68 results on '"Brooks RB"'
Search Results
2. Sewage Treatment by the Sirofloc Process
- Author
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Chemeca 92 (20th : 1992 : Canberra, A.C.T.), Brooks, RB, and Twining, DJ
- Published
- 1992
3. Energy from Biomass
- Author
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Prince, RGH, Barford, JP, Barrett, D, Brooks, RB, Gorrie, I, Greenfield, PF, Keniry, JS, Kirby, KD, Lane, AG, Prince, IG, Ralph, BJ, Rickard, PAD, Stewart, GA, and Wonder, B
- Published
- 1983
4. The Biotechnological Revolution - How Important for Us?
- Author
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Chemeca 83 (11th : 1983 : Brisbane, Qld.), Greenfield, PF, and Brooks, RB
- Published
- 1983
5. Closing Gaps or Holding Steady? The Affordable Care Act, Medicaid Expansion, & Racial Disparities in Coverage, 2010-2021.
- Author
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Sommers BD, Smith RB, and Figueroa JF
- Abstract
Context: The Affordable Care Act's (ACA) Medicaid expansion produced major gains in coverage. However, findings on racial and ethnic disparities are mixed and may depend on how disparities are measured. This study examines both absolute and relative changes in uninsurance from 2010-2021 by race and ethnicity, stratified by Medicaid expansion status., Methods: The sample contained all respondents under age 65 (N = 30,339,104) from the American Community Survey, 2010-2021. Absolute and relative differences in uninsurance, compared to White Non-Hispanic individuals, were calculated for Hispanic; Black; Asian-American, Pacific Islander and Native Hawaiian (AANHPI); American Indian and Alaska Native (AIAN); and multiracial individuals. States were stratified into ever-expanded vs. non-expansion status., Findings: After the ACA, three patterns of coverage disparities emerge. For Hispanic and Black individuals, relative to White individuals, absolute disparities in uninsurance declined but relative disparities were largely unchanged, in both expansion and non-expansion states. For AANHPI individuals, disparities were eliminated entirely in both expansion and non-expansion states. For AIAN individuals, disparities declined in absolute terms but grew in relative terms, particularly in expansion states., Conclusions: All groups experienced coverage gains post-ACA, but with heterogeneity in changes in disparities. Focused interventions are needed to improve coverage rates for Black, Hispanic, and AIAN individuals., (Copyright © 2024 by Duke University Press.)
- Published
- 2024
- Full Text
- View/download PDF
6. Journal Production Guidance for Software and Data Citations.
- Author
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Stall S, Bilder G, Cannon M, Chue Hong N, Edmunds S, Erdmann CC, Evans M, Farmer R, Feeney P, Friedman M, Giampoala M, Hanson RB, Harrison M, Karaiskos D, Katz DS, Letizia V, Lizzi V, MacCallum C, Muench A, Perry K, Ratner H, Schindler U, Sedora B, Stockhause M, Townsend R, Yeston J, and Clark T
- Published
- 2023
- Full Text
- View/download PDF
7. Outcomes of cold snare piecemeal EMR for nonampullary small-bowel adenomas larger than 1 cm: a retrospective study.
- Author
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Dang DT, Suresh S, Vance RB, Singla S, Javia S, Watson A, Chathadi KV, Katukuri V, Pompa R, Stidham RW, Zuchelli T, and Piraka C
- Subjects
- Colonoscopy methods, Humans, Postoperative Complications etiology, Prospective Studies, Retrospective Studies, Adenoma etiology, Adenoma surgery, Colonic Polyps etiology, Duodenal Neoplasms etiology, Endoscopic Mucosal Resection methods
- Abstract
Background and Aims: Nonampullary small-bowel adenomas ≥10 mm are typically resected using cautery-based polypectomy, which is associated with significant adverse events. Studies have demonstrated the safety and efficacy of piecemeal cold snare EMR for removing large colon polyps. Our aim was to assess the safety and efficacy of cold snare EMR for removal of large adenomas in the small bowel., Methods: A retrospective study of patients who underwent lift and piecemeal cold snare EMR of small-bowel adenomas ≥1 cm between January 2014 and March 2019 was conducted at a tertiary care medical center. Polyp characteristics at the time of index and surveillance endoscopy were collected. Primary outcomes were residual or recurrent adenoma (RRA) seen on surveillance endoscopy, polyp eradication rate, and number of endoscopic procedures required for eradication. Adverse events including immediate and delayed bleeding, perforation, stricture, pancreatitis, and postpolypectomy syndrome were assessed., Results: Of 43 patients who underwent piecemeal cold snare EMR, 39 had follow-up endoscopy. Polyps ranged in size from 10 to 70 mm (mean, 26.5 mm). RRA was found in 18 patients (46%), with increased polyp size correlating with higher recurrence (P < .001). Polyp eradication was observed in 35 patients (89%), requiring a median of 2 (range, 1-6) endoscopic procedures. Only 1 patient (2.3%) had immediate postprocedural bleeding. No cases of perforation or postpolypectomy syndrome were seen., Conclusions: Piecemeal cold snare EMR may be a feasible, safe, and efficacious technique for small-bowel polyps >10 mm. Prospective, randomized studies are needed to assess how outcomes compare with traditional cautery-based polypectomy., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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8. Adverse Effects of Low-Dose Methotrexate.
- Author
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Robey RB and Block CA
- Subjects
- Humans, Methotrexate adverse effects, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Drug-Related Side Effects and Adverse Reactions
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- 2020
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9. CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies.
- Author
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Feng WW, Wilkins O, Bang S, Ung M, Li J, An J, Del Genio C, Canfield K, DiRenzo J, Wells W, Gaur A, Robey RB, Guo JY, Powles RL, Sotiriou C, Pusztai L, Febbraio M, Cheng C, Kinlaw WB, and Kurokawa M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, CD36 Antigens genetics, Cell Line, Tumor, Female, Humans, Lapatinib pharmacology, Lapatinib therapeutic use, Mice, Mice, Inbred NOD, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Breast Neoplasms metabolism, CD36 Antigens metabolism, Drug Resistance, Neoplasm, Fatty Acids metabolism, Receptor, ErbB-2 antagonists & inhibitors
- Abstract
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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10. Outbreak investigation of Pseudomonas aeruginosa infections in a neonatal intensive care unit.
- Author
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Weng MK, Brooks RB, Glowicz J, Keckler MS, Christensen BE, Tsai V, Mitchell CS, Wilson LE, Laxton R, Moulton-Meissner H, and Fagan R
- Subjects
- Cross Infection mortality, Female, Humans, Infant, Newborn, Infection Control methods, Intensive Care Units, Neonatal, Male, Pseudomonas Infections mortality, Cross Infection epidemiology, Disease Outbreaks, Drinking Water microbiology, Pseudomonas Infections epidemiology, Pseudomonas aeruginosa isolation & purification
- Abstract
A Pseudomonas aeruginosa outbreak was investigated in a neonatal intensive care unit that had experienced a prior similar outbreak. The 8 cases identified included 2 deaths. An investigation found the cause of the outbreak: tap water from contaminated hospital plumbing which was used for humidifier reservoirs, neonatal bathing, and nutritional preparation. Our findings reinforce a recent Centers for Medicare & Medicaid Services memo recommending increased attention to water management to improve awareness, identification, mitigation, and prevention of water-associated, health care-associated infections., (Published by Elsevier Inc.)
- Published
- 2019
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11. Candida auris in a U.S. Patient with Carbapenemase-Producing Organisms and Recent Hospitalization in Kenya.
- Author
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Brooks RB, Walters M, Forsberg K, Vaeth E, Woodworth K, and Vallabhaneni S
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- Humans, Kenya, United States, Bacterial Proteins biosynthesis, Candida isolation & purification, Candidiasis diagnosis, Hospitalization statistics & numerical data, beta-Lactamases biosynthesis
- Abstract
Candida auris is an emerging drug-resistant yeast that causes outbreaks in health care facilities; cases have been reported from approximately 30 countries. U.S. cases of C. auris are likely the result of importation from abroad followed by extensive local transmission in health care settings (1). Early detection of Candida auris is key to preventing its spread. C. auris frequently co-occurs with carbapenemase-producing organisms (CPOs), like carbapenem-resistant Enterobacteriaceae (CRE), organisms for which testing and public health response capacity substantially increased beginning in 2017. In September 2018, the Maryland Department of Health (MDH) was notified of a hospitalized resident with CPO infection and colonization and recent hospitalization in Kenya. In light of this history, the patient was screened for C. auris and found to be colonized. Public health responses to CPOs can aid in the early identification of C. auris. As part of CPO investigations, health departments should assess whether the patient has risk factors for C. auris and ensure that patients at risk are tested promptly., Competing Interests: All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.
- Published
- 2019
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12. Multistate Outbreak of Burkholderia cepacia Complex Bloodstream Infections After Exposure to Contaminated Saline Flush Syringes: United States, 2016-2017.
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Brooks RB, Mitchell PK, Miller JR, Vasquez AM, Havlicek J, Lee H, Quinn M, Adams E, Baker D, Greeley R, Ross K, Daskalaki I, Walrath J, Moulton-Meissner H, and Crist MB
- Subjects
- Aged, Bacteremia etiology, Burkholderia Infections epidemiology, Burkholderia cepacia complex genetics, Cross Infection epidemiology, Cross Infection microbiology, Electrophoresis, Gel, Pulsed-Field, Humans, Saline Solution, Skilled Nursing Facilities, United States, Bacteremia epidemiology, Burkholderia Infections etiology, Cross Infection etiology, Disease Outbreaks statistics & numerical data, Equipment Contamination, Syringes microbiology
- Abstract
Background: Burkholderia cepacia complex (Bcc) has caused healthcare-associated outbreaks, often in association with contaminated products. The identification of 4 Bcc bloodstream infections in patients residing at a single skilled nursing facility (SNF) within 1 week led to an epidemiological investigation to identify additional cases and the outbreak source., Methods: A case was initially defined via a blood culture yielding Bcc in a SNF resident receiving intravenous therapy after 1 August 2016. Multistate notifications were issued to identify additional cases. Public health authorities performed site visits at facilities with cases to conduct chart reviews and identify possible sources. Pulsed-field gel electrophoresis (PFGE) was performed on isolates from cases and suspect products. Facilities involved in manufacturing suspect products were inspected to assess possible root causes., Results: An outbreak of 162 Bcc bloodstream infections across 59 nursing facilities in 5 states occurred during September 2016-January 2017. Isolates from patients and pre-filled saline flush syringes were closely related by PFGE, identifying contaminated flushes as the outbreak source and prompting a nationwide recall. Inspections of facilities at the saline flush manufacturer identified deficiencies that might have led to the failure to sterilize a specific case containing a partial lot of the product., Conclusions: Communication and coordination among key stakeholders, including healthcare facilities, public health authorities, and state and federal agencies, led to the rapid identification of an outbreak source and likely prevented many additional infections. Effective processes to ensure the sterilization of injectable products are essential to prevent similar outbreaks in the future., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2019
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13. Completeness of HIV nucleotide sequence ascertainment and its potential impact on understanding HIV transmission - Maryland, 2011-2013 .
- Author
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Brooks RB, Feldman KA, Blythe D, and Flynn C
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- Adolescent, Adult, CD4 Lymphocyte Count, Female, HIV Infections epidemiology, HIV Infections transmission, HIV Infections virology, HIV-1 genetics, Humans, Male, Maryland, Middle Aged, Nucleotides, Odds Ratio, Anti-HIV Agents therapeutic use, Drug Resistance, Viral, HIV Infections drug therapy, HIV-1 drug effects, Mass Screening organization & administration, Population Surveillance
- Abstract
HIV nucleotide sequences generated through routine drug resistance testing (DRT) and reported to Maryland's Molecular HIV Surveillance system are most effective for elucidating transmission patterns and identifying outbreaks if DRT is ordered promptly and sequences are reported completely. Among reported cases of HIV infection newly diagnosed during 2011-2013 in Maryland residents aged ≥13 years, we assessed sequence ascertainment completeness. To better understand which populations were most likely to have a sequence, we examined associations between sequence ascertainment and clinical and demographic characteristics. During 2011-2013, 4423 new HIV infection diagnoses were reported; sequences were ascertained for 1282 (29.0%). Among 3267 cases with complete data, odds for having a sequence ascertained were highest for cases in persons living inside Maryland's Central Region with initial CD4 counts ≤500 cells/mm
3 (adjusted odds ratio [aOR] 2.4, 95% confidence interval [CI] 1.9-3.1). Sequence ascertainment did not vary significantly by patient age, sex, race/ethnicity or HIV transmission category. Educational interventions, policy changes and improved processes to increase timely DRT and subsequent sequence reporting with a focus on testing at entry to care, particularly for those with higher CD4 counts and those living outside the Central Region, might improve ascertainment completeness.- Published
- 2019
- Full Text
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14. Multistate Outbreak of an Emerging Burkholderia cepacia Complex Strain Associated With Contaminated Oral Liquid Docusate Sodium.
- Author
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Akinboyo IC, Sick-Samuels AC, Singeltary E, Fackler J, Ascenzi J, Carroll KC, Maldonado Y, Brooks RB, Benowitz I, Wilson LE, LiPuma JJ, and Milstone AM
- Subjects
- Burkholderia Infections epidemiology, Cross Infection epidemiology, Disease Outbreaks, Humans, Burkholderia cepacia complex, Dioctyl Sulfosuccinic Acid
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- 2018
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15. Perspectives from the Kidney Health Initiative on Advancing Technologies to Facilitate Remote Monitoring of Patient Self-Care in RRT.
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Rosner MH, Lew SQ, Conway P, Ehrlich J, Jarrin R, Patel UD, Rheuban K, Robey RB, Sikka N, Wallace E, Brophy P, and Sloand J
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- Cost Savings, Hemodialysis, Home, Humans, Insurance, Health, Reimbursement, Kidney Failure, Chronic economics, Kidney Failure, Chronic physiopathology, Monitoring, Physiologic instrumentation, Patient Acceptance of Health Care, Peritoneal Dialysis, Kidney Failure, Chronic therapy, Monitoring, Physiologic methods, Self Care, Telemedicine legislation & jurisprudence
- Abstract
Telehealth and remote monitoring of a patient's health status has become more commonplace in the last decade and has been applied to conditions such as heart failure, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease. Conversely, uptake of these technologies to help engender and support home RRTs has lagged. Although studies have looked at the role of telehealth in RRT, they are small and single-centered, and both outcome and cost-effectiveness data are needed to inform future decision making. Furthermore, alignment of payer and government (federal and state) regulations with telehealth procedures is needed along with a better understanding of the viewpoints of the various stakeholders in this process (patients, caregivers, clinicians, payers, dialysis organizations, and government regulators). Despite these barriers, telehealth has great potential to increase the acceptance of home dialysis, and improve outcomes and patient satisfaction while potentially decreasing costs. The Kidney Health Initiative convened a multidisciplinary workgroup to examine the current state of telehealth use in home RRTs as well as outline potential benefits and drawbacks, impediments to implementation, and key unanswered questions., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
- Full Text
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16. Gastric Ischemia as a Rare Cause of Hematemesis.
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Vance RB and Mayorga CA
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- 2017
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17. Chronic Kidney Disease Progression and Cardiovascular Outcomes Following Cardiac Catheterization-A Population-Controlled Study.
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Brown JR, Solomon RJ, Robey RB, Plomondon ME, Maddox TM, Marshall EJ, Nichols EL, Matheny ME, Tsai TT, Rumsfeld JS, Lee RE, and Sarnak MJ
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- Aged, Aged, 80 and over, Angina, Stable epidemiology, Angina, Stable surgery, Angina, Unstable epidemiology, Angina, Unstable surgery, Case-Control Studies, Contrast Media, Disease Progression, Female, Humans, Incidence, Kidney Failure, Chronic therapy, Likelihood Functions, Male, Middle Aged, Myocardial Infarction epidemiology, Myocardial Ischemia epidemiology, Non-ST Elevated Myocardial Infarction epidemiology, Non-ST Elevated Myocardial Infarction surgery, Proportional Hazards Models, Renal Dialysis statistics & numerical data, ST Elevation Myocardial Infarction epidemiology, ST Elevation Myocardial Infarction surgery, United States, United States Department of Veterans Affairs, Acute Kidney Injury epidemiology, Cardiac Catheterization, Kidney Failure, Chronic epidemiology, Mortality, Myocardial Ischemia surgery, Percutaneous Coronary Intervention, Postoperative Complications epidemiology, Registries, Renal Insufficiency, Chronic physiopathology
- Abstract
Background: Studies of kidney disease associated with cardiac catheterization typically rely on billing records rather than laboratory data. We examined the associations between percutaneous coronary interventions, acute kidney injury, and chronic kidney disease progression using comprehensive Veterans Affairs clinical and laboratory databases., Methods and Results: Patients undergoing percutaneous coronary interventions between 2005 and 2010 (N=24 405) were identified in the Veterans Affairs Clinical Assessment, Reporting, and Tracking registry and examined for associated acute kidney injury and chronic kidney disease development or progression relative to 24 405 matched population controls. Secondary outcomes analyzed included dialysis, acute myocardial infarction, and mortality. The incidence of chronic kidney disease progression following percutaneous coronary interventions complicated by acute kidney injury, following uncomplicated coronary interventions, and in matched controls were 28.66, 11.15, and 6.81 per 100 person-years, respectively. Percutaneous coronary intervention also increased the likelihood of chronic kidney disease progression in both the presence and absence of acute injury relative to controls in adjusted analyses (hazard ratio [HR], 5.02 [95% CI, 4.68-5.39]; and HR, 1.76 [95% CI, 1.70-1.86]). Among patients with estimated glomerular filtration rate <60 mL/min per 1.73 m
2 , acute kidney injury increased the likelihood of disease progression by 8-fold. Similar results were observed for all secondary outcomes., Conclusions: Acute kidney injury following percutaneous coronary intervention was associated with increased chronic kidney disease development and progression and mortality., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)- Published
- 2016
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18. Likely Sexual Transmission of Zika Virus from a Man with No Symptoms of Infection - Maryland, 2016.
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Brooks RB, Carlos MP, Myers RA, White MG, Bobo-Lenoci T, Aplan D, Blythe D, and Feldman KA
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- Antibodies, Viral isolation & purification, Asymptomatic Infections, Dominican Republic, Female, Humans, Immunoglobulin M blood, Male, Maryland, Travel, Unsafe Sex, Zika Virus immunology, Zika Virus isolation & purification, Sexually Transmitted Diseases, Viral, Zika Virus Infection diagnosis, Zika Virus Infection transmission
- Abstract
In June 2016, the Maryland Department of Health and Mental Hygiene (DHMH) was notified of a nonpregnant woman who sought treatment for a subjective fever and an itchy rash, which was described as maculopapular by her provider. Laboratory testing at the Maryland DHMH Laboratories Administration confirmed Zika virus infection. Case investigation revealed that the woman had not traveled to a region with ongoing transmission of Zika virus, but did have sexual contact with a male partner who had recently traveled to the Dominican Republic. The male partner reported exposure to mosquitoes while traveling, but no symptoms consistent with Zika virus infection either before or after returning to the United States. The woman reported no other sex partners during the 14 days before onset of her symptoms and no receipt of blood products or organ transplants.
- Published
- 2016
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19. How Do We Manage Gastric Intestinal Metaplasia? A Survey of Clinical Practice Trends for Gastrointestinal Endoscopists in the United States.
- Author
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Vance RB Jr, Kubiliun N, and Dunbar KB
- Subjects
- Data Collection, Early Detection of Cancer methods, Endoscopy, Gastrointestinal methods, Female, Gastrointestinal Neoplasms epidemiology, Humans, Male, Physicians, Precancerous Conditions epidemiology, Surveys and Questionnaires, United States epidemiology, Endoscopy standards, Endoscopy, Gastrointestinal standards, Gastrointestinal Neoplasms prevention & control, Precancerous Conditions diagnosis, Precancerous Conditions therapy
- Abstract
Background: Gastric intestinal metaplasia (GIM) is an accepted pathologic precursor to gastric adenocarcinoma (GAC). While surveillance of GIM in Europe and Asia is common, only limited recommendations related to endoscopic surveillance of GIM exist in the United States., Aim: To understand the clinical practice patterns of US gastroenterologists in the management and endoscopic surveillance of GIM., Methods: A 23 item survey was developed to explore endoscopists' opinions regarding the surveillance of GIM and knowledge of current guidelines. Eight clinical vignettes were developed to address specific clinical scenarios where endoscopic surveillance of GIM might be considered., Results: There were 227 respondents, with 60 % working primarily in the private sector and 40 % in academic medicine. While 68 % of the respondents refer to major society guidelines for guidance in patient management, almost 78 % of endoscopist responders believe that there are no specific US guidelines pertaining to surveillance of GIM. Only two-thirds of respondents believe that based on current data, patients at increased risk of GAC should be a part of an endoscopic surveillance program, while 15 % believe all patients with GIM should receive endoscopic surveillance. Respondents use a wide range of biopsy techniques and surveillance intervals for patients with GIM, with no consistent pattern of practice identified., Conclusions: There is variability in the knowledge and practice patterns of US endoscopists related to surveillance of gastric intestinal metaplasia. In the absence of detailed US GI society guidelines, many endoscopists perform surveillance endoscopy on patients with GIM using variable biopsy techniques and surveillance intervals.
- Published
- 2016
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20. Endoscopic options for treatment of dysplasia in Barrett's esophagus.
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Vance RB and Dunbar KB
- Abstract
Recent advances in the endoscopic treatment of dysplasia in Barrett's esophagus (BE) have allowed endoscopists to provide effective and durable eradication therapies. This review summarizes the available endoscopic eradication techniques for dysplasia in patients with BE including endoscopic mucosal resection, endoscopic submucosal dissection, photodynamic therapy, argon plasma coagulation, radiofrequency ablation and cryotherapy.
- Published
- 2015
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21. Designing a broad-spectrum integrative approach for cancer prevention and treatment.
- Author
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Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin ARMR, Amin A, Aquilano K, Arbiser J, Arreola A, Arzumanyan A, Ashraf SS, Azmi AS, Benencia F, Bhakta D, Bilsland A, Bishayee A, Blain SW, Block PB, Boosani CS, Carey TE, Carnero A, Carotenuto M, Casey SC, Chakrabarti M, Chaturvedi R, Chen GZ, Chen H, Chen S, Chen YC, Choi BK, Ciriolo MR, Coley HM, Collins AR, Connell M, Crawford S, Curran CS, Dabrosin C, Damia G, Dasgupta S, DeBerardinis RJ, Decker WK, Dhawan P, Diehl AME, Dong JT, Dou QP, Drew JE, Elkord E, El-Rayes B, Feitelson MA, Felsher DW, Ferguson LR, Fimognari C, Firestone GL, Frezza C, Fujii H, Fuster MM, Generali D, Georgakilas AG, Gieseler F, Gilbertson M, Green MF, Grue B, Guha G, Halicka D, Helferich WG, Heneberg P, Hentosh P, Hirschey MD, Hofseth LJ, Holcombe RF, Honoki K, Hsu HY, Huang GS, Jensen LD, Jiang WG, Jones LW, Karpowicz PA, Keith WN, Kerkar SP, Khan GN, Khatami M, Ko YH, Kucuk O, Kulathinal RJ, Kumar NB, Kwon BS, Le A, Lea MA, Lee HY, Lichtor T, Lin LT, Locasale JW, Lokeshwar BL, Longo VD, Lyssiotis CA, MacKenzie KL, Malhotra M, Marino M, Martinez-Chantar ML, Matheu A, Maxwell C, McDonnell E, Meeker AK, Mehrmohamadi M, Mehta K, Michelotti GA, Mohammad RM, Mohammed SI, Morre DJ, Muralidhar V, Muqbil I, Murphy MP, Nagaraju GP, Nahta R, Niccolai E, Nowsheen S, Panis C, Pantano F, Parslow VR, Pawelec G, Pedersen PL, Poore B, Poudyal D, Prakash S, Prince M, Raffaghello L, Rathmell JC, Rathmell WK, Ray SK, Reichrath J, Rezazadeh S, Ribatti D, Ricciardiello L, Robey RB, Rodier F, Rupasinghe HPV, Russo GL, Ryan EP, Samadi AK, Sanchez-Garcia I, Sanders AJ, Santini D, Sarkar M, Sasada T, Saxena NK, Shackelford RE, Shantha Kumara HMC, Sharma D, Shin DM, Sidransky D, Siegelin MD, Signori E, Singh N, Sivanand S, Sliva D, Smythe C, Spagnuolo C, Stafforini DM, Stagg J, Subbarayan PR, Sundin T, Talib WH, Thompson SK, Tran PT, Ungefroren H, Vander Heiden MG, Venkateswaran V, Vinay DS, Vlachostergios PJ, Wang Z, Wellen KE, Whelan RL, Yang ES, Yang H, Yang X, Yaswen P, Yedjou C, Yin X, Zhu J, and Zollo M
- Subjects
- Antineoplastic Agents, Phytogenic therapeutic use, Drug Resistance, Neoplasm genetics, Humans, Neoplasms genetics, Neoplasms pathology, Neoplasms prevention & control, Signal Transduction, Tumor Microenvironment genetics, Genetic Heterogeneity, Molecular Targeted Therapy, Neoplasms therapy, Precision Medicine
- Abstract
Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. Varenicline for smoking reduction prior to cessation.
- Author
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Robey RB, Block CA, and O'Rourke DJ
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- Female, Humans, Male, Benzazepines therapeutic use, Nicotinic Agonists therapeutic use, Quinoxalines therapeutic use, Smoking Cessation methods, Tobacco Use Disorder drug therapy
- Published
- 2015
- Full Text
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23. Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?
- Author
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Robey RB, Weisz J, Kuemmerle NB, Salzberg AC, Berg A, Brown DG, Kubik L, Palorini R, Al-Mulla F, Al-Temaimi R, Colacci A, Mondello C, Raju J, Woodrick J, Scovassi AI, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Hamid RA, Williams GP, Lowe L, Meyer J, Martin FL, Bisson WH, Chiaradonna F, and Ryan EP
- Subjects
- Animals, Humans, Neoplasms etiology, Carcinogenesis chemically induced, Carcinogenesis metabolism, Carcinogens, Environmental adverse effects, Environmental Exposure adverse effects, Neoplasms chemically induced, Neoplasms metabolism
- Abstract
Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested., (Published by Oxford University Press 2015.)
- Published
- 2015
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24. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.
- Author
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Goodson WH 3rd, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci A, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams G, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi AI, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP Sr, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D'Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar PK, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Sing Leung P, Nangia-Makker P, Cheng QS, Robey RB, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Abd Hamid R, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell WK, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, and Hu Z
- Subjects
- Animals, Humans, Carcinogenesis chemically induced, Carcinogens, Environmental adverse effects, Environmental Exposure adverse effects, Hazardous Substances adverse effects, Neoplasms chemically induced, Neoplasms etiology
- Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., (© The Author 2015. Published by Oxford University Press.)
- Published
- 2015
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25. Endoscopic repair of gastric perforation with an over-the-scope clip after endoscopic mucosal resection.
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Vance RB and Agrawal D
- Subjects
- Female, Gastric Mucosa surgery, Humans, Middle Aged, Adenocarcinoma surgery, Gastroscopy instrumentation, Intraoperative Complications therapy, Stomach injuries, Stomach Neoplasms surgery, Wound Closure Techniques instrumentation
- Published
- 2014
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26. Cyclical dehydration-induced renal injury and Mesoamerican nephropathy: as sweet by any other name?
- Author
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Robey RB
- Subjects
- Animals, Male, Dehydration enzymology, Fructokinases metabolism, Kidney injuries
- Abstract
Severe cyclical dehydration induces chronic renal injury in rodents. This effect is attenuated by global fructokinase deficiency, suggesting possible roles for fructokinase and fructose metabolism in mediating or promoting dehydration-induced injury. Clinical and pathological similarities between this injury model and endemic Mesoamerican nephropathy (MeN) have fueled speculation that dehydration-induced injury and MeN may share common mechanistic underpinnings involving fructokinase that can be targeted to mitigate disease development, progression, and/or severity.
- Published
- 2014
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27. Glass Microparticulate Ingestion: An Unusual and Difficult-to-Diagnose Cause of Chronic Abdominal Pain.
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Vance RB, Mühlbauer M, Dreesen EB, Bagnell CR Jr, Dent GA, Herfarth H, Jobin C, and Dellon ES
- Abstract
In the absence of overt structural abnormalities, the diagnostic approach to chronic abdominal pain can be challenging. Occupational particulate inhalation causing injury to an organ other than the lung is rare. We report a case of inadvertent glass microparticulate ingestion causing chronic abdominal pain with altered local and systemic inflammatory responses.
- Published
- 2014
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28. Changing the terminology of cancer.
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Robey RB
- Subjects
- Humans, Early Detection of Cancer, Neoplasms diagnosis
- Published
- 2014
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- View/download PDF
29. Peptides modeled on the RGG domain of AUF1/hnRNP-D regulate 3' UTR-dependent gene expression.
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Fellows A, Deng B, Mierke DF, Robey RB, and Nichols RC
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Heterogeneous Nuclear Ribonucleoprotein D0, Heterogeneous-Nuclear Ribonucleoprotein D genetics, Macrophages metabolism, Mice, Molecular Sequence Data, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Protein Structure, Tertiary genetics, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Gene Expression Regulation physiology, Heterogeneous-Nuclear Ribonucleoprotein D metabolism
- Abstract
Messenger RNA binding proteins control post-transcriptional gene expression of targeted mRNAs. The RGG (arginine-glycine-glycine) domain of the AUF1/hnRNP-D mRNA binding protein is a regulatory region that is essential for protein function. The AUF1-RGG peptide, modeled on the RGG domain of AUF1, represses expression of the macrophage cytokine, VEGF. This report expands studies on the AUF1-RGG peptide and evaluates the role of post-translational modifications of the AUF1 protein. Results show that a minimal 31-amino acid AUF1-RGG peptide that lacks poly-glutamine and nuclear localization motifs retains suppressive activity on a VEGF-3'UTR reporter. Arginine residues in RGG motifs may be methylated with resulting changes in protein function. Mass spectroscopy analysis was performed on AUF1 expressed in RAW-264.7 cells. In resting cells, arginines in the first and second RGG motifs are monomethylated. Following activation with lipopolysaccharide, the arginines are dimethylated. To evaluate if the arginine residues are essential for AUF1-RGG activity, the methylatable arginines in the AUF1-3RGG peptide were mutated to lysine or alanine. The R→K and R→A mutants lack activity. We also demonstrate that PI3K/AKT inhibitors reduce VEGF gene expression. Although immunoscreening of AUF1 suggests that LPS and PI3K inhibitors alter the phosphorylation status of AUF1-p37, mass spectroscopy results show that the p37 AUF1 isoform is not phosphorylated with or without lipopolysaccharide stimulation. In summary, arginines in the RGG domain of AUF1 are methylated, and AUF1-RGG peptides may be novel reagents that reduce macrophage activation in inflammation., (Published by Elsevier B.V.)
- Published
- 2013
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30. "Does sunscreen promote hypertension?" and other questions. Novel interactions between vitamin D and the renin-angiotensin axis. Focus on "The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system".
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Robey RB and Crane-Godreau MA
- Subjects
- Animals, Humans, Inflammation complications, Pandemics, Renin-Angiotensin System physiology, Vitamin D Deficiency epidemiology, Vitamin D Deficiency etiology
- Published
- 2013
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- View/download PDF
31. The prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis.
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Kim HP, Vance RB, Shaheen NJ, and Dellon ES
- Subjects
- Biopsy, Humans, Predictive Value of Tests, Sensitivity and Specificity, Endoscopy, Digestive System methods, Eosinophilic Esophagitis diagnosis, Eosinophilic Esophagitis pathology
- Abstract
Background & Aims: Endoscopic findings such as esophageal rings, strictures, narrow-caliber esophagus, linear furrows, white plaques, and pallor or decreased vasculature might indicate the presence of eosinophilic esophagitis (EoE). We aimed to determine the prevalence and diagnostic utility of endoscopic features of EoE., Methods: We conducted a systematic review and meta-analysis. PubMed, EMBASE, and gastrointestinal meeting abstracts were searched to identify studies that included more than 10 patients with EoE and reported endoscopic findings. Pooled prevalence, sensitivity, specificity, and predictive values were calculated using random- and mixed-effects models., Results: The search yielded 100 articles and abstracts on 4678 patients with EoE and 2742 without (controls). In subjects with EoE, the overall pooled prevalence was as follows: esophageal rings, 44%; strictures, 21%; narrow-caliber esophagus, 9%; linear furrows, 48%; white plaques, 27%; and pallor/decreased vasculature, 41%. Substantial heterogeneity existed among studies. Results from endoscopy examinations were normal in 17% of patients, but this number decreased to 7% when the analysis was limited to prospective studies (P < .05). Overall levels of sensitivity were modest, ranging from 15% to 48%, whereas levels of specificity were greater, ranging from 90% to 95%. Positive predictive values ranged from 51% to 73% and negative predictive values ranged from 74% to 84%., Conclusions: There is heterogeneity among studies in the reported prevalence of endoscopic findings in patients with EoE, but in prospective studies at least 1 abnormality was detected by endoscopy in 93% of patients. The operating characteristics of endoscopic findings alone are inadequate for diagnosis of EoE. Esophageal biopsy specimens should be obtained from all patients with clinical features of EoE, regardless of the endoscopic appearance of the esophagus., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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32. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease.
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Robey RB and O'Rourke DJ
- Subjects
- Humans, Cardiovascular Diseases mortality, Cardiovascular Diseases prevention & control, Hemorrhage chemically induced, Platelet Aggregation Inhibitors therapeutic use, Renal Insufficiency, Chronic complications
- Published
- 2012
- Full Text
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33. Was that last colonoscopy really negative? A surprising cause of rectal bleeding in a 75-year-old man.
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Vance RB, Duncan D, and Dellon ES
- Subjects
- Aged, Humans, Intestinal Polyps diagnosis, Male, Colonoscopy, Gastrointestinal Hemorrhage etiology, Gastrointestinal Neoplasms complications, Lymphoma, Mantle-Cell complications
- Published
- 2012
- Full Text
- View/download PDF
34. Potassium levels after acute myocardial infarction.
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Robey RB
- Subjects
- Female, Humans, Male, Hospital Mortality, Myocardial Infarction blood, Myocardial Infarction mortality, Potassium blood
- Published
- 2012
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- View/download PDF
35. AUF1/hnRNP D represses expression of VEGF in macrophages.
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Fellows A, Griffin ME, Petrella BL, Zhong L, Parvin-Nejad FP, Fava R, Morganelli P, Robey RB, and Nichols RC
- Subjects
- Animals, Bone Marrow Cells, Gene Expression Regulation, Heterogeneous Nuclear Ribonucleoprotein D0, Heterogeneous-Nuclear Ribonucleoprotein D biosynthesis, Methylation, Mice, Peptides metabolism, Protein Binding genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Deletion, Vascular Endothelial Growth Factor A biosynthesis, 3' Untranslated Regions, Heterogeneous-Nuclear Ribonucleoprotein D metabolism, Macrophages metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Vascular endothelial growth factor (VEGF) is a regulator of vascularization in development and is a key growth factor in tissue repair. In disease, VEGF contributes to vascularization of solid tumors and arthritic joints. This study examines the role of the mRNA-binding protein AUF1/heterogeneous nuclear ribonucleoprotein D (AUF1) in VEGF gene expression. We show that overexpression of AUF1 in mouse macrophage-like RAW-264.7 cells suppresses endogenous VEGF protein levels. To study 3' untranslated region (UTR)-mediated regulation, we introduced the 3' UTR of VEGF mRNA into a luciferase reporter gene. Coexpression of AUF1 represses VEGF-3' UTR reporter expression in RAW-264.7 cells and in mouse bone marrow-derived macrophages. The C-terminus of AUF1 contains arginine-glycine-glycine (RGG) repeat motifs that are dimethylated. Deletion of the RGG domain of AUF1 eliminated the repressive effects of AUF1. Surprisingly, expression of an AUF1-RGG peptide reduced endogenous VEGF protein levels and repressed VEGF-3' UTR reporter activity in RAW-264.7 cells. These findings demonstrate that AUF1 regulates VEGF expression, and this study identifies an RGG peptide that suppresses VEGF gene expression.
- Published
- 2012
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- View/download PDF
36. Complete thoracic myelocystocele: a rare benign spinal dysraphism with clinical significance.
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Carmody RB, Jane J Jr, Shaffrey ME, and Kaufman D
- Subjects
- Diagnosis, Differential, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Pregnancy, Spinal Cord pathology, Spinal Dysraphism diagnostic imaging, Spinal Dysraphism surgery, Ultrasonography, Prenatal, Meningomyelocele diagnosis, Spinal Dysraphism diagnosis, Thoracic Vertebrae diagnostic imaging
- Published
- 2012
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- View/download PDF
37. Anomalous origin of the right coronary artery with multiple coronary bicameral fistulae.
- Author
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Wilson RB, Schoepf UJ, Lee YS, and Bastarrika G
- Subjects
- Aged, Diagnosis, Differential, Female, Humans, Coronary Angiography methods, Coronary Vessel Anomalies diagnostic imaging, Fistula diagnostic imaging, Sinus of Valsalva abnormalities, Tomography, X-Ray Computed methods
- Abstract
Cardiac computed tomography surpasses the limitations of conventional coronary angiography and transthoracic echocardiography in determining the origin, course, and extent of coronary artery anomalies. This case report illustrates a rare combination of congenital coronary artery anomalies consisting of anomalous origin of the right coronary artery arising from the left sinus of Valsalva and multiple coronary bicameral fistulae.
- Published
- 2012
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38. Hexokinase: a novel sugar kinase coupled to renal epithelial cell survival.
- Author
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Robey RB
- Subjects
- Animals, Apoptosis, Cell Survival, Epithelial Cells pathology, Hexokinase genetics, Humans, Kidney Diseases pathology, Kidney Tubules, Proximal blood supply, Kidney Tubules, Proximal pathology, Mitochondrial Membranes pathology, Protein Transport, Reperfusion Injury pathology, Signal Transduction, Stress, Physiological, bcl-2-Associated X Protein metabolism, Epithelial Cells enzymology, Hexokinase metabolism, Kidney Diseases enzymology, Kidney Tubules, Proximal enzymology, Mitochondrial Membranes enzymology, Reperfusion Injury enzymology
- Abstract
Hexokinases have emerged as novel mediators of the antiapoptotic effects of growth factors in a wide variety of cells. These effects have been attributed to highly regulated direct physical and functional interactions with mitochondria. The demonstration that mitochondrial hexokinases can prevent apoptogenic 'Bax attack' in proximal tubule cells suggests a need to reexamine the specific contributions of hexokinases and glucose metabolism in this nephron segment and elsewhere within the kidney.
- Published
- 2011
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39. Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats.
- Author
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Carroll RE, Goodlad RA, Poole AJ, Tyner AL, Robey RB, Swanson SM, and Unterman TG
- Subjects
- Animals, Apoptosis, Colonic Neoplasms pathology, Disease Susceptibility, Growth Hormone metabolism, Male, Rats, Rats, Sprague-Dawley, Azoxymethane toxicity, Carcinogens toxicity, Colon pathology, Colonic Neoplasms chemically induced, Growth Hormone genetics
- Abstract
Objectives: To evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM)., Design: ACF were quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromodeoxyuridine (BrdU) incorporation. Apoptosis was measured by TUNEL staining and cleaved caspase-3 immunohistochemistry. IGF-I was measured by radioimmunoassay (RIA). Hexokinase activity was measured by spectrophotometric assay. PARP cleavage, and IGF-IR, and p27(kip/cip) expression were measured by Western blotting., Results: ACFs detected by stereomicroscopy were markedly reduced ( approximately 85%) in SDRs vs. WT rats at 10, 25, and 28 weeks after AOM. Tumor incidence, number, and weight also were reduced in SDR vs. WT animals. AOM treatment increased cell proliferation in the distal colon (where tumors occur) of WT rats but not SDRs, and these changes corresponded to increased ACF and tumor formation. Apoptosis rates were similar in AOM-treated WT and SDRs. Alterations in serum IGF-I levels may contribute to differences in the proliferative response to AOM and decreased ACF formation in SDR vs. WT rats., Conclusions: We conclude that early neoplastic lesions (ACFs) were reduced in GH-deficient animals. This effect corresponds with differences in AOM-induced proliferation, but not apoptosis. These data indicate that GH is required for the full effect of AOM on colon ACF and tumor development, and that the SDR rat is a promising model for studies regarding the role of GH/IGF system in the initiation and promotion of colon cancer.
- Published
- 2009
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- View/download PDF
40. mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3beta inhibition.
- Author
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Bhaskar PT, Nogueira V, Patra KC, Jeon SM, Park Y, Robey RB, and Hay N
- Subjects
- Animals, Embryo, Mammalian cytology, Enzyme Activation drug effects, Eukaryotic Initiation Factor-4E metabolism, Fibroblasts cytology, Fibroblasts drug effects, Fibroblasts enzymology, Glycogen Synthase Kinase 3 beta, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Intercellular Signaling Peptides and Proteins deficiency, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation drug effects, Proteins, Proto-Oncogene Proteins c-akt metabolism, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Transcription Factors antagonists & inhibitors, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins deficiency, Tumor Suppressor Proteins metabolism, bcl-Associated Death Protein metabolism, Apoptosis drug effects, Glucose Transporter Type 1 metabolism, Glycogen Synthase Kinase 3 antagonists & inhibitors, Hexokinase metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Serum metabolism, Transcription Factors metabolism
- Abstract
The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1alpha (HIF1alpha) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1alpha abundance in these cells is attributed to both an increased level and the sustained translation of HIF1alpha mRNA. Sustained glycogen synthase kinase 3beta inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1alpha abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2(-/)(-) cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2(-/)(-) cells to serum deprivation-induced apoptosis.
- Published
- 2009
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41. A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration.
- Author
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Rohrer B, Long Q, Coughlin B, Wilson RB, Huang Y, Qiao F, Tang PH, Kunchithapautham K, Gilkeson GS, and Tomlinson S
- Subjects
- Animals, Choroid metabolism, Choroidal Neovascularization physiopathology, Complement Activation drug effects, Complement C3 antagonists & inhibitors, Complement C3 genetics, Complement Factor H antagonists & inhibitors, Complement Pathway, Alternative immunology, Electroretinography, Female, Fluorescent Antibody Technique, Indirect, Infusions, Intravenous, Macular Degeneration physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger metabolism, Recombinant Fusion Proteins pharmacokinetics, Retina physiopathology, Retinal Pigment Epithelium metabolism, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A genetics, Choroidal Neovascularization drug therapy, Complement Pathway, Alternative drug effects, Disease Models, Animal, Macular Degeneration drug therapy, Recombinant Fusion Proteins administration & dosage
- Abstract
Purpose: Polymorphisms in factor H (fH), an inhibitor of the alternative pathway (AP) of complement activation, are associated with increased risk for age-related macular degeneration (AMD). The authors investigated the therapeutic use of a novel recombinant form of fH, CR2-fH, which is targeted to sites of complement activation, in mouse choroidal neovascularization (CNV). CR2-fH consists of the N terminus of mouse fH, which contains the AP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products., Methods: Laser-induced CNV was analyzed in factor-B-deficient mice or in mice treated with CR2-fH, soluble CR2 (targeting domain), or PBS. CNV progression was analyzed by molecular, histologic, and electrophysiological readouts., Results: Intravenously administered CR2-fH reduced CNV size, preserved retina function, and abrogated the injury-associated expression of C3 and VEGF mRNA. CR2 and PBS treatment was without effect. In therapeutically relevant paradigms involving delayed treatment after injury, CR2-fH was effective in reducing CNV and provided approximately 60% of the amount of protection of that seen in factor B-deficient mice that lacked functional AP. After intravenous injection, CR2-fH localized to sites of C3 deposition in RPE-choroid., Conclusions: Specific inhibition of the AP reduces angiogenesis in mouse CNV. Of note, intravenous injection of C3d-targeted CR2-fH is protective even though endogenous fH is present in serum at a higher relative concentration, and serum fH contains native C3d and cell surface binding domains that target it to cell surfaces. The most common AMD-associated variant of fH resides within a native cell-binding region of fH (Tyr402His). These data may open new avenues for AMD treatment strategies.
- Published
- 2009
- Full Text
- View/download PDF
42. Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis.
- Author
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Robey RB and Hay N
- Subjects
- Animals, Humans, Mitochondria enzymology, Mitochondria metabolism, Neoplasms metabolism, Adenosine Triphosphate metabolism, Energy Metabolism physiology, Glycolysis physiology, Neoplasms enzymology, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism
- Abstract
The serine/threonine kinase Akt - also known as protein kinase B (PKB) - has emerged as one of the most frequently activated protein kinases in human cancer. In fact, most, if not all, tumors ultimately find a way to activate this important kinase. As such, Akt activation constitutes a hallmark of most cancer cells, and such ubiquity presumably connotes important roles in tumor genesis and/or progression. Likewise, the hypermetabolic nature of cancer cells and their increased reliance on "aerobic glycolysis", as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. In this review, we address the specific contributions of Akt activation to the signature metabolic features of cancer cells, including the so-called "Warburg effect".
- Published
- 2009
- Full Text
- View/download PDF
43. Does furosemide have a role in the management of hypercalcemia?
- Author
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Robey RB, Lash JP, and Arruda JA
- Subjects
- Diphosphonates therapeutic use, Drug Therapy, Combination, Humans, Furosemide therapeutic use, Hypercalcemia drug therapy, Sodium Potassium Chloride Symporter Inhibitors therapeutic use
- Published
- 2009
- Full Text
- View/download PDF
44. Antialiasing procedural shaders with reduction maps.
- Author
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Van Horn RB 3rd and Turk G
- Subjects
- Algorithms, Artificial Intelligence, Lighting methods, Pattern Recognition, Automated methods, Sample Size, Artifacts, Colorimetry methods, Computer Graphics, Image Enhancement methods, Image Interpretation, Computer-Assisted methods, Imaging, Three-Dimensional methods, Signal Processing, Computer-Assisted
- Abstract
Both image textures and procedural textures suffer from minification aliasing, however, unlike image textures, there is no good automatic method to anti-alias procedural textures. Given a procedural texture on a surface, we present a method that automatically creates an anti-aliased version of the procedural texture. The new procedural texture maintains the original texture's details, but reduces minification aliasing artifacts. This new algorithm creates a pyramid similar to MIP-Maps to represent the texture. Instead of storing per-texel color, our texture hierarchy stores weighted sums of reflectance functions, allowing a wider range of effects to be anti-aliased. The stored reflectance functions are automatically selected based on an analysis of the different reflectances found over the surface. When the texture is viewed at close range, the original texture is used, but as the texture footprint grows, the algorithm gradually replaces the texture's result with an anti-aliased one.
- Published
- 2008
- Full Text
- View/download PDF
45. Paradoxical role of BDNF: BDNF+/- retinas are protected against light damage-mediated stress.
- Author
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Wilson RB, Kunchithapautham K, and Rohrer B
- Subjects
- Animals, Cell Survival, Ciliary Neurotrophic Factor genetics, Electroretinography, Female, Glial Cell Line-Derived Neurotrophic Factor genetics, Glutathione Peroxidase metabolism, In Situ Nick-End Labeling, Light adverse effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Growth Factors genetics, RNA, Messenger metabolism, Radiation Injuries, Experimental metabolism, Radiation Injuries, Experimental pathology, Retinal Degeneration metabolism, Retinal Degeneration pathology, Reverse Transcriptase Polymerase Chain Reaction, Brain-Derived Neurotrophic Factor physiology, Oxidative Stress, Radiation Injuries, Experimental prevention & control, Retina radiation effects, Retinal Degeneration prevention & control
- Abstract
Purpose: Photoreceptors can be prevented from undergoing apoptosis in response to constant light by the application of exogenous neuroprotective agents, including brain-derived neurotrophic factor (BDNF). BDNF, however, cannot exert its effect directly on photoreceptors because they do not express receptors for BDNF. It has been proposed that BDNF released from Müller cells provides a feed-forward loop, increasing ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) production in Müller cells, which may enhance photoreceptor survival. The authors hypothesized that retinas with reduced BDNF levels in which the BDNF-mediated release of neuroprotective signals is dampened are more susceptible to light-induced photoreceptor degeneration., Methods: Young adult BDNF+/+ and BDNF+/- littermates (B6.129-BDNF(tm1-LT)) were analyzed. Retinal neurotrophin and growth factor mRNA levels were determined by quantitative RT-PCR, photoreceptor function was assessed through electroretinography, and survival was documented in morphologic sections and in TUNEL assays. Oxidative stress was assayed by measuring glutathione peroxidase activity., Results: At baseline, BDNF+/- animals had significantly increased levels of glial-derived neurotrophic factor (GDNF) mRNA compared with their wild-type littermates. After light damage GDNF, CNTF, and BDNF mRNA levels dropped 14- to 16-fold in the BDNF+/+ mice but remained almost unchanged compared with baseline levels in the BDNF+/- mice. Preservation of neurotrophin levels in BDNF+/- mice correlated with photoreceptor cell survival, preservation of function, and reduced oxidative stress., Conclusions: Contrary to the hypothesis, reducing BDNF levels resulted in photoreceptor protection against light damage. Survival was paralleled by a reduction in oxidative stress and the preservation of neurotrophin levels, suggesting that chronic reduction of BDNF in the retina provides a level of preconditioning against stress.
- Published
- 2007
- Full Text
- View/download PDF
46. Functional polymorphism of the Anpep gene increases promoter activity in the Dahl salt-resistant rat.
- Author
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Kotlo K, Hughes DE, Herrera VL, Ruiz-Opazo N, Costa RH, Robey RB, and Danziger RS
- Subjects
- Animals, CCAAT-Enhancer-Binding Protein-alpha genetics, Disease Models, Animal, Male, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Promoter Regions, Genetic genetics, Rats, Rats, Inbred Dahl, Rats, Inbred Lew, CD13 Antigens genetics, Hypertension genetics
- Abstract
We have reported that aminopeptidase N/CD13, which metabolizes angiotensin III to angiotensin IV, exhibits greater renal tubular expression in the Dahl salt-resistant (SR/Jr) rat than its salt-sensitive (SS/Jr) counterpart. In this work, aminopeptidase N (Anpep) genes from SS/Jr and SR/Jr strains were compared. The coding regions contained only silent single nucleotide polymorphisms between strains. The 5' flanking regions also contained multiple single nucleotide polymorphisms, which were analyzed by electrophoretic mobility-shift assay using renal epithelial cell (HK-2) nuclear extracts and oligonucleotides corresponding with single nucleotide polymorphism-containing regions. A unique single nucleotide polymorphism 4 nucleotides upstream of a putative CCAAT/enhancer binding protein motif (nucleotides -2256 to -2267) in the 5' flanking region of the SR/Jr Anpep gene was associated with DNA-protein complex formation, whereas the corresponding sequences in SS rats were not. A chimeric reporter gene containing approximately 4.4 Kb of Anpep 5' flank from the Dahl SR/Jr rat exhibited 2.5- to 3-fold greater expression in HK-2 cells than the corresponding construct derived from the SS strain (P<0.05). Replacing the CCAAT/enhancer binding protein cis-acting element from the SS rat with that from the SR strain increased reporter gene expression by 2.5-fold (P<0.05) and abolished this difference. CCAAT/enhancer binding protein association was confirmed by chromatin immunoprecipitation and correlated with expression, suggesting selection for a functional CCAAT/enhancer binding protein polymorphism in the 5' flank of Anpep in the Dahl SR/Jr rat. These results highlight a possible association of the Anpep gene with hypertension in Dahl rat and raise the prospect that increased Anpep may play a mechanistic role in adaptation to high salt.
- Published
- 2007
- Full Text
- View/download PDF
47. Mitochondrial hexokinases: guardians of the mitochondria.
- Author
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Robey RB and Hay N
- Subjects
- Animals, Biological Evolution, Cell Survival, Energy Metabolism, Gene Expression Regulation, Enzymologic, Glucose metabolism, Hexokinase genetics, Humans, Models, Biological, Apoptosis, Hexokinase physiology, Homeostasis, Mitochondria enzymology, Mitochondria physiology, Proto-Oncogene Proteins c-akt physiology
- Abstract
There is accumulating evidence that cell survival and energy metabolism are inexorably linked. As a major mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt (also known as protein kinase B or PKB) is particularly well-suited to coordinate the regulation of these interrelated processes. Recent demonstrations that growth factors and Akt require glucose (Glc) to prevent apoptosis and promote cell survival are compatible with this contention, as is a positive correlation between Akt-regulated mitochondrial hexokinase (mtHK) association and apoptotic resistance. From a phylogenetic perspective, the ability of Akt to regulate cellular energy metabolism apparently preceded the capacity to control cell survival, suggesting an evolutionary basis for the Glc dependent anti-apoptotic effects of Akt. We speculate that, somewhere in the course of evolution, the metabolic regulatory function of Akt evolved into an adaptive sensing system involving mtHK that ensures mitochondrial homeostasis, thereby coupling metabolism to cell survival. We also propose that this "guardian" function of mtHK may be specifically exploited for therapeutic purposes.
- Published
- 2005
- Full Text
- View/download PDF
48. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak.
- Author
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Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, and Hay N
- Subjects
- Animals, Binding, Competitive, Cell Line, Cell Proliferation, Cells, Cultured, Clotrimazole pharmacology, Cytochromes c metabolism, Dose-Response Relationship, Drug, Fibroblasts metabolism, Gene Transfer Techniques, Growth Inhibitors pharmacology, Growth Substances metabolism, Immunoblotting, In Situ Nick-End Labeling, Intracellular Membranes metabolism, Membrane Potentials, Mice, Microscopy, Fluorescence, Phosphocreatine metabolism, Protein Binding, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Thapsigargin pharmacology, Time Factors, Ultraviolet Rays, Apoptosis, Hexokinase chemistry, Mitochondria metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism
- Abstract
The serine/threonine kinase Akt inhibits mitochondrial cytochrome c release and apoptosis induced by a variety of proapoptotic stimuli. The antiapoptotic activity of Akt is coupled, at least in part, to its effects on cellular metabolism. Here, we provide genetic evidence that Akt is required to maintain hexokinase association with mitochondria. Targeted disruption of this association impairs the ability of growth factors and Akt to inhibit cytochrome c release and apoptosis. Targeted disruption of mitochondria-hexokinase (HK) interaction or exposure to proapoptotic stimuli that promote rapid dissociation of hexokinase from mitochondria potently induce cytochrome c release and apoptosis, even in the absence of Bax and Bak. These effects are inhibited by activated Akt, but not by Bcl-2, implying that changes in outer mitochondrial membrane (OMM) permeability leading to apoptosis can occur in the absence of Bax and Bak and that Akt inhibits these changes through maintenance of hexokinase association with mitochondria.
- Published
- 2004
- Full Text
- View/download PDF
49. Proinflammatory interleukin-1 cytokines increase mesangial cell hexokinase activity and hexokinase II isoform abundance.
- Author
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Taneja N, Coy PE, Lee I, Bryson JM, and Robey RB
- Subjects
- Animals, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Glomerular Mesangium cytology, Glucose metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System physiology, Mice, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Receptors, Interleukin-1 antagonists & inhibitors, Receptors, Interleukin-1 metabolism, Glomerular Mesangium enzymology, Hexokinase metabolism, Interleukin-1 pharmacology, Isoenzymes metabolism
- Abstract
Mesangial cell hexokinase (HK) activity is increased by a diverse array of factors that share both an association with pathological conditions and a common requirement for classic MAPK pathway activation. To better understand the relationship between glucose (Glc) metabolism and injury and to indirectly test the hypothesis that these changes constitute a general adaptive response to insult, we have sought to identify and characterize injury-associated factors that couple to mesangial cell HK regulation. Proinflammatory interleukin-1 (IL-1) cytokines activate the MAPK pathway and have known salutary effects in this cell type. We therefore examined their ability to influence mesangial cell HK activity, Glc utilization, MAPK pathway activation, and individual HK isoform abundance. IL-1beta increased HK activity in both a time- and concentration-dependent manner: activity increased maximally by approximately 50% between 12 and 24 h with an apparent EC(50) of 3 pM. IL-1alpha mimicked, but did not augment, the effects of IL-1beta. Specific IL-1 receptor antagonism and selective MAPK/ERK kinase or upstream Ras inhibition prevented these increases, whereas PKC inhibition did not. Changes in HK activity were associated with both increased Glc metabolism and selective increases in HKII isoform abundance. We conclude that IL-1 cytokines can regulate cellular Glc phosphorylating capacity via an IL-1 receptor-, Ras-, and classic MAPK pathway-mediated increase in HKII abundance. These findings suggest a novel, previously undescribed mechanism whereby metabolism may be coupled to inflammation and injury.
- Published
- 2004
- Full Text
- View/download PDF
50. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines.
- Author
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Tice AD, Rehm SJ, Dalovisio JR, Bradley JS, Martinelli LP, Graham DR, Gainer RB, Kunkel MJ, Yancey RW, and Williams DN
- Subjects
- Adult, Child, Drug Monitoring, Home Care Services, Humans, Infusions, Intravenous, Outcome Assessment, Health Care, Outpatients, Patient Care Team, Patient Selection, Pediatrics standards, Anti-Bacterial Agents administration & dosage, Home Infusion Therapy standards
- Published
- 2004
- Full Text
- View/download PDF
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