Author: "Michael Khan" / Search Limiters: Available in Library Collection - Searchworks@Jio Institute Digital Library Search Results

39 results on '"Michael Khan"'

1. Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation

Author: Brian Yu, Sung Jun Ma, Michael Khan, Jasmin Gill, Austin Iovoli, Fatemeh Fekrmandi, Mark K. Farrugia, Kimberly Wooten, Vishal Gupta, Ryan McSpadden, Moni A. Kuriakose, Michael R. Markiewicz, Ayham Al-Afif, Wesley L. Hicks, Mukund Seshadri, Andrew D. Ray, Elizabeth A. Repasky, and Anurag K. Singh
Subjects: LMR, Lymphocyte, Monocyte, chemoRT, HN cancer, HPV, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. Methods A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan–Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. Results A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8–74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82–0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72–0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12–2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08–2.63, p = 0.02). Conclusion Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.
Published: 2023
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2. Activity patterns are associated with fractional lifespan, memory, and gait speed in aged dogs

Author: Alejandra Mondino, Michael Khan, Beth Case, Sara Giovagnoli, Andrea Thomson, B. Duncan X. Lascelles, Margaret Gruen, and Natasha Olby
Subjects: Medicine, Science
Abstract: Abstract Maintaining an active lifestyle is considered a hallmark of successful aging. Physical activity significantly reduces the risk of cognitive decline and Alzheimer’s disease in humans. However, pain and lack of motivation are important barriers to exercise. Dogs are a remarkable model for translational studies in aging and cognition as they are prone to Canine Cognitive Dysfunction syndrome, which has many similarities with Alzheimer’s disease. According to owner reports, changes in activity levels are characteristic of this syndrome, with decreased daytime activity, but also excessive pacing, especially at sleep time. We used physical activity monitors to record the activity of 27 senior dogs and evaluated the association between activity level and age, fractional lifespan, cognitive status measured by an owner questionnaire and cognitive tests. We also assessed the relationship between activity and joint/spinal pain, and the off/on leash gait speed ratio (a potential marker of gait speed reserve and motivation). We found that activity patterns in dogs are associated with fractional lifespan and working memory. Additionally, dogs with higher on/off leash gait speed are more active in the afternoon of weekdays. These results encourage future studies evaluating how physical activity can improve or delay cognitive impairment in senior dogs.
Published: 2023
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3. Winning the race with aging: age-related changes in gait speed and its association with cognitive performance in dogs

Author: Alejandra Mondino, Michael Khan, Beth Case, Gilad Fefer, Wojciech K. Panek, Margaret E. Gruen, and Natasha J. Olby
Subjects: canine cognitive dysfunction syndrome, canine gerontology, mobility, walking speed, memory, attention, Veterinary medicine, SF600-1100
Abstract: IntroductionIn humans, gait speed is a crucial component in geriatric evaluation since decreasing speed can be a harbinger of cognitive decline and dementia. Aging companion dogs can suffer from age-related mobility impairment, cognitive decline and dementia known as canine cognitive dysfunction syndrome. We hypothesized that there would be an association between gait speed and cognition in aging dogs.MethodsWe measured gait speed on and off leash in 46 adult and 49 senior dogs. Cognitive performance in senior dogs was assessed by means of the Canine Dementia Scale and a battery of cognitive tests.ResultsWe demonstrated that dogs' food-motivated gait speed off leash is correlated with fractional lifespan and cognitive performance in dogs, particularly in the domains of attention and working memory.DiscussionFood-motivated gait speed off leash represents a relatively easy variable to measure in clinical settings. Moreover, it proves to be a more effective indicator of age-related deterioration and cognitive decline than gait speed on leash.
Published: 2023
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4. Sleep and cognition in aging dogs. A polysomnographic study

Author: Alejandra Mondino, Magaly Catanzariti, Diego Martin Mateos, Michael Khan, Claire Ludwig, Anna Kis, Margaret E. Gruen, and Natasha J. Olby
Subjects: NREM sleep, REM sleep, canine cognitive dysfunction syndrome, quantitative EEG, power spectrum, coherence, Veterinary medicine, SF600-1100
Abstract: IntroductionSleep is fundamental for cognitive homeostasis, especially in senior populations since clearance of amyloid beta (key in the pathophysiology of Alzheimer's disease) occurs during sleep. Some electroencephalographic characteristics of sleep and wakefulness have been considered a hallmark of dementia. Owners of dogs with canine cognitive dysfunction syndrome (a canine analog to Alzheimer's disease) report that their dogs suffer from difficulty sleeping. The aim of this study was to quantify age-related changes in the sleep-wakefulness cycle macrostructure and electroencephalographic features in senior dogs and to correlate them with their cognitive performance.MethodsWe performed polysomnographic recordings in 28 senior dogs during a 2 h afternoon nap. Percentage of time spent in wakefulness, drowsiness, NREM, and REM sleep, as well as latency to the three sleep states were calculated. Spectral power, coherence, and Lempel Ziv Complexity of the brain oscillations were estimated. Finally, cognitive performance was evaluated by means of the Canine Dementia Scale Questionnaire and a battery of cognitive tests. Correlations between age, cognitive performance and sleep-wakefulness cycle macrostructure and electroencephalographic features were calculated.ResultsDogs with higher dementia scores and with worse performance in a problem-solving task spent less time in NREM and REM sleep. Additionally, quantitative electroencephalographic analyses showed differences in dogs associated with age or cognitive performance, some of them reflecting shallower sleep in more affected dogs.DiscussionPolysomnographic recordings in dogs can detect sleep-wakefulness cycle changes associated with dementia. Further studies should evaluate polysomnography's potential clinical use to monitor the progression of canine cognitive dysfunction syndrome.
Published: 2023
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5. Small Mars Mission Architecture Study

Author: Claire E. Parfitt, Adam G. McSweeney, Lisa De Backer, Csilla Orgel, Andrew J. Ball, Michael Khan, and Sanjay Vijendran
Subjects: Astronomy, QB1-991
Abstract: While the vast majority of ESA’s funding for Mars exploration in the 2020s is planned to be invested in ExoMars and Mars Sample Return, there is an interest to assess the possibility of implementing a small mission to Mars in parallel with, or soon after, the completion of the MSR programme. A study was undertaken in the Concurrent Design Facility at ESA ESTEC to assess low-cost mission architectures for small satellite missions to Mars. Given strict programmatic constraints, the focus of the study was on a low-cost (
Published: 2021
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6. Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques.

Author: John G Hattersley, Matthias Möhlig, Michael Roden, Ayman M Arafat, Christian V Loeffelholz, Peter Nowotny, Jürgen Machann, Johannes Hierholzer, Martin Osterhoff, Michael Khan, Andreas F H Pfeiffer, and Martin O Weickert
Subjects: Medicine, Science
Abstract: We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6 ± 1.0 years, BMI 31.5 ± 0.4 kg/m(2); 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6-6(2)H(2)] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39-56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r(2) = 27-32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P
Published: 2012
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7. RAMTaB: robust alignment of multi-tag bioimages.

Author: Shan-e-Ahmed Raza, Ahmad Humayun, Sylvie Abouna, Tim W Nattkemper, David B A Epstein, Michael Khan, and Nasir M Rajpoot
Subjects: Medicine, Science
Abstract: BackgroundIn recent years, new microscopic imaging techniques have evolved to allow us to visualize several different proteins (or other biomolecules) in a visual field. Analysis of protein co-localization becomes viable because molecules can interact only when they are located close to each other. We present a novel approach to align images in a multi-tag fluorescence image stack. The proposed approach is applicable to multi-tag bioimaging systems which (a) acquire fluorescence images by sequential staining and (b) simultaneously capture a phase contrast image corresponding to each of the fluorescence images. To the best of our knowledge, there is no existing method in the literature, which addresses simultaneous registration of multi-tag bioimages and selection of the reference image in order to maximize the overall overlap between the images.Methodology/principal findingsWe employ a block-based method for registration, which yields a confidence measure to indicate the accuracy of our registration results. We derive a shift metric in order to select the Reference Image with Maximal Overlap (RIMO), in turn minimizing the total amount of non-overlapping signal for a given number of tags. Experimental results show that the Robust Alignment of Multi-Tag Bioimages (RAMTaB) framework is robust to variations in contrast and illumination, yields sub-pixel accuracy, and successfully selects the reference image resulting in maximum overlap. The registration results are also shown to significantly improve any follow-up protein co-localization studies.ConclusionsFor the discovery of protein complexes and of functional protein networks within a cell, alignment of the tag images in a multi-tag fluorescence image stack is a key pre-processing step. The proposed framework is shown to produce accurate alignment results on both real and synthetic data. Our future work will use the aligned multi-channel fluorescence image data for normal and diseased tissue specimens to analyze molecular co-expression patterns and functional protein networks.
Published: 2012
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8. Re-expression of IGF-II is important for beta cell regeneration in adult mice.

Author: Luxian Zhou, Stella Pelengaris, Sylvie Abouna, James Young, David Epstein, Julia Herold, Tim Wilhelm Nattkemper, Hassan Nakhai, and Michael Khan
Subjects: Medicine, Science
Abstract: The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration.We employed an in vivo model of 'switchable' c-Myc-induced beta cell ablation, pIns-c-MycER(TAM), in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycER(TAM)/IGF-II(+/+) (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycER(TAM)/IGF-II(+/-) (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed.Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.
Published: 2012
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9. A Simple Matter of Life and Death—The Trials of Postnatal Beta-Cell Mass Regulation

Author: Elena Tarabra, Stella Pelengaris, and Michael Khan
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Pancreatic beta-cells, which secrete the hormone insulin, are the key arbiters of glucose homeostasis. Defective beta-cell numbers and/or function underlie essentially all major forms of diabetes and must be restored if diabetes is to be cured. Thus, the identification of the molecular regulators of beta-cell mass and a better understanding of the processes of beta-cell differentiation and proliferation may provide further insight for the development of new therapeutic targets for diabetes. This review will focus on the principal hormones and nutrients, as well as downstream signalling pathways regulating beta-cell mass in the adult. Furthermore, we will also address more recently appreciated regulators of beta-cell mass, such as microRNAs.
Published: 2012
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10. Local isotropic phase symmetry measure for detection of beta cells and lymphocytes

Author: Manohar Kuse, Yi-Fang Wang, Vinay Kalasannavar, Michael Khan, and Nasir Rajpoot
Subjects: Beta cell mass assessment, cell nuclei detection, lymphocyte detection, local isotropic symmetry, Computer applications to medicine. Medical informatics, R858-859.7, Pathology, RB1-214
Abstract: Diabetes can be associated with a reduction in functional β cell mass, which must be restored if the disease is to be cured or progress is to be arrested. To study the cell count, it is also necessary to determine the number of nuclei within the insulin stained area. It can take a single experimentalist several months to complete a single study of this kind, results of which may still be quite subjective. In this paper, we propose a framework based on a novel measure of local symmetry for detection of cells. The local isotropic phase symmetry measure (LIPSyM) is designed to give high values at or near the cell centers. We demonstrate the effectiveness of our algorithm for detection of two types of specific cells in histology images, cells in mouse pancreatic sections and lymphocytes in human breast tissue. Experimental results for these two problems show that our algorithm performs better than human experts for the former problem, and outperforms the best reported results for the latter.
Published: 2011
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11. Prophylactic High-Dose Gabapentin Reduces Opiate Use during Radiation Therapy for Head and Neck Squamous Cell Carcinoma

Author: Michelle L. Qiu, Austin J. Iovoli, Michael Khan, Mark K. Farrugia, Sung Jun Ma, and Anurag K. Singh
Subjects: Cancer Research, Oncology
Abstract: Background: The role of prophylactic high-dose gabapentin for the management of oral mucositis during radiation therapy for head and neck squamous cell carcinoma (HNSCC) remains controversial. Methods: A retrospective cohort analysis was performed on primary HNSCC patients treated at our institution. Kruskal–Wallis and Fisher’s exact tests were used to compare the patients’ baseline characteristics. Multivariate competing risk and logistic regressions were performed to evaluate time to first opioid use and feeding tube placement. Results: In total, 480 consecutive HNSCC patients were included. Within this cohort, 186 patients received 3600 mg gabapentin, 182 received 300 to 3200 mg gabapentin, and 112 received no gabapentin. The time to first opioid use was greater in the 3600 mg group compared with the no gabapentin group (34.3 vs. 23.9 days, p < 0.001) and to the 300 to 3200 mg group (28.0 days, p < 0.001). The proportion of patients requiring opioids at any point during RT was lower in the 3600 mg gabapentin group compared with the no gabapentin group (31.8% vs. 60.1%, p < 0.001) and with the 300 to 3200 mg group (63.8%, p < 0.001). Conclusions: Prophylactic use of 3600 mg gabapentin was well tolerated, halved overall opioid use, and delayed the time to first opioid use during radiation therapy.
Published: 2023
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12. Association of Pack-Years of Cigarette Smoking With Survival and Tumor Progression Among Patients Treated With Chemoradiation for Head and Neck Cancer

Author: Sung Jun Ma, Han Yu, Brian Yu, Olivia Waldman, Michael Khan, Udit Chatterjee, Sharon Santhosh, Jasmin Gill, Austin J. Iovoli, Mark Farrugia, Alina Shevorykin, Ellen Carl, Kimberly Wooten, Vishal Gupta, Ryan McSpadden, Moni A. Kuriakose, Michael R. Markiewicz, Ayham Al-Afif, Wesley L. Hicks, Mary E. Platek, Mukund Seshadri, Christine Sheffer, Graham W. Warren, and Anurag K. Singh
Subjects: Male, Cohort Studies, Head and Neck Neoplasms, Papillomavirus Infections, Humans, General Medicine, Middle Aged, Cigarette Smoking
Abstract: ImportanceAfter 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear.ObjectiveTo estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer.Design, Setting, and ParticipantsThis single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022.ExposuresHeavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic.Main Outcomes and MeasuresOverall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF).ResultsA total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01).Conclusions and RelevanceIn this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.
Published: 2022
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13. Is Alzheimer's Disease a Liver Disease of the Brain?

Author: Margaret Bassendine, Michael Khan, Simon D. Taylor-Robinson, Dermot Neely, and Michael Fertleman
Subjects: 0301 basic medicine, Apolipoprotein E, hepatitis C virus, Medical knowledge, 1702 Cognitive Sciences, Hepatitis C virus, Disease, Review, medicine.disease_cause, liver, 03 medical and health sciences, Liver disease, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, medicine, Animals, Humans, Cognitive decline, Cholesterol homeostasis, apolipoprotein E, Metabolic Syndrome, Neurology & Neurosurgery, Amyloid beta-Peptides, business.industry, General Neuroscience, Brain, 1103 Clinical Sciences, General Medicine, medicine.disease, Lipid Metabolism, Keywords: Alzheimer’s disease, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, circadian, Immunology, small interfering RNAs, Geriatrics and Gerontology, Metabolic syndrome, 1109 Neurosciences, business, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract: Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer’s disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance.
Published: 2020

14. Cell phenotyping in multi-tag fluorescent bioimages

Author: Adnan Mujahid Khan, Michael Khan, Shan-e-Ahmed Raza, and Nasir M. Rajpoot
Subjects: Self-organizing map, Microscope, business.industry, Functional protein, Computer science, Cognitive Neuroscience, Cancer biology, Cell, Cell segmentation, Pattern recognition, Bioinformatics, Fluorescence, Computer Science Applications, law.invention, Nonlinear embedding, medicine.anatomical_structure, Tissue specimen, Multivariate fluorescence microscopy, Artificial Intelligence, law, medicine, Artificial intelligence, business, Self-Organizing Maps
Abstract: Multi-tag bioimaging systems have recently emerged as powerful tools which provide spatiotemporal localization of several different proteins in the same tissue specimen. The analysis of such multivariate bioimages requires sophisticated analytical methods that extract a molecular signature of various types of cells and assist in analyzing interaction behaviors of functional protein complexes. Previous studies were mainly focused on pixel-level analysis which essentially ignore cellular structures as units which can be crucial when analyzing cancerous cells. In this paper, we present a framework in order to overcome these limitations by incorporating cell-level analysis. We use this framework to identify cell phenotypes based on their high-dimensional co-expression profiles contained within the images generated by the robotically controlled TIS microscope installed at Warwick. The proposed paradigm employs a refined cell segmentation algorithm followed by a locality preserving nonlinear embedding algorithm which is shown to produce significantly better cell classification and phenotype distribution results as compared to its linear counterpart. Qatar National Research Fund (QNRF) under the award number NPRP 5-1345-1-228. Warwick Postgraduate Research Scholarship (WPRS) program and the Department of Computer Science at the University of Warwick, UK. Department of Computer Science, University of Warwick, UK. Scopus
Published: 2014
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15. WHIDE—a web tool for visual data mining colocation patterns in multivariate bioimages

Author: Tim Wilhelm Nattkemper, Jan Kölling, Daniel Langenkämper, Sylvie Abouna, and Michael Khan
Subjects: MALDI imaging, Fluorescence-lifetime imaging microscopy, Colorectal cancer, Computer science, Raman imaging, computer.software_genre, Spectrum Analysis, Raman, Biochemistry, Information visualization, Data Mining, Principal Component Analysis, imaging, neural networks, metabolomics, Original Papers, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, Feature (computer vision), Colonic Neoplasms, Data mining, web technology, information visualization, Data and Text Mining, rich internet application, Statistics and Probability, Diagnostic Imaging, dimension reduction, medical imaging, proteomics, Dimension (vector space), image analysis, bioimax, Medical imaging, medicine, Humans, Molecular Biology, visualization, Internet, Pixel, business.industry, Dimensionality reduction, multi-tag fluorescence microscopy, medicine.disease, Visualization, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, biodata mining, business, Bioimage Informatics, computer
Abstract: Motivation: Bioimaging techniques rapidly develop toward higher resolution and dimension. The increase in dimension is achieved by different techniques such as multitag fluorescence imaging, Matrix Assisted Laser Desorption / Ionization (MALDI) imaging or Raman imaging, which record for each pixel an N-dimensional intensity array, representing local abundances of molecules, residues or interaction patterns. The analysis of such multivariate bioimages (MBIs) calls for new approaches to support users in the analysis of both feature domains: space (i.e. sample morphology) and molecular colocation or interaction. In this article, we present our approach WHIDE (Web-based Hyperbolic Image Data Explorer) that combines principles from computational learning, dimension reduction and visualization in a free web application. Results: We applied WHIDE to a set of MBI recorded using the multitag fluorescence imaging Toponome Imaging System. The MBI show field of view in tissue sections from a colon cancer study and we compare tissue from normal/healthy colon with tissue classified as tumor. Our results show, that WHIDE efficiently reduces the complexity of the data by mapping each of the pixels to a cluster, referred to as Molecular Co-Expression Phenotypes and provides a structural basis for a sophisticated multimodal visualization, which combines topology preserving pseudocoloring with information visualization. The wide range of WHIDE's applicability is demonstrated with examples from toponome imaging, high content screens and MALDI imaging (shown in the Supplementary Material). Availability and implementation: The WHIDE tool can be accessed via the BioIMAX website http://ani.cebitec.uni-bielefeld.de/BioIMAX/; Login: whidetestuser; Password: whidetest. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: tim.nattkemper@uni-bielefeld.de
Published: 2012

16. 15-Lipoxygenase-1 in Colorectal Cancer: A Review

Author: Michael Khan, Sayantan Bhattacharya, David G. Jayne, Grace Mathew, and Stella Pelengaris
Subjects: Adenoma, Oncology, medicine.medical_specialty, Colorectal cancer, Peroxisome proliferator-activated receptor, Biology, Mouse model of colorectal and intestinal cancer, Pathogenesis, Lipoxygenase, Reference Values, GATA6 Transcription Factor, Internal medicine, Cyclic GMP-Dependent Protein Kinases, medicine, Animals, Anticarcinogenic Agents, Arachidonate 15-Lipoxygenase, Humans, PPAR alpha, PPAR delta, Intestinal Mucosa, PPAR-beta, chemistry.chemical_classification, Arachidonic Acid, Reverse Transcriptase Polymerase Chain Reaction, food and beverages, General Medicine, medicine.disease, PPAR gamma, Disease Models, Animal, Histone, chemistry, Apoptosis, Cancer cell, biology.protein, Colorectal Neoplasms
Abstract: Objective: Enzymes involved in the oxidative metabolism of n-6 polyunsaturated fatty acids, like lipoxygenase (LOX) and cyclooxygenase (COX), are significant in the pathogenesis of colorectal cancer. Of these enzymes, 15-LOX-1 is expressed in colon. Aim of this article is to describe the role and regulation of 15-LOX-1 in colorectal cancer and highlight its importance in cancer therapeutics. Methods: For our electronic literature research in PubMed and MEDLINE, key words related to 15-LOX-1 and colorectal cancer were used to find articles for this review. Results: From the evidences, we believe that 15-LOX-1 has anti-carcinogenic effects in colorectal cancer, dependent or independent of its metabolites, and is manifested through downstream pathways involving cGMP, PPAR, p53, p21 and NAG-1, increasing apoptosis and decreasing proliferation in cancer cells. Regulation of 15-LOX-1 expression is achieved at transcription level by global histone acetylation and may also be dependent on GATA-6, IL-4 and IL-13. Positive relationship exists between 15-LOX-1 and survival in colorectal cancer. Conclusion: Evidences strongly support that therapeutic modulation of 15-LOX-1 may be a key to the treatment of colorectal cancer. However, it is still undecided whether the up-regulation of 15-LOX-1 alone can be sufficient to treat colorectal cancer and further studies are awaited. Copyright (C) 2009 S. Karger AG, Basel
Published: 2009
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17. Role of Hyperglycaemia in Pathogenesis of Diabetic Cardiovascular Disease

Author: Michael Khan and Sevasti Zervou
Subjects: Pathogenesis, business.industry, Epidemiology, Medicine, Disease, business, Bioinformatics, Cardiology and Cardiovascular Medicine
Published: 2007
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18. Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes

Author: Edward W.A. Needham, Dimitris J. Richter, Michael Khan, D. J. Betteridge, Maria A Adiseshiah, J. Trevelyan, R. G. Murray, and RK Mattu
Subjects: Male, medicine.medical_specialty, Genotype, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Biology, Polymorphism, Single Nucleotide, White People, Nephropathy, Cohort Studies, chemistry.chemical_compound, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Alleles, Aged, Demography, Lipoprotein lipase, Proteinuria, Triglyceride, Albumin, Genetic Variation, nutritional and metabolic diseases, Middle Aged, medicine.disease, Introns, Lipoprotein Lipase, Endocrinology, Diabetes Mellitus, Type 2, England, chemistry, Creatinine, Female, lipids (amino acids, peptides, and proteins), Microalbuminuria, medicine.symptom, Lipoprotein
Abstract: Lipids and lipoproteins, particularly triglyceride rich lipoproteins, could influence the development and progression of microalbuminuria in diabetes. Lipoprotein lipase gene variants have been found to correlate with lipid/lipoprotein concentrations, especially hypertriglyceridaemia. We assessed the influence of this gene on microalbuminuria in Type II (insulin-dependent) diabetes mellitus.Microalbuminuria was determined quantitatively in 386 sequential Type II diabetic patients by measurement of the albumin-to-creatinine ratio (ACR). DNA was analysed for two common intronic LPL single nucleotide polymorphisms (Pvu II, intron 6, and Hind III, intron 8), and three common exonic mutations (Asp(9)-Asn, exon 2, Asn(291)-Ser, exon 6, and Ser(447)-Ter, exon 9).Individuals with P (2) P (2) (Pvu II) and H (2) H (2) (Hind III) genotypes had significantly greater ACRs ( P(2)P(2) vs P(1)P(1)+ P(1)P(2), 5.0+/-0.5 vs 3.4+/-0.3, p=0.0004 and H(2)H(2) vs H(1)H(1)+ H(1)H(2), 4.3+/-0.4 vs 3.4+/-0.3, p=0.04). Logistic regression analysis demonstrated that only the P(2)P(2) genotype ( p=0.0004), systolic BP ( p=0.008) and creatinine ( p=0.031) were independently associated with the presence of microalbuminuria/proteinuria. P(2) homozygotes were 170% more likely to have microalbuminuria or proteinuria, O.R. 2.7 (1.6-4.5, p=0.0001), 150% more likely to have microalbuminuria, O.R. 2.5 (1.5-4.3, p=0.001), and 330% more likely to have proteinuria, O.R. 4.3 (1.6-11.4, p=0.004). There were no associations of microalbuminuria with any of the exonic polymorphisms.Genetic variants of lipoprotein lipase correlate with presence and severity of microalbuminuria in Type II diabetes, independent of effect on serum lipids. This association is only apparent in genetic variants demonstrating greatest heterozygosity.
Published: 2002
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19. Oncogenic co-operation in beta-cell tumorigenesis

Author: Michael Khan and Stella Pelengaris
Subjects: Adult, endocrine system, Cancer Research, Antigens, Polyomavirus Transforming, Endocrinology, Diabetes and Metabolism, Genes, myc, Apoptosis, Mice, Transgenic, Simian virus 40, Biology, medicine.disease_cause, Proto-Oncogene Mas, Proto-Oncogene Proteins c-myc, Islets of Langerhans, Mice, Endocrinology, Proto-Oncogenes, Multiple Endocrine Neoplasia Type 1, medicine, Animals, Humans, MEN1, Child, Multiple endocrine neoplasia, Insulinoma, geography, geography.geographical_feature_category, Oncogene, Oncogenes, Hyperplasia, Adenoma, Islet Cell, Cell Transformation, Viral, medicine.disease, Islet, Pancreatic Neoplasms, Cell Transformation, Neoplastic, Genes, ras, Oncology, Disease Progression, Cancer research, Beta cell, Carcinogenesis, Cell Division
Abstract: Pancreatic islet neoplasms are rare endocrine tumours. The most common type is of beta-cell origin and is known as insulinoma, which can be either benign or malignant. The majority of insulinomas arise sporadically, but a small proportion develop as part of the hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. As for many human tumours, the genetic events that occur during the initiation and progression of insulinoma are poorly known. The men1 gene product, menin, is deficient in most hereditary cases, but is not obviously affected in the majority of sporadic tumours. Activation of the proto-oncogenes c-myc and ras has been observed during malignant progression, but their role in tumour initiation remains unproven. To address these questions, transgenic mouse models have been increasingly used to explore molecular and genetic events that might also precipitate human neoplasia. Transgenic mice expressing SV40 large T-antigen (Tag) oncogene in beta-cells develop tumours in a multi-stage progression from hyperplasia, angiogenesis, to solid encapsulated tumours. However, Tag, which inactivates the key tumour suppressors p53 and Rb, is not known to be involved in the pathogenesis of human insulinoma. The proto-oncogene, c-myc is implicated in beta-cell growth in both diabetes and tumorigenesis. Activation of Myc appears to be an early event in progression of human insulinoma. The effect of deregulated Myc expression on adult beta-cells in vivo has recently been investigated by developing transgenic mouse models in which the activity of Myc can be regulated ectopically. Although Myc activation initially promotes both proliferation and apoptosis in pancreatic beta-cells, apoptosis is the predominant outcome, giving rise to islet involution and diabetes. Importantly, inhibiting Myc-induced apoptosis (by co-expression of Bcl-x(L)) leads to significantly enlarged islets, many becoming highly vascularized, hyperplastic and invasive. These results suggest that, in the pancreatic beta-cells, early suppression of apoptosis is essential for the survival of Myc-activated beta-cells and islet neoplasia.
Published: 2001
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20. Reversible Activation of c-Myc in Skin

Author: Trevor Littlewood, Michael Khan, Gerard I. Evan, George Elia, and Stella Pelengaris
Subjects: Epidermis (botany), Cell growth, Actinic keratosis, Cell Biology, Papillomatosis, Biology, medicine.disease, Phenotype, Lesion, Apoptosis, Immunology, medicine, Cancer research, medicine.symptom, Molecular Biology, Homeostasis
Abstract: The protooncogene c- myc regulates cell growth, differentiation, and apoptosis, and its aberrant expression is frequently observed in human cancer. However, the consequences of activating c-Myc in an adult tissue, in which these cellular processes are part of normal homeostasis, remain unknown. In order to achieve this, we have targeted expression of a switchable form of the c-Myc protein to the skin epidermis, a well characterized homeostatic tissue. We show that activation of c-MycER TM in adult suprabasal epidermis rapidly triggers proliferation and disrupts differentiation of postmitotic keratinocytes. Sustained activation of c-Myc is sufficient to induce papillomatosis together with angiogenesis—changes that resemble hyperplastic actinic keratosis, a commonly observed human precancerous epithelial lesion. All these premalignant changes spontaneously regress upon deactivation of c-MycER TM .
Published: 1999
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21. DiSWOP: A novel measure for cell-level protein network analysis in localized proteomics image data

Author: Michael Khan, Nasir M. Rajpoot, Violeta N. Kovacheva, Adnan Mujahid Khan, and David B. A. Epstein
Subjects: Statistics and Probability, Proteomics, Normal colon, Cell, Computational biology, Cellular level, Biology, Bioinformatics, Biochemistry, Image (mathematics), Protein–protein interaction, Protein Interaction Mapping, medicine, Image Processing, Computer-Assisted, Humans, Molecular Biology, Phenotype, Computer Science Applications, Computational Mathematics, medicine.anatomical_structure, Computational Theory and Mathematics, Colonic Neoplasms, Protein network, Algorithms
Abstract: Motivation: New bioimaging techniques have recently been proposed to visualize the colocation or interaction of several proteins within individual cells, displaying the heterogeneity of neighbouring cells within the same tissue specimen. Such techniques could hold the key to understanding complex biological systems such as the protein interactions involved in cancer. However, there is a need for new algorithmic approaches that analyze the large amounts of multi-tag bioimage data from cancerous and normal tissue specimens to begin to infer protein networks and unravel the cellular heterogeneity at a molecular level. Results: The proposed approach analyzes cell phenotypes in normal and cancerous colon tissue imaged using the robotically controlled Toponome Imaging System microscope. It involves segmenting the 4',6-diamidino-2-phenylindole-labelled image into cells and determining the cell phenotypes according to their protein–protein dependence profile. These were analyzed using two new measures, Difference in Sums of Weighted cO-dependence/Anti-co-dependence profiles (DiSWOP and DiSWAP) for overall co-expression and anti-co-expression, respectively. These novel quantities were extracted using 11 Toponome Imaging System image stacks from either cancerous or normal human colorectal specimens. This approach enables one to easily identify protein pairs that have significantly higher/lower co-expression levels in cancerous tissue samples when compared with normal colon tissue. Availability and implementation: http://www2.warwick.ac.uk/fac/sci/dcs/research/combi/research/bic/diswop. Contact: v.n.kovacheva@warwick.ac.uk or Nasir.Rajpoot@ieee.org Supplementary Information: Supplementary data are available at Bioinformatics online.
Published: 2014

22. Quantifying the Improvement of Surrogate Indices of Hepatic Insulin Resistance Using Complex Measurement Techniques

Author: Michael Khan, Martin A. Osterhoff, Matthias Möhlig, Ayman M. Arafat, Andreas Pfeiffer, Peter Nowotny, Michael Roden, Jürgen Machann, Martin O. Weickert, John Hattersley, Johannes Hierholzer, and Christian von Loeffelholz
Subjects: Blood Glucose, Male, Epidemiology, lcsh:Medicine, Overweight, Body Mass Index, Endocrinology, Statistics, Insulin, Longitudinal Studies, lcsh:Science, QA, Epidemiological Methods, Metabolic Syndrome, Glucose tolerance test, Multidisciplinary, medicine.diagnostic_test, Fasting, Glucose clamp technique, Middle Aged, Regression, Liver, Medicine, Female, medicine.symptom, Research Article, medicine.medical_specialty, Insulin resistance, Internal medicine, Linear regression, medicine, Humans, Obesity, Nutrition, Diabetic Endocrinology, Endocrine Physiology, business.industry, lcsh:R, Diabetes Mellitus Type 2, Glucose Tolerance Test, medicine.disease, R1, Hormones, Biomarker Epidemiology, Glucose Clamp Technique, lcsh:Q, Metabolic syndrome, Insulin Resistance, business, Body mass index, Mathematics, Biomarkers
Abstract: We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6 ± 1.0 years, BMI 31.5 ± 0.4 kg/m(2); 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6-6(2)H(2)] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39-56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r(2) = 27-32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P
Published: 2012

23. Analyzing multi-tag bioimages with BioIMAX colocation mining tools

Author: Tim Wilhelm Nattkemper, Michael Khan, Dominic Gardner, Jan Kölling, Magnus Rathke, and Sylvie Abouna
Subjects: Association rule learning, business.industry, Computer science, Bioimage informatics, computer.software_genre, Task (project management), Visualization, Set (abstract data type), Upload, Data visualization, Software, Data mining, business, computer
Abstract: The application of multi-tag protocols in fluorescence microscopy allows the visualization of a large number (> 10) of molecules (i. e. proteins) in a sample (like a tissue section). However, the analysis of such high dimensional bioimages is a difficult task for most of the labs, since software solutions for particular data mining steps are difficult to use or just not available. In this paper we present two new free online tools: MICOLT (Multivariate Image COlocation Tool) and MIFIST (Multivariate Image Frequent Item Set Tool). Both tools can be used via our recently proposed online bioimage analysis platform BioIMAX, so users can upload their bioimage data, apply the tools and share the results with other invited users based on BioIMAX' concept of shared virtual projects. Data mining with these tools includes the computation and visualization colocation factors well established in the microscopy community (like Mander's score) and association rule mining following the frequent item set principle, thereby supporting large and small scale analysis.
Published: 2012
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24. Re-Expression of IGF-II Is Important for Beta Cell Regeneration in Adult Mice

Author: David B. A. Epstein, James Young, Tim Wilhelm Nattkemper, Michael Khan, Luxian Zhou, Stella Pelengaris, Hassan Nakhai, Julia Herold, and Sylvie Abouna
Subjects: Blood Glucose, Aging, Mouse, medicine.medical_treatment, lcsh:Medicine, Cell Count, Biochemistry, Mice, Endocrinology, Nucleic Acids, Insulin-Secreting Cells, Molecular Cell Biology, Homeostasis, lcsh:Science, Mice, Knockout, Glucose tolerance test, Multidisciplinary, medicine.diagnostic_test, Immunochemistry, Animal Models, Cell biology, Medicine, Beta cell, Cell Division, Research Article, medicine.medical_specialty, Histology, Biology, Cell Growth, Proto-Oncogene Proteins c-myc, Model Organisms, Insulin-Like Growth Factor II, In vivo, Internal medicine, medicine, Animals, Regeneration, Beta (finance), Diabetic Endocrinology, QL, Regeneration (biology), Growth factor, lcsh:R, Glucose Tolerance Test, Glucagon, Apoptosis, Hyperglycemia, lcsh:Q
Abstract: Background\ud The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration.\ud \ud Methodology/Principal Findings\ud We employed an in vivo model of ‘switchable’ c-Myc-induced beta cell ablation, pIns-c-MycERTAM, in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycERTAM/IGF-II+/+ (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycERTAM/IGF-II+/− (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed.\ud \ud Conclusions/Significance\ud Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.
Published: 2012

25. A simple matter of life and death : the trials of postnatal beta-cell mass regulation

Author: Stella Pelengaris, Elena Tarabra, and Michael Khan
Subjects: lcsh:RC648-665, Endocrine and Autonomic Systems, Endocrinology, Diabetes and Metabolism, Insulin, medicine.medical_treatment, Review Article, Biology, medicine.disease, Bioinformatics, lcsh:Diseases of the endocrine glands. Clinical endocrinology, QP, Endocrinology, Diabetes mellitus, microRNA, medicine, Glucose homeostasis, Secretion, Beta cell, Function (biology), Hormone
Abstract: Pancreatic beta-cells, which secrete the hormone insulin, are the key arbiters of glucose homeostasis. Defective beta-cell numbers and/or function underlie essentially all major forms of diabetes and must be restored if diabetes is to be cured. Thus, the identification of the molecular regulators of beta-cell mass and a better understanding of the processes of beta-cell differentiation and proliferation may provide further insight for the development of new therapeutic targets for diabetes. This review will focus on the principal hormones and nutrients, as well as downstream signalling pathways regulating beta-cell mass in the adult. Furthermore, we will also address more recently appreciated regulators of beta-cell mass, such as microRNAs.
Published: 2012

26. Interaction of fast and slow dynamics in endocrine control systems with an application to β-cell dynamics

Author: Michael Khan, Hugo A. van den Berg, and Yi-Fang Wang
Subjects: Statistics and Probability, Blood Glucose, Pulsatile insulin, Scale (ratio), Computation, Upper and lower bounds, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Control theory, Biological Clocks, Insulin-Secreting Cells, Humans, Insulin, Computer Simulation, Mathematics, General Immunology and Microbiology, Applied Mathematics, Dynamics (mechanics), General Medicine, Function (mathematics), QP, Nonlinear system, Range (mathematics), Nonlinear Dynamics, Modeling and Simulation, General Agricultural and Biological Sciences
Abstract: Endocrine dynamics spans a wide range of time scales, from rapid responses to physiological challenges to with slow responses that adapt the system to the demands placed on it. We outline a non-linear averaging procedure to extract the slower dynamics in a way that accounts properly for the non-linear dynamics of the faster time scale and is applicable to a hierarchy of more than two time scales, although we restrict our discussion to two scales for the sake of clarity. The procedure is exact if the slow time scale is infinitely slow (the dimensionless epsilon-quantity is the period of the fast time scale fluctuation times an upper bound to the slow time scale rate of change). However, even for an imperfect separation of time scales we find that this construction provides an excellent approximation for the slow-time dynamics at considerably reduced computational cost. Besides the computation advantage, the averaged equation provided a qualitative insight into the interaction of the time scales. We demonstrate the procedure and its advantages by applying the theory to the model described by Tolic et al. [I.M. Tolic, E. Mosekilde, J. Stuns, Modeling the insulin-glucose feedback system: the significance of pulsatile insulin secretion, J. Theor. Biol. 207 (2000) 361-375.] for ultradian dynamics of the glucose-insulin homeostasis feedback system, extended to include beta-cell dynamics. We find that the dynamics of the beta-cell mass are dependent not only on the glycemic load (amount of glucose administered to the system), but also on the way this load is applied (i.e. three meals daily versus constant infusion), effects that are lost in the inappropriate methods used by the earlier authors. Furthermore, we find that the loss of the protection against apoptosis conferred by insulin that occurs at elevated levels of insulin has a functional role in keeping the beta-cell mass in check without compromising regulatory function. We also find that replenishment of beta-cells from a rapidly proliferating pool of cells, as opposed to the slow turn-over which characterises fully differentiated beta-cells, is essential to the prevention of type 1 diabetes.
Published: 2011

27. c-Myc and Downstream Targets in the Pathogenesis and Treatment of Cancer

Author: Sam Robson, Inga Pukonen, Sylvie Abouna, Stella Pelengaris, and Michael Khan
Published: 2011
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28. c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

Author: Sylvie Abouna, Michael Khan, Goran Mattsson, Stella Pelengaris, Linda Cheung, Luxian Zhou, Vasiliki Ifandi, and Sevasti Zervou
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Genes, myc, Cell Count, Mice, Transgenic, Biology, Mice, Endocrinology, Mediator, In vivo, Diabetes mellitus, Internal medicine, Insulin-Secreting Cells, Insulin Secretion, medicine, Animals, Insulin, Transgenes, Insulin secretion, Pancreas, geography, geography.geographical_feature_category, Cell Cycle, Cell Differentiation, Organ Size, medicine.disease, Islet, Up-Regulation, Transplantation, Mice, Inbred C57BL, Apoptosis, Hyperglycemia, Mice, Inbred CBA, Female, Function (biology)
Abstract: c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycER(TAM) mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through two distinct pathways.
Published: 2010

29. Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully 'switchable' in vivo mouse model of diabetes

Author: Sevasti Zervou, A. Laiho, Michael Khan, David B. A. Epstein, Sylvie Abouna, L. Kytomaki, Yi-Fang Wang, Stella Pelengaris, R. Hermann, and A. Gyenesei
Subjects: medicine.medical_specialty, Time Factors, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Genes, myc, Gene Expression, 030209 endocrinology & metabolism, Mice, Transgenic, Disease, Biology, Diabetes Mellitus, Experimental, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Internal medicine, medicine.artery, Diabetes mellitus, Gene expression, Internal Medicine, medicine, Animals, Insulin, 030304 developmental biology, 0303 health sciences, Aorta, nutritional and metabolic diseases, Arteries, Recovery of Function, medicine.disease, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Glucose, Hyperglycemia, Circulatory system, Mice, Inbred CBA, Female, Blood vessel, Artery
Abstract: Irreversible arterial damage due to early effects of hypo- or hyperglycaemia could account for the limited success of glucose-lowering treatments in preventing cardiovascular disease (CVD) events. We hypothesised that even brief hypo- or hyperglycaemia could adversely affect arterial gene expression and that these changes, moreover, might not be fully reversible.By controlled activation of a 'switchable' c-Myc transgene in beta cells, adult pIns-c-MycER(TAM) mice were rendered transiently hypo- and then hyperglycaemic, after which they were allowed to recover for up to 3 months. Immediate and sequential changes in aortic global gene expression from normal glycaemia through hypo- and hyperglycaemia to recovery were assessed.Gene expression was compared with that of normoglycaemic transgenic and tamoxifen-treated wild-type controls. Overall, expression of 95 genes was significantly affected by moderate hypoglycaemia (glucose down to 2.5 mmol/l), whereas over 769 genes were affected by hyperglycaemia. Genes and pathways activated included several involved in atherogenic processes, such as inflammation and arterial calcification. Although expression of many genes recovered to initial pre-exposure levels when hyperglycaemia was corrected (74.9%), in one in four genes this did not occur. Quantitative reverse transcriptase PCR and immunohistochemistry verified the gene expression patterns of key molecules, as shown by global gene arrays.Short-term exposure to hyperglycaemia can cause deleterious and persistent changes in arterial gene expression in vivo. Brief hypoglycaemia also adversely affects gene expression, although less substantially. Together, these results suggest that early correction of hyperglycaemia and avoidance of hypoglycaemia may both be necessary to avoid excess CVD risk in diabetes.
Published: 2010

30. Non-β-cell progenitors of β-cells in pregnant mice

Author: Michael Khan, Robert W. Old, Ian Sweeney, Vasiliki Ifandi, Sylvie Abouna, David B. A. Epstein, and Stella Pelengaris
Subjects: Embryology, medicine.medical_specialty, Cell type, Period (gene), Population, Biomedical Engineering, Biology, GPI-Linked Proteins, Mice, Pregnancy, Internal medicine, Insulin-Secreting Cells, medicine, Animals, Humans, Cell Lineage, Progenitor cell, education, Cell Aggregation, Transplantation, education.field_of_study, Integrases, Staining and Labeling, Physiological condition, Stem Cells, Transdifferentiation, Pancreatic Ducts, Epithelial Cells, medicine.disease, Alkaline Phosphatase, Research Papers, Rats, Isoenzymes, Endocrinology, Placental alkaline phosphatase, Cell Transdifferentiation, Female, Developmental Biology
Abstract: Pregnancy is a normal physiological condition in which the maternal beta-cell mass increases rapidly about two-fold to adapt to new metabolic challenges. We have used a lineage tracing of beta-cells to analyse the origin of new beta-cells during this rapid expansion in pregnancy. Double transgenic mice bearing a tamoxifen-dependent Cre-recombinase construct under the control of a rat insulin promoter, together with a reporter Z/AP gene, were generated. Then, in response to a pulse of tamoxifen before pregnancy, beta-cells in these animals were marked irreversibly and heritably with the human placental alkaline phosphatase (HPAP). First, we conclude that the lineage tracing system was highly specific for beta-cells. Secondly, we scored the proportion of the beta-cells marked with HPAP during a subsequent chase period in pregnant and non-pregnant females. We observed a dilution in this labeling index in pregnant animal pancreata, compared to nonpregnant controls, during a single pregnancy in the chase period. To extend these observations we also analyzed the labeling index in pancreata of animals during the second of two pregnancies in the chase period. The combined data revealed statistically-significant dilution during pregnancy, indicating a contribution to new beta cells from a non-beta-cell source. Thus for the first time in a normal physiological condition, we have demonstrated not only beta-cell duplication, but also the activation of a non-beta-cell progenitor population. Further, there was no transdifferentiation of beta-cells to other cell types in a two and half month period following labeling, including the period of pregnancy.
Published: 2010

31. Integrating semantic annotation and information visualization for the analysis of multichannel fluorescence micrographs from pancreatic tissue

Author: Luxian Zhou, David B. A. Epstein, Sylvie Abouna, Tim Wilhelm Nattkemper, Julia Herold, Stella Pelengaris, and Michael Khan
Subjects: Machine vision, Computer science, Bioimage informatics, Health Informatics, Image processing, Pattern Recognition, Automated, Information visualization, Pattern recognition, Image Processing, Computer-Assisted, Humans, Radiology, Nuclear Medicine and imaging, Computer vision, Segmentation, Pancreas, Connective Tissue Cells, Fluorescence microscopy, Radiological and Ultrasound Technology, business.industry, Image segmentation, Computer Graphics and Computer-Aided Design, Visualization, Semantics, Radiography, Microscopy, Fluorescence, Pattern recognition (psychology), Computer Vision and Pattern Recognition, Artificial intelligence, business, alpha- and beta-cell counting, Exploratory data analysis (EDA)
Abstract: The challenging problem of computational bioimage analysis receives growing attention from life sciences. Fluorescence microscopy is capable of simultaneously visualizing multiple molecules by staining with different fluorescent dyes. In the analysis of the result multichannel images, segmentation of ROIs resembles only a first step which must be followed by a second step towards the analysis of the ROI's signals in the different channels. In this paper we present a system that combines image segmentation and information visualization principles for an integrated analysis of fluorescence micrographs of tissue samples. The analysis aims at the detection and annotation of cells of the Islets of Langerhans and the whole pancreas, which is of great importance in diabetes studies and in the search for new anti-diabetes treatments. The system operates with two modules. The automatic annotation module applies supervised machine learning for cell detection and segmentation. The second information visualization module can be used for an interactive classification and visualization of cell types following the link-and-brush principle for filtering. We can compare the results obtained with our system with results obtained manually by an expert, who evaluated a set of example images three times to account for his intra-observer variance. The comparison shows that using our system the images can be evaluated with high accuracy which allows a considerable speed up of the time-consuming evaluation process. (C) 2009 Elsevier Ltd. All rights reserved.
Published: 2009

32. Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets

Author: Séverine Pascal, Michael Khan, Yves Guiot, Stella Pelengaris, and Jean-Christophe Jonas
Subjects: Blood Glucose, Male, medicine.medical_specialty, Preproinsulin, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Apoptosis, Mice, Transgenic, Biology, Calcium in biology, Proto-Oncogene Proteins c-myc, Mice, Physiology (medical), Internal medicine, Insulin-Secreting Cells, medicine, Animals, Insulin, RNA, Messenger, Protein Precursors, Inner mitochondrial membrane, Pancreatic hormone, Crosses, Genetic, geography, geography.geographical_feature_category, Pancreatic islets, Hydrogen Peroxide, Hyperpolarization (biology), Islet, Mice, Inbred C57BL, Tamoxifen, Endocrinology, medicine.anatomical_structure, Glucose, Gene Expression Regulation, Mitochondrial Membranes, Mice, Inbred CBA, Calcium, Female
Abstract: Alteration of pancreatic β-cell survival and Preproinsulin gene expression by prolonged hyperglycemia may result from increased c-MYC expression. However, it is unclear whether c-MYC effects on β-cell function are compatible with its proposed role in glucotoxicity. We therefore tested the effects of short-term c-MYC activation on key β-cell stimulus-secretion coupling events in islets isolated from mice expressing a tamoxifen-switchable form of c-MYC in β-cells (MycER) and their wild-type littermates. Tamoxifen treatment of wild-type islets did not affect their cell survival, Preproinsulin gene expression, and glucose stimulus-secretion coupling. In contrast, tamoxifen-mediated c-MYC activation for 2–3 days triggered cell apoptosis and decreased Preproinsulin gene expression in MycER islets. These effects were accompanied by mitochondrial membrane hyperpolarization at all glucose concentrations, a higher resting intracellular calcium concentration ([Ca2+]i), and lower glucose-induced [Ca2+]i rise and islet insulin content, leading to a strong reduction of glucose-induced insulin secretion. Compared with these effects, 1-wk culture in 30 mmol/l glucose increased the islet sensitivity to glucose stimulation without reducing the maximal glucose effectiveness or the insulin content. In contrast, overnight exposure to a low H2O2 concentration increased the islet resting [Ca2+]i and reduced the amplitude of the maximal glucose response as in tamoxifen-treated MycER islets. In conclusion, c-MYC activation rapidly stimulates apoptosis, reduces Preproinsulin gene expression and insulin content, and triggers functional alterations of β-cells that are better mimicked by overnight exposure to a low H2O2 concentration than by prolonged culture in high glucose.
Published: 2008

33. Proteomics in Cancer Research and Diagnosis; An Update

Author: Vasiliki, Ifandi, Susan E, Slade, and Michael, Khan
Abstract: The availability of reference genomes for, amongst others, man and mouse, coupled with the ability to manipulate the expression of single genes/proteins in model organisms, has fuelled a revolution in biomedical research. Non-invasive diagnosis and treatment, disease prediction and personalised medicine are all expected developments to result from the genomics revolution. Building on this resource, we are now able to employ high-throughput techniques for profiling the expression of thousands of genes/proteins in tissues, body fluids and even individual cells and have evolved a whole new science-systems biology that seeks to reveal the biological information in such data-rich studies. Given that proteins are the ultimate biological effectors within the cell and, due to various post-translational regulatory steps, are more varied and numerous than the protein-encoding genes, researchers are increasingly progressing from genome and gene transcript analyses to powerful proteomics techniques that offer a more complete picture of cell behaviour. Cancer research and clinical oncology, in particular, have been at the forefront in adapting and exploiting the new biology. The road map to cancer is being described for many individual cancers, tumours are profiled for prognostic and therapeutic purposes and biomarkers are sought to help with early diagnosis and disease monitoring. This review will focus on proteomics and its application to cancer research and diagnosis.
Published: 2006

34. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author: S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. Obrosova, J Fruchart, M Ilic, Björn Eliasson, Gilles Chatellier, M A Martín, D M Kendall, Holger Luthman, V F Varillas, D Maccubbin, Jang S-A., Amalia Gastaldelli, E Salzsieder, P. de Mol, A Yoshida, H D Lindner, D Gostiljac, M Just, Pan C-Y., J M Fujitaki, G Eiermann, K Bergenheim, A D Frick, A Agacdiken, K Varytimiadis, K Cseh, D A Jackson, S Calderari, Dena G. Hernandez, H M Liebich, K Min, F. de Zegher, Bernd Kulzer, K Han, Ulrich A. Müller, D Marrero, H Hatakeyama, René Koopman, Doo H-K., Petr Wohl, P. Sharp, P Forder, Thor Aspelund, N Meneveau, R M Schmülling, R Aubert, Thom Sam., H Youshikawa, M Ankelo, D Bowden, I Kelly, Frédéric Fumeron, M Sartini, Robert S. Sherwin, L Varadhan, A Criscimanna, John Betteridge, V Jelic, M Bartnik, N Lemke, B Ursø, A Bertoldo, A M Owona, H Okochi, L Pérez-Tamajó, S L Monfre, Daniel Brandhorst, K T Legg, Andries J. Smit, Veronica Sancho, Masashi Hirai, C Klein, Paul J. Thornalley, A Chaidaroglou, K Miura, B Zinman, O M Dvoynishnikova, J Plank, Jan Bolinder, C Lush, B Rubi, R Pozzilli, M Bashir, S A Shtandel, F Mosca, A Naskalska, Josef Vcelak, U Sausbier, P Cavaiani, T U Baehring, Michele Solimena, P Formisano, M Rastaldi, Bernard Thorens, J Ruzzin, E Arbit, M. Hori, Torkel B. Brismar, E Soltes Rak, A Filo, P Heinke, Matthew P. Coghlan, M Masotti, I Perevozskaya, K Ahn, I Moules, K Van Dyck, I Goldstein, Z Mathe, G Z Zhao, S Fajardo, J Taylor, S Chrul, J C Pareja, D Hadjidakis, A J Scheen, N Siddiqua, D C Cavan, R Grella, Krabbe S, H J Rochlitz, A E Hinkkanen, W Wilpshaar, Richard Stevens, M Dreyer, S Hara, X Wang, Melania Manco, D Gillen, Magalie A. Ravier, Olli Simell, John C. Lawrence, Kohnert K-D., Agardh C-D., A Berghold, L Kristensen, Grant Sfa., N Gursoy, Leif Groop, N Freemantle, Anja Schweizer, L Pala, Legros J-J., C. Di Pietro, N. Yamamoto, J Magyar, B Nikolovski, H Ikeda, D Lee, Bruce A. Buckingham, A O Wollitzer, I Kennedy, C Ernest, Neville H. McClenaghan, S Tanaka, Asimina Mitrakou, T Heinze, W Kerner, Moeenaldeen Al-Sayed, Charles Thivolet, L Klaff, A Miconi, Cristina Valeri, J. O. Christensen, K. Ekberg, A Jardine, T Endo, X Zhang, D F Child, A Kienitz, D K Seidel, H. Tada, Sylvie Abouna, Cyrus Cooper, Catherine R Chittleborough, Roberta Assaloni, S Corbi, A K Bose, K Ozawa, C Ahn, K A Deans, G Jackowski, Martin Gibson, Patrick McElduff, O A Mojiminiyi, Manuel Serrano-Ríos, O Dupuy, A L Davydov, Iwar Klimes, Sten-Anders Ivarsson, N Ichino, R Matsutomo, E R Smith, A Stefanovska, B Dehmel, K Koniavitou, E Agascioglu, M Hatazaki, J. M. Gibson, T Yada, P Ribaux, M Rupnik, K Fridell, G Scutaru, L Chugunova, Henrietta Mulnier, A Kendereski, H Lehnert, C Billi, M Sobczak, Francisco M-Mj., L K Archibald, S Sukumvanich, David B. Dunger, I. Benke, G Yillar, N Stingemore, J. M. Boavida, Y Shi, Jimmy D. Bell, L Bozzetto, Andrew J. Ahmann, E Jebens, J Keiding, Elena Henkel, Mark Fineman, J F McRae, Carol Forsblom, S Martemucci, Lourdes Ibáñez, P G Prieto, L Ringholm Nielsen, S Pratas, B von Stritzky, Julio Rosenstock, Lee K-W., J Stocks, L J Strow, I Samarguliani, L Wennekes, R Cheung, Abhishek Nag, Roberto Gambino, Y Suleymanoglu, E Murphy, T T Durck, M F Peyrot, Y Unno, Alexander Mayorov, Eleuterio Ferrannini, D. C. Rao, D Neely, H Karunajeewa, J Palmisano, Julia B. Lewis, M Ravid, G Pons, E Junca, P Vexiau, S Sailesh, D K Miloslavskiy, O N Bondarenko, U Smith, S Torri, Constantine Tsigos, Cesario Bianchi, Mattia Locatelli, D Jaquet, Virpi Lindi, M Moroi, M E Tushuizen, P Pelicci, R Scognamiglio, Pal Pacher, S M Thyssen, A Péterfalvi, Y Ho, S Guntram, L Romics, T Nakagami, Clive S. Cockram, Irina Kowalska, K Brodbeck, Gojka Roglic, J. Dörig, Lise Tarnow, Therese Tillin, A López-Alba, Martin Krššák, Moses Elisaf, S Hata, D P Snoeck, D Schmoll, O V Udovichenko, A Scaramuzza, J Paul, John H. Fuller, Nicholas Katsilambros, Michele Muggeo, Pia Ekbom, Piero Marchetti, V Melki, C Bailleau, H Stavrianos, A D'Errico, Geremia B. Bolli, Amabile Maier, Kelter A-R., Anders Green, Q J Morélis, Steffen Thiel, C Watkins, R C Cheung, A Clark, Elvira Fioriti, N Ari, Nam J-Y., Y Cottin, L G Krinelke, H Al Mohammedi, Simon C. Fleming, C Jones, Z Kerényi, Ahn Y-H., Meile M-J., P Nánási, M Graner, V Canonico, Gangnerau M-N., Hugh R. Taylor, Giovanni Sartore, A. Dejgaard, Carol Kelley, S. Ali, Stéphane Dalle, Jeffrey S. Gonzalez, Elena Šeböková, Alexander Beck, Ingo B. Leibiger, M Rosu, C Pencea, Werner Waldhäusl, Kaltenbacher M-C., R Butzer, S Thore, Adam G. Tabak, Angelo Avogaro, E Standi, Boris Kovatchev, O Bradescu, Patrizia Dentelli, A Fujita, C Verri, R Chlup, Prasad Ydm., S V Hörsten, van der Merwe M-T., D Hilliard, W Klein, D Worthley, M Udvardy, Berit R. Jensen, A D'Avanzo, J Monaghan, K P Yeo, Guivarch P-H., B Bauduceau, D Weghuber, P Tatti, J Ybarra, S Gwozdziewiczová, E Gasparini, B Saltin, Charlotte Granhall, Howard Leventhal, R Marin, M Tumiati, Cicero Afg., L Csémy, B Berger, S Mikros, D Dall'Asta, M Shahmanesh, Y G Vasiljev, F Potthoff, H S Randeva, G De Berardis, J O Logan, K Warncke, P Uitterlinden, E Rehring, K Gilmore, K Shankhdhar, V V Bojko, M Vahatalo, E A Korolyova, D Wiemann, P G Lankisch, D Hendrie, F Galtier, M Rybarczyk, Gisela Dahlquist, N N Rudovich, G Stein, A Liebl, F Tan, A Westerlund, S Gronemann, I Franklin, Jonathan A. Prince, Peter Arner, E Skliros, T. Sparre, M Vigas, Maddalena Trombetta, L. Bjerre Knudsen, A C Sima, I Dubroca, Alastair Gray, I Weets, R Ferraresi, Schauer Ujw., E. Leinonen, S Corazza, Jonathan Levy, P K Prakash, R Guzder, S. Barnhill, John Blangero, J Herreros, G. de Vries, Cheng Ptw., A Macías-Batista, K. Capito, R Thomas, G Thomas, G Boemi, Lotte Pietraszek, Pierre Fontaine, I Holme, J Smedegaard, C A Harrop, U Helwig, B Levy, A P Gribben, Hiroto Furuta, P Beckett, S Giannini, Ruth L. Coleman, Eva Fernqvist-Forbes, N Cugnardey, A Dumas, Jane Pinaire, S E Hofer, D Shimono, Erik H. Serné, Alain D. Baron, C Battista, M Tanen, M Klementova, V Adams, J Komorowski, Antonio Nicolucci, E. C. Burns, H Sydall, M G Fanara, M G Giovannitti, N Okabayashi, Magdalena Szurkowska, I A Eroshkin, M. I. J. Uusitupa, D Ma, C C Dieguez, J Sutcliffe-Goulden, A V Gaddi, Michał Arabski, Serge Halimi, Wendy C. Burns, S Seclén, H Sugano, A Vinterby, K Backx, L F Diaconu, Fernando Gomez-Peralta, O'Harte Fpm., G Lepeniotis, D Laune, H Kvasničková, N H Wallén, G Boner, G Cieślik, Robert Hermann, Paul Q. Thomas, Y Kumon, Maria Maiello, M Atkins, Kenneth A. Earle, Guowang Xu, H Y Bae, I Reynisdottir, D Perez, D E Cannon, P Fabietti, I Geronooz, J Østergaard, K J Jeitler, S Skourtis, A Zambanini, A Saemann, K Kuboki, Helen L. Lutgers, A C Thai, Arne Melander, D Pinkowski, S G Straub, S A Wolfe-Coote, A Totora, Hayley Dickinson, A Lindenmair, A Ginis, I Faturos, F Van Eylen, C Huard, F Fu, N Wang, B M Rasmussen, Angela Napoli, L Granato, Markus M. Lerch, M. Frandsen, A Lyras, Lawrence S. Phillips, J Mabley, R Goldschmeding, B K Kilhovd, W Liu, Greg Poffenberger, P Cipriano, Anna Maria Charlotte K Lindqvist, A Matsuzawa, J Wang, T Yu, M S Pepper, Lena M. Thorn, Y Sakamoto, Blanche Schwappach, Anna L. Gloyn, P Dupraz, A. M. Schmidt, M Psallas, V Tsirimbis, Carl D. Langefeld, D Sass, H E Scholtz, M. Cailleau, Lauren Julia Brown, K Phillips, M. Iezzi, C Jayawarna, Eleni Anastasiou, R Lobmann, R Lundershausen, H Fujiwara, H R Nan, I C Smith, I A Karpova, A Navazio, S Kang, T. 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D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, EASD, Endocrinology, Diabetes and Metabolism, Human physiology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Family medicine, Internal Medicine, Medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2004

35. Calcitonin gene-related peptide promotes Schwann cell proliferation

Author: Michael Khan, L Cheng, and A W Mudge
Subjects: medicine.medical_specialty, Platelet-derived growth factor, Calcitonin Gene-Related Peptide, Schwann cell, Mitosis, Cell Separation, Calcitonin gene-related peptide, Schwann cell proliferation, chemistry.chemical_compound, Internal medicine, medicine, Cyclic AMP, Animals, Receptor, Cells, Cultured, Platelet-Derived Growth Factor, Forskolin, biology, Dose-Response Relationship, Drug, Colforsin, Isoproterenol, Drug Synergism, Cell Biology, Articles, Fibroblasts, Sciatic Nerve, Rats, Endocrinology, medicine.anatomical_structure, chemistry, nervous system, biology.protein, Neprilysin, Schwann Cells, Platelet-derived growth factor receptor, Intracellular, Cell Division
Abstract: Schwann cells in culture divide in response to defined mitogens such as PDGF and glial growth factor (GGF), but proliferation is greatly enhanced if agents such as forskolin, which increases Schwann cell intracellular cAMP, are added at the same time as PDGF or GGF (Davis, J. B., and P. Stroobant. 1990. J. Cell Biol. 110:1353-1360). The effect of forskolin is probably due to an increase in numbers of PDGF receptors (Weinmaster, G., and G. Lemke. 1990. EMBO (Eur. Mol. Biol. Organ.) J. 9:915-920. Neuropeptides and beta-adrenergic agonists have been reported to have no effect on potentiating the mitogenic response of either PDGF or GGF. We show that the neuropeptide calcitonin gene-related peptide (CGRP) increases Schwann cell cAMP levels, but the cells rapidly desensitize. We therefore stimulated the cells in pulsatile fashion to partly overcome the effects of desensitization and show that CGRP can synergize with PDGF to stimulate Schwann cell proliferation, and that CGRP is as effective as forskolin in the pulsatile regime. CGRP is a good substrate for the neutral endopeptidase 24.11. Schwann cells in vivo have this protease on their surface, so the action of CGRP could be terminated by this enzyme and desensitization prevented. We therefore suggest that CGRP may play an important role in stimulating Schwann cell proliferation by regulating the response of mitogenic factors such as PDGF.
Published: 1995

36. Deciphering c-MYC-regulated genes in two distinct tissues

Author: Heather Turner, Helen Brown, Stella Pelengaris, Michael Khan, Lesley A Ward, Ewan Hunter, Samuel Robson, Robson, Samuel [0000-0001-5702-9160], and Apollo - University of Cambridge Repository
Subjects: Keratinocytes, Transcriptional Activation, lcsh:QH426-470, Cell Survival, lcsh:Biotechnology, Transgene, Cellular differentiation, Regulator, Apoptosis, Cell Cycle Proteins, Mice, Transgenic, Biology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Islets of Langerhans, Mice, 0302 clinical medicine, lcsh:TP248.13-248.65, Gene expression, Genetics, Cell Adhesion, Animals, Gene, Transcription factor, 030304 developmental biology, Regulation of gene expression, QL, 0303 health sciences, Cell Differentiation, QP, Cell biology, lcsh:Genetics, Gene Expression Regulation, 030220 oncology & carcinogenesis, Biotechnology, Research Article, DNA Damage
Abstract: Background The transcription factor MYC is a critical regulator of diverse cellular processes, including both replication and apoptosis. Differences in MYC-regulated gene expression responsible for such opposing outcomes in vivo remain obscure. To address this we have examined time-dependent changes in global gene expression in two transgenic mouse models in which MYC activation, in either skin suprabasal keratinocytes or pancreatic islet β-cells, promotes tissue expansion or involution, respectively. Results Consistent with observed phenotypes, expression of cell cycle genes is increased in both models (albeit enriched in β-cells), as are those involved in cell growth and metabolism, while expression of genes involved in cell differentiation is down-regulated. However, in β-cells, which unlike suprabasal keratinocytes undergo prominent apoptosis from 24 hours, there is up-regulation of genes associated with DNA-damage response and intrinsic apoptotic pathways, including Atr, Arf, Bax and Cycs. In striking contrast, this is not the case for suprabasal keratinocytes, where pro-apoptotic genes such as Noxa are down-regulated and key anti-apoptotic pathways (such as Igf1-Akt) and those promoting angiogenesis are up-regulated. Moreover, dramatic up-regulation of steroid hormone-regulated Kallikrein serine protease family members in suprabasal keratinocytes alone could further enhance local Igf1 actions, such as through proteolysis of Igf1 binding proteins. Conclusions Activation of MYC causes cell growth, loss of differentiation and cell cycle entry in both β-cells and suprabasal keratinocytes in vivo. Apoptosis, which is confined to β-cells, may involve a combination of a DNA-damage response and downstream activation of pro-apoptotic signalling pathways, including Cdc2a and p19Arf/p53, and downstream targets. Conversely, avoidance of apoptosis in suprabasal keratinocytes may result primarily from the activation of key anti-apoptotic signalling pathways, particularly Igf1-Akt, and induction of an angiogenic response, though intrinsic resistance to induction of p19Arf by MYC in suprabasal keratinocytes may contribute.
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37. Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis

Author: Pelengaris, Stella, Abouna, Sylvie, Cheung, Linda, Ifandi, Vasiliki, Zervou, Sevasti I., and Michael Khan
Subjects: Male, Genes, myc, Apoptosis, Mice, Transgenic, Pancreatic Neoplasms, Proto-Oncogene Proteins c-myc, RC0254, Disease Models, Animal, Islets of Langerhans, Mice, lcsh:Biology (General), Disease Progression, Animals, Female, Hydroxytestosterones, Insulinoma, Gene Silencing, Epidermis, lcsh:QH301-705.5, Research Article
Abstract: Background Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform to preclinically evaluate, novel therapeutics to inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc inactivation proved sufficient for sustained osteosarcoma regression; the resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this apply to other tumours? Results We show that brief inactivation of c-Myc does not sustain tumour regression in two distinct tissue types; tumour cells in pancreatic islets and skin epidermis continue to avoid apoptosis after c-Myc reactivation, by virtue of Bcl-xL over-expression or a favourable microenvironment, respectively. Moreover, tumours progress despite reacquiring a differentiated phenotype and partial loss of vasculature during c-Myc inactivation. Interestingly, reactivating c-Myc in β-cell tumours appears to result not only in further growth of the tumour, but also re-expansion of the accompanying angiogenesis and more pronounced β-cell invasion (adenocarcinoma). Conclusions Given that transient c-Myc inactivation could under some circumstances produce sustained tumour regression, the possible application of this potentially less toxic strategy in treating other tumours has been suggested. We show that brief inactivation of c-Myc fails to sustain tumour regression in two distinct models of tumourigenesis: pancreatic islets and skin epidermis. These findings challenge the potential for cancer therapies aimed at transient oncogene inactivation, at least under those circumstances where tumour cell differentiation and alteration of epigenetic context fail to reinstate apoptosis. Together, these results suggest that treatment schedules will need to be informed by knowledge of the molecular basis and environmental context of any given cancer.
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38. Deep-space CubeSats: Thinking inside the box

Author: David Binns, Roger Walker, Mehdi Scoubeau, Paolo Concari, Ian Carnelli, Vasco Pesquita, Michael Khan, Dario Izzo, Massimo Casasco, Davar Feili, Cristina Bramanti, Philipp Hager, Jesus Gil Fernandez, Daniela Taubert, Pablo Fernandez, Detlef Koschny, and Neil Wallace
Subjects: Geophysics, 010504 meteorology & atmospheric sciences, Geochemistry and Petrology, business.industry, Computer science, 0103 physical sciences, Astronomy and Astrophysics, NASA Deep Space Network, Aerospace engineering, business, 010303 astronomy & astrophysics, 01 natural sciences, 0105 earth and related environmental sciences

39. 2194

Author: Michael Khanjyan, Vien Nguyen, Eric Kazangian, Shane Browne, Kevin Healy, Kurosh Ameri, and Yerem Yeghiazarians
Subjects: Medicine
Abstract: OBJECTIVES/SPECIFIC AIMS: A major limitation of cardiac stem cell transplantation following myocardial infarction (MI) is poor retention of cells in the ischemic microenvironment. Our study aims to better understand and promote the survival and differentiation of human cardiosphere-derived cells (hCDCs) in anoxia, a feature of infarcted myocardium. METHODS/STUDY POPULATION: We previously demonstrated that TGFβ1 and heparin-containing hydrogels (TH-hydrogel) can promote murine CDC survival. In this study, hCDCs were incubated in either normoxia or anoxia for 8 hours with and without TH-hydrogel. In addition, hCDCs without TH-hydrogel were assessed in 16 hours of anoxia. Following incubation, hCDCs were assayed for viability using calcein dye and immunostained for CD31, a marker of endothelial differentiation. RESULTS/ANTICIPATED RESULTS: hCDCs incubated for 8 hours in anoxia in both models equally demonstrated increased survival up to 30% when compared with cells incubated in normoxia. However, in contrast to hCDCs alone, hCDCs with TH-hydrogel additionally demonstrated increased differentiation into endothelial cells in both anoxia and normoxia. We found that hCDCs alone were able to upregulate CD31 only when subjected to 16 hours of anoxia. DISCUSSION/SIGNIFICANCE OF IMPACT: We demonstrate a new, previously unknown response of hCDCs to anoxia. This induces increased viability and differentiation of hCDCs into endothelial cells. The differentiation in anoxia was time dependent and could be expedited with use of TH-hydrogel. Anoxic preconditioning of hCDCs together with the TH-hydrogel system may improve the therapeutic potential of stem cell transplantation following MI.
Published: 2017
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