bluuebunny/crossref_metadata_2025_split huggingface dataset:
MUC1 Expression Is Regulated by DNA Methylation and Histone H3 Lysine 9 Modification in Cancer Cells
Authors: Yamada Norishige , Nishida Yukari , Tsutsumida Hideaki , Hamada Tomofumi , Goto Masamichi , Higashi Michiyo , Nomoto Mitsuharu , Yonezawa Suguru 
Published: April 2008

Abstract
MUC1 is a transmembrane mucin that is highly expressed in various cancers and correlates with malignant potential. Important cancer-related genes such as p16 and E-cadherin are controlled epigenetically; however, MUC1 has been overlooked in epigenetics. Herein, we provide the first report that MUC1 gene expression is regulated by DNA methylation and histone H3 lysine 9 (H3-K9) modification of the MUC1 promoter. The recently developed MassARRAY assay was performed to investigate the DNA methylation status of 184 CpG sites from −2,753 to +263. Near the transcriptional start site, the DNA methylation level of MUC1-negative cancer cell lines (e.g., MDA-MB-453) was high, whereas that of MUC1-positive cell lines (e.g., MCF-7) was low. Histone H3-K9 modification status was also closely related to MUC1 gene expression. Furthermore, MUC1 mRNA expression in MUC1-negative cells was restored by treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Our results indicate that DNA methylation and histone H3-K9 modification in the 5′ flanking region play a critical role in MUC1 gene expression, and this study defines MUC1 as a new member of the class of epigenetically controlled genes. An understanding of the epigenetic changes of MUC1 may be of importance for diagnosis of carcinogenic risk and prediction of outcome for cancer patients. [Cancer Res 2008;68(8):2708–16]
Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
Authors: Epardaud Mathieu , Elpek Kutlu G. , Rubinstein Mark P. , Yonekura Ai-ris , Bellemare-Pelletier Angelique , Bronson Roderick , Hamerman Jessica A. , Goldrath Ananda W. , Turley Shannon J. 
Published: April 2008

AbstractTumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8+ T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15Rα. Here, we report that in vivo delivery of IL-15/IL-15Rα complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15Rβ+ cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15Rα complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8+ T cells. Our data provide novel insights into the use of IL-15/IL-15Rα complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections. [Cancer Res 2008;68(8):2972–83]
Secondary BRCA1 Mutations in BRCA1-Mutated Ovarian Carcinomas with Platinum Resistance
Authors: Swisher Elizabeth M. , Sakai Wataru , Karlan Beth Y. , Wurz Kaitlyn , Urban Nicole , Taniguchi Toshiyasu 
Published: April 2008

Abstract
Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors. [Cancer Res 2008;68(8):2581–6]
Noninvasive Imaging of Apoptosis and Its Application in Cancer Therapeutics
Authors: Coppola Julia M. , Ross Brian D. , Rehemtulla Alnawaz 
Published: April 2008

Abstract
Purpose: Activation of the apoptotic cascade plays an important role in the response of tumors to therapy. Noninvasive imaging of apoptosis facilitates optimization of therapeutic protocols regarding dosing and schedule and enables identification of efficacious combination therapies.
Experimental Design: We describe a hybrid polypeptide that reports on caspase-3 activity in living cells and animals in a noninvasive manner. This reporter, ANLucBCLuc, constitutes a fusion of small interacting peptides, peptide A and peptide B, with the NLuc and CLuc fragments of luciferase with a caspase-3 cleavage site (DEVD) between pepANLuc (ANLuc) and pepBCLuc (BCLuc). During apoptosis, caspase-3 cleaves the reporter, enabling separation of ANLuc from BCLuc. A high-affinity interaction between peptide A and peptide B restores luciferase activity by NLuc and CLuc complementation. Using a D54 glioma model, we show the utility of the reporter in imaging of apoptosis in living subjects in response to various chemotherapy and radiotherapy regimens.
Results: Treatment of live cells and mice carrying D54 tumor xenografts with chemotherapeutic agents such as temozolomide and perifosine resulted in induction of bioluminescence activity, which correlated with activation of caspase-3. Treatment of mice with combination therapy of temozolomide and radiation resulted in increased bioluminescence activity over individual treatments and increased therapeutic response due to enhanced apoptosis.
Conclusion: The data provided show the utility of the ANLucBCLuc reporter in dynamic, noninvasive imaging of apoptosis and provides a rationale for use of this technology to optimize dose and schedule of novel therapies or to develop novel combination therapies using existing drugs.
Targeting Ras in Myeloid Leukemias
Authors: Braun Benjamin S. , Shannon Kevin 
Published: April 2008

Abstract
Ras proteins normally relay growth-promoting signals from many activated cell surface receptors, and they are altered by oncogenic point mutations in ∼30% of human cancers. Activating KRAS and NRAS mutations are especially common in malignancies of the pancreas, lung, and colon, and in myeloid leukemia. Here, we discuss general strategies for targeting hyperactive Ras signaling in cancer cells with specific reference to myeloid malignancies.
Activation of Placenta-Specific Transcription FactorDistal-lessHomeobox 5 Predicts Clinical Outcome in Primary Lung Cancer Patients
Authors: Kato Tatsuya , Sato Nagato , Takano Atsushi , Miyamoto Masaki , Nishimura Hitoshi , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro 
Published: April 2008

AbstractPurpose and Experimental Design: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in lung cancers using a cDNA microarray representing 27,648 genes. DLX5 gene, a member of the human distal-less homeobox transcriptional factor family that is expressed during early embryonic development, was found to be overexpressed in the great majority of lung cancers. Tissue microarray consisting of archival non–small cell lung cancer samples from 369 patients was applied to examine the clinicopathologic significance of DLX5 protein. A role of DLX5 in cancer cell growth and/or survival was investigated through small interfering RNA experiments.Results: Northern blot and immunohistochemical analyses detected expression of DLX5 only in placenta among 23 normal tissues examined. Immunohistochemical analysis showed that positive immunostaining of DLX5 was correlated with tumor size (pT classification; P = 0.0053) and poorer prognosis of non–small cell lung cancer patients (P = 0.0045). It was also shown to be an independent prognostic factor (P = 0.0415). Treatment of lung cancer cells with small interfering RNAs for DLX5 effectively knocked down its expression and suppressed cell growth.Conclusions: These data implied that DLX5 is useful as a target for the development of anticancer drugs and cancer vaccines as well as for a prognostic biomarker in clinic.
Understanding the Biological Basis of Autofluorescence Imaging for Oral Cancer Detection: High-Resolution Fluorescence Microscopy in Viable Tissue
Authors: Pavlova Ina , Williams Michelle , El-Naggar Adel , Richards-Kortum Rebecca , Gillenwater Ann 
Published: April 2008

Abstract
Purpose: Autofluorescence imaging is increasingly used to noninvasively identify neoplastic oral cavity lesions. Improving the diagnostic accuracy of these techniques requires a better understanding of the biological basis for optical changes associated with neoplastic transformation in oral tissue.
Experimental Design: A total of 49 oral biopsies were considered in this study. The autofluorescence patterns of viable normal, benign, and neoplastic oral tissue were imaged using high-resolution confocal fluorescence microscopy.
Results: The autofluorescence properties of oral tissue vary significantly based on anatomic site and pathologic diagnosis. In normal oral tissue, most of the epithelial autofluorescence originates from the cytoplasm of cells in the basal and intermediate regions, whereas structural fibers are responsible for most of the stromal fluorescence. A strongly fluorescent superficial layer was observed in tissues from the palate and the gingiva, which contrasts with the weakly fluorescent superficial layer found in other oral sites. Upon UV excitation, benign inflammation shows decreased epithelial fluorescence, whereas dysplasia displays increased epithelial fluorescence compared with normal oral tissue. Stromal fluorescence in both benign inflammation and dysplasia drops significantly at UV and 488 nm excitation.
Conclusion: Imaging oral lesions with optical devices/probes that sample mostly stromal fluorescence may result in a similar loss of fluorescence intensity and may fail to distinguish benign from precancerous lesions. Improved diagnostic accuracy may be achieved by designing optical probes/devices that distinguish epithelial fluorescence from stromal fluorescence and by using excitation wavelengths in the UV range.
Effects of a Topically Applied Bioadhesive Berry Gel on Loss of Heterozygosity Indices in Premalignant Oral Lesions
Authors: Shumway Brian S. , Kresty Laura A. , Larsen Peter E. , Zwick Jared C. , Lu Bo , Fields Henry W. , Mumper Russell J. , Stoner Gary D. , Mallery Susan R. 
Published: April 2008

Abstract
Purpose: The aim of this study was to assess the effects of topical application of a 10% (w/w) freeze-dried black raspberry (FBR) gel on oral intraepithelial neoplasia (IEN) variables that included histologic diagnoses and loss of heterozygosity (LOH) indices. Microsatellite instability and/or LOH at tumor suppressor gene–associated chromosomal loci have been associated with a higher risk for oral IEN progression to oral squamous cell carcinoma. Previously, our laboratories have shown that FBRs are well tolerated and possess potent antioxidant, apoptotic, and differentiation-inducing properties.
Experimental Design: Each participant with IEN served as their own internal control. Before treatment, all lesions were photographed, and lesional tissue was hemisected to obtain a pretreatment diagnosis and baseline biochemical and molecular variables. Gel dosing (0.5 g applied four times daily for 6 weeks) was initiated 1 week after the initial biopsy. Genomic DNA was isolated from laser-captured basilar and suprabasilar surface epithelial cells followed by PCR amplification using primer sets that targeted known and presumed tumor suppressor gene loci associated with INK4a/ARF, p53, and FHIT. Allelic imbalance was determined by sequence analysis using normal participant tissues to establish microsatellite marker peak patterns and allele sizes.
Results: Confirming earlier phase I data, none of the 27 participants developed FBR gel–associated toxicities. Furthermore, our results show histologic regression in a subset of patients as well as statistically significant reduction in LOH at tumor suppressor gene–associated loci.
Conclusions: These preliminary data suggest that further evaluation of berry gels for oral IEN chemoprevention is warranted.
Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3+ Regulatory T Cells
Authors: Ladoire Sylvain , Arnould Laurent , Apetoh Lionel , Coudert Bruno , Martin Francois , Chauffert Bruno , Fumoleau Pierre , Ghiringhelli François 
Published: April 2008

Abstract
Purpose: T-cell infiltration is associated with good tumor prognosis in many cancers. To assess the capacity of neoadjuvant chemotherapy to affect T-cell infiltration in breast cancer, we evaluated CD3 and CD8 infiltrates, and the Foxp3 immunosuppressive T cells.
Experimental Design: CD3+, CD8+, and Foxp3+ cell infiltrates were detected by immunohistochemistry in a series of 56 breast cancer patients before and after the end of neoadjuvant chemotherapy.
Results: Poor prognostic factors (negative hormonal receptors, high tumor grade, and nodal involvement) were associated with a significantly higher number of CD3, CD8, and Foxp3 infiltrates before the beginning of chemotherapy. Chemotherapy resulted in a decrease in Foxp3 infiltrates, whereas the level of CD8 and CD3 infiltrates remained unchanged. Pathologic complete responses (pCR) had a drastic decrease of Foxp3+ cells, whereas these cells remained elevated in nonresponders. A cutoff criterion that combined high CD8 infiltration and no Foxp3 cell infiltration on surgical specimens is associated with pCR with a sensitivity of 75% and a specificity of 93%. The infiltrate of cytotoxic TiA1 and granzyme B–positive cells was dramatically enhanced after chemotherapy only in patients with pCR. By multivariate analysis, association of a high CD8 infiltration and no Foxp3 infiltration on final histologic specimens were independently associated with pCR.
Conclusion: These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells. These results argue for the induction of an antitumor immune response by chemotherapy.
Prediction of Broad Spectrum Resistance of Tumors towards Anticancer Drugs
Authors: Efferth Thomas , Konkimalla V. Badireenath , Wang Yi-Fen , Sauerbrey Axel , Meinhardt Silke , Zintl Felix , Mattern Jürgen , Volm Manfred 
Published: April 2008

Abstract
Purpose: Drug resistance is a major obstacle in cancer chemotherapy. Although the statistical probability of therapeutic success is known for larger patient groups from clinical therapy trials, it is difficult to predict the individual response of tumors. The concept of individualized therapy aims to determine in vitro the drug response of tumors beforehand to choose effective treatment options for each individual patient.
Experimental Design: We analyzed the cross-resistance profiles of different tumor types (cancers of lung, breast, and colon, and leukemia) towards drugs from different classes (anthracyclines, antibiotics, Vinca alkaloids, epipodophyllotoxins, antimetabolites, and alkylating agents) by nucleotide incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Hierarchical cluster analysis and COMPARE analyses were applied.
Results: Tumors exert broad resistance profiles, e.g., tumors resistant to one drug tend to also be resistant to other drugs, whereas sensitive tumors reveal sensitivity towards many drugs. Interestingly, the broad spectrum resistance phenotype could reliably be predicted by doxorubicin alone. Expression of the ATP-binding cassette transporter P-glycoprotein (ABCB1, MDR1) and the proliferative activity of tumors were identified as underlying mechanisms of broad spectrum resistance. To find novel compounds with activity against drug-resistant tumors, a database with 2,420 natural products was screened for compounds acting independent of P-glycoprotein and the proliferative state of tumor cells.
Conclusions: Tumors exert cross-resistance profiles much broader than the classical multidrug resistance phenotype. Broad spectrum resistance can be predicted by doxorubicin due to the multifactorial mode of action of this drug. Novel cytotoxic compounds from natural resources might be valuable tools for strategies to bypass broad spectrum resistance.
Increased Expression of Id Family Proteins in Small Cell Lung Cancer and its Prognostic Significance
Authors: Kamalian Laleh , Gosney John R. , Forootan Shiva S. , Foster Christopher S. , Bao Zheng Z. , Beesley Carol , Ke Youqiang 
Published: April 2008

Abstract
Purpose: To study the molecular pathology of human small cell lung cancer (SCLC), molecular biology approaches were used to identify genes involved in malignant progression of the cancer cells.
Experimental Design: Microquantity differential display was used initially to identify genes expressed differentially between normal and malignant cell lines. The differences were verified by Western blot. Immunohistochemical analysis was done on paired normal and malignant lung tissues and on tissues taken by biopsy to assess the expression status of candidate genes and their prognostic significance.
Results: Inhibitor of DNA/differentiation (Id)1 gene was up-regulated in SCLC cells. Levels of Id1 in 8 of 10 cell lines were increased by 1.7- to 21.4-fold when compared with the benign cells. A similar increase was also found in levels of Id2 and Id3. On 26 pairs of lung tissues, all four Id proteins were significantly (Wilcoxon Signed Rank Test, P &lt; 0.001-0.005) overexpressed in cytoplasm of the malignant cells. In nuclei of SCLC cells, Id1 expression was significantly reduced, whereas the levels of Id2, Id3, and Id4 were significantly (Wilcoxon Signed Rank Test, P &lt; 0.001) increased. Immunohistochemical staining on biopsy specimens showed that the increased expression of Id2 in cytoplasm of cancer cells, not the other three proteins, was significantly associated with the increased survival of SCLC patients.
Conclusion: Changed expression profiles of Id proteins may play important roles in malignant progression of SCLC, and the increased Id2 in cytoplasm is a novel prognostic factor to predict the patient outcomes.
LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis
Authors: Melisi Davide , Ishiyama Satoshi , Sclabas Guido M. , Fleming Jason B. , Xia Qianghua , Tortora Giampaolo , Abbruzzese James L. , Chiao Paul J. 
Published: April 2008

Abstract
Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor β (TGF-β) plays a key role in cancer metastasis, signaling through the TGF-β type I/II receptors (TβRI/II). We hypothesized that targeting TβRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-β1−induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TβRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TβRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis. [Mol Cancer Ther 2008;7(4):829–40]
Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis
Authors: Martínez-Torrecuadrada Jorge L. , Cheung Lawrence H. , López-Serra Paula , Barderas Rodrigo , Cañamero Marta , Ferreiro Sergio , Rosenblum Michael G. , Casal J. Ignacio 
Published: April 2008

AbstractHuman single-chain Fv directed against fibroblast growth factor receptor 3 (FGFR3) have been shown to block proliferation of RT112 bladder carcinoma cells in vitro. Here, we examined the ability of the recombinant gelonin toxin (rGel) to enhance this inhibitory effect in vitro and in vivo on the bladder cancer cell line RT112 and the corresponding xenografts. Immunotoxins were genetically engineered by fusing FGFR3-specific Fv fragments (3C) to the NH2 terminus of rGel and expressed as a soluble protein in Escherichia coli. The 3C/rGel fusion construct showed an IC50 of 200 nmol/L against log-phase RT112 cells compared with 1,500 nmol/L for free rGel. Immunofluorescence studies showed that the 3C/rGel construct internalized rapidly into the cytoplasm of RT112 cells within 1 h of exposure. The mechanism of immunotoxin-induced cell death was found to be mediated by apoptosis. RT112 tumor xenografts in severe combined immunodeficient mice treated with 50 mg/kg 3C/rGel exhibited considerable growth delay relative to control tumors and a significant reduction of 55% to 70% in mean tumor size. Immunohistochemical analysis showed that tumors from mice treated with 3C/rGel displayed considerable apoptotic damage compared with control groups. Subcellular location of FGFR3 in immunotoxin-treated tumors indicated a translocation of FGFR3 to the nuclear membrane in contrast to tumors from saline-treated controls. These results show that FGFR3-driven immunotoxins may be an effective therapeutic agent against human bladder and other tumor types overexpressing FGFR3. [Mol Cancer Ther 2008;7(4):862–73]