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2078: NGF and TNF-α contribute to oral cancer pain by regulating pro-inflammatory cytokines
- Yi Ye, Jihwan Kim, Brian L. Schmidt, Donna G. Albertson, Bradley E. Aouizerat
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- Journal:
- Journal of Clinical and Translational Science / Volume 1 / Issue S1 / September 2017
- Published online by Cambridge University Press:
- 10 May 2018, p. 55
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- Article
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- You have access Access
- Open access
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OBJECTIVES/SPECIFIC AIMS: We hypothesize that both NGF and TNF-α contribute to oral cancer pain by upregulating pro-nociceptive inflammatory cytokines. METHODS/STUDY POPULATION: In total, 48 oral cancer patients were evaluated and their pain scores were measured using a validated oral cancer pain questionnaire. Presence of perineural invasion (PNI) was identified from patients’ pathology reports. We utilized The NIH Cancer Genome Atlas (TCGA) Head and Neck Cancer cohort to investigate the association between pain and genes related to NGF, TNF-α, and their receptors (TRKA, P75, TNF-α receptor 1, and TNF-α receptor 2) in oral cancer samples by employing PNI as a surrogate for pain. Demographic characteristics, clinical characteristics, and genes were analyzed using logistic regression models. A xenograft cancer pain model was created by inoculating human oral cancer cells (HSC-3) into the mouse hind paw. Mice (n=6 per group) were treated with anti-NGF alone, anti-TNF-α alone, a combination of anti-NGF and anti-TNF-α, or PBS (vehicle control). Nociceptive behaviors were measured using an electronic paw withdrawal assay. Paw volume was measured using a plethysmometer. Cytokines in the paw tissues were measured using a multiplex assay kit with 28 cytokines. RESULTS/ANTICIPATED RESULTS: Oral cancer patients with PNI report significantly more pain compared with patients without PNI in our patient cohort (p<0.05). From analysis of TCGA data, we found that PNI is significantly associated with lymphovascular invasion, pathological nodal invasion, and pathological tumor staging (all p<0.05). In adjusted models, we observed that the NGF receptor p75NTR (NGFR) and the TNF-α receptor 1 (TNFRSF1A) were associated with PNI (both p<0.05) and significantly correlated to each other (r=0.25, p<0.001). High levels of TNF-α were present in HSC-3 cell lines and the mouse xenograft cancers. In mice with cancer pain, combined treatment with anti-NGF and anti-TNF-α together provided more effective pain control compared with either anti-NGF or anti-TNF-α treatment alone (p<0.05). We found significantly increased levels of MIP3a, IL-1b, IL-2, IL-4, IL-28b, IL-23, IL17a, IL-31, and IL-33 in cancer mice compared with normal mice (all p<0.05). The combination therapy significantly reduced cytokines MIP3a, IL-1b, IL-4, IL-28b, IL-31, and IL-33 (all p<0.05). DISCUSSION/SIGNIFICANCE OF IMPACT: We show that targeting both NGF and TNF-α provides more effective pain relief in an oral cancer model. These results suggest that therapeutic strategies aimed at both pathways could yield improved pain management for oral cancer patients.
3 - Comparative genomic hybridization
- from Part 1.1 - Analytical techniques: analysis of DNA
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- By Donna G. Albertson, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA, Daniel Pinkel, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 21-27
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- Chapter
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Summary
Cells progress to cancer by the acquisition of genetic and epigenetic alterations that promote growth and survival. The genomic alterations range from mutations in individual nucleotides to rearrangements and changes in the copy number of chromosomal segments or whole chromosomes. The former result in point mutations that inactivate tumor suppressor genes or activate oncogenes, and the latter produce novel fusion genes and/or alter the expression of one or more genes that may individually or co-operatively modify cell behavior.
The technique of comparative genomic hybridization (CGH) was first introduced in 1992 as a means to assess copy number changes in genomes (1). In the original implementation of CGH, a test genomic DNA, such as DNA extracted from a tumor, and a reference DNA, typically genomic DNA from normal cells, were differentially labeled and then hybridized to normal metaphase chromosomes. The chromosomes provided a readily available physical map of the genome. For mammalian genomes it is important to suppress the hybridization of the large number of repetitive sequences. This is typically done by including an excess of unlabeled repetitive DNA (Cot-1 DNA) in the hybridization reaction. Measurement of the relative intensities of the hybridization of the test and reference genomes along the metaphase chromosomes provides a profile of the relative copy number of sequences in the test and reference genomes. Chromosome CGH provided genomic resolution on the order of 10 Mb. Starting in the late 1990s, the physical map provided by metaphase chromosomes was superseded by arrays of mapped genomic clones (2,3), cDNAs, and more recently oligonucleotides, and the technique became known as “array CGH” to distinguish it from CGH using metaphase chromosomes (Figure 3.1).