Archive for the ‘Cardiovascular Research’ Category

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

Curator: Aviva Lev-Ari, PhD, RN


UPDATED on 3/17/2018

An NT-proBNP <300 pg/ml strongly excludes the presence of acute HF.

J Am Coll Cardiol. 2018 Mar 20;71(11):1191-1200. doi: 10.1016/j.jacc.2018.01.021.

N-Terminal Pro-B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study


A breakthrough in emergence of

  • Genetic Testing Aids as a Personalized approach, genomics-based approach to selecting antiplatelet therapy, for reduction in ischemic and bleeding events, and
  • Biochemical Biomarker approaches for dosing anti-thrombotic drugs are presented here.

“This study fills in a part of the puzzle of genomic testing,” said Craig Beavers, PharmD, of the University of Kentucky in Lexington. “It shows we can use genomic information in clinical decision making. It was interesting that there appeared to be a change in prescribing based on genomics.”


At 12 months, 25.9% of patients receiving standard care had experienced the trial’s primary composite endpoint — cardiovascular death, non-fatal MI or stroke, and Bleeding Academic Research Consortium (BARC) 3-5 major bleeding — compared with 15.8% of patients receiving an anticoagulant drug on the basis of genetic testing (P<0.001), reported Diego Ardissino, MD, of Azienda Ospedaliero-Universitaria di Parma in Italy, and colleagues.

PHARMCLO is the first trial to combine clinical characteristics with genetic information to inform the choice of P2Y12 receptor antagonist in patients with ACS, Ardissino said in a presentation at the American College of Cardiology annual meeting. The study was simultaneously published in the Journal of the American College of Cardiology.

“Selecting treatment on the basis of genetic data in addition to considerations concerning the patients’ clinical characteristics may lead to a more personalized, and therefore more efficient, antiplatelet therapy, thus reducing both ischemic and bleeding risk,” he said. “PHARMCLO is the first step of a new approach that will see a shift in emphasis away from trying to discover ever-more potent anti-thrombotic drugs, and toward ensuring that the right therapy is given to each individual patient.”

However, PHARMCLO was halted after about a fourth of the intended population was recruited. The Ethics Committee of Modena (Italy) required the trial to be prematurely stopped because of a lack of in vitro diagnosis certification for the testing instruments. The original patients were still followed, Ardissino stated.

The authors enrolled 888 patients, and randomly assigned them to be tested for

  • three genes associated with resistance to clopidogrel (Plavix), and then were assigned a
  • treatment based on clinical data informed by the testing results.
  • Tested genes were ABCB1, 2C19*2 and 2C19*17 with the STQ3 system.
  • Another group was assigned to treatment without reference to genetic testing.
  • Standard of care treatment was with Clopidogrel, Ticagrelor (Brilinta), or Prasugrel (Effient).
  1. Clopidogrel was more frequently used in the standard arm (50.7% versus 43.3%), while
  2. Ticagrelor in the pharmacogenomic arm (42.6% versus 32.7%, P<0.05) and
  3. Prasugrel were used equally in both.

The primary endpoint hazard ratio was 0.58 versus the standard arm (95% CI 0.43-0.78, P<0.001).

Previous studies have shown Prasugrel and Ticagrelor to be superior to Clopidogrel at preventing ischemic events. However, prasugrel and ticagrelor, which are more potent, are also known to increase the risk of bleeding. The findings suggest that having more information about a specific patient’s likely response to clopidogrel can help doctors weigh this trade-off, Ardissino said.


The STANDARD OF CARE in Diagnosis of Acute Coronary Syndrome (ACS) using BioMarkers in serum blood relays of values of Troponin types and BNP for dosing anti-thrombotic drugs.

The team at LPBI Group published the following articles on this topic:

A search into our Journal Archive for “Acute Coronary Syndrome” yielded 210 articles

  1. High Sensitivity Troponin (hs cTn) Assays 

  • Previously undiscerned value of hs-troponin

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

  • Recent Insights into the High Sensitivity Troponins for Acute Coronary Syndromes

Curator: Larry H Bernstein, MD, FCAP

  • Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays: Preparing the United States for High-Sensitivity Cardiac Troponin Assays

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

  • Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Curator: Larry H Bernstein, MD, FCAP


2. BNP and proBNP

Brain natriuretic peptide (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume, decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis. The net effect of these peptides is a decrease in blood pressure due to the decrease in systemic vascular resistance and, thus, afterload. Additionally, the actions of both BNP and ANP result in a decrease in cardiac output due to an overall decrease in central venous pressure and preload as a result of the reduction in blood volume that follows natriuresis and diuresis.


Maisel A, Krishnaswamy P, Nowak R, McCord J, Hollander J, Duc P, Omland T, Storrow A, Abraham W, Wu A, Clopton P, Steg P, Westheim A, Knudsen C, Perez A, Kazanegra R, Herrmann H, McCullough P (2002). “Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure“. N Engl J Med347 (3): 161–7. 


The team at LPBI Group published the following articles on this topic:

  • Effect of Coronary Atherosclerosis and Myocardial Ischemia on Plasma Levels of High-Sensitivity Troponin T and NT-proBNP in Patients With Stable Angina

  • More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

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

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

Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP. Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP and Article Architecture Curator: Aviva Lev-Ari, PhD, RN

  • Highlights of LIVE Day 1: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017  BOSTON, MA • UNITED STATES

Aviva Lev-Ari, PhD, RN



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Regulatory MicroRNAs in Aberrant Cholesterol Transport and Metabolism

Curator: Marzan Khan, B.Sc

Aberrant levels of lipids and cholesterol accumulation in the body lead to cardiometabolic disorders such as atherosclerosis, one of the leading causes of death in the Western World(1). The physical manifestation of this condition is the build-up of plaque along the arterial endothelium causing the arteries to constrict and resist a smooth blood flow(2). This obstructive deposition of plaque is merely the initiation of atherosclerosis and is enriched in LDL cholesterol (LDL-C) as well foam cells which are macrophages carrying an overload of toxic, oxidized LDL(2). As the condition progresses, the plaque further obstructs blood flow and creates blood clots, ultimately leading to myocardial infarction, stroke and other cardiovascular diseases(2). Therefore, LDL is referred to as “the bad cholesterol”(2).

Until now, statins are most widely prescribed as lipid-lowering drugs that inhibit the enzyme 3-hydroxy-3methylgutaryl-CoA reductase (HMGCR), the rate-limiting step in de-novo cholesterol biogenesis (1). But some people cannot continue with the medication due to it’s harmful side-effects(1). With the need to develop newer therapeutics to combat cardiovascular diseases, Harvard University researchers at Massachusetts General Hospital discovered 4 microRNAs that control cholesterol, triglyceride, and glucose homeostasis(3)

MicroRNAs are non-coding, regulatory elements approximately 22 nucleotides long, with the ability to control post-transcriptional expression of genes(3). The liver is the center for carbohydrate and lipid metabolism. Stringent regulation of endogenous LDL-receptor (LDL-R) pathway in the liver is crucial to maintain a minimal concentration of LDL particles in blood(3). A mechanism whereby peripheral tissues and macrophages can get rid of their excess LDL is mediated by ATP-binding cassette, subfamily A, member 1 (ABCA1)(3). ABCA1 consumes nascent HDL particles- dubbed as the “good cholesterol” which travel back to the liver for its contents of triglycerides and cholesterol to be excreted(3).

Genome-wide association studies (GWASs) meta-analysis carried out by the researchers disclosed 4 microRNAs –(miR-128-1, miR-148a, miR-130b, and miR-301b) to lie close to single-nucleotide polymorphisms (SNPs) associated with abnormal metabolism and transport of lipids and cholesterol(3) Experimental analyses carried out on relevant cell types such as the liver and macrophages have proven that these microRNAs bind to the 3’ UTRs of both LDL-R and ABCA1 transporters, and silence their activity. Overexpression of miR-128-1 and miR148a in mice models caused circulating HDL-C to drop. Corroborating the theory under investigation further, their inhibition led to an increased clearance of LDL from the blood and a greater accumulation in the liver(3).

That the antisense inhibition of miRNA-128-1 increased insulin signaling in mice, propels us to hypothesize that abnormal expression of miR-128-1 might cause insulin resistance in metabolic syndrome, and defective insulin signaling in hepatic steatosis and dyslipidemia(3)

Further examination of miR-148 established that Liver-X-Receptor (LXR) activation of the Sterol regulatory element-binding protein 1c (SREBP1c), the transcription factor responsible for controlling  fatty acid production and glucose metabolism, also mediates the expression of miR-148a(4,5) That the promoter region of miR-148 contained binding sites for SREBP1c was shown by chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq)(4). More specifically, SREBP1c attaches to the E-box2, E-box3 and E-box4 elements on miR-148-1a promoter sites to control its expression(4).

Earlier, the same researchers- Andres Naars and his team had found another microRNA called miR-33 to block HDL generation, and this blockage to reverse upon antisense targeting of miR-33(6).

These experimental data substantiate the theory of miRNAs being important regulators of lipoprotein receptors and transporter proteins as well as underscore the importance of employing antisense technologies to reverse their gene-silencing effects on LDL-R and ABCA1(4). Such a therapeutic approach, that will consequently lower LDL-C and promote HDL-C seems to be a promising strategy to treat atherosclerosis and other cardiovascular diseases(4).


1.Goedeke L1,Wagschal A2,Fernández-Hernando C3, Näär AM4. miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):2047-2052

2.MedicalNewsToday. Joseph Nordgvist. Atherosclerosis:Causes, Symptoms and Treatments. 13.08.2015

3.Wagschal A1,2, Najafi-Shoushtari SH1,2, Wang L1,2, Goedeke L3, Sinha S4, deLemos AS5, Black JC1,6, Ramírez CM3, Li Y7, Tewhey R8,9, Hatoum I10, Shah N11, Lu Y11, Kristo F1, Psychogios N4, Vrbanac V12, Lu YC13, Hla T13, de Cabo R14, Tsang JS11, Schadt E15, Sabeti PC8,9, Kathiresan S4,6,8,16, Cohen DE7, Whetstine J1,6, Chung RT5,6, Fernández-Hernando C3, Kaplan LM6,10, Bernards A1,6,16, Gerszten RE4,6, Näär AM1,2. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. . Nat Med.2015 Nov;21(11):1290

4.Goedeke L1,2,3,4, Rotllan N1,2, Canfrán-Duque A1,2, Aranda JF1,2,3, Ramírez CM1,2, Araldi E1,2,3,4, Lin CS3,4, Anderson NN5,6, Wagschal A7,8, de Cabo R9, Horton JD5,6, Lasunción MA10,11, Näär AM7,8, Suárez Y1,2,3,4, Fernández-Hernando C1,2,3,4. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov;21(11):1280-9.

5.Eberlé D1, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004 Nov;86(11):839-48.

6.Harvard Medical School. News. MicoRNAs and Metabolism.

7. MGH – Four microRNAs identified as playing key roles in cholesterol, lipid metabolism


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


  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics,

on Amazon since 11/29/2015


HDL oxidation in type 2 diabetic patients

Larry H. Bernstein, MD, FCAP, Curator


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

Reporter: Aviva Lev-Ari, PhD, RN


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

Curator: Aviva Lev-Ari, PhD, RN


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

Reporter: Aviva Lev-Ari, PhD., RN


LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN


Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Reporter: Aviva Lev-Ari, PhD, RN

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN


A Concise Review of Cardiovascular Biomarkers of Hypertension

Curator: Larry H. Bernstein, MD, FCAP


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

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


Excess Eating, Overweight, and Diabetic

Larry H Bernstein, MD, FCAP, Curator


Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator


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Cheetah Medical Introduces New Algorithm for Fluid Management

Reporter: Lawrence J Mulligan, PhD


Cheetah Medical Advances the Science of Fluid Management

Cheetah Medical is the pioneer and leading global provider of 100% noninvasive hemodynamic monitoring technologies that are designed for use in critical care, OR and emergency department settings. The CHEETAH NICOM™ and STARLING™ SV technologies use a proprietary algorithm to calculate parameters related to the volume of blood and the functioning of patients’ circulatory systems. Medical professionals use this information to assess patients’ unique volume requirements, guide volume management decisions and maintain adequate organ perfusion. Cheetah Medical technologies are designed to enable more confident, informed therapy decisions that support clinical goals of improving patient outcomes and driving economic efficiencies.

NEWTON, Mass. –(BUSINESS WIRE)– Cheetah Medical announced today that its eighth abstract on fluid management will be presented at Society of Critical Care Medicine meeting in January. Building on previous work, this abstract demonstrates a strong association between large volume fluid administration in septic shock and increased risk of death in more than 23,000 patients.

Each year, millions of patients require hemodynamic monitoring to ensure optimal volume and perfusion management. While intravenous fluid is typical first-line therapy for many critical care situations, volume management has been a challenge for the healthcare community. It is often difficult for a clinician to know the right amount of fluid to administer to patients, and there are serious complications associated with both under and over resuscitation.

“Ever since we’ve been using intravenous fluid, clinicians have been asking, ‘What is the right amount?’” said Doug Hansell, MD and Cheetah’s Chief Physician Executive. “Today, with non-invasive Cheetah technology, we have new tools to answer this question, and we are learning that getting this question right is more important than ever.”

Cheetah Medical has been working with leading researchers using a large U.S. dataset to better understand the risks and benefits of fluid administration. During the past two years, researchers have now released eight clinical abstracts on the importance of fluid management.

  • FLUID ADMINISTRATION IN SEPSIS AND SEPTIC SHOCK – PATTERNS AND OUTCOMES: Sepsis and septic shock is a huge national priority, as it is the most expensive condition to treat, at $24 billion per year (AHRQ). This study identified a strong association between large fluid administration (more than five liters) and excess mortality in septic shock patients. As expected, sicker patients received more fluid. However, even after accounting for the severity of illness, these patients had an increased risk of dying. (Society of Critical Care Medicine Annual Conference, January 2017)
  • FLUID ADMINISTRATION IN OPEN AND LAPAROSCOPIC ABDOMINAL SURGERY: The study looked at the relationship between intraoperative fluid therapy and complications following abdominal surgery.Based on data from 18,633 patients, an increase in complications was found with day-of-surgery fluid use above five liters for open abdominal procedures. The study recommended individualized fluid therapy to reduce potentially negative effects from over/under resuscitation with intravenous fluids. (American Society of Anesthesiologists [ASA] 2016 Annual Meeting)
  • FLUID PRESCRIPTIONS IN HOSPITALIZED PATIENTS WITH RENAL FAILURE: The implication of volume resuscitation and potential complications among patients with acute kidney injuries (AKIs) has been widely debated. This study examined the relationship between fluid administration and outcomesamong 62,695 AKI patients. It found the potential for both under and over resuscitation in those who received treatments with vasopressors. A better understanding of individual fluid needs was seen for patients requiring pressor and mechanical ventilation support. (European Society of Intensive Care Medicine [ESICM] Annual Congress, 2016)
  • EFFECTS OF FLUIDS ADMINISTRATION IN PATIENTS WITH SEPTIC SHOCK WITH OR WITHOUT HEART FAILURE (HF): The study examined the relationship between indications of fluid overload in sepsis patients (with or without diastolic HF) and outcomes. For 29,098 patients, mortality was the highest among those who received the highest volumes of fluid. It also noted that patients with diagnosed diastolic HF received less fluids and exhibited a significantly lower mortality than predicted. These lower mortality rates could be a result of a more conservative fluid treatment strategy applied in patients known to be at risk for fluid overload. (American Thoracic Society [ATS] 2016 International Conference)
  • WIDE PRACTICE VARIABILITY IN FLUID RESUSCITATION OF CRITICALLY ILL PATIENTS WITH ARDS: The study looked at how variable fluid resuscitation testing and treatments impacted the outcomes of patients with acute respiratory distress syndrome (ARDS). An analysis of 1,052 patients highlighted a highly variable fluid resuscitation. The findings suggest a widespread variability in provider decision-making regarding fluid resuscitation, which may be detrimental to quality and costs, lowering the overall value of care. (American Thoracic Society [ATS] 2016 International Conference)
  • POTENTIAL HARM ASSOCIATED WITH SEVERITY-ADJUSTED TREATMENT VARIABILITY IN FLUID RESUSCITATION OF CRITICALLY ILL SEPTIC PATIENTS: The study set out to determine treatment variability for patients with severe sepsis and how it may impact mortality. Retrospectively analyzing 77,032 patients, a high degree of treatment variability was found for fluid resuscitation, with a range of 250 ml to more than 7L of fluid administered. For patients who received less fluid, there was no increased risk of mortality. In those who received the most fluid, there was a strong association with worse hospital mortality. (American Thoracic Society [ATS] 2016 International Conference)
  • ASSOCIATION OF FLUIDS AND OUTCOMES IN EMERGENCY DEPARTMENT PATIENTS HOSPITALIZED WITH COMMUNITY-ACQUIRED PNEUMONIA (CAP): Analyzing 192,806 CAP patients, the study looked at the correlation between fluid-volume overload, hospital mortality and ventilator-free days (VFDs). A significant association was found between the amount of fluid administered on day one, increased mortality and decreased VFDs. The study may have also identified a subset of CAP patients who could benefit from a more restrictive fluid strategy. (36thInternational Symposium on Intensive Care and Emergency Medicine)
  • FLUID ADMINISTRATION IN COMMUNITY-ACQUIRED SEPSISEXAMINATION OF A LARGE ADMINISTRATIVE DATABASE: The study looked at variation in fluid administration practices and compliance with “Surviving Sepsis” guidelines, which recommend a minimum initial fluid administration of 30cc/kg in sepsis-induced tissue hypoperfusion patients. It found that a substantial proportion of patients (47.4 %) with community-acquired sepsis received less than the recommended guidelines within the first 24 hours. (Society of Critical Care Medicine Annual Conference, 2016)

“We are very proud to have supported this work – we are advancing the science of fluid management and helping to improve our understanding of how better fluid management may improve patient outcomes,” said Chris Hutchison, CEO of Cheetah Medical.




Other related articles published in this Open Access On-line Scientific Journal includes the following:

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Thriving Three Groups on LinkedIn

Groups Launcher and Group Manager: Aviva Lev-Ari, PhD, RN


Cardiovascular Biotech & Pharma UK & US Networking Group

906 members



Leaders in Pharmaceutical Business Intelligence

336 members



Innovation in Israel

172 members


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Lysyl Oxidase (LOX) gene missense mutation causes Thoracic Aortic Aneurysm and Dissection (TAAD) in Humans because of inadequate cross-linking of collagen and elastin in the aortic wall

Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions.


Reporting: Aviva Lev-Ari, PhD, RN


Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans

  1. Vivian S. Leea,
  2. Carmen M. Halabia,b,
  3. Erin P. Hoffmanc,1,
  4. Nikkola Carmichaelc,d,
  5. Ignaty Leshchinerc,d,
  6. Christine G. Liand,e,
  7. Andrew J. Bierhalsf,
  8. Dana Vuzmanc,d,
  9. Brigham Genomic Medicine2,
  10. Robert P. Mechama,
  11. Natasha Y. Frankc,d,g,3, and
  12. Nathan O. Stitzielh,i,j,3

Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved June 7, 2016 (received for review January 27, 2016)

  • Author contributions: V.S.L., R.P.M., N.Y.F., and N.O.S. designed research; V.S.L., C.M.H., and N.O.S. performed research; E.P.H., N.C., C.G.L., D.V., B.G.M.P., R.P.M., and N.Y.F. contributed new reagents/analytic tools; V.S.L., C.M.


The mechanical integrity of the arterial wall is dependent on a properly structured ECM. Elastin and collagen are key structural components of the ECM, contributing to the stability and elasticity of normal arteries. Lysyl oxidase (LOX) normally cross-links collagen and elastin molecules in the process of forming proper collagen fibers and elastic lamellae. Here, using whole-genome sequencing in humans and genome engineering in mice, we show that a missense mutation in LOX causes aortic aneurysm and dissection because of insufficient elastin and collagen cross-linking in the aortic wall. These findings confirm mutations in LOX as a cause of aortic disease in humans and identify LOX as a diagnostic and potentially therapeutic target.


Thoracic aortic aneurysms and dissections (TAAD) represent a substantial cause of morbidity and mortality worldwide. Many individuals presenting with an inherited form of TAAD do not have causal mutations in the set of genes known to underlie disease. Using whole-genome sequencing in two first cousins with TAAD, we identified a missense mutation in the lysyl oxidase (LOX) gene (c.893T > G encoding p.Met298Arg) that cosegregated with disease in the family. Using clustered regularly interspaced short palindromic repeats (CRISPR)/clustered regularly interspaced short palindromic repeats-associated protein-9 nuclease (Cas9) genome engineering tools, we introduced the human mutation into the homologous position in the mouse genome, creating mice that were heterozygous and homozygous for the human allele. Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage. These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall. Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions. LOX sequencing for clinical TAAD may identify additional mutation carriers in the future. Additional studies using our mouse model of LOX-associated TAAD have the potential to clarify the mechanism of disease and identify novel therapeutics specific to this genetic cause.


Missense LOX Mutation Linked to Aortic Rupture, Aneurysm

NEW YORK (GenomeWeb) – Researchers from Washington University School of Medicine have linked a LOX gene variant with aortic rupture and aneurysm.

As they reported in the online early edition of the Proceedings of the National Academy of Sciences yesterday, the researchers sequenced two first cousins from a family with a history of aortic ruptures and aneurysms to uncover a missense mutation in the lysyl oxidase (LOX) gene, which encodes a protein that cross-links elastin and collagen. When they used CRISPR/Cas9 genome engineering to introduce the mutation into a mouse model, mice heterogeneous for the mutation had disorganized aortic walls, while mice homozygous for the mutation died shortly after birth of ascending aneurysm and spontaneous hemorrhage, suggesting that the LOX variant might be causal.

Read more @ the Source


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Entire Family of Impella Abiomed Impella® Therapy Left Side Heart Pumps: FDA Approved To Enable Heart Recovery

Reporter: Aviva Lev-Ari, PhD, RN


Abiomed Impella® Therapy Receives FDA Approval for Cardiogenic Shock After Heart Attack or Heart Surgery

Entire Family of Impella Left Side Heart Pumps FDA Approved To Enable Heart Recovery

DANVERS, Mass., April 07, 2016 (GLOBE NEWSWIRE) — Abiomed, Inc. (NASDAQ:ABMD), a leading provider of breakthrough heart support technologies, today announced that it has received U.S. Food and Drug Administration (FDA) Pre-Market Approval (PMA) for its Impella 2.5™, Impella CP®, Impella 5.0™ and Impella LD™ heart pumps to provide treatment of ongoing cardiogenic shock. In this setting, the Impella heart pumps stabilize the patient’s hemodynamics, unload the left ventricle, perfuse the end organs and allow for recovery of the native heart.  This latest approval adds to the prior FDA indication of Impella 2.5 for high risk percutaneous coronary intervention (PCI), or Protected PCI™, received in March 2015.

With this approval, these are the first and only percutaneous temporary ventricular support devices that are FDA-approved as safe and effective for the cardiogenic shock indication, as stated below:

The Impella 2.5, Impella CP, Impella 5.0 and Impella LD catheters, in conjunction with the Automated Impella Controller console, are intended for short-term use (<4 days for the Impella 2.5 and Impella CP and <6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (<48 hours) following acute myocardial infarction (AMI) or open heart surgery as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures with or without an intra-aortic balloon pump.  The intent of the Impella system therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.

The product labeling also allows for the clinical decision to leave Impella 2.5, Impella CP, Impella 5.0 and Impella LD in place beyond the intended duration of four to six days due to unforeseen circumstances.

The Impella products offer the unique ability to both stabilize the patient’s hemodynamics before or during a PCI procedure and unload the heart, which allows the muscle to rest and potentially recover its native function. Heart recovery is the ideal option for a patient’s quality of life and as documented in several clinical papers, has the ability to save costs for the healthcare system1,2,3.

Cardiogenic shock is a life-threatening condition in which the heart is suddenly unable to pump enough blood and oxygen to support the body’s vital organs. For this approval, it typically occurs during or after a heart attack or acute myocardial infarction (AMI) or cardiopulmonary bypass surgery as a result of a weakened or damaged heart muscle. Despite advancements in medical technology, critical care guidelines and interventional techniques, AMI cardiogenic shock and post-cardiotomy cardiogenic shock (PCCS) carry a high mortality risk and has shown an incremental but consistent increase in occurrence in recent years in the United States.

“This approval sets a new standard for the entire cardiovascular community as clinicians continue to seek education and new approaches to effectively treat severely ill cardiac patients with limited options and high mortality risk,” said William O’Neill, M.D., medical director of the Center for Structural Heart Disease at Henry Ford Hospital. “The Impella heart pumps offer the ability to provide percutaneous hemodynamic stability to high-risk patients in need of rapid and effective treatment by unloading the heart, perfusing the end organs and ultimately, allowing for the opportunity to recover native heart function.”

“Abiomed would like to recognize our customers, physicians, nurses, scientists, regulators and employees for their last fifteen years of circulatory support research and clinical applications. This FDA approval marks a significant milestone in the treatment of heart disease. The new medical field of heart muscle recovery has begun,” said Michael R. Minogue, President, Chairman and Chief Executive Officer of Abiomed. “Today, Abiomed only treats around 5% of this AMI cardiogenic shock patient population, which suffers one of the highest mortality risks of any patient in the heart hospital. Tomorrow, Abiomed will be able to educate and directly partner with our customers and establish appropriate protocols to improve the patient outcomes focused on native heart recovery.”

Abiomed Data Supporting FDA Approval

The data submitted to the FDA in support of the PMA included an analysis of 415 patients from the RECOVER 1 study and the U.S. Impella registry (cVAD Registry™), as well as an Impella literature review including 692 patients treated with Impella from 17 clinical studies. A safety analysis reviewed over 24,000 Impella treated patients using the FDA medical device reporting (“MDR”) database, which draws from seven years of U.S. experience with Impella.

In addition, the Company also provided a benchmark analysis of Impella patients in the real-world Impella cVAD registry vs. these same patient groups in the Abiomed AB5000/BVS 5000 Registry. The Abiomed BVS 5000 product was the first ventricular assist device (VAD) ever approved by the FDA in 1991 based on 83 patient PMA study. In 2003, the AB5000 Ventricle received FDA approval and this also included a PMA study with 60 patients.

For this approval, the data source for this benchmark analysis was a registry (“AB/BVS Registry”) that contained 2,152 patients that received the AB5000 and BVS 5000 devices, which were originally approved for heart recovery. The analysis examined by the FDA used 204 patients that received the AB5000 device for the same indications. This analysis demonstrated significantly better outcomes with Impella in these patients.

The Company believes this is the most comprehensive review ever submitted to the FDA for circulatory support in the cardiogenic shock population.

  1. Maini B, Gregory D, Scotti DJ, Buyantseva L. Percutaneous cardiac assist devices compared with surgical hemodynamic support alternatives: Cost-Effectiveness in the Emergent Setting.Catheter Cardiovasc Interv. 2014 May 1;83(6):E183-92.
  2. Cheung A, Danter M, Gregory D. TCT-385 Comparative Economic Outcomes in Cardiogenic Shock Patients Managed with the Minimally Invasive Impella or Extracorporeal Life Support. J Am Coll Cardiol. 2012;60(17_S):. doi:10.1016/j.jacc.2012.08.413.
  3. Gregory D, Scotti DJ, de Lissovoy G, Palacios I, Dixon, Maini B, O’Neill W. A value-based analysis of hemodynamic support strategies for high-risk heart failure patients undergoing a percutaneous coronary intervention. Am Health Drug Benefits. 2013 Mar;6(2):88-99


Impella 2.5 received FDA PMA approval for high risk PCI in March 2015, is supported by clinical guidelines, and is reimbursed by the Centers for Medicare & Medicaid Services (CMS) under ICD-9-CM code 37.68 for multiple indications. The Impella RP® device received Humanitarian Device Exemption (HDE) approval in January 2015. The Impella product portfolio, which is comprised of Impella 2.5, Impella CP, Impella 5.0, Impella LD, and Impella RP, has supported over 35,000 patients in the United States.

The ABIOMED logo, ABIOMED, Impella, Impella CP, and Impella RP are registered trademarks of Abiomed, Inc. in the U.S.A. and certain foreign countries.  Impella 2.5, Impella 5.0, Impella LD, and Protected PCI are trademarks of Abiomed, Inc.

Based in Danvers, Massachusetts, Abiomed, Inc. is a leading provider of medical devices that provide circulatory support.  Our products are designed to enable the heart to rest by improving blood flow and/or performing the pumping of the heart.  For additional information, please visit:

This release includes forward-looking statements.  These forward-looking statements generally can be identified by the use of words such as “anticipate,” “expect,” “plan,” “could,” “may,” “will,” “believe,” “estimate,” “forecast,” “goal,” “project,” and other words of similar meaning.  These forward-looking statements address various matters including, the Company’s guidance for fiscal 2016 revenue. Each forward-looking statement contained in this press release is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statement.  Applicable risks and uncertainties include, among others, uncertainties associated with development, testing and related regulatory approvals, including the potential for future losses, complex manufacturing, high quality requirements, dependence on limited sources of supply, competition, technological change, government regulation, litigation matters, future capital needs and uncertainty of additional financing, and the risks identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended March 31, 2015 and the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, each filed with the Securities and Exchange Commission, as well as other information the Company files with the SEC.  We caution investors not to place considerable reliance on the forward-looking statements contained in this press release.  You are encouraged to read our filings with the SEC, available at, for a discussion of these and other risks and uncertainties.  The forward-looking statements in this press release speak only as of the date of this release and the Company undertakes no obligation to update or revise any of these statements.  Our business is subject to substantial risks and uncertainties, including those referenced above.  Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

For more information, please contact: Aimee Genzler Director, Corporate Communications 978-646-1553 Ingrid Goldberg Director, Investor Relations


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Cancer detection and therapeutics

Larry H. Bernstein, MD, FCAP, Curator



Kurzweill Reports

Machine learning rivals human skills in cancer detection

Two announcements yesterday (April 21) suggest that deep learning algorithms rival human skills in detecting cancer from ultrasound images and in identifying cancer in pathology reports.

Samsung Medison RS80A ultrasound imaging system (credit: Samsung)

Samsung Medison, a global medical equipment company and an affiliate of Samsung Electronics, has just updated its RS80A ultrasound imaging system with a deep learning algorithm for breast-lesion analysis.

The “S-Detect for Breast” feature uses big data collected from breast-exam cases and recommends whether the selected lesion is benign or malignant. It’s used in in lesion segmentation, characteristic analysis, and assessment processes, providing “more accurate results.”

“We saw a high level of conformity from analyzing and detecting lesion in various cases by using the S-Detect,” said professor Han Boo Kyung, a radiologist at Samsung Medical Center.

“Users can reduce taking unnecessary biopsies and doctors-in-training will likely have more reliable support in accurately detecting malignant and suspicious lesions.”

Deep learning is better than humans in extracting meaning from cancer pathology reports

Meanwhile, researchers from the Regenstrief Institute and Indiana University School of Informatics and Computing at Indiana University-Purdue University Indianapolis say they’ve found that open-source machine learning tools are as good as — or better than — humans in extracting crucial meaning from free-text (unstructured) pathology reports and detecting cancer cases. The computer tools are also faster and less resource-intensive.

(U.S. states require cancer cases to be reported to statewide cancer registries for disease tracking, identification of at-risk populations, and recognition of unusual trends or clusters. This free-text information can be difficult for health officials to interpret, which can further delay health department action, when action is needed.)

“We think that its no longer necessary for humans to spend time reviewing text reports to determine if cancer is present or not,” said study senior author Shaun Grannis*, M.D., M.S., interim director of the Regenstrief Center of Biomedical Informatics.

Awash in oceans of data

“We have come to the point in time that technology can handle this. A human’s time is better spent helping other humans by providing them with better clinical care. Everything — physician practices, health care systems, health information exchanges, insurers, as well as public health departments — are awash in oceans of data. How can we hope to make sense of this deluge of data? Humans can’t do it — but computers can.”

This is especially relevant for underserved nations, where a majority of clinical data is collected in the form of unstructured free text, he said.

The researchers sampled 7,000 free-text pathology reports from over 30 hospitals that participate in the Indiana Health Information Exchange and used open source tools, classification algorithms, and varying feature selection approaches to predict if a report was positive or negative for cancer. The results indicated that a fully automated review yielded results similar or better than those of trained human reviewers, saving both time and money.

Major infrastructure advance

“We found that artificial intelligence was as least as accurate as humans in identifying cancer cases from free-text clinical data. For example the computer ‘learned’ that the word ‘sheet’ or ‘sheets’ signified cancer as ‘sheet’ or ‘sheets of cells’ are used in pathology reports to indicate malignancy.

“This is not an advance in ideas; it’s a major infrastructure advance — we have the technology, we have the data, we have the software from which we saw accurate, rapid review of vast amounts of data without human oversight or supervision.”

The study was published in the April 2016 issue of the Journal of Biomedical Informatics. It was conducted with support from the Centers for Disease Control and Prevention.

Co-authors of the study include researchers at the IU Fairbanks School of Public Health, the IU School of Medicine and the School of Science at IUPUI.

* Grannis, a Regenstrief Institute investigator and an associate professor of family medicine at the IU School of Medicine, is the architect of the Regenstrief syndromic surveillance detector for communicable diseases and led the technical implementation of Indiana’s Public Health Emergency Surveillance System — one of the nation’s largest. Studies over the past decade have shown that this system detects outbreaks of communicable diseases seven to nine days earlier and finds four times as many cases as human reporting while providing more complete data.

Yann Lecun is Director of AI Research, Facebook and a noted deep-learning expert. 


Toward better public health reporting using existing off the shelf approaches: A comparison of alternative cancer detection approaches using plaintext medical data and non-dictionary based feature selection

Suranga N. Kasthurirathnea, , Brian E. Dixonb, cJudy GichoyadHuiping XucYuni XiadBurke Mamlinb, dShaun J. Grannisb, d


• Cancer cases can be identified in unstructured clinical data to support public health reporting.
• Such cancer detection methods do not require complex external ontologies or human intervention.
• Such approaches can identify cases with sensitivity, specificity, PPV, accuracy, and AUC exceeding 80–90%.
• Automated cancer detection methods perform as well as approaches that require costly clinician input.
• These approaches may be generalized for other health analytics applications and healthcare domains.



Increased adoption of electronic health records has resulted in increased availability of free text clinical data for secondary use. A variety of approaches to obtain actionable information from unstructured free text data exist. These approaches are resource intensive, inherently complex and rely on structured clinical data and dictionary-based approaches. We sought to evaluate the potential to obtain actionable information from free text pathology reports using routinely available tools and approaches that do not depend on dictionary-based approaches.

Materials and methods

We obtained pathology reports from a large health information exchange and evaluated the capacity to detect cancer cases from these reports using 3 non-dictionary feature selection approaches, 4 feature subset sizes, and 5 clinical decision models: simple logistic regression, naïve bayes, k-nearest neighbor, random forest, and J48 decision tree. The performance of each decision model was evaluated using sensitivity, specificity, accuracy, positive predictive value, and area under the receiver operating characteristics (ROC) curve.


Decision models parameterized using automated, informed, and manual feature selection approaches yielded similar results. Furthermore, non-dictionary classification approaches identified cancer cases present in free text reports with evaluation measures approaching and exceeding 80–90% for most metrics.


Our methods are feasible and practical approaches for extracting substantial information value from free text medical data, and the results suggest that these methods can perform on par, if not better, than existing dictionary-based approaches. Given that public health agencies are often under-resourced and lack the technical capacity for more complex methodologies, these results represent potentially significant value to the public health field.

Graphical abstract
 Image for unlabelled figure

Scientists shoot anticancer drugs deep into tumors

Ultrasonic vibrations cause gas microbubbles to explode, releasing nanoparticles containing anticancer drugs

Schematic of a magnetic microbubble used in the study, containing gas core (blue) and shell of magnetic iron-oxide nanoparticles (red) that form a dense shell (center) around drug-containing nanoparticles. When stimulated by ultrasound at resonant frequencies, the microbubbles explode, releasing the nanoparticles, which can travel hundreds of micrometers into tumor tissue to deliver anticancer drugs and can also be imaged on an MRI machine. (credit: Yu Gao et al./NPG Asia Materials)


Scientists at Nanyang Technological University (NTU Singapore) have invented a new way to deliver cancer drugs deep into tumor cells.

They created micro-sized gas bubbles coated with anticancer drug particles embedded in iron oxide nanoparticles and used MRI or other magnetic sources to direct these microbubbles to gather around a specific tumor. Then they used ultrasound to vibrate the microbubbles, providing the energy to direct the drug particles into a targeted kill zone in the tumor. The magnetic nanoparticles also allow for imaging in an MRI machine.

The microbubbles were successfully tested in mice and the study has been published by the Nature Publishing Group in Asia Materials.

Overcoming limitations of chemotherapy

This innovative technique was developed by a multidisciplinary team of scientists led by Asst Prof C. J. Xu from the School of Chemical and Biomedical Engineering and Assoc. Prof Claus-Dieter Ohl from the School of Physical and Mathematical Sciences.

Xu, who is also a researcher at the NTU-Northwestern Institute for Nanomedicine, said their new method may solve some of the most pressing problems faced in chemotherapy used to treat cancer.

The main problem is that current chemotherapy drugs cannot be easily targeted. The drug particles flow in the bloodstream, damaging both healthy and cancerous cells. Typically, these drugs are flushed away quickly in organs such as the lungs and liver, limiting their effectiveness.

The remaining drugs are also unable to penetrate deep into the core of the tumor, leaving some cancer cells alive, which could lead to a resurgence in tumor growth.

Delivering anticancer drugs deep into tumors

Schematic of the apparatus used to investigate magnetic microbubble oscillation and nanoparticle release (credit: Yu Gao et al./NPG Asia Materials)

The microbubbles are magnetic, so after injecting them into the bloodstream, they can be clustered around the tumor using magnets to ensure that they don’t kill the healthy cells, explains Xu, who has been working on cancer diagnosis and drug delivery systems since 2004.

“More importantly, our invention is the first of its kind that allows drug particles to be directed deep into a tumor in a few milliseconds. They can penetrate a depth of 50 cell layers or more (about 200 micrometers) — twice the width of a human hair. This helps to ensure that the drugs can reach the cancer cells on the surface and also inside the core of the tumor.”

According to Clinical Associate Professor Chia Sing Joo, a Senior Consultant at the Tan Tock Seng Hospital’s Endoscopy Centre and the Urology & Continence Clinic, “For anticancer drugs to achieve their best effectiveness, they need to penetrate into the tumor efficiently in order to reach the cytoplasm of all the cancer cells that are being targeted without affecting the normal cells.

“Currently, this can [only] be achieved by means of a direct injection into the tumor or by administering a large dosage of anticancer drugs, which can be painful, expensive, impractical and might have various side effects. If successful, I envisage [the new drug-delivery system] can be a good alternative treatment in the future, one which is low cost and yet effective for the treatment of cancers involving solid tumors, as it might minimize the side effects of drugs.” Joo is a surgeon experienced in the treatment of prostate, bladder and kidney cancer and a consultant for this study.

According to Ohl, an expert in biophysics who has published previous studies involving drug delivery systems and bubble dynamics, “most prototype drug delivery systems on the market face three main challenges before they can be commercially successful: they have to be non-invasive, patient-friendly, and yet cost-effective. We were able to come up with our solution that addresses these three challenges.”

The 12-person study team included scientists from City University of Hong Kong and Technion – Israel Institute of Technology (Technion). The team plans to use this new drug delivery system in studies on lung and liver cancer using animal models, and eventually clinical studies.

They estimate that it will take another eight to ten years before it reaches human clinical trials.


Abstract of Controlled nanoparticle release from stable magnetic microbubble oscillations

Magnetic microbubbles (MMBs) are microbubbles (MBs) coated with magnetic nanoparticles (NPs). MMBs not only maintain the acoustic properties of MBs, but also serve as an important contrast agent for magnetic resonance imaging. Such dual-modality functionality makes MMBs particularly useful for a wide range of biomedical applications, such as localized drug/gene delivery. This article reports the ability of MMBs to release their particle cargo on demand under stable oscillation. When stimulated by ultrasound at resonant frequencies, MMBs of 450 nm to 200 μm oscillate in volume and surface modes. Above an oscillation threshold, NPs are released from the MMB shell and can travel hundreds of micrometers from the surface of the bubble. The migration of NPs from MMBs can be described with a force balance model. With this technology, we deliver doxorubicin-containing poly(lactic-co-glycolic acid) particles across a physiological barrier bothin vitro and in vivo, with a 18-fold and 5-fold increase in NP delivery to the heart tissue of zebrafish and tumor tissue of mouse, respectively. The penetration of released NPs in tissues is also improved. The ability to remotely control the release of NPs from MMBs suggests opportunities for targeted drug delivery through/into tissues that are not easily diffused through or penetrated.



Artificial protein controls first self-assembly of C60 fullerenes

New discovery expected to lead to new materials with properties such as higher strength, lighter weight, and greater chemical reactivity, resulting in applications ranging from medicine to energy and electronics
Buckminsterfullerene (C60), aka fullerene and buckyball (credit: St Stev via / CC BY-NC-ND)

A Dartmouth College scientist and his collaborators* have created the first high-resolution co-assembly between a protein and buckminsterfullerene (C60), aka fullerene and buckyball (a sphere-like molecule composed of 60 carbon atoms and shaped like a soccer ball).

“This is a proof-of-principle study demonstrating that proteins can be used as effective vehicles for organizing nanomaterials by design,” says senior author Gevorg Grigoryan, an assistant professor of computer science at Dartmouth and senior author of a study discussed in an open-access paper in the journal in Nature Communications.

Proteins organize and orchestrate essentially all molecular processes in our cells. The goal of the new study was to create a new artificial protein that can direct the self-assembly of fullerene into ordered superstructures.

COP, a stable tetramer (a polymer derived from four identical single molecule) in isolation, interacts with C60 (fullerene) molecules via a surface-binding site and further self-assembles into a co-crystalline array called C60Sol–COP (credit: Kook-Han Kim et al./Nature Communications)

Grigoryan and his colleagues show that that their artificial protein organizes a fullerene into a lattice called C60Sol–COP. COP, a protein that is a stable tetramer (a polymer derived from four identical single molecules), interacted with fullerene molecules via a surface-binding site and further self-assembled into an ordered crystalline superstructure. Interestingly, the superstructure exhibits high charge conductance, whereas both the protein-alone crystal and amorphous C60 are electrically insulating.

Grigoryan says that if we learn to do the programmable self-assembly of precisely organized molecular building blocks more generally, it will lead to a range of new materials with properties such as higher strength, lighter weight, and greater chemical reactivity, resulting in a host of applications, from medicine to energy and electronics.

Fullerenes are currently used in nanotechnology because of their high heat resistance and electrical superconductivity (when doped), but the molecule has been difficult to organize in useful ways.

* The study also included researchers from Dartmouth College, Sungkyunkwan University, the New Jersey Institute of Technology, the National Institute of Science Education and Research, the University of California-San Francisco, the University of Pennsylvania, and the Institute for Basic Science.

Abstract of Protein-directed self-assembly of a fullerene crystal

Learning to engineer self-assembly would enable the precise organization of molecules by design to create matter with tailored properties. Here we demonstrate that proteins can direct the self-assembly of buckminsterfullerene (C60) into ordered superstructures. A previously engineered tetrameric helical bundle binds C60 in solution, rendering it water soluble. Two tetramers associate with one C60, promoting further organization revealed in a 1.67-Å crystal structure. Fullerene groups occupy periodic lattice sites, sandwiched between two Tyr residues from adjacent tetramers. Strikingly, the assembly exhibits high charge conductance, whereas both the protein-alone crystal and amorphous C60 are electrically insulating. The affinity of C60 for its crystal-binding site is estimated to be in the nanomolar range, with lattices of known protein crystals geometrically compatible with incorporating the motif. Taken together, these findings suggest a new means of organizing fullerene molecules into a rich variety of lattices to generate new properties by design.


Protein-directed self-assembly of a fullerene crystal

Kook-Han KimDong-Kyun KoYong-Tae KimNam Hyeong Kim,….., Yong Ho Kim Gevorg Grigoryan
Nature Communications 2016;7,(11429)

Programmable self-assembly of molecular building blocks is a highly desirable way of achieving bottom-up control over novel functions and materials. Applications of molecular assemblies are well explored in the literature, ranging from optoelectronic1, 2, magnetic3, and photovoltaic4 devices to chemical and bioanalytical sensing5, and medicine6. However, it has been a daunting challenge to quantitatively describe and control the driving forces that govern self-assembly, particularly given the broad range of molecular building blocks one would like to organize. In this respect, nature’s self-assembling macromolecules hold considerable promise as standard chassis for encoding precise organization. By learning to engineer the assembly of these molecules, myriad other molecular building blocks can be co-organized in desired ways through non-covalent or covalent attachment. The protein polymer is a particularly attractive candidate for a standard assembly chassis given its rich chemical alphabet, diversity of available assembly geometries, broad ability to engage other molecular moieties, and the possibility of engineered function. Considerable progress has been made in the area of engineering protein assemblies7, 8, using either computational9, 10,11, 12, 13, 14 or rational approaches15, 16, 17, 18, but the problem remains a grand challenge. A major difficulty lies in accounting for the enormous continuum of possible assembly geometries available to proteins to engineer a sequence that predictably prefers just one. General design principles, which provide predictive rules of assembly, are thus of enormous utility in limiting the geometric search space and enabling robust design11, 19.

In this work, we demonstrate the first ever high-resolution structure of co-assembly between a protein and buckminsterfullerene (C60), which suggests a simple structural mode for protein–fullerene co-organization. Three separate crystal structures, resolved to 1.67, 1.76 and 2.35Å, reveal a protein lattice with C60 groups occupying periodic sites wedged between two helical segments, each donating a Tyr residue. A half site of the motif is estimated to have nM-scale affinity for C60, such that binding of fullerene appears to direct the organization of protein units in the co-crystal. The assembly exhibits a nm-spaced helical arrangement of fullerenes along a crystallographic axis, endowing the crystal with electrical conductance properties. We closely investigate the interfacial geometry of the C60-binding motif, finding it to be common among protein crystal lattices. C60 and its derivatives have been previously reported to interact with several proteins20, 21, 22, 23, 24, 25, although a high-resolution structure of a protein–C60 has been lacking. Still, prior evidence of interaction indicates that fullerenes and proteins are compatible as materials. This, together with the simple (and naturally recurrent) geometry of the C60-binding motif we discover, suggests that it may be possible to use the structural principles emergent from our study to generate a variety of C60–protein co-assemblies to further explore and exploit the properties of fullerenes26.


The aim of programmable self-assembly is to anticipate and harness unique collective properties that arise from precisely organized molecular building blocks. To this end, achieving atomic-level precision is crucial. This work demonstrates the first atomic resolution structures of a fullerene–protein assembly, establishing the feasibility of creating such objects, and further suggests a possible design principle for engineering such assemblies in general. How robust the discovered C60-binding motif is towards designing novel assemblies will need to be tested through a number of future design studies. However, the straightforward manner in which self-organization arose in our case, the simplicity of the C60-organizing motif in the lattice, together with its high affinity and the ubiquity of associated interfaces in natural protein lattices, are certainly promising with respect to the general applicability of the design principle. Our work also demonstrates the potential utility of exploring C60/protein co-organization, as derived supercrystals already showed synergistic charge conductance properties. Taken together, these results point to an exciting direction of inquiry towards generating protein–fullerene assemblies for the study and design of novel properties.


Scientists turn skin cells into heart and brain cells using only drugs — no stem cells required

Closer to the natural regeneration that happens in animals like newts and salamanders and no medical-safety and embryo concerns
Neurons created from chemically induced neural stem cells. The cells were created from skin cells that were reprogrammed into neural stem cells using a cocktail of only nine chemicals. This is the first time cellular reprogramming has been accomplished without adding external genes to the cells. (credit: Mingliang Zhang, PhD, Gladstone Institutes)

Scientists at the Gladstone Institutes have used chemicals to transform skin cells into heart cells and brain cells, instead of adding external genes — making this accomplishment a breakthrough, according to the scientists.

The research lays the groundwork for one day being able to regenerate lost or damaged cells directly with pharmaceutical drugs — a more efficient and reliable method to reprogram cells and one that avoids medical concerns surrounding genetic engineering.

Instead, in two studies published in an open-access paper in Science and in Cell Stem Cell, the team of scientists at the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone used chemical cocktails to gradually coax skin cells to change into organ-specific stem-cell-like cells and ultimately into heart or brain cells.

“This method brings us closer to being able to generate new cells at the site of injury in patients,” said Gladstone senior investigator Sheng Ding, PhD, the senior author on both studies. “Our hope is to one day treat diseases like heart failure or Parkinson’s disease with drugs that help the heart and brain regenerate damaged areas from their own existing tissue cells. This process is much closer to the natural regeneration that happens in animals like newts and salamanders, which has long fascinated us.”

Chemically Repaired Hearts

A human heart cell that was chemically reprogrammed from a human skin cell (credit: Nan Cao/Gladstone Institutes)

Transplanted adult heart cells do not survive or integrate properly into the heart and few stem cells can be coaxed into becoming heart cells.

Instead, in the Science study, the researchers used a cocktail of nine chemicals to change human skin cells into beating heart cells. By trial and error, they found the best combination of chemicals to begin the process by changing the cells into a state resembling multipotent stem cells (cells that can turn into many different types of cells in a particular organ). A second cocktail of chemicals and growth factors then helped transition the cells to become heart muscle cells.

With this method, more than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The cells also responded appropriately to hormones, and molecularly, they resembled heart muscle cells, not skin cells. What’s more, when the cells were transplanted into a mouse heart early in the process, they developed into healthy-looking heart muscle cells within the organ.

“The ultimate goal in treating heart failure is a robust, reliable way for the heart to create new muscle cells,” said Srivastava, co-senior author on the Science paper. “Reprogramming a patient’s own cells could provide the safest and most efficient way to regenerate dying or diseased heart muscle.”

Rejuvenating the brain with neural stem cell-like cells

In the second study, authored by Gladstone postdoctoral scholar Mingliang Zhang, PhD, and published in Cell Stem Cell, the scientists created neural stem-cell-like cells from mouse skin cells using a similar approach.

The chemical cocktail again consisted of nine molecules, some of which overlapped with those used in the first study. Over ten days, the cocktail changed the identity of the cells, until all of the skin-cell genes were turned off and the genes of the neural stem-cell-like cells were gradually turned on.

When transplanted into mice, the neural stem-cell-like cells spontaneously developed into the three basic types of brain cells: neurons, oligodendrocytes, and astrocytes. The neural stem-cell-like cells were also able to self-replicate, making them ideal for treating neurodegenerative diseases or brain injury.

With their improved safety, these neural stem-cell-like cells could one day be used for cell replacement therapy in neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease, according to co-senior author Yadong Huang, MD, PhD, a senior investigator at Gladstone. “In the future, we could even imagine treating patients with a drug cocktail that acts on the brain or spinal cord, rejuvenating cells in the brain in real time.”


Gladstone Institutes | Chemically Reprogrammed Beating Heart Cell

Abstract of Conversion of human fibroblasts into functional cardiomyocytes by small molecules

Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells to specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds (9C). The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters/enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs. This pharmacological approach for lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.

Abstract of Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.


Ultrafast laser technique identifies brain tumors in real time

04/19/2016  Associate Editor, BioOptics World

A research group at VU University Amsterdam (The Netherlands) has shown that an ultrafast laser technique can reveal exactly where brain tumors are, producing images in less than a minute and enabling surgeons to removetumors without compromising healthy tissue.

Related: OCT-based approach facilitates brain cancer surgery

Pathologists typically use staining methods, in which chemicals like hematoxylin and eosin turn different tissue components blue and red, revealing its structure and whether there are any tumor cells. But for a definitive diagnosis, this process can take up to 24 hours—which means surgeons may not realize some cancerous tissue has escaped from their attention until after surgery, requiring a second operation and more risk.

But the research team’s new ultrafast laser technique is label-free—instead, they fire short, 20-fs-long laser pulses into the tissue, and when three photons converge at the same time and place, the photons interact with the nonlinear optical properties of the tissue. Through well-known phenomena in optics called second- and third-harmonic generation, these interactions produce a single photon.

The key is that the incoming and outgoing photons have different wavelengths. The incoming photons are at 1200 nm, long enough to penetrate deep into the tissue. The single photon that is produced, however, is at 600 or 400 nm, depending on if it’s second- or third-harmonic generation. The shorter wavelengths mean the photon can scatter in the tissue. The scattered photon thus contains information about the tissue, and when it reaches a detector—in this case, a high-sensitivity gallium arsenide phosphide (GaAsP) photomultiplier tube—it reveals what the tissue looks like inside.

Tissue from a patient diagnosed with low-grade glioma. The green image is taken with the new method, while the pink uses conventional hematoxylin and eosin staining. Going from the upper left to the lower right, both images show increasing cell density because of more tumor tissue. The insets reveal the high density of tumor cells. (Credit: N.V. Kuzmin et al, VU University Amsterdam, The Netherlands)

The research team used the technique to analyze glial brain tumors, which are particularly deadly because it’s hard to get rid of tumor cells by surgery, irradiation, and chemotherapy without substantial collateral damage to the surrounding brain tissue. They tested their method on samples of glial brain tumors from humans, finding that the histological detail in these images was as good—if not better—than those made with conventional staining techniques. They were able to make most images in under a minute. The smaller ones took less than a second, while larger images of a few square millimeters took five minutes—making it possible to do it in real time in the operating room, according to Marloes Groot of VU University Amsterdam, who led the work.

Now that they’ve shown their approach works, the researchers are developing a handheld device that a surgeon can use to identify a tumor’s border during surgery. The incoming laser pulses can only reach a depth of about 100 µm into the tissue. To reach farther, Groot envisions attaching a needle that can pierce the tissue and deliver photons deeper, allowing diagnosis during an operation and possibly before surgery begins.

Full details of the work appear in the journal Biomedical Optics Express; for more information, please visit

Third harmonic generation imaging for fast, label-free pathology of human brain tumors

N. V. Kuzmin, P. Wesseling, P. C. de Witt Hamer, D. P. Noske, G. D. Galgano, H. D. Mansvelder, J. C. Baayen, and M. L. Groot
Biomedical Optics Express > Volume 7 > Issue 5 > Page 1889

In brain tumor surgery, recognition of tumor boundaries is key. However, intraoperative assessment of tumor boundaries by the neurosurgeon is difficult. Therefore, there is an urgent need for tools that provide the neurosurgeon with pathological information during the operation. We show that third harmonic generation (THG) microscopy provides label-free, real-time images of histopathological quality; increased cellularity, nuclear pleomorphism, and rarefaction of neuropil in fresh, unstained human brain tissue could be clearly recognized. We further demonstrate THG images taken with a GRIN objective, as a step toward in situ THG microendoscopy of tumor boundaries. THG imaging is thus a promising tool for optical biopsies.



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