bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin
Authors: Witham James , Valenti Melanie R. , De-Haven-Brandon Alexis K. , Vidot Susanne , Eccles Suzanne A. , Kaye Stan B. , Richardson Alan 
Published: December 2007

Abstract
Purpose: The effective treatment of ovarian cancer is hampered by the development of drug resistance, which may be mediated by members of the Bcl-2 family of apoptosis regulators. ABT-737 is a recently described inhibitor of members of this family. We investigated whether this compound could sensitize ovarian cancer cells to chemotherapeutic agents.
Experimental Design: The sensitivity of ovarian cancer cell lines to ABT-737 in combination with either carboplatin or paclitaxel was tested either in vitro by assessing cell growth/survival and apoptosis or in xenograft studies.
Results: As a single agent, ABT-737 inhibited the growth of eight ovarian cancer cell lines, although with relatively poor potency. However, ABT-737, but not a less active enantiomer, increased the sensitivity of several cell lines to carboplatin. The increased sensitivity to carboplatin was accompanied by a decrease in time at which apoptosis was observed when assessed according to the number of attached cells, PARP cleavage, and nucleosome formation. ABT-737 was more effective at sensitizing IGROV-1 cells when ABT-737 was administered after carboplatin. In addition, ABT-737 significantly enhanced the activity of carboplatin in one of three primary cultures derived directly from ascitic tumor cells in patients recently treated with chemotherapy. Small interfering RNA directed to Bcl-XL also increased the sensitivity of ovarian cancer cell lines to carboplatin. ABT-737 was also able to augment the inhibition of IGROV-1 tumor xenograft growth beyond that obtained with carboplatin alone.
Conclusions: These data suggest that ABT-737, in combination with carboplatin, may find utility in the treatment of patients with ovarian cancer.
Telomere DNA Content Predicts Breast Cancer–Free Survival Interval
Authors: Heaphy Christopher M. , Baumgartner Kathy B. , Bisoffi Marco , Baumgartner Richard N. , Griffith Jeffrey K. 
Published: December 2007

Abstract
Background: Telomeres are nucleoprotein complexes that protect chromosome ends from degradation and recombination. Critically shortened telomeres generate genomic instability. It has been postulated that the extent of telomere DNA loss is related to the degree of genomic instability within a tumor and therefore may presage clinical outcome. The objective of this investigation was to evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissues predicts breast cancer–free survival interval.
Materials and Methods: Slot blot titration assay was used to quantitate TC in 530 archival breast tumor tissues in a population-based cohort. The relationships between TC, 12 risk factors for breast cancer adverse events (i.e., death due to breast cancer, breast cancer recurrence, or development of a new primary breast tumor), and breast cancer–free survival interval were evaluated by Fisher's exact test, log-rank analysis, and univariate and multivariate Cox proportional hazards models.
Results: TC was independent of each of the 12 risk factors. Ethnicity, tumor-node-metastasis stage, estrogen receptor, progesterone receptor, and p53 status, chemotherapy sequence, adjuvant therapy, and TC each conferred significant relative hazards. The best overall multivariate Cox proportional hazards model included TC, p53 status, tumor-node-metastasis stage, and estrogen receptor status as independent predictors of breast cancer–free survival interval (P &lt; 0.00005). Low TC (≤200% of standard), relative to the high-TC group (&gt;200% of standard), conferred an adjusted relative hazard of 2.88 (95% confidence interval, 1.16-7.15; P = 0.022) for breast cancer–related adverse events.
Conclusions: TC in breast cancer tissue is an independent predictor in this group of breast cancer–free survival interval.
Reversal of the Estrogen Receptor–Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response
Authors: Bayliss Jill , Hilger Amy , Vishnu Prakash , Diehl Kathleen , El-Ashry Dorraya 
Published: December 2007

Abstract
Purpose: In breast cancer, the presence of estrogen receptor α (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERα correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ERα expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERα− breast cancer cell lines and tumors results in reexpression of ERα, and further, if reexpression of ERα in these ERα− tumors and cell lines could restore antiestrogen responses.
Experimental Design: Established ERα− breast cancer cell lines, ERα− breast tumors, and tumor cell cultures obtained from ERα− tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ERα was used to assess the reexpression of ERα in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells.
Results: Inhibition of MAPK activity in ERα− breast cancer cell lines results in reexpression of ERα; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERα can now mediate an antiestrogen response in a subset of these ERα− breast cancer cell lines. Treatment of ERα− tumor specimens with MAPK inhibitors results in restoration of ERα mRNA, and similarly in epithelial cultures from ERα− tumors, MAPK inhibition restores both ERα protein and antiestrogen response.
Conclusions: These data show both the possibility of restoring ERα expression and antiestrogen responses in ERα− breast cancer and suggest that there exist ERα− breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.
Alteration of Cellular and Humoral Immunity by Mutant p53 Protein and Processed Mutant Peptide in Head and Neck Cancer
Authors: Couch Marion E. , Ferris Robert L. , Brennan Joseph A. , Koch Wayne M. , Jaffee Elizabeth M. , Leibowitz Michael S. , Nepom Gerald T. , Erlich Henry A. , Sidransky David 
Published: December 2007

AbstractPurpose: To determine if serologic recognition of p53 mutations at the protein level depends upon the ability of mutant p53 to express new peptide epitopes that bind to human leukocyte antigen (HLA) class II molecules, we used anti-p53 antibody production as a marker for HLA class II–restricted T-cell involvement in head and neck cancer.Experimental Design: An anti-p53 antibody response was correlated with specific p53 mutations and the patients' HLA class II alleles and haplotypes. HLA binding studies and in vitro stimulation (IVS) of peripheral blood mononuclear cells were done using a mutant versus wild-type HLA-DQ7-binding p53 peptide.Results: Certain HLA-DQ and HLA-DR alleles were frequently present in p53 seropositive patients who produced serum anti-p53 antibodies. Selected mutated p53 peptides fit published allele-specific HLA class II binding motifs for the HLA-DQ7 or HLA-DR1 molecules. Moreover, a mutant p53 peptide bound with a 10-fold greater affinity than the wild-type p53 peptide to HLA-DQ7 molecules. IVS of CD4+ T cells from seven healthy HLA-DQ7+ donors using this mutant p53 peptide (p53220C) was associated with a partial T helper type 2 phenotype compared with IVS using the wild-type p53210-223 peptide.Conclusions: Our results support the hypothesis that mutated p53 neoantigens can bind to specific HLA class II molecules, leading to a break in tolerance. This may lead to skewing of the CD4+ T lymphocyte response toward a tumor-permissive T helper type 2 profile in head and neck cancer patients, as manifested by seropositivity for p53.
CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer
Authors: Kiniwa Yukiko , Miyahara Yoshihiro , Wang Helen Y. , Peng Weiyi , Peng Guangyong , Wheeler Thomas M. , Thompson Timothy C. , Old Lloyd J. , Wang Rong-Fu 
Published: December 2007

Abstract
Purpose: Although elevated proportions of CD4+CD25+ regulatory T (Treg) cells have been shown in several types of cancers, very little is known about the existence and function of CD8+ Treg cells in prostate cancer. In this study, we investigated prostate tumor–derived CD8+ Treg cells and their function.
Experimental Design: Tumor-infiltrating lymphocytes (TIL) from fresh tumor specimens of patients with prostate cancer were generated and subjected to phenotypic and suppressive function analyses. In particular, we investigated the role and function CD8+ Treg cells in prostate cancer.
Results: We show that high percentages of CD4+CD25+ T cells are probably present in the majority (70%) of prostate TILs. Remarkably, both CD4+ and CD8+ T-cell subpopulations possessed potent suppressive activity. T-cell cloning and fluorescence-activated cell sorting analyses showed the presence of CD8+CD25+ Treg cell clones that expressed FoxP3 and suppressed naïve T-cell proliferation, in addition to the previously known CD4+CD25+ Treg cells. These CD8+ Treg cells suppressed naïve T-cell proliferation mainly through a cell contact–dependent mechanism. Importantly, the suppressive function of CD8+ Treg cells could be reversed by human Toll-like receptor 8 (TLR8) signaling.
Conclusion: Our study shows that like CD4+CD25+ Treg cells, CD8+ Foxp3+ Treg cells present in prostate tumor–derived TILs suppress immune responses and that their suppressive function can be regulated by TLR8 ligands, raising the possibility that the manipulation of Treg cell function by TLR8 ligands could improve the efficacy of immunotherapy for prostate cancer patients.
Phase I Study of Temozolomide and Irinotecan for Recurrent Malignant Gliomas in Patients Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study
Authors: Loghin Monica E. , Prados Michael D. , Wen Patrick , Junck Larry , Lieberman Frank , Fine Howard , Fink Karen L. , Metha Minesh , Kuhn John , Lamborn Kathleen , Chang Susan M. , Cloughesy Timothy , DeAngelis Lisa M. , Robins Ian H. , Aldape Kenneth D. , Yung W.K. Alfred 
Published: December 2007

AbstractPurpose: To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38.Design: Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m2) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m2, which was escalated to 550 mg/m2 in 50-mg/m2 increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1.Results: Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m2.Conclusions: The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m2, administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.
Glucocorticoids in the Treatment of Children with Acute Lymphoblastic Leukemia and Hodgkin's Disease: A Pilot Study on the Adverse Psychological Reactions and Possible Associations with Neurobiological, Endocrine, and Genetic Markers
Authors: Felder-Puig Rosemarie , Scherzer Christiane , Baumgartner Michaela , Ortner Magdalena , Aschenbrenner Claudia , Bieglmayer Christian , Voigtländer Till , Panzer-Grümayer E. Renate , Tissing Wim J.E. , Koper Jan W. , Steinberger Karl , Nasel Christian , Gadner Helmut , Topf Reinhard , Dworzak Michael 
Published: December 2007

AbstractPurpose: We did a controlled study to assess adverse psychological reactions (APR) associated with high-dose glucocorticoid therapy and tried to detect somatic correlates for the observed reactions.Patients and Methods: Our study included 37 patients with acute lymphoblastic leukemia (ALL) and 11 patients with Morbus Hodgkin (MH) disease, who were treated with high-dose glucocorticoid therapy, and 26 control patients with other types of malignancies. APRs were assessed with a standardized measure via parent-report. Patients with ALL and MH were further analyzed for signs of neuronal cell death in the cerebrospinal fluid, polymorphisms of the glucocorticoid receptor gene, as well as cortisol, adrenocorticorticotropic hormone, and dehydroepiandrosterone sulfate blood levels.Results: Fifty-four percent of ALL, 36% of MH, and 23% of control patients developed APR in the first few weeks of therapy. Approximately 3.5 months later, the majority of patients with ALL showed no APR, similar to control patients. Patients demonstrating a higher, nonsuppressible secretion of cortisol and/or adrenocorticorticotropic hormone during glucocorticoid therapy were found to be more likely to develop APR. No sign of neuronal cell destruction and no correlation of APR with specific glucocorticoid receptor polymorphisms were found.Conclusion: Our results suggest that the development of APR due to glucocorticoid therapy is measurable and correlates with hormonal reaction patterns.
Selective Inhibition of Fatty Acid Synthase for Lung Cancer Treatment
Authors: Orita Hajime , Coulter Jonathan , Lemmon Colleen , Tully Ellen , Vadlamudi Aravinda , Medghalchi Susan M. , Kuhajda Francis P. , Gabrielson Edward 
Published: December 2007

Abstract
Purpose: Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. However, in vitro use of previous generations of FAS inhibitors has been limited by severe, but reversible, anorexia in treated animals, which is thought to be related to a parallel stimulation of fatty acid oxidation by these agents. This study investigated pharmacologic inhibition of FAS using C93, a rationally designed molecule that inhibits FAS activity without affecting fatty acid oxidation in preclinical models of lung cancer.
Experimental Design: Activity of C93 on FAS and fatty acid oxidation was evaluated in cultured non–small cell lung cancer (NSCLC) cells. Antineoplastic activity of the compound, given orally or by i.p. injection, was evaluated in s.c. and orthotopic NSCLC xenografts.
Results: Our experiments confirm that C93 effectively inhibits FAS without stimulating fatty acid oxidation in lung cancer cells. More importantly, C93 significantly inhibits the growth of both s.c. and orthotopic xenograft tumors from human NSCLC cell lines without causing anorexia and weight loss in the treated animals.
Conclusions: We conclude that inhibition of FAS can be achieved without parallel stimulation of fatty acid oxidation and that inhibition of tumor growth in vivo can be achieved without anorexia and weight loss. Thus, this therapeutic strategy holds promise for clinical treatment of cancers, including non–small cell lung cancer, the leading cause of cancer mortality in the United States and Europe.
Negative Effect of DNA Hypermethylation on the Outcome of Intensive Chemotherapy in Older Patients with High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia following Myelodysplastic Syndrome
Authors: Grövdal Michael , Khan Rasheed , Aggerholm Anni , Antunovic Petar , Astermark Jan , Bernell Per , Engström Lena-Maria , Kjeldsen Lars , Linder Olle , Nilsson Lars , Olsson Anna , Wallvik Jonas , Tangen Jon Magnus , Öberg Gunnar , Jacobsen Sten Eirik , Hokland Peter , Porwit Anna , Hellström-Lindberg Eva 
Published: December 2007

Abstract
Purpose: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy.
Experimental Design: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-β-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15ink4b (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment.
Results: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile.
Conclusions: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
Stem Cell Marker Nestin and c-Jun NH2-Terminal Kinases in Tumor and Peritumor Areas of Glioblastoma Multiforme: Possible Prognostic Implications
Authors: Mangiola Annunziato , Lama Gina , Giannitelli Cecilia , De Bonis Pasquale , Anile Carmelo , Lauriola Libero , La Torre Giuseppe , Sabatino Giovanni , Maira Giulio , Jhanwar-Uniyal Meena , Sica Gigliola 
Published: December 2007

Abstract
Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH2-terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications.
Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance &lt;1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients' age, Karnofsky performance status, gender, protein expression, and survival were analyzed.
Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/tJNK)/nestin ratios in the second area were ≥2.619 and ≥0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis.
Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.
Interleukin-21 Signaling: Functions in Cancer and Autoimmunity
Authors: Davis Ian D. , Skak Kresten , Smyth Mark J. , Kristjansen Paul E.G. , Miller Dennis M. , Sivakumar Pallavur V. 
Published: December 2007

Abstract
Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4+ T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21–specific α chain (IL-21Rα; JAK/STAT) that heterodimerizes with the common γ chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.
Pilot Study of Neoadjuvant Treatment with Erlotinib in Nonmetastatic Head and Neck Squamous Cell Carcinoma
Authors: Thomas Fabienne , Rochaix Philippe , Benlyazid Adil , Sarini Jérôme , Rives Michel , Lefebvre Jean Louis , Allal Ben C. , Courbon Frédéric , Chatelut Etienne , Delord Jean-Pierre 
Published: December 2007

AbstractPurpose: To determine the safety and efficacy of erlotinib given as neoadjuvant treatment in patients with head and neck squamous cell carcinoma (HNSCC). Further objectives were to identify markers of response to erlotinib and to assess the pharmacodynamic effects of erlotinib in tumor cells.Experimental Design: Patients with locally advanced nonmetastatic HNSCC were treated with erlotinib 150 mg daily pending surgical management. Tumor samples were collected before and after erlotinib treatment and were analyzed using immunohistochemistry. Epidermal growth factor receptor copy number was determined in tumors using CISH analysis.Results: Between November 2003 and December 2005, 35 patients were included in the study. Neoadjuvant treatment with erlotinib in HNSCC patients was well tolerated and did not necessitate modification to routine surgical procedures. Among 31 evaluable patients, erlotinib was given for a median of 20 days. At the time of surgery, tumor shrinkage was observed in nine patients (29%). Immunohistochemistry analyses were done for 31 patients and showed a decrease in phosphorylated tyrosine residues and phosphorylated erk immunostaining after erlotinib treatment. In a retrospective analysis, baseline p21waf expression in the basal-like cell layer was statistically positively correlated with clinical response to treatment. Epidermal growth factor receptor copy number did not correlate with response to erlotinib.Conclusion: Neoadjuvant treatment of HNSCC with erlotinib was well tolerated. Baseline p21waf expression was associated with response to erlotinib and so might be useful as a tool to select patients for erlotinib therapy in this setting.