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The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Competition in regenerative stem cell science, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Toxicity, Medical Devices R&D Investment, Pharmaceutical Analytics, Pharmacologic toxicities, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , , , , , , , on June 11, 2014| Leave a Comment »

The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

 

Updated 6/25/2019

Writer. Reporter: Stephen J. Williams, Ph.D.

gottingen minipig2

 

 

The choice of suitable animal model of disease may define future success or failure for drug development, basic and translational research, or biomarker discovery projects.   Indeed, as highlighted in one of my earlier posts “Heroes in Medical Research: Developing Models for Cancer Research”, the choice of animal to model a human disease can have drastic implications in the basic researchers ability to understand metabolic and genetic factors causally associated with disease development. As described in that post the King rat model led to our understanding of the genetics of early development and sex determination while early mouse models helped us to understand the impact of microenvironment on cell fate and the discovery of stem cells. In addition, transgenic and immunodeficient mice resulted in transformational studies on our understanding of cancer. Small rodent models are ideal for following reasons:

  • Ease of genetic manipulation
  • Availability of well-defined models
  • Ease of low cost of use

Regardless of these benefits many investigators in industry and academia are looking to models of human disease in animals more closely resembling human anatomy, physiology, and genetics.

 

There is a growing need for alternative animal models in cancer research.

 

As I had discussed in another of my earlier posts “The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research”, the pig is gaining notoriety and acceptance as a very suitable animal to model human disease as minipigs and humans have:

  • Similar physiology
  • Similar genetics: >90% homology
  • Similar anatomic dimensions: i.e. Adult Gottingen minipigs are 70kg (adult human male weight)
  • Similar organ size and structure to humans organ size and structure
  • Pig genome sequencing project nearly complete
  • Ability to manipulate pig genetics

The post had discussed the development of a severe combined immunodeficient (SCID) pig by investigators at Iowa State and Kansas State University. This line of pigs, selected on a specific diet, could act as recipients for human cancer cell lines, a proof of their SCID phenotype.

A report featured on Fierce Biotech Research “MU Scientists Successfully Transplant, Grow Stem Cells in Pigs” discussed the development of a new genetically-modified immunodeficient porcine model by researchers at the University of Missouri, recently published in Proceedings of the National Academy of Sciences[1].

These pigs are available from the National Swine Resource and Research Center (http://nsrrc.missouri.edu).

For the report on Fierce Biotech Research please follow the link below:

http://www.fiercebiotechresearch.com/press-releases/mu-scientists-successfully-transplant-grow-stem-cells-pigs

 

The report in FierceBiotech highlights the type of studies an immunocompromised pig model would be useful for including:

  • Regenerative medicine
  • Xenotransplantation
  • Tumor growth and efficacy studies

 

Comments in the post from the investigators explained the benefits of developing such a porcine model system including:

“The rejection of transplants and grafts by host bodies is a huge hurdle for medical researchers,” said R. Michael Roberts, Curators Professor of Animal Science and Biochemistry and a researcher in the Bond Life Sciences Center. “By establishing that these pigs will support transplants without the fear of rejection, we can move stem cell therapy research forward at a quicker pace.”

The studies main investigators, Drs. Randall Prather and R. Michael Roberts, both of University of Missouri, along with first authors Kiho Lee, Deug-Nam Kwon and Toshihiko Ezashi, used biallellic mutation of the RAG2 gene in Gottingen minipig fibroblasts and then subsequent somatic cell nuclear transfer (SCNT) to produce the RAG2-/- animals. (Rag2 is a protein involved in V(D)J recombination of antibodies during early B and T cell development. See GeneCard link above)

As proof of their SCID phenotype the authors showed that

  1. these RAG2-/- animals could act as host for human induced pluripotent stem cells
  2. act as recipient for allogeneic porcine stem cells
  3. reduced levels of (CD21+) B cells and (CD3+) T cells
  4. growth retardation if housed under standard, non-sterile conditions

Details of the study are given below:

Methodology Used

For Production of Gottingen minipigs carrying the RAG2 mutation

To produce targeted mutations in RAG2:

  • TALENS () were constructed to produced mutation in exon 2 of RAG2
  • Constructed TALENS and reporter electroporated in fetal-derived pig fibroblasts
  • SCNT used to transfer RAG2 mutant nuclei to donor oocytes
  • 9 embryo transfers resulted in 22 live piglets
  • Piglets genotyped as either monoallelic or biallelic RAG2 mutant
  • RAG2wild-type and mutants housed in either pathogen-free or normal housing conditions

To verify SCID phenotype of litter by either

  1. Graft acceptance of human iPSCs and teratoma formation

–          Fibroblasts from human umbilical cord reprogrammed to pluripotency; verified by pluripotent markers POUSF1, NANOG, SSEA-3)

–          Two human and porcine iPSC lines with trophoblastic properties[2] were injected subcutaneously in ear or flank

–          Tumor formation analyzed by immunohistochemistry using markers:

CTNNBI (B-catenin)

VWF (von Willebrand

DES and ACTG2

GFAP and ENO2

Human specific MFN1 (both antibody and gene primers)

  1. Flow Cytometry

–          Analysis of piglet spleen cells for B cell population (CD21)

–          Analysis of piglet spleen cell for T cell population (CD3)

C.    Histology

– histo evaluation of thymus, spleen

– marker evaluation of spleen using anti-CD79A (B cells), CD3 (T cells),

CD335 (NK cells)

Results

TALEN produced a variety of indels (insertion/deletions) and three RAG2 mutatnt colonies (containing monoallelic, mix of mono and biallelic) used for SCNT.

Three litters produced 16 piglets (eight survived [four mono and four biallelic]

Biallelic RAG2 mutants showed slower weight gain than wild type or monoallelic mutants with signs of inflammation and apoptosis in spleen and designated “failure to thrive” in standard housing…needed a clean environment to thrive.

Biallelic mutant pigs lacked mature CD21 B cells and CD3 T cells but contained macrophages and NK cells.

Implantation of human and allogenic porcine pluripotent stem cells (trophoblastic) showed rapid development of teratomas.
References

  1. Lee K, Kwon DN, Ezashi T, Choi YJ, Park C, Ericsson AC, Brown AN, Samuel MS, Park KW, Walters EM et al: Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(20):7260-7265.
  2. Ezashi T, Matsuyama H, Telugu BP, Roberts RM: Generation of colonies of induced trophoblast cells during standard reprogramming of porcine fibroblasts to induced pluripotent stem cells. Biology of reproduction 2011, 85(4):779-787.

Updated 6/25/2019

The following articles represent an update on the ability to create genetically predisposed porcine models of cancer.  The ability to utilize transposable elements to introduce genetic changes in porcine cells in combination with Somatic Cell Nuclear Transfer technology with the ultimate goal to create a transgenic minipig is discussed.  The next two articles describe the ability of the scid pig to act as a recipient for human ovarian cancer cells and description of a transgenic inducible porcine intestinal tumor model.

Transgenic Res. 2011 Jun;20(3):533-45. doi: 10.1007/s11248-010-9438-x. Epub 2010 Aug 29.

Pig transgenesis by Sleeping Beauty DNA transposition.

Jakobsen JE1, Li J, Kragh PM, Moldt B, Lin L, Liu Y, Schmidt M, Winther KD, Schyth BD, Holm IE, Vajta G, Bolund L, Callesen H, Jørgensen AL, Nielsen AL, Mikkelsen JG.

Author information

Abstract

Modelling of human disease in genetically engineered pigs provides unique possibilities in biomedical research and in studies of disease intervention. Establishment of methodologies that allow efficient gene insertion by non-viral gene carriers is an important step towards development of new disease models. In this report, we present transgenic pigs created by Sleeping Beauty DNA transposition in primary porcine fibroblasts in combination with somatic cell nuclear transfer by handmade cloning. Göttingen minipigs expressing green fluorescent protein are produced by transgenesis with DNA transposon vectors carrying the transgene driven by the human ubiquitin C promoter. These animals carry multiple copies (from 8 to 13) of the transgene and show systemic transgene expression. Transgene-expressing pigs carry both transposase-catalyzed insertions and at least one copy of randomly inserted plasmid DNA. Our findings illustrate critical issues related to DNA transposon-directed transgenesis, including coincidental plasmid insertion and relatively low Sleeping Beauty transposition activity in porcine fibroblasts, but also provide a platform for future development of porcine disease models using the Sleeping Beauty gene insertion technology.

This paper makes use of two technologies: transposon mediated gene transfer to introduce foreign DNA, for example a disease predisposition gene, into oocytes or early embryos, without the use of viral vectors; and use of SCNT to clone a minipig from viable embryos.

 

The transposon mediated system is based on the Sleeping Beauty (SB) vector system, which is a cut and paste DNA transposon belonging to the Tc1/mariner superfamily of transposable elements(1).  Transposable DNA elements are mobile genetic elements which integrate into genomic DNA, in the case of the SB system into discrete sequence elements of actively transcribed genes.  The system consists of two entities: 1) a transposase responsible for cutting and pasting the mobile element and 2) the transposon; the vectorial DNA sequence which is inserted into genomic DNA.  SB transposition has been used to integrate exogenous genetic elements into the genome of various mammalian species(2) and to make tumor models in mice (3-7) and to transform, ex-vivo, porcine ovarian epithelial cells (8) and to stably integrate GFP containing vectors into porcine fibroblast genome(9).  Because of the efficiency and nonviral integration of exogenous vectors into mammalian systems, Sleeping Beauty system has been considered as a potential therapeutic gene transfer modality (10-12).

 

  1. Li, Z.H., Liu, D.P., Wang, J., Guo, Z.C., Yin, W.X., and Liang, C.C. Inversion and transposition of Tc1 transposon of C. elegans in mammalian cells. Somat Cell Mol Genet. 1998; 24:363-369.
  2. Balciuniene, J., Nagelberg, D., Walsh, K.T., Camerota, D., Georlette, D., Biemar, F., et al. Efficient disruption of Zebrafish genes using a Gal4-containing gene trap. BMC Genomics. 2013; 14:619.
  3. Romano, G., Marino, I.R., Pentimalli, F., Adamo, V., and Giordano, A. Insertional mutagenesis and development of malignancies induced by integrating gene delivery systems: implications for the design of safer gene-based interventions in patients. Drug News Perspect. 2009; 22:185-196.
  4. Dupuy, A.J. Transposon-based screens for cancer gene discovery in mouse models. Semin Cancer Biol. 2010; 20:261-268.
  5. Dupuy, A.J., Akagi, K., Largaespada, D.A., Copeland, N.G., and Jenkins, N.A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature. 2005; 436:221-226.
  6. Dupuy, A.J., Clark, K., Carlson, C.M., Fritz, S., Davidson, A.E., Markley, K.M., et al. Mammalian germ-line transgenesis by transposition. Proc Natl Acad Sci U S A. 2002; 99:4495-4499.
  7. Dupuy, A.J., Fritz, S., and Largaespada, D.A. Transposition and gene disruption in the male germline of the mouse. Genesis. 2001; 30:82-88.
  8. Hamilton, T.C., Williams, S.J., and Cvetkovic, D. 2010. Cancer Compositions, Animal Models, and Methods of Use Thereof. U.S.P. Office, editor. USA: Fox Chase Cancer Center.
  9. Clark, K.J., Carlson, D.F., Foster, L.K., Kong, B.W., Foster, D.N., and Fahrenkrug, S.C. Enzymatic engineering of the porcine genome with transposons and recombinases. BMC Biotechnol. 2007; 7:42.
  10. Ivics, Z., and Izsvak, Z. Transposable elements for transgenesis and insertional mutagenesis in vertebrates: a contemporary review of experimental strategies. Methods Mol Biol. 2004; 260:255-276.
  11. Liu, H., Liu, L., Fletcher, B.S., and Visner, G.A. Sleeping Beauty-based gene therapy with indoleamine 2,3-dioxygenase inhibits lung allograft fibrosis. FASEB J. 2006; 20:2384-2386.
  12. Ohlfest, J.R., Lobitz, P.D., Perkinson, S.G., and Largaespada, D.A. Integration and long-term expression in xenografted human glioblastoma cells using a plasmid-based transposon system. Mol Ther. 2004; 10:260-268.

 

A second paper, by Larry Shook and Geoffrey Clark’s groups describe the production of ex vivo transformed porcine breast cancer line, driven by inactivation of BRCA1.  In this paper normal porcine breast epithelial cells were immortalized by transfection with SV large T antigen (SV-LT) and upon inactivation of porcine BRCA1 in these immortalized cell lines, developed phenotype characteristic of transformed cells and exhibited cancer stem cell characteristics.  The end point assay for transformation was growth in soft agar however the authors did not confirm malignancy in either SCID mice or SCID pigs.

Front Genet. 2015 Aug 25;6:269. doi: 10.3389/fgene.2015.00269. eCollection 2015.

A porcine model system of BRCA1 driven breast cancer.

Donninger H1, Hobbing K2, Schmidt ML3, Walters E4, Rund L5, Schook L5, Clark GJ2.

Author information

Abstract

BRCA1 is a breast and ovarian tumor suppressor. Hereditary mutations in BRCA1 result in a predisposition to breast cancer, and BRCA1expression is down-regulated in ~30% of sporadic cases. The function of BRCA1 remains poorly understood, but it appears to play an important role in DNA repair and the maintenance of genetic stability. Mouse models of BRCA1 deficiency have been developed in an attempt to understand the role of the gene in vivo. However, the subtle nature of BRCA1 function and the well-known discrepancies between human and murine breast cancer biology and genetics may limit the utility of mouse systems in defining the function of BRCA1 in cancer and validating the development of novel therapeutics for breast cancer. In contrast to mice, pig biological systems, and cancer genetics appear to more closely resemble their human counterparts. To determine if BRCA1 inactivation in pig cells promotes their transformation and may serve as a model for the human disease, we developed an immortalized porcine breast cell line and stably inactivated BRCA1 using miRNA. The cell line developed characteristics of breast cancer stem cells and exhibited a transformed phenotype. These results validate the concept of using pigs as a model to study BRCA1 defects in breast cancer and establish the first porcine breast tumor cell line.

 

 

Figure 1. Immortalization of pig mammary epithelial cells. Primary pig breast epithelial cells were stably transfected with an SV40 LT expression construct and selected in puromycin. Surviving cells were serially passaged to confirm immortalization.

 

fgene-06-00269-g001 immortalized breast porcine epithelial cells

 

 

Figure 3. Loss of BRCA1 enhances pig mammary epithelial cell growth. (A) Serially passaging the pig mammary epithelial cells stably knocked down for BRCA1 resulted in an altered morphology compared to those cells stably expressing the LacZ miRNA. (B) 2 × 104 cells/well were plated in 6-well plates and cell growth was determined by counting the number of cells at the indicated times. Error bars show standard error, p < 0.05.

fgene-06-00269-g003growthofbrcaminusporbrepith

 

 

Figure 5. Loss of BRCA1 enhances the transformed phenotype of pig mammary epithelial cells. (A) The pig breast epithelial cells stably expressing BRCA1 miRNA were plated in soft agar and scored for growth 14 days later. Representative photomicrographs are shown in the top panel and data from three independent experiments quantitated in the bar graph in the lower panel. (B) 1 × 106 cells/well were plated in polyHEMA-coated 12-well plates and cell viability assessed 48 h later by trypan blue staining. Error bars show standard error, p < 0.05.

fgene-06-00269-g005brca1minuporbrepithcolonies

 

A third paper describes the development, in Gottingen minipigs, of a transgenic inducible model of intestinal cancer.

Mol Oncol. 2017 Nov;11(11):1616-1629. doi: 10.1002/1878-0261.12136. Epub 2017 Oct 10.

A genetically inducible porcine model of intestinal cancer.

Callesen MM1, Árnadóttir SS1, Lyskjaer I1, Ørntoft MW1, Høyer S2, Dagnaes-Hansen F3, Liu Y4, Li R4, Callesen H4, Rasmussen MH1, Berthelsen MF3, Thomsen MK3, Schweiger PJ5, Jensen KB5, Laurberg S6, Ørntoft TF1, Elverløv-Jakobsen JE3, Andersen CL1.

Author information

Abstract

Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase-inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT – which inhibits p53 – and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4-OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 × 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis.

 

Other posts on this site related to Cancer Research Tools include

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

Heroes in Medical Research: Developing Models for Cancer Research

Reprogramming Induced Pleuripotent Stem Cells

The Cancer Research Concentration @ Leaders in Pharmaceutical Business Intelligence

A Synthesis of the Beauty and Complexity of How We View Cancer

Guidelines for the welfare and use of animals in cancer research

Gene Therapy and the Genetic Study of Disease: @Berkeley and @UCSF – New DNA-editing technology spawns bold UC initiative as Crispr Goes Global

 

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Cancer Labs at School of Medicine @ Technion: Janet and David Polak Cancer and Vascular Biology Research Center

Posted in Academic Publishing, Autologous Cell Therapy, Bio Instrumentation in Experimental Life Sciences Research, BioBanking, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiac muscle regeneration, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Circulating Progenitor Cells, Computational Biology/Systems and Bioinformatics, Cytoskeleton, Diagnostic Immunology, Drug Delivery Platform Technology, Drug Toxicity, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Interviews with Scientific Leaders, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Scientist: Career considerations, Signaling, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, Translational Science, Ubiquitinylation on May 28, 2014| Leave a Comment »

Cancer Labs at School of Medicine @ Technion

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #139: Cancer Labs at School of Medicine @ Technion: Janet and David Polak Cancer and Vascular Biology Research Center. Published on 5/28/2014

WordCloud Image Produced by Adam Tubman

Janet and David Polak Cancer and Vascular Biology Research Center. The Rappaport Faculty of Medicine Research Institute and Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

The center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer initiation and progression. We strongly believe that the understanding of basic biological processes that underlie normal development and their deregulation in cancer, is crucial for our ability to identify molecular targets for early detection, intervention, and cure of the disease. We are interested in a broad view of cancer – from the single malignantly transformed cell and its microenvironment, through the entire tumor in the animal. We focus on targeted ubiquitin-mediated degradation of key regulatory proteins that are involved in malignant transformation [Prof. Aaron Ciechanover (Nobel Prize in Chemistry 2004)], angiogenesis and cancer progression (Prof. Gera Neufeld), metastasis and tumor microenvironment (Prof. Israel Vlodavsky), as well as genetic and genomic dissection of embryonic and cancer transcriptional networks (Dr. Amir Orian). Towards these objectives, we combine molecular, biochemical, cell biological with Drosophila genetic and genomics experimental approaches, as well as employing advanced models of angiogenesis and metastasis.

We believe that scientific excellence and collegiality go together. Therefore, the center has an open and friendly atmosphere, creating a highly stimulating environment. The center is located in the 11th Floor of the Rappaport Faculty of Medicine building. It currently trains 45 graduate students, post-doctoral fellows, clinicians and researchers that are at the heart of our research. Formal and informal collaborations between individuals and laboratories are on-going and encouraged. We are running a series of joint seminars to which we invite researchers from Israel and abroad. The Center has advanced state-of-the-art microscopic and image analysis equipment, as well as other shared pieces of infrastructural equipment . The center is an integral part of the Faculty of Medicine and the Rappaport Research Institute which are home for excellent research groups, and enjoys their advanced Interdepartmental Equipment Unit. It is also adjacent to the Rambam Medical Center – the major hospital in the north of Israel – which provides us with access to rich clinical material and collaboration with clinicians. Many of them spend active research periods in our laboratories and bring the bench closer to the patient bed and vice versa. The Center is in an active phase of growth, and offers excellent research opportunities, space and facilities for students, post-doctoral fellows, and physicians.

Research Groups

The Ubiquitin System and Cellular Protein Turnover and Interactions

Immunity and Host Defense

Cardiovascular Biology

The Central Nervous System in Health and Disease

Developmental Biology and Cancer Research

Genetics

SOURCE 

http://www.rappaport.org.il/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=842&FID=76

The cancer and vascular biology research center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer development and progression. Our goal is to advance knowledge in fundamental biological questions that are highly relevant for cancer.

The cancer and vascular biology research center was established in 2003 to promote an in-depth interdisciplinary basic and clinical research on the control of cellular and molecular processes that are involved in cancer development and progression. Our goal is to advance knowledge in fundamental biological questions that are highly relevant for cancer.

SOURCE

http://www.technioncancer.co.il/index.php

Home  >>  Research Groups

Aaron Ciechanover
Protein Turnover

Intracellular protein degradation and mechanisms of cancer
Israel Vlodavsky
Cancer Biology

Impact of heparanase and the tumor microenvironment on cancer progression: Basic aspects and clinical implications
Gera Neufeld
Tumor Progression & Angiogenesis

Blood vessels and tumor progression: The neuropilin connection
Amir Orian
Genetic Networks

Genetic networks in development and cancer
Home
About the Cancer Centers
Research Groups
Administration / Contact
Join – Us		 Seminars and Events
Links
Beyond Science
Friends and supporters
Ms. Sigal Alfasi – Izrael, Center’s coordinator
e-mail: gsigal@tx.technion.ac.il
Tel: +972-4-829-5424
Fax: +972-4-852-3947

SOURCE

http://www.technioncancer.co.il/ResearchGroups.php

Yuval Shaked, PhD

Publications by Yuval Shaked, PhD

Assistant Professor of Molecular Pharmacology
PhD, 2004 – Hebrew University, Israel

Understanding host – tumor interactions during cancer therapy

Personalized medicine holds promise of better cures with fewer side effects for many diseases. Individualized cancer therapy is sometimes utilized after multiple attempts of standard therapies and is based on several considerations, such as tumor type, acquired resistance to a specific therapy, previous treatment protocols, and other tumor-related factors. We have recently demonstrated that many cancer therapies can induce pro-tumorigenic or metastatic effects that derive not only from the tumor cells themselves, but also from host cells within the tumor microenvironment. The focus of research in my laboratory is to identify, characterize, and seek ways to block such pro-tumorigenic host effects observed after anti-cancer therapy, and thus potentially improve the outcome of current cancer therapies. Our findings may foster a paradigm shift in cancer therapy by minimizing the gap between preclinical findings and the clinical setting, laying the foundation for development of entirely new strategies for improving cancer therapy.

SOURCE

http://www.rappaport.org.il/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=610&FID=77&PID=0&IID=1268

 

Other Related articled published on this Open Access Online Scientific Journal included the following:

D&D NT’s Solution: Galectin Proteins for Therapy and Diagnosis of Autoimmune Inflammatory and Cancer Diseases, Dr. Itshak Golan, CEO

http://pharmaceuticalintelligence.com/2014/05/28/dd-nts-solution-galectin-proteins-for-therapy-and-diagnosis-of-autoimmune-inflammatory-and-cancer-diseases-dr-itshak-golan-ceo/

MaimoniDex RA:  Monoclonal Antibodies for Therapy and Diagnosis of Cancer and Autoimmune Inflammatory Diseases – Dr. Itshak Golan, CEO

http://pharmaceuticalintelligence.com/2014/05/28/maimonidex-ra-monoclonal-antibodies-for-therapy-and-diagnosis-of-cancer-and-autoimmune-inflammatory-diseases-dr-itshak-golan-ceo/

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Reprogramming Adult Patient Cells into Stem Cells: the Promise of Personalized Genetic Therapy

Posted in Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Personalized and Precision Medicine & Genomic Research, Regenerative Biology and Medicine, Scientist: Career considerations, Stem Cells for Regenerative Medicine on May 20, 2014| Leave a Comment »

Reprogramming Adult Patient Cells into Stem Cells: the Promise of Personalized Genetic Therapy

Reporter: Aviva Lev-Ari, PhD, RN

 

Major breakthrough in understanding a parental imprinting disorder is achieved by researchers at the Hebrew University

Modeling Prader-Willi syndrome in stem cells published in Nature Genetics
12/05/2014

Scientists at the Hebrew University of Jerusalem have reported a major breakthrough in understanding the molecular basis for Prader-Willi syndrome (PWS), perhaps the most studied among the class of diseases that involves defects in parental imprinting.

The work, described in the latest online edition of the prestigious journal Nature Genetics, was led by Prof. Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research and director of the Stem Cell Unit at the Alexander Silberman Institute of Life Sciences at the Hebrew University; and his PhD student Yonatan Stelzer. Also assisting in the research were graduate student Ido Sagi and Dr. Ofra Yanuka and Dr. Rachel Eiges.

Parental imprinting is a mode of inheritance that results in a small subset of genes to be expressed exclusively from either the mother or father. Prader-Willi syndrome is perhaps the best characterized disease of this sort. It is a multisystem disorder characterized by learning disabilities, excessive weight gain and defective sexual development, and is known to result from aberrations in paternal genes in what is known as the Prader-Willi genomic region of chromosome 15.

“What characterizes this chromosomal region is that paternal genes are active, while the maternal genes are inactive. And while most people would have one normal working and one silenced set of these genes, people with Prader-Willi syndrome have only a defective set (the paternal one) and a silenced (maternal) set,” explains Stelzer.

In order to achieve a greater understanding of this process, the Hebrew University investigators created a model for the Prader-Willi syndrome by reprogramming skin cells from PWS patients into embryonic-like cells. Utilizing this system, the investigators have shown that the genes expressed from the father are actually affecting and silencing the genes that are expressed from the mother. These findings have significance in the way that we view parental imprinting and in particular the molecular basis of Prader-Willi syndrome, the scientists say.

Future research should allow further characterization of the contribution of this novel genetic region to the origin of this disease, and perhaps pave the way for identification of possible treatment and characterization of PWS patients. Furthermore, the identification of functional, genomic cross-talk in regions containing parental imprinted genes may significantly change our overall understanding of the evolution of this phenomenon in placental mammals, say the researchers.

The research study, “The noncoding RNA IPW regulates the imprintedDLK1–DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome,” was partially funded by the Israel Science Foundation–Morasha Foundation and by the Israel Ministry of Science and Technology Infrastructure.

SOURCE

http://new.huji.ac.il/en/article/21168

NATURE GENETICS | ARTICLE

The noncoding RNA IPW regulates the imprintedDLK1–DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Affiliations

  1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.

    • Yonatan Stelzer,
    • Ido Sagi,
    • Ofra Yanuka &
    • Nissim Benvenisty

  2. Stem Cell Research Laboratory, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel.

    • Rachel Eiges

Contributions

Y.S. contributed to the conception and design of the study, the collection and assembly of data, data analysis and interpretation, and manuscript writing. I.S. contributed to the collection and assembly of data and graphic design. O.Y. and R.E. contributed to the collection and assembly of data. N.B. contributed to the conception and design of the study, financial support, data analysis and interpretation, and manuscript writing.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

 Nature Genetics (2014) doi:10.1038/ng.2968
Received05 December 2013 
Accepted 03 April 2014 
Published online 11 May 2014

Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1–DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1–DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1–DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.

 

 

 

  • reprogram adult patient cells into stem cells


    The capacity to reprogram adult patient cells into pluripotent, embryonic-like, stem cells by nuclear transfer has been reported as a breakthrough by scientists from the US and The Hebrew University of Jerusalem.

    The work, described in the journal Nature, was accomplished by researchers from the New York Stem Cell Foundation Research Institute and Columbia University and by Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research and Director of the Stem Cell Unit at the Institute of Life Sciences at The Hebrew University of Jerusalem, and his graduate student Ido Sagi. The latter assisted in the characterization of the pluripotent nature of these cells.

    Pluripotency means the ability of stem cells to develop into all the cells of our body, including those in the brain, heart, liver and blood. In 2012, the Nobel Prize in Physiology or Medicine was awarded for two discoveries showing that mature (differentiated) cells can be converted into pluripotent, embryonic-like cells, either by forced expression of genetic factors or by transfer of cell nuclei into female eggs, in a process called “reprogramming.”

    However, the actual ability to reprogram cells from humans by nuclear transfer had only been accomplished until now by using fetal cells for this purpose, until this latest work involving reprogramming of adult patient cells demonstrated by the researchers from the US and The Hebrew University, as described in the new Nature article.

    Future research should allow further characterization of these novel, pluripotent cell types and their comparison to other stem cells. “Human pluripotent stem cells generated from adult cells may change the face of medicine,” says Professor Benvenisty, leading to totally new, personalized genetic therapy involving the reprograming of a patient’s own cells to achieve cell replacement and healing.

    SOURCE
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    18. Guttman, M. et al. lincRNAs act in the circuitry controlling pluripotency and differentiation.Nature 477, 295–300 (2011).
    19. Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in humanHOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).
    20. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106,11667–11672 (2009).
    21. Li, X. et al. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15, 547–557 (2008).
    22. Collins, R.E. et al. In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J. Biol. Chem. 280, 5563–5570 (2005).
    23. Nishikawa, S., Goldstein, R.A. & Nierras, C.R. The promise of human induced pluripotent stem cells for research and therapy. Nat. Rev. Mol. Cell Biol. 9, 725–729 (2008).
    24. Soldner, F. & Jaenisch, R. Medicine. iPSC disease modeling. Science 338, 1155–1156(2012).
    25. Chamberlain, S.J. et al. Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc. Natl. Acad. Sci. USA 107,17668–17673 (2010).
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    27. Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).
    28. Mann, M.R. & Bartolomei, M.S. Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum. Mol. Genet. 8, 1867–1873 (1999).
    29. Falk, M.J., Curtis, C.A., Bass, N.E., Zinn, A.B. & Schwartz, S. Maternal uniparental disomy chromosome 14: case report and literature review. Pediatr. Neurol. 32, 116–120 (2005).
    30. Hordijk, R. et al. Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype. J. Med. Genet. 36, 782–785 (1999).
    31. Hosoki, K. et al. Maternal uniparental disomy 14 syndrome demonstrates Prader-Willi syndrome–like phenotype. J. Pediatr. 155, 900–903 (2009).
    32. Reik, W. & Walter, J. Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote. Nat. Genet. 27, 255–256 (2001).
    33. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).
    34. Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat. Struct. Mol. Biol. 15, 1176–1183(2008).

 

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On Cancer, On Translational, Post-Translational, Regenerative Medicine and Cell Biological Processes: I told the World in three months while Recovering – Perspectives by LHB, MD, FCAP

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Regenerative Biology and Medicine, S-nitrosylation, Scientist: Career considerations, Signaling, Stem Cells for Regenerative Medicine, Translational Research, Translational Science on May 20, 2014| Leave a Comment »

On Cancer, On Translational, Post-Translational, Regenerative Medicine and Cell Biological Processes: I told the World in three months while Recovering – Perspectives by LHB, MD, FCAP

Reporter: Aviva Lev-Ari, PhD, RN

 

On Cancer – Publications of Dr. Larry H Bernstein

Cancer Volume One – Summary [Placement in Cancer Volume One by Dr. Williams – PENDING]

A Synthesis of the Beauty and Complexity of How We View Cancer

Author: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

 

Epilogue: Envisioning New Insights [Placement in Cancer Volume One by Dr. Williams – PENDING]

Author & Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/

 

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here? [Placement in Cancer Volume One by Dr. Williams – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-how-we-got-here/

 

Epilogue: Envisioning New Insights in Cancer Translational Biology – SEE Epilogue: Envisioning New Insights 3/29/2014 – [Placement in Cancer Volume One by Dr. Williams – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/04/epilogue-envisioning-new-insights-in-cancer-translational-biology/

Prologue to Cancer – e-book Volume One – Where are we in this journey? [Placement in Cancer Volume One by Dr. Williams – PENDING]

Author and Curator: Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/

 

 

On Translational, Post-Translational, Regenerative Medicine – Publications of Dr. Larry H Bernstein

 

Post Acute Care – Driver of Variation in Healthcare Costs [article ID assignment by Dr. Larry – PENDING]

Reporter and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/02/21/post-acute-care-driver-of-variation-in-healthcare-costs/

 

Post-Translational Modifications [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/posttranslational-modifications/

 

Post-Translational Modification of Proteins [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/posttranslational-modification-of-proteins/

 

Introduction to Translational Medicine (TM) – Part 1: Translational Medicine [Aviva will place as Intro to VOL 4 Part 1]

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/04/25/introduction-to-translational-medicine-tm-part-1/

 

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine [Aviva will place as Intro to VOL 4 Part 2]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-translational_medicine-part_2/

 

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1 [Aviva will place as Summary to VOL 4 Part 1]

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/04/28/summary-of-translational-medicine-cardiovascular-diseases-part-1/

A Powerful Tool For Repairing Damaged Hearts [article ID assignment by Dr. Larry – PENDING]

Reporter: Larry H Bernstein, MD

http://pharmaceuticalintelligence.com/2014/04/30/a-powerful-tool-for-repairing-damaged-hearts/

 

Summary – Volume 4, Part 2:  Translational Medicine in Cardiovascular Diseases [Aviva will place as Summary to VOL 4 Part 2]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/05/10/summary-part-2-volume-4-translational-medicine-in-cardiovascular-diseases/

 

Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology [Aviva will place as EPILOGUE to VOL 4]

Larry H Bernstein, MD, FCAP, Author and Curator, Volume Four, Co-Editor

Justin Pearlman, MD, PhD, FACC, Content Consultant for Series A: Cardiovascular Diseases

Aviva Lev-Ari, PhD, RN, Co-Editor of Volume Four and Editor-in-Chief, BioMed e-Series

http://pharmaceuticalintelligence.com/2014/05/12/epilogue-volume-4-post-translational-and-transformative-cardiology/

 

Modified RNA Induces Vascular Regeneration After a Heart Attack [article ID assignment by Dr. Larry – PENDING]

Reporter: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/05/18/modified-rna-induces-vascular-regeneration-after-a-heart-attack/

 

Cell Biological Processes – Publications of Dr. Larry H Bernstein

A Tribute to Johannes Everse [article ID assignment by Dr. Larry – PENDING]

Author: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/a-tribute-to-johannes-everse/

 

What comes after finishing the Euchromatic Sequence of the Human Genome? [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/what-comes-after-finishing-the-euchromatic-sequence-of-the-human-genome/

 

Transcriptional Silencing and Longevity Protein Sir2 [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/transcriptional-silencing-and-longevity-protein-sir2/

 

S-nitrosylation signaling [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/s-nitrosylation-signaling/

 

Analysis of S-nitrosylated Proteins [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/21/analysis-of-s-nitrosylated-proteins/

 

Acetylation and Deacetylation of non-Histone Proteins [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/04/22/acetylation-and-deacetylation-of-non-histone-proteins/

 

Analysis of S-nitrosylated Proteins: Detergent-free biotin switch combined with liquid chromatography/tandem mass spectrometry [article ID assignment by Dr. Larry – PENDING]

Author and Curator: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2014/04/22/detergent-free-biotin-switch-combined-with-liquid-chromatographytandem-mass-spectrometry/

 

 

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NIH Study Demonstrates that a New Cancer Immunotherapy Method could be Effective against a wide range of Cancers

Posted in Autologous Cell Therapy, CANCER BIOLOGY & Innovations in Cancer Therapy, Innovation in Immunology Diagnostics, Stem Cells for Regenerative Medicine on May 12, 2014| Leave a Comment »

NIH Study Demonstrates that a New Cancer Immunotherapy Method could be Effective against a wide range of Cancers

Reporter: Aviva Lev-Ari, PhD, RN

 

  • REPORT

Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer

  1. Eric Tran1,
  2. Simon Turcotte1,*,
  3. Alena Gros1,
  4. Paul F. Robbins1,
  5. Yong-Chen Lu1,
  6. Mark E. Dudley1,†,
  7. John R. Wunderlich1,
  8. Robert P. Somerville1,
  9. Katherine Hogan1,
  10. Christian S. Hinrichs1,
  11. Maria R. Parkhurst1,
  12. James C. Yang1,
  13. Steven A. Rosenberg1,‡

+Author Affiliations


  1. 1Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892, USA.

+Author Notes

  • ↵* Department of Surgery, Université de Montréal, and Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, QC H2X0A9, Canada.

  • ↵† Present address: Cell and Gene Therapies, Novartis Institutes for BioMedical Research Incorporated, Cambridge, MA 02139, USA.

Limited evidence exists that humans mount a mutation-specific T cell response to epithelial cancers. We used a whole-exomic-sequencing-based approach to demonstrate that tumor-infiltrating lymphocytes (TIL) from a patient with metastatic cholangiocarcinoma contained CD4+ T helper 1 (TH1) cells recognizing a mutation in erbb2 interacting protein (ERBB2IP) expressed by the cancer. After adoptive transfer of TIL containing about 25% mutation-specific polyfunctional TH1 cells, the patient achieved a decrease in target lesions with prolonged stabilization of disease. Upon disease progression, the patient was retreated with a >95% pure population of mutation-reactive TH1 cells and again experienced tumor regression. These results provide evidence that a CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer.

 

For Immediate Release: Thursday, May 8, 2014

NIH study demonstrates that a new cancer immunotherapy method could be effective against a wide range of cancers

A new method for using immunotherapy to specifically attack tumor cells that have mutations unique to a patient’s cancer has been developed by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health. The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by cancers that arise in epithelial cells which can line the internal and external surfaces (such as the skin) of the body. These cells give rise to many types of common cancers, such as those that develop in the digestive tract, lung, pancreas, bladder and other areas of the body.

Image of shrunken tumor

Six months after ACT with mutation-specific T-cells, tumors that metastasized to the lung have shrunk.

The research provides evidence that this immune response can be harnessed for therapeutic benefit in patients, according to the scientists. The study appeared May 9, 2014, in the journal Science.

“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research. “The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.”

All malignant tumors harbor genetic alterations, some of which may lead to the production of mutant proteins that are capable of triggering an antitumor immune response. Research led by Rosenberg and his colleagues had shown that human melanoma tumors often contain mutation-reactive immune cells called tumor-infiltrating lymphocytes, or TILs. The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma.

In ACT, a patient’s own TILs are collected, and those with the best antitumor activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers. These cells comprise more than 80 percent of all cancers. It was also not known whether such a response could be used to develop personalized immunotherapies for these cancers.

In this study, Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognize patient-specific mutations. They analyzed TILs from a patient with bile duct cancer that had metastasized to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121).

The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analyzed to identify mutations that the patient’s immune cells might recognize. Further testing showed that some of the patient’s TILs recognized a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25 percent of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 to enhance T-cell proliferation and function.

Following transfer of the TILs, the patient’s metastatic lung and liver tumors stabilized. When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95 percent of the transferred cells were mutation-reactive T cells, and she experienced tumor regression that was ongoing as of the last follow up (six months after the second T-cell infusion). These results provide evidence that a T-cell response against a mutant protein can be harnessed to mediate regression of a metastatic epithelial cell cancer.

“Given that a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumor-reactive T cells, the strategies reported here could be used to generate a T-cell adoptive cell therapy for patients with common cancers,” said Rosenberg.

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

SOURCE

 

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Summary – Volume 4, Part 2: Translational Medicine in Cardiovascular Diseases

Posted in Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Congenital Heart Disease, Cytoskeleton, Diabetes Mellitus, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, HTN, Human Immune System in Health and in Disease, Human neural progenitor cells, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, International Global Work in Pharmaceutical, Medical and Population Genetics, Medical Devices R&D and Inventions, Metabolomics, Mitral Valve: Repair and Replacement, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, PCI, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Signaling, Skeletal muscle regeneration, Stem Cells for Regenerative Medicine, Stents & Tools, Technology Advance Assessment of, Theoretic convergence, Umbilical cord cells, Valves & Tools, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on May 10, 2014| Leave a Comment »

Summary – Volume 4, Part 2:  Translational Medicine in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

 

We have covered a large amount of material that involves

  • the development,
  • application, and
  • validation of outcomes of medical and surgical procedures

that are based on translation of science from the laboratory to the bedside, improving the standards of medical practice at an accelerated pace in the last quarter century, and in the last decade.  Encouraging enabling developments have been:

1. The establishment of national and international outcomes databases for procedures by specialist medical societies

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

On Devices and On Algorithms: Prediction of Arrhythmia after Cardiac Surgery and ECG Prediction of an Onset of Paroxysmal Atrial Fibrillation
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
http://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions
Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) /Coronary Angioplasty
Larry H. Bernstein, MD, Writer And Aviva Lev-Ari, PhD, RN, Curator
http://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

Revascularization: PCI, Prior History of PCI vs CABG
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Endovascular Lower-extremity Revascularization Effectiveness: Vascular Surgeons (VSs), Interventional Cardiologists (ICs) and Interventional Radiologists (IRs)
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

and more

2. The identification of problem areas, particularly in activation of the prothrombotic pathways, infection control to an extent, and targeting of pathways leading to progression or to arrythmogenic complications.

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Anticoagulation genotype guided dosing
Larry H. Bernstein, MD, FCAP, Author and Curator
http://pharmaceuticalintelligence.com/2013/12/08/anticoagulation-genotype-guided-dosing/

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

The Effects of Aprotinin on Endothelial Cell Coagulant Biology
Co-Author (Kamran Baig, MBBS, James Jaggers, MD, Jeffrey H. Lawson, MD, PhD) and Curator
http://pharmaceuticalintelligence.com/2013/07/20/the-effects-of-aprotinin-on-endothelial-cell-coagulant-biology/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Pharmacogenomics – A New Method for Druggability  Author and Curator: Demet Sag, PhD
http://pharmaceuticalintelligence.com/2014/04/28/pharmacogenomics-a-new-method-for-druggability/

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage    Author: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-End-Stage/

3. Development of procedures that use a safer materials in vascular management.

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

Vascular Repair: Stents and Biologically Active Implants
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, RN, PhD
http://pharmaceuticalintelligence.com/2013/05/04/stents-biologically-active-implants-and-vascular-repair/

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES
Author: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
http://PharmaceuticalIntelligence.com/2013/04/25/Contributions-to-vascular-biology/

MedTech & Medical Devices for Cardiovascular Repair – Curations by Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2014/04/17/medtech-medical-devices-for-cardiovascular-repair-curation-by-aviva-lev-ari-phd-rn/

4. Discrimination of cases presenting for treatment based on qualifications for medical versus surgical intervention.

Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)
Author: Larry H Bernstein, MD, FCAP And Curator: Justin D Pearlman, MD, PhD, FACC
http://pharmaceuticalintelligence.com/2013/07/17/treatment-options-for-left-ventricular-failure-temporary-circulatory-support-intra-aortic-balloon-pump-iabp-impella-recover-ldlp-5-0-and-2-5-pump-catheters-non-surgical-vs-bridge-therapy/

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/06/30/mayo-risk-score-for-percutaneous-coronary-intervention/

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/ 

5.  This has become possible because of the advances in our knowledge of key related pathogenetic mechanisms involving gene expression and cellular regulation of complex mechanisms.

What is the key method to harness Inflammation to close the doors for many complex diseases?
Author and Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2014/03/03/cvd-prevention-and-evaluation-of-cardiovascular-imaging-modalities-coronary-calcium-score-by-ct-scan-screening-to-justify-or-not-the-use-of-statin/

Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension
Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)
Curator:  Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/01/15/pathophysiological-effects-of-diabetes-on-ischemic-cardiovascular-disease-and-on-chronic-obstructive-pulmonary-disease-copd/

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))
Reviewer and Co-Curator: Larry H Bernstein, MD, CAP and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

Notable Contributions to Regenerative Cardiology  Author and Curator: Larry H Bernstein, MD, FCAP and Article Commissioner: Aviva Lev-Ari, PhD, RD
http://pharmaceuticalintelligence.com/2013/10/20/notable-contributions-to-regenerative-cardiology/

As noted in the introduction, any of the material can be found and reviewed by content, and the eTOC is identified in attached:

http://wp.me/p2xfv8-1W

 

This completes what has been presented in Part 2, Vol 4 , and supporting references for the main points that are found in the Leaders in Pharmaceutical Intelligence Cardiovascular book.  Part 1 was concerned with Posttranslational Modification of Proteins, vital for understanding cellular regulation and dysregulation.  Part 2 was concerned with Translational Medical Therapeutics, the efficacy of medical and surgical decisions based on bringing the knowledge gained from the laboratory, and from clinical trials into the realm opf best practice.  The time for this to occur in practice in the past has been through roughly a generation of physicians.  That was in part related to the busy workload of physicians, and inability to easily access specialty literature as the volume and complexity increased.  This had an effect of making access of a family to a primary care provider through a lifetime less likely than the period post WWII into the 1980s.

However, the growth of knowledge has accelerated in the specialties since the 1980’s so that the use of physician referral in time became a concern about the cost of medical care.  This is not the place for or a matter for discussion here.  It is also true that the scientific advances and improvements in available technology have had a great impact on medical outcomes.  The only unrelated issue is that of healthcare delivery, which is not up to the standard set by serial advances in therapeutics, accompanied by high cost due to development costs, marketing costs, and development of drug resistance.

I shall identify continuing developments in cardiovascular diagnostics, therapeutics, and bioengineering that is and has been emerging.

1. Mechanisms of disease

REPORT: Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures 

Science 11 April 2014:
Vol. 344 no. 6180 pp. 208-211
http://dx.doi.org/10.1126/science.1250217

Abstract: Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes.

Yeasty HIPHOP

Laura Zahn
Sci. Signal. 15 April 2014; 7(321): ec103.   http://dx.doi.org/10.1126/scisignal.2005362

In order to identify how chemical compounds target genes and affect the physiology of the cell, tests of the perturbations that occur when treated with a range of pharmacological chemicals are required. By examining the haploinsufficiency profiling (HIP) and homozygous profiling (HOP) chemogenomic platforms, Lee et al.(p. 208) analyzed the response of yeast to thousands of different small molecules, with genetic, proteomic, and bioinformatic analyses. Over 300 compounds were identified that targeted 121 genes within 45 cellular response signature networks. These networks were used to extrapolate the likely effects of related chemicals, their impact upon genetic pathways, and to identify putative gene functions

Key Heart Failure Culprit Discovered

A team of cardiovascular researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, Sanford-Burnham Medical Research Institute, and University of California, San Diego have identified a small, but powerful, new player in thIe onset and progression of heart failure. Their findings, published in the journal Nature  on March 12, also show how they successfully blocked the newly discovered culprit.
Investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure.

Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells. According to co-lead study authors Christine Wahlquist and Dr. Agustin Rojas Muñoz, developers of the approach and researchers in Mercola’s lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction.

Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.

“In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process,” says co-lead study author Dr. Dongtak Jeong, a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of  Medicine at Mount Sinai in the laboratory of the study’s co-senior author Dr. Roger J. Hajjar.

Publication: Inhibition of miR-25 improves cardiac contractility in the failing heart.Christine Wahlquist, Dongtak Jeong, Agustin Rojas-Muñoz, Changwon Kho, Ahyoung Lee, Shinichi Mitsuyama, Alain Van Mil, Woo Jin Park, Joost P. G. Sluijter, Pieter A. F. Doevendans, Roger J. :  Hajjar & Mark Mercola.     Nature (March 2014)    http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13073.html

 

“Junk” DNA Tied to Heart Failure

Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNAs in Failing Human Heart and Remodeling With Mechanical Circulatory Support

Yang KC, Yamada KA, Patel AY, Topkara VK, George I, et al.
Circulation 2014;  129(9):1009-21.
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003863              http://circ.ahajournals.org/…/CIRCULATIONAHA.113.003863.full

The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Junk DNA was long thought to have no important role in heredity or disease because it doesn’t code for proteins. But emerging research in recent years has revealed that many of these sections of the genome produce noncoding RNA molecules that still have important functions in the body. They come in a variety of forms, some more widely studied than others. Of these, about 90% are called long noncoding RNAs (lncRNAs), and exploration of their roles in health and disease is just beginning.

The Washington University group performed a comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

In their study, the researchers found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support,” wrote the researchers. “These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.”

‘Junk’ Genome Regions Linked to Heart Failure

In a recent issue of the journal Circulation, Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

“We took an unbiased approach to investigating which types of RNA might be linked to heart failure,” said senior author Jeanne Nerbonne, the Alumni Endowed Professor of Molecular Biology and Pharmacology. “We were surprised to find that long noncoding RNAs stood out.

In the new study, the investigators found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“We don’t know whether these changes in long noncoding RNAs are a cause or an effect of heart failure,” Nerbonne said. “But it seems likely they play some role in coordinating the regulation of multiple genes involved in heart function.”

Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and nonfailing hearts. But only expression of the long noncoding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (nonischemic). Similarly, only long noncoding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.

Comment

Decoding the noncoding transcripts in human heart failure

Xiao XG, Touma M, Wang Y
Circulation. 2014; 129(9): 958–960,  http://dx.doi.org/10.1161/CIRCULATIONAHA.114.007548 

Heart failure is a complex disease with a broad spectrum of pathological features. Despite significant advancement in clinical diagnosis through improved imaging modalities and hemodynamic approaches, reliable molecular signatures for better differential diagnosis and better monitoring of heart failure progression remain elusive. The few known clinical biomarkers for heart failure, such as plasma brain natriuretic peptide and troponin, have been shown to have limited use in defining the cause or prognosis of the disease.1,2 Consequently, current clinical identification and classification of heart failure remain descriptive, mostly based on functional and morphological parameters. Therefore, defining the pathogenic mechanisms for hypertrophic versus dilated or ischemic versus nonischemic cardiomyopathies in the failing heart remain a major challenge to both basic science and clinic researchers. In recent years, mechanical circulatory support using left ventricular assist devices (LVADs) has assumed a growing role in the care of patients with end-stage heart failure.3 During the earlier years of LVAD application as a bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function, structure, and electric properties.4 This led to the recognition that reverse remodeling is potentially an achievable therapeutic goal using LVADs. However, the underlying mechanism for the reverse remodeling in the LVAD-treated hearts is unclear, and its discovery would likely hold great promise to halt or even reverse the progression of heart failure.

 

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis

Circulation. 2014; 129: 951-952     http://dx.doi.org/10.1161/​CIR.0000000000000022

In patients with atrial fibrillation, impaired renal function is associated with a higher risk of thromboembolic events and major bleeding. Oral anticoagulation with vitamin K antagonists reduces thromboembolic events but raises the risk of bleeding. The new oral anticoagulant dabigatran has 80% renal elimination, and its efficacy and safety might, therefore, be related to renal function. In this prespecified analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, outcomes with dabigatran versus warfarin were evaluated in relation to 4 estimates of renal function, that is, equations based on creatinine levels (Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and cystatin C. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily irrespective of renal function. Rates of major bleeding were lower with dabigatran 110 mg and similar with 150 mg twice daily across the entire range of renal function. However, when the CKD-EPI or MDRD equations were used, there was a significantly greater relative reduction in major bleeding with both doses of dabigatran than with warfarin in patients with estimated glomerular filtration rate ≥80 mL/min. These findings show that dabigatran can be used with the same efficacy and adequate safety in patients with a wide range of renal function and that a more accurate estimate of renal function might be useful for improved tailoring of anticoagulant treatment in patients with atrial fibrillation and an increased risk of stroke.

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport.

Robert S Edinger, Claudia Coronnello, Andrew J Bodnar, William A Laframboise, Panayiotis V Benos, Jacqueline Ho, John P Johnson, Michael B Butterworth

Journal of the American Society of Nephrology (Impact Factor: 8.99). 04/2014;     http://dx. DO.org/I:10.1681/ASN.2013090931

Source: PubMed

ABSTRACT A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells.

Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport.

Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein.

A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-3′ untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.

 

2. Diagnostic Biomarker Status

A prospective study of the impact of serial troponin measurements on the diagnosis of myocardial infarction and hospital and 6-month mortality in patients admitted to ICU with non-cardiac diagnoses.

Marlies Ostermann, Jessica Lo, Michael Toolan, Emma Tuddenham, Barnaby Sanderson, Katie Lei, John Smith, Anna Griffiths, Ian Webb, James Coutts, John hambers, Paul Collinson, Janet Peacock, David Bennett, David Treacher

Critical care (London, England) (Impact Factor: 4.72). 04/2014; 18(2):R62.   http://dx.doi.org/:10.1186/cc13818

Source: PubMed

ABSTRACT Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons.
cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into 4 groups: (i) definite MI (cTnT >=15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT >=15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT >=15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event.
Data from 144 patients were analysed [42% female; mean age 61.9 (SD 16.9)]. 121 patients (84%) had at least one cTnT level >=15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180 day mortality were significantly higher in patients with a definite or possible MI.Only 20% of definite MIs were recognised by the clinical team. There was no significant difference in mortality between recognised and non-recognised events.At time of cTNT rise, 100 patients (70%) were septic and 58% were on vasopressors. Patients who were septic when cTNT was elevated had an ICU mortality of 28% compared to 9% in patients without sepsis. ICU mortality of patients who were on vasopressors at time of cTNT elevation was 37% compared to 1.7% in patients not on vasopressors.
The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.

 

Prognostic performance of high-sensitivity cardiac troponin T kinetic changes adjusted for elevated admission values and the GRACE score in an unselected emergency department population.

Moritz Biener, Matthias Mueller, Mehrshad Vafaie, Allan S Jaffe, Hugo A Katus,Evangelos Giannitsis

Clinica chimica acta; international journal of clinical chemistry (Impact Factor: 2.54). 04/2014;   http://dx.doi.org/10.1016/j.cca.2014.04.007

Source: PubMed

ABSTRACT To test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score.
Rising and falling hs-cTnT changes in an unselected emergency department population were compared.
635 patients with a hs-cTnT >99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns (n=254, 44.4%), falling patterns (n=224, 39.2%), or falling patterns following an initial rise (n=94, 16.4%). During 407days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values >14ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8-92.1, p=0.01, death/AMI:6.7, 1.6-27.9, p=0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs 0.561, p=ns, falling: 0.533 vs 0.575, p=ns). A GRACE score ≥140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84-5.36), AMI (OR,95%CI: 1.56, 0.59-4.17), or death/AMI (OR, 95%CI: 2.49, 1.51-4.11). Hs-cTnT changes did not improve prognostic performance of a GRACE score ≥140 points (AUC, 95%CI: death: 0.635, 0.570-0.701 vs. 0.560, 0.470-0.649 p=ns, AMI: 0.555, 0.418-0.693 vs. 0.603, 0.424-0.782, p=ns, death/AMI: 0.610, 0.545-0.676 vs. 0.538, 0.454-0.622, p=ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5-28.0 vs. 20.8, 6.3-59.0, p=0.01).
Neither rising nor falling hs-cTnT changes improve prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy.

 

Troponin assays for the diagnosis of myocardial infarction and acute coronary syndrome: where do we stand?

Arie Eisenman

ABSTRACT: Under normal circumstances, most intracellular troponin is part of the muscle contractile apparatus, and only a small percentage (< 2-8%) is free in the cytoplasm. The presence of a cardiac-specific troponin in the circulation at levels above normal is good evidence of damage to cardiac muscle cells, such as myocardial infarction, myocarditis, trauma, unstable angina, cardiac surgery or other cardiac procedures. Troponins are released as complexes leading to various cut-off values depending on the assay used. This makes them very sensitive and specific indicators of cardiac injury. As with other cardiac markers, observation of a rise and fall in troponin levels in the appropriate time-frame increases the diagnostic specificity for acute myocardial infarction. They start to rise approximately 4-6 h after the onset of acute myocardial infarction and peak at approximately 24 h, as is the case with creatine kinase-MB. They remain elevated for 7-10 days giving a longer diagnostic window than creatine kinase. Although the diagnosis of various types of acute coronary syndrome remains a clinical-based diagnosis, the use of troponin levels contributes to their classification. This Editorial elaborates on the nature of troponin, its classification, clinical use and importance, as well as comparing it with other currently available cardiac markers.

Expert Review of Cardiovascular Therapy 07/2006; 4(4):509-14.   http://dx.doi.org/:10.1586/14779072.4.4.509 

 

Impact of redefining acute myocardial infarction on incidence, management and reimbursement rate of acute coronary syndromes.

Carísi A Polanczyk, Samir Schneid, Betina V Imhof, Mariana Furtado, Carolina Pithan, Luis E Rohde, Jorge P Ribeiro

ABSTRACT: Although redefinition for acute myocardial infarction (AMI) has been proposed few years ago, to date it has not been universally adopted by many institutions. The purpose of this study is to evaluate the diagnostic, prognostic and economical impact of the new diagnostic criteria for AMI. Patients consecutively admitted to the emergency department with suspected acute coronary syndromes were enrolled in this study. Troponin T (cTnT) was measured in samples collected for routine CK-MB analyses and results were not available to physicians. Patients without AMI by traditional criteria and cTnT > or = 0.035 ng/mL were coded as redefined AMI. Clinical outcomes were hospital death, major cardiac events and revascularization procedures. In-hospital management and reimbursement rates were also analyzed. Among 363 patients, 59 (16%) patients had AMI by conventional criteria, whereas additional 75 (21%) had redefined AMI, an increase of 127% in the incidence. Patients with redefined AMI were significantly older, more frequently male, with atypical chest pain and more risk factors. In multivariate analysis, redefined AMI was associated with 3.1 fold higher hospital death (95% CI: 0.6-14) and a 5.6 fold more cardiac events (95% CI: 2.1-15) compared to those without AMI. From hospital perspective, based on DRGs payment system, adoption of AMI redefinition would increase 12% the reimbursement rate [3552 Int dollars per 100 patients evaluated]. The redefined criteria result in a substantial increase in AMI cases, and allow identification of high-risk patients. Efforts should be made to reinforce the adoption of AMI redefinition, which may result in more qualified and efficient management of ACS.

International Journal of Cardiology 03/2006; 107(2):180-7. · 5.51 Impact Factor   http://www.sciencedirect.com/science/article/pii/S0167527305005279

 

3. Biomedical Engineerin3g

Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction 

Sonya B. Seif-Naraghi, Jennifer M. Singelyn, Michael A. Salvatore,  et al.
Sci Transl Med 20 February 2013 5:173ra25  http://dx.doi.org/10.1126/scitranslmed.3005503

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of application with substantial intrinsic hurdles, but where human translation is now occurring.

 Acellular Biomaterials: An Evolving Alternative to Cell-Based Therapies

J. A. Burdick, R. L. Mauck, J. H. Gorman, R. C. Gorman,
Sci. Transl. Med. 2013; 5, (176): 176 ps4    http://stm.sciencemag.org/content/5/176/176ps4

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of applications with substantial intrinsic hurdles, but where human translation is now occurring.


Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair

Yi-Dong Lin, Chwan-Yau Luo, Yu-Ning Hu, Ming-Long Yeh, Ying-Chang Hsueh, Min-Yao Chang, et al.
Sci Transl Med 8 August 2012; 4(146):ra109.   http://dx.doi.org/ 10.1126/scitranslmed.3003841

Angiogenic therapy is a promising approach for tissue repair and regeneration. However, recent clinical trials with protein delivery or gene therapy to promote angiogenesis have failed to provide therapeutic effects. A key factor for achieving effective revascularization is the durability of the microvasculature and the formation of new arterial vessels. Accordingly, we carried out experiments to test whether intramyocardial injection of self-assembling peptide nanofibers (NFs) combined with vascular endothelial growth factor (VEGF) could create an intramyocardial microenvironment with prolonged VEGF release to improve post-infarct neovascularization in rats. Our data showed that when injected with NF, VEGF delivery was sustained within the myocardium for up to 14 days, and the side effects of systemic edema and proteinuria were significantly reduced to the same level as that of control. NF/VEGF injection significantly improved angiogenesis, arteriogenesis, and cardiac performance 28 days after myocardial infarction. NF/VEGF injection not only allowed controlled local delivery but also transformed the injected site into a favorable microenvironment that recruited endogenous myofibroblasts and helped achieve effective revascularization. The engineered vascular niche further attracted a new population of cardiomyocyte-like cells to home to the injected sites, suggesting cardiomyocyte regeneration. Follow-up studies in pigs also revealed healing benefits consistent with observations in rats. In summary, this study demonstrates a new strategy for cardiovascular repair with potential for future clinical translation.

Manufacturing Challenges in Regenerative Medicine

I. Martin, P. J. Simmons, D. F. Williams.
Sci. Transl. Med. 2014; 6(232): fs16.   http://dx.doi.org/10.1126/scitranslmed.3008558

Along with scientific and regulatory issues, the translation of cell and tissue therapies in the routine clinical practice needs to address standardization and cost-effectiveness through the definition of suitable manufacturing paradigms.

 

 

 

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A Powerful Tool For Repairing Damaged Hearts

Posted in Stem Cells for Regenerative Medicine on April 30, 2014| Leave a Comment »

A Powerful Tool For Repairing Damaged Hearts

Very interesting article

Reporter: Larry H Bernstein, MD

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Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Posted in Academic Publishing, Acute Myocardial Infarction, Advanced Drug Manufacturing Technology, Alzheimer's Disease, Atherogenic Processes & Pathology, Autologous Cell Therapy, Automated Cell Processing, Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Bone marrow derived cells, Ca2+ triggered activation, Ca2+ triggered activation, Cachexia, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Endothelial cells, Epigenetics and Cardiovascular Risks, Etiology, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Phosphorylation, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, S-nitrosylation, Signaling, Skeletal muscle regeneration, Statistical Methods for Research Evaluation, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Translational Effectiveness, Translational Science, Ubiquitinylation, Water Transporters, tagged , , , , , , , , , , , , , , , , , , , , , , , , on April 28, 2014| Leave a Comment »

Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Article ID #135: Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1. Published on 4/28/2014

WordCloud Image Produced by Adam Tubman

 

Part 1 of Volume 4 in the e-series A: Cardiovascular Diseases and Translational Medicine, provides a foundation for grasping a rapidly developing surging scientific endeavor that is transcending laboratory hypothesis testing and providing guidelines to:

  • Target genomes and multiple nucleotide sequences involved in either coding or in regulation that might have an impact on complex diseases, not necessarily genetic in nature.
  • Target signaling pathways that are demonstrably maladjusted, activated or suppressed in many common and complex diseases, or in their progression.
  • Enable a reduction in failure due to toxicities in the later stages of clinical drug trials as a result of this science-based understanding.
  • Enable a reduction in complications from the improvement of machanical devices that have already had an impact on the practice of interventional procedures in cardiology, cardiac surgery, and radiological imaging, as well as improving laboratory diagnostics at the molecular level.
  • Enable the discovery of new drugs in the continuing emergence of drug resistance.
  • Enable the construction of critical pathways and better guidelines for patient management based on population outcomes data, that will be critically dependent on computational methods and large data-bases.

What has been presented can be essentially viewed in the following Table:

 

Summary Table for TM - Part 1

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

1. The importance of mitochondrial function in the activity state of the mitochondria in cellular work (combustion) is understood, and impairments of function are identified in diseases of muscle, cardiac contraction, nerve conduction, ion transport, water balance, and the cytoskeleton – beyond the disordered metabolism in cancer.  A more detailed explanation of the energetics that was elucidated based on the electron transport chain might also be in order.

2. The processes that are enabling a more full application of technology to a host of problems in the environment we live in and in disease modification is growing rapidly, and will change the face of medicine and its allied health sciences.

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

Kristala L. J. Prather: Part-1    <iBiology > iBioSeminars > Biophysics & Chemical Biology >

http://www.ibiology.org Lecturers generously donate their time to prepare these lectures. The project is funded by NSF and NIGMS, and is supported by the ASCB and HHMI.
Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”.

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at
Prather 1: Synthetic Biology and Metabolic Engineering  2/6/14IntroductionLecture Overview In the first part of her lecture, Dr. Prather explains that synthetic biology involves applying engineering principles to biological systems to build “biological machines”. The key material in building these machines is synthetic DNA. Synthetic DNA can be added in different combinations to biological hosts, such as bacteria, turning them into chemical factories that can produce small molecules of choice. In Part 2, Prather describes how her lab used design principles to engineer E. coli that produce glucaric acid from glucose. Glucaric acid is not naturally produced in bacteria, so Prather and her colleagues “bioprospected” enzymes from other organisms and expressed them in E. coli to build the needed enzymatic pathway. Prather walks us through the many steps of optimizing the timing, localization and levels of enzyme expression to produce the greatest yield. Speaker Bio: Kristala Jones Prather received her S.B. degree from the Massachusetts Institute of Technology and her PhD at the University of California, Berkeley both in chemical engineering. Upon graduation, Prather joined the Merck Research Labs for 4 years before returning to academia. Prather is now an Associate Professor of Chemical Engineering at MIT and an investigator with the multi-university Synthetic Biology Engineering Reseach Center (SynBERC). Her lab designs and constructs novel synthetic pathways in microorganisms converting them into tiny factories for the production of small molecules. Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.

VIEW VIDEOS

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=0

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=12

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=74

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=129

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk#t=168

https://www.youtube.com/watch?feature=player_embedded&v=ndThuqVumAk

 

II. Regulatory Effects of Mammalian microRNAs

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240
1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.
In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].
Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

Figure 1. Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs.

Left panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Contractile re-sponse is initiated by extracellular Ca influx due to activation of Receptor Operated Ca (through phosphoinositol-coupled receptor) or to activation of L-Type Calcium channels (through an increase in luminal pressure). Small increase of cytosolic due IP3 binding to IP3R (puff) or RyR activation by LTCC or ROC-dependent Ca influx leads to large SR Ca IP3R or RyR clusters (“Ca -induced Ca SR calcium pumps (both SERCA2a and SERCA2b are expressed in quiescent VSMCs), maintaining high concentration of cytosolic Ca and setting the sensitivity of RyR or IP3R for the next spike.
Contraction of VSMCs occurs during oscillatory Ca transient.
Middle panel: schematic representa tion of atherosclerotic vessel wall. Contractile VSMC are located in the media layer, synthetic VSMC are located in sub-endothelial intima.
Right panel: schematic representation of calcium cycling in quiescent /contractile VSMCs. Agonist binding to phosphoinositol-coupled receptor leads to the activation of IP3R resulting in large increase in cytosolic Ca calcium pumps (only SERCA2b, having low turnover and low affinity to Ca depletion leads to translocation of SR Ca sensor STIM1 towards PM, resulting in extracellular Ca influx though opening of Store Operated Channel (CRAC). Resulted steady state Ca transient is critical for activation of proliferation-related transcription factors ‘NFAT).
Abbreviations: PLC – phospholipase C; PM – plasma membrane; PP2B – Ca /calmodulin-activated protein phosphatase 2B (calcineurin); ROC- receptor activated channel; IP3 – inositol-1,4,5-trisphosphate, IP3R – inositol-1,4,5- trisphosphate receptor; RyR – ryanodine receptor; NFAT – nuclear factor of activated T-lymphocytes; VSMC – vascular smooth muscle cells; SERCA – sarco(endo)plasmic reticulum Ca sarcoplasmic reticulum.

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

I’ll start with the productivity plot, as this one isn’t new. For a discussion of the substantial performance increase in sequencing compared to Moore’s Law, as well as the difficulty of finding this data, please see this post. If nothing else, keep two features of the plot in mind: 1) the consistency of the pace of Moore’s Law and 2) the inconsistency and pace of sequencing productivity. Illumina appears to be the primary driver, and beneficiary, of improvements in productivity at the moment, especially if you are looking at share prices. It looks like the recently announced NextSeq and Hiseq instruments will provide substantially higher productivities (hand waving, I would say the next datum will come in another order of magnitude higher), but I think I need a bit more data before officially putting another point on the plot.

 

cost-of-oligo-and-gene-synthesis

cost-of-oligo-and-gene-synthesis

Illumina’s instruments are now responsible for such a high percentage of sequencing output that the company is effectively setting prices for the entire industry. Illumina is being pushed by competition to increase performance, but this does not necessarily translate into lower prices. It doesn’t behoove Illumina to drop prices at this point, and we won’t see any substantial decrease until a serious competitor shows up and starts threatening Illumina’s market share. The absence of real competition is the primary reason sequencing prices have flattened out over the last couple of data points.

Note that the oligo prices above are for column-based synthesis, and that oligos synthesized on arrays are much less expensive. However, array synthesis comes with the usual caveat that the quality is generally lower, unless you are getting your DNA from Agilent, which probably means you are getting your dsDNA from Gen9.

Note also that the distinction between the price of oligos and the price of double-stranded sDNA is becoming less useful. Whether you are ordering from Life/Thermo or from your local academic facility, the cost of producing oligos is now, in most cases, independent of their length. That’s because the cost of capital (including rent, insurance, labor, etc) is now more significant than the cost of goods. Consequently, the price reflects the cost of capital rather than the cost of goods. Moreover, the cost of the columns, reagents, and shipping tubes is certainly more than the cost of the atoms in the sDNA you are ostensibly paying for. Once you get into longer oligos (substantially larger than 50-mers) this relationship breaks down and the sDNA is more expensive. But, at this point in time, most people aren’t going to use longer oligos to assemble genes unless they have a tricky job that doesn’t work using short oligos.

Looking forward, I suspect oligos aren’t going to get much cheaper unless someone sorts out how to either 1) replace the requisite human labor and thereby reduce the cost of capital, or 2) finally replace the phosphoramidite chemistry that the industry relies upon.

IDT’s gBlocks come at prices that are constant across quite substantial ranges in length. Moreover, part of the decrease in price for these products is embedded in the fact that you are buying smaller chunks of DNA that you then must assemble and integrate into your organism of choice.

Someone who has purchased and assembled an absolutely enormous amount of sDNA over the last decade, suggested that if prices fell by another order of magnitude, he could switch completely to outsourced assembly. This is a potentially interesting “tipping point”. However, what this person really needs is sDNA integrated in a particular way into a particular genome operating in a particular host. The integration and testing of the new genome in the host organism is where most of the cost is. Given the wide variety of emerging applications, and the growing array of hosts/chassis, it isn’t clear that any given technology or firm will be able to provide arbitrary synthetic sequences incorporated into arbitrary hosts.

 TrackBack URL: http://www.synthesis.cc/cgi-bin/mt/mt-t.cgi/397

 

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

28 Nov 2013 | PR Web

Dr. Jon Rowley and Dr. Uplaksh Kumar, Co-Founders of RoosterBio, Inc., a newly formed biotech startup located in Frederick, are paving the way for even more innovation in the rapidly growing fields of Synthetic Biology and Regenerative Medicine. Synthetic Biology combines engineering principles with basic science to build biological products, including regenerative medicines and cellular therapies. Regenerative medicine is a broad definition for innovative medical therapies that will enable the body to repair, replace, restore and regenerate damaged or diseased cells, tissues and organs. Regenerative therapies that are in clinical trials today may enable repair of damaged heart muscle following heart attack, replacement of skin for burn victims, restoration of movement after spinal cord injury, regeneration of pancreatic tissue for insulin production in diabetics and provide new treatments for Parkinson’s and Alzheimer’s diseases, to name just a few applications.

While the potential of the field is promising, the pace of development has been slow. One main reason for this is that the living cells required for these therapies are cost-prohibitive and not supplied at volumes that support many research and product development efforts. RoosterBio will manufacture large quantities of standardized primary cells at high quality and low cost, which will quicken the pace of scientific discovery and translation to the clinic. “Our goal is to accelerate the development of products that incorporate living cells by providing abundant, affordable and high quality materials to researchers that are developing and commercializing these regenerative technologies” says Dr. Rowley

 

Life at the Speed of Light

http://kcpw.org/?powerpress_pinw=92027-podcast

NHMU Lecture featuring – J. Craig Venter, Ph.D.
Founder, Chairman, and CEO – J. Craig Venter Institute; Co-Founder and CEO, Synthetic Genomics Inc.

J. Craig Venter, Ph.D., is Founder, Chairman, and CEO of the J. Craig Venter Institute (JVCI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic and environmental research. He is also Co-Founder and CEO of Synthetic Genomics Inc. (SGI), a privately-held company dedicated to commercializing genomic-driven solutions to address global needs.

In 1998, Dr. Venter founded Celera Genomics to sequence the human genome using new tools and techniques he and his team developed.  This research culminated with the February 2001 publication of the human genome in the journal, Science. Dr. Venter and his team at JVCI continue to blaze new trails in genomics.  They have sequenced and a created a bacterial cell constructed with synthetic DNA,  putting humankind at the threshold of a new phase of biological research.  Whereas, we could  previously read the genetic code (sequencing genomes), we can now write the genetic code for designing new species.

The science of synthetic genomics will have a profound impact on society, including new methods for chemical and energy production, human health and medical advances, clean water, and new food and nutritional products. One of the most prolific scientists of the 21st century for his numerous pioneering advances in genomics,  he  guides us through this emerging field, detailing its origins, current challenges, and the potential positive advances.

His work on synthetic biology truly embodies the theme of “pushing the boundaries of life.”  Essentially, Venter is seeking to “write the software of life” to create microbes designed by humans rather than only through evolution. The potential benefits and risks of this new technology are enormous. It also requires us to examine, both scientifically and philosophically, the question of “What is life?”

J Craig Venter wants to digitize DNA and transmit the signal to teleport organisms

http://pharmaceuticalintelligence.com/2013/11/01/j-craig-venter-wants-to-digitize-dna-and-transmit-the-signal-to-teleport-organisms/

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

http://pharmaceuticalintelligence.com/2013/02/11/2013-genomics-the-era-beyond-the-sequencing-human-genome-francis-collins-craig-venter-eric-lander-et-al/

Human Longevity Inc (HLI) – $70M in Financing of Venter’s New Integrative Omics and Clinical Bioinformatics

http://pharmaceuticalintelligence.com/2014/03/05/human-longevity-inc-hli-70m-in-financing-of-venters-new-integrative-omics-and-clinical-bioinformatics/

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

A technology trend analyst offers an overview of synthetic biology, its potential applications, obstacles to its development, and prospects for public approval.

  • In addition to boosting the economy, synthetic biology projects currently in development could have profound implications for the future of manufacturing, sustainability, and medicine.
  • Before society can fully reap the benefits of synthetic biology, however, the field requires development and faces a series of hurdles in the process. Do researchers have the scientific know-how and technical capabilities to develop the field?

Biology + Engineering = Synthetic Biology

Bioengineers aim to build synthetic biological systems using compatible standardized parts that behave predictably. Bioengineers synthesize DNA parts—oligonucleotides composed of 50–100 base pairs—which make specialized components that ultimately make a biological system. As biology becomes a true engineering discipline, bioengineers will create genomes using mass-produced modular units similar to the microelectronics and computer industries.

Currently, bioengineering projects cost millions of dollars and take years to develop products. For synthetic biology to become a Schumpeterian revolution, smaller companies will need to be able to afford to use bioengineering concepts for industrial applications. This will require standardized and automated processes.

A major challenge to developing synthetic biology is the complexity of biological systems. When bioengineers assemble synthetic parts, they must prevent cross talk between signals in other biological pathways. Until researchers better understand these undesired interactions that nature has already worked out, applications such as gene therapy will have unwanted side effects. Scientists do not fully understand the effects of environmental and developmental interaction on gene expression. Currently, bioengineers must repeatedly use trial and error to create predictable systems.

Similar to physics, synthetic biology requires the ability to model systems and quantify relationships between variables in biological systems at the molecular level.

The second major challenge to ensuring the success of synthetic biology is the development of enabling technologies. With genomes having billions of nucleotides, this requires fast, powerful, and cost-efficient computers. Moore’s law, named for Intel co-founder Gordon Moore, posits that computing power progresses at a predictable rate and that the number of components in integrated circuits doubles each year until its limits are reached. Since Moore’s prediction, computer power has increased at an exponential rate while pricing has declined.

DNA sequencers and synthesizers are necessary to identify genes and make synthetic DNA sequences. Bioengineer Robert Carlson calculated that the capabilities of DNA sequencers and synthesizers have followed a pattern similar to computing. This pattern, referred to as the Carlson Curve, projects that scientists are approaching the ability to sequence a human genome for $1,000, perhaps in 2020. Carlson calculated that the costs of reading and writing new genes and genomes are falling by a factor of two every 18–24 months. (see recent Carlson comment on requirement to read and write for a variety of limiting  conditions).

Startup to Strengthen Synthetic Biology and Regenerative Medicine Industries with Cutting Edge Cell Products

http://pharmaceuticalintelligence.com/2013/11/28/startup-to-strengthen-synthetic-biology-and-regenerative-medicine-industries-with-cutting-edge-cell-products/

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Synthesizing Synthetic Biology: PLOS Collections

http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

Capturing ten-color ultrasharp images of synthetic DNA structures resembling numerals 0 to 9

http://pharmaceuticalintelligence.com/2014/02/05/capturing-ten-color-ultrasharp-images-of-synthetic-dna-structures-resembling-numerals-0-to-9/

Silencing Cancers with Synthetic siRNAs

http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

Genomics Now—and Beyond the Bubble

Futurists have touted the twenty-first century as the century of biology based primarily on the promise of genomics. Medical researchers aim to use variations within genes as biomarkers for diseases, personalized treatments, and drug responses. Currently, we are experiencing a genomics bubble, but with advances in understanding biological complexity and the development of enabling technologies, synthetic biology is reviving optimism in many fields, particularly medicine.

BY MICHAEL BROOKS    17 APR, 2014     http://www.newstatesman.com/

Michael Brooks holds a PhD in quantum physics. He writes a weekly science column for the New Statesman, and his most recent book is The Secret Anarchy of Science.

The basic idea is that we take an organism – a bacterium, say – and re-engineer its genome so that it does something different. You might, for instance, make it ingest carbon dioxide from the atmosphere, process it and excrete crude oil.

That project is still under construction, but others, such as using synthesised DNA for data storage, have already been achieved. As evolution has proved, DNA is an extraordinarily stable medium that can preserve information for millions of years. In 2012, the Harvard geneticist George Church proved its potential by taking a book he had written, encoding it in a synthesised strand of DNA, and then making DNA sequencing machines read it back to him.

When we first started achieving such things it was costly and time-consuming and demanded extraordinary resources, such as those available to the millionaire biologist Craig Venter. Venter’s team spent most of the past two decades and tens of millions of dollars creating the first artificial organism, nicknamed “Synthia”. Using computer programs and robots that process the necessary chemicals, the team rebuilt the genome of the bacterium Mycoplasma mycoides from scratch. They also inserted a few watermarks and puzzles into the DNA sequence, partly as an identifying measure for safety’s sake, but mostly as a publicity stunt.

What they didn’t do was redesign the genome to do anything interesting. When the synthetic genome was inserted into an eviscerated bacterial cell, the new organism behaved exactly the same as its natural counterpart. Nevertheless, that Synthia, as Venter put it at the press conference to announce the research in 2010, was “the first self-replicating species we’ve had on the planet whose parent is a computer” made it a standout achievement.

Today, however, we have entered another era in synthetic biology and Venter faces stiff competition. The Steve Jobs to Venter’s Bill Gates is Jef Boeke, who researches yeast genetics at New York University.

Boeke wanted to redesign the yeast genome so that he could strip out various parts to see what they did. Because it took a private company a year to complete just a small part of the task, at a cost of $50,000, he realised he should go open-source. By teaching an undergraduate course on how to build a genome and teaming up with institutions all over the world, he has assembled a skilled workforce that, tinkering together, has made a synthetic chromosome for baker’s yeast.

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

Posted April 22, 2014 by Heather McGaw and Kyrie Vala-Webb

We got a crash course on genetics and protein pathways, and then set out to design and build our own pathways using both the “Genomikon: Violacein Factory” kit and Synbiota platform. With Synbiota’s software, we dragged and dropped the enzymes to create the sequence that we were then going to build out. After a process of sketching ideas, mocking up pathways, and writing hypotheses, we were ready to start building!

The night stretched long, and at midnight we were forced to vacate the school. Not quite finished, we loaded our delicate bacteria, incubator, and boxes of gloves onto the bus and headed back to complete our bacterial transformation in one of our hotel rooms. Jammed in between the beds and the mini-fridge, we heat-shocked our bacteria in the hotel ice bucket. It was a surreal moment.

While waiting for our bacteria, we held an “unconference” where we explored bioethics, security and risk related to synthetic biology, 3D printing on Mars, patterns in juggling (with live demonstration!), and even did a Google Hangout with Rob Carlson. Every few hours, we would excitedly check in on our bacteria, looking for bacterial colonies and the purple hue characteristic of violacein.

Most impressive was the wildly successful and seamless integration of a diverse set of people: in a matter of hours, we were transformed from individual experts and practitioners in assorted fields into cohesive and passionate teams of DIY biologists and science hackers. The ability of everyone to connect and learn was a powerful experience, and over the course of just one weekend we were able to challenge each other and grow.

Returning to work on Monday, we were hungry for more. We wanted to find a way to bring the excitement and energy from the weekend into the studio and into the projects we’re working on. It struck us that there are strong parallels between design and DIYbio, and we knew there was an opportunity to bring some of the scientific approaches and curiosity into our studio.

 

 

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Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Posted in Acute Myocardial Infarction, Biological Networks, Gene Regulation and Evolution, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, De novo synthesis, Diabetes Mellitus, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Endothelial cells, Epigenetics and Cardiovascular Risks, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical Devices R&D and Inventions, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on April 27, 2014| Leave a Comment »

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This document is entirely devoted to medical and surgical therapies that have made huge strides in

  • simplification of interventional procedures,
  • reduced complexity, resulting in procedures previously requiring surgery are now done, circumstances permitting, by medical intervention.

This revolution in cardiovascular interventional therapy is regenerative medicine.  It is regenerative because it is largely driven by

  • the introduction into the impaired vasculature of an induced pleuripotent cell, called a stem cell, although
  • the level of differentiation may not be a most primitive cell line.

There is also a very closely aligned development in cell biology that extends beyond and including vascular regeneration that is called synthetic biology.  These developments have occurred at an accelerated rate in the last 15 years. The methods of interventional cardiology were already well developed in the mid 1980s.  This was at the peak of cardiothoracic bypass surgery.

Research on the endothelial cell,

  • endothelial cell proliferation,
  • shear flow in small arteries, especially at branch points, and
  • endothelial-platelet interactions

led to insights about plaque formation and vessel thrombosis.

Much was learned in biomechanics about the shear flow stresses on the luminal surface of the vasculature, and there was also

  • the concomitant discovery of nitric oxide,
  • oxidative stress, and
  • the isoenzymes of nitric oxide synthase (eNOS, iNOS, and nNOS).

It became a fundamental tenet of vascular biology that

  • atherogenesis is a maladjustment to oxidative stress not only through genetic, but also
  • non-genetic nutritional factors that could be related to the balance of omega (ω)-3 and omega (ω)-6 fatty acids,
  • a pro-inflammatory state that elicits inflammatory cytokines, such as, interleukin-6 (IL6) and c-reactive protein(CRP),
  • insulin resistance with excess carbohydrate associated with type 2 diabetes and beta (β) cell stress,
  • excess trans- and saturated fats, and perhaps
  • the now plausible colonic microbial population of the gastrointestinal tract (GIT).

There is also an association of abdominal adiposity,

  • including the visceral peritoneum, with both T2DM and with arteriosclerotic vessel disease,
  • which is presenting at a young age, and has ties to
  • the effects of an adipokine, adiponectin.

Much important work has already been discussed in the domain of cardiac catheterization and research done to

  • prevent atheroembolization.and beyond that,
  • research done to implant an endothelial growth matrix.

Even then, dramatic work had already been done on

  • the platelet structure and metabolism, and
  • this has transformed our knowledge of platelet biology.

The coagulation process has been discussed in detailed in a previous document.  The result was the development of a

  • new class of platelet aggregation inhibitors designed to block the activation of protein on the platelet surface that
  • is critical in the coagulation cascade.

In addition, the term long used to describe atherosclerosis, atheroma notwithstanding, is “hardening of the arteries”.  This is particularly notable with respect to mid-size arteries and arterioles that feed the heart and kidneys. Whether it is preceded by or develops concurrently with chronic renal insufficiency and lowered glomerular filtration rate is perhaps arguable.  However, there is now a body of evidence that points to

  • a change in the vascular muscularis and vessel stiffness, in addition to the endothelial features already mentioned.

This has provided a basis for

  • targeted pharmaceutical intervention, and
  • reduction in salt intake.

So we have a  group of metabolic disorders, which may alone or in combination,

  • lead to and be associated with the long term effects of cardiovascular disease, including
  • congestive heart failure.

This has been classically broken down into forward and backward failure,

  • depending on decrease outflow through the aorta (ejection fraction), or
  • decreased venous return through the vena cava,

which involves increased pulmonary vascular resistance and decreased return into the left atrium.

This also has ties to several causes, which may be cardiac or vascular. This document, as the previous, has four pats.  They are broadly:

  1. Stem Cells in Cardiovascular Diseases
  2. Regenerative Cell and Molecular Biology
  3. Therapeutics Levels In Molecular Cardiology
  4. Research Proposals for Endogenous Augmentation of circulating Endothelial Progenitor Cells (cEPCs)

As in the previous section, we start with the biology of the stem cell and the degeneration in cardiovascular diseases, then proceed to regeneration, then therapeutics, and finally – proposals for augmenting therapy with circulating endogenous endothelial progenitor cells (cEPCs).

 

context

stem cells

 

theme

regeneration

 

 

 

 

theme

Therapeutics

 

theme

augmentation

 

 

 

 

 

 

 

 

 

 

Key pathways involving NO

Key pathways involving NO

 

 

 

 

stem cell lin28

stem cellLlin28

1479-5876-10-175-1-l translational research with feedback loops

Tranlational Research -Lab to Bedside

 

 

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Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN

Posted in Acute Myocardial Infarction, Anemia in CVD Patients, Atherogenic Processes & Pathology, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Epigenetics and Cardiovascular Risks, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, HTN in Youth, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Resident-cell-based, Spontaneous Coronary Artery Dissection (SCAD), Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science on April 17, 2014| Leave a Comment »

Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN, 2006 – 4/2018

 

+120 articles listed below cover the following topics:

  • National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden
  • Introduction to Drug Types: De Novo Brand, Generic, Biologics, Biosimsilars
  • Anti-Inflammatory & Systemic Inflammatory
  • Anti-thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)
  • Pharmaco-Genetics response to Congenital and Spontaneous Mutations: new drugs and new biomarkers for Atherosclerosis, Genetic-related Novel Anti-Cholesterol, Lipids, LDL, HDL, Hypertriglyceridemia Hyperlipidemia
  • Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics
  • BP Management: Genetics & Human Adaptive Immunity
  • Anti-arrhythmic Drugs – Atrial Fibrillation (AF) & Silent Cerebral Infarctions
  • MI, Acute Coronary Syndrome (ACS) and Heart Failure (HF)
  • Calcium &Cardiovascular Diseases: Contractile Dysfunction, Calcium as Neurotransmitter Sensor
  • Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)
  • Vascular Biology, Atherosclerosis and Molecular Cardiology

 

A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/04/06/a-new-mechanism-of-action-to-attack-in-the-treatment-of-coronary-artery-disease-cad-novartis-developed-ilaris-canakinumab-a-human-monoclonal-antibody-targeting-the-interleukin-1beta-innate-i/

 

Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/20/advantages-and-disadvantages-of-novel-oral-anticoagulants-noacs/

 

Acute Coronary Syndrome (ACS): Strategies in Anticoagulant Selection: Diagnostics Approaches – Genetic Testing Aids vs. Biomarkers (Troponin types and BNP)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/13/acute-coronary-syndrome-acs-strategies-in-anticoagulant-selection-diagnostics-approaches-genetic-testing-aids-vs-biomarkers-troponin-types-and-bnp/

 

Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/12/cholesterol-lowering-novel-pcsk9-drugs-praluent-sanofi-and-regeneron-vs-repatha-amgen-which-drug-cuts-cv-risks-enough-to-make-it-cost-effective/

 

Higher BMI (Obesity Marker): Earlier onset of incident CVD followed by Shorter overall Survival – Men and women of all ages

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/05/higher-bmi-obesity-marker-earlier-onset-of-incident-cvd-followed-by-shorter-overall-survival-men-and-women-of-all-ages/

 

ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/odyssey-outcomes-trial-evaluating-the-effects-of-a-pcsk9-inhibitor-alirocumab-on-major-cardiovascular-events-in-patients-with-an-acute-coronary-syndrome-to-be-presented-at-the-america/

 

Sex and Gender Connections: Heart and Brain Disease in Women

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/sex-and-gender-connections-heart-and-brain-disease-in-women/

 

In 2018 Cardiovascular PharmacoTherapy Market: Anti-thrombotic Drug Class Segment will continue to bring in the biggest profit and dominate production

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/in-2018-cardiovascular-pharmacotherapy-market-anti-thrombotic-drug-class-segment-will-continue-to-bring-in-the-biggest-profit-and-dominate-production/

 

Cost per Inpatient Hospital Stay: Five cardiovascular issues ranked in the top 10 – #1 Heart valve disorders, #2 Acute myocardial infarction (heart attack), #4 Coronary atherosclerosis, #7 Septicemia, #10 Acute cerebrovascular disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/cost-per-inpatient-hospital-stay-five-cardiovascular-issues-ranked-in-the-top-10-1-heart-valve-disorders-2-acute-myocardial-infarction-heart-attack-4-coronary-atherosclerosis/

 

There may be a genetic basis to CAD and that CXCL5 may be of therapeutic interest

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/09/there-may-be-a-genetic-basis-to-cad-and-that-cxcl5-may-be-of-therapeutic-interest/

 

FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/fda-approval-marks-first-presentation-of-bivalirudin-in-frozen-premixed-ready-to-use-formulation/

 

What Level of Blood Pressure (BP) should be Treated? Comments on the New Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/what-level-of-blood-pressure-bp-should-be-treated-comments-on-the-new-guidelines/

 

FDA approval on 12/1/2017 of Amgen’s evolocumb (Repatha) a PCSK9 inhibitor for the prevention of heart attacks, strokes, and coronary revascularizations in patients with established cardiovascular disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/12/01/fda-approval-on-12-1-2017-of-amgens-evolocumb-repatha-a-pcsk9-inhibitor-for-the-prevention-of-heart-attacks-strokes-and-coronary-revascularizations-in-patients-with-established-cardiovascular-di/

 

Long-term Canakinumab Treatment Lowering Inflammation Independent of Lipid Levels for Residual Inflammatory Risk Benefit – Personalized Medicine for Recurrent MI, Strokes and Cardiovascular Death

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/21/long-term-canakinumab-treatment-lowering-inflammation-independent-of-lipid-levels-for-residual-inflammatory-risk-benefit-personalized-medicine-for-recurrent-mi-strokes-and-cardiovascular-death/

 

Daily Highlights at 2017 American Heart Association Annual Meeting Scientific Sessions

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/daily-highlights-at-2017-american-heart-association-annual-meeting-scientific-sessions/

 

2017 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults – A REPORT OF THE American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/2017-guideline-for-the-prevention-detection-evaluation-and-management-of-high-blood-pressure-in-adults-a-report-of-the-american-college-of-cardiology-american-heart-association-task-force-on-clin/

 

2017 American Heart Association Annual Meeting: Sunday’s Science at #AHA17 – Presidential Address

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/13/2017-american-heart-association-annual-meeting-sundays-science-at-aha17-presidential-address/

 

Systemic Inflammatory Diseases as Crohn’s disease, Rheumatoid Arthritis and Longer Psoriasis Duration May Mean Higher CVD Risk

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/10/09/systemic-inflammatory-diseases-as-crohns-disease-rheumatoid-arthritis-and-longer-psoriasis-duration-may-mean-higher-cvd-risk/

 

Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/17/shaun-coughlin-from-ucsf-cardiovascular-research-center-to-cardio-group-for-the-novartis-institute-for-biomedical-research-in-cambridge-ma/

 

In Europe, BigData@Heart aim to improve patient outcomes and reduce societal burden of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/in-europe-bigdataheart-aim-to-improve-patient-outcomes-and-reduce-societal-burden-of-atrial-fibrillation-af-heart-failure-hf-and-acute-coronary-syndrome-acs/

 

SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/snp-based-study-on-high-bmi-exposure-confirms-cvd-and-dm-risks-no-associations-with-stroke/

 

Tweets by @pharma_BI and @AVIVA1950 at World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/05/tweets-by-pharma_bi-and-aviva1950-at-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

 

e-Proceedings for Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Curator and Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/05/e-proceedings-for-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

REAL TIME Highlights and Tweets: Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Author and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/03/deliverables-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-httpsworldmedicalinnovation-orgagenda-highlights-of-live-day-1-world-medical/

 

Expedite Use of Agents in Clinical Trials: New Drug Formulary Created – The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/12/expedite-use-of-agents-in-clinical-trials-new-drug-formulary-created-the-nci-formulary-is-a-public-private-partnership-between-nci-part-of-the-national-institutes-of-health-and-pharmaceutical-and/

 

Reversing Heart Disease: Combination of PCSK9 Inhibitors and Statins – Opinion by Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/29/reversing-heart-disease-combination-of-pcsk9-inhibitors-and-statins-opinion-by-steven-nissen-md-chairman-of-cardiovascular-medicine-at-cleveland-clinicopinion-on-reversing-heart-disease-combinat/

 

Coronary Heart Disease Research: Sugar Industry influenced national conversation on heart disease – Adoption of Low Fat Diet vs Low Carbohydrates Diet

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/09/17/coronary-heart-disease-research-sugar-industry-influenced-national-conversation-on-heart-disease-adoption-of-low-fat-diet-vs-low-carbohydrates-diet/

 

Pathophysiology in Hypertension: Opposing Roles of Human Adaptive Immunity

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/19/pathophysiology-in-hypertension-opposing-roles-of-human-adaptive-immunity/

 

PCSK9 inhibitors: Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold per JAMA

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/17/pcsk9-inhibitors-reducing-annual-drug-prices-from-more-than-14%E2%80%AF000-to-4536-would-be-necessary-to-meet-a-100%E2%80%AF000-per-qaly-threshold-per-jama/

 

The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/16/the-presence-of-any-valvular-heart-disease-vhd-did-not-influence-the-comparison-of-dabigatran-pradaxa-boehringer-ingelheim-with-warfarin/

 

Resveratrol, an antioxidant found in red wine presented since 2003 presented for its potential to lower risk for cardiovascular disease and neurodegeneration by increasing cell survival and slowing aging: 2014 Study – Diet rich in resveratrol offers no health boost

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/25/resveratrol-an-antioxidant-found-in-red-wine-2014-study-resveratrol-offers-no-health-boost/

 

Amgen’s Corlanor® can help Reduce the Risk of Hospitalization for Patients with worsening Heart Failure

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/04/amgens-corlanor-can-help-reduce-the-risk-of-hospitalization-for-patients-with-worsening-heart-failure/

 

Effectiveness of Anti-arrhythmic Drugs: Amiodarone and Lidocaine, for treating sudden cardiac arrest, increasing likelihood of Patients Surviving Emergency Transport to Hospital

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/04/effectiveness-of-anti-arrhythmic-drugs-amiodarone-and-lidocaine-for-treating-sudden-cardiac-arrest-increasing-likelihood-of-patients-surviving-emergency-transport-to-hospital/

 

Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/03/efficacy-and-tolerability-of-pcsk9-inhibitors-by-patients-with-muscle-related-statin-intolerance-new-cleveland-clinic-study-published-in-jama-42016/

 

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/13/triglycerides-is-it-a-risk-factor-or-a-risk-marker-for-atherosclerosis-and-cardiovascular-disease-the-impact-of-genetic-mutations-on-angptl4-gene-encoder-of-angiopoietin-like-4-protein-that-in/

 

In One-Hour: A Diagnosis of Heart Attack made possible by one Blood Test

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/01/14/in-one-hour-a-diagnosis-of-heart-attack-made-possible-by-one-blood-test/

 

Heart-Failure–Related Mortality Rate: CDC Reports comparison of 2000, 2012, 2014  – the decease is steadily reversed

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/05/heart-failure-related-mortality-rate-cdc-reports-comparison-of-2000-2012-2014-the-decease-is-steadily-reversed/

 

PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/08/04/pcsk9-a-recent-discovery-in-understanding-cholesterol-regulation-amgen-cardiovascular/

 

Praluent – FDA approved as Cholesterol-lowering Medicine for Patient non responsive to Statin due to Genetic origin of Hypercholesterolemia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/27/praluent-fda-approved-as-cholesterol-lowering-medicine-for-patient-non-responsive-to-statin-due-to-genetic-origin-of-hypercholesterolemia/

 

Atherosclerosis: What is New in Biomarker Discovery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/01/atherosclerosis-what-is-new-in-biomarker-discovery/

 

Cangrelor wins Clopidogrel (Plavix): reduction of Risk of a composite of all-cause mortality, myocardial infarction, ischemia driven revascularization, and stent thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/cangrelor-wins-clopidogrel-plavix-reduction-of-risk-of-a-composite-of-all-cause-mortality-myocardial-infarction-ischemia-driven-revascularization-and-stent-thrombosis/

 

Sets of co-expressed Genes influence Blood Pressure Regulation: Genome-wide Association and mRNA expression @US National Heart, Lung, and Blood Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/sets-of-co-expressed-genes-influence-blood-pressure-regulation-genome-wide-association-and-mrna-expression-us-national-heart-lung-and-blood-institute/

 

HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/hdl-c-target-of-therapy-steven-e-nissen-md-macc-cleveland-clinic-vs-peter-libby-md-bwh/

 

Atrial Fibrillation and Silent Cerebral Infarctions: A Meta Analysis Study and Literature Review

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/04/atrial-fibrillation-and-silent-cerebral-infarctions-a-meta-analysis-study-and-literature-review/

 

Intracranial Vascular Stenosis: Comparison of Clinical Trials: Percutaneous Transluminal Angioplasty and Stenting (PTAS) vs. Clot-inhibiting Drugs: Aspirin and Clopidogrel (dual antiplatelet therapy) – more Strokes if Stenting

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/intracranial-vascular-stenosis-comparison-of-clinical-trials-percutaneous-transluminal-angioplasty-and-stenting-ptas-vs-clot-inhibiting-drugs-aspirin-and-clopidogrel-dual-antiplatelet-therapy/

 

Hypertension: It is Autoimmunity that Underlies its Development in Humans

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/08/hypertension-it-is-autoimmunity-that-underlies-its-development-in-humans/

 

OPINION LEADERSHIP on Cardiovascular Diseases

Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation

  • Cardiovascular Diseases, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation. On Amazon.com since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

 Epilogue to Volume Two

Author and Curator: Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books

https://pharmaceuticalintelligence.com/2014/07/31/opinion-leadership-on-cardiovascular-diseases/

 

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/29/risk-of-major-cardiovascular-events-by-ldl-cholesterol-level-mgdl-among-those-treated-with-high-dose-statin-therapy-more-than-40-of-patients-failed-to-achieve-an-ldl-cholesterol-target-of-less-th/

 

Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H Bernstein, MD, FCAP

Commissioned article, Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

 

Coagulation Therapy: Leading New Drugs – Efficacy Comparison

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/coagulation-therapy-leading-new-drugs-efficacy-comparison/

 

Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/apixaban-eliquis-mechanism-of-action-drug-comparison-and-additional-indications/

 

Boston Heart Diagnostics (BHD) offers Statin Induced Myopathy (SLCO1B1) Genotype test and genetic tests targeting ApoE, Factor V Leiden, prothrombin (Factor II), and CYP2C19

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/boston-heart-diagnostics-bhd-offers-statin-induced-myopathy-slco1b1-genotype-test-and-genetic-tests-targeting-apoe-factor-v-leiden-prothrombin-factor-ii-and-cyp2c19/

 

@@@ Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN

Curator: Aviva Leve-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/cardiovascular-diseases-and-pharmacological-therapy-curations-by-aviva-lev-ari-phd-rn/

 

Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

 

Differences in Health Services Utilization and Costs between Antihypertensive Medication Users Versus Nonusers in Adults with Diabetes and Concomitant Hypertension from Medical Expenditure Panel Su…

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/28/differences-in-health-services-utilization-and-costs-between-antihypertensive-medication-users-versus-nonusers-in-adults-with-diabetes-and-concomitant-hypertension-from-medical-expenditure-panel-su-2/

 

2014 Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism Conference: San Francisco, Ca. Conference Dates: San Francisco, CA 3/18-21, 2014

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/26/2014-epidemiology-and-prevention-nutrition-physical-activity-and-metabolism-conference-san-francisco-ca-conference-dates-san-francisco-ca-318-21-2014/

 

2014 High Blood Pressure Research Conference, 9/9 – 9/12, 2014 — Hilton SF Union Square, San Francisco, CA

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/24/2014-high-blood-pressure-research-conference-99-912-2014-hilton-sf-union-square-san-francisco-ca/

 

Females and Non-Atherosclerotic Plaque: Spontaneous Coronary Artery Dissection – New Insights from Research and DNA Ongoing Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/female-and-non-atherosclerotic-plaque-spontaneous-coronary-artery-dissection-new-insights-from-research-and-dna-ongoing-study/

 

Hypertension – JNC 8 Guideline: Henry R. Black, MD, Michael A. Weber, MD and Raymond R. Townsend, MD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/hypertension-jnc-8-guideline-henry-r-black-md-michael-a-weber-md-and-raymond-r-townsend-md/

 

Why Don’t You Trust Generic Drugs as Much as Brand Name …

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/10/why-dont-you-trust-generic-drugs-as-much-as-brand-name/

 

National Trends, 2005 – 2011: Adverse-event Rates Declined among Patients Hospitalized for Acute Myocardial Infarction or Congestive Heart Failure

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/04/national-trends-2005-2011-adverse-event-rates-declined-among-patients-hospitalized-for-acute-myocardial-infarction-or-congestive-heart-failure/

 

Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/

 

Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – Indications for Cardiovascular Chrono-therapeutics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/02/prolonged-wakefulness-lack-of-sufficient-duration-of-sleep-as-a-risk-factor-for-cardiovascular-diseases-indications-for-cardiovascular-chrono-therapeutics/

 

Testosterone Therapy for Idiopathic Hypogonadotrophic Hypogonadism has Beneficial and Deleterious Effects on Cardiovascular Risk Factors

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/30/testosterone-therapy-for-idiopathic-hypogonadotrophic-hypogonadism-has-beneficial-and-deleterious-effects-on-cardiovascular-risk-factors/

 

Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/28/calcium-and-cardiovascular-diseases-a-series-of-twelve-articles-in-advanced-cardiology/

 

Acute Myocardial Infarction: Curations of Cardiovascular Original Research – A Bibliography

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/acute-myocardial-infarction-curations-of-cardiovascular-original-research-a-bibliography/

 

On-Hours vs Off-Hours: Presentation to ER with Acute Myocardial Infarction – Lower Survival Rate if Off-Hours

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/on-hours-vs-off-hours-presentation-to-er-with-acute-myocardial-infarction-lower-survival-rate-if-off-hours/

 

2014 Winter in New England: The Effect of Record Cold Temperatures on Cardiovascular Diseases

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/2014-winter-in-new-england-the-effect-of-record-cold-temperatures-on-cardiovascular-diseases/

 

Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/voices-from-the-cleveland-clinic-on-the-new-lipid-guidelines-and-on-the-accaha-risk-calculator/

 

Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/19/is-it-hypertension-or-physical-inactivity-cardiovascular-risk-and-mortality-new-results-in-32013/

 

Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/15/regeneration-cardiac-system-and-vasculature

 

Conceived: NEW Definition for Co-Curation in Medical Research

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/04/conceived-new-definition-for-co-curation-in-medical-research/

 

The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/the-young-surgeon-and-the-retired-pathologist-on-science-medicine-and-healthcare-policy-best-writers-among-the-writers/

 

Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/09/25/diabetes-risk-forecasts-serum-calcium-in-upper-normal-range-2-5-mmoll-as-a-new-biomarker/

 

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) or PRADAXA (dabigatran)

Curators: Lal, V., Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/23/do-novel-anticoagulants-affect-the-ptinr-the-cases-of-xarelto-rivaroxaban-and-pradaxa-dabigatran/

 

Calcium-Channel Blocker, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

 

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Curators: Larry H. Bernstein, MD FCAP, Justin D. Pearlman, MD, PhD, FACC, and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

 

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Curators:  Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

 

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

 

Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/

 

Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/07/09/research-programs-george-m-linda-h-kaufman-center-for-heart-failure-cleveland-clinic/

 

Congenital Heart Disease (CHD) at Birth and into Adulthood: The Role of Spontaneous Mutations

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/06/09/congenital-heart-disease-at-birth-and-into-adulthood-the-role-of-spontaneous-mutations-the-genes-and-the-pathways/

 

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/

 

Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/06/02/inhaled-nitric-oxide-in-adults-with-acute-respiratory-distress-syndrome/

 

Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

 

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

 

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

 

Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/05/03/gene-meis1-regulates-the-hearts-ability-to-regenerate-after-injuries/

 

Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/30/prostacyclin-and-nitric-oxide-adventures-in-vascular-biology-a-tale-of-two-mediators/

 

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

 

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

 

Harnessing New Players in Atherosclerosis to Treat Heart Disease

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/25/harnessing-new-players-in-atherosclerosis-to-treat-heart-disease/

 

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

 

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

 

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

 

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/ 

 

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Curators: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

 

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

 

Thymosin References

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/thymosin-references/

 

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

 

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

 

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

 

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Curators: Larry H. Bernstein and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

 

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

 

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

 

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

 

Sustained Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/16/sustained-cardiac-atrial-fibrillation-management-strategies-by-director-of-the-arrhythmia-service-and-electrophysiology-lab-at-the-johns-hopkins-hospital/

 

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/ 

 

Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

 

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

 

Vascular Medicine and Biology: Classification of Fast Acting Therapy for Patients at High Risk for Macrovascular Events – Macrovascular Disease – Therapeutic Potential of cEPCs

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

 

 

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

 

Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/08/cardiac-arrhythmias-a-risk-for-extreme-performance-athletes/

 

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

 

Biosimilars: Financials 2012 vs. 2008

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

 

Biosimilars: CMC Issues and Regulatory Requirements

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

 

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

 

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/04/30/93/

 

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/05/29/445/

 

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

 

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

 

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Progenitor Cells endogenous augmentation

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

Lev-Ari, A. Heart Vasculature (2007) Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle: A Concept-based Pharmacological Therapy of a Combined Three Drug Regimen.

Bouve College of Health Sciences, Northeastern University, Boston, MA 02115

 

Lev-Ari, A. & Abourjaily, P. (2006a) “An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPC) as a Therapeutic Target for Pharmacologic Therapy Design for Cardiovascular Risk Reduction.”

  • Part I: Macrovascular Disease – Therapeutic Potential of cEPCs – Reduction methods for CV risk.
  • Part II:(2006b) Therapeutic Strategy for cEPCs Endogenous Augmentation: A Concept-based Treatment Protocol for a Combined Three Drug Regimen.
  • Part III: (2006c)Biomarker for Therapeutic Targets of Cardiovascular Risk Reduction by cEPCs Endogenous Augmentation using New Combination Drug Therapy of Three Drug Classes and Several Drug Indications.

Northeastern University, Boston, MA 02115

 

Curator: Medical Research – 557 articles in Books

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

 

 

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