bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationships of serum free thyroxine and erythrocyte measures in euthyroid HFE C282Y homozygotes and control subjects: the HEIRS Study
Authors: BARTON J. C. , LEIENDECKER‐FOSTER C. , REBOUSSIN D. M. , ADAMS P. C. , ACTON R. T. , ECKFELDT J. H. ,   FOR THE HEMOCHROMATOSIS AND IRON OVERLOAD SCREENING STUDY RESEARCH INVESTIGATORS
Published: August 2009

SummaryHemoglobin (Hb) levels and mean corpuscular volume (MCV) are abnormal in some persons with hemochromatosis or thyroid disorders. We sought to determine whether serum free thyroxine (T4) affects erythrocyte measures in euthyroid adults with or without C282Y homozygosity. We evaluated 488 white HFE C282Y homozygotes and controls (no HFE C282Y or H63D; normal serum iron measures) identified in screening; we excluded those with thyroid disorders, anemia, erythrocytosis, or serum ferritin (SF) <34 pmol/l. In the remaining 141 C282Y homozygotes and 243 controls, we evaluated correlations of log10 free T4 with Hb, RBC, MCV, and red blood cell distribution width (RDW). C282Y homozygotes had lower mean age, higher mean Hb, MCV, and log10 SF, and lower mean RBC and RDW than controls; mean log10 free T4 did not differ significantly. In HFE C282Y homozygotes, there was no significant correlation of log10 T4 with erythrocyte measures. In controls, there was a positive correlation of log10 T4 with Hb (P = 0.0096) and a negative correlation with RDW (P = 0.0286). Among euthyroid white adults without iron deficiency, there are significant correlations of log10 free T4 with Hb and RDW in controls, but not in HFE C282Y homozygotes.
Human papillomavirus prevalence and type distribution in penile carcinoma
Authors: Miralles-Guri C , Bruni L , Cubilla A L , Castellsagué X , Bosch F X , de Sanjosé S 
Published: August 2009

Background:Penile carcinoma is an uncommon and potentially mutilating disease with a heterogeneous aetiology. Several risk factors have been established for its development. Human papillomavirus (HPV) infection seems to play an important role in the development of a subset of these carcinomas and its presence is thought to be related to the histological type. HPV prevalence in penile tumours is reported to be associated to a variety of morphological changes. Its determination will provide a better estimate for HPV related cancer burden and its preventable fraction.Methods:A systematic and comprehensive literature review of the major penile cancer studies published from 1986 until June 2008 evaluating the HPV prevalence among the different histological types was carried out.Results:31 studies including 1466 penile carcinomas were reviewed. Global HPV prevalence was 46.9%. Relative contribution was: HPV-16 (60.23%), HPV-18 (13.35%), HPV-6/11 (8.13%), HPV-31 (1.16%), HPV-45 (1.16%), HPV-33 (0.97%), HPV-52 (0.58%), other types (2.47%). Assessment of multiple infections contribution is limited due to study design. Basaloid and warty squamous cell carcinomas were the most frequent HPV-related histological types, but keratinising and non-keratinising subtypes also showed prevalence rates of around 50%.Conclusions:About half of the penile tumours were associated with HPV 16–18 with little presence of other genotypes. Research on the mechanisms behind penile carcinogenesis is warranted. Available HPV vaccines are likely to be effective in penile tumours.
The Role of Transforming Growth Factor-β–Mediated Tumor-Stroma Interactions in Prostate Cancer Progression: An Integrative Approach
Authors: Basanta David , Strand Douglas W. , Lukner Ralf B. , Franco Omar E. , Cliffel David E. , Ayala Gustavo E. , Hayward Simon W. , Anderson Alexander R.A. 
Published: August 2009

Abstract
We have implemented a hybrid cellular automata model based on the structure of human prostate that recapitulates key interactions in nascent tumor foci between tumor cells and adjacent stroma. Model simulations show how stochastic interactions between tumor cells and stroma may lead to a structural suppression of tumor growth, modest proliferation, or unopposed tumor growth. The model incorporates key aspects of prostate tumor progression, including transforming growth factor-β (TGF-β), matrix-degrading enzyme activity, and stromal activation. It also examines the importance of TGF-β during tumor progression and the role of stromal cell density in regulating tumor growth. The validity of one of the key predictions of the model about the effect of epithelial TGF-β production on glandular stability was tested in vivo. These experimental results confirmed the ability of the model to generate testable biological predictions in addition to providing new avenues of experimental interest. This work underscores the need for more pathologically representative models to cooperatively drive computational and biological modeling, which together could eventually lead to more accurate diagnoses and treatments of prostate cancer. [Cancer Res 2009;69(17):7111–20]
Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors
Authors: Mühlenberg Thomas , Zhang Yixiang , Wagner Andrew J. , Grabellus Florian , Bradner James , Taeger Georg , Lang Hauke , Taguchi Takahiro , Schuler Martin , Fletcher Jonathan A. , Bauer Sebastian 
Published: August 2009

Abstract
Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity. [Cancer Res 2009;69(17):6941–50]
Ovarian Cancer Cell Detachment and Multicellular Aggregate Formation Are Regulated by Membrane Type 1 Matrix Metalloproteinase: A Potential Role in I.p. Metastatic Dissemination
Authors: Moss Natalie M. , Barbolina Maria V. , Liu Yueying , Sun Limin , Munshi Hidayatullah G. , Stack M. Sharon 
Published: August 2009

Abstract
An early event in the metastasis of epithelial ovarian carcinoma is shedding of cells from the primary tumor into the peritoneal cavity followed by diffuse i.p. seeding of secondary lesions. Anchorage-independent metastatic cells are present as both single cells and multicellular aggregates (MCA), the latter of which adhere to and disaggregate on human mesothelial cell monolayers, subsequently forming invasive foci. Although this unique metastatic mechanism presents a distinct set of therapeutic challenges, factors that regulate MCA formation and dissemination have not been extensively evaluated. Proteolytic activity is important at multiple stages in i.p. metastasis, catalyzing migration through the mesothelial monolayer and invasion of the collagen-rich submesothelial matrix to anchor secondary lesions, and acquisition of membrane type 1 matrix metalloproteinase (MT1-MMP; MMP-14) expression promotes a collagen-invasive phenotype in ovarian carcinoma. MT1-MMP is regulated posttranslationally through multiple mechanisms including phosphorylation of its cytoplasmic tail, and the current data using ovarian cancer cells expressing wild-type, phosphomimetic (T567E-MT1-MMP), and phosphodefective (T567A-MT1-MMP) MT1-MMP show that MT1-MMP promotes MCA formation. Confluent T567E-MT1-MMP–expressing cells exhibit rapid detachment kinetics, spontaneous release as cell-cell adherent sheets concomitant with MT1-MMP–catalyzed α3 integrin ectodomain shedding, and robust MCA formation. Expansive growth within three-dimensional collagen gels is also MT1-MMP dependent, with T567E-MT1-MMP–expressing cells exhibiting multiple collagen invasive foci. Analysis of human ovarian tumors shows elevated MT1-MMP in metastases relative to paired primary tumors. These data suggest that MT1-MMP activity may be key to ovarian carcinoma metastatic success by promoting both formation and dissemination of MCAs. [Cancer Res 2009;69(17):7121–9]
Mitochondrial Expression and Functional Activity of Breast Cancer Resistance Protein in Different Multiple Drug-Resistant Cell Lines
Authors: Solazzo Michela , Fantappiè Ornella , D'Amico Massimo , Sassoli Chiara , Tani Alessia , Cipriani Greta , Bogani Costanza , Formigli Lucia , Mazzanti Roberto 
Published: August 2009

Abstract
The multidrug resistance (MDR) phenotype is characterized by the overexpression of a few transport proteins at the plasma membrane level, one of which is the breast cancer resistance protein (BCRP). These proteins are expressed in excretory organs, in the placenta and blood-brain barrier, and are involved in the transport of drugs and endogenous compounds. Because some of these proteins are expressed in the mitochondria, this study was designed to determine whether BCRP is expressed at a mitochondrial level and to investigate its function in various MDR and parental drug–sensitive cell lines. By using Western blot analysis, immunofluorescence confocal and electron microscopy, flow cytometry analysis, and the BCRP (ABCG-2) small interfering RNA, these experiments showed that BCRP is expressed in the mitochondrial cristae, in which it is functionally active. Mitoxantrone accumulation was significantly reduced in mitochondria and in cells that overexpress BCRP, in comparison to parental drug–sensitive cells. The specific inhibitor of BCRP, fumitremorgin c, increased the accumulation of mitoxantrone significantly in comparison with basal conditions in both whole cells and in mitochondria of BCRP-overexpressing cell lines. In conclusion, this study shows that BCRP is overexpressed and functionally active in the mitochondria of MDR-positive cancer cell lines. However, its presence in the mitochondria of parental drug–sensitive cells suggests that BCRP can be involved in the physiology of cancer cells. [Cancer Res 2009;69(18):7235–42]
The Neuroendocrine-Derived Peptide Parathyroid Hormone–Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor
Authors: DaSilva John , Gioeli Daniel , Weber Michael J. , Parsons Sarah J. 
Published: August 2009

Abstract
During progression to an androgen-independent state following androgen ablation therapy, prostate cancer cells continue to express the androgen receptor (AR) and androgen-regulated genes, indicating that AR is critical for the proliferation of hormone-refractory prostate cancer cells. Multiple mechanisms have been proposed for the development of AR-dependent hormone-refractory disease, including changes in expression of AR coregulatory proteins, AR mutation, growth factor–mediated activation of AR, and AR protein up-regulation. The most prominent of these progressive changes is the up-regulation of AR that occurs in &gt;90% of prostate cancers. A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine factors and may provide a novel mechanism for the regulation of AR during advanced stages of the disease. In this study, we show that neuroendocrine-derived parathyroid hormone–related protein (PTHrP)–mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr534. PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen. [Cancer Res 2009;69(18):7402–11]
Identification of a Protein, G0S2, That Lacks Bcl-2 Homology Domains and Interacts with and Antagonizes Bcl-2
Authors: Welch Christian , Santra Manas K. , El-Assaad Wissal , Zhu Xiaochun , Huber Wade E. , Keys Richard A. , Teodoro Jose G. , Green Michael R. 
Published: August 2009

Abstract
The Bcl-2 family of proteins consists of both antiapoptotic and proapoptotic factors, which share sequence homology within conserved regions known as Bcl-2 homology domains. Interactions between Bcl-2 family members, as well as with other proteins, regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Here we identify a novel regulator of apoptosis that lacks Bcl-2 homology domains but acts by binding Bcl-2 and modulating its antiapoptotic activity. To identify regulators of apoptosis, we performed expression profiling in human primary fibroblasts treated with tumor necrosis factor-α (TNF-α), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-κB. We found that the gene undergoing maximal transcriptional induction following TNF-α treatment was G0-G1 switch gene 2 (G0S2), the activation of which also required NF-κB. We show that G0S2 encodes a mitochondrial protein that specifically interacts with Bcl-2 and promotes apoptosis by preventing the formation of protective Bcl-2/Bax heterodimers. We further show that ectopic expression of G0S2 induces apoptosis in diverse human cancer cell lines in which endogenous G0S2 is normally epigenetically silenced. Our results reveal a novel proapoptotic factor that is induced by TNF-α through NF-κB and that interacts with and antagonizes Bcl-2. [Cancer Res 2009;69(17):6782–9]
Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease
Authors: Nguyen Truc , Vacek Pamela M. , O'Neill Patrick , Colletti Richard B. , Finette Barry A. 
Published: August 2009

Abstract
The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P &lt; 0.001) and duration of treatment (P &lt; 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P &lt; 0.001), particularly G:C to A:T transitions (P &lt; 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor β CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P &lt; 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention. [Cancer Res 2009;69(17):7004–23]
17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells
Authors: Wang Ying , Ma Xiuquan , Yan Shousheng , Shen Shensi , Zhu Huiling , Gu Yuan , Wang Hongbing , Qin Guowei , Yu Qiang 
Published: August 2009

Abstract
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs frequently in cancer cells and contributes to oncogenesis. Among the members of STAT family, STAT3 plays a pivotal role in the development and progression of human tumors. The STAT3-mediated signaling pathway has been recognized as a promising anticancer target. Here, we show that 17-Hydroxy-jolkinolide B (HJB), a diterpenoid from the Chinese medicinal herb Euphorbia fischeriana Steud, strongly inhibits interleukin (IL)-6–induced as well as constitutive STAT3 activation. Furthermore, we show that HJB directly targets the JAK family kinases, JAK1, JAK2, and TYK2, by inducing dimerization of the JAKs via cross-linking. Addition of DTT or glutathione prevents the JAK cross-linking and blocks the inhibitory effects of HJB on IL-6–induced STAT3 activation, suggesting that HJB may react with cystein residues of JAKs to form covalent bonds that inactivate JAKs. Liquid chromatography/mass spectrometry analysis confirmed that each HJB reacted with two thiols. The effect of HJB on the JAK/STAT3 pathway is specific as HJB has no effect on platelet-derived growth factor, epidermal growth factor, or insulin-like growth factor I signaling pathways. Finally, we show that HJB inhibits growth and induces apoptosis of tumor cells, particularly those tumor cells with constitutively activated STAT3. We propose that the natural compound HJB is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor. [Cancer Res 2009;69(18):7302–10]
MUC1-C Oncoprotein Functions as a Direct Activator of the Nuclear Factor-κB p65 Transcription Factor
Authors: Ahmad Rehan , Raina Deepak , Joshi Maya Datt , Kawano Takeshi , Ren Jian , Kharbanda Surender , Kufe Donald 
Published: August 2009

AbstractNuclear factor-κB (NF-κB) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-κB, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-κB p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-κB p65 and, importantly, blocks the interaction between NF-κB p65 and its inhibitor IκBα. We show that NF-κB p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-κB–mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-κB in the response to tumor necrosis factor-α stimulation. Moreover, tumor necrosis factor-α induces the recruitment of NF-κB p65-MUC1-C complexes to NF-κB target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-κB p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-κB p65 promoter occupancy and expression of NF-κB target genes. These findings indicate that MUC1-C is a direct activator of NF-κB p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-κB pathway. [Cancer Res 2009;69(17):7013–21]
Matrix Metalloproteinase 12 Overexpression in Lung Epithelial Cells Plays a Key Role in Emphysema to Lung Bronchioalveolar Adenocarcinoma Transition
Authors: Qu Peng , Du Hong , Wang Xi , Yan Cong 
Published: August 2009

AbstractChronic obstructive pulmonary disease (COPD) and lung cancer are two diseases that are related to smoking in humans. The molecular mechanism linking these two diseases is poorly understood. Matrix metalloproteinase 12 (MMP12) is a member of the MMP family, which can be induced by smoking. Because MMP12 overexpression in epithelial cells has been reported in inflammation-triggered lung remodeling, a murine CCSP-rtTA/(tetO)7-MMP12 bitransgenic model was created. In this model, MMP12-Flag fusion protein overexpression and its increased enzymatic activity were observed in the lung in an inducible manner, which led to inflammatory cell infiltration and increased epithelial growth. In sequential events, spontaneous emphysema and bronchioalveolar adenocarcinoma were developed as a result of MMP12 overexpression. During this process, the concentration of interleukin-6 was steadily increased in bronchioalveolar lavage fluid, which activated the oncogenic signal transducer and activator of transcription 3 (Stat3) in alveolar type II epithelial cells. Expression of Stat3 downstream genes that are known to stimulate inflammation and tumor formation was significantly increased in the lung. When tested in humans, MMP12 up-regulation was highly associated with COPD and lung cancer in patients. Together, these studies support that MMP12 is a potent proinflammatory and oncogenic molecule. MMP12 up-regulation plays a critical role in emphysema to lung cancer transition that is facilitated by inflammation. [Cancer Res 2009;69(18):7252–61]
RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer
Authors: Iverson Cory , Larson Gary , Lai Chon , Yeh Li-Tain , Dadson Claudia , Weingarten Paul , Appleby Todd , Vo Todd , Maderna Andreas , Vernier Jean-Michel , Hamatake Robert , Miner Jeffrey N. , Quart Barry 
Published: August 2009

Abstract
The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system–related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile. [Cancer Res 2009;69(17):6839–47]