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Full-Text Articles in Physics

Hcp: A Matlab Package To Create Beautiful Heatmaps With Richly Annotated Covariates, Manuela Salvucci, Jochen Hm Prehn Jun 2019

Hcp: A Matlab Package To Create Beautiful Heatmaps With Richly Annotated Covariates, Manuela Salvucci, Jochen Hm Prehn

Physiology and Medical Physics Articles

HCP (HeatmapCovariatePlot) provides a simple high level application programming interface (API) to design elaborated visualizations in a modular fashion. The user can select which elements to include, covariate row annotations and/or heatmaps, by invoking the AddCovariateRow or the AddHeatmap methods. Elements can be vertically stacked and also grouped in functionally related sub-blocks encapsulated by the AddSubBlock method to adjust the figure layout. The plotting options in HCP are chosen sensibly to create production-quality out-of-the-box visualizations in most use-case. HCP features several plotting options to adjust the plot aesthetics to cater for the user preferences in terms of colormaps, labelling ...


Systems Biology Identifies Preserved Integrity But Impaired Metabolism Of Mitochondria Due To A Glycolytic Defect In Alzheimer's Disease Neurons., Pierre Theurey, Niamh M. Connolly, Ilaria Fortunati, Emy Basso, Susette Lauwen, Camilla Ferrante, Catarina Moreira Pinho, Alvin Joselin, Anna Gioran, Daniele Bano, David S. Park, Maria Ankarcrona, Paola Pizzo, Jochen Hm Prehn Jun 2019

Systems Biology Identifies Preserved Integrity But Impaired Metabolism Of Mitochondria Due To A Glycolytic Defect In Alzheimer's Disease Neurons., Pierre Theurey, Niamh M. Connolly, Ilaria Fortunati, Emy Basso, Susette Lauwen, Camilla Ferrante, Catarina Moreira Pinho, Alvin Joselin, Anna Gioran, Daniele Bano, David S. Park, Maria Ankarcrona, Paola Pizzo, Jochen Hm Prehn

Physiology and Medical Physics Articles

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would ...


Meta-Analysis Of The Molecular Associations Of Mucinous Colorectal Cancer., Ian S. Reynolds, S J Furney, Elaine W. Kay, Deborah A. Mcnamara, Jochen Hm Prehn, John P. Burke May 2019

Meta-Analysis Of The Molecular Associations Of Mucinous Colorectal Cancer., Ian S. Reynolds, S J Furney, Elaine W. Kay, Deborah A. Mcnamara, Jochen Hm Prehn, John P. Burke

Physiology and Medical Physics Articles

BACKGROUND: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer.

METHODS: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis.

RESULTS: Data from 46 studies ...


A Machine Learning Platform To Optimize The Translation Of Personalized Network Models To The Clinic., Manuela Salvucci, Arman Rahman, Alexa J. Resler, Girish M. Udupi, Deborah A. Mcnamara, Elaine W. Kay, Pierre Laurent-Puig, Daniel B. Longley, Patrick G. Johnston, Mark Lawler, Richard Wilson, Manuel Salto-Tellez, Sandra Van Schaeybroeck, Mairin Rafferty, William M. Gallagher, Markus Rehm, Jochen Hm Prehn Apr 2019

A Machine Learning Platform To Optimize The Translation Of Personalized Network Models To The Clinic., Manuela Salvucci, Arman Rahman, Alexa J. Resler, Girish M. Udupi, Deborah A. Mcnamara, Elaine W. Kay, Pierre Laurent-Puig, Daniel B. Longley, Patrick G. Johnston, Mark Lawler, Richard Wilson, Manuel Salto-Tellez, Sandra Van Schaeybroeck, Mairin Rafferty, William M. Gallagher, Markus Rehm, Jochen Hm Prehn

Physiology and Medical Physics Articles

PURPOSE: Dynamic network models predict clinical prognosis and inform therapeutic intervention by elucidating disease-driven aberrations at the systems level. However, the personalization of model predictions requires the profiling of multiple model inputs, which hampers clinical translation.

PATIENTS AND METHODS: We applied APOPTO-CELL, a prognostic model of apoptosis signaling, to showcase the establishment of computational platforms that require a reduced set of inputs. We designed two distinct and complementary pipelines: a probabilistic approach to exploit a consistent subpanel of inputs across the whole cohort (Ensemble) and a machine learning approach to identify a reduced protein set tailored for individual patients (Tree ...


When Ron Met Tam In Mesothelioma: All Druggable For One, And One Drug For All?, Anne-Marie Baird, David Easty, Monika A. Jarzabek, Liam Shiels, Alex Soltermann, Sonja Klebe, Stéphane Raeppel, Lauren Macdonagh, Chengguang Wu, Kim Griggs, Michaela B. Kirschner, Bryan Stanfill, Daisuke Nonaka, Chandra M. Goparaju, Bruno Murer, Dean A. Fennell, Dearbhaile M. O'Donnell, Martin P. Barr, Luciano Mutti, Glen Reid, Stephen Finn, Sinead Cuffe, Harvey I. Pass, Isabelle Opitz, Annette Byrne, Kenneth J. O'Byrne, Steven G. Gray Feb 2019

When Ron Met Tam In Mesothelioma: All Druggable For One, And One Drug For All?, Anne-Marie Baird, David Easty, Monika A. Jarzabek, Liam Shiels, Alex Soltermann, Sonja Klebe, Stéphane Raeppel, Lauren Macdonagh, Chengguang Wu, Kim Griggs, Michaela B. Kirschner, Bryan Stanfill, Daisuke Nonaka, Chandra M. Goparaju, Bruno Murer, Dean A. Fennell, Dearbhaile M. O'Donnell, Martin P. Barr, Luciano Mutti, Glen Reid, Stephen Finn, Sinead Cuffe, Harvey I. Pass, Isabelle Opitz, Annette Byrne, Kenneth J. O'Byrne, Steven G. Gray

Physiology and Medical Physics Articles

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON ...


Post-Treatment De-Phosphorylation Of P53 Correlates With Dasatinib Responsiveness In Malignant Melanoma., Josip Skoko, Jan Rožanc, Emilie M. Charles, Leonidas G. Alexopoulos, Markus Rehm Dec 2018

Post-Treatment De-Phosphorylation Of P53 Correlates With Dasatinib Responsiveness In Malignant Melanoma., Josip Skoko, Jan Rožanc, Emilie M. Charles, Leonidas G. Alexopoulos, Markus Rehm

Physiology and Medical Physics Articles

BACKGROUND: Dasatinib (Sprycel) was developed as a tyrosine kinase inhibitor targeting Bcr-Abl and the family of Src kinases. Dasatinib is commonly used for the treatment of acute lymphoblastic and chronic myelogenous leukemia. Previous clinical studies in melanoma returned inconclusive results and suggested that patients respond highly heterogeneously to dasatinib as single agent or in combination with standard-of-care chemotherapeutic dacarbazine. Reliable biomarkers to predict dasatinib responsiveness in melanoma have not yet been developed.

RESULTS: Here, we collected comprehensive in vitro data from experimentally well-controlled conditions to study the effect of dasatinib, alone and in combination with dacarbazine, on cell proliferation and ...


Dual-Center, Dual-Platform Microrna Profiling Identifies Potential Plasma Biomarkers Of Adult Temporal Lobe Epilepsy., Rana Raoof, Sebastian Bauer, Hany El Naggar, Gary P Brennan, Elizabeth Brindley, Thomas Hill, Hazel Mcardle, Elaine Spain, Robert J Forster, Jochen Hm Prehn, Hajo Hamer, Norman Delanty, Felix Rosenow, Catherine Mooney, David C. Henshall Dec 2018

Dual-Center, Dual-Platform Microrna Profiling Identifies Potential Plasma Biomarkers Of Adult Temporal Lobe Epilepsy., Rana Raoof, Sebastian Bauer, Hany El Naggar, Gary P Brennan, Elizabeth Brindley, Thomas Hill, Hazel Mcardle, Elaine Spain, Robert J Forster, Jochen Hm Prehn, Hajo Hamer, Norman Delanty, Felix Rosenow, Catherine Mooney, David C. Henshall

Physiology and Medical Physics Articles

BACKGROUND: There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation.

METHOD: Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase ...


The Significance Of Mucin Pools Following Neoadjuvant Chemoradiotherapy For Locally Advanced Rectal Cancer., Ian S. Reynolds, Deborah A. Mcnamara, Elaine W. Kay, Brian O'Neill, Joseph Deasy, John P. Burke Dec 2018

The Significance Of Mucin Pools Following Neoadjuvant Chemoradiotherapy For Locally Advanced Rectal Cancer., Ian S. Reynolds, Deborah A. Mcnamara, Elaine W. Kay, Brian O'Neill, Joseph Deasy, John P. Burke

Physiology and Medical Physics Articles

BACKGROUND: Neoadjuvant chemo-radiotherapy is utilized for locally advanced rectal cancer to optimize local control. A subset of patients form mucin pools following radiotherapy but the association between mucin pools and pathological and oncological outcomes following curative proctectomy for rectal cancer remains unknown.

OBJECTIVE: The aim of this study was to determine the significance of mucin pool formation after neoadjuvant chemoradiotherapy for rectal cancer.

METHODS: This is a retrospective analysis of a prospectively maintained rectal cancer database. Patients who underwent curative proctectomy for rectal cancer following long course chemoradiotherapy between January 2007 and December 2016 were eligible for inclusion.

RESULTS: A ...


Phosphoprotein Patterns Predict Trametinib Responsiveness And Optimal Trametinib Sensitisation Strategies In Melanoma., Jan Rožanc, Theodore Sakellaropoulos, Asier Antoranz, Cristiano Guttà, Biswajit Podder, Vesna Vetma, Nicole Rufo, Patrizia Agostinis, Vaia Pliaka, Thomas Sauter, Dagmar Kulms, Markus Rehm, Leonidas G. Alexopoulos Oct 2018

Phosphoprotein Patterns Predict Trametinib Responsiveness And Optimal Trametinib Sensitisation Strategies In Melanoma., Jan Rožanc, Theodore Sakellaropoulos, Asier Antoranz, Cristiano Guttà, Biswajit Podder, Vesna Vetma, Nicole Rufo, Patrizia Agostinis, Vaia Pliaka, Thomas Sauter, Dagmar Kulms, Markus Rehm, Leonidas G. Alexopoulos

Physiology and Medical Physics Articles

Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma cell lines with different disease-relevant mutations, to predict responsiveness to MEK inhibitor trametinib. Supported by multivariate statistical analysis and multidimensional pattern recognition algorithms, the responsiveness of individual cell lines ...


Copy Number Load Predicts Outcome Of Metastatic Colorectal Cancer Patients Receiving Bevacizumab Combination Therapy., Dominiek Smeets, Ian S. Miller, Darran P. O'Connor, Sudipto Das, Bruce Moran, Bram Boeckx, Timo Gaiser, Johannes Betge, Ana Barat, Rut Klinger, Nicole Ct Van Grieken, Chiara Cremolini, Hans Prenen, Massimiliano Mazzone, Jeroen Depreeuw, Orna Bacon, Bozena Fender, Joseph Brady, Bryan T. Hennessy, Deborah A. Mcnamara, Elaine W. Kay, Henk M. Verheul, Neerincx Maarten, William M. Gallagher, Verena Murphy, Jochen Hm Prehn, Miriam Koopman, Cornelis Ja Punt, Fotios Loupakis, Matthias Pa Ebert, Bauke Ylstra, Diether Lambrechts, Annette Byrne Oct 2018

Copy Number Load Predicts Outcome Of Metastatic Colorectal Cancer Patients Receiving Bevacizumab Combination Therapy., Dominiek Smeets, Ian S. Miller, Darran P. O'Connor, Sudipto Das, Bruce Moran, Bram Boeckx, Timo Gaiser, Johannes Betge, Ana Barat, Rut Klinger, Nicole Ct Van Grieken, Chiara Cremolini, Hans Prenen, Massimiliano Mazzone, Jeroen Depreeuw, Orna Bacon, Bozena Fender, Joseph Brady, Bryan T. Hennessy, Deborah A. Mcnamara, Elaine W. Kay, Henk M. Verheul, Neerincx Maarten, William M. Gallagher, Verena Murphy, Jochen Hm Prehn, Miriam Koopman, Cornelis Ja Punt, Fotios Loupakis, Matthias Pa Ebert, Bauke Ylstra, Diether Lambrechts, Annette Byrne

Physiology and Medical Physics Articles

Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap ...


Low Cleaved Caspase-7 Levels Indicate Unfavourable Outcome Across All Breast Cancers., Andreas U Lindner, Federico Lucantoni, Damir Varešlija, Alexa Resler, Brona M Murphy, William M Gallagher, Arnold D K Hill, Leonie S. Young, Jochen H.M. Prehn Oct 2018

Low Cleaved Caspase-7 Levels Indicate Unfavourable Outcome Across All Breast Cancers., Andreas U Lindner, Federico Lucantoni, Damir Varešlija, Alexa Resler, Brona M Murphy, William M Gallagher, Arnold D K Hill, Leonie S. Young, Jochen H.M. Prehn

Physiology and Medical Physics Articles

Elevated levels of the anti-apoptotic BCL2 protein associate with favourable outcome in breast cancer. We investigated whether executioner caspase activation downstream of mitochondrial apoptosis was associated with, or independent, of BCL2's prognostic signature in breast cancer. Levels of pro- and anti-apoptotic BCL2 family proteins were quantified in triple negative breast cancer (TNBC) samples and utilised to calculate BCL2 profiles of 845 breast cancer patients. Biomarkers including single apoptosis proteins and network-enriched apoptosis system signatures were evaluated using uni- and multi-variate Cox-models. In both TNBC and non-TNBC breast cancer, the anti-apoptotic BCL2 protein was particularly abundant when compared to other ...


Metabolic Targeting Of Breast Cancer Cells With The 2-Deoxy-D-Glucose And The Mitochondrial Bioenergetics Inhibitor Mdivi-1., Federico Lucantoni, Heiko Düssmann, Jochen Hm Prehn Sep 2018

Metabolic Targeting Of Breast Cancer Cells With The 2-Deoxy-D-Glucose And The Mitochondrial Bioenergetics Inhibitor Mdivi-1., Federico Lucantoni, Heiko Düssmann, Jochen Hm Prehn

Physiology and Medical Physics Articles

Breast cancer cells have different requirements on metabolic pathways in order to sustain their growth. Triple negative breast cancer (TNBC), an aggressive breast cancer subtype relies mainly on glycolysis, while estrogen receptor positive (ER+) breast cancer cells possess higher mitochondrial oxidative phosphorylation (OXPHOS) levels. However, breast cancer cells generally employ both pathways to sustain their metabolic needs and to compete with the surrounding environment. In this study, we demonstrate that the mitochondrial fission inhibitor MDIVI-1 alters mitochondrial bioenergetics, at concentrations that do not affect mitochondrial morphology. We show that this effect is accompanied by an increase in glycolysis consumption. Dual ...


Riluzole Does Not Improve Lifespan Or Motor Function In Three Als Mouse Models., Marion C. Hogg, Luise Halang, Ina Woods, Karen S. Coughlan, Jochen Hm Prehn Aug 2018

Riluzole Does Not Improve Lifespan Or Motor Function In Three Als Mouse Models., Marion C. Hogg, Luise Halang, Ina Woods, Karen S. Coughlan, Jochen Hm Prehn

Physiology and Medical Physics Articles

BACKGROUND: Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1

METHODS: Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression.

RESULTS: Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested ...


Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner Jul 2018

Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner

Department of Physics Papers

We give detailed recipes for a number of classroom demonstrations relevant to biological physics instruction. We developed them mainly for use in 2nd-3rd year undergraduate Physics courses. But you can (and we do) use them for primary school, through high school, up to PhD candidates. You adapt the words for each audience, but a phenomenon is a phenomenon.

We also outline a 1-hour introduction to Python for undergraduate scientific computing.

Finally we document some outcomes from courses taught at U Pennsylvania using these resources and others cited here. This material was presented at a workshop at the AAPT meeting in ...


Anti-Angiogenic Drug Scheduling Optimisation With Application To Colorectal Cancer., Marc Sturrock, Ian S. Miller, Guiyeom Kang, N Hannis Arba'ie, Alice C. O'Farrell, Ana Barat, Gemma Marston, Patricia L. Coletta, Annette Byrne, Jochen Hm Prehn Jul 2018

Anti-Angiogenic Drug Scheduling Optimisation With Application To Colorectal Cancer., Marc Sturrock, Ian S. Miller, Guiyeom Kang, N Hannis Arba'ie, Alice C. O'Farrell, Ana Barat, Gemma Marston, Patricia L. Coletta, Annette Byrne, Jochen Hm Prehn

Physiology and Medical Physics Articles

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by "normalizing" abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic ...


Bcl2 And Bcl(X)L Selective Inhibitors Decrease Mitochondrial Atp Production In Breast Cancer Cells And Are Synthetically Lethal When Combined With 2-Deoxy-D-Glucose., Federico Lucantoni, Heiko Düssmann, Irene Llorente-Folch, Jochen Hm Prehn May 2018

Bcl2 And Bcl(X)L Selective Inhibitors Decrease Mitochondrial Atp Production In Breast Cancer Cells And Are Synthetically Lethal When Combined With 2-Deoxy-D-Glucose., Federico Lucantoni, Heiko Düssmann, Irene Llorente-Folch, Jochen Hm Prehn

Physiology and Medical Physics Articles

Cancer cells display differences regarding their engagement of glycolytic vs. mitochondrial oxidative phosphorylation (OXPHOS) pathway. Triple negative breast cancer, an aggressive form of breast cancer, is characterized by elevated glycolysis, while estrogen receptor positive breast cancer cells rely predominantly on OXPHOS. BCL2 proteins control the process of mitochondrial outer membrane permeabilization during apoptosis, but also regulate cellular bioenergetics. Because BCL2 proteins are overexpressed in breast cancer and targetable by selective antagonists, we here analysed the effect of BCL2 and BCL(X)L selective inhibitors, Venetoclax and WEHI-539, on mitochondrial bioenergetics and cell death. Employing single cell imaging using a FRET-based ...


Increased A20-E3 Ubiquitin Ligase Interactions In Bid-Deficient Glia Attenuate Tlr3- And Tlr4-Induced Inflammation., Sinéad Kinsella, Michael Fichtner, Orla Watters, Hans-Georg König, Jochen Hm Prehn May 2018

Increased A20-E3 Ubiquitin Ligase Interactions In Bid-Deficient Glia Attenuate Tlr3- And Tlr4-Induced Inflammation., Sinéad Kinsella, Michael Fichtner, Orla Watters, Hans-Georg König, Jochen Hm Prehn

Physiology and Medical Physics Articles

Background: Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-κB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation.

Methods: We assessed the activation of mitogen-activated protein kinase (MAPK) and ...


Pleiotropic Activity Of Systemically Delivered Angiogenin In The Sod1, Martin Crivello, Saidhbhe L. O'Riordan, Ina Woods, Sarah Cannon, Luise Halang, Karen S. Coughlan, Marion C. Hogg, Sebastian A. Lewandowski, Jochen Hm Prehn May 2018

Pleiotropic Activity Of Systemically Delivered Angiogenin In The Sod1, Martin Crivello, Saidhbhe L. O'Riordan, Ina Woods, Sarah Cannon, Luise Halang, Karen S. Coughlan, Marion C. Hogg, Sebastian A. Lewandowski, Jochen Hm Prehn

Physiology and Medical Physics Articles

Loss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneuronsin vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1G93A mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1G93A mice (n = 45) and non-transgenic controls (n = 31 ...


Apoptosis-Inducing Factor (Aif) In Physiology And Disease: The Tale Of A Repented Natural Born Killer., Daniele Bano, Jochen Hm Prehn Apr 2018

Apoptosis-Inducing Factor (Aif) In Physiology And Disease: The Tale Of A Repented Natural Born Killer., Daniele Bano, Jochen Hm Prehn

Physiology and Medical Physics Articles

Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms ...


Systemic Delivery Of Selective Ep1 And Ep3 Receptor Antagonists Attenuates Pentylenetetrazole-Induced Seizures In Mice., Cristina R Reschke, Alice B. Poersch, Cíntia J. Masson, Ana C. Jesse, Joseane Rr Marafiga, Quéli F. Lenz, Mauro S. Oliveira, David C. Henshall, Carlos F. Mello Mar 2018

Systemic Delivery Of Selective Ep1 And Ep3 Receptor Antagonists Attenuates Pentylenetetrazole-Induced Seizures In Mice., Cristina R Reschke, Alice B. Poersch, Cíntia J. Masson, Ana C. Jesse, Joseane Rr Marafiga, Quéli F. Lenz, Mauro S. Oliveira, David C. Henshall, Carlos F. Mello

Physiology and Medical Physics Articles

Neuroinflammation plays a major role in brain excitability and may contribute to the development of epilepsy. Prostaglandin E2 (PGE2) is a direct mediator of inflammatory responses and, through EP receptors, plays an important role in neuronal excitability. Pharmacological evidence supports that centrally-administered EP1 and EP3 receptor antagonists reduced acutely evoked seizures in rats. Translation of these findings would benefit from evidence of efficacy with a more clinically relevant route of delivery and validation in another species. In the current study we investigated whether the systemic administration of EP1 and EP3 agonists and antagonists modulate pentylenetetrazole (PTZ)-induced seizures in mice ...


Simulating And Predicting Cellular And In Vivo Responses Of Colon Cancer To Combined Treatment With Chemotherapy And Iap Antagonist Birinapant/Tl32711., Nyree Crawford, Manuela Salvucci, Christian T. Hellwig, Frank A. Lincoln, Ruth E. Mooney, Carla L O'Connor, Jochen Hm Prehn, Daniel B Longley, Markus Rehm Mar 2018

Simulating And Predicting Cellular And In Vivo Responses Of Colon Cancer To Combined Treatment With Chemotherapy And Iap Antagonist Birinapant/Tl32711., Nyree Crawford, Manuela Salvucci, Christian T. Hellwig, Frank A. Lincoln, Ruth E. Mooney, Carla L O'Connor, Jochen Hm Prehn, Daniel B Longley, Markus Rehm

Physiology and Medical Physics Articles

Apoptosis resistance contributes to treatment failure in colorectal cancer (CRC). New treatments that reinstate apoptosis competency have potential to improve patient outcome but require predictive biomarkers to target them to responsive patient populations. Inhibitor of apoptosis proteins (IAPs) suppress apoptosis, contributing to drug resistance; IAP antagonists such as TL32711 have therefore been developed. We developed a systems biology approach for predicting response of CRC cells to chemotherapy and TL32711 combinations in vitro and in vivo. CRC cells responded poorly to TL32711 monotherapy in vitro; however, co-treatment with 5-fluorouracil (5-FU) and oxaliplatin enhanced TL32711-induced apoptosis. Notably, cells from genetically identical populations ...


Molecular Mechanisms Of Cell Death: Recommendations Of The Nomenclature Committee On Cell Death 2018., Lorenzo Galluzzi, Ilio Vitale, Stuart A Aaronson, John M Abrams, Dieter Adam, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Margherita Annicchiarico-Petruzzelli, Alexey V Antonov, Eli Arama, Eric H Baehrecke, Nickolai A Barlev, Nicolas G Bazan, Francesca Bernassola, Mathieu J M Bertrand, Katiuscia Bianchi, Mikhail V Blagosklonny, Klas Blomgren, Christoph Borner, Patricia Boya, Catherine Brenner, Michelangelo Campanella, Eleonora Candi, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Navdeep S Chandel, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gerald M Cohen, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Ted M Dawson, Valina L Dawson, Vincenzo De Laurenzi, Ruggero De Maria, Klaus-Michael Debatin, Ralph J Deberardinis, Mohanish Deshmukh, Nicola Di Daniele, Francesco Di Virgilio, Vishva M Dixit, Scott J Dixon, Colin S Duckett, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Gian Maria Fimia, Simone Fulda, Ana J García-Sáez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Pierre Golstein, Eyal Gottlieb, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Atan Gross, Gyorgy Hajnoczky, J Marie Hardwick, Isaac S Harris, Michael O Hengartner, Claudio Hetz, Hidenori Ichijo, Marja Jäättelä, Bertrand Joseph, Philipp J Jost, Philippe P Juin, William J Kaiser, Michael Karin, Thomas Kaufmann, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Richard A Knight, Sharad Kumar, Sam W Lee, John J Lemasters, Beth Levine, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Scott W Lowe, Tom Luedde, Enrico Lugli, Marion Macfarlane, Frank Madeo, Michal Malewicz, Walter Malorni, Gwenola Manic, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Sonia Melino, Edward A Miao, Jeffery D Molkentin, Ute M Moll, Cristina Muñoz-Pinedo, Shigekazu Nagata, Gabriel Nuñez, Andrew Oberst, Moshe Oren, Michael Overholtzer, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, David M Pereira, Shazib Pervaiz, Marcus E Peter, Mauro Piacentini, Paolo Pinton, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Markus Rehm, Rosario Rizzuto, Cecilia M P Rodrigues, David C Rubinsztein, Thomas Rudel, Kevin M Ryan, Emre Sayan, Luca Scorrano, Feng Shao, Yufang Shi, John Silke, Hans-Uwe Simon, Antonella Sistigu, Brent R Stockwell, Andreas Strasser, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Andrew Thorburn, Yoshihide Tsujimoto, Boris Turk, Tom Vanden Berghe, Peter Vandenabeele, Matthew G Vander Heiden, Andreas Villunger, Herbert W Virgin, Karen H Vousden, Domagoj Vucic, Erwin F Wagner, Henning Walczak, David Wallach, Ying Wang, James A Wells, Will Wood, Junying Yuan, Zahra Zakeri, Boris Zhivotovsky, Laurence Zitvogel, Gerry Melino, Guido Kroemer Mar 2018

Molecular Mechanisms Of Cell Death: Recommendations Of The Nomenclature Committee On Cell Death 2018., Lorenzo Galluzzi, Ilio Vitale, Stuart A Aaronson, John M Abrams, Dieter Adam, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Margherita Annicchiarico-Petruzzelli, Alexey V Antonov, Eli Arama, Eric H Baehrecke, Nickolai A Barlev, Nicolas G Bazan, Francesca Bernassola, Mathieu J M Bertrand, Katiuscia Bianchi, Mikhail V Blagosklonny, Klas Blomgren, Christoph Borner, Patricia Boya, Catherine Brenner, Michelangelo Campanella, Eleonora Candi, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Navdeep S Chandel, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gerald M Cohen, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Ted M Dawson, Valina L Dawson, Vincenzo De Laurenzi, Ruggero De Maria, Klaus-Michael Debatin, Ralph J Deberardinis, Mohanish Deshmukh, Nicola Di Daniele, Francesco Di Virgilio, Vishva M Dixit, Scott J Dixon, Colin S Duckett, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Gian Maria Fimia, Simone Fulda, Ana J García-Sáez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Pierre Golstein, Eyal Gottlieb, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Atan Gross, Gyorgy Hajnoczky, J Marie Hardwick, Isaac S Harris, Michael O Hengartner, Claudio Hetz, Hidenori Ichijo, Marja Jäättelä, Bertrand Joseph, Philipp J Jost, Philippe P Juin, William J Kaiser, Michael Karin, Thomas Kaufmann, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Richard A Knight, Sharad Kumar, Sam W Lee, John J Lemasters, Beth Levine, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Scott W Lowe, Tom Luedde, Enrico Lugli, Marion Macfarlane, Frank Madeo, Michal Malewicz, Walter Malorni, Gwenola Manic, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Sonia Melino, Edward A Miao, Jeffery D Molkentin, Ute M Moll, Cristina Muñoz-Pinedo, Shigekazu Nagata, Gabriel Nuñez, Andrew Oberst, Moshe Oren, Michael Overholtzer, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, David M Pereira, Shazib Pervaiz, Marcus E Peter, Mauro Piacentini, Paolo Pinton, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Markus Rehm, Rosario Rizzuto, Cecilia M P Rodrigues, David C Rubinsztein, Thomas Rudel, Kevin M Ryan, Emre Sayan, Luca Scorrano, Feng Shao, Yufang Shi, John Silke, Hans-Uwe Simon, Antonella Sistigu, Brent R Stockwell, Andreas Strasser, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Andrew Thorburn, Yoshihide Tsujimoto, Boris Turk, Tom Vanden Berghe, Peter Vandenabeele, Matthew G Vander Heiden, Andreas Villunger, Herbert W Virgin, Karen H Vousden, Domagoj Vucic, Erwin F Wagner, Henning Walczak, David Wallach, Ying Wang, James A Wells, Will Wood, Junying Yuan, Zahra Zakeri, Boris Zhivotovsky, Laurence Zitvogel, Gerry Melino, Guido Kroemer

Physiology and Medical Physics Articles

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell ...


The Bax/Bak-Like Protein Bok Is A Prognostic Marker In Colorectal Cancer., Steven Carberry, Beatrice D'Orsi, Naser Monsefi, Manuela Salvucci, Orna Bacon, Joanna Fay, Markus Rehm, Deborah A. Mcnamara, Elaine W. Kay, Jochen H M Prehn Jan 2018

The Bax/Bak-Like Protein Bok Is A Prognostic Marker In Colorectal Cancer., Steven Carberry, Beatrice D'Orsi, Naser Monsefi, Manuela Salvucci, Orna Bacon, Joanna Fay, Markus Rehm, Deborah A. Mcnamara, Elaine W. Kay, Jochen H M Prehn

Physiology and Medical Physics Articles

The intrinsic or mitochondrial apoptosis pathway is controlled by the interaction of antiapoptotic and pro-apoptotic members of the BCL-2 protein family. Activation of this death pathway plays a crucial role in cancer progression and chemotherapy responses. The BCL-2-related ovarian killer (BOK) possesses three BCL-2 homology domains and has been proposed to act in a similar pro-apoptotic pathway as the pro-apoptotic proteins BAX and BAK. In this study, we showed that stage II and III colorectal cancer patients possessed decreased levels of BOK protein in their tumours compared to matched normal tissue. BOK protein levels in tumours were also prognostic of ...


A Constitutively-Active Ikk-Complex At The Axon Initial Segment., Hans-Georg König, Orla Watters, Sinéad Kinsella, Mohammed Ameen, Beau J Fenner, Jochen H.M. Prehn Jan 2018

A Constitutively-Active Ikk-Complex At The Axon Initial Segment., Hans-Georg König, Orla Watters, Sinéad Kinsella, Mohammed Ameen, Beau J Fenner, Jochen H.M. Prehn

Physiology and Medical Physics Articles

BACKGROUND: Previous studies provided evidence for an accumulation of IκB-kinase (IKK) α/β at the axon initial segment (AIS), a neuronal compartment defined by ankyrin-G expression. Here we explored whether the presence of the IKK-complex at the AIS was associated with the activation of IKK signaling at this site.

METHODS AND RESULTS: Proximity-ligation assays (PLAs) using pan-IKKα/β, phospho-IKKα/β-specific as well as ankyrin-G specific antibodies validated their binding to proximal epitopes in the AIS, while antibodies to other phosphorylated signaling proteins showed no preference for the AIS. Small-hairpin mediated silencing of IKKβ significantly reduced anti-phospho-IKKα/β-immunoreactivities in the AIS ...


Guidelines On Experimental Methods To Assess Mitochondrial Dysfunction In Cellular Models Of Neurodegenerative Diseases., Niamh M. Connolly, Pierre Theurey, Vera Adam-Vizi, Nicolas G. Bazan, Paolo Bernardi, Juan P. Bolaños, Carsten Culmsee, Valina L. Dawson, Mohanish Deshmukh, Michael R. Duchen, Heiko Düssmann, Gary Fiskum, Maria F. Galindo, Giles E. Hardingham, J Marie Hardwick, Mika B. Jekabsons, Elizabeth A. Jonas, Joaquin Jordán, Stuart A. Lipton, Giovanni Manfredi, Mark P. Mattson, Bethann Mclaughlin, Axel Methner, Anne N. Murphy, Michael P. Murphy, David G. Nicholls, Brian M. Polster, Tullio Pozzan, Rosario Rizzuto, Jorgina Satrústegui, Ruth S. Slack, Raymond A. Swanson, Russell H. Swerdlow, Yvonne Will, Zheng Ying, Alvin Joselin, Anna Gioran, Catarina Moreira Pinho, Orla Watters, Manuela Salvucci, Irene Llorente-Folch, David S. Park, Daniele Bano, Maria Ankarcrona, Paola Pizzo, Jochen Hm Prehn Dec 2017

Guidelines On Experimental Methods To Assess Mitochondrial Dysfunction In Cellular Models Of Neurodegenerative Diseases., Niamh M. Connolly, Pierre Theurey, Vera Adam-Vizi, Nicolas G. Bazan, Paolo Bernardi, Juan P. Bolaños, Carsten Culmsee, Valina L. Dawson, Mohanish Deshmukh, Michael R. Duchen, Heiko Düssmann, Gary Fiskum, Maria F. Galindo, Giles E. Hardingham, J Marie Hardwick, Mika B. Jekabsons, Elizabeth A. Jonas, Joaquin Jordán, Stuart A. Lipton, Giovanni Manfredi, Mark P. Mattson, Bethann Mclaughlin, Axel Methner, Anne N. Murphy, Michael P. Murphy, David G. Nicholls, Brian M. Polster, Tullio Pozzan, Rosario Rizzuto, Jorgina Satrústegui, Ruth S. Slack, Raymond A. Swanson, Russell H. Swerdlow, Yvonne Will, Zheng Ying, Alvin Joselin, Anna Gioran, Catarina Moreira Pinho, Orla Watters, Manuela Salvucci, Irene Llorente-Folch, David S. Park, Daniele Bano, Maria Ankarcrona, Paola Pizzo, Jochen Hm Prehn

Physiology and Medical Physics Articles

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in ...


The Role Of B Cell Antigen Receptors In Mantle Cell Lymphoma., Michael Fichtner, Martin Dreyling, Mascha Binder, Martin Trepel Oct 2017

The Role Of B Cell Antigen Receptors In Mantle Cell Lymphoma., Michael Fichtner, Martin Dreyling, Mascha Binder, Martin Trepel

Physiology and Medical Physics Articles

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and secondary resistance to currently available therapies in most cases. Therefore, despite recent advances in the treatment of this disease, it is still considered to be incurable in the majority of cases. MCL B cells retain their B cell antigen receptor (BCR) expression during and after neoplastic transformation. BCRs in MCL show distinct patterns of antigen selection and ongoing BCR signaling. However, little is known about the involved antigens and the mechanisms leading to lymphomagenesis and lymphoma progression in MCL. Recent preclinical and clinical studies have established a crucial ...


Assessment Of Concordance Between Fresh-Frozen And Formalin-Fixed Paraffin Embedded Tumor Dna Methylation Using A Targeted Sequencing Approach., Bruce Moran, Sudipto Das, Dominiek Smeets, Gillian Peutman, Ruth Klinger, Bozena Fender, Kate Connor, Matthias Ebert, Timo Gaiser, Jochen Hm Prehn, Orna Bacon, Elaine W. Kay, Bryan T. Hennessy, Verena Murphy, Bauke Ylstra, Diether Lambrechts, Annette T. Byrne, William M Gallagher, Darran P. O'Connor Jul 2017

Assessment Of Concordance Between Fresh-Frozen And Formalin-Fixed Paraffin Embedded Tumor Dna Methylation Using A Targeted Sequencing Approach., Bruce Moran, Sudipto Das, Dominiek Smeets, Gillian Peutman, Ruth Klinger, Bozena Fender, Kate Connor, Matthias Ebert, Timo Gaiser, Jochen Hm Prehn, Orna Bacon, Elaine W. Kay, Bryan T. Hennessy, Verena Murphy, Bauke Ylstra, Diether Lambrechts, Annette T. Byrne, William M Gallagher, Darran P. O'Connor

Physiology and Medical Physics Articles

DNA methylation is altered in many types of disease, including metastatic colorectal cancer. However, the methylome has not yet been fully described in archival formalin-fixed paraffin embedded (FFPE) samples in the context of matched fresh-frozen (FF) tumor material at base-pair resolution using a targeted approach. Using next-generation sequencing, we investigated three pairs of matched FFPE and FF samples to determine the extent of their similarity. We identified a 'bowing' pattern specific to FFPE samples categorized by a lower CG proportion at the start of sequence reads. We have found no evidence that this affected methylation calling, nor concordance of results ...


Targeting The Proteasome In Epilepsy., Tobias Engel, Jose J Lucas, David C. Henshall Jul 2017

Targeting The Proteasome In Epilepsy., Tobias Engel, Jose J Lucas, David C. Henshall

Physiology and Medical Physics Articles

No abstract provided.


The Influence Of Nuclear Compartmentalisation On Stochastic Dynamics Of Self-Repressing Gene Expression., Marc Sturrock, Shiyu Li, Vahid Shahrezaei Jul 2017

The Influence Of Nuclear Compartmentalisation On Stochastic Dynamics Of Self-Repressing Gene Expression., Marc Sturrock, Shiyu Li, Vahid Shahrezaei

Physiology and Medical Physics Articles

Gene expression is an inherently noisy process. This noise is generally thought to be deleterious as precise internal regulation of biochemical reactions is essential for cell growth and survival. Self-repression of gene expression, which is the simplest form of a negative feedback loop, is commonly believed to be employed by cellular systems to decrease the stochastic fluctuations in gene expression. When there is some delay in autoregulation, it is also believed that this system can generate oscillations. In eukaryotic cells, mRNAs that are synthesised in the nucleus must be exported to the cytoplasm to function in protein synthesis, whereas proteins ...


Apelin: A Putative Novel Predictive Biomarker For Bevacizumab Response In Colorectal Cancer., Linda Zuurbier, Arman Rahman, Martijn Cordes, Jennifer Scheick, Tse J. Wong, François Rustenburg, Jesu C. Joseph, Peter Dynoodt, Rory Casey, Paul Drillenburg, Michael Gerhards, Ana Barat, Rut Klinger, Bozena Fender, Darran P. O'Connor, Johannes Betge, Matthias P. Ebert, Timo Gaiser, Jochen Hm Prehn, Arjan W. Griffioen, Nicole Ct Van Grieken, Bauke Ylstra, Annette Byrne, Laurens G. Van Der Flier, William M. Gallagher, Ruben Postel Jun 2017

Apelin: A Putative Novel Predictive Biomarker For Bevacizumab Response In Colorectal Cancer., Linda Zuurbier, Arman Rahman, Martijn Cordes, Jennifer Scheick, Tse J. Wong, François Rustenburg, Jesu C. Joseph, Peter Dynoodt, Rory Casey, Paul Drillenburg, Michael Gerhards, Ana Barat, Rut Klinger, Bozena Fender, Darran P. O'Connor, Johannes Betge, Matthias P. Ebert, Timo Gaiser, Jochen Hm Prehn, Arjan W. Griffioen, Nicole Ct Van Grieken, Bauke Ylstra, Annette Byrne, Laurens G. Van Der Flier, William M. Gallagher, Ruben Postel

Physiology and Medical Physics Articles

Bevacizumab (bvz) is currently employed as an anti-angiogenic therapy across several cancer indications. Bvz response heterogeneity has been well documented, with only 10-15% of colorectal cancer (CRC) patients benefitting in general. For other patients, clinical efficacy is limited and side effects are significant. This reinforces the need for a robust predictive biomarker of response. To identify such a biomarker, we performed a DNA microarray-based transcriptional profiling screen with primary endothelial cells (ECs) isolated from normal and tumour colon tissues. Thirteen separate populations of tumour-associated ECs and 10 of normal ECs were isolated using fluorescence-activated cell sorting. We hypothesised that VEGF-induced ...