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https://www.readbyqxmd.com/read/29150544/estimation-of-circulating-drug-metabolite-exposure-in-human-using-in-vitro-data-and-physiologically-based-pharmacokinetic-modelling-example-of-a-high-metabolite-parent-drug-ratio
#1
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
https://www.readbyqxmd.com/read/29123240/dna-methylation-regulates-tmem16a-ano1-expression-through-multiple-cpg-islands-in-head-and-neck-squamous-cell-carcinoma
#2
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
https://www.readbyqxmd.com/read/29075776/defining-the-prevalence-and-prognostic-value-of-perineural-invasion-and-angiolymphatic-invasion-in-human-papillomavirus-positive-oropharyngeal-carcinoma
#3
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
https://www.readbyqxmd.com/read/29068059/recent-progress-of-retroauricular-robotic-thyroidectomy-with-the-new-surgical-robotic-system
#4
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
https://www.readbyqxmd.com/read/29061643/a-phase-ib-study-of-immune-biomarker-modulation-with-neoadjuvant-cetuximab-and-tlr8-stimulation-in-head-and-neck-cancer-to-overcome-suppressive-myeloid-signals
#5
Gulidanna Shayan, Benjamin A Kansy, Sandra P Gibson, Raghvendra M Srivastava, James Kyle Bryan, Julie E Bauman, James Ohr, Seungwon Kim, David A Clump, Umamaheswar Duvvuri, Dwight E Heron, Jonas T Johnson, Robert Hershberg, Robert L Ferris
PURPOSE: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory 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 3-4 weekly doses of motolimod (2...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28940431/targeting-metabolic-abnormalities-to-reverse-fibrosis-in-iatrogenic-laryngotracheal-stenosis
#6
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
https://www.readbyqxmd.com/read/28913897/studying-the-progression-of-amyloid-pathology-and-its-therapy-using-translational-longitudinal-model-of-accumulation-and-distribution-of-amyloid-beta
#7
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
https://www.readbyqxmd.com/read/28899969/tmem16a-ano1-inhibits-apoptosis-via-downregulation-of-bim-expression
#8
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...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28715559/interferon-%C3%AE-treatment-of-human-laryngotracheal-stenosis-derived-fibroblasts
#9
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
https://www.readbyqxmd.com/read/28715148/lineage-specific-epitope-profiles-for-hpai-h5-pre-pandemic-vaccine-selection-and-evaluation
#10
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
https://www.readbyqxmd.com/read/28571112/a-translational-systems-pharmacology-model-for-a%C3%AE-kinetics-in-mouse-monkey-and-human
#11
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
https://www.readbyqxmd.com/read/28570011/effect-of-transcervical-arterial-ligation-on-the-severity-of-postoperative-hemorrhage-after-transoral-robotic-surgery
#12
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
https://www.readbyqxmd.com/read/28524800/swelling-mechanism-of-urea-cross-linked-starch-lignin-films-in-water
#13
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
https://www.readbyqxmd.com/read/28485188/quantification-of-inflammatory-markers-in-laryngotracheal-stenosis
#14
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/28467606/a-prospective-evaluation-of-short-term-dysphagia-after-transoral-robotic-surgery-for-squamous-cell-carcinoma-of-the-oropharynx
#15
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
https://www.readbyqxmd.com/read/28394767/concurrent-chemoradiotherapy-in-the-adjuvant-treatment-of-high-risk-primary-salivary-gland-malignancies
#16
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
https://www.readbyqxmd.com/read/28383396/role-of-endoscopic-esophageal-dilation-in-managing-eosinophilic-esophagitis-a-systematic-review-and-meta-analysis
#17
REVIEW
Harsha Moole, Kavitha Jacob, Abhiram Duvvuri, Vishnu Moole, Sowmya Dharmapuri, Raghuveer Boddireddy, Achuta Uppu, Srinivas R Puli
BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disorder of the esophagus characterized by mucosal eosinophilic infiltration. Topical glucocorticoids are considered standard line of treatment, whereas endoscopic dilations are performed for patients presenting with treatment-resistant disease or manifestations of dysphagia and/or food impactions. Efficacy and safety of esophageal dilation in these patients are currently unclear. AIMS: Primary outcomes were to evaluate the efficacy, adverse events, and mortality rates of endoscopic esophageal dilation in patients with EoE...
April 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28352657/randomized-placebo-controlled-window-trial-of-egfr-src-or-combined-blockade-in-head-and-neck-cancer
#18
Julie E Bauman, Umamaheswar Duvvuri, William E Gooding, Tanya J Rath, Neil D Gross, John Song, Antonio Jimeno, Wendell G Yarbrough, Faye M Johnson, Lin Wang, Simion Chiosea, Malabika Sen, Jason Kass, Jonas T Johnson, Robert L Ferris, Seungwon Kim, Fred R Hirsch, Kimberly Ellison, John T Flaherty, Gordon B Mills, Jennifer R Grandis
BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo...
March 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28349784/fibroblasts-in-hypoxic-conditions-mimic-laryngotracheal-stenosis
#19
COMPARATIVE STUDY
Linda X Yin, Kevin M Motz, Idris Samad, Madhavi Duvvuri, Michael Murphy, Dacheng Ding, Alexander T Hillel
Objective To elucidate the role of hypoxia and inflammatory pathways in the pathogenesis of iatrogenic laryngotracheal stenosis (iLTS). Study Design (1) Examination of mucosal surface gene expression in human iLTS. (2) In vitro comparison of normal and scar laryngotracheal fibroblasts under normoxic and hypoxic conditions. Setting Tertiary care hospital in a research university (2012-2016). Subjects and Methods Brush biopsies were obtained from normal laryngotracheal tissue and scar in iLTS patients; gene expression was compared...
May 2017: Otolaryngology—Head and Neck Surgery
https://www.readbyqxmd.com/read/28298902/global-distribution-and-evolutionary-history-of-enterovirus-d68-with-emphasis-on-the-2014-outbreak-in-ontario-canada
#20
Alireza Eshaghi, Venkata R Duvvuri, Sandra Isabel, Philip Banh, Aimin Li, Adriana Peci, Samir N Patel, Jonathan B Gubbay
Despite its first appearance in 1962, human enterovirus D68 (EV-D68) has been recognized as an emerging respiratory pathogen in the last decade when it caused outbreaks and clusters in several countries including Japan, the Philippines, and the Netherlands. The most recent and largest outbreak of EV-D68 associated with severe respiratory illness took place in North America between August 2014 and January 2015. Between September 1 and October 31 2014, EV-D68 infection was laboratory confirmed among 153/907 (16...
2017: Frontiers in Microbiology
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