bluuebunny/crossref_metadata_2025_split huggingface dataset:
The HCCR Oncoprotein as a Biomarker for Human Breast Cancer
Authors: Jung Sang Seol , Park Hyung Soon , Lee Insong James , Namkoong Hong , Shin Seung Min , Cho Goang Won , Ha Seon-Ah , Park Yong Gyu , Lee Youn Soo , Ko Jesang , Kim Jin Woo 
Published: March 2006

Abstract
Purpose: HCCR oncoprotein is reported to be related to tumorigenesis, including breast cancer, functioning as a negative regulator of p53. Mice transgenic for HCCR developed breast cancers. The objective of this study was to validate the HCCR oncoprotein as a candidate biomarker for breast cancer.
Experimental Design: HCCR expression in breast cancer cells was analyzed by quantitative PCR, ELISA, immunohistochemistry, Western blotting, fluorescence-activated cell sorting, and confocal microscopy. Epitope areas were determined using mass spectrometry through the analysis of time-dependent tryptic fragment patterns of HCCR. HCCR expression profiles in breast cancer patient sera were analyzed, and correlations with clinicopathologic data and carbohydrate antigen 15-3 (CA15-3) levels were determined.
Results: HCCR was up-regulated in breast cancer cells and tissues. The epitope regions of HCCR recognized by monoclonal antibody (BCS-1) were HFWTPK and QQTDFLDIYHAFR. According to fluorescence-activated cell sorting and confocal microscopic analysis, BCS-1 was bound to HCCR antigen on the cell surface. Serum HCCR concentrations were measured using ELISA from 299 subjects, including 129 patients with breast cancer, 24 patients with benign breast disease, and 158 normal volunteers, and comparisons were made to CA15-3. Serologic studies revealed an 86.8% sensitivity for HCCR in breast cancer, which was higher than 21.0% for CA15-3. Eighty-six of 98 (87.8%) patients with breast cancers that were negative for CA15-3 were positive for HCCR-1. A positive response rate of 83.3% was identified even at early stages for pathologic factors in breast cancer.
Conclusions: The HCCR assay has an advantage over CA15-3 in diagnosing breast cancer and detecting early stages of the disease.
CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients
Authors: Ozsahin Mahmut , Crompton Nigel E.A. , Gourgou Sophie , Kramar Andrew , Li Ling , Shi YuQuan , Sozzi Wendy Jeanneret , Zouhair Abderrahim , Mirimanoff René O. , Azria David 
Published: March 2006

Abstract
Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment.
Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence.
Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray's test, P &lt; 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of ≤16, 16 to 24, and &gt;24, respectively.
Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.
Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors
Authors: Cunningham Casey , Appleman Leonard J. , Kirvan-Visovatti Miora , Ryan David P. , Regan Eileen , Vukelja Svetislava , Bonate Peter L. , Ruvuna Francis , Fram Robert J. , Jekunen Antti , Weitman Steve , Hammond Lisa A. , Eder Joseph P. 
Published: March 2006

Abstract
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.
Patients and Methods: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m2. Pharmacokinetic samples were collected during the first course.
Results: Neutropenia was the principal DLT at the 45.7 mg/m2/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m2, experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of ≤55 minutes, and ∼11% was excreted unchanged in the urine.
Conclusion: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m2. The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.
Phase II Trial of the O6-Alkylguanine DNA Alkyltransferase Inhibitor O6-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma
Authors: Gajewski Thomas F. , Sosman Jeffrey , Gerson Stanton L. , Liu Lili , Dolan Eileen , Lin Shang , Vokes Everett E. 
Published: March 2006

Abstract
Purpose: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) induces DNA damage via a chloroethyl adduct at the O6 position of guanine, which can be repaired by O6-alkylguanine DNA alkyltransferase (AGT) expressed in melanoma. We postulated that the addition of O6 benzylguanine (O6BG), a potent inactivator of AGT, would improve the clinical response to BCNU in melanoma.
Experimental Design: Patients had measurable disease, adequate organ function, and a corrected Diffusing capacity of the lung for carbon monoxide (DLCO) of ≥70% predicted. They were accrued into two cohorts based on prior chemotherapy. O6BG (120 mg/m2) was administered i.v. followed by BCNU (40 mg/m2) on an outpatient basis. Peripheral blood mononuclear cells (PBMC) were collected pre- and 18 hours post-O6BG to analyze AGT depletion. Treatment was every 6 weeks, and clinical response was assessed after every two cycles.
Results: Forty-two patients were enrolled, 22 of these patients were chemotherapy-naïve. In the chemotherapy-naïve cohort, there was a patient with a complete response (CR), 4 with stable disease (SD), 13 with progressive disease (PD), and 4 nonevaluable patients; the median time to progression was 80 days and the median survival was 211 days. In the prior-chemotherapy cohort, there were no responses, 3 SD, 15 PD, and 2 nonevaluable patients; median time to progression was 54 days and median survival was 120 days. AGT was depleted from PBMC in the 15 patients tested. Grades 3 to 4 myelosuppression was seen in 57% of patients; toxicities were similar between the two cohorts.
Conclusions: O 6BG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppression was observed and the clinical outcome was not improved. Alternative mechanisms of resistance to melanoma cell death need to be investigated.
Gene expression profiles of head and neck carcinomas from Sudanese and Norwegian patients reveal common biological pathways regardless of race and lifestyle.
Authors: Dysvik Bjarte , Vasstrand Endre N , L√∏vlie Roger , Elgindi Osman A-Aziz , Kross Kenneth W , Aarstad Hans J , Johannessen Anne Chr , Jonassen Inge , Ibrahim Salah O 
Published: March 2006

Abstract
PURPOSE: To explore possible range of gene expression profiles in head and neck squamous cell carcinomas (HNSCC) and pairwised normal controls from Sudanese (n = 72) and Norwegian (n = 45) patients using a 15K cDNA microarray and to correlate the findings with clinicopathologic variables. EXPERIMENTAL DESIGN: Samples from Sudan were grouped according to anatomic location/patients' habit of toombak (snuff) use, and 37 pools of 2 to 11 tumors matched to 37 pools of their normal controls from the same patients, respectively, were prepared. For Norway, eight pools of 3 to 11 tumors matched to eight pools of their normal controls from the same patients, respectively, were prepared according to anatomic location. Pools (n = 45) were hybridized to microarrays. For controls, 33 of the pools were hybridized against Human Reference RNA. Scanned array images were recorded, and data analysis was done in groups. For verification, results for selected genes were analyzed using quantitative real-time PCR/immunohistochemistry. RESULTS: We identified 136 genes from Sudan and 154 from Norway as differentially expressed between tumors and controls. Changes of the genes found were confirmed in &gt;70% of the pools by hybridization against Reference RNA. Seventy-three genes and three main pathways (signal transduction, cell communication, and ligand-receptor interaction) were of relevance to the HNSCCs from both countries. Hierarchical clustering of the 73 genes identified subclasses of mixed tumors from the two populations, two independent subgroups for Norwegian tumors by their anatomic sites, and five subgroups for Sudanese tumors by their toombak habits. Quantitative real-time PCR/immunohistochemistry validated the microarray-based data. CONCLUSIONS: Differences in gene expression between tumor and nontumor tissues were identified in HNSCCs. Analysis of the two population groups revealed a common set of 73 genes within three main biological pathways. This indicates that the development of HNSCCs is mediated by similar biological pathways regardless of differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. Of particular interest, however, was the valuable association of gene expression signature found with toombak use and anatomic site of the tumors.
Definition of an Immunologic Response Using the Major Histocompatibility Complex Tetramer and Enzyme-Linked Immunospot Assays
Authors: Comin-Anduix Begoña , Gualberto Antonio , Glaspy John A. , Seja Elisabeth , Ontiveros Maribel , Reardon Deborah L. , Renteria Roberto , Englahner Brigitte , Economou James S. , Gomez-Navarro Jesus , Ribas Antoni 
Published: March 2006

Abstract
Purpose: Define an immunologic response using the tetramer and enzyme-linked immunospot (ELISPOT) assays.
Experimental Design: Ten healthy subjects and 21 patients with melanoma (all HLA-A*0201) donated a total of 121 blood samples to determine the lower limit of detection (LLD), analytic coefficient of variation (aCV), and physiologic CV (pCV) of the tetramer and ELISPOT assays. The mean, SD, and reference change value (RCV) were calculated to define changes beyond the assay imprecision, and its application was tested in the monitoring of T-cell expansion after CTLA4 blockade with ticilimumab (CP-675,206).
Results: The LLD for the tetramer assay was 0.038% CD8+ cells and seven spots per 105 peripheral blood mononuclear cells for the ELISPOT assay. The aCV of the tetramer assay was &lt;10% and was higher for the ELISPOT (24.69-36.32%). There was marked between-subject variability on baseline homeostatic values, which was correlated to prior antigen exposure. An immunologic response was defined as an increase beyond the mean + 3 SD in antigen-specific cells for subjects with baseline levels below the LLD, or beyond the assay RCV for baseline levels above the LLD. In four patients receiving ticilimumab, expansions of antigen-specific T cells beyond the assay variability were noted for EBV and MART1 antigens.
Conclusions: A combined approach of change from negative (below the LLD) to positive (above the LLD) and a percentage change beyond the assay variability using the RCV score can be computed to define which change in circulating antigen-specific T cells represents a response to immunotherapy.
14-3-3σ in Endometrial Cancer–A Possible Prognostic Marker in Early-Stage Cancer
Authors: Ito Kiyoshi , Suzuki Takashi , Akahira Jun-ichi , Sakuma Michiko , Saitou Sumika , Okamoto Satoshi , Niikura Hitoshi , Okamura Kunihiro , Yaegashi Nobuo , Sasano Hironobu , Inoue Satoshi 
Published: March 2006

Abstract
Purpose: We examined expression of 14-3-3σ, a regulator of cell proliferation, and evaluated its clinical significance in endometrioid endometrial carcinoma.
Experimental Design: One hundred three endometrioid endometrial adenocarcinoma cases were examined using immunohistochemistry with archival specimens. We correlated this finding with various clinicopathologic variables, including the status of estrogen receptor, progesterone receptor, and MIB-1 (Ki-57).
Results: 14-3-3σ Immunoreactivity was detected in 78 of 103 (75.3%) of carcinoma cases. No statistically significant correlation was detected between status of 14-3-3σ and any of clinicopathologic variables examined. There was, however, a statistically significant correlation between loss of 14-3-3σ expression and adverse clinical outcome of the patients (P = 0.0007). In the early stages of cancer (stages I and II), 14-3-3σ immunoreactivity was absent in 5 of 10 (50.0%) patients who showed recurrence during follow-up, whereas its absence was detected in only 13 of 68 (19.1%) disease-free patients in the same period. In addition, 14-3-3σ immunoreactivity was absent in 4 of 5 (80.0%) patients who died, whereas its absence was detected in only 14 of 73 (19.2%) patients who had lived during the same period. Patients whose tumors were negative for 14-3-3σ were at much greater risk to develop recurrent and/or mortal disease (P = 0.0372 and 0.0067). In multivariate analysis using the Cox proportional hazards model, absence of 14-3-3σ turned out to be statistically independent risk factor in disease-free survival and overall survival even in patients with early-stage disease (P = 0.0321 and 0.0191).
Conclusions: Results of our study showed that loss or absence of 14-3-3σ determined by immunohistochemistry may be an important tool to identify endometrial carcinoma cases at high risk of recurrence and/or death, who are otherwise not detected by current clinical and pathologic evaluation, especially in the early stages of the disease. In addition, results of 14-3-3σ immunohistochemistry in the early stage of endometrial carcinoma could contribute to planning postoperative follow-up and adjuvant therapy.
Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice
Authors: Huang Gloria S. , Lopez-Barcons Lluis , Freeze B. Scott , Smith Amos B. , Goldberg Gary L. , Horwitz Susan Band , McDaid Hayley M. 
Published: March 2006

Abstract
Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.
Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.
Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.
Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.
Ovarian Carcinomas: CCN Genes Are Aberrantly Expressed and CCN1 Promotes Proliferation of these Cells
Authors: Gery Sigal , Xie Dong , Yin Dong , Gabra Hani , Miller Carl , Wang Heming , Scott Diane , Yi William S. , Popoviciu Miriam L. , Said Johathan W. , Koeffler H. Phillip 
Published: March 2006

Abstract
Purpose: The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family consists of six matricellular proteins that are involved in various cellular functions, such as proliferation, development, and angiogenesis. The purpose of this study was to explore the possibility that CCN genes are involved in ovarian cancers.
Experimental Design: We quantified CCN expression in a series of 59 ovarian cancers using quantitative real-time reverse transcription-PCR. CCN1 protein levels were further determined by immunohistochemistry and Western blot analysis. Overexpression and inhibition of CCN1 expression by small interfering RNA were used to examine its role in ovarian cancer cell proliferation in vitro and in vivo.
Results: We found dysregulation of levels of the various CCN mRNAs in ovarian cancers compared with their expression in normal whole ovaries. Expression of CCN1 protein was detected in normal ovarian epithelial cells and ovarian tumors as well as in ovarian cancer cell lines. Furthermore, estrogen increased CCN1 mRNA and protein levels in ovarian cancer cells. Ectopic expression of CCN1 enhanced the growth of ovarian cancer cells in liquid culture, whereas inhibition of its expression decreased proliferation and increased apoptosis in these cells. The observed changes in cell growth were accompanied with activation of Akt and extracellular signal-regulated kinase (ERK) signaling pathways. Stable expression of CCN1 in SKOV3 cells significantly increased tumorigenicity in nude mice. Finally, overexpression of CCN1 conferred resistant to carboplatin-induced apoptosis in SKOV3 cells.
Conclusions: This is the first study to show abnormalities in CCN expression in ovarian carcinomas. Furthermore, our results suggest that CCN1 may play a role in ovarian carcinogenesis by stimulating survival and antiapoptotic signaling pathways.
Optical Coherence Tomography: Real-time Imaging of Bronchial Airways Microstructure and Detection of Inflammatory/Neoplastic Morphologic Changes
Authors: Whiteman Suzanne C. , Yang Ying , van Pittius Daniel Gey , Stephens Mark , Parmer Jitendra , Spiteri Monica A. 
Published: March 2006

Abstract
Purpose: Current diagnostic imaging modalities for human bronchial airways do not possess sufficient resolution and tissue penetration depth to detect early morphologic changes and to differentiate in real-time neoplastic pathology from nonspecific aberrations. Optical coherence tomography (OCT) possesses the requisite high spatial resolution for reproducible delineation of endobronchial wall profiling.
Experimental Design: To establish whether OCT could differentiate between the composite microstructural layers of the human airways and simultaneously determine in situ morphologic changes, using a bench-top OCT system, we obtained cross-sectional images of bronchi from 15 patients undergoing lung resections for cancer. All scanned sections underwent subsequent detailed histologic analysis, allowing direct comparisons to be made.
Results: OCT imaging enables characterization of the multilayered microstructural anatomy of the airways, with a maximum penetration depth up to 2 to 3 mm and 10-μm spatial resolution. The epithelium, subepithelial components, and cartilage are individually defined. The acquired OCT images closely match histologically defined patterns in terms of structural profiles. Furthermore, OCT identifies in situ morphologic changes associated with inflammatory infiltrates, squamous metaplasia, and tumor presence.
Conclusions: Our results confirm that OCT is a highly feasible optical tool for real-time near-histologic imaging of endobronchial pathology, with potential for lung cancer surveillance applications in diagnosis and treatment.
Expression of Phosphorylated Ser70 of Bcl-2 Correlates with Malignancy in Human Colorectal Neoplasms
Authors: Kondo Eisaku , Miyake Takayoshi , Shibata Masao , Kimura Toshikazu , Iwagaki Hiromi , Nakamura Shin-ichi , Tanaka Takehiro , Ohara Nobuya , Ichimura Koichi , Oka Takashi , Yanai Hiroyuki , Shibasaki Futoshi , Yoshino Tadashi 
Published: March 2006

Abstract
Purpose: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser70 to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser70 of Bcl-2 (pSer70) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer70 Bcl-2.
Experimental Design: An antibody specific against pSer70 Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas.
Results: Loss of pSer70 Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer70 Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P &lt; 0.01). It was further observed that loss of pSer70 Bcl-2 expression was associated with significantly shorter survival (P &lt; 0.05) and correlated with clinical stages and lymph node metastasis (P &lt; 0.05 and P &lt; 0.05, respectively).
Conclusions: Loss of pSer70 Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.