41 results on '"Stein AP"'
Search Results
2. Endoscopic recannulation of long-segment, grade IV suprastomal tracheal stenosis: An operative technique.
- Author
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Stein AP, Edwards ER, and Puchi C
- Subjects
- Humans, Tracheostomy methods, Quality of Life, Trachea surgery, Severity of Illness Index, Treatment Outcome, Female, Tracheal Stenosis surgery, Endoscopy methods
- Abstract
Background: Long-segment, grade IV suprastomal tracheal stenosis is rare and difficult to treat (Carpenter et al., 2022 [1]). Patients with grade IV stenosis have significant quality of life impairments since they are tracheostomy dependent and aphonic. Open airway surgery is often needed to improve tracheal patency, restore the patient's voice, and progress towards decannulation (Abouyared et al., 2017 [2]). However, not all patients are candidates for upfront open surgery (Abouyared et al., 2017; Shamji, 2018 [2,3]). Therefore, it is important to develop and refine endoscopic interventions to improve quality of life for these patients., Methods: We describe a step-by-step endoscopic approach to the recannulation of long-segment, grade IV suprastomal tracheal stenosis. Briefly, our approach utilizes dual (proximal & distal) visualization of the stenosis prior to passing a 25 gauge needle through the stenosis to identify the proper trajectory for recannulation. Then a 16 gauge needle is passed in the same manner, and a wire is placed through the needle and into the distal airway. Once the airway is recannulated, the initial pinpoint opening is gradually widened in Seldinger fashion over the wire with Savary dilators followed by balloon dilation. Finally, a suprastomal L-stent (modified Montgomery T-Tube) is placed to reduce the risk of restenosis (Edwards et al., 2023 [4])., Case Discussion: A 39-year-old woman with a past medical history significant for poorly controlled type I diabetes mellitus and polysubstance abuse presented with tracheostomy dependence and aphonia. She was diagnosed with a long-segment, grade IV suprastomal tracheal stenosis and initially underwent endoscopic recannulation. This intervention restored her voice and allowed for optimization of her medical conditions before open airway surgery., Conclusion: Most patients experience a significant improvement in their quality of life as their voice is typically restored following this procedure. Additionally, individuals who eventually require open airway surgery gain additional time for medical optimization. In our experience, this procedure represents a safe and effective means of extending the utility of traditional endoscopic airway interventions for the management of patients with grade IV stenosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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3. Single Nucleotide Polymorphisms in Coronary Microvascular Dysfunction.
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Stein AP, Harder J, Holmes HR, Merz CNB, Pepine CJ, and Keeley EC
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- Humans, Coronary Circulation, Polymorphism, Single Nucleotide, Coronary Vessels diagnostic imaging, Microcirculation, Myocardial Ischemia, Coronary Artery Disease genetics
- Abstract
Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. There are data to suggest that coronary microvascular dysfunction, in some cases, may be genetically determined. We present an updated review of single nucleotide polymorphisms in coronary microvascular dysfunction.
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- 2024
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4. Transthyretin Cardiac Amyloidosis Disguised as Light Chain Amyloidosis or Multiple Myeloma?
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Stein AP, Matthia EL, Petty SA, Stewart B, Vilaro JR, Al-Ani MAZ, Ahmed MM, Aranda JM Jr, Hiemenz JW, and Parker AM
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- Humans, Prealbumin, Heart, Multiple Myeloma complications, Multiple Myeloma diagnosis, Cardiomyopathies diagnosis, Amyloid Neuropathies, Familial complications, Amyloid Neuropathies, Familial diagnosis
- Abstract
We describe 2 challenging cases of cardiac transthyretin amyloidosis initially treated as cardiac amyloidosis light chain in the setting of active myeloma. Endomyocardial biopsy with mass spectrometry was essential to confirm the appropriate diagnosis to direct the treatment., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Published by Elsevier Inc.)
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- 2024
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5. The impact of digital inequities on laryngeal cancer disparities in the US.
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Edwards ER, Fei-Zhang DJ, Stein AP, Lott DG, Chelius DC, Sheyn A, and Rastatter J
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- Humans, Delivery of Health Care, Communication, Prognosis, Income, Laryngeal Neoplasms epidemiology, Laryngeal Neoplasms therapy
- Abstract
Objectives: To develop and implement a novel, comprehensive tool, the Digital Inequity Index (DII), that quantifiably measures modern-technology access in the US to assess the impact of digital inequity on laryngeal cancer (LC) care nationwide., Methods: DII was calculated based on 17 census-tract level variables derived from the American Community Survey and Federal Communications Commission. Variables were categorized as infrastructure-access (i.e., electronic device ownership, type of broadband, internet provider availability, income-broadband subscription ratio) or sociodemographic (i.e., education, income, disability status), ranked and then averaged into a composite score. 22,850 patients from 2008 to 2017 in SEER were assessed for regression trends in long-term follow-up, survival, prognosis, and treatment across increasing overall digital inequity, as measured by the DII. This methodology allows for us to assess the independent contribution of digital inequity adjusted for socioeconomic confounders., Results: With increasing overall digital inequity, length of long-term follow-up (p < 0.001) and survival (p = 0.025) decreased. Compared to LC patients with low DII, high DII was associated with increased odds of advanced preliminary staging (OR 1.06; 95 % CI 1.03-1.08), treatment with chemotherapy (OR 1.06; 95 % CI 1.04-1.08), and radiation therapy (OR 1.02; 95 % CI 1.00-1.04), as well as decreased odds of surgical resection (OR 0.96; 95 % CI 0.94-97)., Conclusions: Digital inequities are associated with detrimental trends in LC patient outcomes in the US, allowing discourse for targeted means of alleviating disparities while contextualizing national sociodemographic trends of the impact of online access on informed care., Competing Interests: Declaration of competing interest Dr. Chelius reported receiving a coordinator stipend from the American-Academy of Otolaryngology outside the submitted work. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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6. Recurrent Cardiac Sarcoidosis and Giant Cell Myocarditis After Heart Transplant: A Case Report and Systematic Literature Review.
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Stein AP, Stewart BD, Patel DC, Al-Ani M, Vilaro J, Aranda JM Jr, Ahmed MM, and Parker AM
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- Adult, Humans, Male, Biopsy, Giant Cells pathology, Cardiomyopathies diagnosis, Cardiomyopathies etiology, Cardiomyopathies pathology, Heart Transplantation adverse effects, Myocarditis diagnosis, Myocarditis etiology, Myocarditis therapy, Sarcoidosis diagnosis, Sarcoidosis pathology
- Abstract
Recurrence of cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) after heart transplant is rare, with rates of 5% in CS and 8% in GCM. We aim to identify all reported cases of recurrence in the literature and to assess clinical course, treatments, and outcomes to improve understanding of the conditions. A systematic review, utilizing Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, was conducted by searching MEDLINE/PubMed and Embase of all available literature describing post-transplant recurrent granulomatous myocarditis, CS, or GCM. Data on demographics, transplant, recurrence, management, and outcomes data were collected from each publication. Comparison between the 2 groups were made using standard statistical approaches. Post-transplant GM recurrence was identified in 39 patients in 33 total publications. Reported cases included 24 GCM, 12 CS, and 3 suspected cases. Case reports were the most frequent form of publication. Mean age of patients experiencing recurrence was 42 years for GCM and 48 years for CS and favored males (62%). Time to recurrence ranged from 2 weeks to 9 years post-transplant, occurring earlier in GCM (mean 1.8 vs 3.0 years). Endomyocardial biopsies (89%) were the most utilized diagnostic method over cardiac magnetic resonance and positron emission tomography. Recurrence treatment regimens involved only steroids in 40% of CS, whereas other immunomodulatory regimens were utilized in 70% of GCM. In conclusion, GCM and CS recurrence after cardiac transplantation holds associated risks including concurrent acute cellular rejection, a higher therapeutic demand for GCM recurrence compared with CS, and mortality. New noninvasive screening techniques may help modify post-transplant monitoring regimens to increase both early detection and treatment of recurrence., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Published by Elsevier Inc.)
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- 2023
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7. Endoscopic L-stent for suprastomal tracheal stenosis.
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Edwards ER, Sachse S, Howard NS, Maronian NC, Morrison RJ, and Stein AP
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- Humans, Endoscopy, Trachea diagnostic imaging, Trachea surgery, Stents adverse effects, Tracheostomy adverse effects, Tracheal Stenosis diagnostic imaging, Tracheal Stenosis etiology, Tracheal Stenosis surgery
- Abstract
Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose relevant to this work.
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- 2023
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8. Assessment of Cardiovascular Risk for Noncardiac and Nonsurgical Activities.
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Perry C, Budweg JB, Stein AP, Harder J, Gupta S, Nusbickel AJ, Smoot M, Patel K, and Winchester DE
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- Male, Humans, Risk Factors, Testosterone therapeutic use, Heart Disease Risk Factors, Risk Assessment, Cardiovascular Diseases etiology, Cardiovascular Diseases prevention & control, Erectile Dysfunction
- Abstract
Cardiovascular risk stratification is a frequent evaluation performed by health professionals. Not uncommonly, requests for risk stratification involve activities or procedures that fall outside of the scope of current evidence-based guidelines. Estimating risk and providing guidance for these requests can be challenging due to limited available evidence. This review focuses on some of these unique requests, each of which are real examples encountered in our practice. We offer guidance by synthesizing the available medical literature and formulating recommendations on topics such as the initiation of testosterone and erectile dysfunction therapy, SCUBA and skydiving, polygraphy, and electroconvulsive therapy., (Published by Elsevier Inc.)
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- 2023
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9. A 43-Year-Old Woman With Pleuritic Chest Pain, Shortness of Breath, and Weakness of All Extremities.
- Author
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Stein AP, Minish JM, Caulkins H, Patel DC, and Ataya A
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- Adult, Dyspnea diagnosis, Dyspnea etiology, Extremities, Female, Humans, Smoking, Activities of Daily Living, Chest Pain diagnosis, Chest Pain etiology
- Abstract
Case Presentation: A 43-year-old woman with a medical history of hypothyroidism, psoriasis, and tobacco abuse (30-pack year history) who had quit smoking several months prior to presentation presented with pleuritic chest pain. She also noted a 2-year history of progressive numbness and weakness in her bilateral upper and lower extremities that now prevented her from completing her activities of daily living. She had worsening exertional dyspnea and a subjective 50-lb weight loss over the past year., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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10. Temporary Permanent Pacers for RBBB Undergoing TAVR: Could This Be a Solution?
- Author
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Stein AP and Anderson RD
- Subjects
- Aortic Valve diagnostic imaging, Aortic Valve surgery, Humans, Risk Factors, Treatment Outcome, Aortic Valve Stenosis diagnostic imaging, Aortic Valve Stenosis surgery, Transcatheter Aortic Valve Replacement adverse effects
- Abstract
Competing Interests: Declaration of competing interest None.
- Published
- 2022
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11. Bed bug ( Cimex spp.) colonization of human host.
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Harrison IS, Stein AP, Zeb L, and Radhakrishnan NS
- Abstract
Competing Interests: None disclosed.
- Published
- 2022
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12. Retraction.
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Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, Stein AP, Salgia R, Rolff J, Kimple RJ, and Wheeler DL
- Published
- 2021
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13. Discordant SARS-CoV-2 Detection in the Nasopharynx Versus Trachea for Patients With Tracheostomies.
- Author
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Smith JD, Correll JA, Stein JL, Kupfer RA, Hogikyan ND, Morrison RJ, and Stein AP
- Subjects
- Adult, Aged, Aged, 80 and over, COVID-19 virology, COVID-19 Nucleic Acid Testing methods, Female, Humans, Male, Middle Aged, Nasopharynx virology, Reproducibility of Results, Retrospective Studies, Trachea virology, Young Adult, COVID-19 diagnosis, COVID-19 Nucleic Acid Testing statistics & numerical data, RNA, Viral analysis, SARS-CoV-2 genetics, Tracheostomy
- Abstract
Objectives/hypothesis: Patients with tracheostomies have an anatomically altered connection between their upper and lower airways that could impact SARS-CoV-2 testing. Our goal was to evaluate for discordance in SARS-CoV-2 detection in hospitalized patients with COVID-19 and tracheostomies based on the site analyzed., Study Design: Retrospective chart review., Methods: This single-institution study evaluated hospitalized patients with COVID-19 who had tracheostomies placed during their treatment. We analyzed SARS-CoV-2 RNA nucleic acid amplification test (NAAT) results after tracheostomy. All included patients had nasopharyngeal (NP) and tracheal (TR) samples taken within a 48-hour period, allowing us to characterize rate of test concordance., Results: Forty-five patients met our inclusion criteria. Thirty-two (71.1%) patients had entirely concordant results after tracheostomy. However, 13 (28.9%) patients had at least one set of discordant results, the majority of which were NP negative and TR positive. There were no statistically significant differences in demographic or clinical variables, including time to tracheostomy and time to testing, among patients with concordant versus discordant SARS-CoV-2 results., Conclusion: This represents the first study to examine SARS-CoV-2 RNA NAAT concordance between NP and TR sites in hospitalized patients with COVID-19 and tracheostomies. One-third of patients demonstrated discordant testing when NP and TR specimens were collected within a 48-hour time period. Thus, patients with tracheostomies may have a higher false-negative rate if only one site is assessed for SARS-CoV-2. We recommend analyzing samples from both the nasopharynx and trachea for these patients until more prospective data exist., Level of Evidence: 4 Laryngoscope, 131:E2634-E2638, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)
- Published
- 2021
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14. Postacute COVID-19 Laryngeal Injury and Dysfunction.
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Neevel AJ, Smith JD, Morrison RJ, Hogikyan ND, Kupfer RA, and Stein AP
- Abstract
Objective: Patients with COVID-19 are at risk for laryngeal injury and dysfunction secondary to respiratory failure, prolonged intubation, and other unique facets of this illness. Our goal is to report clinical features and treatment for patients presenting with voice, airway, and/or swallowing concerns postacute COVID-19., Study Design: Case series., Setting: Academic tertiary care center., Methods: Patients presenting with laryngeal issues following recovery from COVID-19 were included after evaluation by our laryngology team. Data were collected via retrospective chart review from March 1, 2020, to April 1, 2021. This included details of the patient's COVID-19 course, initial presentation to laryngology, and subsequent treatment., Results: Twenty-four patients met inclusion criteria. Twenty (83%) patients were hospitalized, and 18 required endotracheal intubation for a median (range) duration of 14 days (6-31). Ten patients underwent tracheostomy. Patients were evaluated at a median 107 days (32-215) after their positive SARS-CoV-2 test result. The most common presenting concerns were dysphonia (n = 19, 79%), dyspnea (n = 17, 71%), and dysphagia (n = 6, 25%). Vocal fold motion impairment (50%), early glottic injury (39%), subglottic/tracheal stenosis (22%), and posterior glottic stenosis (17%) were identified in patients who required endotracheal intubation. Patients who did not need intubation were most frequently treated for muscle tension dysphonia (67%)., Conclusion: Patients may develop significant voice, airway, and/or swallowing issues postacute COVID-19. These complications are not limited to patients requiring intubation or tracheostomy. Multidisciplinary laryngology clinics will continue to play an integral role in diagnosing and treating patients with COVID-19-related laryngeal sequelae., (© The Authors 2021.)
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- 2021
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15. Heparin-mediated antibiotic delivery from an electrochemically-aligned collagen sheet.
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Cheng OT, Stein AP, Babajanian E, Hoppe KR, Li S, Jung H, Abrol A, Akkus A, Younesi M, Altawallbeh G, Ghannoum MA, Bonfield T, Akkus O, and Zender CA
- Subjects
- Anti-Bacterial Agents, Collagen, Gentamicins, Pseudomonas aeruginosa, Heparin
- Abstract
Background: Implantable medical devices and hardware are prolific in medicine, but hardware associated infections remain a major issue., Objective: To develop and evaluate a novel, biologic antimicrobial coating for medical implants., Methods: Electrochemically compacted collagen sheets with and without crosslinked heparin were synthesized per a protocol developed by our group. Sheets were incubated in antibiotic solution (gentamicin or moxifloxacin) overnight, and in vitro activity was assessed with five-day diffusion assays against Pseudomonas aeruginosa. Antibiotic release over time from gentamicin-infused sheets was determined using in vitro elution and high performance liquid chromatography (HPLC)., Results: Collagen-heparin-antibiotic sheets demonstrated larger growth inhibition zones against P. aeruginosa compared to collagen-antibiotic alone sheets. This activity persisted for five days and was not impacted by rinsing sheets prior to evaluation. Rinsed collagen-antibiotic sheets did not produce any inhibition zones. Elution of gentamicin from collagen-heparin-gentamicin sheets was gradual and remained above the minimal inhibitory concentration for gentamicin-sensitive organisms for 29 days. Conversely, collagen-gentamicin sheets eluted their antibiotic load within 24 hours. Overall, heparin-associated sheets demonstrated larger inhibition zones against P. aeruginosa and prolonged elution profile via HPLC., Conclusion: We developed a novel, local antibiotic delivery system that could be used to coat medical implants/hardware in the future and reduce post-operative infections.
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- 2021
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16. Extracardiac Rhabdomyoma of the Larynx.
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Stein AP and Weidenbecher M
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- Aged, Diagnosis, Differential, Humans, Laryngeal Muscles pathology, Male, Medical Illustration, Laryngeal Neoplasms diagnosis, Rhabdomyoma diagnosis
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- 2020
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17. A Destructive Sinonasal Process Leading to Sudden Blindness.
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Weber MH, Stein AP, and D'Anza BD
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- Acute Disease, Aged, Female, Granulomatosis with Polyangiitis complications, Granulomatosis with Polyangiitis pathology, Humans, Paranasal Sinus Diseases complications, Paranasal Sinus Diseases pathology, Blindness etiology, Granulomatosis with Polyangiitis diagnosis, Paranasal Sinus Diseases diagnosis
- Published
- 2019
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18. Correction: AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma.
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Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, Saha S, Yang D, Gill PS, Lingen MW, Saloura V, Villaflor VM, Salgia R, Kimple RJ, and Wheeler DL
- Published
- 2018
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19. Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma.
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Redlich N, Robinson AM, Nickel KP, Stein AP, Wheeler DL, Adkins DR, Uppaluri R, Kimple RJ, Van Tine BA, and Michel LS
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- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Cetuximab pharmacology, Cetuximab therapeutic use, Cobalt pharmacology, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mice, Neuregulin-1 antagonists & inhibitors, Neuregulin-1 genetics, Neuregulin-1 metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, RNA Interference, RNA, Small Interfering metabolism, Receptor, ErbB-3 antagonists & inhibitors, Receptor, ErbB-3 immunology, Signal Transduction drug effects, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck metabolism, Squamous Cell Carcinoma of Head and Neck pathology, Transplantation, Heterologous, Antigens, Neoplasm metabolism, Cell Adhesion Molecules metabolism, Receptor, ErbB-3 metabolism
- Abstract
ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.
- Published
- 2018
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20. Factors influencing sialocele or salivary fistula formation postparotidectomy.
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Britt CJ, Stein AP, Gessert T, Pflum Z, Saha S, and Hartig GK
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- Adult, Aged, Cohort Studies, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Postoperative Complications diagnosis, Postoperative Complications epidemiology, Reoperation methods, Retrospective Studies, Risk Factors, Salivary Gland Fistula epidemiology, Treatment Outcome, United States, Parotid Gland surgery, Parotid Neoplasms pathology, Parotid Neoplasms surgery, Salivary Gland Fistula etiology, Salivary Gland Fistula surgery
- Abstract
Background: Does the extent of parotidectomy or other patient or tumor characteristics influence the rate of sialocele/salivary fistula formation?, Methods: All patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013 were considered. Patients who developed a sialocele/salivary fistula were identified. Extent of dissection, age, sex, body mass index (BMI), volume of specimen, and rate of malignancy were examined., Results: Seventy of 771 patients (9.1%) developed a sialocele/salivary fistula. Sixty-seven fistulae (96%) developed within 1 month and all resolved by 6 months. Age, sex, pathology, and BMI were not increased in the sialocele group. Inferior and middle superficial parotidectomy had a significantly higher rate of sialocele than other extents of dissection. Volume of tissue removed was not significantly different between dissection groups., Conclusion: Sialocele/salivary fistula is common postparotidectomy and is more likely with inferior and middle superficial parotidectomy. © 2016 Wiley Periodicals, Inc. Head Neck 39: 387-391, 2017., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2017
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21. RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.
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Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, Stein AP, Salgia R, Rolff J, Kimple RJ, and Wheeler DL
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- Active Transport, Cell Nucleus, Animals, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cetuximab pharmacology, Drug Resistance, Neoplasm, ErbB Receptors genetics, Humans, Immunoblotting, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Inbred NOD, Mice, SCID, Microscopy, Confocal, Neuregulin-1 genetics, Neuregulin-1 metabolism, Proto-Oncogene Proteins genetics, RNA Interference, Receptor Protein-Tyrosine Kinases genetics, Transplantation, Heterologous, src-Family Kinases genetics, src-Family Kinases metabolism, Axl Receptor Tyrosine Kinase, Carcinoma, Non-Small-Cell Lung metabolism, Cell Nucleus metabolism, ErbB Receptors metabolism, Lung Neoplasms metabolism, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process., (Copyright © 2017, American Association for the Advancement of Science.)
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- 2017
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22. Defining the boundaries and expanding the utility of head and neck cancer patient derived xenografts.
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Swick AD, Stein AP, McCulloch TM, Hartig GK, Ong IM, Sampene E, Prabakaran PJ, Liu CZ, and Kimple RJ
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- Animals, Female, Head and Neck Neoplasms genetics, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Head and Neck Neoplasms pathology, Xenograft Model Antitumor Assays
- Abstract
Background: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system., Methods: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach., Results: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft., Conclusions: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation., Competing Interests: None, (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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23. Distribution and sources of sterol biomarkers in sediments collected from a tropical estuary in Northeast Brazil.
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Frena M, Santos AP, Santos E, Silva RP, Souza MR, Madureira LA, and Alexandre MR
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- Biomarkers analysis, Brazil, Gas Chromatography-Mass Spectrometry, Sewage analysis, Water Pollutants, Chemical analysis, Estuaries, Geologic Sediments chemistry, Sterols analysis
- Abstract
The Piauí-Real estuary is located along the southern coast of Sergipe state, Northeast Brazil. This estuary has great economic importance due to its physical, biological, and socioeconomic diversity, but it is subject to anthropogenic stress since the resident population in the town bordered by the estuarine system has grown in recent years. Thus, the possibility of sewage contamination originating from the approximately 450,000 inhabitants living within its drainage basin was investigated in this study. Sediment samples were collected from 15 sampling stations along the estuarine system and extracted, followed by gas chromatography-mass spectrometry (GC-MS) analysis. Six sterols were quantified, indicating natural and anthropogenic sources. Coprostanol concentrations higher than 100 ng g
-1 were observed in 47 % of the stations analyzed, indicating sewage contamination, which was confirmed by the diagnostic ratios calculated. Based on the Pearson correlation test, a significant correlation between coprostanol concentrations and total organic carbon content (TOC) was observed, indicating that sterols record the history of sewage inputs in this area. These results indicate that control of the organic inputs into the estuarine system is required. Graphical abstract Sterol markers were determined and sources assessed in surface sediments from Piauí-Real estuarine system.- Published
- 2016
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24. Incidental Parotid Neoplasms: Pathology and Prevalence.
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Britt CJ, Stein AP, Patel PN, Harari PM, and Hartig GK
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- Electronic Health Records, Humans, Incidental Findings, Parotid Neoplasms epidemiology, Parotid Neoplasms surgery, Prevalence, Parotid Neoplasms pathology
- Abstract
Objective: To better characterize parotid masses incidentally identified on imaging., Study Design: Case series with chart review., Setting: Academic medical center., Subjects and Methods: Medical records were reviewed for 771 patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients were stratified into 2 groups: those with tumors identified solely on imaging (parotid incidentalomas [PIs]) and those with palpable masses, pain, facial nerve dysfunction, or other reasons their mass was identified (nonincidentals [NIs]). A χ(2) test was employed to compare the prevalence of malignancy in PIs compared with NIs. Trend analysis was performed to determine the prevalence of PIs over the 20-year period., Results: Of the 771 patients, 67 (8.7%) had their mass discovered incidentally on imaging (PIs). There was a significant difference in the rate of malignancy in the NI (32.7%) compared with the PI group (6.0%) (P < .01). During the 1994 to 2003 time period, 4.0% of all parotoidectomies performed were for PIs, while during the second decade (2004-2013), this proportion increased to 10.2%. This represents a 155.0% increase in the percentage of parotidectomies carried out for PIs between these 2 periods., Conclusion: In this study, the rate of malignancy in PIs was significantly lower than the rate of malignancy in patients with NIs. The occurrence of PIs has increased over time and now represents greater than 10.0% of all parotidectomies performed at the University of Wisconsin. This information is important to consider when consenting a patient for resection of a PI., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)
- Published
- 2015
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25. AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma.
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Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, Saha S, Yang D, Gill PS, Lingen MW, Saloura V, Villaflor VM, Salgia R, Kimple RJ, and Wheeler DL
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- Animals, Benzocycloheptenes administration & dosage, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic drug effects, Head and Neck Neoplasms pathology, Humans, Mice, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, RNA, Small Interfering genetics, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics, Squamous Cell Carcinoma of Head and Neck, Triazoles administration & dosage, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Molecular Targeted Therapy, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis
- Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical., Experimental Design: In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC., Results: AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance., Conclusions: This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC., (©2015 American Association for Cancer Research.)
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- 2015
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26. Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review.
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Stein AP, Saha S, Kraninger JL, Swick AD, Yu M, Lambert PF, and Kimple RJ
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- Carcinoma, Squamous Cell virology, Humans, Oropharyngeal Neoplasms virology, Papillomaviridae pathogenicity, Papillomavirus Infections virology, Prognosis, Carcinoma, Squamous Cell epidemiology, Oropharyngeal Neoplasms epidemiology, Papillomavirus Infections epidemiology
- Abstract
Purpose: The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing, and it has been proposed that a rising rate of human papillomavirus (HPV)-associated cancers is driving the observed changes in OPSCC incidence. We carried out this systematic review to further examine the prevalence of HPV in OPSCC over time worldwide., Methods: A systematic literature search was performed to identify all articles through January 31, 2014, which reported on the prevalence of HPV in OPSCC. Articles that met the inclusion criteria were divided into 4 time frames (pre-1995, 1995-1999, 2000-2004, and 2005 to present) based on the median year of the study's sample collection period. Using a weighted analysis of variance model, we examined the trends of HPV-positivity over time worldwide, in North America, and in Europe., Results: Our literature search identified 699 unique articles. One hundred seventy-five underwent review of the entire study, and 105 met the inclusion criteria. These 105 articles reported on the HPV prevalence in 9541 OPSCC specimens across 23 nations. We demonstrated significant increases in the percentage change of HPV-positive OPSCCs from pre-1995 to present: 20.6% worldwide (P for trend: P < 0.001), 21.6% in North America (P = 0.013), and 21.5% in Europe (P = 0.033)., Conclusions: Interestingly, whereas in Europe there was a steady increase in HPV prevalence across all time frames, reaching nearly 50% most recently, in North America HPV prevalence appears to have plateaued over the past decade at about 65%. These findings may have important implications regarding predictions for the future incidence of OPSCC.
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- 2015
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27. Patient and tumor characteristics predictive of primary parotid gland malignancy: A 20-year experience at the University of Wisconsin.
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Stein AP, Britt CJ, Saha S, McCulloch TM, Wieland AM, Harari PM, and Hartig GK
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- Adult, Age Factors, Aged, Aged, 80 and over, Body Mass Index, Female, Humans, Logistic Models, Male, Middle Aged, Parotid Neoplasms surgery, Retrospective Studies, Risk Factors, Sex Factors, Tumor Burden, Wisconsin, Neoplasm Recurrence, Local epidemiology, Parotid Neoplasms complications, Parotid Neoplasms pathology
- Abstract
Purpose: To identify patient and tumor characteristics predictive of primary parotid malignancy., Materials and Methods: Records were reviewed for patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients with primary parotid neoplasms were separated into benign or malignant subgroups. A multivariate logistic regression model was employed to compare categorical (gender, lesion side, nature of presentation, recurrence) and numerical variables (age, tumor size) between the benign and malignant groups. Mean BMI was compared between the groups by univariate analysis., Results: 771 patients underwent parotidectomy from 1994 to 2013, and 474 had a primary parotid neoplasm. No relationship existed between malignancy and gender (p=0.610), lesion side (p=0.110), or BMI (p=0.196). Mean age (p=0.015) and tumor size (p=0.011) were significantly different between the benign and malignant groups. Patient presentation was classified into three categories: symptomatic (n=109), palpable and asymptomatic (n=303), and incidentally noted on imaging (n=57). From all patients with symptomatic, asymptomatic or incidentally noted masses, 41.3%, 10.6% and 5.3%, respectively, were diagnosed with malignant disease. There was a significant relationship between the patient's initial presentation and malignancy (p<0.001), and patients with facial nerve dysfunction or skin involvement had the greatest likelihood of malignancy. Finally, there was a significant association between malignancy and recurrence (p=0.001)., Conclusions: In this study, age, tumor size, and nature of presentation were all associated with primary parotid malignancy. Understanding the impact of these features on the probability of malignancy is valuable in decision making and counseling of patients presenting with a newly diagnosed parotid neoplasm., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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28. Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies.
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Stein AP, Swick AD, Smith MA, Blitzer GC, Yang RZ, Saha S, Harari PM, Lambert PF, Liu CZ, and Kimple RJ
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- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Biomarkers, Cell Line, Tumor, Cetuximab administration & dosage, Cetuximab pharmacology, Cisplatin administration & dosage, Cisplatin pharmacology, DNA-Binding Proteins metabolism, Disease Models, Animal, Endonucleases metabolism, ErbB Receptors metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Head and Neck Neoplasms pathology, Head and Neck Neoplasms therapy, Head and Neck Neoplasms virology, Humans, Immunohistochemistry, Mice, Prognosis, Proto-Oncogene Proteins c-akt metabolism, Radiotherapy, Signal Transduction drug effects, Signal Transduction radiation effects, Xenograft Model Antitumor Assays, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms mortality
- Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50-60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2015
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29. Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.
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Leung W, Shaffer CD, Reed LK, Smith ST, Barshop W, Dirkes W, Dothager M, Lee P, Wong J, Xiong D, Yuan H, Bedard JE, Machone JF, Patterson SD, Price AL, Turner BA, Robic S, Luippold EK, McCartha SR, Walji TA, Walker CA, Saville K, Abrams MK, Armstrong AR, Armstrong W, Bailey RJ, Barberi CR, Beck LR, Blaker AL, Blunden CE, Brand JP, Brock EJ, Brooks DW, Brown M, Butzler SC, Clark EM, Clark NB, Collins AA, Cotteleer RJ, Cullimore PR, Dawson SG, Docking CT, Dorsett SL, Dougherty GA, Downey KA, Drake AP, Earl EK, Floyd TG, Forsyth JD, Foust JD, Franchi SL, Geary JF, Hanson CK, Harding TS, Harris CB, Heckman JM, Holderness HL, Howey NA, Jacobs DA, Jewell ES, Kaisler M, Karaska EA, Kehoe JL, Koaches HC, Koehler J, Koenig D, Kujawski AJ, Kus JE, Lammers JA, Leads RR, Leatherman EC, Lippert RN, Messenger GS, Morrow AT, Newcomb V, Plasman HJ, Potocny SJ, Powers MK, Reem RM, Rennhack JP, Reynolds KR, Reynolds LA, Rhee DK, Rivard AB, Ronk AJ, Rooney MB, Rubin LS, Salbert LR, Saluja RK, Schauder T, Schneiter AR, Schulz RW, Smith KE, Spencer S, Swanson BR, Tache MA, Tewilliager AA, Tilot AK, VanEck E, Villerot MM, Vylonis MB, Watson DT, Wurzler JA, Wysocki LM, Yalamanchili M, Zaborowicz MA, Emerson JA, Ortiz C, Deuschle FJ, DiLorenzo LA, Goeller KL, Macchi CR, Muller SE, Pasierb BD, Sable JE, Tucci JM, Tynon M, Dunbar DA, Beken LH, Conturso AC, Danner BL, DeMichele GA, Gonzales JA, Hammond MS, Kelley CV, Kelly EA, Kulich D, Mageeney CM, McCabe NL, Newman AM, Spaeder LA, Tumminello RA, Revie D, Benson JM, Cristostomo MC, DaSilva PA, Harker KS, Jarrell JN, Jimenez LA, Katz BM, Kennedy WR, Kolibas KS, LeBlanc MT, Nguyen TT, Nicolas DS, Patao MD, Patao SM, Rupley BJ, Sessions BJ, Weaver JA, Goodman AL, Alvendia EL, Baldassari SM, Brown AS, Chase IO, Chen M, Chiang S, Cromwell AB, Custer AF, DiTommaso TM, El-Adaimi J, Goscinski NC, Grove RA, Gutierrez N, Harnoto RS, Hedeen H, Hong EL, Hopkins BL, Huerta VF, Khoshabian C, LaForge KM, Lee CT, Lewis BM, Lydon AM, Maniaci BJ, Mitchell RD, Morlock EV, Morris WM, Naik P, Olson NC, Osterloh JM, Perez MA, Presley JD, Randazzo MJ, Regan MK, Rossi FG, Smith MA, Soliterman EA, Sparks CJ, Tran DL, Wan T, Welker AA, Wong JN, Sreenivasan A, Youngblom J, Adams A, Alldredge J, Bryant A, Carranza D, Cifelli A, Coulson K, Debow C, Delacruz N, Emerson C, Farrar C, Foret D, Garibay E, Gooch J, Heslop M, Kaur S, Khan A, Kim V, Lamb T, Lindbeck P, Lucas G, Macias E, Martiniuc D, Mayorga L, Medina J, Membreno N, Messiah S, Neufeld L, Nguyen SF, Nichols Z, Odisho G, Peterson D, Rodela L, Rodriguez P, Rodriguez V, Ruiz J, Sherrill W, Silva V, Sparks J, Statton G, Townsend A, Valdez I, Waters M, Westphal K, Winkler S, Zumkehr J, DeJong RJ, Hoogewerf AJ, Ackerman CM, Armistead IO, Baatenburg L, Borr MJ, Brouwer LK, Burkhart BJ, Bushhouse KT, Cesko L, Choi TY, Cohen H, Damsteegt AM, Darusz JM, Dauphin CM, Davis YP, Diekema EJ, Drewry M, Eisen ME, Faber HM, Faber KJ, Feenstra E, Felzer-Kim IT, Hammond BL, Hendriksma J, Herrold MR, Hilbrands JA, Howell EJ, Jelgerhuis SA, Jelsema TR, Johnson BK, Jones KK, Kim A, Kooienga RD, Menyes EE, Nollet EA, Plescher BE, Rios L, Rose JL, Schepers AJ, Scott G, Smith JR, Sterling AM, Tenney JC, Uitvlugt C, VanDyken RE, VanderVennen M, Vue S, Kokan NP, Agbley K, Boham SK, Broomfield D, Chapman K, Dobbe A, Dobbe I, Harrington W, Ibrahem M, Kennedy A, Koplinsky CA, Kubricky C, Ladzekpo D, Pattison C, Ramirez RE Jr, Wande L, Woehlke S, Wawersik M, Kiernan E, Thompson JS, Banker R, Bartling JR, Bhatiya CI, Boudoures AL, Christiansen L, Fosselman DS, French KM, Gill IS, Havill JT, Johnson JL, Keny LJ, Kerber JM, Klett BM, Kufel CN, May FJ, Mecoli JP, Merry CR, Meyer LR, Miller EG, Mullen GJ, Palozola KC, Pfeil JJ, Thomas JG, Verbofsky EM, Spana EP, Agarwalla A, Chapman J, Chlebina B, Chong I, Falk IN, Fitzgibbons JD, Friedman H, Ighile O, Kim AJ, Knouse KA, Kung F, Mammo D, Ng CL, Nikam VS, Norton D, Pham P, Polk JW, Prasad S, Rankin H, Ratliff CD, Scala V, Schwartz NU, Shuen JA, Xu A, Xu TQ, Zhang Y, Rosenwald AG, Burg MG, Adams SJ, Baker M, Botsford B, Brinkley B, Brown C, Emiah S, Enoch E, Gier C, Greenwell A, Hoogenboom L, Matthews JE, McDonald M, Mercer A, Monsma N, Ostby K, Ramic A, Shallman D, Simon M, Spencer E, Tomkins T, Wendland P, Wylie A, Wolyniak MJ, Robertson GM, Smith SI, DiAngelo JR, Sassu ED, Bhalla SC, Sharif KA, Choeying T, Macias JS, Sanusi F, Torchon K, Bednarski AE, Alvarez CJ, Davis KC, Dunham CA, Grantham AJ, Hare AN, Schottler J, Scott ZW, Kuleck GA, Yu NS, Kaehler MM, Jipp J, Overvoorde PJ, Shoop E, Cyrankowski O, Hoover B, Kusner M, Lin D, Martinov T, Misch J, Salzman G, Schiedermayer H, Snavely M, Zarrasola S, Parrish S, Baker A, Beckett A, Belella C, Bryant J, Conrad T, Fearnow A, Gomez C, Herbstsomer RA, Hirsch S, Johnson C, Jones M, Kabaso R, Lemmon E, Vieira CM, McFarland D, McLaughlin C, Morgan A, Musokotwane S, Neutzling W, Nietmann J, Paluskievicz C, Penn J, Peoples E, Pozmanter C, Reed E, Rigby N, Schmidt L, Shelton M, Shuford R, Tirasawasdichai T, Undem B, Urick D, Vondy K, Yarrington B, Eckdahl TT, Poet JL, Allen AB, Anderson JE, Barnett JM, Baumgardner JS, Brown AD, Carney JE, Chavez RA, Christgen SL, Christie JS, Clary AN, Conn MA, Cooper KM, Crowley MJ, Crowley ST, Doty JS, Dow BA, Edwards CR, Elder DD, Fanning JP, Janssen BM, Lambright AK, Lane CE, Limle AB, Mazur T, McCracken MR, McDonough AM, Melton AD, Minnick PJ, Musick AE, Newhart WH, Noynaert JW, Ogden BJ, Sandusky MW, Schmuecker SM, Shipman AL, Smith AL, Thomsen KM, Unzicker MR, Vernon WB, Winn WW, Woyski DS, Zhu X, Du C, Ament C, Aso S, Bisogno LS, Caronna J, Fefelova N, Lopez L, Malkowitz L, Marra J, Menillo D, Obiorah I, Onsarigo EN, Primus S, Soos M, Tare A, Zidan A, Jones CJ, Aronhalt T, Bellush JM, Burke C, DeFazio S, Does BR, Johnson TD, Keysock N, Knudsen NH, Messler J, Myirski K, Rekai JL, Rempe RM, Salgado MS, Stagaard E, Starcher JR, Waggoner AW, Yemelyanova AK, Hark AT, Bertolet A, Kuschner CE, Parry K, Quach M, Shantzer L, Shaw ME, Smith MA, Glenn O, Mason P, Williams C, Key SC, Henry TC, Johnson AG, White JX, Haberman A, Asinof S, Drumm K, Freeburg T, Safa N, Schultz D, Shevin Y, Svoronos P, Vuong T, Wellinghoff J, Hoopes LL, Chau KM, Ward A, Regisford EG, Augustine L, Davis-Reyes B, Echendu V, Hales J, Ibarra S, Johnson L, Ovu S, Braverman JM, Bahr TJ, Caesar NM, Campana C, Cassidy DW, Cognetti PA, English JD, Fadus MC, Fick CN, Freda PJ, Hennessy BM, Hockenberger K, Jones JK, King JE, Knob CR, Kraftmann KJ, Li L, Lupey LN, Minniti CJ, Minton TF, Moran JV, Mudumbi K, Nordman EC, Puetz WJ, Robinson LM, Rose TJ, Sweeney EP, Timko AS, Paetkau DW, Eisler HL, Aldrup ME, Bodenberg JM, Cole MG, Deranek KM, DeShetler M, Dowd RM, Eckardt AK, Ehret SC, Fese J, Garrett AD, Kammrath A, Kappes ML, Light MR, Meier AC, O'Rouke A, Perella M, Ramsey K, Ramthun JR, Reilly MT, Robinett D, Rossi NL, Schueler MG, Shoemaker E, Starkey KM, Vetor A, Vrable A, Chandrasekaran V, Beck C, Hatfield KR, Herrick DA, Khoury CB, Lea C, Louie CA, Lowell SM, Reynolds TJ, Schibler J, Scoma AH, Smith-Gee MT, Tuberty S, Smith CD, Lopilato JE, Hauke J, Roecklein-Canfield JA, Corrielus M, Gilman H, Intriago S, Maffa A, Rauf SA, Thistle K, Trieu M, Winters J, Yang B, Hauser CR, Abusheikh T, Ashrawi Y, Benitez P, Boudreaux LR, Bourland M, Chavez M, Cruz S, Elliott G, Farek JR, Flohr S, Flores AH, Friedrichs C, Fusco Z, Goodwin Z, Helmreich E, Kiley J, Knepper JM, Langner C, Martinez M, Mendoza C, Naik M, Ochoa A, Ragland N, Raimey E, Rathore S, Reza E, Sadovsky G, Seydoux MI, Smith JE, Unruh AK, Velasquez V, Wolski MW, Gosser Y, Govind S, Clarke-Medley N, Guadron L, Lau D, Lu A, Mazzeo C, Meghdari M, Ng S, Pamnani B, Plante O, Shum YK, Song R, Johnson DE, Abdelnabi M, Archambault A, Chamma N, Gaur S, Hammett D, Kandahari A, Khayrullina G, Kumar S, Lawrence S, Madden N, Mandelbaum M, Milnthorp H, Mohini S, Patel R, Peacock SJ, Perling E, Quintana A, Rahimi M, Ramirez K, Singhal R, Weeks C, Wong T, Gillis AT, Moore ZD, Savell CD, Watson R, Mel SF, Anilkumar AA, Bilinski P, Castillo R, Closser M, Cruz NM, Dai T, Garbagnati GF, Horton LS, Kim D, Lau JH, Liu JZ, Mach SD, Phan TA, Ren Y, Stapleton KE, Strelitz JM, Sunjed R, Stamm J, Anderson MC, Bonifield BG, Coomes D, Dillman A, Durchholz EJ, Fafara-Thompson AE, Gross MJ, Gygi AM, Jackson LE, Johnson A, Kocsisova Z, Manghelli JL, McNeil K, Murillo M, Naylor KL, Neely J, Ogawa EE, Rich A, Rogers A, Spencer JD, Stemler KM, Throm AA, Van Camp M, Weihbrecht K, Wiles TA, Williams MA, Williams M, Zoll K, Bailey C, Zhou L, Balthaser DM, Bashiri A, Bower ME, Florian KA, Ghavam N, Greiner-Sosanko ES, Karim H, Mullen VW, Pelchen CE, Yenerall PM, Zhang J, Rubin MR, Arias-Mejias SM, Bermudez-Capo AG, Bernal-Vega GV, Colon-Vazquez M, Flores-Vazquez A, Gines-Rosario M, Llavona-Cartagena IG, Martinez-Rodriguez JO, Ortiz-Fuentes L, Perez-Colomba EO, Perez-Otero J, Rivera E, Rodriguez-Giron LJ, Santiago-Sanabria AJ, Senquiz-Gonzalez AM, delValle FR, Vargas-Franco D, Velázquez-Soto KI, Zambrana-Burgos JD, Martinez-Cruzado JC, Asencio-Zayas L, Babilonia-Figueroa K, Beauchamp-Pérez FD, Belén-Rodríguez J, Bracero-Quiñones L, Burgos-Bula AP, Collado-Méndez XA, Colón-Cruz LR, Correa-Muller AI, Crooke-Rosado JL, Cruz-García JM, Defendini-Ávila M, Delgado-Peraza FM, Feliciano-Cancela AJ, Gónzalez-Pérez VM, Guiblet W, Heredia-Negrón A, Hernández-Muñiz J, Irizarry-González LN, Laboy-Corales ÁL, Llaurador-Caraballo GA, Marín-Maldonado F, Marrero-Llerena U, Martell-Martínez HA, Martínez-Traverso IM, Medina-Ortega KN, Méndez-Castellanos SG, Menéndez-Serrano KC, Morales-Caraballo CI, Ortiz-DeChoudens S, Ortiz-Ortiz P, Pagán-Torres H, Pérez-Afanador D, Quintana-Torres EM, Ramírez-Aponte EG, Riascos-Cuero C, Rivera-Llovet MS, Rivera-Pagán IT, Rivera-Vicéns RE, Robles-Juarbe F, Rodríguez-Bonilla L, Rodríguez-Echevarría BO, Rodríguez-García PM, Rodríguez-Laboy AE, Rodríguez-Santiago S, Rojas-Vargas ML, Rubio-Marrero EN, Santiago-Colón A, Santiago-Ortiz JL, Santos-Ramos CE, Serrano-González J, Tamayo-Figueroa AM, Tascón-Peñaranda EP, Torres-Castillo JL, Valentín-Feliciano NA, Valentín-Feliciano YM, Vargas-Barreto NM, Vélez-Vázquez M, Vilanova-Vélez LR, Zambrana-Echevarría C, MacKinnon C, Chung HM, Kay C, Pinto A, Kopp OR, Burkhardt J, Harward C, Allen R, Bhat P, Chang JH, Chen Y, Chesley C, Cohn D, DuPuis D, Fasano M, Fazzio N, Gavinski K, Gebreyesus H, Giarla T, Gostelow M, Greenstein R, Gunasinghe H, Hanson C, Hay A, He TJ, Homa K, Howe R, Howenstein J, Huang H, Khatri A, Kim YL, Knowles O, Kong S, Krock R, Kroll M, Kuhn J, Kwong M, Lee B, Lee R, Levine K, Li Y, Liu B, Liu L, Liu M, Lousararian A, Ma J, Mallya A, Manchee C, Marcus J, McDaniel S, Miller ML, Molleston JM, Diez CM, Ng P, Ngai N, Nguyen H, Nylander A, Pollack J, Rastogi S, Reddy H, Regenold N, Sarezky J, Schultz M, Shim J, Skorupa T, Smith K, Spencer SJ, Srikanth P, Stancu G, Stein AP, Strother M, Sudmeier L, Sun M, Sundaram V, Tazudeen N, Tseng A, Tzeng A, Venkat R, Venkataram S, Waldman L, Wang T, Yang H, Yu JY, Zheng Y, Preuss ML, Garcia A, Juergens M, Morris RW, Nagengast AA, Azarewicz J, Carr TJ, Chichearo N, Colgan M, Donegan M, Gardner B, Kolba N, Krumm JL, Lytle S, MacMillian L, Miller M, Montgomery A, Moretti A, Offenbacker B, Polen M, Toth J, Woytanowski J, Kadlec L, Crawford J, Spratt ML, Adams AL, Barnard BK, Cheramie MN, Eime AM, Golden KL, Hawkins AP, Hill JE, Kampmeier JA, Kern CD, Magnuson EE, Miller AR, Morrow CM, Peairs JC, Pickett GL, Popelka SA, Scott AJ, Teepe EJ, TerMeer KA, Watchinski CA, Watson LA, Weber RE, Woodard KA, Barnard DC, Appiah I, Giddens MM, McNeil GP, Adebayo A, Bagaeva K, Chinwong J, Dol C, George E, Haltaufderhyde K, Haye J, Kaur M, Semon M, Serjanov D, Toorie A, Wilson C, Riddle NC, Buhler J, Mardis ER, and Elgin SC
- Subjects
- Animals, Codon, Computational Biology, DNA Transposable Elements, Drosophila melanogaster genetics, Exons, Gene Rearrangement, Heterochromatin, Introns, Molecular Sequence Annotation, Polytene Chromosomes, Repetitive Sequences, Nucleic Acid, Selection, Genetic, Species Specificity, Drosophila genetics, Drosophila Proteins genetics, Evolution, Molecular, Genome, Genomics
- Abstract
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu., (Copyright © 2015 Leung et al.)
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- 2015
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30. AXL mediates resistance to cetuximab therapy.
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Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Luthar N, Toulany M, Gill PS, Salgia R, Kimple RJ, and Wheeler DL
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- Animals, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Growth Processes drug effects, Cell Line, Tumor, Cetuximab, Drug Resistance, Neoplasm, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Humans, Lung Neoplasms pathology, Mice, Mice, Nude, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Squamous Cell Carcinoma of Head and Neck, Transfection, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell enzymology, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms enzymology, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis
- Abstract
The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152-64. ©2014 AACR., (©2014 American Association for Cancer Research.)
- Published
- 2014
- Full Text
- View/download PDF
31. Influence of handling conditions on the establishment and propagation of head and neck cancer patient derived xenografts.
- Author
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Stein AP, Saha S, Liu CZ, Hartig GK, Lambert PF, and Kimple RJ
- Subjects
- Animals, Disease Models, Animal, Female, Heterografts, Humans, Male, Mice, Neoplasm Grading, Tumor Burden, Head and Neck Neoplasms pathology, Specimen Handling
- Abstract
Background: Patient derived xenografts (PDXs) for head and neck cancer (HNC) and other cancers represent powerful research platforms. Most groups implant patient tissue into immunodeficient mice immediately although the significance of this time interval is anecdotal. We tested the hypothesis that the time from tumor excision to implantation is crucial for PDX passaging and establishment., Methods: We examined whether time or storage medium affected PDX viability for passaging two established HNC PDXs (UW-SCC34, UW-SCC52). Tumors were harvested, stored in ice-cold media or saline for 0-48 hours, and implanted into new mice. Tumor growth was compared by two-way ANOVA with respect to time and storage condition. Three new HNC PDXs (UW-SCC63-65) were generated by implanting patient tissue into mice immediately (Time 0) and 24 hours after receiving tissue from the operating room., Results: Similar quantities of tumor were implanted into each mouse. At the end of the experiment, no significant difference was seen in mean tumor weight between the media and saline storage conditions for UW-SCC34 or UW-SCC52 (p = 0.650 and p = 0.177, respectively). No difference in tumor formation prevalence was seen on the basis of time from harvest to implantation (≥13 of 16 tumors grew at every time point). Histological analysis showed strong similarity to the initial tumor across all groups. Tumors developed at both Time 0 and 24 hours for UW-SCC63 and UW-SCC64., Conclusions: We demonstrated that neither storage medium nor time from tumor excision to implantation (up to 48 hours) affected viability or histological differentiation in a subsequent passage for two HNC PDXs. Moreover, we revealed that fresh patient tissue is viable up to 24 hours post-resection. This information is important as it applies to the development and sharing of PDXs.
- Published
- 2014
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32. Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time.
- Author
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Stein AP, Saha S, Yu M, Kimple RJ, and Lambert PF
- Subjects
- Alphapapillomavirus genetics, DNA, Viral isolation & purification, Humans, In Situ Hybridization, Polymerase Chain Reaction, United States, Alphapapillomavirus isolation & purification, Carcinoma, Squamous Cell virology, Oropharyngeal Neoplasms virology
- Abstract
Human papillomaviruses (HPVs) are involved in approximately 5% of all human cancer. Although initially recognized for causing nearly all cases of cervical carcinoma, much data has now emerged implicating HPVs as a causal factor in other anogenital cancers as well as a subset of head and neck squamous cell carcinomas (HNSCCs), most commonly oropharyngeal cancers. Numerous clinical trials have demonstrated that patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) have improved survival compared to patients with HPV- cancers. Furthermore, epidemiological evidence shows the incidence of OPSCC has been steadily rising over time in the United States. It has been proposed that an increase in HPV-related OPSCCs is the driving force behind the increasing rate of OPSCC. Although some studies have revealed an increase in HPV+ head and neck malignancies over time in specific regions of the United States, there has not been a comprehensive study validating this trend across the entire country. Therefore, we undertook this meta-analysis to assess all literature through August 2013 that reported on the prevalence of HPV in OPSCC for patient populations within the United States. The results show an increase in the prevalence of HPV+ OPSCC from 20.9% in the pre-1990 time period to 51.4% in 1990-1999 and finally to 65.4% for 2000-present. In this manner, our study provides further evidence to support the hypothesis that HPV-associated OPSCCs are driving the increasing incidence of OPSCC over time in the United States.
- Published
- 2014
- Full Text
- View/download PDF
33. Potential role of mesenchymal stromal cells in pancreatic islet transplantation.
- Author
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Hematti P, Kim J, Stein AP, and Kaufman D
- Subjects
- Humans, Islets of Langerhans Transplantation immunology, Diabetes Mellitus, Type 1 surgery, Islets of Langerhans Transplantation methods, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells cytology
- Abstract
Pancreatic islet transplantation is an attractive option for treatment of type 1 diabetes mellitus but maintaining long term islet function remains challenging. Mesenchymal stromal cells (MSCs), derived from bone marrow or other sources, are being extensively investigated in the clinical setting for their immunomodulatory and tissue regenerative properties. Indeed, MSCs have been already tested in some feasibility studies in the context of islet transplantation. MSCs could be utilized to improve engraftment of pancreatic islets by suppressing inflammatory damage and immune mediated rejection. In addition to their immunomodulatory effects, MSCs are known to provide a supportive microenvironmental niche by secreting paracrine factors and depositing extracellular matrix. These properties could be used for in vivo co-transplantation to improve islet engraftment, or for in vitro co-culture to prime freshly isolated islets prior to implantation. Further, tissue specific pancreatic islet derived MSCs may open new opportunities for its use in islet transplantation as those cells might be more physiological to pancreatic islets., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
34. Biologic and immunomodulatory properties of mesenchymal stromal cells derived from human pancreatic islets.
- Author
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Kim J, Breunig MJ, Escalante LE, Bhatia N, Denu RA, Dollar BA, Stein AP, Hanson SE, Naderi N, Radek J, Haughy D, Bloom DD, Assadi-Porter FM, and Hematti P
- Subjects
- Antigens, Surface analysis, Cadaver, Cell Differentiation, Cell Proliferation, Cells, Cultured, Flow Cytometry, Gene Expression, Humans, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Islets of Langerhans cytology, Islets of Langerhans immunology, Islets of Langerhans metabolism, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells immunology, Mesenchymal Stem Cells metabolism
- Abstract
Background Aims: Mesenchymal stromal cells (MSC) have now been shown to reside in numerous tissues throughout the body, including the pancreas. Ex vivo culture-expanded MSC derived from many tissues display important interactions with different types of immune cells in vitro and potentially play a significant role in tissue homeostasis in vivo. In this study, we investigated the biologic and immunomodulatory properties of human pancreatic islet-derived MSC., Methods: We culture-expanded MSC from cadaveric human pancreatic islets and characterized them using flow cytometry, differentiation assays and nuclear magnetic resonance-based metabolomics. We also investigated the immunologic properties of pancreatic islet-derived MSC compared with bone marrow (BM) MSC., Results: Pancreatic islet and BM-derived MSC expressed the same cell-surface markers by flow cytometry, and both could differentiate into bone, fat and cartilage. Metabolomics analysis of MSC from BM and pancreatic islets also showed a similar set of metabolic markers but quantitative polymerase chain reactions showed that pancreatic islet MSC expressed more interleukin(IL)-1b, IL-6, STAT3 and FGF9 compared with BM MSC, and less IL-10. However, similar to BM MSC, pancreatic islet MSC were able to suppress proliferation of allogeneic T lymphocytes stimulated with anti-CD3 and anti-CD28 antibodies., Conclusions: Our in vitro analysis shows pancreatic islet-derived MSC have phenotypic, biologic and immunomodulatory characteristics similar, but not identical, to BM-derived MSC. We propose that pancreatic islet-derived MSC could potentially play an important role in improving the outcome of pancreatic islet transplantation by promoting engraftment and creating a favorable immune environment for long-term survival of islet allografts.
- Published
- 2012
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35. Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain.
- Author
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Morse DC, Stein AP, Thomas PE, and Lowndes HE
- Subjects
- Animals, Arachnoid drug effects, Arachnoid enzymology, Blotting, Western, Brain drug effects, Dura Mater drug effects, Dura Mater enzymology, Enzyme Induction, Enzyme Inhibitors pharmacology, Male, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Rats, Rats, Sprague-Dawley, beta-Naphthoflavone pharmacology, Brain enzymology, Cytochrome P-450 CYP1A1 metabolism, Cytochrome P-450 CYP1A2 metabolism
- Abstract
Cytochromes P450 1A1 and 1A2 are involved in the oxidation of a wide spectrum of endogenous compounds and xenobiotics. Although their presence has been repeatedly confirmed in brain tissue, reports regarding their distribution in the brain are often contradictory. In the present study the possibility was examined that CYP1A1 and CYP1A2 are localized and inducible in the brain-CSF barrier and regions with a leaky blood brain barrier, where they may serve as a protective metabolic barrier. CYP1A1 and CYP1A2 levels were determined in subcellular fractions of multiple brain regions, as well as tissue homogenates of circumventricular organs, and the meninges by Western blotting and catalytic activity in control male rats and rats treated with the inducer beta-naphthoflavone (BNF). In control animals CYP1A1 immunoreactive protein was undetectable in regional brain microsomes or whole tissue homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, median eminence, and pituitary. However, low levels of ethoxyresorufin O-deethylase (EROD) activity were observed in homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, and pituitary. Western blotting revealed only low levels of CYP1A2 immunoreactive protein in brain microsomes from the cortex, cerebellum, brainstem, thalamus, hippocampus, and striatum from control animals. Following BNF treatment, EROD activity was induced 12-42-fold in the arachnoid, choroid plexus, dura mater, pineal gland, pituitary, and median eminence. Western blot analysis revealed CYP1A1 to be induced in the arachnoid, dura mater, choroid plexus, pineal gland, and pituitary, while CYP1A2 was undetectable. No induction of CYP1A1 or CYP1A2 protein was observed in brain microsomes from the olfactory bulb, cortex, striatum, hippocampus, cerebellum, or brainstem following BNF treatment, providing that the arachnoid membranes and choroid plexus had been carefully removed prior to brain dissection. Neither CYP1A1, 1A2 protein, nor EROD activity were detected in purified brain mitochondria, regardless of treatment or region. In conclusion, catalytically active CYP1A1 is located in the meninges as well as certain circumventricular organs, is inducible by BNF, and appears to be absent or expressed constitutively at very low levels in the majority of the brain parenchyma. The localization of CYP1A1 in the blood-CSF barrier and circumventricular tissues likely plays a role in protecting the brain from xenobiotics., (Copyright 1998 Academic Press.)
- Published
- 1998
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36. Effects of phenethyl isothiocyanate on acetaminophen metabolism and hepatotoxicity in mice.
- Author
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Li Y, Wang EJ, Chen L, Stein AP, Reuhl KR, and Yang CS
- Subjects
- Acetaminophen metabolism, Administration, Oral, Alanine Transaminase metabolism, Animals, Enzyme Inhibitors administration & dosage, Ethanol pharmacology, Fasting, Glutathione metabolism, Isothiocyanates administration & dosage, L-Lactate Dehydrogenase metabolism, Liver metabolism, Liver pathology, Liver Diseases blood, Liver Diseases pathology, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Survival Rate, Acetaminophen toxicity, Cytochrome P-450 CYP2E1 Inhibitors, Enzyme Inhibitors pharmacology, Isothiocyanates pharmacology, Liver drug effects, Liver Diseases prevention & control
- Abstract
Phenethyl isothiocyanate (PEITC), a compound derived from cruciferous and other vegetables, is a potent inhibitor of cytochrome P450 2E1. This enzyme catalyzes the bioactivation of acetaminophen (APAP) and many other xenobiotics. The present study investigated the effects of PEITC on APAP metabolism and associated hepatotoxicity in Swiss-Webster mice. When PEITC (19-150 micromol/kg) was given to mice intragastrically 1 hr before or immediately prior to a toxic dose of APAP, the APAP-induced hepatotoxicity was significantly decreased or was completely prevented. The extent of toxicity was evaluated by mortality, serum levels of glutamic-pyruvic transaminase, lactate dehydrogenase, and liver histopathology. Pretreatment of mice with ethanol enhanced APAP hepatotoxicity; this enhanced toxicity could also be prevented by the administration of PEITC. PEITC treatment prevented the depletion of hepatic glutathione levels caused by oxidized APAP metabolites. PEITC treatment also significantly decreased the plasma levels of oxidized APAP metabolites (analyzed as APAP-glutathione, APAP-cysteine, and APAP-N-acetylcysteine) and reduced the urinary excretion of APAP-cysteine. In microsomal incubations, PEITC effectively inhibited the rate of APAP-glutathione formation from APAP as well as the P450 2E1-dependent N-nitrosodimethylamine demethylase and the P450 1A2-dependent ethoxyresorufin O-deethylase activities. The protective action of PEITC against APAP toxicity is attributed to the blocking of APAP activation through inhibition of P450 enzymes.
- Published
- 1997
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- View/download PDF
37. Protective effects of garlic and related organosulfur compounds on acetaminophen-induced hepatotoxicity in mice.
- Author
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Wang EJ, Li Y, Lin M, Chen L, Stein AP, Reuhl KR, and Yang CS
- Subjects
- Acetaminophen administration & dosage, Acetaminophen urine, Alanine Transaminase blood, Analgesics, Non-Narcotic administration & dosage, Analgesics, Non-Narcotic urine, Animals, Antioxidants administration & dosage, Antioxidants pharmacology, Biotransformation, Cytochrome P-450 CYP2E1, Cytochrome P-450 Enzyme System metabolism, Dose-Response Relationship, Drug, Glutathione metabolism, L-Lactate Dehydrogenase blood, Liver enzymology, Liver pathology, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Oxidation-Reduction, Oxidoreductases, N-Demethylating metabolism, Plant Extracts pharmacology, Plant Oils administration & dosage, Plant Oils pharmacology, Sulfides pharmacology, Acetaminophen toxicity, Allyl Compounds, Analgesics, Non-Narcotic toxicity, Garlic metabolism, Liver drug effects, Plants, Medicinal, Sulfur pharmacology
- Abstract
In previous studies, we have demonstrated that diallyl sulfide, a flavor component of garlic, protects against chemically induced hepatotoxicity. The present study examined the activities of fresh garlic homogenates (FGH) and related organosulfur compounds in the protection against acetaminophen (APAP)-induced hepatotoxicity and the possible mechanisms involved in this protection. When FGH (5 g/kg) was administered to Swiss-Webster mice 2 hr prior to, or immediately after, an APAP treatment (0.2 g/kg), APAP-induced hepatotoxicity was essentially prevented as indicated by serum levels of alanine aminotransferase and lactate dehydrogenase and by liver histopathology. Partial protection was observed with a lower dose of FGH (0.5 g/kg). FGH also prevented APAP-induced hepatic glutathione depletion in a dose-dependent manner. FGH significantly inhibited the formation of APAP-oxidized metabolites, as indicated by decreased plasma levels of oxidized APAP metabolites. The amount of APAP excreted as oxidized metabolites in the 24 hr urine samples was also significantly lower in the mice pretreated with FGH. FGH supernatant inhibited cytochrome P450-dependent APAP oxidation in microsomal incubations. The results suggest that the protection against APAP-induced hepatotoxicity by FGH is mainly due to its inhibition of P450-mediated APAP bioactivation. Several garlic-derived organosulfur compounds and structurally related compounds were examined for their abilities to protect against APAP-induced hepatotoxicity. An S-allyl structure appears to be a common feature for most sulfides to inhibit P450 2E1-dependent activity and to display good protective activities.
- Published
- 1996
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- View/download PDF
38. N-cadherin in normal and abnormal brain development.
- Author
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Lagunowich LA, Stein AP, and Reuhl KR
- Subjects
- Animals, Brain drug effects, Brain Chemistry drug effects, Cadherins isolation & purification, Calcium pharmacology, Cell Adhesion drug effects, Cells, Cultured, Chick Embryo, Electrophoresis, Polyacrylamide Gel, Lead toxicity, Retina cytology, Brain growth & development, Brain Chemistry physiology, Brain Diseases metabolism, Cadherins metabolism
- Abstract
The brain relies upon numerous morphoregulatory molecules to control cell-cell interactions, cell migration and neurite extension. N-cadherin, a calcium-dependent cell adhesion molecule, is essential for normal CNS development. Homophilic binding of N-cadherin depends upon a specific conformation assumed by the molecule when it binds calcium. N-cadherin is a substrate for a specific zinc-dependent protease that may be involved in the regulation of N-cadherin at the cell surface. The reliance of N-cadherin on two cations for proper function makes it a potential target for toxicants which act by replacing or modifying calcium or zinc at ion-binding sites. Exposure of the developing brain to lead, an ubiquitous toxicant known to interact with calcium, disturbs neural tube closure and subsequent maturation of the nervous system. Preliminary data indicates that lead may induce these effects by direct interaction with N-cadherin. Numerous common toxicants, including metals and solvents, also perturb cadherins and cause defective CNS development. These data indicate that changes in the spatio-temporal expression of cadherin can result in profound alterations in neural structure and function, and may underlie CNS malformations caused by numerous toxic agents.
- Published
- 1994
39. Tips on outreach programs that involve and educate.
- Author
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Stein AP and Deichman ES
- Subjects
- Adolescent, Aged, Child, Preschool, Humans, New York, Interpersonal Relations, Nursing Homes, Recreation, Students
- Published
- 1987
40. Developing the potentials of the elderly: a publishing dream.
- Author
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Stein AP
- Subjects
- Aged, Humans, New York, Leisure Activities, Nursing Homes, Publishing
- Published
- 1987
41. Nursing implication of toxic shock syndrome.
- Author
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Stein AP and Baughman DC
- Subjects
- Adolescent, Adult, Child, Female, Humans, Male, Shock, Septic etiology, Staphylococcal Infections, Syndrome, Tampons, Surgical, Menstruation, Shock, Septic nursing
- Published
- 1981
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