bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bladder Cancer Stage and Outcome by Array-Based Comparative Genomic Hybridization
Authors: Blaveri Ekaterini , Brewer Jeremy L. , Roydasgupta Ritu , Fridlyand Jane , DeVries Sandy , Koppie Theresa , Pejavar Sunanda , Mehta Kshama , Carroll Peter , Simko Jeff P. , Waldman Frederic M. 
Published: March 2006

Abstract
Purpose: Bladder carcinogenesis is believed to follow alternative pathways of disease progression driven by an accumulation of genetic alterations. The purpose of this study was to evaluate associations between measures of genomic instability and bladder cancer clinical phenotype.
Experimental Design: Genome-wide copy number profiles were obtained for 98 bladder tumors of diverse stages (29 pTa, 14 pT1, 55 pT2-4) and grades (21 low-grade and 8 high-grade superficial tumors) by array-based comparative genomic hybridization (CGH). Each array contained 2,464 bacterial artificial chromosome and P1 clones, providing an average resolution of 1.5 Mb across the genome. A total of 54 muscle-invasive cases had follow-up information available. Overall outcome analysis was done for patients with muscle-invasive tumors having “good” (alive &gt;2 years) versus “bad” (dead in &lt;2 years) prognosis.
Results: Array CGH analysis showed significant increases in copy number alterations and genomic instability with increasing stage and with outcome. The fraction of genome altered (FGA) was significantly different between tumors of different stages (pTa versus pT1, P = 0.0003; pTa versus pT2-4, P = 0.02; and pT1 versus pT2-4, P = 0.03). Individual clones that differed significantly between different tumor stages were identified after adjustment for multiple comparisons (false discovery rate &lt; 0.05). For muscle-invasive tumors, the FGA was associated with patient outcome (bad versus good prognosis patients, P = 0.002) and was identified as the only independent predictor of overall outcome based on a multivariate Cox proportional hazards method. Unsupervised hierarchical clustering separated “good” and “bad” prognosis muscle-invasive tumors into clusters that showed significant association with FGA and survival (Kaplan-Meier, P = 0.019). Supervised tumor classification (prediction analysis for microarrays) had a 71% classification success rate based on 102 unique clones.
Conclusions: Array-based CGH identified quantitative and qualitative differences in DNA copy number alterations at high resolution according to tumor stage and grade. Fraction genome altered was associated with worse outcome in muscle-invasive tumors, independent of other clinicopathologic parameters. Measures of genomic instability add independent power to outcome prediction of bladder tumors.
Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity
Authors: Ko Sae Hee , Ueno Tomio , Yoshimoto Yasunori , Yoo Jin Soo , Abdel-Wahab Omar I. , Abdel-Wahab Zeinab , Chu Edward , Pruitt Scott K. , Friedman Henry S. , Dewhirst Mark W. , Tyler Douglas S. 
Published: March 2006

Abstract
Purpose: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion.
Experimental Design: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5°C), or hyperthermic (43°C) conditions.
Results: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion.
Conclusion: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide.
Inhibition of Nuclear Translocation of Nuclear Factor-κB Despite Lack of Functional IκBα Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies
Authors: Thomas Roman K. , Sos Martin L. , Zander Thomas , Mani Özlem , Popov Alexey , Berenbrinker Daniel , Smola-Hess Sigrun , Schultze Joachim L. , Wolf Jürgen 
Published: March 2006

AbstractPurpose: Defective apoptosis signaling is a typical feature of classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. In these malignancies, the transcription factor nuclear factor-κB (NF-κB) is a critical mediator of apoptosis resistance and oncogenic growth, making it an attractive therapeutic target. Here, we sought to determine how to overcome apoptosis resistance experimentally in these malignancies by targeting NF-κB.Experimental Design: We investigated the effect of different inhibitors of NF-κB on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively.Results: The cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2, a known inhibitor of NF-κB, induced caspase-dependent apoptosis; it restored mitochondrial apoptotic signaling by down-regulation of X-linked inhibitor of apoptosis protein and heat shock protein 27 and led to breakdown of the mitochondrial membrane potential and, finally, cleavage of caspase-3 irrespective of IκBα mutational status. Surprisingly, 15-deoxy-Δ12,14-prostaglandin J2 and the IκB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IκBα, suggesting that inhibition of nuclear translocation of NF-κB can occur in the absence of IκBα. Finally, a synthetic peptide that specifically abrogates the assembly of the IκB kinase complex killed IκBα-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-κB.Conclusions: These results show that molecular defects in apoptotic signaling, such as IκBα mutations, can be circumvented by targeting NF-κB through inhibition of the IκB kinase complex followed by induction of apoptosis in classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. Thus, targeting IκB kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status of IκBα.
Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology.
Authors: Gerber Bernd , Krause Annette , Reimer Toralf , Mylonas Ionas , Makovitzky Josef , Kundt G√ºnther , Janni Wolfgang 
Published: March 2006

Abstract
PURPOSE: To investigate the effect of switching from adjuvant tamoxifen to anastrozole (Arimidex) treatment in postmenopausal women with endocrine-responsive breast cancer and histologically proven tamoxifen-induced benign endometrial pathology. EXPERIMENTAL DESIGN: Two hundred twenty-six postmenopausal women who had received adjuvant tamoxifen 20 mg/d (&gt; or =12 months, &lt; or =48 months) and developed abnormal vaginal bleeding and/or an asymptomatic endometrial thickness &gt;10 mm [measured by transvaginal ultrasound (TVUS)] were subjected to hysteroscopy and dilation and curettage (D&C). Thereafter, 171 patients were randomized in a phase III study to continue tamoxifen treatment (n = 88) or switch to anastrozole 1 mg/d (n = 83). Patients were monitored for &lt; or =42 months using TVUS at 6-monthly intervals. RESULTS: At study entry, there were no significant differences in vaginal bleeding, endometrial thickness, and histologic findings between the two treatment groups. Throughout the treatment period, there was no significant difference in recurrent vaginal bleeding between groups [anastrozole, 4 of 83 (4.8%); tamoxifen, 9 of 88 (10.2%); P = 0.18]. Six months after randomization, the mean endometrial thickness for patients who switched to anastrozole was significantly reduced compared with those who continued tamoxifen treatment (P &lt; 0.0001). Significantly fewer anastrozole patients required a repeat hysteroscopy and D&C compared with those on tamoxifen [4 of 83 (4.8%) and 29 of 88 (33.0%), respectively; P &lt; 0.0001]. Repeat hysteroscopy and D&C revealed endometrial atrophy in all 4 cases in the anastrozole group and 14 polyps, 8 hyperplasias, and 7 atrophies in the tamoxifen group. CONCLUSIONS: Switching from tamoxifen to anastrozole treatment significantly reduced the need for a second hysteroscopy and D&C due to recurrent vaginal bleeding or thickening of the endometrium in postmenopausal breast cancer patients with tamoxifen-induced endometrial abnormalities.
Expressions of Nuclear Factor κB, Inducible Nitric Oxide Synthase, and Vascular Endothelial Growth Factor in Adenoid Cystic Carcinoma of Salivary Glands: Correlations with the Angiogenesis and Clinical Outcome
Authors: Zhang Jiali , Peng Bin , Chen Xinming 
Published: March 2006

Abstract
Objective: To evaluate the expressions of nuclear factor κB (NF-κB p65), inducible nitric oxide synthase enzyme (iNOS), and vascular endothelial growth factor (VEGF) in relation to angiogenesis (microvessel density, MVD) and clinical outcomes in adenoid cystic carcinoma (ACC) of salivary glands.
Methods: Immunohistochemical staining was used to quantify the protein expression levels of NF-κB p65, iNOS, and VEGF in 80 surgically resected ACCs and 20 normal salivary tissues. In all cases of ACCs, MVD was evaluated by counting CD34-reactive endothelial cells or endothelial cell clusters.
Results: The nuclear localization of NF-κB p65 was only detected in ACC cells. Both iNOS and VEGF staining activities in ACCs were more significant than those in normal gland tissues (P &lt; 0.01). MVD had significant correlations with NF-κB p65, iNOS, and VEGF expressions (P &lt; 0.01). In three histologic types of ACCs, the NF-κB, iNOS, VEGF expressions, and MVD were significantly higher in solid type than in cribriform and tubular types (P &lt; 0.01). The NF-κB, iNOS, VEGF expressions, and MVD were significantly correlated with clinical stage, tumor size, vascular invasion, recurrence, and metastasis (P &lt; 0.05). Multivariate analysis showed NF-κB, iNOS and VEGF expression, MVD, solid histotype, and perineural invasion had an independent prognostic effect on overall survival.
Conclusion: The expressions of NF-κB p65, iNOS, and VEGF were related with MVD. Clinical outcomes raised the possibility that the overexpression of these cytokines might contribute to tumor angiogenesis and have prognostic value in ACCs.
Phase I Trial of a Monoclonal Antibody Specific for αvβ3 Integrin (MEDI-522) in Patients with Advanced Malignancies, Including an Assessment of Effect on Tumor Perfusion
Authors: McNeel Douglas G. , Eickhoff Jens , Lee Fred T. , King David M. , Alberti Dona , Thomas James P. , Friedl Andreas , Kolesar Jill , Marnocha Rebecca , Volkman Jennifer , Zhang Jianliang , Hammershaimb Luz , Zwiebel James A. , Wilding George 
Published: March 2006

Abstract
At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the αvβ3 integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the αvβ3 integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at αvβ3 could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the αvβ3 integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, &gt;1 and &gt;2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.
Estrogen Receptor β Polymorphism Is Associated with Prostate Cancer Risk
Authors: Thellenberg-Karlsson Camilla , Lindström Sara , Malmer Beatrice , Wiklund Fredrik , Augustsson-Bälter Katarina , Adami Hans-Olov , Stattin Par , Nilsson Maria , Dahlman-Wright Karin , Gustafsson Jan-Åke , Grönberg Henrik 
Published: March 2006

Abstract
Purpose: After cloning of the second estrogen receptor, estrogen receptor β (ERβ) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ERβ is thought to exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ERβ gene are associated with prostate cancer risk.
Experimental Design: We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ERβ gene from the promoter to the 3′-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects.
Results: There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen.
Conclusion: We found an association with a SNP located in the promoter region of the ERβ gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ERβ is of importance for risk of prostate cancer.
Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis
Authors: Hagan Suzanne , Al-Mulla Fahd , Mallon Elizabeth , Oien Karin , Ferrier Rhona , Gusterson Barry , Curto García Jorge J. , Kolch Walter 
Published: March 2006

Abstract
Purpose: Raf-1 kinase inhibitor protein (RKIP) was originally identified as the first physiologic inhibitor of the Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway. This pathway regulates fundamental cellular functions, including those that are subverted in cancer cells, such as proliferation, transformation, survival, and metastasis. Recently, RKIP has been recognized as a strong candidate for a metastasis suppressor gene in cell and animal model systems. Therefore, we investigated whether RKIP expression is altered in clinical specimens of human primary breast cancers and their lymph node metastases.
Experimental Design: Paraffin-embedded tumor samples from 103 breast cancer patients were examined immunohistochemically for the expression of RKIP, activated ERK, and apoptosis. The specificity of the antibodies used was validated by competition experiments with purified recombinant RKIP protein.
Results: RKIP expression was high in breast duct epithelia and retained to varying degrees in primary breast tumors. However, in lymph node metastases, RKIP expression was highly significantly reduced or lost (P = 0.000003). No significant correlations were observed between RKIP expression and histologic type, tumor differentiation grade, size, or estrogen receptor status.
Conclusion: This is the first study of RKIP expression in a large clinical cohort. It confirms the results of cell culture and animal studies, suggesting that in human breast cancer, RKIP is a metastasis suppressor gene whose expression must be down-regulated for metastases to develop. RKIP expression is independent of other markers for breast cancer progression and prognosis.
Curcumin Suppresses Growth of Head and Neck Squamous Cell Carcinoma
Authors: LoTempio Maria M. , Veena Mysore S. , Steele Helen L. , Ramamurthy Bharathi , Ramalingam Tirunelveli S. , Cohen Alen N. , Chakrabarti Rita , Srivatsan Eri S. , Wang Marilene B. 
Published: March 2006

Abstract
Purpose: The purpose of this study was to determine whether curcumin would trigger cell death in the head and neck squamous cell carcinoma (HNSCC) cell lines CCL 23, CAL 27, and UM-SCC1 in a dose-dependent fashion.
Experimental Design: HNSCC cells were treated with curcumin and assayed for in vitro growth suppression using 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide and fluorescence-activated cell sorting analyses. Expression of p16, cyclin D1, phospho-Iκβ, and nuclear factor-κβ (NF-κβ) were measured by Western blotting, gel shift, and immunofluorescence.
Results: Addition of curcumin resulted in a dose-dependent growth inhibition of all three cell lines. Curcumin treatment resulted in reduced nuclear expression of NF-κβ. This effect on NF-κβ was further reflected in the decreased expression of phospho-Iκβ-α. Whereas the expression of cyclin D1, an NF-κβ–activated protein, was also reduced, there was no difference in the expression of p16 at the initial times after curcumin treatment. In vivo growth studies were done using nude mice xenograft tumors. Curcumin was applied as a noninvasive topical paste to the tumors and inhibition of tumor growth was observed in xenografts from the CAL27 cell line.
Conclusions: Curcumin treatment resulted in suppression of HNSCC growth both in vitro and in vivo. Our data support further investigation into the potential use for curcumin as an adjuvant or chemopreventive agent in head and neck cancer.
Radiation Sensitivity of Human Carcinoma Cells Transfected with Small Interfering RNA Targeted against Cyclooxygenase-2
Authors: Palayoor Sanjeewani T. , Arayankalayil Moly J. , Shoaibi Azadeh , Coleman C. Norman 
Published: March 2006

Abstract
Purpose: Cyclooxygenase-2 (COX-2) is considered a potential target for cancer therapy, because COX-2 levels are elevated in the majority of human tumors compared with the normal tissues. COX-2 inhibitors inhibit tumor growth and enhance radiation response in vitro as well as in vivo. However, the precise role of COX-2 in radiation response is not clear. The purpose of the present study was to investigate the in vitro radiosensitivity of tumor cells as a function of COX-2 expression.
Experimental Design and Results: PC3 and HeLa cells express COX-2 protein constitutively. We silenced the COX-2 gene in these cells using small interfering RNA (siRNA). Transfection of PC3 cells with 100 nmol/L siRNA targeted against COX-2 resulted in reduction of COX-2 protein by 75% and inhibition of arachidonic acid–induced prostaglandin E2 synthesis by ∼50% compared with the vehicle control. In HeLa cells, 100 nmol/L COX-2 siRNA inhibited COX-2 protein expression by 80%. Cell cycle analysis showed that transfection with COX-2 siRNA did not alter the cell cycle distribution. Radiosensitivity was determined by clonogenic cell survival assay. There was no significant difference in the radiosensitivity of cells in which COX-2 was silenced compared with the cells transfected vehicle or with negative control siRNAs (enhancement ratio = 1.1).
Conclusions: These data indicate that the in vitro radiosensitivity of tumor cells is minimally dependent on the cellular COX-2 status. Given that a number of potential mechanisms are attributed to COX-2 inhibitors for radiosensitization, specific intervention of COX-2 by RNA interference could help elucidate the precise role of COX-2 in cancer therapy and to optimize strategies for COX-2 inhibition.
The Schedule-Dependent Effects of the Novel Antifolate Pralatrexate and Gemcitabine Are Superior to Methotrexate and Cytarabine in Models of Human Non-Hodgkin's Lymphoma
Authors: Toner Lorraine E. , Vrhovac Radovan , Smith Emily A. , Gardner Jeffrey , Heaney Mark , Gonen Mithat , Teruya-Feldstein Julie , Sirotnak Frank , O'Connor Owen A. 
Published: March 2006

Abstract
Purpose: Methotrexate is known to synergize with cytarabine [1-β-d-arabinofuranosylcytosine (ara-C)] in a schedule-dependent manner. The purpose of this article is to compare and contrast the activity of pralatrexate (10-propargyl-10-deazaminopterin)/gemcitabine to the standard combination of methotrexate/ara-C and to determine if schedule dependency of this combination is important in lymphoma.
Experiment Design: Cytotoxicity assays using the standard trypan blue exclusion assay were used to explore the in vitro activity of pralatrexate and gemcitabine against a panel of lymphoma cell lines. Both severe combined imunodeficient beige and irradiated nonobese diabetic/severe combined imunodeficient mouse xenograft models were used to compare and contrast the in vivo activity of these combinations as a function of schedule. In addition, apoptosis assays were conducted.
Results: Compared with methotrexate-containing combinations, pralatrexate plus gemcitabine combinations displayed improved therapeutic activity with some schedule dependency. The combination of pralatrexate and gemcitabine was superior to any methotrexate and ara-C combination in inducing apoptosis and in activating caspase-3. In vivo, the best therapeutic effects were obtained with the sequence of pralatrexate → gemcitabine. Complete remissions were only appreciated in animals receiving pralatrexate followed by gemcitabine.
Conclusions: These data show that the combination of pralatrexate followed by gemcitabine was superior to methotrexate/ara-C in vitro and in vivo, and was far more potent in inducing apoptosis in a large B-cell lymphoma. These data provide strong rationale for further study of this combination in lymphomas where methotrexate and ara-C are used.