bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Analysis of Hypermethylated Wnt-Antagonist Family Genes as a Novel Epigenetic Biomarker Panel for Bladder Cancer Detection
Authors: Urakami Shinji , Shiina Hiroaki , Enokida Hideki , Kawakami Toshifumi , Kawamoto Ken , Hirata Hiroshi , Tanaka Yuichiro , Kikuno Nobuyuki , Nakagawa Masayuki , Igawa Mikio , Dahiya Rajvir 
Published: April 2006

Abstract
Purpose: Aberrant promoter hypermethylation of Wnt-antagonist genes contributes to the pathogenesis of several cancers. We hypothesized that combined methylation analysis of Wnt-antagonist genes could improve their use as a panel of biomarkers for diagnosing and staging of bladder cancers.
Experimental Design: Samples (54 total) of bladder tumor and corresponding normal bladder mucosa were analyzed for the methylation and expression levels of six Wnt-antagonist genes (sFRP-1, sFRP-2, sFRP-4, and sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of bladder tumor detection, the methylation score (M score), a new method for multigene methylation analysis, was developed. The M score of each sample was calculated as the sum of the corresponding log hazard ratio coefficients derived from multivariate logistic regression analysis of the methylation status for each Wnt-antagonist gene. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal sensitivity/specificity of the M score. Urine DNA from 24 matched patients with bladder tumor and 20 cancer-free volunteers was also used to investigate the methylation status of Wnt-antagonist genes.
Results: The methylation levels of Wnt-antagonists were significantly higher and mRNA levels were significantly lower in bladder tumor than in bladder mucosa. Each methylation level was inversely correlated with the corresponding mRNA level. In multivariate regression analysis, the methylation levels of sFRP-2 and Dkk-3 were significant independent predictors of bladder tumor (P &lt; 0.05 and P &lt; 0.01, respectively), whereas with sFRP-1, sFRP-5, and Wif-1 there was a trend towards significance as independent predictors. The M score of Wnt-antagonist genes was significantly higher in bladder tumor than in bladder mucosa (P &lt; 0.05). Overall, the M score had a sensitivity of 77.2% and a specificity of 66.7% as a diagnostic biomarker (areas under the curve, 0.763). The M score could distinguish superficial from invasive bladder tumors with a sensitivity of 72.2% and a specificity of 61.1% as a staging biomarker (areas under the curve, 0.671). In patients with bladder tumor, 80.6% of the methylation-specific PCR results had identical methylation in samples of tumor- and urine-derived DNA. Most urine DNA in normal controls showed no aberrant methylation of the Wnt-antagonist genes.
Conclusions: Hypermethylation of Wnt-antagonist genes plays an important role in the pathogenesis of bladder tumor and can be detected using cellular DNA extracted from urine samples. This is the first report demonstrating that M score analysis of Wnt-antagonist genes could serve as an excellent epigenetic biomarker panel for bladder tumors.
Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma
Authors: Flaherty Keith T. 
Published: April 2006

Abstract
For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only “standard” agent. With response rates of &lt;10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion.
Sentinel Lymph Node Biopsy and Melanoma Biology
Authors: Essner Richard 
Published: April 2006

Abstract
Minimally invasive intraoperative lymphatic mapping and sentinel node biopsy has become the standard approach for staging the regional lymph nodes for early-stage melanoma. The procedure requires close collaboration of surgeon, pathologist, and nuclear medicine physician. The strength of lymphatic mapping and sentinel node biopsy is its accuracy of detecting occult lymph node metastases. Reverse transcriptase-PCR (RT-PCR) analyses of either fresh-frozen or paraffin-embedded sections of the sentinel lymph nodes have been found to be more sensitive than H&E staining or immunohistochemistry techniques, but lack of specificity and limits in the availability of tissue specimens make this technique impractical for routine use. Three randomized clinical trials are examining the therapeutic value of lymphatic mapping and sentinel node biopsy for melanoma. Preliminary results of the Multicenter Lymphadenectomy Trial I show the high level of accuracy and low morbidity of lymphatic mapping and sentinel node biopsy done through an international working group. The therapeutic value of lymphatic mapping and sentinel node biopsy is still unclear. Multicenter Lymphadenectomy Trial II will test the clinical significance of lymph nodes evaluated by RT-PCR and the value of completion lymph node dissection for patients found to have tumor-positive sentinel lymph nodes by H&E, immunohistochemistry, or RT-PCR. The Sunbelt Melanoma Trial examines the therapeutic value of completion dissection and benefits of Intron A. The ability to detect occult nodal metastases and evaluate the interaction of primary tumor with the regional lymph nodes may provide for better understanding of the metastatic process in patients with melanoma and help to determine the function of the regional lymph nodes as markers of metastases or incubators of tumor cells in the metastatic cascade.
Identifying and Overcoming Immune Resistance Mechanisms in the Melanoma Tumor Microenvironment
Authors: Gajewski Thomas F. 
Published: April 2006

Abstract
The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific T cells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4+CD25+ regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell–mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.
Genetic Alterations in Signaling Pathways in Melanoma
Authors: Haluska Frank G. , Tsao Hensin , Wu Helen , Haluska Frank S. , Lazar Alexander , Goel Vikas 
Published: April 2006

Abstract
Alterations in the RAS signaling cascade are almost uniformly present in melanoma. RAS itself is only infrequently mutated in melanoma although downstream of RAS lie BRAF on the mitogen-activated protein kinase pathway and PTEN on the protein kinase B/Akt pathway. These genes are often altered in melanomas; indeed, the most frequent target of mutation in melanomas is BRAF, which is mutated in ∼60% to 70% of superficial spreading melanomas. These mutations occur in a background that is not normal, with the CDKN2A locus also typically being mutated. We review herein the data that suggest that the distribution of the signaling mutations is important. In general, melanomas carry a mutated NRAS, a mutated BRAF, or concurrent BRAF and PTEN mutations. These data support the hypothesis that the biochemical functions of RAS are portioned by mutations in the pathways lying downstream. Moreover, these mutations have no apparent relationship to the patterns of alteration of CDKN2A and its downstream effectors. Thus, the data also suggest that successful exploitation of mutations in melanoma will be dependent on understanding not only mutations and their frequency but their genetic context as well.
Low and High Tenascin-Expressing Tumors Are Efficiently Targeted by ST2146 Monoclonal Antibody
Authors: De Santis Rita , Albertoni Claudio , Petronzelli Fiorella , Campo Silvia , D'Alessio Valeria , Rosi Antonio , Anastasi Anna Maria , Lindstedt Ragnar , Caroni Nadia , Arseni Brunilde , Chiodi Pierino , Verdoliva Antonio , Cassani Giovanni , Chinol Marco , Paganelli Giovanni , Carminati Paolo 
Published: April 2006

Abstract
ST2146biot is a biotinylated anti-tenascin monoclonal antibody (mAb) to be used for Pretargeted Antibody Guided Radioimmunotherapy (PAGRIT) of solid tumors. In vivo biodistribution studies of 125I-labeled ST2146biot were done in nude mice transplanted with human HT-29 colon carcinoma and/or human U-118MG glioblastoma cells characterized for low and high tenascin expression, respectively. In vitro results show that ST2146 retains immunoreactivity upon biotinylation, in contrast to other anti-tenascin mAbs. In vivo biodistribution of ST2146 shows specific tumor accumulation up to 10 days after the i.v. injection, with no relevant differences between biotinylated and nonbiotinylated ST2146. A dose of 4 μg/mouse saturates the low tenascin-expressing human colon carcinoma HT-29, whereas the high tenascin-expressing human glioblastoma U-118MG seems to be saturated at a ST2146biot dose between 320 and 640 μg/mouse. The percentage of injected dose per gram of tumor ranges from 10% to 30%, corresponding to an amount of ST2146biot/g of tumor of ∼400 ng/g and &gt;200 μg/g for HT-29 and U-118MG, respectively. Tumor to normal organs uptake ratios are between 15 and 60, confirming high tumor selectivity of ST2146biot despite its cross-reactivity with the tenascin expressed at low level in the normal mouse organs. The ST2146biot localization data are substantially confirmed even when both low and high tenascin-expressing tumors are implanted in the same animal. To our knowledge, the absolute amount of ST2146biot, specifically localized in xenotransplanted human tumors, is the highest thus far described and supports the clinical use of this mAb in PAGRIT®.
Celecoxib Up-Regulates the Expression of the ζ Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer
Authors: Ferrandina Gabriella , Ranelletti Franco Oreste , Legge Francesco , Salutari Vanda , Martinelli Enrica , Fattorossi Andrea , Lorusso Domenica , Zannoni Gianfranco , Vellone Valerio , Paglia Amelia , Scambia Giovanni 
Published: April 2006

AbstractPurpose: We evaluated the effects of celecoxib treatment on tumor-infiltrating lymphocyte (TIL) subsets [CD3+, CD4+,CD8+, CD25+, and T cell receptor (TCR)-ζ–expressing cells] and tryptase-positive mast cells in cervical tumors. Circulating levels of cytokines [interleukin (IL)-1β, IL-10, tumor necrosis factor-α, IL-6, and IL-12] and angiogenesis-modulating factors (vascular endothelial growth factor and endostatin) have also been analyzed.Experimental Design: Cervical tumor biopsies and blood samples were obtained at the time of diagnosis and after 10 days of celecoxib treatment (400 mg b.i.d., at 8:00 a.m. and 8:00 p.m.) in 27 cases. Immunohistochemistry and ELISA assays were used to assess the expression of biological factors in tumor tissue and circulating levels of cytokines and angiogenic molecules.Results: We showed a statistically significant increase in the percentage of TIL expressing the TCR-ζ chain after celecoxib treatment: indeed, in cases exposed to celecoxib, the percentage of TCR-ζ+ cells ranged from 5.0 to 50.0 (median, 22.5) with respect to baseline expression (range, 3.0-50.0; median, 10.0; P = 0.0016). There was no significant treatment-related difference in the percentage of CD3+, CD4+, CD8+, and CD25+ TIL as well as in tryptase-positive cells. IL-12 levels were significantly reduced in posttreatment samples with respect to baseline levels (P = 0.002). We also found a reduction in the circulating levels of vascular endothelial growth factor, and a statistically significant increase of serum endostatin levels (P = 0.035).Conclusions: We reported the first evidence in humans that celecoxib restores ζ expression by TIL in primary cervical tumors, suggesting that a positive modulation of immune function may serve as an additional mechanism supporting the antitumor effect of this class of drugs.
Immunosuppression in Melanoma Immunotherapy: Potential Opportunities for Intervention
Authors: Lizée Gregory , Radvanyi Laszlo G. , Overwijk Willem W. , Hwu Patrick 
Published: April 2006

AbstractAlthough melanomas are substantially more immunogenic than other tumors, current immunotherapeutic approaches for melanoma patients have met with only limited success. Although melanoma-specific CD8+ T-cell responses can often be generated in patients naturally or through vaccination regimens, tumors frequently continue to grow unabated, suggesting that tumor-specific immune responses may be actively dampened in vivo. Research over the past decade has brought to light several mechanisms used by melanomas and other tumors to suppress tumor-specific immune responses. These include the presence of regulatory immune cells within the tumor microenvironment and draining lymph nodes that serve to shut down effector T-cell function. In addition, melanoma tumors themselves express a number of soluble and membrane-bound molecules that are responsible for inhibiting activated immune cells. The identification of these suppressive mechanisms has provided significant opportunities for designing novel therapeutic interventions that could augment current vaccination and adoptive transfer approaches for treatment of melanoma.
Allogeneic and Autologous Melanoma Vaccines: Where Have We Been and Where Are We Going?
Authors: Sondak Vernon K. , Sabel Michael S. , Mulé James J. 
Published: April 2006

Abstract
The past three decades have seen substantial research on vaccines for the treatment of metastatic melanoma and the prevention of recurrence following resection. Despite their enormous promise, the actual results have been disappointing, with several high-profile vaccine clinical trials failing to show a benefit. Nonetheless, enthusiasm for melanoma vaccines remains and has increased with our expanding understanding of the immune response to tumor. Cellular vaccines can be divided into autologous, derived from the patient's own tumor and allogeneic vaccines. Autologous vaccines have the advantage of containing all potentially relevant tumor-associated antigens for that particular patient. However, autologous vaccines are difficult to obtain from most patients with advanced disease and impossible to obtain from patients who present after resection of all clinically evident disease. No consensus exists for how tumors should be processed, preserved, modified, and delivered to serve as an effective vaccine. The amount of autologous tumor available is rarely enough to produce more than two or three vaccination doses, and the time between initial tumor harvest and ultimate availability of the vaccine may result in interval tumor progression that diminishes the likelihood of vaccine efficacy. All these drawbacks of autologous tumor vaccination limit its applicability and also limit the ability to test autologous vaccines in prospective trials. Allogeneic vaccines avoid many of these problems, but may not contain all of the tumor-associated antigens present on the patient's own tumor. In particular, neoantigens created by mutations in the patient's tumor would be unlikely to be represented in an allogeneic vaccine. Although allogeneic vaccines can be manufactured in sufficient quantities to allow large-scale trials, there remain significant limiting issues in the manufacture and standardization of the vaccine product.
Innovations and Challenges in Melanoma: Summary Statement from the First Cambridge Conference
Authors: Atkins Michael B. , Elder David E. , Essner Richard , Flaherty Keith T. , Gajewski Thomas F. , Haluska Frank G. , Hwu Patrick , Keilholz Ulrich , Kirkwood John M. , Mier James W. , Ross Merrick I. , Slingluff Craig L. , Sondak Vernon K. , Sosman Jeffrey A. , Weinstock Martin A. , King Laura 
Published: April 2006

Abstract
Innovations and Challenges in Melanoma, chaired by Michael Atkins and cochaired by Ulrich Keilholz, John Kirkwood, and Jeffrey Sosman, was held July 15 to 16, 2005, in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, surgical oncology, anatomic pathology, dermatology, and immunotherapy who wished to advance the field of melanoma treatment by exchanging information and perspectives regarding recent advances and recommendations for further study. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on how genetics, biology, and data information can enhance our understanding of melanoma biology and help inform the use of therapies for this disease.
Reversal of the Malignant Phenotype of Cervical Cancer CaSki Cells through Adeno-Associated Virus–Mediated Delivery of HPV16 E7 Antisense RNA
Authors: Wu Sufang , Meng Li , Wang Shixuan , Wang Wei , Xi Ling , Tian Xun , Chen Gang , Wu Ying , Zhou Jianfeng , Xu Gang , Lu Yunping , Ma Ding 
Published: April 2006

Abstract
Human papillomavirus (HPV) infection is the most important risk factor for the development of cervical cancer. The oncogene E7 from high-risk HPV strains has the ability to immortalize epithelial cells and increase cellular transformation in culture. In this study, we explored the possibility of preventing cervical cancer growth by inhibiting HPV16 E7 expression through gene transfer of an antisense construct. A recombinant adeno-associated virus (rAAV) vector was chosen for the transfer, based on its transfection efficiency, in vivo stability, and lack of detectable pathology. In vitro transfer of an rAAV vector expressing antisense HPV16 E7 (AAV-HPV16E7AS) inhibited cell proliferation, induced apoptosis, reduced cell migration, and restrained in vivo proliferation of HPV16/HPV18–positive cervical cancer CaSki cells. These results indicate that down-regulation of HPV16 E7 with antisense RNA is beneficial in reducing the tumorigenicity of CaSki cells, and rAAV vectors ought to be a new efficient approach for delivering the expression of therapeutic genes.
Prevention of Ultraviolet Radiation–Induced Immunosuppression by (−)-Epigallocatechin-3-Gallate in Mice Is Mediated through Interleukin 12–Dependent DNA Repair
Authors: Meeran Syed M. , Mantena Sudheer K. , Katiyar Santosh K. 
Published: April 2006

AbstractPurpose: Solar UV radiation–induced immunosuppression is considered to be a risk factor for melanoma and nonmelanoma skin cancers. We previously have shown that topical application of (−)-epigallocatechin-3-gallate (EGCG) prevents UV-induced immunosuppression in mice. We studied whether prevention of UV-induced immunosuppression by EGCG is mediated through interleukin 12 (IL-12)–dependent DNA repair.Experimental Design: IL-12 knockout (KO) mice on C3H/HeN background and DNA repair–deficient cells from xeroderma pigmentosum complementation group A (XPA) patients were used in this study. The effect of EGCG was determined on UV-induced suppression of contact hypersensitivity and UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) in mice and XPA-deficient cells using immunohistochemistry and dot-blot analysis.Results: Topical treatment with EGCG prevented UV-induced suppression of the contact hypersensitivity in wild-type (WT) mice but did not prevent it in IL-12 KO mice. Injection of anti-IL-12 monoclonal antibody to WT mice blocked the preventive effect of EGCG on UV-induced immunosuppression. EGCG reduced or repaired UV-induced DNA damage in skin faster in WT mice as shown by reduced number of CPDs+ cells and reduced the migration of CPD+ antigen-presenting cells from the skin to draining lymph nodes. In contrast, this effect of EGCG was not seen in IL-12 KO mice. Further, EGCG was able to repair UV-induced CPDs in XPA-proficient cells obtained from healthy person but did not repair in XPA-deficient cells, indicating that nucleotide excision repair mechanism is involved in DNA repair.Conclusions: These data identify a new mechanism by which EGCG prevents UV-induced immunosuppression, and this may contribute to the chemopreventive activity of EGCG in prevention of photocarcinogenesis.