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Search Results: 1 - 10 of 470451 matches for " Joseph A. Califano "
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Chronic CSE Treatment Induces the Growth of Normal Oral Keratinocytes via PDK2 Upregulation, Increased Glycolysis and HIF1α Stabilization
Wenyue Sun,Steven S. Chang,Yumei Fu,Yan Liu,Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016207
Abstract: Exposure to cigarette smoke is a major risk factor for head and neck squamous cell carcinoma (HNSCC). We have previously established a chronic cigarette smoke extract (CSE)-treated human oral normal keratinocyte model, demonstrating an elevated frequency of mitochondrial mutations in CSE treated cells. Using this model we further characterized the mechanism by which chronic CSE treatment induces increased cellular proliferation.
Cellular Traction Stresses Increase with Increasing Metastatic Potential
Casey M. Kraning-Rush, Joseph P. Califano, Cynthia A. Reinhart-King
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032572
Abstract: Cancer cells exist in a mechanically and chemically heterogeneous microenvironment which undergoes dynamic changes throughout neoplastic progression. During metastasis, cells from a primary tumor acquire characteristics that enable them to escape from the primary tumor and migrate through the heterogeneous stromal environment to establish secondary tumors. Despite being linked to poor prognosis, there are no direct clinical tests available to diagnose the likelihood of metastasis. Moreover, the physical mechanisms employed by metastatic cancer cells to migrate are poorly understood. Because metastasis of most solid tumors requires cells to exert force to reorganize and navigate through dense stroma, we investigated differences in cellular force generation between metastatic and non-metastatic cells. Using traction force microscopy, we found that in human metastatic breast, prostate and lung cancer cell lines, traction stresses were significantly increased compared to non-metastatic counterparts. This trend was recapitulated in the isogenic MCF10AT series of breast cancer cells. Our data also indicate that increased matrix stiffness and collagen density promote increased traction forces, and that metastatic cells generate higher forces than non-metastatic cells across all matrix properties studied. Additionally, we found that cell spreading for these cell lines has a direct relationship with collagen density, but a biphasic relationship with substrate stiffness, indicating that cell area alone does not dictate the magnitude of traction stress generation. Together, these data suggest that cellular contractile force may play an important role in metastasis, and that the physical properties of the stromal environment may regulate cellular force generation. These findings are critical for understanding the physical mechanisms of metastasis and the role of the extracellular microenvironment in metastatic progression.
Dose-Dependent Activation of Putative Oncogene SBSN by BORIS
Daria Gaykalova, Rajita Vatapalli, Chad A. Glazer, Sheetal Bhan, Chunbo Shao, David Sidransky, Patrick K. Ha, Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040389
Abstract: Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.
Comparison of Promoter Hypermethylation Pattern in Salivary Rinses Collected with and without an Exfoliating Brush from Patients with HNSCC
Wenyue Sun, David Zaboli, Yan Liu, Demetri Arnaoutakis, Tanbir Khan, Hao Wang, Wayne Koch, Zubair Khan, Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033642
Abstract: Background Salivary rinses have been recently proposed as a valuable resource for the development of epigenetic biomarkers for detection and monitoring of head and neck squamous cell carcinoma (HNSCC). Both salivary rinses collected with and without an exfoliating brush from patients with HNSCC are used in detection of promoter hypermethylation, yet their correlation of promoter hypermethylation has not been evaluated. This study was to evaluate the concordance of promoter hypermethylation between salivary rinses collected with and without an exfoliating brush from patients with HNSCC. Methodolgy 57 paired salivary rinses collected with or without an exfoliating brush from identical HNSCC patients were evaluated for promoter hypermethylation status using Quantitative Methylation-Specific PCR. Target tumor suppressor gene promoter regions were selected based on our previous studies describing a panel for HNSCC screening and surveillance, including P16, CCNA1, DCC, TIMP3, MGMT, DAPK and MINT31. Principal Findings In salivary rinses collected with and without brush, frequent methylation was detected in P16 (8.8% vs. 5.2%), CCNA1 (26.3% vs. 22.8%), DCC (33.3% vs. 29.8%), TIMP3 (31.6% vs. 36.8%), MGMT (29.8% vs. 38.6%), DAPK (14.0% vs. 19.2%), and MINT31 (10.5% vs. 8.8%). Spearman's rank correlation coefficient showed a positive correlation between salivary rinses collected with and without brush for P16 (ρ = 0.79), CCNA1 (ρ = 0.61), DCC (ρ = 0.58), TIMP3 (ρ = 0.10), MGMT (ρ = 0.70), DAPK (ρ = 0.51) and MINT31 (ρ = 0.72) (P<0.01). The percent agreement of promoter methylation between salivary rinses with brush and without brush were 96.5% for P16, 82.5% for CCNA1, 78.9% for DCC, 59.7% for TIMP3, 84.2% for MGMT, 84.2% for DAPK, and 94.7% for MINT31. Conclusions Our study demonstrated strong correlations of gene promoter hypermethylation between salivary rinses collected with and without an exfoliating brush. Salivary rinse collection without using an exfoliating brush may offer a cost effective, rapid, non-invasive, and reliable means for development of epigenetic salivary rinse biomarkers.
Promoter Methylation in Head and Neck Squamous Cell Carcinoma Cell Lines Is Significantly Different than Methylation in Primary Tumors and Xenografts
Patrick T. Hennessey, Michael F. Ochs, Wojciech W. Mydlarz, Wayne Hsueh, Leslie Cope, Wayne Yu, Joseph A. Califano
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020584
Abstract: Studies designed to identify novel methylation events related to cancer often employ cancer cell lines in the discovery phase of the experiments and have a relatively low rate of discovery of cancer-related methylation events. An alternative algorithm for discovery of novel methylation in cancer uses primary tumor-derived xenografts instead of cell lines as the primary source of nucleic acid for evaluation. We evaluated DNA extracted from primary head and neck squamous cell carcinomas (HNSCC), xenografts grown from these primary tumors in nude mice, HNSCC-derived cell lines, normal oral mucosal samples, and minimally transformed oral keratinocyte-derived cell lines using Illumina Infinum Humanmethylation 27 genome-wide methylation microarrays. We found >2,200 statistically significant methylation differences between cancer cell lines and primary tumors and when comparing normal oral mucosa to keratinocyte cell lines. We found no statistically significant promoter methylation differences between primary tumor xenografts and primary tumors. This study demonstrates that tumor-derived xenografts are highly accurate representations of promoter methylation in primary tumors and that cancer derived cell lines have significant drawbacks for discovery of promoter methylation alterations in primary tumors. These findings also support use of primary tumor xenografts for the study of methylation in cancer, drug discovery, and the development of personalized cancer treatments.
Integrative Discovery of Epigenetically Derepressed Cancer Testis Antigens in NSCLC
Chad A. Glazer,Ian M. Smith,Michael F. Ochs,Shahnaz Begum,William Westra,Steven S. Chang,Wenyue Sun,Sheetal Bhan,Zubair Khan,Steven Ahrendt,Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008189
Abstract: Cancer/testis antigens (CTAs) were first discovered as immunogenic targets normally expressed in germline cells, but differentially expressed in a variety of human cancers. In this study, we used an integrative epigenetic screening approach to identify coordinately expressed genes in human non-small cell lung cancer (NSCLC) whose transcription is driven by promoter demethylation.
Serum microRNA Biomarkers for Detection of Non-Small Cell Lung Cancer
Patrick T. Hennessey, Tiffany Sanford, Ashish Choudhary, Wojciech W. Mydlarz, David Brown, Alex Tamas Adai, Michael F. Ochs, Steven A. Ahrendt, Elizabeth Mambo, Joseph A. Califano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032307
Abstract: Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73–0.91), sensitivity of 100% (95% CI; 0.93–1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results.
Mitochondrial DNA mutations in preneoplastic lesions of the gastrointestinal tract: A biomarker for the early detection of cancer
Guoping Sui, Shaoyu Zhou, Jean Wang, Marcia Canto, Edward E Lee, James R Eshleman, Elizabeth A Montgomery, David Sidransky, Joseph A Califano, Anirban Maitra
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-73
Abstract: A total of 513,639 bases of mtDNA were sequenced in the 14 samples, with 490,224 bases (95.4%) bases assigned by the automated genotyping software. All preneoplastic lesions examined demonstrated at least one somatic mtDNA sequence alteration. Of the 100 somatic mtDNA alterations observed in the 14 cases, 27 were non-synonymous coding region mutations (i.e., resulting in an amino acid change), 36 were synonymous, and 37 involved non-coding mtDNA. Overall, somatic alterations most commonly involved the COI, ND4 and ND5 genes. Notably, somatic mtDNA alterations were observed in preneoplastic lesions of the gastrointestinal tract even in the absence of histopathologic evidence of dysplasia, suggesting that the mitochondrial genome is susceptible at the earliest stages of multistep cancer progression.Our findings further substantiate the rationale for exploring the mitochondrial genome as a biomarker for the early diagnosis of cancer, and confirm the utility of a high-throughput array-based platform for this purpose from a clinical applicability standpoint.Somatic mutations of the mitochondrial DNA (mtDNA) are common in many human cancers, likely a reflection of altered DNA repair mechanisms and predisposition of mtDNA to free radical damage [1-3]. Although the functional significance of these mutations has been debated vis-à-vis their "cause and effect" relationship in cancer cells, there is little doubt that mtDNA mutations can serve an important role as a biomarker for human cancers [4-6]. Nevertheless, despite the frequency and widespread nature of mtDNA alterations in human cancers, the ability to use this property for biomarker development has been stymied due to the absence of high-throughput platforms for mutation detection. Unlike many nuclear genes that demonstrate mutational hotspots, mtDNA mutations can occur anywhere along the 16.5 kB bases of its genome [7-11]. Therefore, assays for mutational analysis of mtDNA in cancers, unlike those meant to detect spec
Preferential Activation of the Hedgehog Pathway by Epigenetic Modulations in HPV Negative HNSCC Identified with Meta-Pathway Analysis
Elana J. Fertig, Ana Markovic, Ludmila V. Danilova, Daria A. Gaykalova, Leslie Cope, Christine H. Chung, Michael F. Ochs, Joseph A. Califano
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078127
Abstract: Head and neck squamous cell carcinoma (HNSCC) is largely divided into two groups based on their etiology, human papillomavirus (HPV)-positive and –negative. Global DNA methylation changes are known to drive oncogene and tumor suppressor expression in primary HNSCC of both types. However, significant heterogeneity in DNA methylation within the groups results in different transcriptional profiles and clinical outcomes. We applied a meta-pathway analysis to link gene expression changes to DNA methylation in distinguishing HNSCC subtypes. This approach isolated specific epigenetic changes controlling expression in HPV? HNSCC that distinguish it from HPV+ HNSCC. Analysis of genes identified Hedgehog pathway activation specific to HPV? HNSCC. We confirmed that GLI1, the primary Hedgehog target, showed higher expression in tumors compared to normal samples with HPV? tumors having the highest GLI1 expression, suggesting that increased expression of GLI1 is a potential driver in HPV? HNSCC. Our algorithm for integration of DNA methylation and gene expression can infer biologically significant molecular pathways that may be exploited as therapeutics targets. Our results suggest that therapeutics targeting the Hedgehog pathway may be of benefit in HPV? HNSCC. Similar integrative analysis of high-throughput coupled DNA methylation and expression datasets may yield novel insights into deregulated pathways in other cancers.
Mixed layer in a stably stratified fluid
F. Califano,A. Mangeney
Nonlinear Processes in Geophysics (NPG) , 1994,
Abstract: We present a numerical study of the generation and evolution of a mixed layer in a stably stratified layer of Boussinesq fluid. We use an external forcing in the equation of motion to model the experimental situation where the mechanical energy input is due to an oscillating grid. The results of 2D and 3D numerical simulations indicate that the basic mechanism for the entrainment is the advection of the temperature field. This advection tends to produce horizontally thin regions of small temperature vertical gradients (jets) where the hydrodynamics forces are nearly zero. At the bottom of these structures, the buoyancy brakes the vertical motions. The jets are also characterized by the presence of very short horizontal scales where the thermal diffusion time turn out to be comparable with the dynamics time. As a result, the temperature field is well mixed in a few dynamics times. This process stops when the mechanical energy injected becomes comparable with the energy dissipated by viscosity.
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