bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications
Authors: Chung Christine H. , Gillison Maura L. 
Published: October 2009

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with an annual incidence of approximately 400,000 worldwide. Although the principal risk factors for head and neck cancer remain tobacco and alcohol use, human papillomavirus (HPV) has recently been found to be etiologically associated with 20 to 25 of HNSCC, mostly in the oropharynx. HPV causes human cancers by expressing two viral oncoproteins, E6 and E7. These oncoproteins degrade and destabilize two major tumor suppressor proteins, p53 and pRb, through ubiquitination. Additional studies have shown that E6 and E7 can directly bind to multiple host proteins other than p53 and pRb (e.g., Bak and p21Cip1), further contributing to genetic instability. However, expression of E6 and E7 alone is not sufficient for cellular transformation, and the additional genetic alterations necessary for malignant progression in the setting of virus-induced genomic instability are unknown. In addition to the etiological differences, HPV-positive cancers are clinically distinct when compared with HPV-negative cancers with regard to treatment response and survival outcome, with tumor HPV-positivity being a favorable prognostic biomarker. Further understanding of carcinogenesis and clinical behavior of HPV-positive cancers will improve disease prevention, patient care, and surveillance strategies for HNSCC patients. (Clin Cancer Res 2009;15(22):675862)
MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities
Authors: Dang Chi V. , Le Anne , Gao Ping 
Published: October 2009

AbstractAlthough cancers have altered glucose metabolism, termed the Warburg effect, which describes the increased uptake and conversion of glucose to lactate by cancer cells under adequate oxygen tension, changes in the metabolism of glutamine and fatty acid have also been documented. The MYC oncogene, which contributes to the genesis of many human cancers, encodes a transcription factor c-Myc, which links altered cellular metabolism to tumorigenesis. c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism. With E2F1, c-Myc induces genes involved in nucleotide metabolism and DNA replication, and microRNAs that homeostatically attenuate E2F1 expression. With the hypoxia inducible transcription factor HIF-1, ectopic c-Myc cooperatively induces a transcriptional program for hypoxic adaptation. Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA), or indirectly, such as repression of microRNAs miR-23a/b to increase glutaminase (GLS) protein expression and glutamine metabolism. Ectopic MYC expression in cancers, therefore, could concurrently drive aerobic glycolysis and/or oxidative phosphorylation to provide sufficient energy and anabolic substrates for cell growth and proliferation in the context of the tumor microenvironment. Collectively, these studies indicate that Myc-mediated altered cancer cell energy metabolism could be translated for the development of new anticancer therapies. (Clin Cancer Res 2009;15(21):6479–83)
Synergistic Enhancement of CD8+ T Cell–Mediated Tumor Vaccine Efficacy by an Anti–Transforming Growth Factor-β Monoclonal Antibody
Authors: Terabe Masaki , Ambrosino Elena , Takaku Shun , O'Konek Jessica J. , Venzon David , Lonning Scott , McPherson John M. , Berzofsky Jay A. 
Published: October 2009

AbstractPurpose: Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine, having direct suppressive activity against conventional CD4+ and CD8+T cells and natural killer cells, thereby inhibiting tumor immunosurveillance. Here, we investigated possible synergy between anti–TGF-β (1D11) and a peptide vaccine on induction of antitumor immunity, and the mechanisms accounting for synergistic efficacy.Experimental Design: The effect of combination treatment with a peptide vaccine and anti–TGF-β was examined in a subcutaneous TC1 tumor model, as well as the mechanisms of protection induced by this treatment.Results: Anti–TGF-β significantly and synergistically improved vaccine efficacy as measured by reduction in primary tumor growth, although anti–TGF-β alone had no impact. The number of tumor antigen–specific CTL with high functional avidity as measured by IFN-γ production and lytic activity was significantly increased in vaccinated mice by TGF-β neutralization. Although TGF-β is known to play a critical role in CD4+Foxp3+ Treg cells, Treg depletion/suppression by an anti-CD25 monoclonal antibody (PC61) before tumor challenge did not enhance vaccine efficacy, and adding anti–TGF-β did not affect Treg numbers in lymph nodes or tumors or their function. Also, TGF-β neutralization had no effect on interleukin-17–producing T cells, which are induced by TGF-β and interleukin-6. Absence of type II NKT cells, which induce myeloid cells to produce TGF-β, was not sufficient to eliminate all sources of suppressive TGF-β. Finally, the synergistic protection induced by anti–TGF-β vaccine augmentation was mediated by CD8+ T cells since anti-CD8 treatment completely abrogated the effect.Conclusions: These results suggest that TGF-β blockade may be useful for enhancing cancer vaccine efficacy. (Clin Cancer Res 2009;15(21):6560–9)
Systemic Inhibition of Transforming Growth Factor-β in Glioma-Bearing Mice Improves the Therapeutic Efficacy of Glioma-Associated Antigen Peptide Vaccines
Authors: Ueda Ryo , Fujita Mitsugu , Zhu Xinmei , Sasaki Kotaro , Kastenhuber Edward R. , Kohanbash Gary , McDonald Heather A. , Harper Jay , Lonning Scott , Okada Hideho 
Published: October 2009

AbstractPurpose: A variety of cancers, including malignant gliomas, overexpress transforming growth factor-β (TGF-β), which helps tumors evade effective immune surveillance through a variety of mechanisms, including inhibition of CD8+ CTLs and enhancing the generation of regulatory T (Treg) cells. We hypothesized that inhibition of TGF-β would improve the efficacy of vaccines targeting glioma-associated antigen (GAA)–derived CTL epitopes by reversal of immunosuppression.Experimental Design: Mice bearing orthotopic GL261 gliomas were treated systemically with a TGF-β–neutralizing monoclonal antibody, 1D11, with or without s.c. vaccinations of synthetic peptides for GAA-derived CTL epitopes, GARC-1 (77-85) and EphA2 (671-679), emulsified in incomplete Freund's adjuvant.Results: Mice receiving the combination regimen exhibited significantly prolonged survival compared with mice receiving either 1D11 alone, GAA vaccines alone, or mock treatments alone. TGF-β neutralization enhanced the systemic induction of antigen-specific CTLs in glioma-bearing mice. Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-γ–producing CD8+ T cells, and reduced CD4+/FoxP3+ Treg cells in the glioma microenvironment. Neutralization of TGF-β also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1α, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8+ T cells in glioma-bearing mice.Conclusions: These data suggest that systemic inhibition of TGF-β by 1D11 can reverse the suppressive immunologic environment of orthotopic tumor-bearing mice both systemically and locally, thereby enhancing the therapeutic efficacy of GAA vaccines. (Clin Cancer Res 2009;15(21):6551–9)
A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia
Authors: Friedman Daphne R. , Weinberg J. Brice , Barry William T. , Goodman Barbara K. , Volkheimer Alicia D. , Bond Karen M. , Chen Youwei , Jiang Ning , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , Decastro Carlos M. , Potti Anil , Nevins Joseph R. 
Published: October 2009

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.
Experimental Design: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients.
Results: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients.
Conclusions: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients. (Clin Cancer Res 2009;15(22):694755)
The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting
Authors: Lunghi Paolo , Costanzo Antonio , Mazzera Laura , Rizzoli Vittorio , Levrero Massimo , Bonati Antonio 
Published: October 2009

Abstract
The p53 tumor suppressor is part of a small family of related proteins that includes two other members, p73 and p63. Interest in the p53 family members, their functions and their complex interactions and regulation, has steadily grown over recent years and does not show signs of waning. p73 is a major determinant of chemosensitivity in humans, and mutant p53 proteins carrying specific polymorphisms can induce drug resistance by inhibiting TAp73. Cooperation between TA (transactivating, proapoptotic, antiproliferative) and ΔN (truncated, antiapoptotic, pro-proliferative) p73 isoforms and among the three family members guarantees equilibrium between proliferation, differentiation, and cell death, thus creating a harmony that is lost in several human cancers. In this article, we review our current knowledge of the role of p73 in cancer chemosensitivity and the real prospect of therapy targeting this molecule. We also draw attention to the crucial role of specific phosphorylation and acetylation events for p73-induced apoptosis and drug chemosensitivity. (Clin Cancer Res 2009;15(21):6495–502)
Mechanisms of Sunitinib Resistance in Gastrointestinal Stromal Tumors Harboring KITAY502-3ins Mutation: An In vitro Mutagenesis Screen for Drug Resistance
Authors: Guo Tianhua , Hajdu Mihai , Agaram Narasimhan P. , Shinoda Hiroko , Veach Darren , Clarkson Bayard D. , Maki Robert G. , Singer Samuel , DeMatteo Ronald P. , Besmer Peter , Antonescu Cristina R. 
Published: October 2009

Abstract
Purpose: Although tyrosine kinase inhibitors have improved survival in advanced gastrointestinal stromal tumor (GIST), complete response is rare and most patients eventually fail the first-line treatment with imatinib. Sunitinib malate is the only approved second-line therapy for patients with imatinib-resistant or imatinib-intolerant GIST. The clinical benefit of sunitinib is genotype-dependent in regards to both primary and secondary mutations, with GIST patients harboring the KITAY502-3ins exon 9 mutation being the most sensitive.
Experimental Design: As sunitinib resistance is now emerging, our goal was to investigate mechanisms of progression and to test the efficacy of novel tyrosine kinase inhibitor on these resistant mutants in vitro. N-ethyl-N-nitrosourea mutagenesis of Ba/F3 cells expressing the KITAY502-3ins mutant was used to investigate novel patterns of resistant mutations evolving in the presence of sunitinib.
Results: Tumors from patients who developed sunitinib resistance after at least 1 year of radiographic response were analyzed, showing similar findings of a primary KITAY502-3ins mutation and a secondary mutation in the KIT activation loop. Ba/F3 cells expressing these sunitinib-resistant double mutants showed sensitivity to both dasatinib and nilotinib.
Conclusions: Sunitinib resistance in GIST shares similar pathogenetic mechanisms identified in imatinib failure, with acquisition of secondary mutations in the activation domain after an extended initial response to the drug. Moreover, in vitro mutagenesis with or without N-ethyl-N-nitrosourea of Ba/F3 cells expressing KITAY502-3ins showed acquisition of secondary mutations restricted to the second kinase domain of KIT. In contrast, in vitro resistance to imatinib produces a broader spectrum of secondary mutations including mutations in both KIT kinase domains. (Clin Cancer Res 2009;15(22):686270)
The Neuropharmacokinetics of Temozolomide in Patients with Resectable Brain Tumors: Potential Implications for the Current Approach to Chemoradiation
Authors: Portnow Jana , Badie Behnam , Chen Mike , Liu An , Blanchard Suzette , Synold Timothy W. 
Published: October 2009

Abstract
Purpose: Intracerebral microdialysis (ICMD) is an accepted method for monitoring changes in neurochemistry from acute brain injury. The goal of this pilot study was to determine the feasibility of using ICMD to examine the neuropharmacokinetics of temozolomide in brain interstitium following oral administration.
Experimental Design: Patients with primary or metastatic brain tumors had a microdialysis catheter placed in peritumoral brain tissue at the time of surgical debulking. Computerized tomography scan confirmed the catheter location. Patients received a single oral dose of temozolomide (150 mg/m2) on the first postoperative day, serial plasma and ICMD samples were collected over 24 hours, and temozolomide concentrations were determined by tandem mass spectrometry.
Results: Nine patients were enrolled. Dialysate and plasma samples were successfully collected from seven of the nine patients. The mean temozolomide areas under the concentration-time curve (AUC) in plasma and brain interstitium were 17.1 and 2.7 g/mL hour, with an average brain interstitium/plasma AUC ratio of 17.8. The mean peak temozolomide concentration in the brain was 0.6 0.3 g/mL, and the mean time to reach peak level in brain was 2.0 0.8 hours.
Conclusions: The use of ICMD to measure the neuropharmacokinetics of systemically administered chemotherapy is safe and feasible. Concentrations of temozolomide in brain interstitium obtained by ICMD are consistent with published data obtained in a preclinical ICMD model, as well as from clinical studies of cerebrospinal fluid. However, the delayed time required to achieve maximum temozolomide concentrations in brain suggests that current chemoradiation regimens may be improved by administering temozolomide 2 to 3 hours before radiation. (Clin Cancer Res 2009;15(22):70928)
Effects of Src kinase inhibition induced by dasatinib in non–small cell lung cancer cell lines treated with cisplatin
Authors: Ceppi Paolo , Papotti Mauro , Monica Valentina , Iacono Marco Lo , Saviozzi Silvia , Pautasso Marisa , Novello Silvia , Mussino Stefano , Bracco Enrico , Volante Marco , Scagliotti Giorgio V. 
Published: October 2009

Abstractc-Src is a tyrosine kinase involved in tumor proliferation, migration, and angiogenesis and has been shown to modulate the cytotoxicity following cisplatin-induced DNA damages. c-Src is frequently activated in non–small cell lung cancer (NSCLC) tissues and cell lines, but no preclinical data regarding the effects of the novel potent Src inhibitor, dasatinib (BMS-354825), in the modulation of cisplatin resistance are currently available. The present study reports that treatment with dasatinib completely abrogated Src phosphorylation in the majority of the NSCLC cell lines tested (n = 7), with modest effects on cell proliferation and survival. In five cell lines, a higher cytotoxicity was observed delivering cisplatin in combination with dasatinib: the most evident effects were found in the squamous H520 cells due to the effective block of cisplatin-induced Src phosphorylation. Moreover, dasatinib treatment significantly blocked cisplatin-induced transcription of a panel of DNA repair and synthesis genes. In addition, a real-time PCR analysis done on tumor and matched normal lung specimens from 44 surgically resected NSCLC patients showed that Src transcripts are significantly upregulated in 23% of cases. In conclusion, Src-directed therapeutic strategies could interfere with cisplatin resistance, possibly allowing to reduce cisplatin doses, thus improving its efficacy. The data of this study support further clinical studies aimed to evaluate the efficacy of Src-inhibiting agents in combination with cisplatin in the treatment of NSCLC. [Mol Cancer Ther 2009;8(11):3066–74]
RhoC Expression and Head and Neck Cancer Metastasis
Authors: Islam Mozaffarul , Lin Giant , Brenner John C. , Pan Quintin , Merajver Sofia D. , Hou Yanjun , Kumar Pawan , Teknos Theodoros N. 
Published: October 2009

AbstractRhoC protein, a known marker of metastases in aggressive breast cancers and melanoma, has also been found to be overexpressed in certain head and neck cancers, thus we investigated the correlation between RhoC expression and the metastatic behavior of head and neck squamous cell carcinoma. Selective inhibition of RhoC expression was achieved using lentiviral small hairpin RNA (shRNA) transduced and tracked with green fluorescent protein to achieve 70% to 80% RhoC inhibition. Fluorescence microscopy of the RhoC knockdown stable clones showed strong green fluorescence in the majority of cells, signifying a high efficiency of transduction. Importantly, quantitative real-time PCR showed no significant decrease in the mRNA expression levels of other members of the Ras superfamily. Cell motility and invasion were markedly diminished in RhoC-depleted cell lines as compared with control transduced lines. H&E staining of lung tissue obtained from severe combined immunodeficiency mice, which had been implanted with RhoC knockdown cells, showed a marked decrease in lung metastasis and inflammation of the blood vessels. The cultured lung tissue showed a significant decrease in cell growth in mice implanted with RhoC-depleted cell lines as compared with shRNA-scrambled sequence control lines. Microscopic studies of CD31 expression revealed substantial quantitative and qualitative differences in the primary tumor microvessel density as compared with parental and shRNA-scrambled controls. This study is the first of its kind to establish the involvement of RhoC specifically in head and neck metastasis. These findings suggest that RhoC warrants further investigation to delineate its robustness as a novel potentially therapeutic target. (Mol Cancer Res 2009;7(11):1771–80)
Effect of Orally Administered Bovine Lactoferrin on the Growth of Adenomatous Colorectal Polyps in a Randomized, Placebo-Controlled Clinical Trial
Authors: Kozu Takahiro , Iinuma Gen , Ohashi Yasuo , Saito Yutaka , Akasu Takayuki , Saito Daizo , Alexander David B. , Iigo Masaaki , Kakizoe Tadao , Tsuda Hiroyuki 
Published: October 2009

Abstract
Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps ≤5 mm in diameter and likely to be adenomas. Participants were assigned to receive placebo, 1.5-g bLF, or 3.0-g bLF daily for 12 months. Target adenomatous polyps were monitored by colonoscopy. Ingestion of 3.0-g bLF significantly retarded adenomatous polyp growth in participants 63 years old or younger. Removal of adenomatous colorectal polyps is done as a preventative measure against colorectal cancer; however, polyps can be overlooked, and when detected, polypectomy is not always 100% effective in eradicating a polyp. Our study suggests that daily intake of 3.0 g of bLF could be a clinically beneficial adjunct to colorectal polyp extraction.
Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease
Authors: Kaczmarek Przemyslaw , Sladek Krzysztof , Stepien Ewa , Skucha Wojciech , Rzeszutko Marcin , Gorkiewicz-Kot Izabela , Tracz Wieslawa , Undas Anetta 
Published: October 2009

SummaryIncreased risk of thrombotic events occurs in chronic obstructive pulmonary disease (COPD). Elevated fibrinogen and C-reactive protein (CRP), being common in COPD, are associated with formation of dense fibrin clots resistant to lysis. Statins have been found to display anti-inflammatory and antithrombotic effects. We investigated fibrin clot properties in COPD patients prior to and following statin therapy. Ex vivo plasma fibrin clot permeability, compaction, and fibrinolysis were assessed in 56 patients with stable COPD,aged 64.9 ±9.2 years (mean FEV1, 54.7 ±15.9% predicted), versus 56 controls matched for age, sex and cardiovascular risk factors. Patients were then randomly assigned to receive simvastatin 40 mg/day (n = 28) or to remain without statins for three months (n = 28). Patients with COPD had lower clot permeability (6.1±1.07 versus 9.2 ±0.9 10−9 cm2; p <0.0001), decreased compaction (44.9 ±4.5 versus 63.9 ± 6.1%; p <0.0001), higher maximum D-dimer levels released from clots (4.23 ±0.55 versus 3.53 ±0.31 mg/l; p <0.0001) with a decreased rate of this release (75.0 ±8.3 versus 80.9 ±8.0 43;g/ l/min; p = 0.03) and prolonged lysis time (9.84 ±1.33 versus 8.02 ±0.84 min; p <0.0001) compared with controls. Scanning electron microscopy confirmed denser clot structure in COPD. Multiple linear regression analysis after adjustment for age and fibrinogen showed that in the COPD patients, CRP was the only independent predictor of permeability (R2 = 0.47; p <0.001) and lysis time (R2 = 0.43; p <0.001). Simvastatin improved clot properties (p <0.05) despite unaltered CRP and irrespective of cholesterol reduction. Our study shows that fibrin clots in COPD patients are composed of much denser networks that are more resistant to lysis, and these properties can be improved by statin administration.