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Rachel Gurrell, Sridhar Duvvuri, Pengling Sun, Nicholas DeMartinis
BACKGROUND AND OBJECTIVES: There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA. METHODS: Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days...
February 24, 2018: Clinical Drug Investigation
Toni M Brand, Stefan Hartmann, Neil E Bhola, Hua Li, Yan Zang, Rachel A O'Keefe, Max V Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E Johnson, Michelle A Ozbun, Julie E Bauman, Jennifer R Grandis
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC...
February 12, 2018: Cancer Research
Phillip Huyett, Umamaheswar Duvvuri, Robert L Ferris, Jonas T Johnson, Barry M Schaitkin, Seungwon Kim
Objectives To investigate the clinical predictors and survival implications of perineural invasion (PNI) in parotid gland malignancies. Study Design Case series with chart review. Setting Tertiary care medical center. Subjects and Methods Patients with parotid gland malignancies treated surgically from 2000 to 2015 were retrospectively identified in the Head and Neck Cancer Registry at a single institution. Data points were extracted from the medical record and original pathology reports. Results In total, 186 patients with parotid gland malignancies were identified with a mean follow-up of 5...
January 1, 2018: Otolaryngology—Head and Neck Surgery
Michael J Persky, William G Albergotti, Tanya J Rath, Mark W Kubik, Shira Abberbock, Mathew Geltzeiler, Seungwon Kim, Umamaheswar Duvvuri, Robert L Ferris
Objective To compare positive margin rates between the 2 most common subsites of oropharyngeal transoral robotic surgery (TORS), the base of tongue (BOT) and the tonsil, as well as identify preoperative imaging characteristics that predispose toward positive margins. Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods We compared the final and intraoperative positive margin rate between TORS resections for tonsil and BOT oropharyngeal squamous cell carcinoma (OPSCC), as well as the effect of margins on treatment...
November 1, 2017: Otolaryngology—Head and Neck Surgery
R Scott Obach, Jian Lin, Emi Kimoto, Sridhar Duvvuri, Timothy Nicholas, Eugene P Kadar, Larry M Tremaine, Aarti Sawant Basak
TBPT ((R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product (M1) and a cyclized oxazolidine structure (M2). After administration to humans, the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent ratios for M1 and M2 was attempted, using in vitro metabolism, binding, and permeability data in static and dynamic PBPK models...
November 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Andrey Finegersh, Scott Kulich, Theresa Guo, Alexander V Favorov, Elana J Fertig, Ludmila V Danilova, Daria A Gaykalova, Joseph A Califano, Umamaheswar Duvvuri
ANO1 is a calcium-activated chloride channel that is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and other cancers. While ANO1 expression negatively correlates with survival in several cancers, its epigenetic regulation is poorly understood. We analyzed HNSCC samples from TCGA and a separate dataset of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples to identify differentially methylated regions. E6 and E7 transfected normal oral keratinocytes (NOK) were used to induce hypermethylation of the ANO1 promoter...
November 9, 2017: Scientific Reports
William G Albergotti, Hannah L Schwarzbach, Shira Abberbock, Robert L Ferris, Jonas T Johnson, Umamaheswar Duvvuri, Seungwon Kim
Importance: Recently, the American Joint Committee on Cancer (AJCC) updated its staging system for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The prognostic significance of perineural invasion (PNI) and angiolymphatic invasion (ALI) within this staging system is unknown. Objective: To examine the prevalence and prognostic significance of PNI and ALI in HPV-positive OPSCC. Design, Setting, and Participants: A retrospective review was performed of all patients with HPV-positive OPSCC treated surgically at the University of Pittsburgh Medical Center from January 1, 1980, through December 31, 2015, with at least 1 year of follow-up or death within 1 year...
October 26, 2017: JAMA Otolaryngology—Head & Neck Surgery
Hyung Kwon Byeon, F Christopher Holsinger, Umamaheswar Duvvuri, Da Hee Kim, Jae Hong Park, Estelle Chang, Se-Heon Kim, Yoon Woo Koh
OBJECTIVE: Previously, we have reported the feasibility of retroauricular (RA) robotic thyroidectomy. Despite its promising surgical outcomes, there were certain intrinsic mechanical limitations inherent to the da Vinci Si System (Intuitive Surgical, Sunnyvale, California, U.S.A.). Since the advent of an upgraded model, the Xi System (Intuitive Surgical), we have actively incorporated the new model into performing RA thyroidectomy. Here, we intend to verify the feasibility of RA robotic thyroidectomy using the new da Vinci Xi System (Intuitive Surgical) with comparison of the former Si-applied surgery (Intuitive Surgical)...
October 25, 2017: Laryngoscope
Gulidanna Shayan, Benjamin A Kansy, Sandra P Gibson, Raghvendra M Srivastava, James Kyle Bryan, Julie E Bauman, James Ohr, Seungwon Kim, Umamaheswar Duvvuri, David A Clump, Dwight E Heron, Jonas T Johnson, Robert M Hershberg, Robert L Ferris
Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti-EGFR-specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2...
January 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Michael K Murphy, Kevin M Motz, Dacheng Ding, Linda Yin, Madhavi Duvvuri, Michael Feeley, Alexander T Hillel
OBJECTIVE: Management of laryngotracheal stenosis (LTS) remains primarily surgical, with a critical need to identify targets for adjuvant therapy. Laryngotracheal stenosis scar fibroblasts exhibit a profibrotic phenotype with distinct metabolic shifts, including an increased glycolysis/oxidative phosphorylation ratio. This study examines the effects of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) on collagen production, gene expression, proliferation, and metabolism of human LTS-derived fibroblasts in vitro...
September 20, 2017: Laryngoscope
Tatiana Karelina, Oleg Demin, Oleg Demin, Sridhar Duvvuri, Timothy Nicholas
Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
Neal R Godse, Nayel Khan, Zachary A Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J Shiwarski, Raja S Seethala, Scott Kulich, Mukund Seshadri, Timothy F Burns, Umamaheswar Duvvuri
Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation. Experimental Design: Combination of (i) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) in vivo studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kevin Motz, Idris Samad, Linda X Yin, Michael K Murphy, Madhavi Duvvuri, Dacheng Ding, Alexander T Hillel
Importance: Laryngotracheal stenosis (LTS) is a fibroproliferative disorder of the glottis, subglottis, and trachea. In models of fibrosis from other organ systems, the CD4+ T-cell response has been shown to regulate extracellular matrix deposition. Specifically, helper T cell 2 (TH2) promotes fibrosis, whereas TH1 and associated cytokines have been shown to be antifibrotic. However, this antifibrotic effect of the TH1 response has not been demonstrated in LTS. Objective: To determine whether the TH1 cytokine interferon-γ inhibits the function of LTS-derived fibroblasts in vitro...
November 1, 2017: JAMA Otolaryngology—Head & Neck Surgery
Xueting Qiu, Venkata R Duvvuri, Jonathan B Gubbay, Richard J Webby, Ghazi Kayali, Justin Bahl
BACKGROUND: Multiple highly pathogenic avian influenza (HPAI) H5 viruses continue to co-circulate. This has complicated pandemic preparedness and confounded effective vaccine candidate selection and evaluation. OBJECTIVES: In this study, we aimed to predict and map the diversity of CD8+ T-cell epitopes among H5 hemagglutinin (HA) gene lineages to estimate CD8+ T-cell immunity in humans induced by vaccine candidates. METHODS: A dataset consisting of 1125 H5 HA sequences collected between 1996 and 2017 from avian and humans was assembled for phylogenetic and lineage-specific epitope analyses...
July 17, 2017: Influenza and Other Respiratory Viruses
T Karelina, O Demin, T Nicholas, Y Lu, S Duvvuri, H A Barton
A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single-dose avagacestat treatment demonstrate that the Aβ42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ40 inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
Mark Kubik, Rajarsi Mandal, William Albergotti, Umamaheswar Duvvuri, Robert L Ferris, Seungwon Kim
BACKGROUND: The value of transcervical arterial ligation during transoral robotic surgery (TORS) as a measure to decrease postoperative bleeding incidence or severity is unclear. METHODS: A retrospective single institution study was performed to identify risk factors for hemorrhage after TORS for oropharyngeal squamous cell carcinoma (SCC). RESULTS: Overall, 13.2% of patients (35/265) experience postoperative hemorrhage. T classification, perioperative use of anticoagulants, surgeon experience >50 cases, and tumor subsite were not predictors of postoperative hemorrhage...
August 2017: Head & Neck
Ariyanti Sarwono, Zakaria Man, M Azmi Bustam, Duvvuri Subbarao, Alamin Idris, Nawshad Muhammad, Amir Sada Khan, Zahoor Ullah
Coating fertilizer particles with thin films is a possibility to control fertilizer release rates. It is observed that novel urea cross-linked starch-lignin composite thin films, prepared by solution casting, swell on coming into contact with water due to the increase in volume by water uptake by diffusion. The effect of lignin content, varied from 0% to 20% in steps of 5% at three different temperatures (25°C, 35°C and 45°C), on swelling of the film was investigated. By gravimetric analysis, the equilibrium water uptake and diffusion coefficient decrease with lignin content, indicating that the addition of lignin increases the hydrophobicity of the films...
June 7, 2017: Environmental Technology
Kevin M Motz, Linda X Yin, Idris Samad, Dacheng Ding, Michael K Murphy, Madhavi Duvvuri, Alexander T Hillel
Objectives (1) Develop a novel method for serial assessment of gene and protein expression in laryngotracheal stenosis (LTS). (2) Assess cytokine expression and determine an immunophenotype in LTS. Study Design A matched comparison of endolaryngeal brush biopsy samples from laryngotracheal scar and normal airway. Setting Tertiary care hospital, 2015-2016. Methods Brush biopsy specimens of laryngotracheal scar and normal trachea were obtained from 17 patients with LTS at the time of operating room dilation and were used for protein and RNA extraction...
September 2017: Otolaryngology—Head and Neck Surgery
William G Albergotti, Jessica Jordan, Keely Anthony, Shira Abberbock, Tamara Wasserman-Wincko, Seungwon Kim, Robert L Ferris, Umamaheswar Duvvuri
BACKGROUND: Transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) has been associated with improved long-term dysphagia symptomatology compared with chemoradiation. Dysphagia in the perioperative period has been inadequately characterized. The objective of this study was to characterize short-term swallowing outcomes after TORS for OPSCC. METHODS: Patients undergoing TORS for OPSCC were enrolled prospectively. The Eating Assessment Tool 10 (EAT-10) was used as a measure of swallowing dysfunction (score >2) and was administered on postoperative day (POD) 1, 7, and 30...
August 15, 2017: Cancer
Brian J Gebhardt, James P Ohr, Robert L Ferris, Umamaheswar Duvvuri, Seungwon Kim, Jonas T Johnson, Dwight E Heron, David A Clump
OBJECTIVES: Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. MATERIALS AND METHODS: Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24...
April 7, 2017: American Journal of Clinical Oncology
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