See on Scoop.it – Cardiovascular and vascular imaging
Amiodarone in the Prehospital Environment
EMS1.com
… from myocardial ischemia is correction of the ischemic state.
See on www.ems1.com
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Reprogramming Cell in Tissue Repair
Reporter and Curator: Larry H Bernstein, MD, FCAP
This is a novel concept in regenerative medicine that needs attention.
Lin28 enhances tissue repair by reprogramming cellular metabolism
Shyh-Chang N, Zhu H, Yvanka de Soysa T, Shinoda G, Seligson M T, Tsanov K M, Nguyen L, Asara J M, Cantley L C and Daley G Q.
Stem Cell Transplantation Program,Boston Children’s Hospital and Dana Farber Cancer Institute, Boston; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Harvard Stem Cell Institute;
Manton Center for Orphan Disease Research; Howard Hughes Medical Institute; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115.
Cell. 7 Nov 2013; 155(4):778-792. http://dx.doi.org/10.1016/j.cell.2013.09.059.
Copyright © 2013 Elsevier Inc. PMID: 23561442 PMCID: PMC3652335
Abstract
In recent years, the highly conserved Lin28 RNA-binding proteins have emerged as factors that define stemness in several tissue lineages. Lin28 proteins repress let-7 microRNAs and influence mRNA translation, thereby regulating the self-renewal of mammalian embryonic stem cells. Subsequent discoveries revealed that Lin28a and Lin28b are also important in organismal growth and metabolism, tissue development, somatic reprogramming, and cancer. In this review, we discuss the Lin28 pathway and its regulation, outline its roles in stem cells, tissue development, and pathogenesis, and examine the ramifications for re-engineering mammalian physiology.
Figure 1. Overview of Molecular Mechanisms Underlying Lin28 Function. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.
Both Lin28a and Lin28b have been observed to shuttle between the nucleus and cytoplasm, binding both mRNAs and pri-/prelet-7. In the nucleus, Lin28a/b could potentially work in tandem with the heterogeneous nuclear ribonucleoproteins (hnRNPs) to regulate splicing, or with Musashi-1 (Msi1) to block pri-let-7 processing. In the cytoplasm, Lin28a recruits Tut4/7 to oligouridylate pre-let-7, and block Dicer processing to mature let-7 miRNA (right, violet). Lin28a also recruits RNA helicase A (RHA) to regulate mRNA processing in messenger ribonucleoprotein (mRNP) complexes, in tandem with the Igf2bp’s, poly(A)-binding protein (PABP), and the eukaryotic translation initiation factors (eIFs). In response to unknown signals and stimuli, the mRNAs are either shuttled into poly-ribosomes for translation, stress granules for temporary sequestering, or P-bodies for degradation, in part via miRNAs and the Ago2 endonuclease (left, orange).
Figure 2. Signals Upstream and Targets Downstream of Lin28 in the Lin28 Pathway. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.
The lin-4 homolog miR-125a/b represses both Lin28a and Lin28b during stem cell differentiation. The core pluripotency transcription factors Oct4, Sox2, Nanog and Tcf3 can activate Lin28a transcription in ESCs and iPSCs, whereas the growth regulator Myc and the inflammation-/stress-responsive NF-κB can transactivate Lin28b. A putative steroid hormone-activated nuclear receptor, conserved from C. elegans daf-12, might also regulate both Lin28a/b and let-7 expression. Downstream of Lin28a/b, the let-7 family represses a network of proto-oncogenes, including the insulin-PI3K-mTOR pathway, Ras, Myc, Hmga2, and the Igf2bp’s. At the same time, Lin28a can also directly bind to and regulate translation of mRNAs, including Igf2bp’s, Igf2, Hmga1, and mRNAs encoding metabolic enzymes, ribosomal peptides, and cell-cycle regulators. Together, this broad network of targets allows Lin28 to program both metabolism and growth to regulate self-renewal.
Figure 3. Potential of Lin28 in Re-Engineering Adult Mammalian Physiology. From: Lin28: Primal Regulator of Growth and Metabolism in Stem Cells.
Lin28a, in conjunction with the pluripotency factors Oct4, Sox2 and Nanog, can reprogram somatic cells into iPSCs. Alone, Lin28a/b can reprogram adult HSPCs into a fetal-like state, and enhance insulin sensitivity in the skeletal muscles to improve glucose homeostasis, resist obesity and prevent diabetes. Emergent clues suggest that optimal doses of Lin28a/b might have the potential to re-engineer adult mammalian tissue repair capacities and extend longevity, although Lin28a/b could also cooperate with oncogenes to initiate tumorigenesis. Future work might elucidate these mysteries.
Cell. 2013 Nov 7;155(4):778-92. doi: 10.1016/j.cell.2013.09.059.
Posted in Genome Biology, Stem Cells for Regenerative Medicine | Tagged Dana–Farber Cancer Institute, Harvard Medical School, Lin28, RNA-binding protein, self-renewlal, somatic reprogramming, Stem cell, tissue re-engineering | Leave a Comment »
Warburg Effect Revisited
Reporter: Larry H. Bernstein, MD, FCAP
We have previously covered the Warburg Effect, and there has been a number of comments about the chicken or the egg! There is an underlying factor that makes it difficult to comprehend that the initiation of cancer is mutation driven, although we are clear that smoking and a number of environmental factors are instigators of the change. The main problem that I have referred to is the chemical, thermodynamic, and evolutionary state of our existence. I strongly refer to the work of Ilya Prigogene. There is a progressive series of changes over time, and it is not possible to determine the initial state. Consequently, a progressive series of adaptations progresses, involving gene expression, non-genetic changes, and metabolic equilibrium that is maintained, but becomes non-adaptive.
Previous discussions at LPI are:
AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo
Reporter-Curator: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-tumor-growth-in-vivo/
Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?
Author: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/
Otto Warburg, A Giant of Modern Cellular Biology
Reporter: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/11/02/otto-warburg-a-giant-of-modern-cellular-biology/
Targeting Mitochondrial-bound Hexokinase for Cancer Therapy
Author: Ziv Raviv, PhD
http://pharmaceuticalintelligence.com/2013/04/06/targeting-mito…cancer-therapy
Portrait of a great scientist and mentor: Nathan Oram Kaplan
Writer and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/01/26/portrait-of-a-great-scientist-and-mentor-nathan-oram-kaplan/
Quantum Biology And Computational Medicine
Author and Curator, Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/03/quantum-biology-and-computational-medicine/
Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III
Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/
Differentiation Therapy – Epigenetics Tackles Solid Tumors
Author-Writer: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/
Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition
Reporter-Curator: Stephen J. Williams, Ph.D.
http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/
Mitochondrial Damage and Repair under Oxidative Stress
Curator: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/
Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation
Curator: Larry H Bernsatein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/
Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function
Curator, Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/
Potential Drug Target: Glucolysis Regulation – Oxidative stress-responsive microRNA-320
Reporter: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/07/25/potential-drug-target-glucolysis-regulation-oxidative-stress-responsive-microrna-320/
Expanding the Genetic Alphabet and Linking the Genome to the Metabolome
Reporter& Curator: Larry Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/
What can we expect of tumor therapeutic response?
Author: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/
A Second Look at the Transthyretin Nutrition Inflammatory Conundrum
Larry H. Bernstein, MD, FACP
http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/
Radoslav Bozov
Date: 3/26/2013
Subject: RE: comment
The process of genomic evolution cannot be revealed throughout comparative genomics as structural data representation does not illuminate either the integral path of particles-light interference, as Richard Feynman suggests, in stable forms of matter such as interference/entanglement of the nature of particles/strings/waves to first approximation as I have claimed. Towards the compressibility principle realization, I have claimed that DNA would be entropic- favorable stable state going towards absolute ZERO temp in the space defined itself. In other words themodynamics measurement in subnano discrete space would go negative towards negativity. DNA is sort of like a cold melting/growing crystal, quite stable as it appears not due to hydrogen bonding , but due to interference of C-N-O. That force is contradicted via proteins onto which we now know large amount of negative quantum redox state carbon attaches. Chemistry is just a language as it is math following certain rules based on observation. Most stable states are most observed ones. The more locally one attempts to observe, the more hidden variables would emerge as a consequence of discrete energy spaces opposing continuity of matter/time. Still, stability emerges out of non stability states. And if life was in absolute stability, there will be neither feelings nor freedom. What is feelings and freedom is a far reaching philosophical question with sets of implications, to one may be a driving car, to another riding a horse or a bicycle etc cetera or simply seeing the unobservable …No wonder genome size differs among organisms and even tissue types as an outcome of carbon capacity.
PIM2 phosphorylates PKM2 and promotes Glycolysis in Cancer Cells
Yu Z, Huang L, Zhang T, Yang F, Xie L, Liu J, Song S, Miao P, Zhao L, Zhao X, Huang G.
Shanghai Jiao Tong University, China;
J Biol Chem. 2013 Oct 18. [Epub ahead of print]
- Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells.
- the mechanisms of regulating PKM2 are not fully elucidated.
- we identified the serine/threonine protein kinase PIM2, a known oncogene,
- as a novel binding partner of PKM2.
The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that
- PIM2 could directly phosphorylate PKM2 on the Thr454 residue, resulting in
- an increase of PKM2 protein levels.
Compared to wild-type, PKM2 with the phosphorylation-defective mutation
- displayed a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation,
- while enhanced mitochondria respiration and chemotherapeutic sensitivity of cancer cells.
These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer,
- highlighting PIM2 as a potential therapeutic target.
KEYWORDS: Cancer, Cell proliferation, Glycolysis, Pyruvate kinase, phosphorylation
PMID: 24142698
Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment.
Iommarini L, Kurelac I, Capristo M, Calvaruso MA, Giorgio V, Bergamini C, Ghelli A, et al.
Dipartimento di Farmacia e Biotecnologie (FABIT).
Hum Mol Genet. 2013 Nov 11. [Epub ahead of print]
Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness,
- having been found in virtually all cancer types and
- most commonly affecting genes encoding mitochondrial complex I (CI) subunits.
It is still unclear whether they exert a pro- or anti-tumorigenic effect.
We here analyzed the impact of three homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1) on osteosarcoma progression,
- chosen since they induce different degrees of oxidative phosphorylation impairment.
In fact, the m.3460G>A/MT-ND1 mutation caused only a reduction in CI activity, whereas
- the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutations induced a severe structural and functional CI alteration.
As a consequence, this severe CI dysfunction determined an energetic defect associated with a compensatory increase in glycolytic metabolism and AMP-activated protein kinase activation.
Osteosarcoma cells carrying such marked CI impairment
- displayed a reduced tumorigenic potential both in vitro and in vivo, when compared with cells with mild CI dysfunction, suggesting that
- mtDNA mutations may display diverse impact on tumorigenic potential depending on
- the type and severity of the resulting oxidative phosphorylation dysfunction.
The modulation of tumor growth was independent from reactive oxygen species production but correlated with
- hypoxia-inducible factor 1α stabilization, indicating that
- structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression.
PMID: 24163135 [PubMed – as supplied by publisher]
Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer
Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, et al.
Cell, 24 Oct 2013; 155 (3): 552-566, doi:10.1016/j.cell.2013.09.041
Systematic isolation of context-dependent vulnerabilities in NSCLC
Highlights
- NLRP3 mutations drive addiction to FLIP expression
- Lysosome maturation is a metabolic bottleneck for KRAS/LKB1 tumors
- Selective sensitivity to an indolotriazine discriminates a NSCLC expression subtype
Posted in Anaerobic Glycolysis, Cachexia, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Expression, Hexokinase, Metabolomics, Methylation, mtDNA, Oxidative phosphorylation, Personalized and Precision Medicine & Genomic Research, Proteomics, Pyruvate Kinase, Warburg effect | Tagged cancer biology, carcinogenesis, FLIP expression, Glycolysis, HIF1a, Kras/LKB1 tumors, mitochondrial complex I, mitochondrial function, mitochondrial mutations, mtDNA, NSCLC subtype, PIM2, PIM2-dependent phosphorylation of PKM2, PKM2, Pyruvate Kinase, Warburg Effect | Leave a Comment »
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CaKMII Inhibition in Obese, Diabetic Mice leads to Lower Blood Glucose Levels
Reporter: Larry H Bernstein, MD, FCAP
This recent publication was reported in MedPage today. It is different than, but highly suggestive of our recent report about the Univesity of Iowa discovery of “Oxidized CaKMII inhibition” as a therapeutic target for atrial arrhythmia.
Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation
Author: Larry H. Bernstein, MD, FCAP, and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/10/26/oxidized-calcium-calmodulin-kinase-and-atrial-fibrillation/
http://pharmaceuticalintelligence.com/2013/10/26/oxidized-calcium-calmodulin-kinase-and-atrial-fibrillation/
This is a review of a recent work from the laboratory of Mark E. Anderson and associates at the University of Iowa. We have covered the role of CaMKII in calcium signaling and myocardiocyte contraction, as well as signaling in smooth muscle, skeletal muscle, and nerve transmission. There are tissue specific modus operandi, partly related to the ryanogen receptor, and also related to tissue specific isoenzymes of CaMKII. There is much ground that has been traversed in exploring these mechanisms, most recently, the discoverey of hormone triggering by the release from vesicles at the nerve muscle junction, and much remains open to investigation. The recently published work by Mark E. Anderson and associates in Mannheim and Heidelberg, Germany, clarifies the relationship between the oxidized form of CaMKII and the triggering of atrial fibrillation. The following studies show:
- Ang II infusion increased the susceptibility of mice to AF induction by rapid right atrial pacing and established a framework for us to test the hypothesized role of ox-CaMKII in promoting AF. ox-CaMKII is critical for AF.
- Established a critical role of ox-CaMKII in promoting AF
- Ang II induced increases in ROS production seen in WT atria were absent in atria from MsrA TG mice suggesting that MsrA sensitive targets represent an important component of Ang II mediated atrial oxidation.
- The protection from AF in MsrA TG mice appeared to be independent of pressor effects that are critical for the proarrhythmic actions.
- These findings suggest that NADPH oxidase dependent ROS and elevated ox-CaMKII
- drive Ang II -pacing-induced AF and that
- targeted antioxidant therapy, by MsrA over-expression,
- can reduce or prevent AF in Ang -II-infused mice.
Atrial myocytes from Ang II treated WT mice showed a significant (p<0.05) increase in spontaneous Ca2+ sparks compared to atrial myocytes from saline treated control mice
In contrast to findings in WT mice, the atrial myocytes isolated from Ang II treated MM-VV mice did not show an increase in Ca2+ sparks compared to saline treated MM-VV mice
These data to suggest that in ox–the proarrhythmic effects of Ang II infusion depend upon an increaseCaMKII, sarcoplasmic reticulum Ca2+ leak and DADs.
Enhanced CaMKII-mediated phosphorylation of serine 2814 on RyR2
- is associated with an increased susceptibility to acquired arrhythmias, including AF
Proarrhythmic actions of ox-CaMKII
- require access to RyR2 serine 2814.
Mutant S2814A knock-in mice (lacking serine 2814) were highly resistant to Ang II mediated AF
AC3-I mice with transgenic myocardial expression of a CaMKII inhibitory peptide were also resistant to the proarrhythmic effects of Ang II infusion on pacing-induced AF
S2814A, AC3-I and WT mice, all developed similar BP increases and cardiac hypertrophy in response to Ang II, indicating that
- these mice were not resistant to the hemodynamic effects of Ang II, but were nevertheless protected from AF.
selectively targeted antioxidant therapies could be effective in preventing or reducing AF
half of patients enrolled in the Mode Selection Trial (MOST) with sinus node dysfunction had a history of AF
Ang II and diabetes-induced CaMKII oxidation caused sinus node dysfunction by increased pacemaker cell death and fibrosis
ox-CaMKII increases susceptibility for AF via increased diastolic sarcoplasmic reticulum Ca2+ release
clinical association between sinus node dysfunction and AF might have a mechanistic basis because
- sinus node dysfunction and AF are downstream consequences of elevated ox-CaMKII.
We refer the reader to the following related articles published in pharmaceutical Intelligence:
- Contributions to cardiomyocyte interactions and signaling
Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/10/21/contributions-to-cardiomyocyte-interactions-and-signaling/ - Cardiac Contractility & Myocardium Performance: Therapeutic Implications for Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Editor: Justin Pearlman, MD, PhD, FACC, Author and Curator: Larry H Bernstein, MD, FCAP, and Article Curator: Aviva Lev-Ari, PhD, RN
http://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/ - Part I. Identification of Biomarkers that are Related to the Actin Cytoskeleton
Curator and Writer: Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/ - Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/ - Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/ - Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD
Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/ - Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://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/ - Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/ - Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/ - Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/ - Genetic Analysis of Atrial Fibrillation
Author and Curator: Larry H Bernstein, MD, FCAP , and Curator: Aviva-Lev Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/10/27/genetic-analysis-of-atrial-fibrillation/
This article is a followup of the wonderful study of the effect of oxidation of a methionine residue in calcium dependent-calmodulin kinase Ox-CaMKII on stabilizing the atrial cardiomyocyte, giving protection from atrial fibrillation. It is also not so distant from the work reviewed, mostly on the ventricular myocyte and the calcium signaling by initiation of the ryanodyne receptor (RyR2) in calcium sparks and the CaMKIId isoenzyme.
Diabetes: Mouse Studies Point to Kinase as Treatment Target
Published: Nov 24, 2013
By Kristina Fiore, Staff Writer, MedPage Today
Targeting a pathway that plays a major role in both hepatic glucose production and insulin sensitivity may eventually help treat type 2 diabetes, researchers reported.
In a series of experiments in mice, researchers found that inhibition of the kinase CaKMII — or even some of its downstream components — lowered blood glucose and insulin levels, Ira Tabas, MD, PhD, of Columbia University Medical Center in New York City, and colleagues reported online in Cell Metabolism.
The pathway is activated by glucagon signaling in the liver, and appears to have roles in both insulin resistance as well as hepatic glucose production in the liver.
In an earlier study, Tabas and colleagues showed that inhibiting the CaKMII pathway lowered hepatic glucose production by suppressing p38-mediated FoxO1 nuclear localization.
In the current study, they found CaKMII inhibition suppresses levels of the pseudo-kinase TRB3 to improve Akt-phosphorylation, thereby improving insulin sensitivity.
Thus this single pathway targets “two cardinal features of type 2 diabetes — hyperglycemia and defective insulin signaling,” the researchers wrote.
“When we realized we had one common pathway that was responsible for these two disparate processes that, in essence, comprises all of type 2 diabetes, we though it would be an ideal target for new drug therapy,” Tabas told MedPage Today.
Tabas and colleagues conducted several experiments to evaluate the CaKMII pathway.
In one experiment in obese mice, they found that no matter how CaKMII was knocked out, it led to lower blood glucose levels and lower fasting plasma insulin levels in response to a glucose challenge.
The improvements also occurred when they
- knocked out downstream processes, including p38 and MAPK-activating protein kinase 2 (MK2).
“Thus liver p38 and MK2, like CaKMII, play an important role in the development of hyperglycemia and hyperinsulinemia in obese mice,” they wrote.
In further analyses, the researchers discovered deleting or inhibiting any of these three elements ultimately
- improved insulin-induced Akt-phosphorylation in obese mice —
- an important part of improving insulin sensitivity.
And unlike the effects on hepatic glucose production,
- these changes didn’t occur through effects on FoxO1.
Instead, inhibiting the CaKMII pathway suppressed levels of the pseudo-kinase TRB3, which likely occurred because of
- suppression of ATF4 — all of which led to an
- increase in Akt-phosphorylation and insulin sensitivity.
Indeed, when mice were made to overexpress TRB3, the improvement in phosphorylation disappeared, “indicating that
- the suppression of TRB3 by CaKMII deficiency is
- causally important in the improvement in insulin signaling,
As a result, there “appear to be two separate CaKMII pathways”,
- one involved in CaKMII-p38-FoxO1 dependent hepatic glucose production, and
- the other involved in defective insulin-induced p-Akt,
The findings suggest the possibility of a drug that can target
- both hyperglycemia and insulin resistance in type 2 diabetes
The authors have started developing such an agent. Although kinases can act very generally, Tabas said he and colleagues are working on
- an allosteric version that will more specifically target MK2
- by binding to a site that is unique to this enzyme.
He said this should help to avoid problems with drugs that targeted p38 but ultimately failed, with little efficacy and too many side effects.
The reason for this is now known at a very detailed level –
- when you inhibit p38 by that mechanism, mainly by inhibiting MK2,
- you avoid the adverse effects,
“When we realized all of this and had to make a choice [for further development], the obvious choice was MK2.”
- CaKMII inhibitors are in development for heart failure and
- MK2 inhibitors are being looked at as an alternative to p38 inhibitors for inflammatory diseases.
Tabas also said the drug may be valuable in treating prediabetes, since early data have suggested that
- CaKMII is generally overactive in obese patients
- who have not yet progressed to full blown diabetes, but is not overactive in lean people.
“One of the areas we’re most excited about in potential clinical use is in obese people before they get diabetic,” Tabas told MedPage Today. “There are hundreds of millions of people who are obese but not yet diabetic even though
- they have the hallmarks that they’re going to get diabetes.”
This recent publication was reported in MedPage Today. [CaKMII overactivity in obesity] Tabas noted that his group’s early human data “suggest that our pathway is turned on in prediabetes. If we can block that pathway before people get diabetes, it would even be better.”
The study was supported by the NIH, the American Heart Association, the German Center for Cardiovascular Research, the German Ministry of Education and Research, and the European Union.
Tabas and a co-author are among the founders of Tabomedex Biosciences, which is developing MK2 inhibitors.
Primary source: Cell Metabolism
Source reference: Ozcan L, et al. “Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling” Cell Metab 2013.
Posted in Calcium Signaling, Calmodulin Kinase and Contraction, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Proteomics, Translational Research, Translational Science | Tagged Atrial fibrillation, Ca2+/calmodulin-dependent protein kinase, CaKMII, CaKMII overactive in obesity, CaMKII-insulin induced p-Akt, CaMKII-p38-FOXO1 dependent hepatic glucose production, cardiac contraction, Cardiac muscle, Diabetes, Heart Failure, hyperglycemia, inhibitor of glucose elevation, Larry H. Bernstein, Mark E. Anderson, MK2 inhibitors, p38, target of both insulin resistance and type 2 diabetes, target of MK2 binding site, University of Iowa, upregulated in prediabetes | Leave a Comment »
Coronary Atherectomy New System approved by FDA for Coronary Lesions: Market Size – $1.5 billion
Reporter: Aviva Lev-Ari, PhD, RN
With FDA nod, Cardiovascular Systems targets $1.5B market
October 22, 2013 | By Damian Garde
 |
| Cardiovascular Solutions won FDA approval for its Diamondback 360 system.–Courtesy of Cardiovascular Solutions |
Cardiovascular Systems ($CSII) has won FDA approval to sell its Diamondback 360 device for patients with calcified coronary arteries, a long-awaited signoff that gives the company a chance to serve a large unmet need and significantly expand the market for its technology.
Diamondback 360 is an orbital atherectomy system designed to get rid of arterial calcium buildups in vessels before stenting, improving outcomes for patients and slashing rates of major adverse cardiac events, the company said. The device has been FDA-cleared to treat calcified plaque in arterial vessels throughout the leg and heart since 2007, and now approval for coronary lesions exposes Cardiovascular Systems to a $1.5 billion market dominated by last-generation technologies, CEO David Martin said.
“FDA approval of our Diamondback 360 Coronary OAS allows us to bring to market the first new coronary atherectomy system in more than two decades,” Martin said in a statement. “Severe coronary arterial calcium is an underestimated problem in medicine, with limited options for treatment.”
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In its pivotal trial, Diamondback 360 exceeded its two primary endpoints, charting a procedural success rate of 89.1% and leaving 89.8% of patients free of major adverse cardiac events.
The company has poured millions into the device’s development, and despite growing revenue 26% to $103.9 million last fiscal year, Cardiovascular Systems has yet to turn a profit. Now, with FDA approval in hand for an in-demand technology, Martin and his team have their work cut out for them.
Cardiovascular Systems said it’s planning a phased rollout of the device, targeting the country’s top medical centers over the next few quarters and in the meantime running postmarket studies to affirm Diamondback 360’s value in coronary atherectomy.
– read the announcement
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SOURCE
Posted in Cardiac and Cardiovascular Surgical Procedures | Tagged Clinical trial, Food and Drug Administration | Leave a Comment »
Invitae been Sued for BRCA1/2 Patent Violation by Myriad Genetics
Reporter: Aviva Lev-Ari, PhD, RN
Myriad Genetics Sues Invitae over BRCA1/2 Gene Patents
November 26, 2013
NEW YORK (GenomeWeb News) – Myriad Genetics has sued a fifth firm alleging infringement of its patents covering BRCA1 and BRCA2 gene testing.
In a lawsuit filed on Monday in US District Court for the District of Utah, Central Division, Myriad claims that Invitae infringes 11 patents held by Myriad, along with other assignees – the University of Utah Research Foundation, the Trustees of the University of Pennsylvania, HSC Research Development Limited Partnership (Hospital for Sick Children in Toronto), and Endorecherche.
Each of the assignees are listed as plaintiffs in the case, the latest volley by Myriad as it tries to fend off competitors following a decision by the US Supreme Court in Junethat invalidated certain claims by Myriad. The court found that human genes cannot be patented, but that synthetic DNA is patentable.
In its complaint, Myriad accuses Invitae – which was formed in the summer of 2012 from a Genomic Health subsidiary, also called InVitae, combined with a genetics firm called Locus Development – of infringing 11 patents. They are US Patent No. 5,747,282; No. 5,753,441; No. 6,033,857; No. 6,051.379; No. 6.951,721; No. 7,250,497; No. 7,470,510; No. 7,622,258; No. 7,838,237; No. 7,670,776; and No. 7,563,571.
Myriad asks the court for damages, a temporary and permanent injunction against Invitae from selling or using products it believes infringes on its patents, and the delivery of all products to Myriad that it believes infringes the patents.
Invitae in a statement on Tuesday called the lawsuit meritless and said it would defend itself vigorously, noting the June SCOTUS ruling, as well as an earlier SCOTUS ruling, Mayo Collaborative Services v. Prometheus Labs.
“The breast cancer community will benefit from these decisions with the introduction of multiple new diagnostic tests to analyze BRCA1 and BRCA2 mutations, increasing the availability and options for patients and physicians,” Invitae said.
The company’s Co-founder Randy Scott added, “The issue of DNA patents goes far beyond BRCA testing. Our company was founded around the core belief that every individual has the right to self-knowledge (meaning they have a right to know their own DNA sequence information), and we believe that the Supreme Court rulings validate our view that no company can claim ownership over naturally occurring genetic information.”
Invitae offers full gene sequencing for both BRCA1 and BRCA2 with deletion and duplication analysis for $1,500, it said.
The company is one of several that since the SCOTUS ruling have launched their own BRCA1/2 gene tests, going head to head with Myriad’s BRACAnalysis test, which prior to the ruling had had a monopoly on the US BRCA1/2 test market.
Myriad has responded to those launches by taking its competitors to court. Before this week’s lawsuit, the Salt Lake City-based firm sued Ambry Genetics, Gene by Gene,GeneDx, and most recently Quest Diagnostics.
Ambry and Gene by Gene have countersued Myriad alleging it of antitrust violations, while Quest and another firm, Counsyl, separately sued Myriad seeking preemptive declarations that they do not infringe Myriad’s patents.
Related Stories
- Myriad Sues Quest over BRCA1/2 Patents
October 24, 2013 / GenomeWeb Daily News
- U. Washington’s Targeted Gene Panel Pinpoints Breast Cancer Mutations in Quarter of Patients with Negative BRACAnalysis Test Results
October 25, 2013 / GenomeWeb Daily News
- Myriad Sues Third Firm, BioReference’s GeneDx, Alleging BRCA1/2 Patent Infringement
October 22, 2013 / GenomeWeb Daily News
- Gene by Gene Joins Ambry in Countersuit against Myriad Alleging Antitrust Violations
August 15, 2013 / GenomeWeb Daily News
- US Supreme Court Agrees to Hear Myriad Patent Case Again
December 3, 2012 / GenomeWeb Daily News
SOURCE
Related Articles were published in this Open Access Online Journal, including the following:
Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?
Genomic Liberty of Ownership, Genome Medicine and Patenting the Human Genome
Posted in Personalized and Precision Medicine & Genomic Research | Tagged Invitae, Myriad Genetic | Leave a Comment »
Google Glass in the Medical Field
Reporter: Aviva Lev-Ari, PhD, RN
Technology and medicine: Applying Google Glass in the medical field
VIEW VIDEO
Rosemary Sparacio
Friday, November 15, 2013
Every day, new strides in technology make headlines in all kinds of areas. Nowhere is it is more prevalent or exciting than in the medical field. And one of the most talked about new tech “gadgets” to come onto the scene and into the consciousness of just about everyone who follows the news is Google Glass.
The last few months have seen story after story about Goggle Glass being used by physicians. But as far back as a year ago, when Pelu Tran, a third-year medical student at Stanford, and Ian Shakil, a consultant at a West Coast start-up, saw and tried out Google Glass, they realized that the implications in medicine alone would be compelling. So much so that they founded a startup exclusively to investigate the use of Glass for medicine.
Basically, Google Glass is a small hands-free computer, head-mounted as a small glass block, on a conventional glass frame, that can have Wi-Fi, Bluetooth and a camera and voice activation. Proponents see the potential for the device’s use over a wide range of medical applications, from cutting down the time a physician has to do paperwork — thus giving the physician more time to focus on the patient’s problem — to assisting in surgery.
Dr. Pierre Theodore, M.D., was the first surgeon to receive permission to utilize Google Glass as an auxiliary surgical tool, while performing thoracic surgery in October. He was able to preload his patient’s information, like CT scans and X-rays, so that access to it would be right there on the “screen,” and he would not have to turn away during the surgery.
Theodore described it as similar to looking at the rearview mirror of your car: “That rearview is always there when I need it, but it’s not there when I don’t.”
Wikipedia
Using Google Glass to consult with a distant colleague, Dr. Christopher Kaeding, a surgeon at the Ohio State University Medical Center, streamed a live, point-of-view video while he operated to repair a torn ACL in August. At the same time across town, medical students at OSU College of Medicine were able to view the surgery real-time.
One of Kaeding’s colleagues watched the surgery sitting in his office. According to Kaeding: “Once we got into the surgery, I often forgot the device was there. It just seemed very intuitive and fit seamlessly.”
In early 2012, a surgical team at the University of Alabama at Birmingham (UAB) performed the first surgery using a technology called VIPAAR partnered with Google Glass. VIPAAR, which stands for virtual interactive presence in augmented reality, is a technology developed by UAB in 2003, which provides real-time, two-way interactive video conferencing to enhance surgery.
In this surgery, UAB orthopedic surgeon Brent Ponce, M.D., performed shoulder replacement surgery using Google Glass during the operation. At the same time, Dr. P. Danturuli, a surgeon sitting in his Atlanta office, was interacting with Ponce. The built-in camera in Google Glass transmitted the image of the surgical field to Atlanta. VIPAAR allowed Danturuli to introduce his hands into the virtual operating room. At the same time, Ponce saw Danturuli’s hands as a ghostly image in his heads-up display.
This technology can revolutionize telemedicine. What used to be a telephone call between two physicians, now has the potential for a small regional hospital to get hands and instruments into the field of a surgeon who has the skill but has perhaps performed the surgery only a few times. Obviously, adjustments will need to be made to fine tune VIPAAR and Google Glass.
And, of course, the potential goes beyond medicine. Imagine having the potential to connect to an expert in any field and have that expert be able to reach in to show you how to solve a problem.
Right now, Google Glass is in the hands of only about 10,000 people, (1,000 only in medical fields) using and experimenting with the technology. The thinking is that in less than five years, this kind of innovation has the potential to improve many fields and afford greater teaching opportunities through better high-tech access to information.
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About the Author
Rosemary Sparacio is a freelance medical and technical writer, and she substitute teaches in her current home in South Carolina. Rosemary has always been involved in healthcare and education, starting out in the lab as a med tech and in R&D. Her career lead her to teaching microbiology at a community college, while working in the pharmaceutical industry for Pfizer.
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Posted in Cardiac and Cardiovascular Surgical Procedures | Tagged Google, Google Glass, University of Alabama at Birmingham, VIPAAR | Leave a Comment »
Stanford Dropout is Already Drawing Comparisons with Steve Jobs
Larry H Bernstein, MD, Reporter
Article ID #89: Stanford Dropout is Already Drawing Comparisons with Steve Jobs. Published on 11/26/2013
WordCloud Image Produced by Adam Tubman
An interview by Eric Topol on Medscape of a 29 year-old Stanford University dropout is fascinating.
Editor’s Note:
If 29-year-old Elizabeth Holmes has her way, patients will no longer have to go to physicians’ offices, hospitals or laboratories to get high-complexity diagnostic blood tests. Nor will vial after vial of blood draws be necessary to do these tests.
Barely out of the gate after a decade of secrecy, the Stanford dropout is already drawing comparisons with Steve Jobs (she often wears the same black turtleneck). And her company, Theranos, Inc., which emerged from the shadows in September, just might be healthcare’s answer to Apple.[1] The so-called disruptive technology that Ms. Holmes, a former engineering major, and Theranos have created is said to have the potential to shake up and forever change the way laboratory medicine is conducted. Since forgoing college at 19, Ms. Holmes has secured millions of dollars in funding for her new venture, including $45 million in private equity funding in 2010.[2] The board of directors of her company is a Who’s Who of distinguished former and current technology, academic, and government officials.[2,3]
In an exclusive interview, Ms. Holmes talks to Medscape Editor-in-Chief Eric J. Topol, MD, about the decade she spent building her company; plans for the present and the future, including a recent deal with Walgreens drugstores; and whether she’s on the path to the creative destruction of laboratory medicine.
Leaving Stanford at Age 19
Dr. Topol: Hello. I’m Dr. Eric Topol, Editor-in-Chief of Medscape. Joining me today for Medscape One-on-One is Elizabeth Holmes, Founder, President, and CEO of Theranos. We are here in Palo Alto, California, at the company’s headquarters. Elizabeth, welcome. This is going to be a fascinating discussion.
Ms. Holmes: Thank you. It’s wonderful to be here and have you here.
Dr. Topol: This is a story that has been brewing for a long time. You were at Stanford University, and at age 19 you decided to change your path. Is that right?
Ms. Holmes: Yes.
Dr. Topol: What made you think, “I’m on to something, and I don’t want to do college; I’ve got something else that’s probably bigger than that”?
Ms. Holmes: I knew that I wanted to do something that could make a difference in the world.
To me, there was nothing greater that I could build than something that would change the reality in our healthcare system today, which is that when someone you love gets really, really sick, usually by the time you find that out, it’s too late to be able to do something about it. And in those moments it’s heartbreaking, because there is nothing you wouldn’t do.
Posted in Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Healthcare costs and reimbursement, HealthCare IT, Healthcare Reform, Interviews with Scientific Leaders, Technology Capital Expenses, Uninsured and Underinsured | Tagged computerized report, Elizabeth Holmes, Eric Topol, instantaneous reporting, microsample analysis, point of care technology, smart phone, Stanford University, Steve Jobs, testing near the patient, Theranos | Leave a Comment »
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