bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Use of Plasma Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Proteomic Patterns for Detection of Head and Neck Squamous Cell Cancers
Authors: Soltys Scott G. , Le Quynh-Thu , Shi Gongyi , Tibshirani Robert , Giaccia A. J. , Koong Albert C. 
Published: September 2005

Abstract
Purpose: Our study was undertaken to determine the utility of plasma proteomic profiling using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry for the detection of head and neck squamous cell carcinomas (HNSCCs).
Experimental Design: Pretreatment plasma samples from HNSCC patients or controls without known neoplastic disease were analyzed on the Protein Biology System IIc SELDI-TOF mass spectrometer (Ciphergen Biosystems, Fremont, CA). Proteomic spectra of mass:charge ratio (m/z) were generated by the application of plasma to immobilized metal-affinity-capture (IMAC) ProteinChip arrays activated with copper. A total of 37,356 data points were generated for each sample. A training set of spectra from 56 cancer patients and 52 controls were applied to the “Lasso” technique to identify protein profiles that can distinguish cancer from noncancer, and cross-validation was used to determine test errors in this training set. The discovery pattern was then used to classify a separate masked test set of 57 cancer and 52 controls. In total, we analyzed the proteomic spectra of 113 cancer patients and 104 controls.
Results: The Lasso approach identified 65 significant data points for the discrimination of normal from cancer profiles. The discriminatory pattern correctly identified 39 of 57 HNSCC patients and 40 of 52 noncancer controls in the masked test set. These results yielded a sensitivity of 68% and specificity of 73%. Subgroup analyses in the test set of four different demographic factors (age, gender, and cigarette and alcohol use) that can potentially confound the interpretation of the results suggest that this model tended to overpredict cancer in control smokers.
Conclusions: Plasma proteomic profiling with SELDI-TOF mass spectrometry provides moderate sensitivity and specificity in discriminating HNSCC. Further improvement and validation of this approach is needed to determine its usefulness in screening for this disease.
Hypoxia Increases Resistance of Human Pancreatic Cancer Cells to Apoptosis Induced by Gemcitabine
Authors: Yokoi Kenji , Fidler Isaiah J. 
Published: September 2005

AbstractPurpose: Hypoxia, frequently found in the center of solid tumor, is associated with resistance to chemotherapy by activation of signaling pathways that regulate cell pro-liferation, angiogenesis, and apoptosis. We determined whether hypoxia can increase the resistance of human pancreatic carcinoma cells to gemcitabine-induced apoptosis by activation of phosphatidylinositol 3′-kinase (PI3K)/Akt, MEK/mitogen-activated protein kinase (extracellular signal-regulated kinase) [MAPK(Erk) kinase (MEK)], and nuclear factor κB (NF-κB) signaling pathways.Experimental Design: We evaluated the phosphorylation of Akt and MAPK(Erk), DNA binding activity of NF-κB, and apoptosis induced by gemcitabine in L3.6pl human pancreatic cancer cells under normoxic and hypoxic conditions. We then examined the effects of the PI3K inhibitor LY294002, MEK inhibitor U0126, and the epidermal growth factor receptor tyrosine kinase inhibitor PKI 166 on these signaling pathways and induction of apoptosis.Results: Hypoxic conditions increased phosphorylation of Akt and MAPK(Erk) and NF-κB DNA binding activity in L3.6pl cells. The activation of Akt and NF-κB was prevented by LY294002, whereas the activity of MAPK(Erk), but not NF-κB, was inhibited by U0126. The increased activation of Akt, NF-κB, and MAPK(Erk) was inhibited by PKI 166. Under hypoxic conditions, L3.6pl cells were resistant to apoptosis induced by gemcitabine. The addition of LY294002 or PKI 166 abrogated cell resistance to gemcitabine, whereas U0126 only partially decreased this resistance.Conclusions: These data demonstrate that hypoxia can induce resistance of pancreatic cancer cells to gemcitabine mainly through the PI3K/Akt/NF-κB pathways and partially through the MAPK(Erk) signaling pathway. Because PKI 166 prevented the activation of PI3K/Akt/NF-κB and MAPK(Erk) pathways, the combination of this tyrosine kinase inhibitor with gemcitabine should be an effective therapy for pancreatic cancer.
A Cross-Study Comparison of Gene Expression Studies for the Molecular Classification of Lung Cancer
Authors: Parmigiani Giovanni , Garrett-Mayer Elizabeth S. , Anbazhagan Ramaswamy , Gabrielson Edward 
Published: September 2005

Abstract
Purpose: Recent studies sought to refine lung cancer classification using gene expression microarrays. We evaluate the extent to which these studies agree and whether results can be integrated.
Experimental Design: We developed a practical analysis plan for cross-study comparison, validation, and integration of cancer molecular classification studies using public data. We evaluated genes for cross-platform consistency of expression patterns, using integrative correlations, which quantify cross-study reproducibility without relying on direct assimilation of expression measurements across platforms. We then compared associations of gene expression levels to differential diagnosis of squamous cell carcinoma versus adenocarcinoma via reproducibility of the gene-specific t statistics and to survival via reproducibility of Cox coefficients.
Results: Integrative correlation analysis revealed a large proportion of genes in which the patterns agreed across studies more than would be expected by chance. Correlation of t statistics for diagnosis of squamous cell carcinoma versus adenocarcinoma is high (0.85) and increases (0.925) when using only the most consistent genes identified by integrative correlation. Correlations of Cox coefficients ranged from 0.13 to 0.31 (0.33–0.49 with genes selected for consistency). Although we find genes that are significant in multiple studies but show discordant effects, their number is approximately that expected by chance. We report genes that are reproducible by integrative analysis, significant in all studies, and concordant in effect.
Conclusions: Cross-study comparison revealed significant, albeit incomplete, agreement of gene expression patterns related to lung cancer biology and identified genes that reproducibly predict outcomes. This analysis approach is broadly applicable to cross-study comparisons of gene expression profiling projects.
Gene Expression Profiling in Non-Small Cell Lung Cancer
Authors: Petty Russell D. , Nicolson Marianne C. , Kerr Keith M. , Collie-Duguid Elaina , Murray Graeme I. 
Published: September 2005

Abstract
Non-small cell lung cancer (NSCLC) is the most common cause of premature death from malignant disease in western countries. A better understanding of the molecular mechanisms underlying NSCLC etiology, pathogenesis, and therapeutics will lead to improved clinical outcomes. Recent technological advances in gene expression profiling (in particular, with cDNA and oligonucleotide microarrays) allow the simultaneous analysis of the expression of thousands of genes. In this review, the technology of global gene expression profiling is discussed, and the progress made thus far with it in NSCLC is reviewed. A new molecular classification of NSCLC has been developed, which has provided important insights into etiology and pathogenesis. Other studies have found potential biomarkers for NSCLC that may be of use in diagnosis, screening, and assessing the effectiveness of therapy. Finally, advances have been made in the understanding of the molecular mechanisms of NSCLC progression and the molecular mechanisms of action of currently used cytotoxic drugs. This may facilitate the improvement of current therapeutics and the identification of novel targets. Taken together, these advances hold the promise of an improved understanding of the molecular biology of NSCLC and its treatment, which in turn will lead to improved outcomes for this deadly disease.
Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias
Authors: Cortes Jorge , Thomas Deborah , Koller Charles , Giles Francis , Estey Elihu , Faderl Stefan , Garcia-Manero Guillermo , McConkey David , Patel Gira , Guerciolini Roberto , Wright John , Kantarjian Hagop 
Published: September 2005

Abstract
Bortezomib (Velcade, formerly PS-341) is proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies. We performed a Phase I study to investigate the maximum tolerated dose and dose-limiting toxicity of bortezomib in patients with acute leukemias refractory to or relapsing after prior therapy. Fifteen patients were treated with 0.75 (n = 3), 1.25 (n = 7), or 1.5 (n = 5) mg/m2 bortezomib administered twice weekly for 4 weeks every 6 weeks. Dose-limiting toxicity included orthostatic hypotension (n = 2), nausea (n = 2), diarrhea (n = 1), and fluid retention (n = 1), all at 1.5 mg/m2 bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m2 bortezomib. Peak inhibition was observed 1 h after treatment and returned to near baseline levels by 72 h after treatment. Incubation of blast cells with bortezomib in vitro showed induction of apoptosis in three of five patients investigated. We conclude that the maximum tolerated dose of bortezomib in patients with acute leukemia is 1.25 mg/m2, using a twice-weekly for 4 weeks every 6 weeks schedule. The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents.
Synergistic Cytotoxicity and Pharmacogenetics of Gemcitabine and Pemetrexed Combination in Pancreatic Cancer Cell Lines
Authors: Giovannetti Elisa , Mey Valentina , Danesi Romano , Mosca Irene , Del Tacca Mario 
Published: September 2005

AbstractPurpose: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines.Experimental Design: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5′-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination.Results: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed→gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2′-deoxycytidine.Conclusions: These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.
Classification of Human Breast Cancer Using Gene Expression Profiling as a Component of the Survival Predictor Algorithm
Authors: Glinsky Gennadi V. , Higashiyama Takuya , Glinskii Anna B. 
Published: September 2005

Abstract
Purpose: Selection of treatment options with the highest likelihood of successful outcome for individual breast cancer patients is based to a large degree on accurate classification into subgroups with poor and good prognosis reflecting a different probability of disease recurrence and survival after therapy. Here we propose a breast cancer classification algorithm taking into account three main prognostic features determined at the time of diagnosis: estrogen receptor (ER) status; lymph node (LN) status; and gene expression signatures associated with distinct therapy outcome.
Experimental Design: Using microarray expression profiling and quantitative reverse transcription-PCR analyses, we compared expression profiles of the 70-gene breast cancer survival signature in established breast cancer cell lines and primary breast carcinomas from cancer patients. We classified 295 breast cancer patients using 14-, 13-, 6-, and 4-gene survival predictor signatures into subgroups having statistically distinct probability of therapy failure (P &lt; 0.0001). We evaluated the prognostic power of breast cancer survival predictor signatures alone and in combination with ER and LN status using Kaplan-Meier analysis.
Results: The breast cancer survival predictor algorithm allowed highly accurate classification into subgroups with dramatically distinct 5- and 10-year survival after therapy of a large cohort of 295 breast cancer patients with either ER+ or ER− tumors as well as LN+ or LN− disease (P &lt; 0.0001, log-rank test).
Conclusions: Our data imply that quantitative laboratory tests measuring expression profiles of a limited set of identified small gene clusters may be useful in stratification of breast cancer patients at the time of diagnosis into subgroups with statistically distinct probability of positive outcome after therapy and assisting in selection of optimal treatment strategies. The estimated increase in survival due to the optimization of treatment protocols may reach many thousands of breast cancer survivors every year at the 10-year follow-up check point.
In vitro
Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines
Authors: Dasmahapatra Girija P. , Didolkar Parijat , Alley Michael C. , Ghosh Somiranjan , Sausville Edward A. , Roy Krishnendu K. 
Published: September 2005

Abstract
Purpose: Antineoplastic agents often achieve antitumor activity at the expense of close to unacceptable toxicity. One potential avenue to improve therapeutic index might combine agents targeting distinct components of the same growth regulatory pathway. This might lead to more complete modulation of the target pathway at concentrations lower than those associated with limiting adventitious toxicities from either agent alone. The protein kinase antagonist UCN-01 is currently used in Phase I/II trials and has recently been demonstrated to inhibit potently PDK1 (S. Sato et al., Oncogene, 21: 1727–1738, 2002). We have recently documented that the alkylphospholipid perifosine potently also inhibits Akt kinase (PKB) activation by interfering with membrane localization of Akt (S. Kondapaka et al., Mol. Cancer Ther., 2: 1093–1103, 2003). This leads to the hypothesis that these two agents might act synergistically through distinct mechanisms in the PI3K/Akt proliferation and survival-related signaling pathway.
Experimental Design: The synergistic effects of UCN-01 and perifosine, on two cell lines (A-549 and PC-3), were examined using various long-term in vitro assays for cell growth, cell cycle distribution, clonogenicity, survival morphology, and apo-ptosis. Along with Western blotting experiments were performed to determine whether this synergistic combination of two drugs has significant effect on their downstream targets and on biochemical markers of apoptosis.
Results: After 72 h, perifosine at concentrations of 1.5 and 10 μm UCN-01 at 40 and 250 nm did not significantly affect the growth of PC-3 and A459 cells, respectively. However, in combination at the same respective individual concentrations (1.5 μm and 40 nm of perifosine and UCN-01, respectively, in PC-3 cells and 10 μm perifosine and 0.25 μm UCN-01 in the somewhat more resistant A549 cells), virtually complete growth inhibition of both the cell lines resulted. Supra-additive inhibition of growth was also demonstrated in independent clonogenic assays. Mechanistic studies in cell culture models suggest enhanced depletion of the S-phase population in cells treated by the combination. This correlated with enhanced inactivation of Akt along with activation of caspases 3 and 9 and poly(ADP-ribose) polymerase cleavage. Evidence of synergy was formally demonstrated and occurred across a wide range of drug concentrations and was largely independent of the order or sequence of drug addition.
Conclusions: As the concentrations of UCN-01 and perifosine causing synergistic inhibition of cell growth are clinically achievable without prominent toxicity, these data support the development of clinical studies with this combination.
Long-Term Analysis and Prospective Validation of a Prognostic Model for Patients with High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy
Authors: Nieto Yago , Nawaz Samia , Shpall Elizabeth J. , Bearman Scott I. , Murphy James , Jones Roy B. 
Published: September 2005

Abstract
Purpose: We described previously a prognostic model for high-risk primary breast cancer patients receiving high-dose chemotherapy (HDC). Such model included nodal ratio (no. involved nodes:no. dissected nodes), tumor size, hormone receptors, and HER2. In the present study we intended to test this model prospectively in a second patient cohort. In addition, we analyzed the long-term overall outcome of our HDC trials.
Experimental Design: We analyzed all 264 patients enrolled since 1990 in our prospective trials for 4–9+, ≥10+ nodes, or inflammatory disease. Patients of the second cohort (treated since 1997) had their prognostic score estimated prospectively before receiving HDC.
Results: Fourteen patients (5.3%) died from HDC-related complications. At median follow-up of 7.1 years, relapse-free survival and overall survival of the whole group were 69.8% and 73%, respectively. Median time to relapse was 14 months (63.5% relapses within the first 2 years, 6.7% after year 5). The model was validated in the second cohort, establishing the following pretransplant risk categories: low risk (low score, HER2−), 44% patients, 87% freedom from relapse (FFR); intermediate risk (low score, HER2+), 29% patients, 68% FFR; and high risk (high score, any HER2), 27% patients, 49% FFR.
Conclusions: Few relapses are seen after year 5 of follow-up, which indicates the need for mature results of the randomized trials before their final interpretation or meta-analysis. Our prospectively validated prognostic model, if additionally confirmed in the randomized trial populations, may provide an insight into the relative benefit of HDC in different risk patient subsets.
Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial
Authors: Kisanga Elton R. , Gjerde Jennifer , Guerrieri-Gonzaga Aliana , Pigatto Francesca , Pesci-Feltri Adriana , Robertson Chris , Serrano Davide , Pelosi Giuseppe , Decensi Andrea , Lien Ernst A. 
Published: September 2005

Abstract
Purpose: Both therapeutic and adverse effects of tamoxifen may be related to its tissue concentrations. We investigated concentrations of tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, and N-didesmethyltamoxifen in serum, normal breast, and breast cancer tissues during conventional dosage and two low-dose regimens. Furthermore we studied tamoxifen effects on the cancer proliferation marker Ki-67, and on sex hormone-binding globulin (SHBG).
Experimental Design: From September 1999 to August 2001, 120 breast cancer patients were randomized to 20-, 5-, or 1-mg tamoxifen daily. We measured serum and tissue concentrations of tamoxifen and three metabolites after 28 days of treatment, and the changes between baseline and post-treatment levels of SHBG and Ki-67.
Results: The median (range) tamoxifen concentrations (ng/ml) at doses of 1, 5, and 20 mg daily (n = 38, 37, and 36) were 7.5 (2.9–120.9), 25.2 (1.9–180.9), and 83.6 (8.7–134.4) in serum, and 78.2 (35.9–184), 272.3 (122–641), and 744.4 (208.6–2556) in breast cancer tissue, respectively. Tamoxifen levels followed a dose-concentration relationship. The concentrations of tamoxifen and metabolites were related to each other. Serum and tissue concentrations of tamoxifen were associated with corresponding changes of SHBG levels, whereas changes of Ki-67 levels were not related.
Conclusions: Estrogen agonistic effects of tamoxifen on SHBG decreased with lower dosage, whereas tamoxifen effects on Ki-67 expression did not change. This together with a &gt;10-fold variation in serum tamoxifen concentrations and a serum to tissue concentration relationship suggest that tamoxifen treatment may be improved by administration of lower doses and therapeutic drug monitoring.
Carbonic Anhydrase IX as a Marker for Poor Prognosis in Soft Tissue Sarcoma
Authors: Måseide Kårstein , Kandel Rita A. , Bell Robert S. , Catton Charles N. , O’Sullivan Brian , Wunder Jay S. , Pintilie Melania , Hedley David , Hill Richard P. 
Published: September 2005

Abstract
Purpose: Hypoxia is associated with malignant progression and poor outcome in several human tumors, including soft tissue sarcoma. Recent studies have suggested that carbonic anhydrase (CA) IX is an intrinsic marker of hypoxia, and that CA IX correlates with poor prognosis in several types of carcinoma. The aim of this study was to quantify the extent of CA IX expression and to investigate whether CA IX is a marker for poor prognosis in soft tissue sarcoma patients at high risk of developing metastasis.
Experimental Design: Archival paraffin-embedded blocks were retrieved from 47 patients with deep, large, high-grade soft tissue sarcoma. Sections from two separate and representative tumor areas were immunostained for CA IX, and the CA IX-positive area fraction was quantified by image analysis, excluding areas of normal stroma and necrosis that were identified from serial H&E-stained sections. Patients were then subject to survival analysis.
Results: CA IX-positive area fractions of viable tumor tissue varied significantly between tumors (range, 0–0.23; median, 0.004), with positive membranous CA IX staining in 66% (31 of 47) of the tumors. Patients with CA IX-positive tumors had a significantly lower disease-specific and overall survival than patients with CA IX-negative tumors (P = 0.033 and P = 0.044, respectively).
Conclusions: These data suggest that CA IX, a potential intrinsic marker of hypoxia, predicts for poor prognosis in patients with deep, large, high-grade soft tissue sarcoma. Larger studies are required to determine whether CA IX has independent prognostic value in this group of tumors.