bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salivary Transcriptome Diagnostics for Oral Cancer Detection
Authors: Li Yang , St. John Maie A. R. , Zhou Xiaofeng , Kim Yong , Sinha Uttam , Jordan Richard C. K. , Eisele David , Abemayor Elliot , Elashoff David , Park No-Hee , Wong David T. 
Published: September 2005

Abstract
Purpose: Oral fluid (saliva) meets the demand for noninvasive, accessible, and highly efficient diagnostic medium. Recent discovery that a large panel of human RNA can be reliably detected in saliva gives rise to a novel clinical approach, salivary transcriptome diagnostics. The purpose of this study is to evaluate the diagnostic value of this new approach by using oral squamous cell carcinoma (OSCC) as the proof-of-principle disease.
Experimental Design: Unstimulated saliva was collected from patients (n = 32) with primary T1/T2 OSCC and normal subjects (n = 32) with matched age, gender, and smoking history. RNA isolation was done from the saliva supernatant, followed by two-round linear amplification with T7 RNA polymerase. Human Genome U133A microarrays were applied for profiling human salivary transcriptome. The different gene expression patterns were analyzed by combining a t test comparison and a fold-change analysis on 10 matched cancer patients and controls. Quantitative polymerase chain reaction (qPCR) was used to validate the selected genes that showed significant difference (P &lt; 0.01) by microarray. The predictive power of these salivary mRNA biomarkers was analyzed by receiver operating characteristic curve and classification models.
Results: Microarray analysis showed there are 1,679 genes exhibited significantly different expression level in saliva between cancer patients and controls (P &lt; 0.05). Seven cancer-related mRNA biomarkers that exhibited at least a 3.5-fold elevation in OSCC saliva (P &lt; 0.01) were consistently validated by qPCR on saliva samples from OSCC patients (n = 32) and controls (n = 32). These potential salivary RNA biomarkers are transcripts of IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT. The combinations of these biomarkers yielded sensitivity (91%) and specificity (91%) in distinguishing OSCC from the controls.
Conclusions: The utility of salivary transcriptome diagnostics is successfully demonstrated in this study for oral cancer detection. This novel clinical approach could be exploited to a robust, high-throughput, and reproducible tool for early cancer detection. Salivary transcriptome profiling can be applied to evaluate its usefulness for other major disease applications as well as for normal health surveillance.
Mouse Homologue of a Novel Human Oncofetal Antigen, Glypican-3, Evokes T-Cell–Mediated Tumor Rejection without Autoimmune Reactions in Mice
Authors: Nakatsura Tetsuya , Komori Hiroyuki , Kubo Tatsuko , Yoshitake Yoshihiro , Senju Satoru , Katagiri Toyomasa , Furukawa Yoichi , Ogawa Michio , Nakamura Yusuke , Nishimura Yasuharu 
Published: September 2005

Abstract
Purpose and Experimental Design: We recently identified glypican-3 (GPC3) overexpressed specifically in human hepatocellular carcinoma, as based on cDNA microarray analysis of 23,040 genes, and we reported that GPC3 is a novel tumor marker for human hepatocellular carcinoma and melanoma. GPC3, expressed in almost all hepatocellular carcinomas and melanomas, but not in normal tissues except for placenta or fetal liver, is a candidate of ideal tumor antigen for immunotherapy. In this study, we attempted to identify a mouse GPC3 epitope for CTLs in BALB/c mice, and for this, we set up a preclinical study to investigate the usefulness of GPC3 as a target for cancer immunotherapy in vivo.
Results: We identified a mouse GPC3-derived and Kd- restricted CTL epitope peptide in BALB/c mice. Inoculation of this GPC3 peptide-specific CTL into s.c. Colon26 cancer cells transfected with mouse GPC3 gene (C26/GPC3) led to rejection of the tumor in vivo, and i.v. inoculation of these CTLs into sublethally irradiated mice markedly inhibited growth of an established s.c. tumor. Inoculation of bone marrow-derived dendritic cells pulsed with this peptide prevented the growth of s.c. and splenic C26/GPC3 accompanied with massive infiltration of CD8+ T cells into tumors. Evidence of autoimmune reactions was never observed in surviving mice that had rejected tumor cell challenges.
Conclusions: We found the novel oncofetal protein GPC3 to be highly immunogenic in mice and elicited effective antitumor immunity with no evidence of autoimmunity. GPC3 is useful not only for diagnosis of hepatocellular carcinoma and melanoma but also for possible immunotherapy or prevention of these tumors.
Intermittent Hypoxia Induces Proteasome-Dependent Down-Regulation of Estrogen Receptor α in Human Breast Carcinoma
Authors: Cooper Charlton , Liu Guang-Yu , Niu Yu-Lian , Santos Sylvia , Murphy Leigh C. , Watson Peter H. 
Published: September 2005

Abstract
Purpose: Hypoxia may influence gene expression to promote malignancy, and acute hypoxia has been shown to transiently repress estrogen receptor (ER)-α expression in breast cell lines. However, the effect of intermittent hypoxia, which is likely more prevalent in breast cancers, remains to be determined.
Experimental Design: ER-α expression was assessed by Western blot and immunohistochemistry in a selected cohort of 51 ER-α–positive breast carcinomas, in relation to markers of hypoxia. The effect of acute and intermittent hypoxia on ER-α expression was also determined in MCF7 and ZR-75 breast cell lines, together with the role of proteasome function with the proteasome inhibitor bortezomib.
Results: Regional loss of ER-α expression occurs in breast tumors and is consistently present in hypoxic regions defined by the proximity of necrosis and induction of hypoxia-induced genes carbonic anhydrase IX (CA-IX) and glucose transporter 1 (Glut-1), in both in situ (n = 29; P &lt; 0.0001) and invasive (n = 20; P = 0.0001) carcinomas. In MCF7 and ZR-75 cells, ER-α is transiently down-regulated by acute hypoxia and rapidly restored by reoxygenation. However, intermittent, acute hypoxia can cause a similar down-regulation of ER-α that is not attributable to decreased mRNA and persists in MCF7 cells despite reoxygenation for up to 14 days. This effect occurs with no change in cell viability but a corresponding reduction in growth response to estradiol. However, ER-α expression can be restored by bortezomib.
Conclusions: Intermittent hypoxia can cause persistent changes in proteasome function that may contribute to reduced ER-α expression in breast tumors and consequently to diminished response and development of resistance to endocrine therapy.
Proteinase Activity in Human and Murine Saliva as a Biomarker for Proteinase Inhibitor Efficacy
Authors: Fingleton Barbara , Menon Ramkumar , Carter Kathy J. , Overstreet P. Dawn , Hachey David L. , Matrisian Lynn M. , McIntyre J. Oliver 
Published: September 2005

AbstractAs molecularly targeted agents reach the clinic, there is a need for assays to detect their presence and effectiveness against target molecules in vivo. Proteinase inhibitors are one example of a class of therapeutic agent for which satisfactory methods of identifying successful target modulation in vivo are lacking. This is of particular importance while these drugs are in clinical trials because standard maximum-tolerated dose-finding studies often are not suitable due to lack of toxicity. Saliva represents a readily accessible bodily fluid that can be repeatedly sampled and used for assaying in vivo effects of systemic drugs. Here we show the development of a simple assay that can be used to measure proteinase activity in saliva and proteinase inhibition after systemic treatment with three different proteinase inhibitors. A variety of gelatinolytic activities present in human and murine saliva have been assayed with a fluorescent dye-labeled substrate and assigned to different proteinase categories by inclusion of specific classes of inhibitors. Treatment of mice with either matrix metalloproteinase inhibitors or a urokinase inhibitor for a period as short as 48 hours results in levels of the drugs that can be detected in saliva by mass spectrometry and concomitant decreases in salivary proteinase activity, thus demonstrating that these inhibitors successfully modulate their targets in vivo.
Gain of OGP, an Estrogen-Regulated Oviduct-Specific Glycoprotein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer
Authors: Woo Michelle M. M. , Alkushi Abdulmohsen , Verhage Harold G. , Magliocco Anthony M. , Leung Peter C. K. , Gilks C. Blake , Auersperg Nelly 
Published: September 2005

Abstract
Purpose: Lesions in the endometrium are difficult to differentially diagnose. The present study examined whether oviduct-specific glycoprotein is differentially expressed in normal, hyperplastic, and malignant endometrium.
Experimental Design: The expression of oviduct-specific glycoprotein was characterized by immunohistochemical methods with whole sections of endometrium from 90 women. An endometrial cancer tissue microarray with 200 cases of endometrial cancer was also assessed for oviduct-specific glycoprotein, estrogen receptor, and PTEN expression.
Results: In normal endometrium, there was focal oviduct-specific glycoprotein expression in the basalis layer, where the stem cells reside, in 10 of 15 cases. On average, atypical hyperplastic endometria stained more intensely than hyperplastic endometria (P = 0.017), whereas the percentage of positively stained cells was not significantly different. The mean staining indices (intensity × percentage of positive cells score) for hyperplasia and atypical hyperplastic were 4.7 and 5.5 and were significantly higher than staining indices seen in normal cycling endometria or well-differentiated endometrioid endometrial carcinomas (P &lt; 0.0001 and P &lt; 0.001, respectively). The endometrial cancer tissue microarray showed that of 139 endometrioid endometrial carcinomas, 11 cases were strongly oviduct-specific glycoprotein positive, whereas the other 128 cases were negative or weakly positive. Analysis of Kaplan-Meier curves with log-rank statistics showed a trend toward significance, with strong oviduct-specific glycoprotein staining serving as a predictor of good prognosis (P = 0.1). There was a significant positive correlation between oviduct-specific glycoprotein staining and loss of PTEN in the cases of endometrial cancer (P = 0.004).
Conclusions: Oviduct-specific glycoprotein may be a useful diagnostic adjunct to more accurately classify premalignant and early malignant change in the endometrium, improving on the current irreproducible histologic classification system.
Transcription Factor AP-2γ Is a Developmentally Regulated Marker of Testicular CarcinomaIn situand Germ Cell Tumors
Authors: Hoei-Hansen Christina E. , Nielsen John E. , Almstrup Kristian , Sonne Si Brask , Graem Niels , Skakkebaek Niels E. , Leffers Henrik , Meyts Ewa Rajpert-De 
Published: September 2005

AbstractPurpose: Transcription factor activator protein-2γ (TFAP2C, AP-2γ) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2γ in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2γ and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia.Experimental Design: We analyzed expression pattern of AP-2γ at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2γ in normal and dysgenetic samples. We also investigated the regulation of AP-2γ by steroids and retinoic acid.Results: We detected abundant AP-2γ in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2γ in somatic tumors. We found that AP-2γ expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2γ protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2γ was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells.Conclusions: AP-2γ is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2γ is a novel marker of testicular CIS and CIS-derived tumors.
Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients
Authors: Baker Sharyn D. , van Schaik Ron H. N. , Rivory Laurent P. , ten Tije Albert J. , Dinh Kimberly , Graveland Wilfried J. , Schenk Paul W. , Charles Kellie A. , Clarke Stephen J. , Carducci Michael A. , McGuire William P. , Dawkins Fitzroy , Gelderblom Hans , Verweij Jaap , Sparreboom Alex 
Published: September 2005

AbstractPurpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patientsExperimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).Results: CYP3A activity (AUC0–40min) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P &gt; 0.2954). CYP3A activity was reduced by ∼50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P &lt; 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P &gt; 0.05), but liver function combined with the concentration of the acute-phase reactant, α-1 acid glycoprotein, explained ∼18% of overall variation in CYP3A activity (P &lt; 0.001).Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
Paclitaxel-Loaded Gelatin Nanoparticles for Intravesical Bladder Cancer Therapy
Authors: Lu Ze , Yeh Teng-Kuang , Tsai Max , Au Jessie L.-S. , Wientjes M. Guill 
Published: September 2005

Abstract
Purpose: The present report describes the development of paclitaxel-loaded gelatin nanoparticles for use in intravesical therapy of superficial bladder cancer. The commercial formulation of paclitaxel contains Cremophor, which forms micelles and thereby entraps the drug and reduces its partition across the urothelium.
Experimental Design: Paclitaxel-loaded gelatin nanoparticles were prepared using the desolvation method, and their physicochemical and biological properties were characterized.
Results: The size of the particles ranged from 600 to 1,000 nm and increased with the molecular weight of the gelatin polymer. Under optimal conditions, the yield was &gt;80%, and the drug loading was 0.7%. Wide-angle X-ray diffraction analysis showed that the entrapped paclitaxel was present in an amorphous state, which has higher water solubility compared with the crystalline state. Identical, rapid drug release from nanoparticles was observed in PBS and urine, with ∼90% released at 37°C after 2 hours. Treatment with a protease (i.e., Pronase) rapidly degraded the nanoparticles, with half-lives of 23.8 minutes, 0.6 minute, and 0.4 minute in the presence of 0.01, 0.05, and 0.25 mg/mL Pronase, respectively. The paclitaxel-loaded nanoparticles were active against human RT4 bladder transitional cancer cells; the IC50 paclitaxel-equivalent concentrations were nearly identical to those of aqueous solutions of paclitaxel, i.e., ∼30 nmol/L (equivalent to ∼25 ng/mL) for 2-hour treatments and ∼4 nmol/L for 96-hour treatments. In dogs given an intravesical dose of paclitaxel-loaded particles, the drug concentrations in the urothelium and lamina propria tissue layers, where Ta and T1 tumors would be located, were 7.4 ± 4.3 μg/g (mean ± SD; 3 dogs; 9 tissue sections), which were 2.6× the concentrations we reported for dogs treated with the Cremophor formulation.
Conclusions: Paclitaxel-loaded gelatin nanoparticles represent a rapid release, biologically active paclitaxel formulation that can be used for intravesical bladder cancer therapy.
3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor, Fluvastatin, as a Novel Agent for Prophylaxis of Renal Cancer Metastasis
Authors: Horiguchi Akio , Sumitomo Makoto , Asakuma Junichi , Asano Takako , Asano Tomohiko , Hayakawa Masamichi 
Published: September 2005

Abstract
Purpose: Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also called statins, are currently used widely as a safe, effective therapeutic in the treatment of hypercholesterolemia. Recently, statins have been recognized for their activity against cancer. In the present study, we examined the effect of a synthetic statin, fluvastatin, on the development of renal cancer.
Experimental Design: The effects of fluvastatin on cell viability, cell cycle, in vitro angiogenesis, and invasive properties were examined in murine renal cancer cell Renca. The changes in cell cycle-associated proteins, p21Waf1/Cip1 and p53, and rac1 phosphorylation were analyzed by Western blotting. The prophylactic efficacy of fluvastatin to murine pulmonary metastasis of Renca was examined.
Results: Fluvastatin inhibited in vitro growth of Renca cells in a time- and dose-dependent manner, with up to 70% inhibition at a concentration of 10 μmol/L. This inhibitory effect was due to cell cycle arrest at the G1 phase and induction of apoptosis accompanied by up-regulation of p21Waf1/Cip1 and p53. The invasive properties of Renca cells through Matrigel were inhibited by fluvastatin, with decreased phosphorylation of rac1. In vitro angiogenesis was also inhibited by fluvastatin. Furthermore, oral administration at doses of 1 to 10 mg/kg/d, for 12 days after inoculation of Renca cells via the tail vein, significantly decreased the amount of pulmonary metastasis.
Conclusions: Because our results suggest that fluvastatin may effectively inhibit in vitro tumor growth, invasion, angiogenesis, and metastasis of Renca cells, oral administration of fluvastatin could be a novel, safe, and effective agent for preventing metastasis of renal cancer.
In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells
Authors: Minderman Hans , Conroy Jeffrey M. , O'Loughlin Kieran L. , McQuaid Devin , Quinn Paul , Li Song , Pendyala Lakshmi , Nowak Norma J. , Baer Maria R. 
Published: September 2005

Abstract
Objective: To study irinotecan (CPT-11)–induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cells in vitro and in vivo. Methods: HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. Results: cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle–associated genes, consistent with loss of S-phase cells and temporary delay of G1-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G2-M and G1 were delayed in G1 and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed following in vitro SN-38 exposure were also seen following in vivo administration of 10 or 15 mg/m2 CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. Conclusion: CPT-11-induced changes in gene expression profiles in vitro and in vivo are consistent with temporary delay in G1-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.
Resveratrol-induced apoptotic death in human U251 glioma cells
Authors: Jiang Hao , Zhang Lijie , Kuo Jarret , Kuo Kelly , Gautam Subhash C. , Groc Laurent , Rodriguez Alba I. , Koubi David , Jackson Hunter Tangella , Corcoran George B. , Seidman Michael D. , Levine Robert A. 
Published: September 2005

Abstract
Resveratrol (trans-3,4′,5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G0/G1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.