Institute for Molecular Medicine

Huntington Beach, CA, United States

Institute for Molecular Medicine

Huntington Beach, CA, United States
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News Article | April 28, 2017
Site: www.eurekalert.org

Researchers at the University Medical Center of Johannes Gutenberg University Mainz and the German Research Center for Environmental Health, Helmholtz Zentrum München have discovered that too much of the oncogene Bcl-3 leads to chronic intestinal diseases. They describe in Nature Communications exactly how it throws the immune system off-balance. Chronic intestinal disorders such as ulcerative colitis and Crohn's disease are caused by the body's own immune defense system. Sufferers frequently experience episodic symptoms such as abdominal pain, cramps, and diarrhea. Researchers are still trying to identify the precise underlying origins of these problems. A team led by Dr. Nadine Hövelmeyer and Professor Ari Waisman of the Mainz University Medical Center in collaboration with Dr. Elke Glasmacher of Helmholtz Zentrum München has discovered a new mechanism that causes intestinal inflammation. "With the help of our cooperation partners, we were able to demonstrate that the level of the Bcl-3 protein, which also plays a role in the development of various cancerous diseases, is elevated in the intestinal tract of colitis patients and is indeed a trigger of the disease," said Dr. Nadine Hövelmeyer, head of the work group at the Mainz-based Institute for Molecular Medicine. According to the study, Bcl-3 develops its effect on intestinal health through interaction with the so-called regulatory T-cells (Tregs). Their main task is to prevent overreaction of the immune system and to develop a level of tolerance towards the body they serve. "We were able to demonstrate that Bcl-3 suppresses the activation of Tregs by preventing the necessary genes from being read," explained Dr. Elke Glasmacher, head of the team at the Institute for Diabetes and Obesity in Munich. "Bcl-3 interacts with the transcription factor p50, which is otherwise responsible for activation, and blocks it." "Consequentially, the regulatory T-cells remain passive, the immune system is no longer regulated, and inflammatory processes begin to take place. Experiments using various models have revealed that elevated quantities of Bcl-3 cause certain cells to migrate to the intestines, where they trigger a severe inflammatory response," Dr. Sonja Reissig, lead author of the publication and research associate at Mainz University Medical Center, pointed out. "The results represent a major contribution towards our understanding of chronic intestinal inflammation and hopefully over the long-term will help us discover aspects that we can target with new therapies," concluded Hövelmeyer. Her colleague Professor Ari Waisman, Director of the Institute for Molecular Medicine at the Mainz University Medical Center, added: "We are currently focusing on the search for new active agents that will prevent the interaction between Bcl-3 and p50, thus maintaining normal Treg functionality." Reissig, S. et al. (2017): Bcl-3 Inhibits NF-κB Gene Activity in Regulatory T cells and Modulates their Suppressive Capacity. Nature Communications, DOI: 10.1038/NCOMMS15069


News Article | May 15, 2017
Site: www.chromatographytechniques.com

A new study shows that whole tomato extracts from two different Southern Italy cultivars inhibit gastric cancer cell growth and malignant features, paving the way for future studies aimed at implementing lifestyle habits not only for prevention, but potentially as a support to conventional therapies. “Their antitumoral effect seem not related to specific components, such as lycopene, but rather suggest that tomatoes should be considered in their entirety,” says Daniela Barone, researcher at the Oncology Research Center of Mercogliano (CROM), and one of the authors of the study. Experiments analyzed whole tomato lipophilic extracts for their ability to tackle various neoplastic features of gastric cancer cell lines. Extracts of both the San Marzano and Corbarino tomato varieties were able to inhibit the growth and cloning behavior of malignant cells. Treatment with the whole tomato extracts affected key processes within the cells hindering their migration ability, arresting cell cycle through the modulation of retinoblastoma family proteins and specific cell cycle inhibitors, and ultimately inducing cancer cell death through apoptosis. The study, published in the Journal of Cellular Physiology, details findings by Daniela Barone and Letizia Cito, from the research group at the National Cancer Institute of Naples, Pascale Foundation, CROM, coordinated by Prof. Antonio Giordano, Director of the Sbarro Institute for Molecular Medicine, Temple University, Philadelphia Pa. “Our results prompt further assessment of the potential use of specific nutrients not only in the cancer prevention setting but also as a supportive strategy along with conventional therapies,” says Giordano. “Distinct species may exert different effects, in different stages of a certain neoplasm,” adds Barone. Gastric cancer is the fourth most common type of cancer worldwide and has been associated with genetic causes, Helicobacter pylori infection, and eating habits, such as consumption of smoked and salted food. Tomatoes are consumed worldwide and are a staple of the Mediterranean diet, which is popularly thought to lower cancer risk. Various tomato components have also been analyzed for their ability to counteract tumor growth in experimental systems, although few studies have analyzed the effects of tomatoes in their entirety. The study authors worked in collaboration with researchers from Barbara Nicolaus’ group and Rocco De Prisco at the National Research Council of Pozzuoli, Italy. “This work stems from the SHRO research program performed through a longstanding collaboration with the Department of Medicine, Surgery and Neuroscience, University of Siena, and the Pascale Institute, CROM of Mercogliano. On the wake of these results Dr Attilio Bianchi, General Director of the Pascale Institute and CROM, and I teamed up to renew the collaboration with SHRO implementing the nutrigenomics studies for the benefit of cancer patients,” concludes Giordano.


News Article | April 22, 2016
Site: news.yahoo.com

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.


News Article | April 22, 2016
Site: news.yahoo.com

Genetic researcher Craig Venter is shown with a multiple camera exposure in his office in La Jolla, California March 7, 2014. REUTERS/Mike Blake 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 (697 pounds) 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.


Nicolson G.L.,Institute for Molecular Medicine | Ash M.E.,Clinical Education
Biochimica et Biophysica Acta - Biomembranes | Year: 2014

Lipid Replacement Therapy, the use of functional oral supplements containing cell membrane phospholipids and antioxidants, has been used to replace damaged, usually oxidized, membrane glycerophospholipids that accumulate during aging and in various clinical conditions in order to restore cellular function. This approach differs from other dietary and intravenous phospholipid interventions in the composition of phospholipids and their defense against oxidation during storage, ingestion, digestion and uptake as well as the use of protective molecules that noncovalently complex with phospholipid micelles and prevent their enzymatic and bile disruption. Once the phospholipids have been taken in by transport processes, they are protected by several natural mechanisms involving lipid receptors, transport and carrier molecules and circulating cells and lipoproteins until their delivery to tissues and cells where they can again be transferred to intracellular membranes by specific and nonspecific transport systems. Once delivered to membrane sites, they naturally replace and stimulate removal of damaged membrane lipids. Various chronic clinical conditions are characterized by membrane damage, mainly oxidative but also enzymatic, resulting in loss of cellular function. This is readily apparent in mitochondrial inner membranes where oxidative damage to phospholipids like cardiolipin and other molecules results in loss of trans-membrane potential, electron transport function and generation of high-energy molecules. Recent clinical trials have shown the benefits of Lipid Replacement Therapy in restoring mitochondrial function and reducing fatigue in aged subjects and patients with a variety of clinical diagnoses that are characterized by loss of mitochondrial function and include fatigue as a major symptom. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. © 2013 The Authors.


News Article | March 2, 2017
Site: www.eurekalert.org

CINCINNATI - As people get older so do the hematopoietic stem cells (HSCs) that form their blood, creating an increased risk for compromised immunity and certain blood cancers. Now researchers are reporting in the scientific journal EMBO that the bone marrow niche where HSC's form also ages, contributing to the problem. In a study published March 2, scientists from the University of Ulm in Germany and Cincinnati Children's Hospital Medical Center in the United States propose rejuvenating the bone marrow niche where HSCs are created. This could mean younger acting HSCs that form healthier blood cells, boosted immunity in older people, and a better defense mechanism against certain cancers, according to study authors. Conducting their study in mouse models, the scientists point to cells in the bone marrow called osteoblasts, which help form bone. Osteoblasts make a protein called osteopontin, which is important to supporting a vibrant bone marrow environment in the creation of blood-forming HSCs. "We show that the place where HSCs form in the bone marrow loses osteopontin upon aging, but if you give back the missing protein to the blood-forming cells they suddenly rejuvenate and act younger," says Hartmut Geiger, PhD, study lead investigator at the Institute for Molecular Medicine and Aging Research Center at the University of Ulm, and the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. "Our study points to exciting novel ways to have a better immune system and possibly less blood cancer upon aging by therapeutically targeting the place where blood stem cells form." Because the study was in mice, its findings cannot at this stage be extended to clinical treatment of human patients, the authors say. But the data provide interesting leads that one day could benefit human health. The researchers conducted a number of experiments to test the formation and vitality of cells in and near the bone marrow microenvironment. One test in aging mice looked at the formation of endosteum stroma cells, which form a thin layer of connective tissue on the inner surface of bones. Another experiment monitored levels of osteopontin and other proteins linked to distinct cells in bone marrow during the aging process. Study authors say they observed reduced production of osteoblasts and other stroma cells in the endosteum of older mice. They also saw decreased osteopontin protein levels in the bone marrow of older animals, which they note was associated with reduced vigor and function of blood-forming HSCs. Scientists followed up the earlier experiments by transplanting bone marrow cells from older mice (19-21 months) into young mice (8 to 10 weeks). In two other experiments, the authors also transplanted aged HSCs from older mice into younger mice, and they treated aged HSCs with a recombinant form of the osteopontin protein. Transplantation into the younger animals caused cells to act in a younger more vital manner, the authors report. This includes the presence of smaller numbers of HSCs with greater potential for forming different types of blood cells, which included larger populations of B and T cells and smaller production of myeloid cells. The authors also saw aged HSCs treated with recombinant osteopontin regain their youthful characteristics and capacity to form different blood-cell types. Also observed was diminished signaling of the protein Cdc42, a protein that Geiger and his team previously showed causes HSCs to age. Osteopontin levels are not only low in the bone marrow niche, but also in the blood upon aging. As a follow up to the current study, the researchers are investigating the possibility to use osteopontin replacement therapy in mice to counter the influence of an aging niche directly in the animals. First author on the paper was Novella Guidi, a PhD student and member of the Geiger laboratory. Funding support for the study came from the Deutsche Forschungsgemeinschaft (KFO 142 and SFB 1074), the BMBF-funded Program SyStaR, and the National Institutes of Health (HL076604, DK077762, AG040118).


News Article | November 3, 2016
Site: www.eurekalert.org

New Rochelle, NY, November 3, 2016-Analysis of a single urine sample using a metabolomics-based screening approach can identify multiple different inborn errors of metabolism (IEMs), facilitating early disease detection and rapid initiation of treatment, as described in an article published in Genetic Testing and Molecular Biomarkers, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Genetic Testing and Molecular Biomarkers website until November 30, 2016. Adam Kennedy, Sarah Elsea, and coauthors from Metabolon, Inc. (Durham, NC) and Baylor College of Medicine (Houston, TX), present the automated IEM screening platform they have designed and implemented in the article entitled "Metabolomic Profiling of Human Urine as a Screen for Multiple Inborn Errors of Metabolism". Biochemical signatures have been identified in urine for more than 30 IEMs, which have traditionally been detected in various different bodily fluids including blood and cerebrospinal fluid. This study demonstrates the potential to detect numerous IEMs in a single urine sample using one metabolomics-based assay performed on an automated screening platform. "This is both transformative research and an economical and efficient way to provide precision medicine on a population-based scale," says Genetic Testing and Molecular Biomarkers Editor-in-Chief Garth D. Ehrlich, PhD, FAAAS, Center for Genomic Sciences and Center for Advanced Microbial Processing, Institute for Molecular Medicine and Infectious Disease, Drexel College of Medicine (Philadelphia, PA). Genetic Testing and Molecular Biomarkers is an authoritative peer-reviewed journal published 12 times per year online with open access options and in print that reports on all aspects of genetic testing, including molecular and biochemical based tests and varied clinical situations; ethical, legal, social, and economic aspects of genetic testing; and issues concerning effective genetic counseling. Tables of content and a free sample issue may be viewed on the Genetic Testing and Molecular Biomarkers website. Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Human Gene Therapy and OMICS: A Journal of Integrative Biology. Its biotechnology trade magazine, GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.


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.


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.


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.

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