bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer
Authors: Chen Aoshuang , Liu Shanrong , Park David , Kang Youmin , Zheng Guoxing 
Published: February 2007

AbstractOne strategy for improving adoptive therapy is preconditioning the host immune environment by depleting CD4+CD25+ regulatory T cells (Treg) suppressive to antitumor responses. Given that Treg increase, or selectively accumulate, within tumors and are sensitive to FasL-mediated apoptosis, we test here the hypothesis that inducing apoptosis of intratumoral Treg using FasL may improve adoptive T cell therapy. We show that FasL applied intratumorally via protein transfer decreases intratumoral Treg via inducing apoptosis in these cells. Significantly, we show that the use of FasL prior to the infusion of tumor-reactive CD8+ T cells enhances the therapeutic efficacy of adoptive T cell transfer against established tumors, which is mediated by persistent, systemic antitumor immunity. Intratumoral FasL protein transfer also results in neutrophil infiltration of tumor. However, we show that intratumoral immunodepletion of neutrophils does not abolish the effect of FasL on adoptive transfer. Rather, the effect of FasL is completely abolished by cotransfer of Treg, isolated from the tumor-draining lymph nodes. Hence, our study shows for the first time that using FasL to predeplete intratumoral Treg provides a useful means for optimizing adoptive therapy. [Cancer Res 2007;67(3):1291–8]
Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer
Authors: Pulukuri Sai Murali Krishna , Estes Norman , Patel Jitendra , Rao Jasti S. 
Published: February 2007

AbstractIncreased expression of urokinase plasminogen activator (uPA) has been reported in various malignancies including prostate cancer. However, the mechanism by which uPA is abnormally expressed in prostate cancer remains elusive. Here, we show that uPA is aberrantly expressed in a high percentage of human prostate cancer tissues but rarely expressed either in tumor-matched nonneoplastic adjacent tissues or benign prostatic hyperplasia samples. This aberrant expression is associated with cancer-linked demethylation of the uPA promoter. Furthermore, treatment with demethylation inhibitor S-adenosylmethionine or stable expression of uPA short hairpin RNA significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and incidence of lung metastasis in vivo. Collectively, these findings strongly suggest that DNA demethylation is a common mechanism underlying the abnormal expression of uPA and is a critical contributing factor to the malignant progression of human prostate tumors. [Cancer Res 2007;67(3):930–9]
Modulation of Telomerase Promoter Tumor Selectivity in the Context of Oncolytic Adenoviruses
Authors: Bilsland Alan E. , Merron Andrew , Vassaux Georges , Keith W. Nicol 
Published: February 2007

Abstract
The telomerase RNA (hTR) and reverse transcriptase (hTERT) promoters are active in most cancer cells, but not in normal cells, and are useful for transcriptional targeting in gene therapy models. Telomerase-specific conditionally replicating adenoviruses (CRAd) are attractive vectors because they should selectively lyse tumor cells. Here, we compare CRAds, in which either the hTR or hTERT promoter controls expression of the adenovirus E1A gene. In replication-defective reporter adenoviruses, the hTR promoter was up to 57-fold stronger in cancer cells than normal cells and up to 49-fold stronger than hTERT. In normal cells, hTERT promoter activity was essentially absent. Doses of telomerase-specific CRAds between 1.8 and 28 infectious units per cell efficiently killed cancer cells, but normal cells required higher doses. However, CRAd DNA replication and E1A expression were detected in both cancer and normal cells. Overall, tumor specificity of the CRAds was limited compared with nonreplicating vectors. Surprisingly, both CRAds expressed similar E1A levels and functional behavior, despite known differentials between hTR and hTERT promoter activities, suggesting that the promoters are deregulated. Rapid amplification of cDNA ends analysis of hTR-/hTERT-E1A transcripts ruled out cryptic transcription from the vector backbone. Blocking E1A translation partially restored the hTR-/hTERT-E1A mRNA differential, evidencing feedback regulation by E1A. [Cancer Res 2007;67(3):1299–307]
Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1
Authors: Chin King-Tung , Chun Abel C.S. , Ching Yick-Pang , Jeang Kuan-Teh , Jin Dong-Yan 
Published: February 2007

Abstract
Human T-cell leukemia virus type 1 oncoprotein Tax is a transcriptional regulator that interacts with a large number of host cell factors. Here, we report the novel characterization of the interaction of Tax with a human cell protein named Tax1-binding protein 1 (TAX1BP1). We show that TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. TAX1BP1 and Tax colocalize into intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 directly, induces the dissociation of TAX1BP1 from the glucocorticoid receptor–containing protein complex, and represses the coactivator function of TAX1BP1. Genetic knockout of Tax1bp1 in mice abrogates the influence of Tax on the activation of nuclear receptors. We propose that Tax-TAX1BP1 interaction mechanistically explains the previously reported repression of nuclear receptor activity by Tax. [Cancer Res 2007;67(3):1072–81]
Tamoxifen Induces Oxidative Stress and Mitochondrial Apoptosis via Stimulating Mitochondrial Nitric Oxide Synthase
Authors: Nazarewicz Rafal R. , Zenebe Woineshet J. , Parihar Arti , Larson Sarah K. , Alidema Enver , Choi Jiho , Ghafourifar Pedram 
Published: February 2007

Abstract
Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)–dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca2+ concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen. [Cancer Res 2007;67(3):1282–90]
The Type III Transforming Growth Factor-β Receptor as a Novel Tumor Suppressor Gene in Prostate Cancer
Authors: Turley Ryan S. , Finger Elizabeth C. , Hempel Nadine , How Tam , Fields Timothy A. , Blobe Gerard C. 
Published: February 2007

Abstract
The transforming growth factor-β (TGF-β) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation–induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-β. Although the loss of expression of either the type I (TβRI) or type II (TβRII) TGF-β receptor has been documented in ∼30% of prostate cancers, most prostate cancers become TGF-β resistant without mutation or deletion of TβRI, TβRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-β receptor (TβRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TβRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TβRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TβRIII promoter. Functionally, restoring TβRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TβRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity. [Cancer Res 2007;67(3):1090–8]
BRCA1 Ubiquitinates RPB8 in Response to DNA Damage
Authors: Wu Wenwen , Nishikawa Hiroyuki , Hayami Ryosuke , Sato Ko , Honda Akeri , Aratani Satoko , Nakajima Toshihiro , Fukuda Mamoru , Ohta Tomohiko 
Published: February 2007

Abstract
The breast and ovarian tumor suppressor BRCA1 catalyzes untraditional polyubiquitin chains that could be a signal for processes other than proteolysis. However, despite intense investigations, the mechanisms regulated by the enzyme activity remain only partially understood. Here, we report that BRCA1-BARD1 mediates polyubiquitination of RPB8, a common subunit of RNA polymerases, in response to DNA damage. A proteomics screen identified RPB8 as a protein modified after epirubicin treatment in BRCA1-dependent manner. RPB8 interacted with BRCA1-BARD1 and was polyubiquitinated by BRCA1-BARD1 in vivo and in vitro. BRCA1-BARD1 did not destabilize RPB8 in vivo but rather caused an increase in the amount of soluble RPB8. Importantly, RPB8 was polyubiquitinated immediately after UV irradiation in a manner sensitive to BRCA1 knockdown by RNA interference. Substitution of five lysine residues of RPB8 with arginine residues abolished its ability to be ubiquitinated while preserving its polymerase activity. HeLa cell lines stably expressing this ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity. Our findings suggest that ubiquitination of a common subunit of RNA polymerases is a mechanism underlying BRCA1-dependent cell survival after DNA damage. [Cancer Res 2007;67(3):951–8]
Breast Cancer: Should Gastrointestinal Bacteria Be on Our Radar Screen?
Authors: Rao Varada P. , Poutahidis Theofilos , Fox James G. , Erdman Susan E. 
Published: February 2007

Abstract
Anti-inflammatory drugs and antibiotics alter the risk of breast cancer in women, but roles for bacteria and inflammation in breast malignancies are poorly understood. A recent study in mice suggests that intestinal bacteria can trigger mammary carcinoma. The mechanisms involved in this effect suggest that dysregulated host immune responses to enteric bacteria can influence the development of extraintestinal cancers, highlighting the opportunities for prevention and treatment aimed at promoting intestinal homeostasis. [Cancer Res 2007;67(3):847–50]
Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis
Authors: Yeager Nicole , Klein-Szanto Andres , Kimura Shioko , Di Cristofano Antonio 
Published: February 2007

Abstract
Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroid-stimulating hormone–induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter. [Cancer Res 2007;67(3):959–66]
Establishment of a New Interleukin-6 (IL-6) Receptor Inhibitor Applicable to the Gene Therapy for IL-6–Dependent Tumor
Authors: Yoshio-Hoshino Naoko , Adachi Yasuo , Aoki Chieko , Pereboev Alexander , Curiel David T. , Nishimoto Norihiro 
Published: February 2007

Abstract
Interleukin-6 (IL-6) is a key molecule involved in the pathogenesis of several inflammatory diseases and malignancies. Treatments that inhibit IL-6 mitigate the clinical conditions of such diseases. Here, we report on the development of a new receptor inhibitor of IL-6 (NRI) by genetically engineering tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody which specifically blocks IL-6 signaling. This NRI consists of VH and VL of tocilizumab in a single-chain fragment format dimerized by fusing to the Fc portion of human immunoglobulin G1. The binding activity to IL-6 receptor and the biological activity of the purified NRI were found to be similar to those of parental tocilizumab. Because NRI is encoded on a single gene, it is easily applicable to a gene delivery system using virus vehicles. We administered an adenovirus vector encoding NRI to mouse i.p. and monitored the serum NRI level and growth reduction property on S6B45, an IL-6–dependent multiple myeloma cell line, in vivo. Adequate amount of the serum NRI level to exert anti-IL-6 action could be obtained by the NRI gene introduction combined with adenovirus gene delivery, and this treatment inhibited the in vivo S6B45 cell growth significantly. These findings indicate that NRI is a promising agent applicable to the therapeutic gene delivery approach for IL-6–driven diseases. [Cancer Res 2007;67(3):871–5]
Differential Patterns of MicroRNA Expression in Neuroblastoma Are Correlated with Prognosis, Differentiation, and Apoptosis
Authors: Chen Yongxin , Stallings Raymond L. 
Published: February 2007

Abstract
Neuroblastoma accounts for 15% of pediatric cancer deaths, and although a few protein-coding genes, such as MYCN, are involved with aggressive pathogenicity, the identification of novel biological targets for therapeutic intervention is still a necessary prerequisite for improving patient survival. Expression profiling of 157 microRNA (miRNA) loci in 35 primary neuroblastoma tumors indicates that 32 loci are differentially expressed in favorable and unfavorable tumor subtypes, indicating a potential role of miRNAs in neuroblastoma pathogenesis. Many of these loci are significantly underexpressed in tumors with MYCN amplification, which have particularly poor prognoses. Interestingly, we found that miRNA expression levels substantially change in a MYCN-amplified cell line following exposure to retinoic acid, a compound which is well known for causing reductions in MYCN expression and for inducing neuroblastoma cell lines to undergo neuronal differentiation. We also show that small interfering RNA inhibition of MYCN by itself causes similar alterations in the expression of miRNA loci. In vitro functional studies of one locus, miR-184, indicate that it plays a significant role in apoptosis. The association of experimentally induced alterations of miRNA expression in neuroblastoma cell lines with differentiation or apoptosis leads us to conclude that these loci play important roles in neuroblastoma pathogenesis. We further suggest that MYCN may mediate a tumorigenic effect, in part, through directly or indirectly regulating the expression of miRNAs that are involved with neural cell differentiation and/or apoptosis, warranting substantial further studies of miRNAs as potential therapeutic targets. [Cancer Res 2007;67(3):976–83]
Therapy-Induced Tumor Immunosurveillance Involves IFN-Producing Killer Dendritic Cells
Authors: Ullrich Evelyn , Bonmort Mathieu , Mignot Grégoire , Chaput Nathalie , Taieb Julien , Ménard Cédric , Viaud Sophie , Tursz Thomas , Kroemer Guido , Zitvogel Laurence 
Published: February 2007

Abstract
A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]
Risks for Familial and Contralateral Breast Cancer Interact Multiplicatively and Cause a High Risk
Authors: Hemminki Kari , Ji Jianguang , Försti Asta 
Published: February 2007

Abstract
The reasons for the high risk of contralateral breast cancer are not understood, although polygenic mechanisms have been suggested to be involved. The nationwide Swedish Family-Cancer Database was used to examine the interaction of the risks for contralateral and familial cancer. Relative risks were separately determined for contralateral and familial breast cancers, and these were tested for additive and multiplicative interactions. The Database contained information on 102,176 first breast cancers. Familial risk for breast cancer was 1.76 and the risk for contralateral breast cancer was 3.40, or 5.80 when extrapolated to two breasts. When women had a family history, the risk for contralateral breast cancer was remarkably high, 5.48, or 9.96 when the risk was extrapolated to two breasts, almost identical with 10.21, which was predicted by the multiplicative model. Although the data do not rule out polygenic mechanisms, they suggest that epigenetic imprinting events may be involved for the contralateral breast cancer. [Cancer Res 2007;67(3):868–70]
Deregulated CDC25A Expression Promotes Mammary Tumorigenesis with Genomic Instability
Authors: Ray Dipankar , Terao Yasuhisa , Fuhrken Peter G. , Ma Zhi-Qing , DeMayo Francesco J. , Christov Konstantin , Heerema Nyla A. , Franks Roberta , Tsai Sophia Y. , Papoutsakis Eleftherios T. , Kiyokawa Hiroaki 
Published: February 2007

Abstract
Checkpoint pathways help cells maintain genomic integrity, delaying cell cycle progression in response to various risks of fidelity, such as genotoxic stresses, compromised DNA replication, and impaired spindle control. Cancer cells frequently exhibit genomic instability, and recent studies showed that checkpoint pathways are likely to serve as a tumor-suppressive barrier in vivo. The cell cycle–promoting phosphatase CDC25A is an activator of cyclin-dependent kinases and one of the downstream targets for the CHK1-mediated checkpoint pathway. Whereas CDC25A overexpression is observed in various human cancer tissues, it has not been determined whether deregulated CDC25A expression triggers or promotes tumorigenesis in vivo. Here, we show that transgenic expression of CDC25A cooperates markedly with oncogenic ras or neu in murine mammary tumorigenesis. MMTV-CDC25A transgenic mice exhibit alveolar hyperplasia in the mammary tissue but do not develop spontaneous mammary tumors. The MMTV-CDC25A transgene markedly shortens latency of tumorigenesis in MMTV-ras mice. The MMTV-CDC25A transgene also accelerates tumor growth in MMTV-neu mice with apparent cell cycle miscoordination. CDC25A-overexpressing tumors, which invade more aggressively, exhibit various chromosomal aberrations on fragile regions, including the mouse counterpart of human 1p31-36, according to array-based comparative genomic hybridization and karyotyping. The chromosomal aberrations account for substantial changes in gene expression profile rendered by transgenic expression of CDC25A, including down-regulation of Trp73. These data indicate that deregulated control of cellular CDC25A levels leads to in vivo genomic instability, which cooperates with the neu-ras oncogenic pathway in mammary tumorigenesis. [Cancer Res 2007;67(3):984–91]
Accounting for Fluorine: Production, Use, and Loss
Authors: Villalba Gara , Ayres Robert U. , Schroder Hans 
Published: February 2007

SummaryFluorine is an essential element to human health and to the chemical industry. In spite of our dependence on fluorine and fluorine compounds, we have yet to learn to use them wisely. Our fluorine history, which spans about a hundred years, has had negative effects such as hydrofluoric acid pollution caused by aluminum smelters and ozone depletion due to chlorofluorocarbon (CFC) emissions. More recent concerns center on greenhouse effects from CFCs, hydrofluorocarbons (HFCs), and sulfur hexafluoride (SF6). In this article we note also that fluorine is a nonrenewable resource that is nonsubstitutable for many purposes. This article tracks fluorine from sources through conversion processes to end uses, most of which are dissipative. We present a stock‐flow model of the fluorine system. Based on this model we consider some possible measures that could be taken to increase the degree of recovery. To mention one example, a large percentage of the world demand for fluorspar could be supplied by the phosphate rock (fertilizer) industry, which currently dissipates a great deal of recoverable fluorine in waste phospho‐gypsum.
Industrial Symbiosis in the Australian Minerals Industry: The Cases of Kwinana and Gladstone
Authors: van Beers Dick , Bossilkov Albena , Corder Glen , van Berkel Rene 
Published: February 2007

SummaryThe realization of regional synergies in industrial areas with intensive minerals processing provides a significant avenue toward sustainable resource processing. This article provides an overview of past and current synergy developments in two of Australia's major heavy industrial regions, Kwinana (Western Australia) and Gladstone (Queensland), and includes a comparative review and assessment of the drivers, barriers, and trigger events for regional synergies initiatives in both areas. Kwinana and Gladstone compare favorably with well‐known international examples in terms of the current level and maturity of industry involvement and collaboration and the commitment to further explore regional resource synergies. Kwinana stands out with regard to the number, diversity, complexity, and maturity of existing synergies. Gladstone is remarkable with regard to unusually large geographic boundaries and high dominance of one industry sector. Many diverse regional synergy opportunities still appear to exist in both industrial regions (particularly in Kwinana), mostly in three broad areas: water, energy, and inorganic by‐product reuse. To enhance the further development of new regional synergies, the Centre for Sustainable Resource Processing (CSRP), a joint initiative of Australian minerals processing companies, research providers, and government agencies, has undertaken several collaborative projects. These include research to facilitate the process of identifying and evaluating potential synergy opportunities and assistance for the industries with feasibility studies and implementation of selected synergy projects in both regions. The article also reports on the progress to date from this CSRP research.