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Oral Cancer: Genetics and the Role of Precision Medicine

Li, Chia-Cheng; Shen, Zhen; Bavarian, Roxanne; Yang, Fan; Bhattacharya, Aditi
Oral squamous cell carcinoma (OSCC) is one of the leading cancers in the world. OSCC patients are managed with surgery and/or chemoradiation. Prognoses and survival rates are dismal, however, and have not improved for more than 20 years. Recently, the concept of precision medicine was introduced, and the introduction of targeted therapeutics demonstrated promising outcomes. This article reviews the current understanding of initiation, progression, and metastasis of OSCC from both genetic and epigenetic perspectives. In addition, the applications and integration of omics technologies in biomarker discovery and drug development for treating OSCC are reviewed.
PMID: 29126492
ISSN: 1558-0512
CID: 2773392

Neutrophil-Mediated Endogenous Analgesia Contributes to Sex Differences in Oral Cancer Pain

Scheff, Nicole N; Bhattacharya, Aditi; Dowse, Edward; Dang, Richard X; Dolan, John C; Wang, Susanna; Kim, Hyesung; Albertson, Donna G; Schmidt, Brian L
The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta-endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain.
PMID: 30405367
ISSN: 1662-5145
CID: 3458152

Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation

Scheff, Nicole N; Ye, Yi; Bhattacharya, Aditi; MacRae, Justin; Hickman, Dustin H; Sharma, Atul K; Dolan, John C; Schmidt, Brian L
Oral cancer patients report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we utilized two oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the two models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. While the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer-induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFa), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFa signaling abolished oral cancer cell line supernatant-evoked functional allodynia and disrupted T cell infiltration. With these data, we identified TNFa as a prominent mediator in oral cancer-induced nociception and inflammation highlighting the need for further investigation in neural-immune communication in cancer pain.
PMCID:5680143
PMID: 28885456
ISSN: 1872-6623
CID: 2688872

Oral and Maxillofacial Pathology. Case of the Month. Cherubism [Case Report]

Bhattacharya, Aditi; Wright, John M; Hadavand, Richard Reza
PMID: 26237934
ISSN: 0040-4284
CID: 2433322

Oral and Maxillofacial Pathology. Case of the Month. Diagnosis: Verruciform Xanthoma

Bhattacharya, A; Kessler, H
ORIGINAL:0012782
ISSN: 0040-4284
CID: 3203182

Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis

Uchida, Kenichiro; Veeramachaneni, Ratna; Huey, Bing; Bhattacharya, Aditi; Schmidt, Brian L; Albertson, Donna G
BACKGROUND: Metastasis to the cervical (neck) lymph nodes is one of the most significant clinical factors responsible for death from oral squamous cell carcinoma (SCC). Therefore, the lymph nodes are frequently removed when the tumor is excised (neck dissection), even though the majority of patients will not benefit from the extra surgery. Two subtypes of oral SCC distinguished by the presence of tumor genomic aberrations +3q, -8p, +8q and/or +20 differ in risk for metastasis - high for the 3q8pq20 subtype, harboring one or more of the aberrations and low for the non-3q8pq20 subtype, lacking these alterations. A prior analysis of the literature suggested genes differentially methylated in the two subtypes. Therefore, the goal of this study was to further investigate the methylation status of candidate biomarkers of the non-3q8pq20 subtype, and evaluate their utility for identifying patients at low risk for metastasis. METHODS: Methylation status of genes in a cohort of 52 oral SCC patients with at least five year follow up was determined by pyrosequencing. Gene expression levels were determined by quantitative RT-PCR. Growth following re-expression of HOXA9 in cultured oral SCC cells was assessed by proliferation and colony formation assays. RESULTS: A pilot study evaluating methylation levels of HOXA9, MT1A and HOXA11 promoters in DNA from 12 tumors (six each of the 3q8pq20 and non-3q8pq20 subtypes) revealed that only HOXA9 was differentially methylated. Significant differences in methylation levels of HOXA9 were observed amongst the 52 oral SCCs with respect to genomic subtype and nodal status (p = 0.014, and p = 0.024, respectively, Wilcoxon rank sum test). High levels of HOXA9 methylation and low levels of expression in oral SCC cell lines were observed compared to HaCaT, a non-tumorigenic keratinocyte cell line. Re-expression of HOXA9 in the SCC4 oral cancer cell line resulted in diminished proliferation and colony formation. CONCLUSIONS: HOXA9 methylation is frequent in oral cancers and levels are higher in tumors with greater risk of metastasis. Expression of HOXA9 is low in cells with high levels of methylation and reduced expression appears to confer a growth advantage.
PMCID:4045880
PMID: 24886209
ISSN: 1471-2407
CID: 1030672

Changes in abundance of oral microbiota associated with oral cancer

Schmidt, Brian L; Kuczynski, Justin; Bhattacharya, Aditi; Huey, Bing; Corby, Patricia M; Queiroz, Erica L S; Nightingale, Kira; Kerr, A Ross; DeLacure, Mark D; Veeramachaneni, Ratna; Olshen, Adam B; Albertson, Donna G
Individual bacteria and shifts in the composition of the microbiome have been associated with human diseases including cancer. To investigate changes in the microbiome associated with oral cancers, we profiled cancers and anatomically matched contralateral normal tissue from the same patient by sequencing 16S rDNA hypervariable region amplicons. In cancer samples from both a discovery and a subsequent confirmation cohort, abundance of Firmicutes (especially Streptococcus) and Actinobacteria (especially Rothia) was significantly decreased relative to contralateral normal samples from the same patient. Significant decreases in abundance of these phyla were observed for pre-cancers, but not when comparing samples from contralateral sites (tongue and floor of mouth) from healthy individuals. Weighted UniFrac principal coordinates analysis based on 12 taxa separated most cancers from other samples with greatest separation of node positive cases. These studies begin to develop a framework for exploiting the oral microbiome for monitoring oral cancer development, progression and recurrence.
PMCID:4041887
PMID: 24887397
ISSN: 1932-6203
CID: 1030742

Oral and maxillofacial pathology. Case of the month. Diagnosis: Necrotizing sialometaplasia [Case Report]

Bhattacharya, Aditi; Crossland, Jay A; Wright, John M
PMID: 23930450
ISSN: 0040-4284
CID: 2433332

Two distinct routes to oral cancer differing in genome instability and risk for cervical node metastasis

Bhattacharya, Aditi; Roy, Ritu; Snijders, Antoine M; Hamilton, Gregory; Paquette, Jesse; Tokuyasu, Taku; Bengtsson, Henrik; Jordan, Richard C K; Olshen, Adam B; Pinkel, Daniel; Schmidt, Brian L; Albertson, Donna G
PURPOSE: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis. EXPERIMENTAL DESIGN: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort. RESULTS: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%-80% of lesions, termed 3q8pq20 subtype) from the remainder (20%-30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts. CONCLUSIONS: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,-8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC.
PMCID:3226754
PMID: 22068658
ISSN: 1078-0432
CID: 155557