1,941 results on '"Califano, Joseph A."'
Search Results
2. Defining the relationship of salivary gland malignancies to novel cell subpopulations in human salivary glands using single nucleus RNA‐sequencing
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Nakagawa, Takuya, Santos, Jessica, Nasamran, Chanond A, Sen, Prakriti, Sadat, Sayed, Monther, Abdula, Bendik, Joseph, Ebisumoto, Koji, Hu, Jingjing, Preissl, Sebastian, Guo, Theresa, Vavinskaya, Vera, Fisch, Kathleen M, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Dental/Oral and Craniofacial Disease ,Rare Diseases ,Genetics ,Digestive Diseases ,2.1 Biological and endogenous factors ,Humans ,Biomarkers ,Tumor ,Salivary Glands ,Salivary Gland Neoplasms ,Carcinoma ,Adenoid Cystic ,Carcinoma ,Carcinoma ,Acinar Cell ,RNA ,immunohistochemistry ,salivary gland cancer ,salivary glands ,single nucleus RNA-seq ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Salivary glands have essential roles in maintaining oral health, mastication, taste and speech, by secreting saliva. Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including adenoid cystic carcinoma (ACC), acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In our study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2 and myoepithelial cells/stromal cells. The localization of each cell group was verified by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Furthermore, in comparison with SGC RNA-seq data, acinar cell markers were upregulated in AciCC, but downregulated in ACC and ductal cell markers were upregulated in SDC but downregulated in MECA, suggesting that markers of origin are highly expressed in some SGC. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship.
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- 2024
3. Human papillomavirus E5 suppresses immunity via inhibition of the immunoproteasome and STING pathway.
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Miyauchi, Sayuri, Kim, Sangwoo, Jones, Riley, Zhang, Lin, Guram, Kripa, Sharma, Sonia, Schoenberger, Stephen, Califano, Joseph, Sharabi, Andrew, and Cohen, Ezra
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CP: Immunology ,HPV ,HPV E5 ,MAVS ,STING ,anti-viral response ,head and neck squamous cell carcinoma ,immunoproteasome ,type I interferon ,Humans ,Human Papillomavirus Viruses ,Papillomavirus Infections ,Human papillomavirus 16 ,Head and Neck Neoplasms ,Interferons - Abstract
The role that human papillomavirus (HPV) oncogenes play in suppressing responses to immunotherapy in cancer deserves further investigation. In particular, the effects of HPV E5 remain poorly understood relative to E6 and E7. Here, we demonstrate that HPV E5 is a negative regulator of anti-viral interferon (IFN) response pathways, antigen processing, and antigen presentation. Using head and neck cancer as a model, we identify that E5 decreases expression and function of the immunoproteasome and that the immunoproteasome, but not the constitutive proteasome, is associated with improved overall survival in patients. Moreover, immunopeptidome analysis reveals that HPV E5 restricts the repertoire of antigens presented on the cell surface, likely contributing to immune escape. Mechanistically, we discover a direct interaction between E5 and stimulator of interferon genes (STING), which suppresses downstream IFN signaling. Taken together, these findings identify a powerful molecular mechanism by which HPV E5 limits immune detection and mediates resistance to immunotherapy.
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- 2023
4. Randomized Controlled Trials in Periodontology and Implantology
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Sehgal, Harjit Singh, Kohli, Richie, Califano, Joseph V., Kohli, Richie, editor, Sehgal, Harjit S., editor, and Milgrom, Peter, editor
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- 2024
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5. A Network Landscape of HPVOPC Reveals Methylation Alterations as Significant Drivers of Gene Expression via an Immune-Mediated GPCR Signal
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Qualliotine, Jesse R, Nakagawa, Takuya, Rosenthal, Sara Brin, Sadat, Sayed, Ballesteros-Merino, Carmen, Xu, Guorong, Mark, Adam, Nasamran, Art, Gutkind, J Silvio, Fisch, Kathleen M, Guo, Theresa, Fox, Bernard A, Khan, Zubair, Molinolo, Alfredo A, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,network analysis ,head and neck squamous cell carcinoma ,human papillomavirus ,HPV ,oropharyngeal neoplasms ,epigenetics ,exome sequencing ,The Cancer Genome Atlas ,Oncology and carcinogenesis - Abstract
HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16-human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor-immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.
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- 2023
6. Interdisciplinary Approach to Expedited Outpatient Gastrostomy Tube Placement in Head and Neck Cancer Patients: A Single Center Retrospective Study
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Haldeman, Pearce B., Ghani, Mansur A., Rubio, Patricia, Pineda, Minette, Califano, Joseph, Sacco, Assuntina G., Minocha, Jeet, and Berman, Zachary T.
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- 2024
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7. Radiation Therapy for HPV-Positive Oropharyngeal Squamous Cell Carcinoma: An ASTRO Clinical Practice Guideline
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Margalit, Danielle N., Anker, Christopher J., Aristophanous, Michalis, Awan, Musaddiq, Bajaj, Gopal K., Bradfield, Lisa, Califano, Joseph, Caudell, Jimmy J., Chapman, Christina H., Garden, Adam S., Harari, Paul M., Helms, Amanda, Lin, Alexander, Maghami, Ellie, Mehra, Ranee, Parker, Lance, Shnayder, Yelizaveta, Spencer, Sharon, Swiecicki, Paul L., Tsai, Jillian Chiaojung, and Sher, David J.
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- 2024
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8. Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC
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Saddawi-Konefka, Robert, O’Farrell, Aoife, Faraji, Farhoud, Clubb, Lauren, Allevato, Michael M, Jensen, Shawn M, Yung, Bryan S, Wang, Zhiyong, Wu, Victoria H, Anang, Nana-Ama, Msari, Riyam Al, Schokrpur, Shiruyeh, Pietryga, Ida Franiak, Molinolo, Alfredo A, Mesirov, Jill P, Simon, Aaron B, Fox, Bernard A, Bui, Jack D, Sharabi, Andrew, Cohen, Ezra EW, Califano, Joseph A, and Gutkind, J Silvio
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Cancer ,Dental/Oral and Craniofacial Disease ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Animals ,Dendritic Cells ,Head and Neck Neoplasms ,Humans ,Immune Checkpoint Inhibitors ,Immunotherapy ,Mice ,Squamous Cell Carcinoma of Head and Neck - Abstract
Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity.
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- 2022
9. Activated B Cells and Plasma Cells Are Resistant to Radiation Therapy.
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Franiak-Pietryga, Ida, Miyauchi, Sayuri, Kim, Sangwoo Shawn, Sanders, Philip Dominick, Sumner, Whitney, Zhang, Lin, Mundt, AJ, Califano, Joseph A, and Sharabi, Andrew B
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B-Lymphocytes ,Plasma Cells ,CD8-Positive T-Lymphocytes ,Animals ,Humans ,Mice ,Lymphocyte Count ,Tumor Microenvironment ,Vaccine Related ,Cancer ,Immunization ,Inflammatory and immune system ,Other Physical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeB cells play a key role in outcomes of cancer patients and responses to checkpoint blockade immunotherapies. However, the effect of radiation therapy on B cell populations is poorly understood. Here we characterize the effects of radiation on the development, survival, and phenotype of physiological B-cell subsets.Methods and materialsNaïve and immunized tumor bearing and nontumor bearing mice were treated with large-field or focal stereotactic radiation and distinct B-cell subsets of varying developmental stages were analyzed by flow cytometry and real-time reverse transcription polymerase chain reaction.ResultsWe first report that focal stereotactic radiation is highly superior to large-field radiation at inducing tumor infiltration of B cells, CD8+ T cells, and macrophages. We observed that radiation affects B cell development in the bone marrow, increasing frequencies of early pro-B cells and late pro-B cells while inducing upregulation of programmed cell death protein 1. We then demonstrate that class switched B cells and plasma cells are highly resistant to radiation therapy compared with naïve B cells and upregulate activation markers programmed cell death 1 ligand 2 and major histocompatibility complex class II) after radiation. Mechanistically, radiation upregulates Xbp1 and Bcl6 in plasma cells, conferring radioresistance. Furthermore, using an immunization approach, we demonstrate that radiation enhances activation-induced cytidine deaminase mediated class switching and somatic hypermutation in primed B cells.ConclusionsThese data demonstrate that stereotactic radiation is superior to large-field radiation at inducing infiltration of immune cells into tumors and that plasma cells and class switched B cells are highly resistant to radiation therapy. These results represent the most comprehensive analysis of the effects of radiation on B cells to date and identify novel mechanisms by which radiation modulates immune cells within the tumor microenvironment.
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- 2022
10. Computational and AI-driven 3D structural analysis of human papillomavirus (HPV) oncoproteins E5, E6, and E7 reveal significant divergence of HPV E5 between low-risk and high-risk genotypes
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Jones, Riley N., Miyauchi, Sayuri, Roy, Souvick, Boutros, Nathalie, Mayadev, Jyoti S., Mell, Loren K., Califano, Joseph A., Venuti, Aldo, and Sharabi, Andrew B.
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- 2024
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11. Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
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Pang, John, Nguyen, Nam, Luebeck, Jens, Ball, Laurel, Finegersh, Andrey, Ren, Shuling, Nakagawa, Takuya, Flagg, Mitchell, Sadat, Sayed, Mischel, Paul S, Xu, Guorong, Fisch, Kathleen, Guo, Theresa, Cahill, Gabrielle, Panuganti, Bharat, Bafna, Vineet, and Califano, Joseph
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Dental/Oral and Craniofacial Disease ,Digestive Diseases ,Genetics ,Infectious Diseases ,Women's Health ,Human Genome ,Cancer Genomics ,Sexually Transmitted Infections ,Cancer ,2.1 Biological and endogenous factors ,Alphapapillomavirus ,DNA ,Circular ,DNA ,Viral ,Head and Neck Neoplasms ,Humans ,Oncogene Proteins ,Viral ,Oncogenes ,Oropharyngeal Neoplasms ,Papillomaviridae ,Papillomavirus Infections ,Proteomics ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeHuman papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.Experimental designForty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets.ResultsOur analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition.ConclusionsNonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.
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- 2021
12. End of treatment cone-beam computed tomography (CBCT) is predictive of radiation response and overall survival in oropharyngeal squamous cell carcinoma
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Sumner, Whitney, Kim, Sangwoo S, Vitzthum, Lucas, Moore, Kevin, Atwood, Todd, Murphy, James, Miyauchi, Sayuri, Califano, Joseph A, Mell, Loren K, Mundt, Arno J, and Sharabi, Andrew B
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Rare Diseases ,Cancer ,Biomedical Imaging ,Clinical Research ,Dental/Oral and Craniofacial Disease ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Adult ,Aged ,Aged ,80 and over ,Carcinoma ,Squamous Cell ,Cone-Beam Computed Tomography ,Female ,Follow-Up Studies ,Humans ,Image Processing ,Computer-Assisted ,Male ,Middle Aged ,Organs at Risk ,Oropharyngeal Neoplasms ,Prognosis ,Radiotherapy Dosage ,Radiotherapy Planning ,Computer-Assisted ,Radiotherapy ,Image-Guided ,Radiotherapy ,Intensity-Modulated ,Retrospective Studies ,Survival Rate ,Head and neck squamous cell carcinoma ,Head and neck cancer ,Radiotherapy ,Radiation ,Cone beam CT ,CBCT ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundImage guidance in radiation oncology has resulted in significant improvements in the accuracy and precision of radiation therapy (RT). Recently, the resolution and quality of cone beam computed tomography (CBCT) for image guidance has increased so that tumor masses and lymph nodes are readily detectable and measurable. During treatment of head and neck squamous cell carcinoma (HNSCC), on-board CBCT setup imaging is routinely obtained; however, this CBCT imaging data is not utilized to predict patient outcomes. Here, we analyzed whether changes in CBCT measurements obtained during a course of radiation therapy correlate with responses on routine 3-month follow-up diagnostic imaging and overall survival (OS).Materials/methodsPatients with oropharyngeal primary tumors who received radiation therapy between 2015 and 2018 were included. Anatomical measurements were collected of largest nodal conglomerate (LNC) at CT simulation, end of radiation treatment (EOT CBCT), and routine 3-month post-RT imaging. At each timepoint anteroposterior (AP), mediolateral (ML) and craniocaudal (CC) measurements were obtained and used to create a 2-dimensional (2D) maximum.ResultsCBCT data from 64 node positive patients were analyzed. The largest nodal 2D maximum and CC measurements on EOT CBCT showed a statistically significant correlation with complete response on 3-month post-RT imaging (r = 0.313, p = 0.02 and r = 0.318, p = 0.02, respectively). Furthermore, patients who experienced a 30% or greater reduction in the CC dimension had improved OS (Binary Chi-Square HR 4.85, p = 0.028).ConclusionDecreased size of pathologic lymph nodes measured using CBCT setup imaging during a radiation course correlates with long term therapeutic response and overall survival of HNSCC patients. These results indicate that CBCT setup imaging may have utility as an early predictor of treatment response in oropharyngeal HNSCC.
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- 2021
13. Asymptomatic detection of SARS‐CoV‐2 among cancer patients receiving infusional anti‐cancer therapy
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Shaya, Justin, Cabal, Angelo, Nonato, Taylor, Torriani, Francesca, Califano, Joseph, Lippman, Scott, Sacco, Assuntina, and McKay, Rana R
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Prevention ,Biodefense ,Lung ,Cancer ,Emerging Infectious Diseases ,Vaccine Related ,Clinical Research ,Infectious Diseases ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Asymptomatic Infections ,COVID-19 ,California ,Female ,Hospitalization ,Humans ,Male ,Mass Screening ,Middle Aged ,Neoplasms ,Retrospective Studies ,SARS-CoV-2 ,Young Adult ,asymptomatic ,cancer ,Covid-19 ,PCR testing ,screening ,Biochemistry and Cell Biology ,Oncology and Carcinogenesis - Abstract
BackgroundLittle is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS-CoV-2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high-risk cohort.MethodsRetrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti-cancer therapy to undergo a symptom/exposure screen and SARS-CoV-2 PCR testing 24-96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS-CoV-2 infection. Secondary outcomes included the rate of COVID-19-related hospitalization and mortality and delays in oncologic therapy.ResultsAmong a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS-CoV-2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID-19-related symptoms. Four patients required hospitalization for complications of COVID-19 infection. No patient died from COVID-related complications. 97.7% (N = 42/43) had their anti-cancer therapy delayed or deferred with a median delay of 21 days (range: 7-77 days).ConclusionsOverall, among a cohort of active cancer patients receiving anti-cancer therapy, an asymptomatic SARS-CoV2 PCR-based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long-term follow-up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID-19 infection.
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- 2021
14. Role of B Cells in Responses to Checkpoint Blockade Immunotherapy and Overall Survival of Cancer Patients
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Kim, Sangwoo S, Sumner, Whitney A, Miyauchi, Sayuri, Cohen, Ezra EW, Califano, Joseph A, and Sharabi, Andrew B
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Cancer ,Clinical Research ,Immunization ,Vaccine Related ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Animals ,Antibody Formation ,Antigen-Presenting Cells ,B-Lymphocytes ,Biomarkers ,Disease Management ,Humans ,Immune Checkpoint Inhibitors ,Immunomodulation ,Lymphopoiesis ,Molecular Targeted Therapy ,Neoplasms ,Prognosis ,Treatment Outcome ,Tumor Microenvironment ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The role of B cells in the tumor microenvironment and B-cell-mediated antitumor immune responses remains relatively understudied. Recent seminal studies have discovered that B cells and associated tertiary lymphoid structures correlate with responses to checkpoint blockade immunotherapy and are prognostic for overall survival of cancer patients. B-cell subsets have remarkable functional diversity and include professional antigen-presenting cells, regulatory cells, memory populations, and antibody-producing plasma cells. Importantly, secreted antibodies can independently activate innate immune responses and induce the cancer immunity cycle. Thus, B cells and B-cell-mediated antibody responses comprise the largely underappreciated second arm of the adaptive immune system and certainly deserve further attention in the field of oncology. Here, we review the known functions of B cells in the tumor microenvironment, the contribution of B cells to the antitumor activity of immunotherapies, and the role of B cells in the overall survival of cancer patients.
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- 2021
15. Preclinical experience with a novel single-port platform for transoral surgery
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Funk, Emily K, Weissbrod, Philip, Horgan, Santiago, Orosco, Ryan K, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Endoscopes ,Humans ,Hypopharynx ,Laryngoscopes ,Microsurgery ,Minimally Invasive Surgical Procedures ,Robotic Surgical Procedures ,Transoral surgery ,Minimally invasive surgery ,Head and neck surgery ,Laryngeal microsurgery ,Surgery ,Clinical sciences - Abstract
BackgroundWe investigated a novel minimally invasive surgical platform for use in the oropharynx, hypopharynx, and larynx for single-port transoral surgery used in concert with standard transoral laryngeal and pharyngeal instrumentation.MethodsThe preclinical investigational device by Fortimedix Surgical B.V. (Netherlands) features two channels for manually controlled flexible articulating surgical instruments. A third central channel accepts both rigid and flexible endoscopes. The system is coupled to a standard laryngoscope for transoral access. In three cadaver models, we evaluated the surgical capabilities using wristed grasping instruments, microlaryngeal scissors, monopolar cautery, and a laser fiber sheath. Procedures were performed within the oropharynx, supraglottis, glottis, subglottis, and hypopharynx.ResultsWithin the oropharynx, we found adequate strength, range of motion, and dexterity to perform lateral oropharyngectomy and tongue base resection. Within the larynx, visualization was achieved with a variety of instruments including a flexible, 0° and 30° rigid endoscope. The glottis, supraglottis, pyriform sinuses, post-cricoid space, and esophageal inlet were readily accessible. Visualization and manipulation of grasping, laser, and monopolar cautery instruments were also possible within the subglottis. Instrument reach and accuracy facilitated completion of a delicate micro-flap on the true vocal fold. Other procedures included vocal fold resection, cricopharyngeal myotomy, and resection of subglottic mucosa.ConclusionsFrom this initial proof of concept experience with this novel platform, we found a wide range of procedures within the oropharynx, larynx, and hypopharynx to be feasible. Further work is needed to evaluate its applicability to the clinical setting. The ability of this platform to be used with conventional instrumentation may provide an opportunity for complex transoral surgery to be performed in a facile manner at greatly reduced cost.
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- 2021
16. Disruption of the HER3-PI3K-mTOR oncogenic signaling axis and PD-1 blockade as a multimodal precision immunotherapy in head and neck cancer.
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Wang, Zhiyong, Goto, Yusuke, Allevato, Michael M, Wu, Victoria H, Saddawi-Konefka, Robert, Gilardi, Mara, Alvarado, Diego, Yung, Bryan S, O'Farrell, Aoife, Molinolo, Alfredo A, Duvvuri, Umamaheswar, Grandis, Jennifer R, Califano, Joseph A, Cohen, Ezra EW, and Gutkind, J Silvio
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Head and Neck Neoplasms ,Receptor ,erbB-3 ,Antineoplastic Combined Chemotherapy Protocols ,Protein Kinase Inhibitors ,Immunotherapy ,Xenograft Model Antitumor Assays ,Signal Transduction ,Cell Proliferation ,Mutation ,Female ,Class I Phosphatidylinositol 3-Kinases ,TOR Serine-Threonine Kinases ,Tumor Microenvironment ,Programmed Cell Death 1 Receptor ,Precision Medicine ,Squamous Cell Carcinoma of Head and Neck ,Immune Checkpoint Inhibitors ,Receptor ,ErbB-3 ,Cancer ,Dental/Oral and Craniofacial Disease ,Rare Diseases - Abstract
Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but
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- 2021
17. Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma
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Fukusumi, Takahito, Guo, Theresa W, Ren, Shuling, Haft, Sunny, Liu, Chao, Sakai, Akihiro, Ando, Mizuo, Saito, Yuki, Sadat, Sayed, and Califano, Joseph A
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Dental/Oral and Craniofacial Disease ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Basic Helix-Loop-Helix Transcription Factors ,Cell Cycle Proteins ,Cell Line ,Tumor ,Cell Transformation ,Neoplastic ,Datasets as Topic ,Epithelial-Mesenchymal Transition ,Feedback ,Physiological ,Gene Expression Regulation ,Neoplastic ,Humans ,Mice ,Receptor ,Notch4 ,SOXB1 Transcription Factors ,Signal Transduction ,Spheroids ,Cellular ,Squamous Cell Carcinoma of Head and Neck ,Up-Regulation ,Xenograft Model Antitumor Assays ,head and neck squamous cell carcinoma ,TCGA ,SOX2 ,NOTCH4 ,HEY1 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.
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- 2021
18. AHNS endocrine surgery section consensus statement on nasopharyngolaryngoscopy and clinic reopening during COVID‐19: How to get back to optimal safe care
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Bleier, Benjamin, Workman, Alan, Burks, Ciersten, Maxfield, Alice, Stack, Brendan C, Nathan, Cherie‐Ann, McCammon, Susan, Varvares, Mark, Schmalbach, Cecelia, Wang, Steven, Califano, Joseph, Shnayder, Yelizaveta, Gillespie, Marion B, Enepekides, Danny, Witterick, Ian, El‐Sayed, Ivan, Lin, Derrick, Patel, Urjeet, Kraus, Dennis, and Randolph, Gregory
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Biomedical and Clinical Sciences ,Clinical Sciences ,Patient Safety ,Good Health and Well Being ,COVID-19 ,COVID-19 Testing ,Disease Transmission ,Infectious ,Endocrinology ,Humans ,Mass Screening ,Nasal Surgical Procedures ,Otolaryngology ,Personal Protective Equipment ,Risk ,SARS-CoV-2 ,clinic reopening ,consensus statement ,nasopharyngolaryngoscopy ,Otolaryngology-Head and Neck Surgery ,Dentistry ,Otorhinolaryngology ,Clinical sciences - Abstract
This article provides best practice guidelines regarding nasopharyngolaryngoscopy and OHNS clinic reopening during the COVID-19 pandemic. The aim is to provide evidence-based recommendations defining the risks of COVID-19 in clinic, the importance of pre-visit screening in addition to testing, along with ways to adhere to CDC guidelines for environmental, source, and engineering controls.
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- 2021
19. Outcomes of the facelift incisional approach to neck dissection without endoscopic or robotic assistance
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Ostrander, Benjamin T., Harmon, Matthew N., Yu, Vanessa K., and Califano, Joseph
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- 2023
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20. Identifying predictors of HPV‐related head and neck squamous cell carcinoma progression and survival through patient‐derived models
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Facompre, Nicole D, Rajagopalan, Pavithra, Sahu, Varun, Pearson, Alexander T, Montone, Kathleen T, James, Claire D, Gleber‐Netto, Frederico O, Weinstein, Gregory S, Jalaly, Jalal, Lin, Alexander, Rustgi, Anil K, Nakagawa, Hiroshi, Califano, Joseph A, Pickering, Curtis R, White, Elizabeth A, Windle, Bradford E, Morgan, Iain M, Cohen, Roger B, Gimotty, Phyllis A, and Basu, Devraj
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Infectious Diseases ,Rare Diseases ,Cervical Cancer ,Genetics ,Cancer ,Dental/Oral and Craniofacial Disease ,Sexually Transmitted Infections ,Human Genome ,Aetiology ,4.1 Discovery and preclinical testing of markers and technologies ,2.1 Biological and endogenous factors ,Detection ,screening and diagnosis ,Good Health and Well Being ,Animals ,Class I Phosphatidylinositol 3-Kinases ,ErbB Receptors ,Female ,Genetic Association Studies ,Head and Neck Neoplasms ,Humans ,Male ,Mice ,Mutation ,Neoplasm Transplantation ,Papillomaviridae ,Papillomavirus E7 Proteins ,Papillomavirus Infections ,Patient-Specific Modeling ,Prognosis ,Squamous Cell Carcinoma of Head and Neck ,Survival Analysis ,TNF Receptor-Associated Factor 3 ,Exome Sequencing ,biomarkers ,head and neck cancer ,HPV ,outcomes ,patient-derived xenografts ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
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- 2020
21. HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers
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Ren, Shuling, Gaykalova, Daria A, Guo, Theresa, Favorov, Alexander V, Fertig, Elana J, Tamayo, Pablo, Callejas-Valera, Juan Luis, Allevato, Mike, Gilardi, Mara, Santos, Jessica, Fukusumi, Takahito, Sakai, Akihiro, Ando, Mizuo, Sadat, Sayed, Liu, Chao, Xu, Guorong, Fisch, Kathleen M, Wang, Zhiyong, Molinolo, Alfredo A, Gutkind, J Silvio, Ideker, Trey, Koch, Wayne M, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Cervical Cancer ,Infectious Diseases ,Genetics ,Human Genome ,Sexually Transmitted Infections ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Carcinogenesis ,Cell Line ,Tumor ,Cell Proliferation ,Datasets as Topic ,Disease Models ,Animal ,Disease-Free Survival ,Female ,Gene Expression Regulation ,Neoplastic ,Gene Expression Regulation ,Viral ,Host-Pathogen Interactions ,Human papillomavirus 16 ,Humans ,Mice ,Mice ,Transgenic ,Oncogene Proteins ,Viral ,Papillomavirus Infections ,Pharyngeal Neoplasms ,Primary Cell Culture ,Receptors ,Fibroblast Growth Factor ,Signal Transduction ,Squamous Cell Carcinoma of Head and Neck ,TOR Serine-Threonine Kinases ,Tumor Suppressor Protein p53 ,Uterine Cervical Neoplasms ,Clinical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.
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- 2020
22. B Cells Improve Overall Survival in HPV-Associated Squamous Cell Carcinomas and Are Activated by Radiation and PD-1 Blockade
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Kim, Sangwoo S, Shen, Sarek, Miyauchi, Sayuri, Sanders, P Dominick, Franiak-Pietryga, Ida, Mell, Loren, Gutkind, J Silvio, Cohen, Ezra EW, Califano, Joseph A, and Sharabi, Andrew B
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Prevention ,Sexually Transmitted Infections ,Clinical Research ,Infectious Diseases ,Dental/Oral and Craniofacial Disease ,Rare Diseases ,Immunization ,Biotechnology ,Vaccine Related ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Animals ,B-Lymphocytes ,Biomarkers ,Carcinoma ,Squamous Cell ,Cell Line ,Tumor ,Disease Models ,Animal ,Female ,Humans ,Lymphocyte Activation ,Mice ,Papillomavirus Infections ,Prognosis ,Programmed Cell Death 1 Receptor ,Radiotherapy ,Survival Analysis ,Treatment Outcome ,Xenograft Model Antitumor Assays ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeTo characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on B-cell populations.Experimental designTumor RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV+ HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)-sequencing. Human protein microarray was then used to quantify B-cell-mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade.ResultsRNA-sequencing identified CD19 and IGJ as novel B-cell prognostic biomarkers for 3-year OS (HR, 0.545; P < 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCR-sequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade.ConclusionsThese findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPV-associated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.
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- 2020
23. Procedural precautions and personal protective equipment during head and neck instrumentation in the COVID‐19 era
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Panuganti, Bharat A, Pang, John, Califano, Joseph, and Chan, Jason YK
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Biomedical and Clinical Sciences ,Clinical Sciences ,Dental/Oral and Craniofacial Disease ,Prevention ,Rare Diseases ,Good Health and Well Being ,Air Pollutants ,Occupational ,Betacoronavirus ,COVID-19 ,COVID-19 Testing ,Clinical Laboratory Techniques ,Coronavirus Infections ,Humans ,Infection Control ,Infectious Disease Transmission ,Patient-to-Professional ,Occupational Exposure ,Otorhinolaryngologic Surgical Procedures ,Pandemics ,Personal Protective Equipment ,Pneumonia ,Viral ,SARS-CoV-2 ,high-risk procedures ,perioperative protocols ,personal protective equipment ,Dentistry ,Otorhinolaryngology ,Clinical sciences - Abstract
BackgroundOtolaryngologists represent a subset of health care workers uniquely vulnerable to COVID-19 transmission. Given the segmentation of extant guidelines concerning precautions and protective equipment for SARS-CoV2, we aimed to provide consolidated recommendations regarding appropriate personal protective equipment (PPE) in head neck surgery during the COVID-19 era.MethodsGuidelines published by international and US governing bodies were reviewed in conjunction with published literature concerning COVID-19 transmission risk, testing, and PPE, to compile situation-specific recommendations for head and neck providers managing COVID-19 patients.ResultsHigh-quality data regarding the aerosolization potential of head and neck instrumentation and appropriate PPE during head and neck surgeries are lacking. However, extrapolation of recommendations by governing bodies suggests strongly that head and neck mucosal instrumentation warrants strict adherence to airborne-level precautions.ConclusionWe present a series of situation-specific recommendations for PPE use and other procedural precautions for otolaryngology providers to consider in the COVID-19 era.
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- 2020
24. Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation
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Liu, Chao, Sadat, Sayed H, Ebisumoto, Koji, Sakai, Akihiro, Panuganti, Bharat A, Ren, Shuling, Goto, Yusuke, Haft, Sunny, Fukusumi, Takahito, Ando, Mizuo, Saito, Yuki, Guo, Theresa, Tamayo, Pablo, Yeerna, Huwate, Kim, William, Hubbard, Jacqueline, Sharabi, Andrew B, Gutkind, J Silvio, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Drug Abuse (NIDA only) ,Sexually Transmitted Infections ,Infectious Diseases ,Substance Misuse ,Genetics ,Dental/Oral and Craniofacial Disease ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Cannabinoids ,Cell Movement ,Cell Proliferation ,Female ,Head and Neck Neoplasms ,Humans ,Mice ,Mice ,Nude ,Papillomaviridae ,Papillomavirus Infections ,Prognosis ,Receptors ,Cannabinoid ,Squamous Cell Carcinoma of Head and Neck ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,p38 Mitogen-Activated Protein Kinases ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeHuman papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.Experimental designThe expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).ResultsIn TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.ConclusionsCannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.
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- 2020
25. Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma
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Saito, Yuki, Favorov, Alexander V, Forman, Michael, Ren, Shuling, Sakai, Akihiro, Fukusumi, Takahito, Liu, Chao, Sadat, Sayed, Ando, Mizuo, Xu, Guorong, Khan, Zubair, Pang, John, Valsamakis, Alex, Fisch, Kathleen M, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Sexually Transmitted Infections ,Cancer ,Infectious Diseases ,Biotechnology ,Cervical Cancer ,Genetics ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,DNA ,Viral ,Genomics ,Head and Neck Neoplasms ,Human papillomavirus 16 ,Humans ,Papillomaviridae ,Papillomavirus Infections ,Squamous Cell Carcinoma of Head and Neck ,DNA primer ,head and neck squamous cell carcinoma ,human papillomavirus ,polymerase chain reaction ,whole-genome sequencing ,Clinical Sciences ,Dentistry ,Otorhinolaryngology ,Clinical sciences - Abstract
BackgroundWe aimed to use genomic data for optimizing polymerase chain reaction (PCR) primer/probe sets for detection of human papillomavirus (HPV)-16 in body fluids of patients with HPV-related head and neck squamous cell carcinoma (HPV-HNSCC).MethodsWe used genomic HPV-HNSCC sequencing data from a single institutional and a TCGA cohort. Optimized primer/probe sets were designed and tested for analytical performance in CaSki HPV-16 genome and confirmed in salivary rinse samples from patients with HPV-HNSCC.ResultsThe highest read density was observed between E5 and L2 regions. The E1 region contained a region that was universally present. Among candidate PCR primer/probe sets created, six reliably detected 30 HPV-16 copy number. In a CLIA certified laboratory setting, the combination of two novel primer/probe with E7 sets improved performance in salivary rinse samples with a sensitivity of 96% and specificity of 100%.ConclusionsPCR-based detection of HPV-16 DNA in HPV-HNSCC can be improved using rational genomic design.
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- 2020
26. Targeting Viral DNA and Promoter Hypermethylation in Salivary Rinses for Recurrent HPV‐Positive Oropharyngeal Cancer
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Shen, Sarek, Saito, Yuki, Ren, Shuling, Liu, Chao, Guo, Theresa, Qualliotine, Jesse, Khan, Zubair, Sadat, Sayed, and Califano, Joseph A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Digestive Diseases ,Sexually Transmitted Infections ,Prevention ,Dental/Oral and Craniofacial Disease ,Genetics ,Cancer ,Infectious Diseases ,4.4 Population screening ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Good Health and Well Being ,Aged ,Cohort Studies ,DNA Methylation ,DNA ,Viral ,Female ,Humans ,Male ,Middle Aged ,Neoplasm Recurrence ,Local ,Oropharyngeal Neoplasms ,Papillomaviridae ,Promoter Regions ,Genetic ,Retrospective Studies ,Saliva ,Squamous Cell Carcinoma of Head and Neck ,oropharyngeal squamous cell carcinoma ,human papillomavirus ,HPV ,saliva ,promoter hypermethylation ,epigenetics ,screening ,recurrence ,Clinical Sciences ,Otorhinolaryngology ,Clinical sciences - Abstract
OBJECTIVE:The incidence and survivorship of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) are increasing. Presence of HPV DNA and epigenetic alterations in salivary rinses are independently associated with clinical prognosis. We evaluated the utility of a combined panel in detecting disease recurrence during surveillance. We also assessed the assay's applicability in screening for HPV+ OPSCC. STUDY DESIGN:Retrospective cohort study. SETTING:Two tertiary academic hospitals. SUBJECTS AND METHODS:Forty-nine patients with posttreatment OPSCC were enrolled. Separately, 21 treatment-naive patients and 40 controls were included in the screening analysis. Salivary rinses were obtained from these cohorts and biomarker levels were quantified. Receiver operative characteristic (ROC) curves and multivariate logistic models were used to assess performance of biomarker combinations. RESULTS:Eight patients (16.3%) in the posttreatment cohort developed locoregional recurrence. Recurrence was associated with alcohol use (odds ratio [OR], 6.12; 95% confidence interval [CI], 0.26-3.79) and advanced nodal disease (OR, 2.21; 95% CI, 1.52-3.01). A panel of HPV DNA and methylated EDNRB improved detection of recurrent disease (area under the curve [AUC], 0.88) compared to single markers (AUC, 0.69-0.78). Positive biomarkers preceded clinical detection by 2.4 ± 1.6 months and was associated with nearly 40-fold risk of recurrence (OR, 36.4; 95% CI, 1.15-45.22). Within the screening analysis, single biomarkers demonstrated moderate sensitivity and specificity (AUC, 0.59-0.83) in the detection of primary disease. A panel combining HPV DNA markers with methylated EDNRB and methylated PAX5 improved AUC to 0.93. CONCLUSION:Detection of high-risk HPV DNA or aberrant hypermethylation in oral rinses is associated with presence and recurrence of OPSCC. Targeting both markers in saliva may have utility in long-term surveillance.
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- 2020
27. HPV16 E5 Mediates Resistance to PD-L1 Blockade and Can Be Targeted with Rimantadine in Head and Neck Cancer
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Miyauchi, Sayuri, Sanders, P Dominick, Guram, Kripa, Kim, Sangwoo S, Paolini, Francesca, Venuti, Aldo, Cohen, Ezra EW, Gutkind, J Silvio, Califano, Joseph A, and Sharabi, Andrew B
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Sexually Transmitted Infections ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,Vaccine Related ,Cervical Cancer ,Cancer ,Infectious Diseases ,HIV/AIDS ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Animals ,Antigen Presentation ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,B7-H1 Antigen ,Cell Line ,Tumor ,Chemoradiotherapy ,Cohort Studies ,Disease Models ,Animal ,Down-Regulation ,Drug Resistance ,Neoplasm ,Female ,Gene Expression Regulation ,Neoplastic ,HEK293 Cells ,Head and Neck Neoplasms ,Healthy Volunteers ,Histocompatibility Antigens Class II ,Human papillomavirus 16 ,Humans ,Male ,Mice ,Middle Aged ,Oncogene Proteins ,Viral ,Papillomavirus Infections ,RAW 264.7 Cells ,RNA-Seq ,Rimantadine ,Squamous Cell Carcinoma of Head and Neck ,Young Adult ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.
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- 2020
28. Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing
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Sakai, Akihiro, Ando, Mizuo, Fukusumi, Takahito, Ren, Shuling, Liu, Chao, Qualliotine, Jesse, Haft, Sunny, Sadat, Sayed, Saito, Yuki, Guo, Theresa W, Xu, Guorong, Sasik, Roman, Fisch, Kathleen M, Gutkind, J Silvio, Fertig, Elana J, Molinolo, Alfredo A, and Califano, Joseph A
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Dental/Oral and Craniofacial Disease ,Human Genome ,Rare Diseases ,Genetics ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Alternative Splicing ,Biomarkers ,Tumor ,Cleavage And Polyadenylation Specificity Factor ,Gene Expression Regulation ,Neoplastic ,Head and Neck Neoplasms ,Humans ,Squamous Cell Carcinoma of Head and Neck ,General Science & Technology - Abstract
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.
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- 2020
29. Effect of CBD on anti-tumor immune response and interaction with GPR55 on MAPK signaling in head and neck squamous cell carcinoma.
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Sen, Prakriti, primary, Sadat, Sayed, additional, Ebisumoto, Koji, additional, Nakagawa, Takuya, additional, Msari, Riyam Al, additional, Konefka, Robert Saddawi, additional, Inoue, Asuka, additional, and Califano, Joseph, additional
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- 2024
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30. Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer.
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Flam, Emily L, Danilova, Ludmila, Kelley, Dylan Z, Stavrovskaya, Elena, Guo, Theresa, Considine, Michael, Qian, Jiang, Califano, Joseph A, Favorov, Alexander, Fertig, Elana J, and Gaykalova, Daria A
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Humans ,Papillomaviridae ,Carcinoma ,Squamous Cell ,Head and Neck Neoplasms ,Reproducibility of Results ,DNA Methylation ,Gene Expression Regulation ,Neoplastic ,Enhancer Elements ,Genetic ,Promoter Regions ,Genetic ,Carcinoma ,Squamous Cell ,Enhancer Elements ,Genetic ,Gene Expression Regulation ,Neoplastic ,Promoter Regions - Abstract
Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.
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- 2019
31. Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus–positive oropharyngeal squamous cell carcinoma
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Haft, Sunny, Ren, Shuling, Xu, Guorong, Mark, Adam, Fisch, Kathleen, Guo, Theresa W, Khan, Zubair, Pang, John, Ando, Mizuo, Liu, Chao, Sakai, Akihiro, Fukusumi, Takahito, and Califano, Joseph A
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Clinical Research ,Cancer ,Sexually Transmitted Infections ,Human Genome ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,Biotechnology ,Infectious Diseases ,Genetics ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Aged ,Chromatin Assembly and Disassembly ,Class I Phosphatidylinositol 3-Kinases ,Cohort Studies ,Female ,Human papillomavirus 16 ,Humans ,Male ,Middle Aged ,Mutation ,Oropharyngeal Neoplasms ,Papillomavirus Infections ,Receptor ,Fibroblast Growth Factor ,Type 3 ,Squamous Cell Carcinoma of Head and Neck ,Exome Sequencing ,epigenetics ,exome sequencing ,head and neck squamous cell carcinoma ,human papillomavirus ,oropharyngeal squamous cell carcinoma ,The Cancer Genome Atlas ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundHuman papillomavirus (HPV)-associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied.MethodsThis article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort.ResultsThere was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV- counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV- HNSCC.ConclusionsThis analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.
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- 2019
32. Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics.
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Miyauchi, Sayuri, Kim, Sangwoo S, Pang, John, Gold, Kathryn A, Gutkind, J Silvio, Califano, Joseph A, Mell, Loren K, Cohen, Ezra EW, and Sharabi, Andrew B
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Animals ,Humans ,Head and Neck Neoplasms ,Immunotherapy ,Combined Modality Therapy ,Immunomodulation ,Tumor Microenvironment ,Squamous Cell Carcinoma of Head and Neck ,Oncology And Carcinogenesis ,Oncology & Carcinogenesis ,Oncology and Carcinogenesis - Abstract
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 600,000 cases and 380,000 deaths annually worldwide. Although human papillomavirus (HPV)-associated HNSCCs have better overall survival compared with HPV-negative HNSCC, loco-regional recurrence remains a significant cause of mortality and additional combinatorial strategies are needed to improve outcomes. The primary conventional therapies to treat HNSCC are surgery, radiation, and chemotherapies; however, multiple other targeted systemic options are used and being tested including cetuximab, bevacizumab, mTOR inhibitors, and metformin. In 2016, the first checkpoint blockade immunotherapy was approved for recurrent or metastatic HNSCC refractory to platinum-based chemotherapy. This immunotherapy approval confirmed the critical importance of the immune system and immunomodulation in HNSCC pathogenesis, response to treatment, and disease control. However, although immuno-oncology agents are rapidly expanding, the role that the immune system plays in the mechanism of action and clinical efficacy of standard conventional therapies is likely underappreciated. In this article, we focus on how conventional and targeted therapies may directly modulate the immune system and the tumor microenvironment to better understand the effects and combinatorial potential of these therapies in the context and era of immunotherapy.
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- 2019
33. Publisher Correction: Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.
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Ando, Mizuo, Saito, Yuki, Xu, Guorong, Bui, Nam Q, Medetgul-Ernar, Kate, Pu, Minya, Fisch, Kathleen, Ren, Shuling, Sakai, Akihiro, Fukusumi, Takahito, Liu, Chao, Haft, Sunny, Pang, John, Mark, Adam, Gaykalova, Daria A, Guo, Theresa, Favorov, Alexander V, Yegnasubramanian, Srinivasan, Fertig, Elana J, Ha, Patrick, Tamayo, Pablo, Yamasoba, Tatsuya, Ideker, Trey, Messer, Karen, and Califano, Joseph A
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Genetics ,Cancer - Abstract
The original version of this Article contained an error in the author affiliations. Trey Ideker was incorrectly associated with 'Department of Medicine (Oncology), Stanford University School of Medicine, 875 Blake Wilbur Dr, Palo Alto, CA 94304, USA.' This has now been corrected in both the PDF and HTML versions of the Article.
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- 2019
34. Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.
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Ando, Mizuo, Saito, Yuki, Xu, Guorong, Bui, Nam Q, Medetgul-Ernar, Kate, Pu, Minya, Fisch, Kathleen, Ren, Shuling, Sakai, Akihiro, Fukusumi, Takahito, Liu, Chao, Haft, Sunny, Pang, John, Mark, Adam, Gaykalova, Daria A, Guo, Theresa, Favorov, Alexander V, Yegnasubramanian, Srinivasan, Fertig, Elana J, Ha, Patrick, Tamayo, Pablo, Yamasoba, Tatsuya, Ideker, Trey, Messer, Karen, and Califano, Joseph A
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Cell Line ,Tumor ,Chromatin ,Humans ,Neoplasms ,Proto-Oncogene Proteins c-myc ,Histones ,Signal Transduction ,DNA Methylation ,Gene Expression Regulation ,Neoplastic ,Gene Silencing ,Mutation ,Transcription Initiation Site ,E1A-Associated p300 Protein ,CREB-Binding Protein ,Datasets as Topic ,Human Genome ,Cancer ,Genetics ,Rare Diseases ,2.1 Biological and endogenous factors - Abstract
Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.
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- 2019
35. 4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
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Wang, Zhiyong, Feng, Xiaodong, Molinolo, Alfredo A, Martin, Daniel, Vitale-Cross, Lynn, Nohata, Nijiro, Ando, Mizuo, Wahba, Amy, Amornphimoltham, Panomwat, Wu, Xingyu, Gilardi, Mara, Allevato, Michael, Wu, Victoria, Steffen, Dana J, Tofilon, Philip, Sonenberg, Nahum, Califano, Joseph, Chen, Qianming, Lippman, Scott M, and Gutkind, J Silvio
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biotechnology ,Clinical Research ,Cancer ,Rare Diseases ,Genetics ,Dental/Oral and Craniofacial Disease ,2.1 Biological and endogenous factors ,Aetiology ,Adaptor Proteins ,Signal Transducing ,Animals ,Benzoxazoles ,Biomarkers ,Tumor ,CRISPR-Cas Systems ,Cell Cycle Proteins ,Cell Line ,Tumor ,Cell Proliferation ,Head and Neck Neoplasms ,Humans ,Mice ,Mice ,Knockout ,Phosphorylation ,Prognosis ,Pyrimidines ,Squamous Cell Carcinoma of Head and Neck ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Aberrant activation of the PI3K-mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTOR inhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCC animal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on EIF4E-BP1 (4E-BP1), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the PIK3CA-mTOR pathway in HNSCC revealed that 4E-BP1 is rarely mutated, but at least one 4E-BP1 gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. 4E-BP1 gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, 4e-bp1/2 knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4E-BP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation-initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9-targeted 4E-BP1 HNSCC cells resulted in reduced sensitivity to mTORi in vitro and in vivo. Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC. SIGNIFICANCE: These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.
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- 2019
36. Variations in HPV function are associated with survival in squamous cell carcinoma
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Gleber-Netto, Frederico O, Rao, Xiayu, Guo, Theresa, Xi, Yuanxin, Gao, Meng, Shen, Li, Erikson, Kelly, Kalu, Nene N, Ren, Shuling, Xu, Guorong, Fisch, Kathleen M, Akagi, Keiko, Seiwert, Tanguy, Gillison, Maura, Frederick, Mitchell J, Johnson, Faye M, Wang, Jing, Myers, Jeffrey N, Califano, Joseph, Skinner, Heath D, and Pickering, Curtis R
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Infectious Diseases ,Clinical Research ,Sexually Transmitted Infections ,Dental/Oral and Craniofacial Disease ,Digestive Diseases ,HIV/AIDS ,Cervical Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Cervical cancer ,Expression profiling ,Head & neck cancer ,Oncology ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV- tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.
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- 2019
37. Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma
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Kelley, Dylan Z, Flam, Emily L, Guo, Theresa, Danilova, Ludmila V, Zamuner, Fernando T, Bohrson, Craig, Considine, Michael, Windsor, Eric J, Bishop, Justin A, Zhang, Chi, Koch, Wayne M, Sidransky, David, Westra, William H, Chung, Christine H, Califano, Joseph A, Wheelan, Sarah, Favorov, Alexander V, Florea, Liliana, Fertig, Elana J, and Gaykalova, Daria A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Dental/Oral and Craniofacial Disease ,Genetics ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Alternative Splicing ,Cell Line ,Tumor ,Cell Movement ,Cell Proliferation ,Cell Survival ,Gelsolin ,Gene Expression Regulation ,Neoplastic ,Humans ,Models ,Biological ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Squamous Cell Carcinoma of Head and Neck ,Clinical Sciences ,General Clinical Medicine ,Biochemistry and cell biology ,Clinical sciences - Abstract
We have recently performed the characterization of alternative splicing events (ASEs) in head and neck squamous cell carcinoma, which allows dysregulation of protein expression common for cancer cells. Such analysis demonstrated a high ASE prevalence among tumor samples, including tumor-specific alternative splicing in the GSN gene.In vitro studies confirmed that overall expression of either ASE-GSN or wild-type GSN (WT-GSN) isoform inversely correlated with cell proliferation, whereas the high ratio of ASE-GSN to WT-GSN correlated with increased cellular invasion. Additionally, a change in expression of either isoform caused compensatory changes in expression of the other isoform. Our results suggest that the overall expression and the balance between GSN isoforms are mediating factors in proliferation, while increased overall expression of ASE-GSN is specific to cancer tissues. As a result, we propose ASE-GSN can serve not only as a biomarker of disease and disease progression, but also as a neoantigen for head and neck squamous cell carcinoma treatment, for which only a limited number of disease-specific targeted therapies currently exist.
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- 2018
38. Role of protein kinase N2 (PKN2) in cigarette smoke-mediated oncogenic transformation of oral cells
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Rajagopalan, Pavithra, Nanjappa, Vishalakshi, Patel, Krishna, Jain, Ankit P, Mangalaparthi, Kiran K, Patil, Arun H, Nair, Bipin, Mathur, Premendu P, Keshava Prasad, TS, Califano, Joseph A, Sidransky, David, Gowda, Harsha, and Chatterjee, Aditi
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Lung ,Tobacco Smoke and Health ,Dental/Oral and Craniofacial Disease ,Prevention ,Cancer ,Rare Diseases ,Lung Cancer ,Tobacco ,2.1 Biological and endogenous factors ,Aetiology ,Orbitrap fusion ,High-throughput ,Carcinogenesis ,Smoking ,Cell adhesion ,Biochemistry and Cell Biology ,Clinical Sciences ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Smoking is the leading cause of preventable death worldwide. Though cigarette smoke is an established cause of head and neck cancer (including oral cancer), molecular alterations associated with chronic cigarette smoke exposure are poorly studied. To understand the signaling alterations induced by chronic exposure to cigarette smoke, we developed a cell line model by exposing normal oral keratinocytes to cigarette smoke for a period of 12 months. Chronic exposure to cigarette smoke resulted in increased cellular proliferation and invasive ability of oral keratinocytes. Proteomic and phosphoproteomic analyses showed dysregulation of several proteins involved in cellular movement and cytoskeletal reorganization in smoke exposed cells. We observed overexpression and hyperphosphorylation of protein kinase N2 (PKN2) in smoke exposed cells as well as in a panel of head and neck cancer cell lines established from smokers. Silencing of PKN2 resulted in decreased colony formation, invasion and migration in both smoke exposed cells and head and neck cancer cell lines. Our results indicate that PKN2 plays an important role in oncogenic transformation of oral keratinocytes in response to cigarette smoke. The current study provides evidence that PKN2 can act as a potential therapeutic target in head and neck squamous cell carcinoma, especially in patients with a history of smoking.
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- 2018
39. Locally advanced high-risk HPV related oropharyngeal squamous cell carcinoma (OPSCC); have we forgotten it is a different disease?
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Saba, Nabil F, Li, Shuli, Hussain, Zain A, Subramanian, Rathan, Califano, Joseph A, and Chung, Christine H
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,Infectious Diseases ,Cancer ,Dental/Oral and Craniofacial Disease ,Sexually Transmitted Infections ,Rare Diseases ,Good Health and Well Being ,Oncology and carcinogenesis - Abstract
HPV related OPSCC has a distinct behavior and improved outcome. As immunotherapy has recently evolved into a new standard for advanced (SCCHN), trials for high-risk SCCHN have trended to encompass both HPV related and unrelated diseases. In this invited editorial, we question the wisdom of this approach and argue for the design of trials focused specifically on HPV related locally advanced oropharyngeal squamous cell carcinoma as a unique disease entity.
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- 2018
40. Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance
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Stein-O’Brien, Genevieve, Kagohara, Luciane T, Li, Sijia, Thakar, Manjusha, Ranaweera, Ruchira, Ozawa, Hiroyuki, Cheng, Haixia, Considine, Michael, Schmitz, Sandra, Favorov, Alexander V, Danilova, Ludmila V, Califano, Joseph A, Izumchenko, Evgeny, Gaykalova, Daria A, Chung, Christine H, and Fertig, Elana J
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Biological Sciences ,Genetics ,Biotechnology ,Cancer ,Rare Diseases ,Orphan Drug ,Antimicrobial Resistance ,Human Genome ,Aetiology ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Algorithms ,Cell Line ,Tumor ,Cetuximab ,Clone Cells ,DNA Methylation ,Disease-Free Survival ,Drug Resistance ,Neoplasm ,Epigenesis ,Genetic ,ErbB Receptors ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Genomics ,Head and Neck Neoplasms ,Humans ,Neoplasms ,Squamous Cell ,Protein Kinase Inhibitors ,Receptor ,Fibroblast Growth Factor ,Type 1 ,Time Factors ,Treatment Outcome ,Acquired resistance ,Data integration ,Epigenetics ,Precision medicine ,Time course analysis ,Clinical Sciences - Abstract
BACKGROUND:Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. METHODS:To determine the dynamics of these molecular changes, we obtained high throughput omics data (RNA-sequencing and DNA methylation) weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. The CoGAPS unsupervised algorithm was used to determine the dynamics of the molecular changes associated with resistance during the time course of resistance development. RESULTS:CoGAPS was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS:Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize the resistant phenotype. These genes include FGFR1, which was associated with EGFR inhibitors resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. This understanding of the time course progression of molecular changes in acquired resistance is important for the development of alternative treatment strategies that would introduce appropriate selection of new drugs to treat cancer before the resistant phenotype develops.
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- 2018
41. Prognostic Role of p16 in Nonoropharyngeal Head and Neck Cancer
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Bryant, Alex K, Sojourner, Elena J, Vitzthum, Lucas K, Zakeri, Kaveh, Shen, Hanjie, Nguyen, Cammie, Murphy, James D, Califano, Joseph A, Cohen, Ezra EW, and Mell, Loren K
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Digestive Diseases ,Cancer ,Rare Diseases ,Clinical Research ,Dental/Oral and Craniofacial Disease ,Aged ,Biomarkers ,Tumor ,Combined Modality Therapy ,Cyclin-Dependent Kinase Inhibitor p16 ,Female ,Follow-Up Studies ,Hospitals ,Veterans ,Humans ,Male ,Middle Aged ,Odds Ratio ,Oropharyngeal Neoplasms ,Population Surveillance ,Prognosis ,Treatment Outcome ,United States ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPrevious studies have reported conflicting information regarding the prognostic role of p16 in nonoropharyngeal head and neck squamous cell carcinoma (HNSCC).MethodsUsing the US Veterans Affairs database, we analyzed 1448 patients with locoregionally advanced HNSCC and known p16 status diagnosed between 2005 and 2015 and treated with surgery, radiotherapy, or chemoradiotherapy. Tumor p16 status was determined through manual review of pathology reports of primary tumor specimens. Oropharyngeal (n = 1061) or nonoropharyngeal (n = 387; hypopharyngeal, laryngeal, or oral cavity) tumor site was determined from tumor registry data and manually reviewed for accuracy. We used multivariable Cox regression to analyze the effect of p16 status on overall survival (OS), cancer-specific survival (CSS), and competing mortality (CM) for oropharyngeal or nonoropharyngeal tumor sites. All statistical tests were two-sided.ResultsIn multivariable models adjusting for treatment, stage, age, comorbidity, and body mass index, patients with p16-positive tumors had improved OS, CSS, and CM compared with patients with p16-negative tumors in both oropharyngeal (OS: hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40 to 0.71, P < .001; CSS: HR = 0.50, 95% CI = 0.35 to 0.73, P < .001; CM: HR = 0.59, 95% CI = 0.38 to 0.93, P = .02) and nonoropharyngeal primary sites (OS: HR = 0.41, 95% CI = 0.25 to 0.69, P < .001; CSS: HR = 0.37, 95% CI = 0.18 to 0.77, P = .008; CM: HR = 0.46, 95% CI = 0.23 to 0.95, P = .04). The prognostic impact of p16 status did not statistically significantly differ by primary tumor site for OS, CSS, or CM (Pinteraction > .05).ConclusionsOur findings support the hypothesis that p16 has a similar prognostic role in both nonoropharyngeal and oropharyngeal cancer. Consideration should be given to increased testing for p16 in laryngeal, hypopharyngeal, and oral cavity primaries.
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- 2018
42. Development of process analytical tools for rapid monitoring of live virus vaccines in manufacturing
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Yi, Sijia, McCracken, Reilly, Davide, Joseph, Salovich, Daniel Ryan, Whitmer, Travis, Bhat, Aditya, Vlasak, Josef, Ha, Sha, Sehlin, Darrell, Califano, Joseph, Ploeger, Kristin, and Mukherjee, Malini
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- 2022
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43. High-risk HPV infection-associated hypermethylated genes in oropharyngeal squamous cell carcinomas
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Inokawa, Yoshikuni, Hayashi, Masamichi, Begum, Shahnaz, Noordhuis, Maartje G., Sidransky, Daivd, Califano, Joseph, Koch, Wayne, Brait, Mariana, Westra, William H., and Hoque, Mohammad O.
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- 2022
- Full Text
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44. Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant
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Liu, Chao, Guo, Theresa, Xu, Guorong, Sakai, Akihiro, Ren, Shuling, Fukusumi, Takahito, Ando, Mizuo, Sadat, Sayed, Saito, Yuki, Khan, Zubair, Fisch, Kathleen M, and Califano, Joseph
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Rare Diseases ,Sexually Transmitted Infections ,Dental/Oral and Craniofacial Disease ,Infectious Diseases ,Cancer ,Human Genome ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Alternative Splicing ,Cell Line ,Tumor ,Cell Movement ,Cell Proliferation ,Cell Survival ,Female ,Gene Expression Regulation ,Neoplastic ,Genetic Variation ,Genomics ,Guanine Nucleotide Exchange Factors ,Humans ,MAP Kinase Signaling System ,Male ,Oncogenes ,Papillomaviridae ,Papillomavirus Infections ,RNA ,Small Interfering ,Squamous Cell Carcinoma of Head and Neck ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)-negative HNSCC.Experimental Design: RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays.Results: A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival.Conclusions: Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. Clin Cancer Res; 24(20); 5123-32. ©2018 AACR.
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- 2018
45. Molecular alterations associated with chronic exposure to cigarette smoke and chewing tobacco in normal oral keratinocytes
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Rajagopalan, Pavithra, Patel, Krishna, Jain, Ankit P, Nanjappa, Vishalakshi, Datta, Keshava K, Subbannayya, Tejaswini, Mangalaparthi, Kiran K, Kumari, Anjali, Manoharan, Malini, Coral, Karunakaran, Murugan, Sakthivel, Nair, Bipin, Prasad, TS Keshava, Mathur, Premendu P, Gupta, Ravi, Gupta, Rohit, Khanna-Gupta, Arati, Califano, Joseph, Sidransky, David, Gowda, Harsha, and Chatterjee, Aditi
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Dental/Oral and Craniofacial Disease ,Tobacco Smoke and Health ,Tobacco ,Prevention ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Biomarkers ,Cell Transformation ,Neoplastic ,Environmental Exposure ,Gene Expression Profiling ,Humans ,Keratinocytes ,Mouth Mucosa ,Phenotype ,Proteome ,Proteomics ,Smoking ,Tobacco Use ,Transcriptome ,Exome Sequencing ,Orbitrap Fusion ,high-throughput ,carcinogenesis ,smoking ,chronic exposure ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Tobacco usage is a known risk factor associated with development of oral cancer. It is mainly consumed in two different forms (smoking and chewing) that vary in their composition and methods of intake. Despite being the leading cause of oral cancer, molecular alterations induced by tobacco are poorly understood. We therefore sought to investigate the adverse effects of cigarette smoke/chewing tobacco exposure in oral keratinocytes (OKF6/TERT1). OKF6/TERT1 cells acquired oncogenic phenotype after treating with cigarette smoke/chewing tobacco for a period of 8 months. We employed whole exome sequencing (WES) and quantitative proteomics to investigate the molecular alterations in oral keratinocytes chronically exposed to smoke/ chewing tobacco. Exome sequencing revealed distinct mutational spectrum and copy number alterations in smoke/ chewing tobacco treated cells. We also observed differences in proteomic alterations. Proteins downstream of MAPK1 and EGFR were dysregulated in smoke and chewing tobacco exposed cells, respectively. This study can serve as a reference for fundamental damages on oral cells as a consequence of exposure to different forms of tobacco.
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- 2018
46. Identification of potential biomarkers of head and neck squamous cell carcinoma using iTRAQ based quantitative proteomic approach
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Babu, Niraj, Mohan, Sonali, Nanjappa, Vishalakshi, Chavan, Sandip, Advani, Jayshree, Khan, Aafaque Ahmed, Renuse, Santosh, Radhakrishnan, Aneesha, Prasad, TS Keshava, Kumar, Rekha V, Ray, Jay Gopal, Biswas, Manjusha, Thiyagarajan, Saravanan, Califano, Joseph A, Sidransky, David, Gowda, Harsha, and Chatterjee, Aditi
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Biotechnology ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,HNSCC ,iTRAQ ,Parallel reaction monitoring ,Mass spectrometry ,OKF6/TERT1 - Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in India. Despite improvements in treatment strategy, the survival rates of HNSCC patients remain poor. Thus, it is necessary to identify biomarkers that can be used for early detection of disease. In this study, we employed iTRAQ-based quantitative mass spectrometry analysis to identify dysregulated proteins from a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. We identified 2468 proteins, of which 496 proteins were found to be dysregulated in at least two out of three HNSCC cell lines compared to immortalized normal oral keratinocytes. We detected increased expression of replication protein A1 (RPA1) and heat shock protein family H (Hsp110) member 1 (HSPH1), in HNSCC cell lines compared to control. The differentially expressed proteins were further validated using parallel reaction monitoring (PRM) and western blot analysis in HNSCC cell lines. Immunohistochemistry-based validation using HNSCC tissue microarrays revealed overexpression of RPA1 and HSPH1 in 15.7% and 32.2% of the tested cases, respectively. Our study illustrates quantitative proteomics as a robust approach for identification of potential HNSCC biomarkers. The proteomic data has been submitted to ProteomeXchange Consortium (http://www.proteomecentral.proteomexchange.org) via the PRIDE public data repository accessible using the data identifier - PXD009241.
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- 2018
47. Splice Expression Variation Analysis (SEVA) for inter-tumor heterogeneity of gene isoform usage in cancer
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Afsari, Bahman, Guo, Theresa, Considine, Michael, Florea, Liliana, Kagohara, Luciane T, Stein-O’Brien, Genevieve L, Kelley, Dylan, Flam, Emily, Zambo, Kristina D, Ha, Patrick K, Geman, Donald, Ochs, Michael F, Califano, Joseph A, Gaykalova, Daria A, Favorov, Alexander V, and Fertig, Elana J
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Cancer ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Alternative Splicing ,Computational Biology ,Gene Expression Regulation ,Neoplastic ,Head and Neck Neoplasms ,Humans ,Models ,Genetic ,Neoplasms ,Protein Isoforms ,Sequence Analysis ,RNA ,Software ,Mathematical Sciences ,Information and Computing Sciences ,Bioinformatics ,Biological sciences ,Information and computing sciences ,Mathematical sciences - Abstract
MotivationCurrent bioinformatics methods to detect changes in gene isoform usage in distinct phenotypes compare the relative expected isoform usage in phenotypes. These statistics model differences in isoform usage in normal tissues, which have stable regulation of gene splicing. Pathological conditions, such as cancer, can have broken regulation of splicing that increases the heterogeneity of the expression of splice variants. Inferring events with such differential heterogeneity in gene isoform usage requires new statistical approaches.ResultsWe introduce Splice Expression Variability Analysis (SEVA) to model increased heterogeneity of splice variant usage between conditions (e.g. tumor and normal samples). SEVA uses a rank-based multivariate statistic that compares the variability of junction expression profiles within one condition to the variability within another. Simulated data show that SEVA is unique in modeling heterogeneity of gene isoform usage, and benchmark SEVA's performance against EBSeq, DiffSplice and rMATS that model differential isoform usage instead of heterogeneity. We confirm the accuracy of SEVA in identifying known splice variants in head and neck cancer and perform cross-study validation of novel splice variants. A novel comparison of splice variant heterogeneity between subtypes of head and neck cancer demonstrated unanticipated similarity between the heterogeneity of gene isoform usage in HPV-positive and HPV-negative subtypes and anticipated increased heterogeneity among HPV-negative samples with mutations in genes that regulate the splice variant machinery. These results show that SEVA accurately models differential heterogeneity of gene isoform usage from RNA-seq data.Availability and implementationSEVA is implemented in the R/Bioconductor package GSReg.Contactbahman@jhu.edu or favorov@sensi.org or ejfertig@jhmi.edu.Supplementary informationSupplementary data are available at Bioinformatics online.
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- 2018
48. Cigarette smoke and chewing tobacco alter expression of different sets of miRNAs in oral keratinocytes.
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Bhat, Mohd Younis, Advani, Jayshree, Rajagopalan, Pavithra, Patel, Krishna, Nanjappa, Vishalakshi, Solanki, Hitendra S, Patil, Arun H, Bhat, Firdous A, Mathur, Premendu P, Nair, Bipin, Prasad, TS Keshava, Califano, Joseph A, Sidransky, David, Gowda, Harsha, and Chatterjee, Aditi
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Mouth Mucosa ,Keratinocytes ,Humans ,Tobacco ,Smokeless ,MicroRNAs ,Smoking ,Computational Biology ,Environmental Exposure ,Gene Expression Regulation ,Phenotype ,Biomarkers ,Tobacco ,Smokeless - Abstract
Carcinogenic effect of tobacco in oral cancer is through chewing and/or smoking. Significant differences exist in development of oral cancer between tobacco users and non-users. However, molecular alterations induced by different forms of tobacco are yet to be fully elucidated. We developed cellular models of chronic exposure to chewing tobacco and cigarette smoke using immortalized oral keratinocytes. Chronic exposure to tobacco resulted in increased cell scattering and invasiveness in immortalized oral keratinocytes. miRNA sequencing using Illumina HiSeq 2500 resulted in the identification of 10 significantly dysregulated miRNAs (4 fold; p ≤ 0.05) in chewing tobacco treated cells and 6 in cigarette smoke exposed cells. We integrated this data with global proteomic data and identified 36 protein targets that showed inverse expression pattern in chewing tobacco treated cells and 16 protein targets that showed inverse expression in smoke exposed cells. In addition, we identified 6 novel miRNAs in chewing tobacco treated cells and 18 novel miRNAs in smoke exposed cells. Integrative analysis of dysregulated miRNAs and their targets indicates that signaling mechanisms leading to oncogenic transformation are distinct between both forms of tobacco. Our study demonstrates alterations in miRNA expression in oral cells in response to two frequently used forms of tobacco.
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- 2018
49. Positive Surgical Margins in the 10 Most Common Solid Cancers.
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Orosco, Ryan K, Tapia, Viridiana J, Califano, Joseph A, Clary, Bryan, Cohen, Ezra EW, Kane, Christopher, Lippman, Scott M, Messer, Karen, Molinolo, Alfredo, Murphy, James D, Pang, John, Sacco, Assuntina, Tringale, Kathryn R, Wallace, Anne, and Nguyen, Quyen T
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Humans ,Neoplasms ,Prognosis ,Treatment Outcome ,Prevalence ,Cost-Benefit Analysis ,United States ,Female ,Male ,Neoplasm Grading ,Margins of Excision ,Urologic Diseases ,Cancer - Abstract
A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes.
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- 2018
50. The NOTCH4–HEY1 Pathway Induces Epithelial–Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma
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Fukusumi, Takahito, Guo, Theresa W, Sakai, Akihiro, Ando, Mizuo, Ren, Shuling, Haft, Sunny, Liu, Chao, Amornphimoltham, Panomwat, Gutkind, J Silvio, and Califano, Joseph A
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Cancer ,Genetics ,Dental/Oral and Craniofacial Disease ,Aetiology ,2.1 Biological and endogenous factors ,Basic Helix-Loop-Helix Transcription Factors ,Cell Cycle ,Cell Cycle Proteins ,Cell Line ,Tumor ,Cisplatin ,Drug Resistance ,Neoplasm ,Epithelial-Mesenchymal Transition ,Gene Expression Regulation ,Neoplastic ,Humans ,Receptor ,Notch4 ,Signal Transduction ,Squamous Cell Carcinoma of Head and Neck ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood.Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1, and epithelial-mesenchymal transition (EMT)-related genes using the TCGA data set and in vitro assays.Results:HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration.Conclusions: In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619-33. ©2017 AACR.
- Published
- 2018
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