bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-β and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas
Authors: Pagel John M. , Laugen Christian , Bonham Lynn , Hackman Robert C. , Hockenbery David M. , Bhatt Rama , Hollenback David , Carew Heather , Singer Jack W. , Press Oliver W. 
Published: September 2005

Abstract
Purpose: Lysophosphatidic acid acyltransferase-β (LPAAT-β) is a transmembrane enzyme critical for the biosynthesis of phosphoglycerides whose product, phosphatidic acid, plays a key role in raf and AKT/mTor-mediated signal transduction.
Experimental Design: LPAAT-β may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-β on multiple human non–Hodgkin's lymphoma cell lines in vitro and in vivo.
Results: We showed that five LPAAT-β inhibitors at doses of 500 nmol/L routinely inhibited growth in a panel of human lymphoma cell lines in vitro by &gt;90%, as measured by [3H]thymidine incorporation. Apoptotic effects of the LPAAT-β inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-β inhibitors induced caspase-mediated apoptosis at 50 to 100 nmol/L in up to 90% of non–Hodgkin's lymphoma cells. The combination of Rituximab and an LPAAT-β inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-β inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-β inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk × 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly × 4 weeks (4 doses total), or CT-32228 plus Rituximab combined. Treatment with either CT-32228 or Rituximab alone showed an approximate 50% xenograft growth delay; however, complete responses were only observed when the two agents were delivered together.
Conclusions: These data suggest that Rituximab, combined with a LPAAT-β inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.
Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue
Authors: Townsend Kelly , Banwell Claire M. , Guy Michelle , Colston Kay W. , Mansi Janine L. , Stewart Paul M. , Campbell Moray J. , Hewison Martin 
Published: September 2005

Abstract
Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer.
Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D–activating enzyme 1α-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41 tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1α-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.
Results: Expression of mRNA for 1α-hydroxylase (27-fold; P &lt; 5 × 10−11), vitamin D receptor (7-fold; P &lt; 1.5 × 10−8), and 24-hydroxylase (4-fold; P &lt; 0.02) was higher in breast tumors. 1α-Hydroxylase enzyme activity was also higher in tumors (44.3 ± 11.4 versus 12.4 ± 4.8 fmol/h/mg protein in nonneoplastic tissue; P &lt; 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D3 was also significantly higher in tumors (84.8 ± 11.7 versus 33.6 ± 8.5 fmol/h/mg protein; P &lt; 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH)2D3.
Conclusion: These data indicate that the vitamin D–activating enzyme 1α-hydroxylase is up-regulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)2D3 production in tumors by catalyzing catabolism to less active vitamin D metabolites. The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer.
Increased Cyclooxygenase-2 Expression in Duodenal Compared with Colonic Tissues in Familial Adenomatous Polyposis and Relationship to the −765G → C COX-2 Polymorphism
Authors: Brosens Lodewijk A.A. , Iacobuzio-Donahue Christine A. , Keller Josbert J. , Hustinx Steven R. , Carvalho Ralph , Morsink Folkert H. , Hylind Linda M. , Offerhaus G. Johan , Giardiello Francis M. , Goggins Michael 
Published: September 2005

Abstract
Background: Colorectal cancers arising in patients with familial adenomatous polyposis (FAP) can be largely prevented by polyp surveillance and prophylactic colectomy. As a result, duodenal adenocarcinoma has become a leading cause of death in patients with FAP. Cyclooxygenase 2 (COX-2) inhibition is effective against colorectal polyposis in FAP, but is less effective in treating duodenal polyps. We compared the expression of COX-2 in duodenal and colorectal adenomas from patients with FAP and from patients with sporadic neoplasms and correlated expression to a COX-2 promoter polymorphism (−765G/→C) that is reported to influence COX-2 expression.
Methods: The study population included 36 FAP patients with colonic adenomas, 22 FAP patients with duodenal adenomas, 22 patients with sporadic duodenal adenomas, and 17 patients with sporadic duodenal adenocarcinoma. Neoplastic and corresponding normal tissue COX-2 expressions were determined using immunohistochemistry on tissue microarrays. The prevalence and ethnic distribution of a polymorphism in the COX-2 promoter that influences COX-2 expression (−765G → C) were determined in DNA from 274 individuals by real-time quantitative PCR.
Results: Among patients with FAP, histologically normal duodenal mucosa showed higher COX-2 expression than normal colonic mucosa (P &lt; 0.02), and duodenal adenomas had higher COX-2 expression than colonic adenomas (P ≤ 0.01). In addition, the normal duodenum of patients with FAP showed higher COX-2 expression than the normal duodenal mucosa of patients with sporadic adenomas (P &lt; 0.05). COX-2 expression was significantly higher in the normal-appearing (P &lt; 0.01) mucosa of patients with FAP carrying the −765GG genotype compared with those carrying the −765GC or −765CC genotypes. The −765C genotype was more common in African Americans than in Caucasians (52% versus 33%, P &lt; 0.01).
Conclusions: High COX-2 expression in the normal and adenomatous duodenal mucosa of patients with FAP may explain the poorer response of these neoplasms to chemoprevention with COX-2 inhibitors.
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent
Authors: Yang Bo , Reynolds C. Patrick 
Published: September 2005

Abstract
Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.
The IgLON Family in Epithelial Ovarian Cancer: Expression Profiles and Clinicopathologic Correlates
Authors: Ntougkos Evangelos , Rush Robert , Scott Diane , Frankenberg Tobias , Gabra Hani , Smyth John F. , Sellar Grant C. 
Published: September 2005

Abstract
Purpose: The IgLON family of cell adhesion molecules, comprising OPCML, HNT, LSAMP, and NEGR1, has recently been linked to cancer, through two of its members being proposed as tumor suppressors. We examined the expression profile of the family in human sporadic epithelial ovarian cancer and the normal ovary.
Experimental Design: We determined the expression level of each IgLON in a panel comprising 57 tumor and 11 normal ovarian samples by quantitative real-time reverse transcription-PCR. The results were statistically tested for associations with clinicopathologic variables.
Results: OPCML, LSAMP and NEGR1 exhibited reduced expression in the tumor samples relative to the normal samples, whereas HNT expression was elevated. Statistically significant changes were specific to histologic type. The expression levels of individual IgLONs were correlated, the most significant finding being a positive correlation between LSAMP and NEGR1. LSAMP expression was also negatively correlated with overall survival and was found to be a negative predictor of outcome.
Conclusions: The expression of the IgLON family is altered in sporadic epithelial ovarian tumors in comparison to the normal ovary. In our small but representative cohort of patients, we have found significant correlations and associations in expression and clinicopathology that suggest a wider role of the family in ovarian cancer.
Patterns of Gene Expression That Characterize Long-term Survival in Advanced Stage Serous Ovarian Cancers
Authors: Berchuck Andrew , Iversen Edwin S. , Lancaster Johnathan M. , Pittman Jennifer , Luo Jingqin , Lee Paula , Murphy Susan , Dressman Holly K. , Febbo Phillip G. , West Mike , Nevins Joseph R. , Marks Jeffrey R. 
Published: September 2005

Abstract
Purpose: A better understanding of the underlying biology of invasive serous ovarian cancer is critical for the development of early detection strategies and new therapeutics. The objective of this study was to define gene expression patterns associated with favorable survival.
Experimental Design: RNA from 65 serous ovarian cancers was analyzed using Affymetrix U133A microarrays. This included 54 stage III/IV cases (30 short-term survivors who lived &lt;3 years and 24 long-term survivors who lived &gt;7 years) and 11 stage I/II cases. Genes were screened on the basis of their level of and variability in expression, leaving 7,821 for use in developing a predictive model for survival. A composite predictive model was developed that combines Bayesian classification tree and multivariate discriminant models. Leave-one-out cross-validation was used to select and evaluate models.
Results: Patterns of genes were identified that distinguish short-term and long-term ovarian cancer survivors. The expression model developed for advanced stage disease classified all 11 early-stage ovarian cancers as long-term survivors. The MAL gene, which has been shown to confer resistance to cancer therapy, was most highly overexpressed in short-term survivors (3-fold compared with long-term survivors, and 29-fold compared with early-stage cases). These results suggest that gene expression patterns underlie differences in outcome, and an examination of the genes that provide this discrimination reveals that many are implicated in processes that define the malignant phenotype.
Conclusions: Differences in survival of advanced ovarian cancers are reflected by distinct patterns of gene expression. This biological distinction is further emphasized by the finding that early-stage cancers share expression patterns with the advanced stage long-term survivors, suggesting a shared favorable biology.
Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy
Authors: Rouzier Roman , Perou Charles M. , Symmans W. Fraser , Ibrahim Nuhad , Cristofanilli Massimo , Anderson Keith , Hess Kenneth R. , Stec James , Ayers Mark , Wagner Peter , Morandi Paolo , Fan Chang , Rabiul Islam , Ross Jeffrey S. , Hortobagyi Gabriel N. , Pusztai Lajos 
Published: September 2005

Abstract
Purpose: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy.
Experimental Design: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported “breast intrinsic” gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class.
Results: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor–negative subtypes.
Conclusions: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.
Primary Allogeneic T-Cell Responses against Mantle Cell Lymphoma Antigen-Presenting Cells for Adoptive Immunotherapy after Stem Cell Transplantation
Authors: Hoogendoorn Mels , Olde Wolbers Judith , Smit Willem M. , Schaafsma M. Ronald , Jedema Inge , Barge Renee M.Y. , Willemze Roel , Falkenburg J.H. Frederik 
Published: September 2005

Abstract
Purpose: In patients treated with allogeneic stem cell transplantation for advanced mantle cell lymphoma (MCL), complete sustained remissions have been observed illustrating susceptibility of MCL cells to a graft-versus-lymphoma effect. To potentiate this graft-versus-lymphoma effect, adoptive transfer of in vitro selected MCL-specific CTL can be an attractive approach. The lack of expression of costimulatory molecules on MCL cells hampers the generation of MCL-reactive T-cell responses. The purpose of this study was to modify MCL cells into antigen-presenting cells (APC) and to use these MCL-APCs to induce allogeneic MCL-reactive T-cell responses.
Experimental Design: Interleukin (IL)-4, IL-10, CpG, and CD40 activation were tested for their capacity to up-regulate costimulatory molecules on MCL cells. Primary MCL cells or the modified MCL-APCs were then used to evaluate the induction of MCL-reactive T-cell responses in HLA-matched donors.
Results: Ligation of CD40 on MCL cells was essential to up-regulate costimulatory molecules and to induce production of high amounts of IL-12. In contrast to primary MCL cells, MCL-APC cells as stimulators were capable of inducing CD8+ CTL lines from HLA class I–matched donors. High numbers of CTL clones could be generated capable of efficiently killing the primary MCL cells and MCL-APC but not donor-specific targets.
Conclusion: These results show the feasibility to generate primary allogeneic T-cell responses against MCL-APC, and may provide new immunotherapeutic tools to further exploit the graft-versus-lymphoma effect following allogeneic stem cell transplantation in patients with MCL.
Estrogen Inhibits Cell Proliferation through In situ Production in Human Thymoma
Authors: Ishibashi Hironori , Suzuki Takashi , Suzuki Satoshi , Moriya Takuya , Kaneko Chika , Nakata Taisuke , Sunamori Makoto , Handa Masashi , Kondo Takashi , Sasano Hironobu 
Published: September 2005

Abstract
Purpose: We showed previously estrogen receptor (ER) α as an independent prognostic marker in human thymoma. Estrogen sulfotransferase (EST), steroid sulfatase (STS), 17β-hydroxysteroid dehydrogenase (17β-HSD), and aromatase are considered to play important roles in hormone metabolism of estrogen-dependent tumors.
Experimental Design: We examined estrogen production using primary cultures of human thymoma epithelial cells (TEC), intratumoral estradiol (E2) concentrations, and status of these enzymes above using immunohistochemistry or semiquantitative reverse transcription-PCR. We then correlated these findings with clinicopathologic variables and/or clinical outcome in 132 patients.
Results: E2 inhibited cell proliferation via ERα in TEC, which synthesized estrone and E2. Intratumoral E2 concentrations were inversely correlated with EST, positively correlated with STS or 17β-HSD type 1, and significantly higher in lower-grade or early-stage thymoma. EST status was positively correlated with tumor size, clinical stage, histologic differentiation, and Ki-67 labeling index and significantly associated with adverse clinical outcome and turned out to be a potent independent prognostic factor. STS and/or 17β-HSD type 1 status was inversely correlated with Ki-67 labeling index and associated with lower histologic grade or early clinical stages.
Conclusions: E2 inhibits proliferation of TEC through ERα, which suggests that E2 may be effective in treatment of thymoma, especially inoperable tumor, possibly through suppressing its cell proliferation activity. EST status is a potent prognostic factor in thymoma through inactivating estrogens. In situ estrogen synthesis through intracrine mechanism therefore may play important roles in tumorigenesis and/or development of thymoma through regulation of cell proliferation in an intracrine manner.
Tumor Dose Response to the Vascular Disrupting Agent, 5,6-Dimethylxanthenone-4-Acetic Acid, Using In vivo Magnetic Resonance Spectroscopy
Authors: McPhail Lesley D. , Chung Yuen-Li , Madhu Basetti , Clark Simon , Griffiths John R. , Kelland Lloyd R. , Robinson Simon P. 
Published: September 2005

Abstract
Purpose: To use 31P and 1H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response.
Experimental Design: In vivo 31P and 1H MRS measurements of (a) tumor bioenergetics [β-nucleoside triphosphate/inorganic phosphate (β-NTP/Pi)], (b) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), (c) choline (mmol/L), and (d) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution 31P and 1H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography.
Results: Both β-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in β-NTP/Pi with 15 mg/kg (P &lt; 0.001) and 21 mg/kg (P &lt; 0.01). A significant decrease in total choline in vivo was found 24 hours posttreatment with 21 mg/kg DMXAA (P &lt; 0.05); this was associated with a significant reduction in the concentration of the membrane degradation products glycerophosphoethanolamine and glycerophosphocholine measured in tissue extracts (P &lt; 0.05).
Conclusions: The reduction in tumor energetics and membrane turnover is consistent with the vascular-disrupting activity of DMXAA. 31P MRS revealed tumor response to DMXAA at doses below the maximum tolerated dose for mice. Both 31P and 1H MRS provide biomarkers of tumor response to DMXAA that could be used in clinical trials.
Gefitinib-Sensitive Mutations of the Epidermal Growth Factor Receptor Tyrosine Kinase Domain in Chinese Patients with Non–Small Cell Lung Cancer
Authors: Mu Xin Lin , Li Long Yun , Zhang Xiao Tong , Wang Men Zhao , Feng Rui E. , Cui Quan Cai , Zhou Hai Sheng , Guo Bing Qing 
Published: September 2005

Abstract
Purpose: Studies have shown that mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with response of lung cancer to gefitinib (Iressa, AstraZeneca Corp., Shanghai, China). A higher incidence of EGFR mutation was observed in non–small cell lung cancer (NSCLC) patients of Japanese origin compared with those of American origin. However, no data about such mutations in Chinese patients with NSCLC could be obtained.
Methods: Primary NSCLC tissues were obtained for analysis of mutations in exons 18 to 21 of EGFR from a total of 76 patients, of whom 54 did not receive gefitinib therapy and 22 did. PCR products were sequenced directly and mutations were confirmed by an independent PCR and sequence analysis. All types of mutation were cloned and sequenced.
Results: A total of 10 types of mutation were found in the series of patients, including two different silent mutations in exon 20 from 11 patients. More than half of the silent mutations (6 of 11) in exon 20 coexisted with other mutations. Mutations were more frequent in adenocarcinoma (17 of 35; 48.6%) compared with squamous carcinoma (1 of 19; 5.3%) among untreated patients. Similar mutations were observed in all seven gefitinib-treated patients with partial response, and no mutations were detected in all eight patients with progressive disease (P &lt; 0.001), except two silent mutations. Three mutations were observed in seven patients with stable disease.
Conclusions: Mutations in the epidermal growth factor receptor tyrosine kinase domain in lung adenocarcinomas from Chinese patients were more frequent than reported previously in lung adenocarcinomas from American patients. Such mutations were well correlated with tumor response to gefitinib.