Nicolson G.L.,Institute for Molecular Medicine
Cancer Research | Year: 2015
Cancer cells are surrounded by a fluid-mosaic membrane that provides a highly dynamic structural barrier with the microenvironment, communication filter and transport, receptor and enzyme platform. This structure forms because of the physical properties of its constituents, which can move laterally and selectively within the membrane plane and associate with similar or different constituents, forming specific, functional domains. Over the years, data have accumulated on the amounts, structures, and mobilities of membrane constituents after transformation and during progression and metastasis. More recent information has shown the importance of specialized membrane domains, such as lipid rafts, protein-lipid complexes, receptor complexes, invadopodia, and other cellular structures in the malignant process. In describing the macrostructure and dynamics of plasma membranes, membrane-associated cytoskeletal structures and extracellular matrix are also important, constraining the motion of membrane components and acting as traction points for cell motility. These associations may be altered in malignant cells, and probably also in surrounding normal cells, promoting invasion and metastatic colonization. In addition, components can be released from cells as secretory molecules, enzymes, receptors, large macromolecular complexes, membrane vesicles, and exosomes that can modify the microenvironment, provide specific cross-talk, and facilitate invasion, survival, and growth of malignant cells. ©2015 AACR.
Nicolson G.L.,Institute for Molecular Medicine
Cancer and Metastasis Reviews | Year: 2010
Cancer-associated fatigue is one of the most common symptoms in all forms and stages of cancer, yet scant attention is usually given to patients who have symptomatic complaints of fatigue. Cancer-associated fatigue is also associated with cellular oxidative stress, and during cancer therapy, excess drug-induced oxidative stress can limit therapeutic effectiveness and cause a number of side effects, including fatigue, nausea, vomiting, and more serious adverse effects. Cancer-associated fatigue and the chronic adverse effects of cancer therapy can be reduced by lipid replacement therapy using membrane lipids along with antioxidants and enzymatic cofactors, such as coenzyme Q10, given as food supplements. Administering these nutraceutical supplements can reduce oxidative membrane damage and restore mitochondrial and other cellular functions. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefits of lipid replacement therapy in reducing fatigue and restoring mitochondrial electron transport function. © 2010 Springer Science+Business Media, LLC.
Croxford A.L.,University of Zurich |
Croxford A.L.,Institute for Molecular Medicine |
Buch T.,University of Zurich |
Buch T.,TU Munich
Immunology | Year: 2011
Cytokines are soluble messenger molecules with important regulatory functions throughout the immune system. 'Cytokine reporter' strains express marker molecules under control of elements from cytokine genes allowing for easy identification of their cellular sources. Such systems are well-accepted tools for research of cytokine function. The value of these strains lies in the ability to perform experiments relying on identification and isolation of live cytokine-expressing cells, provided that the reporter faithfully reflects the proper cytokine mRNA and protein production. As more diverse cell subsets are defined by their cytokine expression, the field has adapted with the generation of more sophisticated strains. In this review we summarize the evolution of cytokine detection methods and give examples of knowledge gained using cytokine reporter mice for cell types expressing interferon-γ and interleukin-4, -10 and -17. We also discuss current options for generating such reporter strains and their potential pitfalls. © 2010 The Authors. Immunology © 2010 Blackwell Publishing Ltd.
Nicolson G.L.,Institute for Molecular Medicine
Biochimica et Biophysica Acta - Biomembranes | Year: 2014
In 1972 the Fluid - Mosaic Membrane Model of membrane structure was proposed based on thermodynamic principals of organization of membrane lipids and proteins and available evidence of asymmetry and lateral mobility within the membrane matrix [S. J. Singer and G. L. Nicolson, Science 175 (1972) 720-731]. After over 40 years, this basic model of the cell membrane remains relevant for describing the basic nano-structures of a variety of intracellular and cellular membranes of plant and animal cells and lower forms of life. In the intervening years, however, new information has documented the importance and roles of specialized membrane domains, such as lipid rafts and protein/glycoprotein complexes, in describing the macrostructure, dynamics and functions of cellular membranes as well as the roles of membrane-associated cytoskeletal fences and extracellular matrix structures in limiting the lateral diffusion and range of motion of membrane components. These newer data build on the foundation of the original model and add new layers of complexity and hierarchy, but the concepts described in the original model are still applicable today. In updated versions of the model more emphasis has been placed on the mosaic nature of the macrostructure of cellular membranes where many protein and lipid components are limited in their rotational and lateral motilities in the membrane plane, especially in their natural states where lipid-lipid, protein-protein and lipid-protein interactions as well as cell-matrix, cell-cell and intracellular membrane-associated protein and cytoskeletal interactions are important in restraining the lateral motility and range of motion of particular membrane components. The formation of specialized membrane domains and the presence of tightly packed integral membrane protein complexes due to membrane-associated fences, fenceposts and other structures are considered very important in describing membrane dynamics and architecture. These structures along with membrane-associated cytoskeletal and extracellular structures maintain the long-range, non-random mosaic macro-organization of membranes, while smaller membrane nano- and submicro-sized domains, such as lipid rafts and protein complexes, are important in maintaining specialized membrane structures that are in cooperative dynamic flux in a crowded membrane plane. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. © 2013 Elsevier B.V.
A sign is seen at an AstraZeneca site in Macclesfield, central England May 19, 2014. REUTERS/Phil Noble CAMBRIDGE, England (Reuters) - AstraZeneca, working with genome pioneer Craig Venter, is launching a massive gene hunt in the most comprehensive bet yet by a pharmaceutical firm on the potential of genetic variations to unlock routes to new medicines. The initiative, announced on Friday, involves sequencing up to 2 million human genomes - the complete set of genetic code that acts as the software of life - including 500,000 DNA samples collected by AstraZeneca in global clinical trials. Financial details of the 10-year project were not disclosed but Mene Pangalos, head of early drug development, said the company would be investing "hundreds of millions of dollars". AstraZeneca aims to identify rare genetic mutations involved in every kind of disease by scanning DNA from volunteers who agreed to have their genomes sequenced and to provide access to detailed medical records. The project is made possible by a dramatic fall in the cost of genetic sequencing. It took government-funded scientists $3 billion and 13 years to sequence the first human genome by 2003. Today, it costs around $1,000 and takes just three days. AstraZeneca will work with Venter's U.S. company Human Longevity Inc (HLI), which will sequence the genomes, including 1 million from HLI's database, and use machine-learning software to find patterns in genetic variations. The British group, which is establishing an in-house Centre for Genomics Research in Cambridge, where it is relocating its global headquarters, has also partnered with the Wellcome Trust Sanger Institute and Finland's Institute for Molecular Medicine. AstraZeneca is not the first drugmaker to start amassing troves of human DNA in this way but Venter, one of the first scientists to sequence the human genome, said it was the biggest commitment to date by any pharmaceutical company. Regeneron Pharmaceuticals signed a deal with Pennsylvania's Geisinger Health System two years ago to sequence partial genomes of some 250,000 volunteers, while Roche's Genentech unit signed a deal last year for HLI to sequence tens of thousands of genomes. "The big thing here is the magnitude of what we are trying to do," Pangalos said. "This takes it to a completely different level and I think it is going to be relevant of every therapeutic area." Until now, the field of genomics has largely failed to live up to the hype of hoped-for medical breakthroughs, although more recently genetic understanding has been crucial in the development of some cancer treatments. Now, thanks to industrial-scale sequencing and advances in gene editing that allow scientists to quickly test the effects of genetic variations, progress is expected to accelerate. Venter believes it could also unleash a new era of forensics, with HLI trying to predict what people might look like from their DNA. AstraZeneca’s decision to embed genomics across its research and development follows a push last year by the company to expand gene testing into areas including heart disease and asthma. “I believe we really have finally turned the corner and genomics will become central in drug development efforts,” said David Goldstein, a genetics expert from Columbia University, who chairs AstraZeneca’s Genomics Advisory Board.