone interface. In contrast, the MSC-enhanced reconstructions showed a mature zone of fibrocartilage blending from bone to the allograft, strongly resembling a normal ACL insertion. On biomechanical testing, the MSC-enhanced grafts had significantly higher load-to-failure rates than controls. However, the stiffness and Young's modulus were lower in the treatment group. Conclusions The application of MSCs at the allograft tendon-bone interface during ACL reconstruction results in the development of an intervening zone of fibrocartilage. The use of MSCs to enhance allograft osteointegration is a novel method offering the potential of more physiologic and earlier healing, although further investigation must be conducted to improve the biomechanical strength. Clinical Relevance Mesenchymal stem cells can improve the biologic properties of soft tissue allograft healing. Combined with the decrease in donor-site morbidity, allografts are a viable choice for the sports medicine surgeon.