bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiologic Levels of 2-Methoxyestradiol Interfere with Nongenomic Signaling of 17β-Estradiol in Human Breast Cancer Cells
Authors: Vijayanathan Veena , Venkiteswaran Sripriya , Nair Sandhya K. , Verma Arti , Thomas T.J. , Zhu Bao Ting , Thomas Thresia 
Published: April 2006

AbstractPurpose: The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2ME) on the growth of estrogen receptor (ER)–positive breast cancer cells and provide insights into its mechanism(s) of action.Experimental Design: Using the ERα-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17β-estradiol (E2) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E2.Results: E2 stimulated the growth of MCF-7 and T-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E2, 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E2, 2ME inhibited E2-induced cell growth and prevented E2-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERα in response to E2 in MCF-7 and T-47D cells. 2ME also down-regulated E2-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E2 resulted in a decrease in ERα level by 72 hours. Accelerated down-regulation of ERα may contribute to growth inhibition in the presence of E2/2ME combinations. In contrast, a concentration of up to 2.5 μmol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E2.Conclusions: Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E2, 2ME suppressed E2-induced cell growth, Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E2. The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.
Coengagement of CD16 and CD94 Receptors Mediates Secretion of Chemokines and Induces Apoptotic Death of Naive Natural Killer Cells
Authors: Jewett Anahid , Cacalano Nicholas A. , Head Christian , Teruel Antonia 
Published: April 2006

AbstractDown-modulation of CD16 (FcγRIII) receptors and loss of natural killer (NK) cell function have been observed in oral cancer patients. However, neither the mechanisms nor the significance of the decrease in CD16 receptors have been fully understood. The cytotoxic activity and survival of NK cells are negatively regulated by antibodies directed against CD16 surface receptor. The addition of anti-CD94 antibody in combination with either F(ab′)2 fragment or intact anti-CD16 antibody to NK cells resulted in significant inhibition of NK cell cytotoxic function and induction of apoptosis in resting human peripheral blood NK cells. Addition of interleukin-2 to anti-CD16 and/or anti-CD94 antibody-treated NK cells significantly inhibited apoptosis and increased the function of NK cells. There was a significant increase in tumor necrosis factor-α (TNF-α) but not IFN-γ secretion in NK cells treated either with anti-CD16 antibody alone or in combination with anti-CD94 antibodies. Consequently, the addition of anti-TNF-α antibody partially inhibited apoptosis of NK cells mediated by the combination of anti-CD94 and anti-CD16 antibodies. Increase in apoptotic death of NK cells also correlated with an increase in type 2 inflammatory cytokines and in the induction of chemokines. Thus, we conclude that binding of antibodies to CD16 and CD94 NK cell receptors induces death of the NK cells and signals for the release of chemokines.
Ribosomal Protein L19 Is a Prognostic Marker for Human Prostate Cancer
Authors: Bee Alix , Ke Youqianq , Forootan Shiva , Lin Ke , Beesley Carol , Forrest Sharon E. , Foster Christopher S. 
Published: April 2006

Abstract
Microquantity differential display analysis of gene expression profiles between benign (PNT2) and malignant (PC3M) human prostate cell lines identified the gene encoding ribosomal protein L19 (RPL19) to be overexpressed in the malignant cells. Northern blot hybridization analysis done on a wide range of human cell lines and tissues confirmed the level of RPL19 mRNA to be 5-fold higher in malignant cell lines and 8-fold higher in malignant tissues, when compared with their benign counterparts. Analysis of RPL19 mRNA expression by in situ hybridization revealed a significant increase of RPL19 expression in a substantial number of prostate cancers. All of the eight normal prostatic tissues were unstained (100%). Of 32 benign prostatic hyperplasia (BPH) tissues, 15 (46.9%) were unstained, 9 (28.1%) stained weakly, and 8 (25%) stained moderately. Among 87 carcinomas, only 7 (8.1%) were unstained, whereas 22 (25.2%) stained weakly, 21 (24.1%) stained moderately, and 37 (42.61%) stained strongly. The intensity of staining of the malignant specimens was significantly higher than that of normal and BPH specimens (χ2: n = 127, P &lt; 0.001). Gleason scores of the carcinomas correlated with RPL19 expression (χ2: n = 87, P &lt; 0.001). Kaplan-Meier survival analysis confirmed increased RPL19 expression to be highly predictive of shorter patient survival (P &lt; 0.05), revealing RPL19 to be a sensitive predictor of prostate cancer progression. Expression of this protein could be a valuable marker in prostate cancer diagnosis and patient management.
Cytokine-Based Therapy and Biochemotherapy for Advanced Melanoma
Authors: Atkins Michael B. 
Published: April 2006

Abstract
A variety of immunotherapeutic approaches have shown activity in patients with metastatic melanoma with the best results being observed with interleukin 2 (IL-2). Follow-up data through 2004 confirm the durability of responses produced by the Food and Drug Administration–approved high-dose IL-2 regimen in this patient population. Efforts to develop more tolerable and/or effective IL-2–based treatment regimens by either prolonged administration of lower doses or the combination of IL-2 with other cytokines, monoclonal antibodies, or vaccines have yet to produce results superior to those seen with high-dose IL-2 alone. Recent investigations have suggested that, in some patients, IL-2 may expand regulatory T-cell populations leading to immune tolerance rather than antitumor immunity. Efforts to shift this balance in favor of immune rejection by reducing the confounding effects of regulatory T cells on IL-2 therapy or the use of novel and potentially more purely immunostimulatory cytokines are ongoing. Despite promising phase 2 data, phase 3 studies have failed to show meaningful clinical benefit for the combination of cytokines with cytotoxic chemotherapy, so-called “biochemotherapy.” Nonetheless, recent investigations with biochemotherapy followed by maintenance immunotherapy suggest that biochemotherapy may still have a role as a “bridge to immunotherapy” in some patients with rapidly progressive disease. Given the low number of patients achieving durable benefit with cytokine-based immunotherapy, considerable recent effort has focused on identifying predictors of therapeutic response. Investigations suggest that immune responsiveness may be predetermined by a tumor microenvironment conducive to immune recognition and the host propensity to develop autoimmunity. Efforts to understand and further define pretreatment predictors of response through the use of gene expression and proteomic techniques are ongoing and raise the potential for eventually limiting cytokine-based immunotherapy to those most likely to benefit.
Pathology of Melanoma
Authors: Elder David E. 
Published: April 2006

Abstract
The purposes of pathologic examination of a lesion suspected of being a malignant melanoma are to provide an accurate diagnosis of melanoma (or not), and to provide prognostic information useful in the clinical management of the patient. In the near future, pathologic attributes will also likely be used to predict responses to therapy, as a guide to the selection of specific therapeutic agents such as “small molecule” inhibitors of signaling pathways.
Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation Response
Authors: Sarkaria Jann N. , Carlson Brett L. , Schroeder Mark A. , Grogan Patrick , Brown Paul D. , Giannini Caterina , Ballman Karla V. , Kitange Gaspar J. , Guha Abjahit , Pandita Ajay , James C. David 
Published: April 2006

Abstract
Purpose: The influence of epidermal growth factor receptor (EGFR) amplification on glioblastoma patient prognosis following definitive radiotherapy has been extensively investigated in clinical studies, and yet the relationship between EGFR status and radiation response remains unclear. The intent of the current study was to address this relationship using several EGFR-amplified glioblastoma xenografts in an orthotopic athymic mouse model.
Experimental Design: We examined the effect of radiation on the survival of nude mice with intracranial xenografts derived from 13 distinct patient tumors, 7 of which have amplified EGFR. Mice with established intracranial tumors were randomized to sham treatment or 12-Gy radiation in six fractions delivered over 12 days.
Results: For six of the xenografts, radiation of mice with intracranial tumor significantly extended survival, and four of these xenografts had EGFR amplification. For seven other xenografts, radiation treatment did not significantly extend survival, and three of these, including GBM12, had EGFR amplification. Similar to EGFR, the tumor genetic status of p53 or PTEN did not show preferential association with radiation-sensitive or radiation-resistant xenografts whereas hyperphosphorylation of Akt on Ser473 was associated with increased radioresistance. To specifically investigate whether inhibition of EGFR kinase activity influences radiation response, we examined combined radiation and EGFR inhibitor treatment in mice with intracranial GBM12. The combination of oral erlotinib administered concurrently with radiation resulted only in additive survival benefit relative to either agent alone.
Conclusions: Our results indicate that EGFR amplification, as a biomarker, is not singularly predictive of glioblastoma response to radiation therapy, nor does the inhibition of EGFR enhance the intrinsic radiation responsiveness of glioblastoma tumors. However, efficacious EGFR inhibitor and radiation monotherapy regimens can be used in combination to achieve additive antitumor effect against a subset of glioblastoma.
Strategies for the Development of More Effective Adjuvant Therapy of Melanoma: Current and Future Explorations of Antibodies, Cytokines, Vaccines, and Combinations
Authors: Kirkwood John M. , Moschos Stergios , Wang Wenjun 
Published: April 2006

Abstract
Adjuvant trials have evaluated the influence of multiple agents on relapse and mortality for patients with intermediate-risk (stage IIA, American Joint Committee on Cancer staging manual, 6th ed.), high-risk (stage IIB-III), or very high-risk (stage IIIB-IV) operable melanoma. A 25% to 33% reduction of relative relapse risk with high-dose IFN-α2b therapy has been documented in stage groups overall, with survival prolongation in two of these trials. In contrast, no large cooperative group trial has ever shown a significant prolongation of survival for inoperable advanced stage IV melanoma. The basis for the failure of therapies in advanced disease may lie in differences in the immune function of patients with active metastatic stage IV disease. These observations argue for the exploration of promising new therapies in adjuvant settings. Past adjuvant studies have targeted stage IIB-III patients, focusing less on the more advanced but resectable stage IIIB and IV (M1a-b) disease groups. Current chemobiotherapy (S0008) and granulocyte-macrophage colony-stimulating factor plus peptide vaccination (E4697) trials have now evaluated the higher-risk disease groups where trials may soon be expected to yield results. Predictive markers that would allow us to focus treatment on those patients who are most likely to respond would accelerate our development of adjuvant therapy for melanoma. We have recently developed a neoadjuvant approach to high-dose IFN in which the molecular and immunologic effects of IFN have been correlated with clinical antitumor effects of this therapy. In addition, the Hellenic Oncology group has shown that the benefit of high-dose IFN is closely correlated with serologic and clinical manifestations of autoimmunity. These new insights will allow us to develop more efficient approaches to adjuvant therapy of melanoma, focusing on autoimmunity and antitumor immunity with new immunomodulators, such as anti-CTLA4 antibodies and vaccination.
Molecular Targets in Melanoma from Angiogenesis to Apoptosis
Authors: Sosman Jeffrey A. , Puzanov Igor 
Published: April 2006

AbstractAngiogenesis is a hallmark of melanoma progression. Antiangiogenic agents have been infrequently tested in patients with advanced melanoma. Experience with most other cancers suggests that single-agent application of angiogenic inhibitors is unlikely to have substantial clinical antitumor activity in melanoma. It is more likely that combinations of antiangiogenic agents with either chemotherapy or other targeted therapy will be needed to produce significant clinical benefit. In melanoma, numerous cellular pathways important to cell proliferation, apoptosis, or metastases have recently been shown to be activated. Activation occurs through specific mutations (B-RAF, N-RAS, and PTEN) or changes in expression levels of various proteins (PTEN, BCL-2, NF-κB, CDK2, and cyclin D1). Agents that block these pathways are rapidly entering the clinical setting, including RAF inhibitors (sorafenib), mitogen-activated protein kinase inhibitors (PD0325901), mammalian target of rapamycin inhibitors (CCI-779), and farnesyl transferase inhibitors (R115777) that inhibit N-RAS and proteasome inhibitors (PS-341) that block activation of nuclear factor-κB (NF-κB). It will be a challenge to evaluate these agents alone, in combination with each other, or with chemotherapy in patients with melanoma. Trials with large populations of biologically ill-defined tumors run the risk of missing clinical antitumor activity that is important for a particular yet-to-be-defined subset of patients. To rationally and optimally develop these targeted agents, it will be critical to adequately test for the presence of the presumed cellular target in tumor specimens and the effect of therapy on the proposed target (biological response). Investigators in this field will need to carefully plan these trials so that at the end of the day, we learn from both the failures and successes of targeted therapy.
Progress and Prospects on Melanoma: The Way Forward for Early Detection and Reduced Mortality
Authors: Weinstock Martin A. 
Published: April 2006

Abstract
The public health problem of melanoma is difficult. Recent decades have seen substantial efforts directed at primary prevention, yet the incidence of melanoma continues to increase. Substantial efforts have been devoted to improving treatment, yet melanoma retains a poor prognosis if simple surgical excision is not curative. Early detection has made remarkable progress, however. Five-year relative survival has increased from approximately 80% in 1975 to greater than 90% in 1996. Even so, almost 8,000 Americans are projected to succumb to melanoma in 2005. Because most of these fatal melanomas are visible on the skin surface at a curable phase in their evolution, more can and must be done. To improve the early detection practices of clinicians, we have developed an eight-step Basic Skin Cancer Triage algorithm, which forms the core of a curriculum that we have shown can result in improved skills, attitudes, and practices. We are now in the process of attempting to test a Web-based version of that curriculum in a randomized trial. Skin self-examination also has tremendous potential for contributing to early detection of melanoma. We have tested an intervention to encourage thorough skin self-examination in a randomized trial and found it effective in increasing the performance of this procedure, on increase that is sustained for at least a year, while resulting in only short-term increases in surgical procedures on the skin. Early detection has not yet reached its full potential effect on the public health problem of melanoma and is poised to further reduce melanoma mortality.
Development and Therapeutic Options for the Treatment of Raloxifene-Stimulated Breast Cancer in Athymic Mice
Authors: O'Regan Ruth M. , Osipo Clodia , Ariazi Eric , Lee Eun Sook , Meeke Kathleen , Morris Caroline , Bertucci Anne , Sarker Mohammad A.B. , Grigg Ronald , Jordan V. Craig 
Published: April 2006

Abstract
Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women.
Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance.
Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERα in cells derived from the MCF-7RALT tumors.
Conclusions: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERα activity.
Early-Stage Melanoma: Staging Criteria and Prognostic Modeling
Authors: Ross Merrick I. 
Published: April 2006

AbstractAccurate risk assessment is central to the process of making rational surgical and systemic treatment recommendations for melanoma patients and in establishing appropriate clinical trial stratification criteria. The current American Joint Commission on Cancer melanoma staging system incorporated relevant prognostic variables to provide a framework for the estimation of risk for recurrence; however, significant prognostic heterogeneity exists within the stage groupings. In the stage I/II group, survival rates range from 40% to 95% as defined by the combination of tumor thickness and ulceration. The use of novel prognostic factors, such as mitotic rate, sentinel node biopsy, and prognostic modeling using a variety of factors, can minimize this prognostic heterogeneity and provide a more accurate and individualized prognostic profile. Recent modifications in the stage III criteria include the number of positive nodes, whether the nodal disease is microscopic or clinically apparent, and the presence of an ulcerated primary. Through these factors, survival estimates can be provided, but like the stage I/II group, wide ranges in prognosis exist. The complexion of the stage III population is in evolution as a result of increasing numbers of patients being diagnosed as having microscopic sentinel node disease. Contemporary efforts are focused on defining the prognosis and natural history of this group. Through prognostic modeling using the number of nodes involved, ulceration status, and a measure of disease burden—disease in the sentinel node—relatively homogeneous subgroups can be identified. Long-term follow-up of patients staged with PCR molecular techniques on sentinel nodes shows conflicting value in assessing prognosis and therefore cannot be routinely used outside a clinical trial. The combination of genomic profiling using microarray analyses and the development of targeted therapy holds the future promise of individualizing prognosis and therapy.
Allogeneic MHC Gene Transfer Enhances Antitumor Activity of Allogeneic Hematopoietic Stem Cell Transplantation without Exacerbating Graft-versus-Host Disease
Authors: Ohashi Masaki , Kobayashi Akihiko , Hara Hidehiko , Miura Yoshiaki , Yoshida Kimiko , Kushida Miwa , Ikarashi Yoshinori , Mandai Masaki , Kitajima Masaki , Yoshida Teruhiko , Aoki Kazunori 
Published: April 2006

AbstractEnhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen–mismatched alloHSCT (DBA/2→BALB/c: H-2d) recipients, alloMHC gene (H-2Kb) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2Kb gene transfer provides only a limited antitumor effect after syngeneic (BALB/c→BALB/c) HSCT. By contrast, the H-2Kb gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2Kb gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.
Josephus' Rewriting of the Babel Narrative (Gen 11:1-9)
Authors: Inowlocki Sabrina 
Published: April 2006

AbstractThis paper analyzes Josephus' appropriation of the biblical episode of the tower of Babel. It aims to highlight its originality as well as its purposes. Its methodology is two-fold: firstly, it recasts Josephus' passage in the context of the contemporary Jewish literature in general and of Josephus' writings in particular; secondly, it closely examines its language. This analysis reveals that Josephus was inspired by his own experience during the war in Judaea, and therefore presents the episode of Babel as a political-theological myth. In addition, this study explores the manner in which Josephus used the biblical narrative in order to polemicize against the Greeks.