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Human Stem Cell Therapies: UCSD New Discovery addressing the Limiting Factor and Providing the Solution

Reporter: Aviva Lev-Ari, PhD, RN

Biologists Discover Solution to Problem Limiting Development of Human Stem Cell Therapies

<p>The biologists developed “humanized” laboratory mice that contained a functional human immune system. Credit: Zhili Rong, UC San Diego</p>

The biologists developed “humanized” laboratory mice that contained a functional human immune system. Credit: Zhili Rong, UC San Diego

Biologists at UC San Diego have discovered an effective strategy that could prevent the human immune system from rejecting the grafts derived from human embryonic stem cells, a major problem now limiting the development of human stem cell therapies. Their discovery may also provide scientists with a better understanding of how tumors evade the human immune system when they spread throughout the body.

The achievement, published in a paper in this week’s early online edition of the journal Cell Stem Cell by a collaboration that included scientists from China, was enabled by the development of “humanized” laboratory mice that contained a functional human immune system capable of mounting a vigorous immune rejection of foreign cells derived from human embryonic stem cells.

Because human embryonic stem cells are different from our own body’s cells, or “allogenic,” a normally functioning human immune system will attack these foreign cells. One way to reduce the body’s “allogenic immune response” is to suppress the immune system with immunosuppressant drugs.

“For organ transplantation to save patients with terminal diseases that has been quite successful,” says Yang Xu, a professor of biology who headed the team of researchers that included Ananda Goldrath, an associate biology professor at UC San Diego. “But for stem cell therapies, the long term use of toxic immunosuppressant drugs for patients who are being treated for chronic diseases like Parkinson’s disease or diabetes pose serious health problems.”

Researchers had long been searching for a human immunity relevant model that would allow them to develop strategies to implant allogenic cells derived from embryonic stem cells safely.  “The problem is that we only had data from mouse immune system and those are not usually translatable in humans, because human and mouse immune systems are quite different,” explains Xu. “So what we decided to do was to optimize the humanized mouse that carries a functional human immune system.”

To do that, the biologists took immune deficient laboratory mice and grafted into their bodies human fetal thymus tissues and hematopoietic stem cells derived from fetal liver of the same human donor. “That reconstituted in these mice a normally functioning human immune system that effectively rejects cells derived human embryonic stem cells,” says Xu. With these “humanized” mouse models, the biologists then tested a variety of immune suppressing molecules alone or in combination and discovered one combination that worked perfectly to protect cells derived from human embryonic stem cells from immune rejection.

That combination was CTLA4-lg, an FDA-approved drug for treating rheumatoid arthritis that suppresses T-cells responsible for immune rejection, and a protein called PD-L1 known to be important for inducing immune tolerance in tumors. The researchers discovered that the combination of these two molecules allowed the allogeneic cells to survive in humanized mice without triggering an immune rejection.

“If we express both molecules in cells derived from human embryonic cells, we can protect these cells from the allogenic immune rejection,” says Xu. “If you have only one such molecule expressed, there is absolutely no impact. We still don’t know exactly how these pathways work together to suppress immune rejection, but now we’ve got an ideal system to study this.”

He and his team of researchers also believe their discovery and the development of their humanized mouse models may offer the much needed tools to develop ways to activate immune response to tumors, because these molecules are known to be important in allowing tumors to evade the human immune system.

“You’re dealing with the same exact pathways that protect tumors from our immune system,” says Xu. “If we can develop strategies to disrupt or silence these pathways in tumors, we might be able to activate immunity to tumors. The humanized mouse system is really a powerful model with which to study human tumor immunity.”

Other researchers involved in the study, besides Xu and Goldrath, were Zhili Rong, Meiyan Wang, Martin Stradner and Huijuan Kong of UC San Diego; Zheng Hu, Huanfa Yi and Yong-Guang Yang of China’s Jilin University; Shengyun Zhu and Xuemei Fu of Shenzhen Children’s Hospital in China. The study was financed by grants from the California Institute for Regenerative Medicine, the National Institutes of Health (AI-064569 and AI-045897), the Chinese Ministry of Science and Technology, and the Natural Sciences Foundation of China.

Center for Personalized Cancer Therapy, a joint initiative between the University of Massachusetts Boston and the Dana-Farber/Harvard Cancer Center (DF/HCC) received 8M from The Massachusetts Life Sciences Center

Reporter: Aviva Lev-Ari, PhD, RN

Massachusetts Injects $8M into Joint UMass Boston, Dana-Farber/Harvard Cancer Center

January 06, 2014

NEW YORK (GenomeWeb News) – The Massachusetts Life Sciences Center has provided $8 million in funding to support continued development of the Center for Personalized Cancer Therapy, a joint initiative between the University of Massachusetts Boston and the Dana-Farber/Harvard Cancer Center (DF/HCC), MSLC said today.

The MLSC, a 10-year, $1 billion state-funded program to support life sciences research, development, and commercialization in Massachusetts, provided $2 million to launch the CPCT in 2011. The center’s goal is to spur and support collaborative and translational research focused on cancer diagnosis and prognosis, individualized treatments, and response to therapy.

The center currently is located in UMass Boston’s Venture Development Center, but it is moving into a permanent home at the university’s Integrated Science Complex this coming fall.

The center plans to use the funding to complete its biomarker facility and a vivarium. The investment also will support a research project seeking to develop, validate, and implement biomarker-based assays that distinguish cancer subtypes and can be used to predict patient responses to treatment.

The center opened its wet lab last March, formed the UMB Cancer Research Network in May, and initiated building of its biomarker facility last October.

The CPCT also has undertaken collaborations with pharmaceutical and biotech companies so that it may develop and commercialize the clinical tests it is developing.

MLSC said its funding will supplement $18 million in federal grant funding that has already been committed to the center.

Edward Benz, director of the DF/HCC said the grant also will support the center’s efforts to “improve research and training opportunities for our students and staff members from diverse backgrounds.”

Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
  1. Genomics and Medicine
  2. Epigenetics – Modifyable Factors Causing CVD
  3. Determinants of CVD – Genetics, Heredity and Genomics Discoveries
  4. Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
  • rapidly evolving science of genomics
  • aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
  • cardiovascular diseases,
  • hypercoagulable state,
  • atherosclerosis,
  • microvascular disease,
  • endothelial disruption, and
  • type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
  • essentially because the involvement of the circulation is systemic in nature.

Part 1

establishes an important connection between RNA and disease expression.  This development has led to
  • the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix.  It was also
  • the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
  • carbohydrate,
  • protein, and
  • lipid metabolism,
such as –  glycogen storage disease, and some are immense challenges, such as
  • Tay Sachs, or
  • Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
  • multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery.  This resulted in the identification of
genomic alterations in
  • cardiovascular disease,
  • cancer,
  • microbial,
  • plant,
  • prion, and
  • metabolic diseases.
This has also led to
  • the identification of genomic targets
  • that are either involved in transcription or
  • are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
  • codevelop with new drugs,
  • biomarkers that are indicators of toxicity or
  • of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
  • this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
  • an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
  • changes in Van der Waal forces and internucleotide distances lead to
  • conformational changes that could have an effect on cell activity.

Part 2

is an exploration of epigenetics in cardiovascular diseases.  Epigenetics is
  • the post-genomic modification of genetic expression
  • by the substitution of nucleotides or by the attachment of carbohydrate residues, or
  • by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described.  These changes
  • may be modifiable, and they
  • may be highly influenced by environmental factors, such as
    1. smoking and environmental toxins,
    2. diet,
    3. physical activity, and
    4. neutraceuticals.
While neutraceuticals is a black box industry that evolved from
  • the extraction of ancient herbal remedies of agricultural derivation
    (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).

The best examples are the importance of

  • n-3 fatty acids, and
  • fiber
  • dietary sulfur (in the source of methionine), folic acid, vitamin B12
  • arginine combined with citrulline to drive eNOS
  • and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains

  • the proinflammatory n-6 fatty acid.

The importance of the ratio of n-3/n-6 fatty acids in diet is not seriously discussed when

  • we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics. The signaling pathways are
  • critical to understanding the inflammatory process, just as
  • dietary factors tie in with a balance that is maintained by dietary intake,
    • possibly gut bacteria utilization of delivered substrate, and
    • proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
  • elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
  1. for identifying and classifying types of disease pathobiology, and
  2. for following treatment measures.

Part 3

connected with genetics and genomic discoveries in cardiovascular diseases.

Part 4

is the tie between life style habits and disease etiology, going forward with
  • the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease.  But the most interesting presentations are
  • in the pharmacogenomics for cardiovascular diseases, with
    1. volyage-gated calcium-channels, and
    2. ApoE in the statin response.

This volume is a splendid example representative of the entire collection on cardiovascular diseases.

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals.  The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA).  The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).  The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease.  There is also a long history of the measurement of  circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity.  Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke.  Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation.  A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium.   Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life.  Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association.  In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age.  The establishment of an epigenetic change is diluted in a diverse population.  There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series.  Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO:  Implementing Biomarker Programs ­ P Ridker PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
   Environmental Contributors
Implicated as Causing CVD
   Diet: Solids and Fluid Intake
and Nutraceuticals
   Physical Activity and
Prevention of CVD
   Psychological Stress and
Mental Health: Risk for CVD
   Correlation between
Cancer and CVD
PART 3  Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
    Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
     Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
     Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
     Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
    Preventive Medicine: Cardiovascular Diseases
    Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
http://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/
    Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
http://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/
Gene-Therapy for CVD
Congenital Heart Disease/Defects
   Medical Etiologies: EBM – LEADING DIAGNOSES, Risks Pharmacogenomics for Cardio-
vascular Diseases
   Signaling Pathways     Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect
http://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
   Proteomics and Metabolomics      Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
http://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
      SNPs in apoE are found to influence statin response
significantly. Less frequent variants in
PCSK9 and smaller effect sizes in SNPs in HMGCR
http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

conceived: NEW Definition for Co-Curation in Medical Research

Curator: Aviva Lev-Ari, PhD, RN

Article ID #100: conceived: NEW Definition for Co-Curation in Medical Research. Published on 1/4/2014

WordCloud Image Produced by Adam Tubman

This article has the following FOUR Parts:

PART 1: NEW Definition for Co-Curation in Medical Research by Aviva Lev-Ari, PhD, RN

PART 2: Curation is Uniquely Distinguished by the Historical Exploratory Ties that Bind by Larry H Bernstein, MD, FCAP

PART 3: Evaluation of the Methodology of Curation in Medical Research by Justin D Pearlman, MD, PhD, FACC and Larry H Bernstein, MD, FCAP

PART 4: FOUR alternative models to the Academic Publishing Industry by Aviva Lev-Ari, PhD, RN

PART 1

NEW Definition for Co-Curation in Medical Research

Forward to Volume Two

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

Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books

Since 4/2012, Leaders in Pharmaceutical Business Intelligence, is developing an innovative methodology for the facilitation of Global access to Biomedical knowledge rather than the access to sheer search results on Scientific subject matters in the Life Sciences and Medicine. For the methodology to attain this complex goal it is to be dealing with popularization of ORIGINAL Scientific Research via Content Curation of Scientific Research Results by Experts, Authors, Writers using the critical  thinking process of expert interpretation of the original research results.

We make a distinction between Curation by a Single Curator and Co-Curation by Several Experts, Authors, Writers.

Curation by a Single Curator

One curator edifies the e-Reader via his/hers OWN creative mental processes of knowledge synthesis following the personal creative mental process of analytical critique of the subject matter. The outcome is a new FORM of writing Science and of writing about Science, as well as, a new FORM of framework been created for the organization of the interrelations exposed in the analytical phase of a dialectically generated original synthesis. This process has multi phases:

  • the conception of the structure of the knowledge presented,
  • culling in the midst of inclusion/exclusion dialectics, and finally
  • the exposition of the Curator’s own original synthetic statements of the new Art, a new conceptual perspective on Science.

Co-Curation by Several Experts, Authors, Writers

A similar process to the one in Curation by a Single Curator is taking place and  is been applied. However, the Co-Curation, brings on stage several players. The Actors in the Scientific Writers Theater,  all own scientific knowledge and master the process of creation of a new Synthesis for most writing engagements. Since the Co-curators are educated in different disciplines, they are skillfully providing interpretations for others’ and their own new conception of ideas. Thus, they are developing new views of the original scientific results presented in peer reviewed journals, just the leading ones in every field. The Co-Curators, their creation represents a new layer of comprehension for the subject matter derived from intersecting mental processes coming into being by cross fertilizations of ideas.

Example #1:

Action Potential, a well define concept in Physiology. For us,  Action Potential was a conceptual creation for the process of Co-Curation. Dr. Lev-Ari, requesting Dr. Bernstein to elaborate creatively, on the function of actin in cytoskeleton mobility, he did,  THEN a new conceptual creation process emerged and had YIELDED the following article:

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Curator: Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Example #2:

The e-Reader reads first

High Serum Calcium Linked to Developing Diabetes: IRAS Study

 Sep 24, 2013

http://www.medscape.com/viewarticle/811536

The e-Reader reads second the curation of that Source Interview

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

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

The e-Reader will compare which of the two is more beneficial for the e-Reader.

We believe that the curation of the Source Interview has remarkable value added analysis that the Reader can benefit from.

The unique process as described for the Single Curator and for Co-Curation, above, will be demonstrated, in this volume with an emphasis on Co-Curation,  by presentation of concrete cases, as we applied the methodology of curation by one or by several Experts, Authors, Writers in the field of Cardiovascular Diseases.

The Process:

  • We culled the scene for Cardiovascular Original Research in +24 Journals,
  • We pre-select domains of research to cover:

The Etiology of the Disease, the Risks of dysfunction at cellular, tissue, organelle, organ, anatomy, physiology, pathophysiology and diagnostics for all of the above.

  • We interpret the Disease Management Options in a comprehensive fashion, exposing the e-Reader to an integrative approach for the treatment of Cardiovascular Disease.

PART 2

Curation is Uniquely Distinguished by the Historical Exploratory Ties that Bind

Larry H Bernstein, MD, FCAP

The process of Curation is explained by the contrasting of the process of Curation with the Art of Scientific Creation, both are explored below by examples.

Concept 1: The Scientific Creation

I shall try to identify the important features and criteria that contribute to scientific curation of medical, biological, and pharmaceutical research, including structural and functional content from the sciences of anatomy, physiology, physics and chemistry.

The principles that I seek to realized is a foundation in the body of knowledge thatprecedes the discovery or innovation.  Is the discovery essential, but unnoticed because of unlinkings to prior established concepts.  This is extremely difficult to cull out, but it has had a recurrent history.  It might be easiest to refer to examples in physics, such as, the unique Nobel Prize discovery of pseudo-crystals that has had an impact on materials science. But actually, in the history of mathematics, astronomy, and physics, and later in anatomy and physiology, we have an “audit trail” in writings from the Hellenistic period, interrupted by the dark ages and the Bubonic Plague, and a reawakening in the period preceding and through the enlightenment and reformation. This carried significant risks for great thinkers in a society that changes slowly, and with repeated interruptions throughout all periods by wars.  One might say that this has no relevance to curation, but repeatedly, libraries and museums preserved discovery that could be re-examined later. Thus, we can’t discard the brilliance of Hipparchos, whose influence on Ptolemy is known, and who discovered the centrality of the Sun to our universe, even though the extent to which he accepted societal belief in astrology is at best limited.  The work of Copernicus later was under great duress, but gave precedence to Galileo and Newton.

The Hellenistic period also gave us Euclid and Archimedes, which was critical for the development of mathematics and measurement, and El Gibr’ gave us algebra. In his time, Archimedes found no-one who he could share his ideas with other than Conon, who died too early, but he was later read by Omar Kayyam,  Leonardo da Vinci, Galileo and Newton.  The Greek diagrams used by Archimedes of Syracuse were a major contribution to cognition and inference.  The Archimedes Palimpses, which were given to us as by the priest-scribe, Ioannes Myronas in 1229, is historically a major contribution revealing Archimedes work in the Method. There is the center of gravity of a triangle, and the treatise on Balancing Planes, from which he deduces that if you place two objects on a balance on which the distances are movable from the fulcrum, the distance of the lighter object is five times the distance of the heavier object.  The rule is that weights balance when they are reciprocal to their distance. Then there is Fermat’s Last Theorem, unsolved problem for centuries since the seventeenth century.The theorem state that while the square of a whole number can can be broken down into two other squares of whole numbers the same cannot be done for cubes or any higher power. The theorem took seven years to write, with a ynother year to edit.The principle was incorporated into the Pythagorean Theorem, and in 1955 two japanese mathematicians made a far reaching conjecture that paved the way to the solution by Andrew Wiles at Princeton in 1995.

Notably, the great mathematician, Gauss, who published Disquisition on Mathematics in 1801, on  number theory at age 24, refused to engage in the solution, but his work in complex analysis, based on earlier work by Euler involving imaginary numbers was crucial to the 20th century understanding.Perhaps another apt example is Einstein’s general theory of relativity, the prediction of gravitational radiation bringing a new attention to the tiny ripples in space-time that has opened our eyes to modern cosmology. Finally, we find that a small piece of our universe is viewed as a chunk of Hilbert space, developing as a nest of interacting probability waves. The waves of Hilbert space are actually the waves Schroedinger derived before we had the tools to observe their behavior.The mathematics of entanglement identifies the high-probability areas of a joint-Hilbert space developed from the interaction having consistent histories. This has led to the description of Schroedinger’s principle, the things that we consider to be real are stable persistent patterns. This gives rise to debate about many worlds.

We leave the seemingly esoteric world of problems in mathematics and theoretic physics and return to the world of biochemistry, molecular biology, genomics, proteomics and allied medical sciences.

The scientific underpinnings of biology and medicine transitioned from a largely observational and descriptive phase in the 19th century with the scientifc leadership of Rudolph VirchowLouis Pasteur, Robert Koch, John Hunter, Edward Jennings, Walter Reed, Karl Landsteiner, and Thomas Hunt Morgan.  Pasteur, Koch, Landsteiner and Morgan were outstanding experimentalists.  The latter two were to receive Nobel Prizes that began in 2001.  The idea of a more fundamental basis for biological sciences was concerned with studying the chemical structures and processes of biological phenomena that involve the basic units of life, and it developed out of the related fields of biochemistrygenetics, and biophysics. The primary focus became the study of proteins and nucleic acids—i.e., the macromolecules that are essential to life processes. A great impetus was provided by enabling the three-dimensional structure of these macromolecules through such techniques as X-ray diffraction and electron microscopy. In seeking to understand the molecular basis of genetic processes; molecular biologists map the location of genes on specific chromosomes, associate these genes with particular characters of an organism, and use recombinant DNA technology to isolate, sequence, and modify specific genes.

The above is tied to a dominance of Western scientific discovery, as seen in the recipients of the Nobel Prize, but it is only a two dimensional view. Here another type of graphical display would be more informative, and it has been developed. I might consider a separation by type for physics, chemistry and medicine, leaving out the others, and then, in combination. I would bet that there are interactions.

For instance – 2001 – Roentgen, Physics; Pierre and Marie Curie, Physics; E.O. Lawrence, Chemistry, Berkeley Radiation Lab; Max Planck, following on Boltzmann and on Josiah Willard Gibbs (pre-Nobel) work. Then you have radiology and radioisotope chemistry and photosynthesis, Martin Kamen. Of course, modern physiology and metabolism traces back to the work on oxygen, carcon dioxide, and heat, adiabatic systems, and leads to the calorimeter, the Warburg apparatus, which credits Pasteur’s work 60 years earlier. The fruit fly genetics was an impetus for cracking the genetic code, but the impetus for that was both from Gregor Mendel and Charles Darwin, and then the mathematical work of Pearson and of Fischer. The work on the chemical bond by Linus Pauling really opened up a foundation for understanding organic and inorganic reactions based on atomic orbital theory that was essential for pursuit of the double helix. This was so important that it unlocked the structure of polymeric proteins through the disulfide bond, and also metalloprotein complexes (heme, …). Wouldn’t it be incredible to map the Nobel work to seminal work done in the 100 years before the Prize with different colored arrows to show stromg and weaker associations? This is in a strong sense, a method of CURATION (as opposed to creation), that is very important for a fundamental grasp of the growth of and ties in the development of the knowledgebase.

Wouldn’t it be incredible to map the Nobel work to seminal work done in the 100 years before the Prize with different colored arrows to show stromg and weaker associations? This is in a strong sense, a method of CURATION (as opposed to creation), that is very important for a fundamental grasp of the growth of and ties in the development of the knowledge-base.

Such a discussion in depth is the curation that is intended for http://pharmaceuticalintelligence.com/biomed-e-books/series-e-titles-in the strategic-plan-for-2014-1015/2014-milestones-in-physiology-discoveries-in-medicine

Concept 2: Scientifc Results – The Art of Curation

Dr. Lev-Ari continued her work, beyond Volume Two, above, on Curation as a Methodology for Critique of the Scientific Frontier and the most effective method for synthesis of scientific milestones in the following selective list of articles:

e-Recognition via Friction-free Collaboration over the Internet: “Open Access to Curation of Scientific Research by Aviva Lev-Ari, PhD, RN

Digital Publishing Promotes Science and Popularizes it by Access to Scientific Discourse by Aviva Lev-Ari, PhD, RN

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

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

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

The Fatal Self Distraction of the Academic Publishing Industry: The Solution of the Open Access Online Scientific Journals

SOURCE

PART 3

Evaluation of the Methodology of Curation in Medical Research

Justin D Pearlman, MD, PhD, FACC and Larry H. Bernstein, MD, FCAP

The Voice of Justin D Pearlman, MD, PhD, FACC

This volume introduces a fresh look at keeping abreast of cardiovascular disease. In particular it explains and exemplifies the how and why of curation as a methodology for discourse. Curation is designed to edify and facilitate awareness and cohesive access to biomedical knowledge otherwise buried in subspecialty scientific journals in the Life Sciences and Medicine. Particular themes of focus include discovery, innovation and translation to clinical care, including linkages and underpinnings that might otherwise be mislabeled as esoteric. Key components of curation include expert identification of data, ideas and innovations of interest, expert interpretation of the original research results, integration with context, digesting, highlighting, correlating and presenting in novel light.

Three aspects of curation are notable:

(1) self-driven analytic reviews by a content expert,

(2) exciting topics assigned to an expert curator for analytic coherent fusion,

(3) teamwork of multiple experts on a focused theme, complementing each others’ contributions by weaving distinct threads.

Examples presented included review of electro-mechanical coupling and action potential, the roles of calicium redistribution in biology, the roles of biomarkers, healthcare and the Affordable Care Act, the human genome as basis for cardiovascular diseases, and the evolution of treatment options to manage cardiovascular diseases. These examples of Curation demonstrate added value of curation over traditional stand alone single author or multi-author research reports and review articles.

The superstructure of curations includes multiple additional creative elements:

1. eTOCs = electronic table of contents: fresh thought-provoking organizing themes link a path to a diverse trail of publications (analogous to creating a path in the forest)
2. Extracts highlighting notable elements of publications that mark a path
3. Voice of Expert commentary providing context and direction

The Electronic Table of Contents (eTOCs) serves several functions:
1. eTOCs collates information from multiple sources into coherent themes
2. eTOCs enables multiple pathways to information, including both Longitudinal and cross-sectional organizational themes.
3. eTOCs presents nested pathways through the forest, including nesting of topics by overreaching theme, chapters, Curations, reports and references.
4. eTOCs assemblies of thought provide fresh vistas that promote innovation and rethinking

In ekistics (urban design) Francis Bacon emphasized the importance of pathways linked to purpose, recommending a landmark magnet as an attractor for pursuits along a created path. Analogously, if the continually expanding collective knowledge embodied in subspecialty publications represents a forest of data and ideas, then Curation creates pathways in that forest that serve not only to keep the reader from getting lost, but also, as recommended by Francis Bacon, creates pathways that serve attractive purposes, with special vistas, highlights, themes, coherence, motivations and purposes.

CONTEXT (for each, Causes, Risks, Biomarkers and Therapeutics):
Volume One: Perspectives on Nitric Oxide

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

Volume Three: Etiologies of CVD: Epigenetics, Genetics & Genomics:
Causes, Risks and Biomarkers, Therapeutic Implications

Volume Four: Therapeutic Promise: CVD, Regenerative & Translational Medicine

Volume Five: Pharmaco-Therapies for CVD

Volume Six: Interventional Cardiology and Cardiac Surgery

Volume Seven: CVD Imaging for Disease Diagnosis and Guidance of Treatment

Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

Larry H. Bernstein, MD, FCAP

This portion summarises what we have covered and is now familiar to the reader.  There are three related topics, and an extension of this embraces other volumes and chapters before and after this reading.  This approach to the document has advantages over the multiple authored textbooks that are and have been pervasive as a result of the traditional publication technology.  It has been stated by the founder of ScoopIt, that amount of time involved is considerably less than required for the original publications used, but the organization and construction is a separate creative process.  In these curations we amassed on average five articles in one curation, to which, two or three curators contributed their views.  There were surprises, and there were unfulfilled answers along the way.  The greatest problem that is being envisioned is the building a vision that bridges and unmasks the hidden “dark matter” between the now declared “OMICS”, to get a more real perspective on what is conjecture and what is actionable.  This is in some respects unavoidable because the genome is an alphabet that is matched to the mino acid sequences of proteins, which themselves are three dimensional drivers of sequences of metabolic reactions that can be altered by the accumulation of substrates in critical placements, and in addition, the proteome has functional proteins whose activity is a regulatory function and not easily identified.  In the end, we have to have a practical conception, recognizing the breadth of evolutionary change, and make sense of what we have, while searching for more.

We introduced the content as follows:

1. We introduce the concept of curation in the digital context, and it’s application to medicine and related scientific discovery.

Topics were chosen were used to illustrate this process in the form of a pattern, which is mostly curation, but is significantly creative, as it emerges in the context of this e-book.

  • Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy is handled all in one chapter.
  • PCI for valves vs Open heart Valve replacement
  • PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.

2. The etiology, or causes, of cardiovascular diseases consist of mechanistic explanations for dysfunction relating to the heart or vascular system. Every one of a long list of abnormalities has a path that explains the deviation from normal. With the completion of the analysis of the human genome, in principle all of the genetic basis for function and dysfunction are delineated. While all genes are identified, and the genes code for all the gene products that constitute body functions, there remains more unknown than known.

3. Human genome, and in combination with improved imaging methods, genomics offers great promise in changing the course of disease and aging.

4. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.

Curation

Curation is an active filtering of the web’s  and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes.
Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view.  Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blindmen of the Sufi tale.  One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive.  The same source says “Scoop.it is my content marketing testing “sandbox”. In sharing, he says that comments provide the framework for what and how content is shared.

Healthcare and Affordable Care Act

We enter year 2014 with the Affordable Care Act off to a slow start because of the implementation of the internet signup requiring a major repair, which is, unfortunately, as expected for such as complex job across the US, and with many states unwilling to participate.  But several states – California, Connecticut, and Kentucky – had very effective state designed signups, separate from the federal system.  There has been a very large rush and an extension to sign up. There are many features that we can take note of:

1. The healthcare system needed changes because we have the most costly system, are endowed with advanced technology, and we have inexcusable outcomes in several domains of care, including, infant mortality, and prenatal care – but not in cardiology.

2. These changes that are notable are:

  • The disparities in outcome are magnified by a large disparity in highest to lowest income bracket.
  • This is also reflected in educational status, and which plays out in childhood school lunches, and is also affected by larger class size and cutbacks in school programs.
  • This is not  helped by a large paralysis in the two party political system and the three legs of government unable to deal with work and distraction.
  • Unemployment is high, and the banking and home construction, home buying, and rental are in realignment, but interest rates are problematic.

3.  The  medical care system is affected by the issues above, but the complexity is not to be discounted.

  •  The medical schools are unable at this time to provide the influx of new physicians needed, so we depend on a major influx of physicians from other countries
  • The technology for laboratories, proteomic and genomic as well as applied medical research is rejuvenating the practice in cardiology more rapidly than any other field.
  • In fields that are imaging related the life cycle of instruments is shorter than the actual lifetime use of the instruments, which introduces a shortening of ROI.
  • Hospitals are consolidating into large consortia in order to maintain a more viable system for referral of specialty cases, and also is centralizing all terms of business related to billing.
  • There is reduction in independent physician practices that are being incorporated into the hospital enterprise with Part B billing under the Physician Organization – as in Partners in Greater Boston, with the exception of “concierge” medical practices.
  • There is consolidation of specialty laboratory services within state, with only the most specialized testing going out of state (Quest, LabCorp, etc.)
  • Medicaid is expanded substantially under the new ACA.
  • The federal government as provider of services is reducing the number of contractors for – medical devices, diabetes self-testing, etc.
  • The current rearrangements seeks to provide a balance between capital expenses and fixed labor costs that it can control, reduce variable costs (reagents, pharmaceutical), and to take in more patients with less delay and better performance – defined by outside agencies.

Cardiology, Genomics, and calcium ion signaling and ion-channels in cardiomyocyte function in health and disease – including heart failure, rhythm abnormalities, and the myoneural release of neurotransmitter at the vesicle junction.

This portion is outlined as follows:

2.1 Human Genome: Congenital Etiological Sources of Cardiovascular Disease

2.2 The Role of Calcium in Health and Disease

2.3 Vasculature and Myocardium: Diagnosing the Conditions of Disease

Genomics & Genetics of Cardiovascular Disease Diagnoses

actin cytoskeleton

wall stress, ventricular workload, contractile reserve

Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

calcium and actin skeleton, signaling, cell motility

hypertension & vascular compliance

Genetics of Conduction Disease

Ca+ stimulated exostosis: calmodulin & PKC (neurotransmitter)

surgical complications & MVR

disruption of Ca2+ homeostasis cardiac & vascular smooth muscle

synaptotagmin as Ca2+ sensor & vesicles

atherosclerosis & ion channels

It is increasingly clear that there are mutations that underlie many human diseases, and this is true of the cardiovascular system.  The mutations are mistakes in the insertion of a purine nucleotide, which may or may not have any consequence.  This is why the associations that are being discovered in research require careful validation, and even require demonstration in “models” before pursuing the design of pharmacological “target therapy”.  The genomics in cardiovascular disease involves very serious congenital disorders that are asserted early in life, but the effects of and development of atherosclerosis involving large and medium size arteries has a slow progression and is not dominated by genomic expression.  This is characterized by loss of arterial elasticity. In addition there is the development of heart failure, which involves the cardiomyocyte specifically.  The emergence of regenerative medical interventions, based on pleuripotent inducible stem cell therapy is developing rapidly as an intervention in this sector.

Finally, it is incumbent on me to call attention to the huge contribution that research on calcium (Ca2+) signaling has made toward the understanding of cardiac contraction and to the maintenance of the heart rhythm.  The heart is a syncytiumdifferent than skeletal and smooth muscle, and the innervation is by the vagus nerve, which has terminal endings at vesicles which discharge at the myocyte junction.  The heart specifically has calmodulin kinase CaMK II, and it has been established that calmodulin is involved in the calcium spark that triggers contraction.  That is only part of the story.  Ion transport occurs into or out of the cell, the latter termed exostosis.  Exostosis involves CaMK II and pyruvate kinase (PKC), and they have independent roles.  This also involves K+-Na+-ATPase.  The cytoskeleton is also discussed, but the role of aquaporin in water transport appears elsewhere, as the transport of water between cells.  When we consider the Gibbs-Donnan equilibrium, which precedes the current work by a century, we recall that there is an essential balance between extracellular Na+ + Ca2+ and theintracellular K+ + Mg2+, and this has been superceded by an incompletely defined relationship between ions that are cytoplasmic and those that are mitochondrial.  The glass is half full!

PART 4

FOUR alternative models to the Academic Publishing Industry

Alternative #1

PeerJ MODEL for Open Access Online Scientific Journal

UPDATED on 1/21/2014

Berkeley recently took out an ‘institutional arrangement’ with PeerJ. This means that any Berkeley author who has an article accepted at PeerJ will not need to pay for their personal publication plan (the university library will automatically pay this fee for them via functionality on our site). Information about this arrangement can be found at: https://peerj.com/institutions/6/uc-berkeley/  

This is a significant benefit for faculty from Berkeley, and so I would like to ask for your help in promoting it to your colleagues. Please note: your library has already pre-paid for this benefit, so I am not trying to sell anything to your colleagues, I simply want to make them aware it already exists so that they can take advantage of it!

Peter Binfield, PhD
Co-Founder and Publisher, PeerJ
email: pete@peerj.com
Web: http://PeerJ.com
Twitter: @p_binfield & @ThePeerJ

SOURCE

From: pete@peerj.com

To: Avivalev-ari@alum.Berkeley.edu

Sent:Tue Jan 21 04:57:26 UTC 2014

The Peer J Scientific Online Journal introduces the need for this new order of publication as follows:
We are fully aware that being appropriately indexed and maximally discoverable is extremely important for our authors. We understand that you publish your research so that others can discover, read, discuss, cite and build upon it. If no one can discover, let alone read, the article that you spent years researching, and months writing, then it was pointless to even publish it in the first place.
We see that Open Access, and the associated benefits of open and early sharing are increasingly being understood by academia; and finally we hear from a lot of scientists who are now looking for a suitable preprint venue for their work.
http://blog.peerj.com/post/47445954946/http://blog.peerj.com/post/47030855181/
This journal has full legitimacy as an acceptable peer reviewed publication for researchers who are already establish researchers publishing in their professional society publications, and for young academic professionals who need to establish a publication resume for academic advancement.This has become very important because of the long timelines for research publications in peer reviewed journals, and the effect on establishing an earned reputation needed for advancement.

Alternative #2

Read Cube

http://www.readcube.com/#features

ReadCube is an architecture for workflow efficient citation that is compatible with

  • writing ,
  • managing a collection of papers, and
  • annotation and

improves the creation of a readable PDF. What app does it uniquely provide in one program?

  • Enhanced PDF
    1. Supplements
    2. Clickable inline references
    3. Full reference list
    4. Editor summaries
    5. Related articles
    6. Inline notes and highlights
  • Recommendations
  • Instant searchability
  • Bookmarklet
  • Tablet compatible
  • Sync and Backup

The features enumerated are not trivial. When writing for scientific publication, the

  • finding of relevant related research publication, and
  • adequate citation of other work is both important and laborious
    • in constructing the discussion and support of a novel concept.

Evaluation of Alternative #1 and #2

Larry H Bernstein, MD, FCAP

These two developments are a strong emergence of a process as significant as Guttenberg’s introduction of the printing press, which opened the door to a

  • flourishing Western Culture enriched by
  • theater, opera, literary arts, journals, and the newspaper.

Just as the newspaper, radio, television, and the traditional movie have been in transformation in response to an

  • all the time noisy and stressfully hard to discern target audience,
  • the scholarly publications are under pressure to change and to go to the next level.

These two events are followed by the announcement of eLife, in life sciences research.

I tip my hat to IBMs Watson for creating a vision of man and computer as partners, although it was perhaps germinated by the earlier work by the physician who

  • first created the structure for the medical record, then went on without the technology we have today
  • to create the first feasible, but labor intensive EHR.

The ICHOR lab system was first to  focus on WORKFLOW, but it also

  • did not have the advantages of technology that emerged in the last decade.

In a separate parallel advance, Eugene Rypka in Albuquerque advance the feature extraction and analysis of bacterial classification. Then,  Rosser Rudolf showed that it
had an underlying structure related to Solomon Kullback’s work on entropy, calling it “effective information”. We now use Akaike and Bayes information criteria as measures of classification adequacy.

p3

Alternative #3

eLife is a collaboration between the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust, and over 200 of the world’s most talented biomedical scientists.

eLife is a unique collaboration between funders and practitioners of research to communicate influential discoveries in the life and biomedical sciences in the most effective way.

We are a joint initiative of the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Along with a growing number of public and private research funders worldwide, these three organisations recognise that the communication of research results is as fundamental a component of the research process as the experiments themselves. Disseminating new findings as widely and effectively as possible maximises the value of research investments. The first step in the initiative is to establish a new, open-access venue for the most important advances — from basic biological research through to applied, translational and clinical studies.

The eLife journal will be a platform for extending the reach and influence of new discoveries and to showcase new approaches to the presentation, use, and assessment of research.

eLife is not just a journal. That’s just the beginning.

VIEW VIDEO

http://www.elifesciences.org/about/

Our initiative has four aims:

  • To make publishing more efficient, by providing outstanding service to authors through a swift, constructive, and fair editorial process.
  • To exploit digital media in the presentation of results, by increasing their utility for further research and broadening participation to the widest possible audience.
  • To drive open access, by providing an outstanding new publishing option for authors with ground-breaking research.
  • To catalyse innovation in research communication, by experimentation, collaboration, and continuous improvement.

Learn more about the journal


eLife Sciences Publications, Ltd is a limited liability non-profit non-stock 501(c)3 corporation incorporated in the State of Delaware, USA, with company number 5030732, and is registered in the UK with company number FC030576 and branch number BR015634 at the address 1st Floor, 24 Hills Road, Cambridge CB2 1JP.

The eLife journal (ISSN 2050-084X) is published by eLife Sciences Publications, Ltd.

 SOURCE

Alternative #4

http://pharmaceuticalintelligence.com

This alternative model for Scientific Publishing involve the following steps:

#1: CURATION and Co-CURATION of Scientific articles in conjunction with Experts, Authors, Writers critique and synthesis

Examples

  • Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

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

http://pharmaceuticalintelligence.com/2013/12/10/epo-as-therapeutics-for-anemia-in-chf/

Vivek Lal, MBBS, MD, F.Cl.R,  Justin D Pearlman, MD, PhD, FACC
 and Aviva Lev-Ari, PhD, RN

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

  • Alternative Designs for the Human Artificial Heart: The Patients in Heart Failure – Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community

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

http://pharmaceuticalintelligence.com/2013/08/05/alternative-designs-for-the-human-artificial-heart-the-patients-in-heart-failure-outcomes-of-transplant-donorimplantation-artificial-and-monitoring-technologies-for-the-transplantimplant-pat/

#2: Assembly of articles into e-Books using ONE of a Kind electronic Table of Contents (eTOCs) architecture

Example

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

This e-Book has the following Parts:

PART 1
Genomics and Medicine

Introduction to Volume Three

1.1  Genomics and Medicine: The Physician’s View
1.2  Ribozymes and RNA Machines – Work of Jennifer A. Doudna
1.3  Genomics and Medicine: Contributions of Genetics and Genomics to Cardiovascular Disease Diagnoses
1.4  Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data

PART 2
Epigenetics – Modifiable Factors Causing Cardiovascular Diseases

2.1 Diseases Etiology

2.1.1 Environmental Contributors Implicated as Causing Cardiovascular Diseases
2.1.2 Diet: Solids and Fluid Intake and Nutraceuticals

2.1.3 Physical Activity and Prevention of Cardiovascular Diseases

2.1.4 Psychological Stress and Mental Health: Risk for Cardiovascular Diseases

2.1.5 Correlation between Cancer and Cardiovascular Diseases
2.1.6 Medical Etiologies for Cardiovascular Diseases: Evidence-based Medicine – Leading DIAGNOSES of Cardiovascular Diseases, Risk Biomarkers and Therapies
2.1.7 Signaling Pathways
2.1.8 Proteomics and Metabolomics

2.2 Assessing Cardiovascular Disease with Miomarkers

2.2.1 Issues in Genomics of Cardiovascular Diseases
2.2.2 Endothelium, Angiogenesis, and Disordered Coagulation
2.2.3 Hypertension BioMarkers
2.2.4 Inflammatory, Atherosclerotic and Heart Failure Markers
2.2.5 Myocardial Markers

2.3  Therapeutic Implications: Focus on Ca(2+) signaling, platelets, endothelium

2.3.1 The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors

2.3.2 Platelets in Translational Research ­ 2

2.3.3 The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis

2.3.4 Nitric Oxide Synthase Inhibitors (NOS-I)

2.3.5 Resistance to Receptor of Tyrosine Kinase

2.3.6 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation

2.3.7 Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

2.4 Comorbidity of Diabetes and Aging

2.4.1 Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients

PART 3
Determinants of Cardiovascular Diseases
Genetics, Heredity and Genomics Discoveries

Introduction
3.1 Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)

3.1.1 Aneuploidy and Carcinogenesis

3.2 Functional Characterization of Cardiovascular Genomics: Disease Case Studies @ 2013 ASHG

3.3 Leading DIAGNOSES of Cardiovascular Diseases covered in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013

3.3.1: Heredity of Cardiovascular Disorders

3.3.2: Myocardial Damage

3.3.3: Hypertention and Atherosclerosis

3.3.4: Ethnic Variation in Cardiac Structure and Systolic Function

3.3.5: Aging: Heart and Genetics

3.3.6: Genetics of Heart Rhythm

3.3.7: Hyperlipidemia, Hyper Cholesterolemia, Metabolic Syndrome

3.3.8: Stroke and Ischemic Stroke

3.3.9: Genetics and Vascular Pathologies and Platelet Aggregation, Cardiac Troponin T in Serum

3.3.10: Genomics and Valvular Disease

3.4  Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease

PART 4
Individualized Medicine Guided by Genetics and Genomics Discoveries

4.1 Preventive Medicine: Cardiovascular Diseases

4.1.1  Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges

4.2 Gene-Therapy for Cardiovascular Diseases

4.2.1 Genetic Basis of Cardiomyopathy

4.3 Congenital Heart Disease/Defects

4.4 Pharmacogenomics for Cardiovascular Diseases

4.4.1 Hypertension Susceptibility Loci and Blood Pressure Response to Antihypertensives

4.4.2 Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction

4.4.3 Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

4.4.4 Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes

4.4.5 Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction – The GEOSTAT-1 Study

#3: Assembly of e-Books into e-Series

Example

Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC

#4: Publishing of e-Series on Amazon.com

The BioMedicine e- Book Series has published of the following e-Books Titles with Amazon KINDLE:

http://www.amazon.com/dp/B00DINFFYC

Perspectives on Nitric Oxide in Disease Mechanisms (2013) 

#5: Distribution of e-Series to Professional Associations via their Internet websites

In 2013 and Beyond, we are launching a Series of e-Books (electronic Books) in BioMedicine made up by articles published in this Open Access Online Scientific Journal.

Series Editor-in-Chief, Aviva Lev-Ari, PhD, RN has curated over 800 articles in an inventory of 1,544 available on 1/4/2014 on http://pharmaceuticalintelligence.com.

The Open Access Online Scientific Journal was launched on 4/30/2012.

BioMed e-Series was launched by Dr. Lev-Ari in 10/2013:

BioMed e-Series – Five Titles

Scientific Journal Site Statistics

Date

Views to Date

# of articles

NIH Clicks

Nature Clicks

6/24/2013

199,857

1,034

1,275

661

 7/29/2013  217,356  1,138  1,389  705
 12/1/2013  287,645  1,428  1,676  828
 12/30/13  301,584 1,506   1,734  868
 1/3/2014  303,342  1,541  1,736  868

SOURCE

http://pharmaceuticalintelligence.com/open-access-scientific-journal/the-open-access-online-scientific-journals-solution-vs-the-fetal-self-distraction-of-the-academic-publishing-industry/

REFERENCES
For a complete list of Dr. Aviva Lev-Ari Curations, go to
For a complete list of Dr. larry H Bernstein Curations, go to
For Dr. Pearlman’s Publications, go to
 

SOURCES on Curation in Science & Business

Curation-ism, Part I: The Case for Content Curation, MARCH 28, 2012 BY 

http://blog.openviewpartners.com/curation-ism-part-1-the-case-for-content-curation/?utm_source=dlvr.it&utm_medium=twitter&goback=%2Egde_4346921_member_5827771813869944836#%21

« Curation is the new research, »… et le nouveau média, Benoit Raphael, 2011

http://benoitraphael.com/2011/01/17/curation-is-the-new-search/

La curation : la révolution du webjournalisme?, non-fiction.fr

http://www.nonfiction.fr/article-4158-la_curation__la_revolution_du_webjournalisme_.htm

La curation : les 10 raisons de s’y intéresser, Pierre Tran

http://pro.01net.com/editorial/529947/la-curation-les-10-raisons-de-sy-interesser/

Curation : quelle valeur pour les entreprises, les médias, et sa « marque personnelle »?, Marie-Laure Vie

http://marilor.posterous.com/curation-et-marketing-de-linformation

Cracking Open the Scientific Process, Thomas Lin, New York Times

http://www.nytimes.com/2012/01/17/science/open-science-challenges-journal-tradition-with-web-collaboration.html?_r=4&pagewanted=1

La « massification » du web transforme les relations sociales, Valérie Varandat, INRIA

http://www.inria.fr/actualite/actualites-inria/internet-du-futur

Internet a révolutionné le métier de chercheur, AgoraVox

http://www.agoravox.fr/actualites/technologies/article/internet-a-revolutionne-le-metier-103514

Gérer ses références numériques, Université de Genève

http://www.unige.ch/medecine/udrem/Unit/actualites/biblioManager.html

Notre liste Scoop-it : Scientific Social Network, MyScienceWork

Other related articles were published in this Open Access Online Scientific Journal, include the following: 

Series A: e-Books on Cardiovascular DiseasesSeries A Content Consultant: Justin D Pearlman, MD, PhD, FACC 

The Art of Scientific & Medical Curation

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

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/volume-two-cardiovascular-original-research-cases-in-methodology-design-for-content-co-curation/ 

Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP 

These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years.  The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation.  The world health organization (WHO) standard definition then was the presence of two of three:

1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm

2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.

3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.

The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel.  Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.

So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century.  However, the role of biomarkers broadened.  Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury.  This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP).  The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.

Thus, we have identified the use of traditional cardiac biomarkers for:

1. Diagnosis
2. Therapeutic monitoring

The story is only the beginning.  Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic.  This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium.  The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease.  Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.

While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature.  There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require

1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement  on multitest automated analyzers with high capability in proteomic measurement  (MS, time of flight, MS-MS)

nejmra1216063_f1   Atherosclerotic Plaques Associated with Various Presentations               nejmra1216063_f2     Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.        atherosclerosis progression

Reconstructed Science Communication for Open Access Online Scientific Curation

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

 

PEER J Model for Open Access

The Peer J Scientific Online Journal introduces the need for this new order of publication as follows:
We are fully aware that being appropriately indexed and maximally discoverable is extremely important for our authors. We understand that you publish your research so that others can discover, read, discuss, cite and build upon it. If no one can discover, let alone read, the article that you spent years researching, and months writing, then it was pointless to even publish it in the first place.
We see that Open Access, and the associated benefits of open and early sharing are increasingly being understood by academia; and finally we hear from a lot of scientists who are now looking for a suitable preprint venue for their work.
http://blog.peerj.com/post/47445954946/ http://blog.peerj.com/post/47030855181/
This journal has full legitimacy as an acceptable peer reviewed publication for researchers who are already establish researchers publishing in their professional society publications, and for young academic professionals who need to establish a publication resume for academic advancement.This has become very important because of the long timelines for research publications in peer reviewed journals, and the effect on establishing an earned reputation needed for advancement.

ReadCube

ReadCube is an architecture for workflow efficient citation that is compatible with

  • writing ,
  • managing a collection of papers, and
  • annotation and

improves the creation of a readable PDF. What app does it uniquely provide in one program?

  • Enhanced PDF
    1. Supplements
    2. Clickable inline references
    3. Full reference list
    4. Editor summaries
    5. Related articles
    6. Inline notes and highlights
  • Recommendations
  • Instant searchability
  • Bookmarklet
  • Tablet compatible
  • Sync and Backup

The features enumerated are not trivial. When writing for scientific publication, the

  • finding of relevant related research publication, and
  • adequate citation of other work is both important and laborious
    • in constructing the discussion and support of a novel concept.

These two developments are a strong emergence of a process as significant as Guttenberg’s introduction of the printing press, which opened the door to a

  • flourishing Western Culture enriched by
  • theater, opera, literary arts, journals, and the newspaper.

Just as the newspaper, radio, television, and the traditional movie have been in transformation in response to an

  • all the time noisy and stressfully hard to discern target audience,
  • the scholarly publications are under pressure to change and to go to the next level.

These two events are followed by the announcement of eLife, in life sciences research.

I tip my hat to IBMs Watson for creating a vision of man and computer as partners, although it was perhaps germinated by the earlier work by the physician who

  • first created the structure for the medical record, then went on without the technology we have today
  • to create the first feasible, but labor intensive EHR.

The ICHOR lab system was first to  focus on WORKFLOW, but it also

  • did not have the advantages of technology that emerged in the last decade.

In a separate parallel advance, Eugene Rypka in Albuquerque advance the feature extraction and analysis of bacterial classification. Then,  Rosser Rudolf showed that it
had an underlying structure related to Solomon Kullback’s work on entropy, calling it “effective information”. We now use Akaike and Bayes information criteria as measures of classification adequacy.

p3

Genomics and Medicine: The Physician’s View

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

 

Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease.  This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market.   Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured.  That is the first issue of concern.

Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked.  It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects.  In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.

A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon.  Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient.  Historically, insurance is an actuarial discipline.  But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention.  Only the timing cannot be predicted.  As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.

How does this compute for the physician provider.  The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm.   Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today.  It may provide assessment of risk, or of survival expectation.  The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams.  Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid.  They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.

The relevant questions are:

1. acuity of symptoms and signs.
2. actions to be taken.
3. tests that are needed to clarify the examination findings.

once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.

Where does genetic testing fit into this? At this point, it will only be used

  1. to confirm a restricted list of diagnoses that have a high association with the condition, and
  2. only with the participation of a medical geneticist, when
  3. profiling the patient and other members of the family is required.

10d0de1 Vitruvian Man by Leonardo da Vinci

Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect

Reporter: Aviva Lev-Ari, PhD, RN

 

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial Infarction

The GEOSTAT-1 Study

Kristian M. Bailey, MBChB, Simon P.R. Romaine, BSc, Beryl M. Jackson, RGN, Amanda J. Farrin, MSc, Maria Efthymiou, MSc, Julian H. Barth, MD, Joanne Copeland, BSc,Terry McCormack, MBBS, Andrew Whitehead, MSc, Marcus D. Flather, MBBS, Nilesh J. Samani, MD, FMedSci, Jane Nixon, PhD, Alistair S. Hall, MD, PhD, Anthony J. Balmforth, PhD and on behalf of the SPACE ROCKET Trial Group

Author Affiliations

From the Division of Cardiovascular and Diabetes Research (K.M.B., S.P.R.R., B.M.J., A.J.B.), and Division of Cardiovascular and Neuronal Remodelling (A.S.H.), Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; Clinical Trials Research Unit (A.J.F., M.E., J.C., J.N.), University of Leeds, Leeds, United Kingdom; Clinical Biochemistry (J.H.B.), Leeds General Infirmary, Leeds, United Kingdom; Whitby Group Practice (T.M.), Spring Vale Medical Centre, Whitby, North Yorkshire, United Kingdom; Pharmacy Department (A.W.), Leeds General Infirmary, Leeds, United Kingdom; Clinical Trials and Evaluation Unit (M.D.F.), Royal Brompton and Harefield NHS Trust and Imperial College, London, United Kingdom; and Department of Cardiovascular Sciences (N.J.S.), University of Leicester, Leicester, United Kingdom.

Correspondence to Alistair S. Hall, Clinical Cardiology, Multidisciplinary Cardiovascular Research Centre (MCRC), G Floor, Jubilee Building, Leeds General Infirmary, Leeds, LS1 3EX, United Kingdom. E-mail A.S.Hall@leeds.ac.uk

* Dr Bailey, Mr Romaine, Dr Hall, and Dr Balmforth contributed equally to this study.

Abstract

Background— Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy.

Methods and Results— The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415).

Conclusion— The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg.

Clinical Trial Registration— URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

SOURCE:

Circulation: Cardiovascular Genetics.2010; 3: 276-285

Published online before print March 5, 2010,

doi: 10.1161/ CIRCGENETICS.109.898502

Voltage-Gated Calcium Channel and Pharmacogenetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES)

Yuxin Niu, PhD*Yan Gong, PhD*Taimour Y. Langaee, PhD, Heather M. Davis, PharmD, Hazem Elewa, PhD, Amber L. Beitelshees, PharmD, MPH, James I. Moss, PhD, Rhonda M. Cooper-DeHoff, PharmD, Carl J. Pepine, MD and Julie A. Johnson, PharmD

Author Affiliations

From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.N., Y.G., T.Y.L., H.M.D., H.E., J.I.M., R.M.C.-D., J.A.J.), College of Pharmacy, University of Florida, Gainesville, Fla; Division of Endocrinology, Diabetes and Nutrition (A.L.B.), University of Maryland School of Medicine, Baltimore, Md; and Division of Cardiovascular Medicine (R.M.C.-D., C.J.P., J.A.J.), University of Florida College of Medicine, Gainesville, Fla.

Correspondence to Julie A. Johnson, PharmD, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, Gainesville, FL 32610. E-mail Johnson@cop.ufl.edu

* Drs Niu and Gong contributed equally to this work.

Abstract

Background— Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.

Methods and Results— SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.

Conclusions— These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.

Our association study suggests significant pharmacogenetic effects for the promoter SNP rs2357928 in CACNB2 such that for minor allele homozygotes, a verapamil SR-based CCB treatment strategy is associated with substantially higher risk for adverse cardiovascular outcome compared with an atenolol-based BB treatment strategy. These findings were validated in a second ethnic group and further supported by in vitro studies suggesting differential transcriptional activity with this promoter SNP. Additional studies in other cohorts are required, but these data suggest that this CACNB2 SNP may have future potential for guiding selection of antihypertensive drug therapy among patients with CAD.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier:NCT00133692.

SOURCE:

Circulation: Cardiovascular Genetics.2010; 3: 548-555

http://circgenetics.ahajournals.org/content/3/6/548.full?related-urls=yes&legid=circcvg;3/6/548

doi: 10.1161/ CIRCGENETICS.110.957654