Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Archive for the ‘Origins of Cardiovascular Disease’ Category

Endothelial Cell Dysfunction plays a role in the Pathogenesis of Alzheimer’s Disease, Atherosclerosis, Diabetes, and Pulmonary Hypertension: New Research @Cleveland Clinic

Posted in Alzheimer's Disease, Atherogenic Processes & Pathology, Cell Biology, Signaling & Cell Circuits, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease on June 2, 2014| Leave a Comment »

Endothelial Cell Dysfunction plays a role in the Pathogenesis of Alzheimer’s Disease, Atherosclerosis, Diabetes, and Pulmonary Hypertension: New Research @Cleveland Clinic

Reporter: Aviva Lev-Ari, PhD, RN

Cleveland Clinic: Improving Endothelial Cell Recovery

TAGS:

Cleveland Clinic, Life Sciences, Nature, Theoretical-IP Transfer

STATUS: Awarded  |  ACTIVE SOLVERS: 174  |  POSTED: 11/05/13

 

Endothelial cell dysfunction plays a role in the pathogenesis of Alzheimer’s disease, atherosclerosis, diabetes, and pulmonary hypertension. Research in these areas hinges upon successful isolation and growth of endothelial progenitor cells (EPC). These cells may be obtained directly from diseased tissue or isolated from peripheral blood samples. To maintain maximum viability, EPC must be processed and plated within two hours of a blood draw. The challenge is to identify a method that preserves EPC and allows processing to take place the next day while maintaining the yield and viability of the cells.

This Challenge requires only a written proposal.

 

Source: InnoCentive      Challenge ID: 9933159

Challenge Overview

Pulmonary arterial hypertension (PAH) is a chronic and currently incurable disease that affects the walls of the arteries that carry blood to the lungs. In PAH, these arteries constrict abnormally leading to increased blood pressure and extra strain on the heart. Some forms of PAH are hereditary and research at the Cleveland Clinic focuses on characterizing signaling defects resulting from genetic mutations. Experiments require endothelial progenitor cells (EPC) isolated from peripheral blood samples. The EPC are exquisitely sensitive and must be processed and cultured within two hours of a blood draw, thereby limiting the available patient pool. Cleveland Clinic is searching for a new method to preserve EPC in blood, so that samples can be shipped overnight for processing the next day.

Dr. Micheala Aldred of the Cleveland Clinic Genomic Medicine Institute is a translational genetics researcher with a specific interest in pulmonary arterial hypertension. Cleveland Clinic strives to make scientific advances that will benefit patient care and support outside relationships that promise public benefit.

This is a Theoretical Challenge that requires only a written proposal to be submitted.  The Challenge award will be contingent upon theoretical evaluation of the proposal by the Seeker.

To receive an award, the Solvers must transfer to the Seeker their exclusive Intellectual Property (IP) rights to the solution.  However, the Seeker may be willing to consider a licensing agreement for a partial award if exclusive IP cannot be transferred by the Solver.

SOURCE

https://www.innocentive.com/ar/challenge/9933159?cc=Nature9933159&utm_source=nature&utm_medium=pavilion&utm_campaign=challenges

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

CardioMEMS sold to St. Jude Medical: Boston Millennia Partners announced that St. Jude Medical (NYSE: STJ) is acquiring the remaining 81 percent of CardioMEMS, Inc. it does not own for $375 million

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Congenital Heart Disease, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease on June 2, 2014| Leave a Comment »

CardioMEMS sold to St. Jude Medical: Boston Millennia Partners announced that St. Jude Medical (NYSE: STJ) is acquiring the remaining 81 percent of CardioMEMS, Inc. it does not own for $375 million

Reporter: Aviva Lev-Ari,  PhD, RN

 

UPDATED on 6/3/2014

 

Boston Millennia Partners announces the sale of its portfolio company CardioMEMS to St. Jude Medical Boston, MA – June 3, 2014 Boston Millennia Partners is pleased to announce that St. Jude Medical (NYSE: STJ) is acquiring the remaining 81 percent of CardioMEMS, Inc. it does not own for $375 million. Dana Callow, Managing General Partner at Boston Millennia Partners, said, “We congratulate the management team of CardioMEMS for the recent FDA approval of the company’s remote heart monitoring device. We agree with the belief of many cardiology experts that the CardioMEMS HF System represents the most significant advancement in the treatment of congestive heart failure in the past twenty years. With the subsequently announced acquisition of CardioMEMS by St. Jude Medical, this device will receive broad distribution and improve the lives of patients worldwide. The CardioMEMS HF System uses a miniaturized, wireless monitoring sensor that is implanted in the pulmonary artery (PA) during a minimally invasive procedure to directly measure PA pressure. Directly measuring PA pressure via a procedure called a right-heart catheterization is a standard-of-care practice for managing worsening HF in patients who have been hospitalized. The CardioMEMS HF System allows patients to transmit the same information from their homes to their health care providers, allowing for personalized and proactive management to reduce the likelihood of hospitalization. “The approval of the CHAMPION Heart Failure Monitoring System is a significant event for both patients and for those who pay for healthcare. Avoiding unnecessary hospitalizations and reducing the risk of acute decompensation in patients with this chronic disease benefits everyone”, said Pat Fortune, Venture Partner at Boston Millennia Partners. About CardioMEMS Headquartered in Atlanta, CardioMEMS is a medical device company that has developed a proprietary wireless sensing and communication technology for the human body. The company’s technology platform is designed to improve the management of severe chronic cardiovascular diseases such as heart failure, aneurysms, and hypertension. The sensors can be permanently implanted into the heart and blood vessels due to their small size, durability and lack of wires and batteries. CardioMEMS developed this technology based on the belief that frequent, on-demand, real-time monitoring of vital information enables proactive patient management leading to fewer hospitalizations, improved patient quality of life, and more efficient and cost-effective health care. CardioMEMS was founded by Jay Yadav, M.D., an interventional cardiologist and entrepreneur. Lead investors in CardioMEMS include Arcapita Ventures, Boston Millennia Partners and Foundation Medical Partners. For more information, please visit http://www.cardiomems.com. About St. Jude Medical St. Jude Medical is a global medical device manufacturer dedicated to transforming the treatment of some of the world’s most expensive, epidemic diseases. The company does this by developing cost-effective medical technologies that save and improve lives of patients around the world. Headquartered in St. Paul, Minn., St. Jude Medical has four major clinical focus areas that include cardiac rhythm management, atrial fibrillation, cardiovascular and neuromodulation. For more information, please visit sjm.com.

SOURCE

http://campaign.r20.constantcontact.com/render?ca=a5d4772f-7673-449c-9b09-2bb48d802dc6&c=6407cc90-31f8-11e3-946e-d4ae527b895a&ch=64ad3450-31f8-11e3-959c-d4ae527b895a

FDA News Release

FDA approves first implantable wireless device with remote monitoring to measure pulmonary artery pressure in certain heart failure patients

For Immediate Release

May 28, 2014

Release

The U.S. Food and Drug Administration today approved the CardioMEMS HF System that measures the pulmonary artery (PA) pressures and heart rates of patients with New York Heart Association (NYHA) Class III heart failure who have been hospitalized for heart failure in the previous year. The device allows health care professionals to monitor the condition of their patients remotely.

About 5.8 million people in the United States have heart failure, a condition in which the heart cannot pump enough blood to meet the body’s needs. With proper treatment and lifestyle changes, people with heart failure can live longer and more active lives. The NYHA Functional Classification further defines the extent of heart failure in patients. Patients with Class III heart failure experience marked limitation in physical activity, even during less-than-ordinary activity such as walking short distances.

The CardioMEMS HF System is used by the patient in the home or other remote location. This is the first permanently implantable wireless system intended to provide PA pressure measurements, including systolic, diastolic and mean PA pressures. The PA pressure data are reviewed by physicians who can make decisions regarding the status of the patient and, if necessary, initiate changes in medical therapy, with the goal of  reducing hospitalization due to heart failure.

The system consists of three parts:

• A battery-free Implantable Sensor/Monitor implanted permanently in the PA;
• Delivery System, a transvenous catheter designed to deploy the Implantable Sensor, within the distal PA; and
• CardioMEMS Hospital and Patient Electronics Systems where the Electronics System acquires and processes signals from the Implantable Sensor/Monitor and transfers PA pressure measurements to a secure database.

“Heart failure is one of the most common reasons for hospitalizations for people aged 65 and older,” said Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health. “The goal of this first-of-its-kind implantable wireless device with remote monitoring of pulmonary artery pressure is to reduce heart failure-related hospitalizations.”

To support the approval, the company submitted data from its pivotal clinical study. Concerns about the clinical study were discussed at the December 8, 2011 meeting of the Circulatory System Devices Panel of FDA’s Medical Devices Advisory Committee. The company provided additional follow-up data and analyses that were discussed at the October 9, 2013 meeting of the Circulatory System Devices Panel to address these concerns.

The clinical study, in which 550 participants had the device implanted and were randomized into either the control group or investigational group, showed a clinically and statistically significant reduction in heart failure-related hospitalizations for the participants whose doctors had access to pulmonary artery pressure data. Of the participants who had the device implanted (or in whom there was an attempt to implant the device), 98.6 percent were free from device/system-related complications at six months. Of the devices implanted, 100 percent were operational at 6 months, and there were no device explants or repeat implants during this time period.

The FDA believes that there is reasonable assurance that the device is safe and effective for heart failure management with the goal of reducing the rate of heart failure-related hospitalizations in certain patients. The FDA is requiring a thorough Post-Approval Study to continue to learn about the device’s performance when used outside the context of a clinical study.

The CardioMEMS HF System is manufactured by CardioMEMS, Inc., located in Atlanta, Ga.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

SOURCE

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm399024.htm

 

 

The FDA recent approval of a heart failure monitoring device will allow physicians to check up on patients’ health remotely. Intel Free Press, CC BY-SA 2.0

The Food and Drug Administration (FDA) announced Thursday its approval for the first wireless implantable device, known as CardioMEMS HF System, designed to monitor the health of heart failure patients remotely.

Manufactured by CardioMEMS Inc., located in Atlanta, Ga., the device is meant to give health care professionals an early look at pulmonary artery (PA) pressure data, which they can use to change medication dosage or treatment method before the need for hospitalization. In the clinical study leading up to the FDA’s approval, 98.6 percent of subjects using the device saw no device-related complications within six months, and, of the devices implanted, 100 percent were operational within the same timeframe.

“Heart failure is one of the most common reasons for hospitalizations for people aged 65 and older,” said Christy Foreman, director in the FDA’s Center for Devices and Radiological Health, in the news release. According to the Centers for Disease Control and Prevention, roughly half of all people who develop heart failure die within five years of diagnosis, straining the national economy to the tune of $32 billion annually.

Heart failure occurs when the heart is no longer able to pump enough blood and oxygen to the surrounding parts of the body. While this doesn’t mean the heart necessarily stops beating altogether, the pulse it sends is too weak to replenish major organs. In typical cases, the blood that would normally leave the heart through the aorta never exits the muscle, recycling back into the heart and pooling in the surrounding valves. In congestive heart failure cases, blood may pool in other major organs as well.

The new device is intended to monitor the pressure of this outgoing blood. If the data shows the pressure is too low, physicians located remotely can check up on patients to gauge their health. Not all heart failure patients qualify for the device, the FDA explains. Only people with New York Heart Association (NYHA) Class III heart failure, who have been hospitalized for heart failure in the previous year, are eligible.

SOURCE

http://www.medicaldaily.com/fda-approves-implantable-device-cardiomems-hf-system-heart-failure-patients-285184

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

Posted in Acute Myocardial Infarction, Bone marrow derived cells, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Hematopoiesis, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, PCI, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, tagged ACS, AMI, Atrial fibrillation, cell regulatory processes, miRNA, myocardial remodelling, myocardial repair, NT-proBNP risk ratio, Omega 3 index, stem cells, ventricullar tachyarrhythmia on May 12, 2014| Leave a Comment »

Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

• Larry H Bernstein, MD, FCAP, Author and Curator, Volume Four, Co-Editor
• Justin Pearlman, MD, PhD, FACC, Content Consultant for Series A: Cardiovascular Diseases
• Aviva Lev-Ari, PhD, RN, Co-Editor of Volume Four and Editor-in-Chief, BioMed e-Series

 

This completes Chapter 4 in two parts on the most dynamic developments in the regulatory pathways guiding cardiovascular dynamics and function in health and disease.  I have covered key features of these in two summaries, so I shall try to look further into important expected future directions and their anticipated implications.

1. Mechanisms of Disease

Signal Transduction: Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

David J. Roberts, Valerie P. Tan-Sah, Jeffery M. Smith and Shigeki Miyamoto
J. Biol. Chem. 2013, 288:23798-23806.  http://dx.doi.org/ 10.1074/jbc.M113.482026

Backgound: Hexokinase II binds to mitochondria and promotes cell survival.
Results: Akt phosphorylates HK-II but not the threonine 473 mutant. The phosphomimetic T473D mutant decreases its dissociation from mitochondria induced by G-6P and increases cell viability against stress.
Conclusion: Akt phosphorylates HK-II at Thr-473, resulting in increased mitochondrial HK-II and cell protection.
Significance: The Akt-HK-II signaling nexus is important in cell survival.

HK-II Phosphorylation

 

 

 

 

 

 

It has been demonstrated that an increased level of HK-II at mitochondria is protective and is increased by protective interventions but decreased under stress.

It   has not  been fully determined   which  molecular  signals  regulate  the    level    of  HK-II at mitochondria.

Thr-473 in HK-II  is phosphorylated by Akt and this phosphorylation  leads to  increases  in  mitochondrial  HK-II binding  through inhibition  of  G-6P-dependent  dissociation, conferring resistance to oxidative stress  (Fig.     7).

Overexpression of  WTHK-II increases mitochondrial HK-II and confers protection against  hydrogen peroxide,  which  is enhanced significantly  in   HK-II   T473D-expressing  cells, whereas  NHK-II, lacking the ability to bind to mitochondria, does not confer protection.   Conversely,  mitochondrial  HK-II from mitochondria (Fig.6, A and B) inhibits  the  IGF-1-mediated increase in mitochondrial HK-II and cellular protection.   Similar   dose-dependent  curves were obtained in mitochondrial   HK-II     against stress    (15–25).

Gene Expression and Genetic Variation in Human Atria

Honghuang Lin PhD, Elena V. Dolmatova MD, Michael P. Morley, PhD, Kathryn L. Lunetta PhD, David D. McManus MD, ScM, et al.
Heart Rhythm  2013   http://dx.doi.org/10.1016/j.hrthm.2013.10.051

Background— The human left and right atria have different susceptibilities to develop atrialfibrillation (AF). However, the molecular events related to structural and functional changes that
enhance AF susceptibility are still poorly understood.
Objective— To characterize gene expression and genetic variation in human atria.
Results— We found that 109 genes were differentially expressed between left and right atrial tissues. A total of 187 and 259 significant cis-associations between transcript levels and genetic
variants were identified in left and right atrial tissues, respectively. We also found that a SNP at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right
atrial tissues.
Conclusion— We found a distinct transcriptional profile between the right and left atrium, and extensive cis-associations between atrial transcripts and common genetic variants. Our results
implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF.

Long-Term Caspase Inhibition Ameliorates Apoptosis, Reduces Myocardial Troponin-I Cleavage, Protects Left Ventricular Function, and Attenuates Remodeling in Rats With Myocardial Infarction

Y. Chandrashekhar,  Soma Sen, Ruth Anway,  Allan Shuros,  Inder Anand,

J Am Col  Cardiol  2004; 43(2)   http://dx.doi.org/10.1016/j.jacc.2003.09.026

This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling.
Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction.

A 28-day infusion of caspase inhibitor was administeredimmediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry.

Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to- body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI.

Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling.

These findings may have important therapeutic implications in post-MI HF. J Am Col Cardiol 2004;43:295–301)

Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors

Lincoln T Shenje,  Peter P Rainer , Gun-sik Cho , Dong-ik Lee , Weimin Zhong , Richard P Harvey , David A Kass , Chulan Kwon *,  et al.
eLife 2014.    http://dx.doi.org/10.7554/eLife.02164.001

Cardiac progenitor cells (CPCs) must control their number and fate to sustain the rapid heart growth during development, yet the intrinsic factors and environment governing these processes remain unclear. Here, we show that deletion of the ancient cell-fate regulator Numb (Nb) and its homologue Numblike (Nbl) depletes CPCs in second pharyngeal arches (PA2s) and is associated with an atrophic heart. With histological, fow cytometric and functional analyses, we fnd that CPCs remain undifferentiated and expansive in the PA2, but differentiate into cardiac cells as they exit the arch. Tracing of Nb- and Nbl-defcient CPCs by lineage-specifc mosaicism reveals that the CPCs normally populate in the PA2, but lose their expansion potential in the PA2. These fndings demonstrate that Nb and Nbl are intrinsic factors crucial for the renewal of CPCs in the PA2 and
that the PA2 serves as a microenvironment for their expansion.

2. Diagnostics and Risk Assessment

Classical and Novel Biomarkers for Cardiovascular Risk Prediction in the United States

Aaron R. Folsom
J Epidemiol 2013;23(3):158-162   http://dx.doi.org/10.2188/jea.JE20120157

Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of
cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction
beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely,

1. hemoglobin A1c (in all adults),
2. microalbuminuria (in patients with hypertension or diabetes), and
3. C-reactive protein,
4. lipoprotein-associated phospholipase,
5. coronary calcium,
6. carotid intima-media thickness, and
7. ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).

Diagnostic accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of tachycardia-mediated cardiomyopathy: a pilot study

Amir M. Nia, Natig Gassanov, Kristina M. Dahlem, Evren Caglayan, Martin Hellmich, et al.
Clin Res Cardiol (2011) 100:887–896    http://dx.doi.org/10.1007/s00392-011-0319-y

Tachycardia-mediated cardiomyopathy (TMC) occurs as a consequence of prolonged high heart rate due to ventricular and supraventricular tachycardia. In animal models, rapid pacing induces severe biventricular remodeling with dilation and dysfunction [7]. On a cellular basis, cardiomyocytes exert fundamental morphological and functional roles.

When heart failure and tachycardia occur simultaneously, a useful diagnostic tool for early discrimination of patients with benign tachycardia-mediated  cardiomyopathy (TMC) versus major structural heart disease  (MSHD) is not available. Such a tool is required to prevent unnecessary and wearing diagnostics in patients with reversible TMC. Moreover, it could lead to early additional diagnostics and therapeutic approaches in patients with  MSHD.

A total of 387 consecutive patients with supraventricular arrhythmia underwent assessment.  Of these patients, 40 fulfilled the inclusion criteria
with a resting heart rate C100 bpm and an impaired left ventricular ejection fraction \40%. In all patients, successful electrical cardioversion was performed. At baseline, day 1 and weekly for 4 weeks, levels of NT-proBNP and echocardiographic parameters were evaluated.

NT-proBNP ratio (BNP-R) was calculated as a quotient of baseline NT-proBNP/follow-up NT-proBNP. After 4 weeks, cardiac catheterization was performed to identify patients with a final diagnosis of TMC versus MSHD.

Initial NT-proBNP concentrations were elevated and consecutively decreased after cardioversion in all patients studied. The area under the ROC curve for BNP-R to detect TMC was 0.90 (95% CI 0.79–1.00; p \ 0.001) after 1 week  and 0.995 (95% CI 0.99–1.00; p \ 0.0001) after 4 weeks. One week after cardioversion already, a BNP-R cutoff C2.3 was useful for TMC diagnosis indicated by an accuracy of 90%, sensitivity of 84% and specificity of 95%.

BNP-R was found to be highly accurate for the early diagnosis of TMC.

Omega-3 Index and Cardiovascular Health

Clemens von Schacky
Nutrients 2014; 6: 799-814;  http://dx. doi.org/10.3390/nu602099

Fish, marine oils, and their concentrates all serve as sources of the two marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as do some products from algae.
To demonstrate an effect of EPA + DHA on heart health, a number of randomized, controlled intervention studies with clinical endpoints like overall mortality or a combination of adverse cardiac events were conducted in populations with elevated cardiovascular risk. One early intervention study with oily fish, rich in EPA + DHA, and some early studies with fish oil or fish oil concentrate or even purified EPA at doses ranging between 0.9 and 1.8 g/day indeed demonstrated effects in terms of fewer sudden cardiac deaths, fatal or non-fatal myocardial infarctions, or a combination of adverse cardiac events.

Recent meta-analyses found no significant benefits on total mortality, cardiovascular mortality, and other adverse cardiac or cardiovascular events [13–18]. This is in contrast to findings in epidemiologic studies, where intake of EPA + DHA had been found to correlate generally with an up to 50% lower incidence of adverse cardiac events [18,19], and in even sharper contrast to epidemiologic studies based on levels of EPA + DHA, demonstrating e.g., a 10-fold lower incidence of sudden cardiac death associated with high levels of the
fatty acids, as compared to low levels.

This seemingly contradictory evidence has led the American Heart Association to recommend “omega-3 fatty acids from fish or fish oil capsules (1 g/day) for cardiovascular disease risk reduction” for secondary prevention, whereas the European Society for Cardiology recommends “Fish at least twice a week, one of which to be oily fish”, but no supplements for cardiovascular prevention.

A similar picture emerges for atrial fibrillation: In epidemiologic studies, consumption of EPA + DHA or higher levels of EPA + DHA were associated with lower risk for developing atrial fibrillation, while intervention studies found no effect. Pertinent guidelines do not mention EPA + DHA. A similar picture also emerges for severe ventricular rhythm disturbances.

Why is it that trial results are at odds with results from epidemiology? What needs to be done to better translate the epidemiologic findings into trial results? The current review will try to shed some light on this  issue, with a special consideration of the Omega-3 Index.

Recent large trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the cardiovascular field did not demonstrate a beneficial effect in terms of reductions of clinical endpoints like

• total mortality,
• sudden cardiac arrest or
• other major adverse cardiac events.

Pertinent guidelines do not uniformly recommend EPA + DHA for cardiac patients. In contrast,

• in epidemiologic findings, higher blood levels of EPA + DHA were consistently associated with a lower risk for the endpoints mentioned.

The following points argue for the use of erythrocytes: erythrocyte fatty acid
composition has a low biological variability, erythrocyte fat consists almost exclusively of phospholipids, erythrocyte fatty acid composition reflects tissue fatty acid composition, pre-analytical stability, and other points.  In 2004, EPA + DHA in erythrocyte fatty acids were defined as the Omega-3 Index and suggested as a risk factor for sudden cardiac death [39]. Integral to the definition was a specific and standardized analytical procedure, conforming the quality management routinely implemented in the field of clinical chemistry.

The laboratories adhering to the HS-Omega-3 Index methodology perform regular proficiency testing, as mandated in routine Clinical Chemistry labs. So far, the HS-Omega-3 Index is the only analytical procedure used in several laboratories. A standardized analytical procedure is a prerequisite to generate the data base necessary to transport a laboratory parameter from research into clinical routine. Moreover, standardization of the analytical procedure is the first important criterion for establishing a new biomarker for cardiovascular risk set forth by the American Heart Association and the US Preventive Services Task Force.

Because of low biological and analytical variability, a standardized analytical procedure, a large database and for other reasons,

• blood levels of EPA + DHA are frequently assessed in erythrocytes, using the HS-Omega-3 Index methodology.

Table 1. Mean HS-Omega-3 Index values in various populations, Mean (±standard deviation (SD)). Please note that in every population studied, a lower value was found to be associated with a worse condition than a higher value. References are given, if not, unpublished, n = number of individuals measured.

All levels of fatty acids are determined by the balance of substance entering the body and those leaving the body. Neither a recent meal, even if rich in EPA + DHA, nor severe cardiac events altered the HS-Omega-3 Index. However, while long-term intake of EPA + DHA, e.g., as assessed with food questionnaires, was the main predictor of the HS-Omega-3 Index, long-term intake explained only 12%–25% of its variability. A hereditary component of 24% exists. A number of other factors correlated positively (+) or negatively (−), like age (+), body mass index (−), socioeconomic status (+), smoking (−), but no other conventional cardiac risk factors. More factors determining the level of the HS-Omega-3 Index, especially regarding efflux remain to be  defined. Therefore, it is impossible to predict the HS-Omega-3 Index in an individual, as it is impossible to predict the increase in the HS-Omega-3 Index in an individual in response to a given dose of EPA + DHA. In Table 2, current evidence is presented on the relation of the HS-Omega-3 Index to CV events.

The HS-Omega-3 Index has made it possible to reclassify individuals from intermediate cardiovascular risk into the respective high risk and low risk strata, the third criterion for establishing a new biomarker for CV  risk.

A low Omega-3 Index fulfills the current criteria for a novel cardiovascular risk factor.

Increasing the HS-Omega-3 Index by increased intake of EPA + DHA in randomized controlled trials improved a number of surrogate parameters for cardiovascular risk:

1. heart rate was reduced,
2. heart rate variability was increased,
3. blood pressure was reduced,
4. platelet reactivity was reduced,
5. triglycerides were reduced,
6. large buoyant low-density lipoprotein (LDL)-particles were increased and
7. small dense LDL-particles were reduced,
8. large buoyant high-density lipoproteins (HDL)2 were increased,
9. very low-density lipoprotein (VLDL1) + 2 was reduced,
10. pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-1β, interleukins-6,8,10 and monocyte chemoattractant protein-1) were reduced,
11. anti-inflammatory oxylipins were increased.

Importantly, in a two-year randomized double-blind angiographic intervention trial, increased erythrocyte EPA + DHA

• reduced progression and increased regression of coronary lesions, an intermediate parameter.

Taken together, increasing the HS-Omega-3 Index improved surrogate and intermediate parameters for cardiovascular events. A large intervention trial with clinical endpoints based on the HS-Omega-3 Index remains to be conducted. Therefore, the fourth criterion, proof of therapeutic consequence of determining the HS-Omega- Index, is only partially fulfilled.

 

Neutral results of intervention trials can be explained by issues of bioavailability and trial design that surfaced after the trials were initiated.

In the future, incorporating the Omega-3 Index into trial designs by

1. recruiting participants with a low Omega-3 Index and
2. treating them within a pre-specified target range (e.g., 8%–11%),
3. will make more efficient trials possible and
   • provide clearer answers to the questions asked than previously possible.

 

3. Stem Cells and Regenerative Biology

Adult Stem Cells Reverse Muscle Atrophy In Elderly Mice   http://www.science20.com/profile/news_staff

Bioengineers at the University of California, Berkeley in a new study published in Nature say they have identified two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue. They then tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice’s much younger counterparts. Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), led the research team conducting this study. Because the findings relate to adult stem cells that reside in existing tissue, this approach to rejuvenating degenerating muscle eliminates the ethical and medical complications associated with transplanting tissues grown from embryonic stem cells. The researchers focused on

• the interplay of two competing molecular pathways that control the stem cells,

which sit next to the mature, differentiated cells that make up our working body parts. When the mature cells are damaged or wear out, the stem cells are called into action to begin the process of rebuilding.

old muscle tissue is left with

 

 

 

 

 

 

 

 

 

 

 

 

“We don’t realize it, but as we grow our bodies are constantly being remodeled,” said Conboy. “We are constantly falling apart, but we don’t notice it much when we’re young because we’re always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs.” The good news, the researchers said, is that

• the stem cells in old tissue are still ready and able to perform their regenerative function
• if they receive the appropriate chemical signals.

Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again. “Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice,” said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering.

• Adult stem cells have a receptor called Notch that, when activated,
• tells them that it is time to grow and divide
• stem cells also have a receptor for the protein TGF-beta
• that sets off a chain reaction activatingthemoleculepSmad3 and
  • ultimately producing cyclin-dependent kinase (CDK) inhibitors, which regulate the cell’s ability to divide.
• activated Notch competeswithactivatedpSmad3 for
  • binding to the regulatory regions of the same CDK inhibitors in the stem cell

“We found that Notch is capable of physically kicking off pSmad3 from the promoters for the CDK inhibitors within the stem cell’s nucleus, which tells us that a precise manipulation of the balance of these pathways would allow the ability to control stem cell responses.” Notch and TGF-beta are well known in molecular biology, but Conboy’s lab is the first to connect them to the process of aging, and the first to show that they act in opposition to each other within the nucleus of the adult stem cell. Aging and the inevitable march towards death are, in part, due to the progressive decline of Notch and the increased levels of TGF-beta , producing a one-two punch to the stem cell’s capacity to effectively rebuild the body, the researchers said.

The researchers disabled the “aging pathway” that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3. The researchers then examined the muscle of the different groups of mice one to five days after injury to compare how well the tissue repaired itself. As expected,

•  muscle tissue in the young mice easily replaced damaged cells with new, healthy cells. In contrast,
• the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue. However,
• muscles in the old mice whose stem cell “aging pathway”had been dampened showed levels of cellular regeneration that were
  • comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of “untreated” old mice.

Adult Stem Cells To Repair Damaged Heart Muscle

http://www.science20.com/profile/news_staff

In the first trial of its kind in the world, 60 patients who have recently suffered a major heart attack will be injected with selected stem cells from their own bone marrow during routine coronary bypass surgery. The Bristol trial will test

• whether the stem cells will repair heart muscle cells damaged by the heart attack,
• by preventing late scar formation and hence impaired heart contraction.

“ Cardiac stem cell therapy aims to repair the damaged heart as it has the potential to replace the damaged tissue.” We have elected to use a very promising stem cell type selected from the patient’s own bone marrow. This approach ensures no risk of rejection or infection. It also gets around the ethical issues that would result from use of stem cells from embryonic or foetal tissue.

In this trial (known as TransACT), all patients will have bone marrow harvested before their heart operation. Then either stem cells from their own bone marrow or a placebo will be injected into the patients’ damaged hearts during routine coronary bypass surgery. The feasibility and safety of this technique has already been demonstrated. As a result of the chosen double blind placebo-controlled design, neither the patients nor the surgeon knows whether the patient is going to be injected with stem cells or placebo. This ensures that results are not biased in any way, and is the most powerful way to prove whether or not the new treatment is effective.

Research of Stem Cells Repair Damaged Heart

By Kelvinlew Minhan | March 26th 2008

Under highly specific growth conditions in laboratory culture dishes, stem cells

• can be coaxed into developing as new cardiomyocytes and vascular endothelial cells (Kirschstein and Skirboll, 2001).

Discoveries that have triggered the interest in the application of adult stem cells to heart muscle repair in animal models have been made by researchers in the past few years (Kirschstein and Skirboll, 2001). One  study demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow (Kirschstein and Skirboll, 2001). These cells were transplanted into the marrow of irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack thru tying off different major heart blood vessel, the left anterior descending (LAD) coronary artery. The survival rate was 26 percent at two to four weeks after the induced cardiac injury (Kirschstein and Skirboll, 2001). Another study of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells (Kirschstein and Skirboll, 2001).

• the mouse hematopoietic stem cells transplanted into the bone marrow had migrated to the border part of the damaged area, and differentiated into several types of tissue for cardiac repair.

Regenerating heart tissue through stem cell therapy

http://www.mayo.edu/research/discoverys-edge/regenerating-heart-tissue-stem-cell-therapy

Summary

A groundbreaking study on repairing damaged heart tissue through stem cell therapy has given patients hope that they may again live active lives. An international team of Mayo Clinic researchers and collaborators has done it by discovering a way to regenerate heart tissue.

“It’s a paradigm shift,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine and senior investigator of the stem cell trial. “We are moving from traditional medicine, which addresses the symptoms of disease to cure disease.” Treating patients with cardiac disease has typically involved managing heart damage with medication.  In collaboration with European researchers, Mayo Clinic researchers have discovered a novel way to repair a damaged heart. In Mayo Clinic’s breakthrough process,

• stem cells are harvested from a patient’s bone marrow.
•  undergo a laboratory treatment that guides them into becoming cardiac cells,
• which are then injected into the patient’s heart in an effort to grow healthy heart tissue.

The study is the first successful demonstration in people of the feasibility and safety of transforming adult stem cells into cardiac cells. Beyond heart failure, the Mayo Clinic research also is a milestone in the emerging field of regenerative medicine, which seeks to fully heal damaged tissue and organs.

Creating a heart repair kit

This image shows the process used in the clinical trials to repair damaged hearts. Cardioprogenitor cells is another term for cardiopoietic cells, those that were transformed into cardiac cells.

Transformation: The cardiopoietic cells on the left react to the cardiac environment, cluster together with like cells and form tissue.

 Mayo Clinic researchers pursued this research, inspired by an intriguing discovery. In the early 2000s, they analyzed stem cells from 11 patients undergoing heart bypass surgery. The stem cells from two of the patients had an unusually high expression of certain transcription factors — the proteins that control the flow of genetic information between cells. Clinically, the two patients appeared no different from the others, yet their stem cells seemed to show unique capacity for heart repair.

That observation drove them to  determine how to convert  nonreparative stem cells to become reparative. Doing so required determining precisely how the human heart naturally develops, at a subcellular level. That painstaking work was led by Atta Behfar, M.D., Ph.D., a cardiovascular researcher at Mayo Clinic in Rochester, Minn. With other members of the Terzic research team, Dr. Behfar identified hundreds of proteins involved in the process of heart development (cardiogenesis). The researchers then set out to identify which of these proteins are essential in driving a stem cell to become a cardiac cell. Using computer models,

• they simulated the effects of eliminating proteins one by one from the process of heart development.
• That method yielded about 25 proteins.
  • The team then pared that number down to 8 proteins that their data indicated were essential.

The research team was then able to develop the lab procedure that guides stem cells to become heart cells.

The treated stem cells were dubbed cardiopoietic, or heart creative. A proof of principle study about guided cardiopoiesis, whose results were published in the Journal of the American College of Cardiology in 2010, demonstrated that animal models with heart disease that had been injected with caridiopoietic cells had improved heart function compared with animals injected with untreated stem cells. Hailed as “landmark work,” by the journal’s editorial writer, the study showed it was indeed possible to teach stem cells to become cardiac cells. Stem cells from each patient in the cardiopoiesis group were successfully guided to become cardiac cells. The treated cells were injected into the heart wall of each of those patients without apparent complications.
“Ihis newprocessofcardiopoiesiswas achieved in 100 percent of cases, with a very good safety profile,” Dr.Terzic says. “We are enabling the heart toregainitsinitial structure and function,” Dr.Terzic says, “and we will not stop here.” The clinicaltrialfindingsareexpectedto be published in the Journal of the American College of Cardiology in 2013.  Meanwhile, research to improve the injection process and effectiveness is underway.

Stem Cells from Humans Repair Heart Damage in Monkeys

• Kevin Mayer

GEN News Highlights  May1, 2014

implanted graft of cardiac cells derived from human stem cells (green)

Regeneration of the heart by 4 different classes of proteins

Stem cells have shown promise in small-animal models, that is, in mice and rats. Still, it was unclear whether human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) could be produced in adequate numbers, and cryopreserved with sufficient viability, to even approach human application In a step up from small-animal models, scientists at the University of Washington used a monkey model of myocardial infarction to test how well hESC-CMs could replace damaged tissue with new heart cells and restore failing hearts to normal function. The scientists injected 1 billion heart muscle cells derived from hESC-CMs into the infarcted muscle of pigtail macaques (Macaca nemestrina). This was 10 times more of these types of cells than researchers have ever been able to generate before.

The researchers found that over subsequent weeks, the stem-cell derived heart muscle cells infiltrated into the damaged heart tissue, then matured, assembled into muscle fibers, and began to beat in synchrony with the macaque heart cells. After three months, the cells appeared to have fully integrated into the macaque heart muscle. The research team published its results April 30 in Nature, in an article entitled “Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.” In this article, the authors indicated that their work demonstrated that

• hESCs can be grown,
• differentiated into cardiomyocytes, and
• cryopreserved at a scale sufficient to treat a large-animal model of myocardial infarction.

“With further refinements in manufacturing, the scale up to trials in humanpatientsseemsfeasible,” the researchers wrote. “Large-animal models are important forerunners to human trials, because they impart real-world rigor to issues such as cell production, delivery, and end-point analyses, while permitting mechanistic studies not possible in patients.”

Molecule Implicated In Leukemia Also Important In Muscle Repair

http://www.science20.com/profile/news_staff

The study shows that immature muscle cells require the molecule, called miR-29, to become mature, and that

• the molecule is nearly missing in cells from rhabdomyosarcoma, a cancer caused by the proliferation of immature muscle cells.

Cells from human rhabdomyosarcoma tumors showed levels of the molecule that were

• 10 percent or less of those in normal muscle cells.
• Artificially raising the level of the molecule in the cancer cells
  • cut their growth by half and caused them
  • to begin maturing, slowing down tumor growth.

MiR-29 is a type of microRNA, a family of molecules that helps regulate the proteins cells produce. Researchers say this study is unusual because
it also sheds light on the how a microRNA itself is regulated.

• The gene for miR-29 is silenced by the action of a protein, called NF kappa B.
•  this protein is present at highlevelsinrhabdomyosarcoma cells, and
  • this keeps miR-29 shut off,
  • preventing muscle progenitor cells from maturing.

When they raised the level of the microRNA molecule in the cells,

• or lowered the level of the NF kappa B protein,
  • the cells’ growth rate dropped two fold, and

they began taking on the appearance of mature muscle cells.

4. Drug Discovery

GPCR Insights Brighten Drug Discovery Outlook

Ken Doyle, Ph.D.

GEN Apr 15, 2014 (Vol. 34, No. 8)

Recent years have seen major advances in understanding the structure-function relationships of G protein-coupled receptors (GPCRs). This large superfamily of transmembrane receptors comprises over 800 members in humans.

GPCRs regulate a wide variety of physiological processes including

• sensation (vision, taste, and smell),
• growth,
• hormone responses, and
• regulation of the immune and
• autonomic nervous systems.

Their involvement in multiple disease pathways makes GPCRs attractive targets for drug discovery efforts.

These multifaceted proteins will be the subject of “GPCR Structure, Function and Drug Discovery,” a Global Technology Community conference scheduled to take place May 22–23 in Boston. The conference is expected to cover a broad range of topics including biased signaling, membrane protein structures, GPCR signaling dynamics, computational approaches to disease.

According to Bryan Roth, M.D., Ph.D., Michael Hooker Distinguished Professor at the University of North Carolina, Chapel Hill,

• drugs that can selectively target various downstream GPCR pathways hold the most promise.

Dr. Roth’s laboratory studies approximately 360 different GPCRs with therapeutic potential using massively parallel screening methods. His research focuses on “functional selectivity,” which he describes as

• “the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor.”

Dr. Roth notes that structural data have demonstrated that GPCRs exist in multiple conformations: “The structures of the 5-hydroxytryptamine 2B receptor and the recent high-resolution delta-opioid receptor structure have provided evidence for conformational rearrangements that contribute to functional selectivity.” Drugs that take advantage of this selectivity by preferentially stabilizing certain conformations may have unique therapeutic utility.

“Generally, we look at G protein versus arrestin-based signaling, although it’s also possible to examine how drugs activate one G protein-mediated signaling pathway versus another.

 

fluorescently tagged Arrestin and GPRC of interest

 

 

 

 

 

 

 

• β-Arrestins constitute a major class of intracellular scaffolding proteins that regulate GPCR signaling by preventing or enhancing the binding of GPCRs to intracellular signaling molecules. Laura Bohn, Ph.D., associate professor at Scripps Florida,  studies the roles that β-arrestins play in GPCR-mediated signaling.
• a particular β-arrestin can play multiple, tissue-specific roles—shutting down the signaling of a receptor in one tissue while activating signaling in another.
• different ligands can direct GPCR signaling to different effectors, which could result in different physiological effects,” comments Dr. Bohn. “Our challenge is in determining what signaling pathways to harness to promote certain effects, while avoiding others.”

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

 

 

 

 

 

 

 

 

 

 

 

Using Designer Proteins

The multifunctional signaling abilities of β-arrestins has prompted large-scale study of their properties. Vsevolod Gurevich, Ph.D., professor of pharmacology at Vanderbilt University, studies

1. the structure,
2. function, and
3. biology of arrestin proteins.

β-arrestins have three main functions.

1. First, they prevent the coupling of GPCRs to G proteins, thereby blocking further G protein-mediated signaling (a process known as desensitization).
2. Second, the binding of a GCPR releases the β-arrestin’s carboxy-terminal “tail” and promotes internalization of the receptor.
3. Third, receptor-bound β-arrestins bind other signaling proteins, resulting in a second wave of arrestin-mediated signaling.

Dr. Gurevich’s laboratory studies β-arrestin biology through the use of three types of specially designed mutants—

1. enhanced phosphorylation-dependent,
2. receptor-specific, and
3. signaling-biased mutants.

an enhanced mutant of visual β-arrestin-1 partially compensates for defects of rhodopsin phosphorylation in vivo,

“Several congenital disorders are caused by mutant GPCRs that cannot be normally phosphorylated because they have lost GPCR kinase (GRK) sites. Enhanced super-active arrestins have the potential to compensate for these defects, bringing the signaling closer to normal.”

• Dr. Gurevich explains the strategy involved in creating designer β-arrestins: “We identify residues critical for individual β-arrestin functions by mutagenesis, using limited structural information as a guide.
• We also work on getting more structural information. In collaboration with different crystallographers, we solved the crystal structures of all four vertebrate β-arrestin subtypes in the basal state, as well as the structure of the arrestin-1-rhodopsin complex.”
• Dr. Gurevich believes that designer β-arrestins “are the next step in research and therapy, moving way beyond what small molecules can achieve.
• The difference in capabilities between redesigned signaling proteins, including β-arrestins, and conventional small molecule drugs is about the same as that between airplanes and horse-driven carriages.”
• Dr. Gurevich observes that redesigned signaling proteins face considerable obstacles in terms of gene delivery, but that the efforts are worth it. “Using designer signaling proteins, we can tell the cell what to do in a language it cannot disobey,” asserts Dr. Gurevich.

Synthesis and Antihypertensive Screening of Novel Substituted 1,2- Pyrazoline Sulfonamide Derivatives

Avinash M. Bhagwat , Anilchandra R. Bha , Mahesh S. Palled , Anand P. Khadke , Anuradha M. Patil, et al.

Am. J. PharmTech Res. 2014; 4(2).    http://www.ajptr.com/ 

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension, diabetic nephropathy and congestiveheart failure. These substances are AT1-receptor antagonists which

• block the activationof angiotensin II AT1 receptors.

Blockade of AT1 receptors directly causes

1 vasodilation,

2 reduces secretion of vasopressin,

3 reduces production and secretion of aldosterone, amongst other actions –

4 the combined effect of which is reduction of blood pressure.

Irbesartan is a safe and effectiveangiotensin II receptor antagonist with an affinity for the AT1 receptor that is more than 8,500times greater than its affinity for AT2 receptor. This agent has a higher bioavailability (60-80%) than other drugs in its class . In both Losartan and Irbesartan structures imidazole moiety is being present. A structure analog of losartan and Irbesartan are designed by incorporating the heterocycles like pyrazoline group. We felt it would be interesting to explore the possibilities of 1,2-pyrazoline derivatives for Angiotensin II receptor antagonistic activity.

The Irbesartan structure was a modified Losartan structure, which had all the identity of a Losartan molecule but with groups that would fit the hydrophobic cavity with a tetramethylene group and an alkyl side chain that would fit in the pocket in the AT1 receptor. The hydroxyl methyl group of Losartan being replaced with carbonyl group of Irbesartan. With a view to introduce a hydrogen bonding interaction with AT1 receptor, these structures were further modified with a view of retaining both hydrogen bonding characteristics and as well as lipophilic groups. Losartan and Irbesartan structure contains a diphenyl molecule & imidazole ring.

In Losartan and Irbesartan diphenyl molecule is attached to the nitrogen of the imidazole ring. It is interesting to to see the activity of compounds containing two phenyl rings attached at two different positions namely3,5 position of 1, 2-pyrazoline ring. The sulphonamide derivatives known for its diuretics activity which reduces renal hypertension. We use to synthesize sulphonamide and pyrazoline in one molecule to check its possible Angiotensin II receptor antagonist property. For this reason chalcones were synthesized reacted with hydrazine hydrate to yield the corresponding 1,2-pyrazoline derivatives which further condensed with sulphanilamide and formaldehyde by mannich condensation reaction.

Acute Toxicity Study (LD50)

This study was carried out in order to establish the therapeutic and toxic doses of the newly synthesized 1,2 pyrazoline derivatives. To establish LD50 of these compounds the method described by Miller & Tainter was employed.

We report new 1,2 pyrazolines which defined combination of substituents confers appropriate polarity and charge distribution for good activity. The spectral data of compounds confirms the structures.

We also report various derivatives of 1,2 pyrazolines from Chalcones to achieve the promising and selective inhibition. The synthesized 1,2 pyrazoline derivatives have resemblance to some of Angiotensin II blocking agents like Irbesartan and Losartan. Hence it was thought of carrying out Angiotensin II blocking screening by 1K-1C Goldblatt noninvasive blood pressure measurement method. As a result, the screened compounds have shown significant Angiotensin II blocking activity. Irbesartan was used as the standard drug for Angiotensin II blocking activity.
Compounds synthesized have shown the significant Angiotensin II blocking activity when compared with the control but however are not comparable to the standard Irbesartan. The results were calculated by taking mean SE and finding the ‘P’ values. Hence from the SAR studies the chloro substituted compounds PH-2 and PH-7 exhibit better Angiotensin II blocking activityamongst the synthesized compounds. The structures of all the synthesized compounds were established on the basis of M.P., TLC, IR, NMR (PMR) . The compounds synthesized were found to be non-toxic and could be synthesized in good yields. The active compounds could be taken as lead for structural and molecular modification was thought of in future.

The present work, which was undertaken is a bonafide and novel work on the synthesis of 1,2 pyrazoline derivatives. We have made an attempt in reviewing the literature on 1,2 pyrazoline derivatives for their medicinal uses with the help of chemical abstract, journals and internet surfing. For the synthesis of 1,2 pyrazoline derivatives scheme were established. Around eight derivatives were synthesized. The synthesized compounds were tested for their purity, preliminary tests, physical constants and TLC. The structure of the final compound were confirmed by IR, H-NMR spectra and GCMS. The compounds synthesized were found to be non-toxic and could be synthesized in good yields.

5. Synthetic Biology

Artists and biologists team up to ush boundaries of synthetic biology

Kenrick Vezina | May 1, 2014 | Genetic Literacy Project

Synthetic biologists are often accused of “playing God,” of tampering with his Creation. Well, if you’re going to Create then you might as well do so with the help of some creative individuals? That’s just what the biologists in the pages of the new book Synthetic Aesthetics, from MIT Press, aims to do. Its arrival is well-timed, with the

first synthetic yeast chromosome having been created last month amid a flurry of scientific milestones in biotechnology.

Alun Anderson has reviewed the new book for New Scientist. Unlike the typically defensive posture found in biotech broadly, he writes, the spirit captured by this book is “freewheeling” and collaborative, with 20 authors ranging from the arts and sciences putting their minds together to generate original ideas. Anderson notes that parts of the book “may irritate conventional scientists – some of the ideas were dreamed up while ‘performing a dance based on the myth of the Golem’, for example. But it certainly explains the key ideas of the field and leads you to many lateral conversations about what it may become.” The book is itself an offshoot of a larger project, which you can check out at its official page. It describes itself as an “experimental, international research project between synthetic biology, art, design and social science” It has roots at the University of Edinburgh, Scotland, and Stanford University, California. And the main project team is comprised of bioengineers Drew Endy (Stanford) and Alistair Elfick (Edinburgh), social scientists Jane Calvert (Edinburgh) and Pablo Schyfter (Edinburgh), and designer/artist Alexandra Daisy Ginsberg.

In the book Synthetic Aesthetics, Ginsberg provides a thought-provoking counterpoint to the engineering definition of “design”.  Anderson explains in his review: An engineer might think of designing a bridge to a particular specification; a synthetic biologist of designing a microorganism with a new commercial application, pumping out green gasoline for example; but a real designer, a fashion designer, for example, is doing something else. As artist Daisy Ginsberg puts it, design “is about possibility”, the unimagined things that life could be.

Synthetic biology, she writes, has been addressing “humanity’s needs” – limitless fuel, for example – rather than “our needs as individual, diverse and complex humans”.  This is refreshing: worries about the separation between the top-down design of the future and those who must live with the results are quite rare in science. These words ring true, given the intensely “problem oriented” approach to most synthetic biology research. This approach extends to the coverage of this research in the media, where even a research achievement with sweeping potential like the synthetic yeast chromosome ends up broken down into pragmatic chunks. (Yeast could mass-produce medicines! Help process fuels!) Alistair Elfick, one of the leads on the Synthetics Aesthetics project, has written a fascinating opinion piece at The Conversation to accompany the release of his book. In it, he puts forth the idea it’s time for synthetic biologists to stop thinking “like scientists,” lest they hamstring themselves.

Kenrick Vezina is Gene-ius Editor for the Genetic Literacy Project and a freelance science writer, educator, and naturalist based in the Greater Boston area. Sources:

•  ”Synthetic biology gets reborn as an aesthetic dream,” Alun Anderson | New Scientist
• “If synthetic biologists think like scientists, they may miss their eureka moment,” Alistair Elfick | The Conversation
• Synthetic Aesthetics project

• “Breakthrough biology: First synthetic chromosome for yeast created, capping month of biotech innovations,” Kenrick Vezina | Genetic Literacy Project

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

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

Posted in Coagulation Therapy and Internal Bleeding, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, tagged Dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation on May 10, 2014| Leave a Comment »

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

Curator: Aviva Lev-Ari, PhD, RN

WordCloud by Zach Day; Article Title: Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

Updated on 9/30/2022

PROACT Xa Trial of Apixaban With On-X Heart Valve Stopped

Megan Brooks, September 29, 2022

Artivion Inc. has halted the PROACT Xa clinical trial that was testing whether patients with an On-X mechanical aortic valve could be safely and effectively managed with the direct oral anticoagulant (DOAC) apixaban (Eliquis) rather than warfarin.

The decision to stop the trial was based on the recommendation of the independent data and safety monitoring board (DSMB), which cited a lack of evidence supporting noninferiority of apixaban over warfarin for valve thrombosis and thromboembolism.

Currently, warfarin is the only approved anticoagulant for patients with mechanical valves.

In the PROACT Xa trial, which began enrollment in April 2020, patients with an On-X mechanical aortic valve were randomly allocated to receive anticoagulation with warfarin or apixaban.

“The DSMB found that blood clots, resulting in stroke, occurred more frequently in patients receiving apixaban and that continuing the trial was unlikely to achieve the primary endpoint while possibly exposing patients to increased risk,” Artivion said in a statement.

“The PROACT Xa trial was designed to determine whether apixaban would yield equivalent safety to the standard anticoagulant, warfarin. Unfortunately, it appears that it does not,” John Alexander, MD, chair of the PROACT Xa trial and professor of medicine/cardiology at Duke University School of Medicine, Durham, North Carolina, said in the statement.

SOURCE

https://www.medscape.com/viewarticle/981644?src=WNL_mdpls_220930_mscpedit_card&uac=93761AJ&spon=2&impID=4698929

 

@@@@

During the past 20 years, the approval of anticoagulants such as low-molecular-weight heparins (LMWHs), indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, bivalirudin, lepirudin, and desirudin) has signaled a growing interest in antithrombotic compounds that have relatively discrete targets within the coagulation pathway. Although these medications offer several potential advantages over unfractionated heparin, they all require parenteral administration and are substantially more expensive than oral vitamin K antagonists (VKAs). Thus VKAs, despite disadvantages such as variability in dose response, a narrow therapeutic index, and numerous drug and dietary interactions, are the only option for most patients requiring chronic anticoagulation.

http://bloodjournal.hematologylibrary.org/content/115/1/15.full

Eliquis Approval History

• FDA approved: Yes (First approved December 28th, 2012)

• Brand name: Eliquis
• Generic name: apixaban
• Company: Bristol-Myers Squibb Company and Pfizer Inc.
• Treatment for: Prevention of Thromboembolism in Atrial Fibrillation, Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery, Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery

Eliquis (apixaban) is a factor Xa inhibitor anticoagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the prophylaxis of deep vein thrombosis (DVT) in patients who have undergone hip or knee replacement surgery.

FDA Approval History for Eliquis

Date	Article
Mar 18, 2014	FDA Approves Eliquis to Reduce Risk of Blood Clots Following Hip Or Knee Replacement Surgery
Jul 11, 2013	FDA Accepts Eliquis (apixaban) Supplemental New Drug Application for Review for Prophylaxis of Deep Vein Thrombosis Following Hip Or Knee Replacement Surgery
Dec 28, 2012	FDA Approves Eliquis to Reduce the Risk of Stroke, Blood Clots in Patients with Non-Valvular Atrial Fibrillation
Sep 26, 2012	FDA Acknowledges Receipt of Resubmission of the Eliquis (apixaban) New Drug Application to Reduce the Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation
Jun 25, 2012	Bristol-Myers Squibb and Pfizer Receive Complete Response Letter From U.S. Food and Drug Administration for Eliquis (Apixaban)
Mar  1, 2012	U.S. Food and Drug Administration Extends Action Date for Eliquis (apixaban) by Three Months
Nov 29, 2011	FDA Accepts Eliquis (apixaban) New Drug Application for Review for the Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation

http://www.drugs.com/history/eliquis.html 

Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation

Gregory Y.H. Lip, MD^?; Torben Bjerregaard Larsen, MD, PhD^†; Flemming Skjøth, PhD^†; Lars Hvilsted Rasmussen, MD, PhD^†

[+] Author Information

J Am Coll Cardiol. 2012;60(8):738-746. doi:10.1016/j.jacc.2012.03.019

Results  There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared with rivaroxaban, as well as hemorrhagic stroke and nondisabling stroke. There were no significant differences for apixaban versus dabigatran (both doses) or rivaroxaban; or rivaroxaban versus dabigatran 110 mg BID in preventing stroke and systemic embolism. For ischemic stroke, there were no significant differences between the new OACs. Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (by 26%) and rivaroxaban (by 34%), but not significantly different from dabigatran 110 mg BID. There were no significant differences between apixaban and dabigatran 110 mg BID in safety endpoints. Apixaban also had lower major or clinically relevant bleeding (by 34%) compared with rivaroxaban. When compared with rivaroxaban, dabigatran 110 mg BID was associated with less major bleeding (by 23%) and intracranial bleeding (by 54%). There were no significant differences in myocardial infarction events between the dabigatran (both doses) and apixaban.

Conclusions  Notwithstanding the limitations of an indirect comparison study, we found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. Dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Only a head-to-head direct comparison of the different new OACs would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.

http://content.onlinejacc.org/article.aspx?articleid=1182715

Clinical trials with new oral anticoagulants

Journal:	Hämostaseologie
ISSN:	0720-9355
Topic:	57. Jahrestagung der Gesellschaft für Hämostase- und Thromboseforschung e.V. HÄMOSTASEOLOGIE INTERDISZIPLINÄR
DOI:	http://dx.doi.org/10.5482/HAMO-12-11-0021
Issue:	Issues of 2013 (Vol. 33): Issue 1 2013 (1-76)
Pages:	62-70

New Eliquis® (apixaban) Post-hoc Subanalysis of the Phase III ARISTOTLE trial Demonstrated that within 30 Days of a Procedure, Stroke or Systemic Embolism and Major Bleeding were Uncommon –

About ARISTOTLE

The ARISTOTLE study was designed to demonstrate the efficacy and safety of Eliquis versus warfarin for the prevention of stroke or systemic embolism. In ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis and 9,081 to warfarin). ARISTOTLE was an active-controlled, randomized, double-blind, multi-national trial in patients with nonvalvular atrial fibrillation or atrial flutter, and at least one additional risk factor for stroke. Patients were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, representing 4.7 percent of all patients) or warfarin (target INR range 2.0-3.0), and followed for a median of 1.8 years.

Results presented today at the ESC Congress 2013

“For NVAF patients for whom interruption of anticoagulation for a procedure is required, these findings suggest that using apixaban instead of warfarin, which is more challenging to stop and restart, may simplify the management of peri-operative anticoagulation in NVAF patients.”

http://news.bms.com/press-release/partnering-news/new-eliquis-apixaban-post-hoc-subanalysis-phase-iii-aristotle-trial-de#sthash.39684mmp.dpuf

The new oral anticoagulants

1. David Garcia1,
2. Edward Libby1, and
3. Mark A. Crowther2
   1. ¹University of New Mexico, Albuquerque; and
   2. 
      
      ²McMaster University, Hamilton, ON

Apixaban

Phase 2 data for apixaban in the prevention and treatment of venous thromboembolism (VTE) suggested that this compound may be a safe and effective anticoagulant over a wide range of doses.^16,17 The first phase 3 orthopedic prophylaxis trial (ADVANCE-1) randomized 3195 patients, in double-blind fashion, to either apixaban (2.5 mg orally twice a day) or enoxaparin (30 mg subcutaneously every 12 hours). In both arms, treatments were begun 12 to 24 hours after surgery; all patients underwent venography approximately 2 weeks later. The proportion of patients who reached the primary endpoint (VTE, both symptomatic and venographically detected, or death from any cause) was similar for the apixaban (8.99%) and enoxaparin (8.85%) arms; however, the predetermined noninferiority endpoint was not met.⁷ It is unclear whether the failure to prove noninferiority can be explained by inaccurately low prestudy estimates of event rates, the dose/timing of apixaban, or some other cause. In any case, the comparable event rates (neither regimen was found superior to the other), along with less clinically relevant bleeding in the apixaban arm, strongly suggest that apixaban is an effective anticoagulant. Results from ADVANCE-2, a randomized double-blind multicenter trial comparing apixaban 2.5 mg orally twice a day with enoxaparin 40 mg subcutaneously once daily for preventing VTE after total knee replacement were presented at the congress of the International Society of Thrombosis and Hemostasis in July 2009. The primary efficacy outcome (all VTE) occurred in 147 of 976 evaluable patients (15.1%) in the apixaban group and 243 of 997 evaluable patients (24.4%) in the enoxaparin group (relative risk = 0.62; 95% confidence interval, 0.51-0.74, 1-sidedP < .001). A nonsignificant trend toward less clinically relevant bleeding also favored apixaban (53 patients, 3.5% vs 72 patients, 4.8%; P = .09).

A phase 3 study (AMPLIFY) of patients with acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) will compare apixaban (10 mg twice daily for 7 days, followed by apixaban 5 mg, twice daily for 6 months) to a standard strategy using enoxaparin followed by VKA. A phase 3 “extension” study will enroll patients for whom there is clinical uncertainty about whether to continue oral anticoagulation after 6 months of routine treatment with a VKA. Participants will be randomly assigned to receive 1 of 3 possible interventions for 12 months: placebo, apixaban 2.5 mg twice daily, or apixaban 5 mg twice daily. In both trials, the primary outcome measure will be a composite of symptomatic, objectively confirmed recurrent VTE or death during the treatment period.

The APPRAISE trial was a phase 2 dose-finding study in which 1700 patients were randomized to receive placebo or 1 of 4 apixaban doses for the 6 months after standard acute therapy for acute coronary syndrome.¹⁸ For patients receiving the 2 highest doses of apixaban, the trial was terminated prematurely because of excess bleeding. In this population of patients receiving one or more concomitant antiplatelet agents, the 2 lower-dose apixaban arms had higher rates of the primary endpoint (major bleeding plus clinically relevant nonmajor bleeding) than did the placebo group. The trial was not powered to detect a statistically significant difference in the rates in the composite efficacy endpoint of cardiovascular death, nonfatal heart attack, severe recurrent ischemia, and nonhemorrhagic stroke but showed trends favoring apixaban over placebo for these endpoints. A phase 3 trial (APPRAISE-2) comparing apixaban 5 mg twice daily versus placebo in this clinical setting is under way.

Finally, apixaban is being studied as a stroke prevention strategy for patients with atrial fibrillation (AF). When completed, the ARISTOTLE trial will randomize approximately 18 000 patients with chronic nonvalvular AF to apixaban 5 mg orally twice daily or warfarin, target international normalized ratio (INR) 2.0 to 3.0. This event-driven, double-blind, parallel arm study is designed to show that apixaban is noninferior to well-managed warfarin in the prevention of stroke or systemic embolism. In a different randomized, double-blind study (AVERROES), apixaban (5 mg orally twice daily) is being compared with aspirin (81-324 mg daily) among AF patients who have failed or are unsuitable for VKA treatment. This trial will include 5000 to 6000 patients; follow-up will be up to 36 months.

http://bloodjournal.hematologylibrary.org/content/115/1/15.full

Clinical Studies

Reduction Of Risk Of Stroke And Systemic Embolism In Nonvalvular Atrial Fibrillation

ARISTOTLE

Evidence for the efficacy and safety of ELIQUIS was derived from ARISTOTLE, a multinational, double-blind study in patients with nonvalvular AF comparing the effects of ELIQUIS and warfarin on the risk of stroke and non-central nervous system (CNS) systemic embolism. In ARISTOTLE, patients were randomized to ELIQUIS 5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 2 of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL) or to warfarin (targeted to an INR range of 2.0–3.0). Patients had to have one or more of the following additional risk factors for stroke:

• prior stroke or transient ischemic attack (TIA)
• prior systemic embolism
• age ≥ 75 years
• arterial hypertension requiring treatment
• diabetes mellitus
• heart failure ≥ New York Heart Association Class 2
• left ventricular ejection fraction ≤ 40%

The primary objective of ARISTOTLE was to determine whether ELIQUIS 5 mg twice daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS to warfarin was also examined for the primary endpoint (rate of stroke and systemic embolism), major bleeding, and death from any cause.

A total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. Forty-three percent of patients were vitamin Kantagonist (VKA) “naive,” defined as having received ≤ 30 consecutive days of treatment with warfarin or another VKA before entering the study. The mean age was 69 years and the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk) was 2.1. The population was 65% male, 83% Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 19% of patients. Concomitant diseases of patients in this study included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular ejection fraction ≤ 40%) 35%, and prior myocardial infarction14%. Patients treated with warfarin in ARISTOTLE had a mean percentage of time in therapeutic range (INR 2.0–3.0) of 62%.

ELIQUIS was superior to warfarin for the primary endpoint of reducing the risk of stroke and systemic embolism (Table 5 and Figure 4). Superiority to warfarin was primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs.

ELIQUIS also showed significantly fewer major bleeds than warfarin [seeADVERSE REACTIONS].

Table 5: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE (Intent-to-Treat Analysis)

	ELIQUIS  N=9120  N (%/YEAR)	WARFARIN N=9081 N (%/YEAR)	HAZARD RATIO (95% CI)	P-VALUE
Stroke or systemic embolism	212 (1.27)	265 (1.60)	0.79 (0.66, 0.95)	0.01
Stroke	199 (1.19)	250 (1.51)	0.79 (0.65, 0.95)
Ischemic without hemorrhage	140 (0.83)	136 (0.82)	1.02 (0.81, 1.29)
Ischemic with hemorrhagic conversion	12 (0.07)	20 (0.12)	0.60 (0.29, 1.23)
Hemorrhagic	40 (0.24)	78 (0.47)	0.51 (0.35, 0.75)
Unknown	14 (0.08)	21 (0.13)	0.65 (0.33, 1.29)
Systemic embolism	15 (0.09)	17 (0.10)	0.87 (0.44, 1.75)
The primary endpoint was based on the time to first event (one per subject). Component counts are for subjects with any event, not necessarily the first.

Figure 4: Kaplan-Meier Estimate of Time to First Stroke or Systemic Embolism in ARISTOTLE (Intent-to-Treat Population)

http://www.rxlist.com/eliquis-drug/clinical-pharmacology.htm

Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro : Comparison with direct inhibitors of factor VIIa, XIa and thrombin

P. C. Wong (1), X. Jiang (1)

(1) Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA

Keywords

Tissue factor, platelet aggregation, rivaroxaban, direct factor Xa inhibitor, dabigatran, Apixaban

Summary

Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development. This study evaluated the in vitro effect of apixaban on human platelet aggregation induced by thrombin derived via the extrinsic pathway. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for comparison. Citrated human platelets-rich plasma (PRP) was treated with 50 mg/ml corn trypsin inhibitor (to block the contact factor pathway) and 3 mM H-Gly-Pro-Arg-Pro-OH-AcOH (to prevent fibrin polymerisation). Human tissue factor (TF) (Innovin®; dilution 1:1,000 to 1:1,500) plus 7.5 mM CaCl2 was added to PRP pre-incubated with vehicle or increasing concentrations of inhibitors. The TF-induced platelet aggregation was measured by optical aggregometry. TF produced 85 ± 3% aggregation of human platelets in the vehicle-treated group (n=10). Apixaban and other factor inhibitors, except the FXIa inhibitor, inhibited TF-induced platelet aggregation with IC50 (nM) values as follows: 4 ± 1 (apixaban), 8 ± 2 (rivaroxaban), 13 ± 1 (BMS-593214), 46 ± 1 (dabigatran) and 79 ± 1 (argatroban). BMS-262084 (IC50 = 2.8 nM vs. human FXIa) had no effect on TF-induced platelet aggregation at 10 μM. These inhibitors at 10 μM had no effect on platelet aggregation induced by ADP and collagen, as expected from their mechanism of action. This study demonstrates that inhibition of thrombin generation by blocking upstream proteases (FVIIa and FXa) in the blood coagulation cascade is as effective as direct thrombin inhibition in preventing TF-induced platelet aggregation. Under these experimental conditions, a FXIa inhibitor did not prevent TF-induced platelet aggregation.

http://th.schattauer.de/en/contents/archive/issue/1099/manuscript/13269.html

Mechanism Of Action

Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombusdevelopment.

Pharmacodynamics

As a result of FXa inhibition, apixaban prolongs clotting tests such asprothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose, however, are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of apixaban.

The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on FXa activity in humans during the apixaban development program. A concentration-dependent increase in anti-FXa activity was observed in the dose range tested and was similar in healthy subjects and patients with AF.

This test is not recommended for assessing the anticoagulant effect of apixaban.

Pharmacodynamic Drug Interaction Studies

Pharmacodynamic drug interaction studies with aspirin, clopidogrel, aspirin and clopidogrel, prasugrel, enoxaparin, and naproxen were conducted. No pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel [see WARNINGS AND PRECAUTIONS]. A 50% to 60% increase in anti-FXa activity was observed when apixaban was coadministered with enoxaparin or naproxen.

Specific Populations

Renal impairment: Anti-FXa activity adjusted for exposure to apixaban was similar across renal function categories.

Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild-tomoderate hepatic impairment and healthy subjects. However, in patients with moderate hepatic impairment, there is no clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding. Patients with severe hepatic impairment were not studied.

Cardiac Electrophysiology

Apixaban has no effect on the QTc interval in humans at doses up to 50 mg.

Pharmacokinetics

Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.

http://www.rxlist.com/eliquis-drug/clinical-pharmacology.htm

The Lancet, Volume 383, Issue 9921, Pages 955 – 962, 15 March 2014

<Previous Article|Next Article>

doi:10.1016/S0140-6736(13)62343-0Cite or Link Using DOI

This article can be found in the following collections: Cardiology & Vascular Medicine (Ischaemic heart disease, Pericardial & endocardial disease); Neurology (Cerebrovascular disease, Neurology-other)

Published Online: 04 December 2013

Copyright © 2014 Elsevier Ltd All rights reserved.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials

Dr Christian T Ruff MD a , Robert P Giugliano MD a, Prof Eugene Braunwald MD a, Elaine B Hoffman PhD a, Naveen Deenadayalu MPH a, Prof Michael D Ezekowitz MBChB b c, Prof A John Camm MD d, Prof Jeffrey I Weitz MD e, Prof Basil S LewisMD f, Prof Alexander Parkhomenko MD g, Prof Takeshi Yamashita MD h, Prof Elliott M Antman MD a

a Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

b Jefferson Medical College, Philadelphia, PA, USA

c Cardiovascular Research Foundation, New York, NY, USA

d St George’s University, London, UK

e McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada

f Lady Davis Carmel Medical Center, Haifa, Israel

g Institute of Cardiology, Kiev, Ukraine

h The Cardiovascular Institute, Tokyo, Japan

 Correspondence to: Dr Christian T Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115, USA

Background

Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.

Methods

We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF—TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.

Findings

42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73—0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38—0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85—0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39—0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01—1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59—0·81 vs 0·93, 0·76—1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84—1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43—1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02—1·60; p=0·045).

Interpretation

This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk—benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.

Funding

None.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62343-0/abstract

HSR Proc Intensive Care Cardiovasc Anesth. 2013; 5(1): 40–54.

PMCID: PMC3670724

Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses

G Biondi-Zoccai,¹ V Malavasi,² F D’Ascenzo,³ A Abbate,⁴ P Agostoni,⁵ M Lotrionte,⁶ D Castagno,³ B Van Tassell,⁴ E Casali,² M Marietta,⁷ M G Modena,² K A Ellenbogen,⁴ and G Frati^1,8

 

Table 1

Introduction

Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta-analyses of novel oral anticoagulants for atrial fibrillation.

Methods

Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS.

Results

Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52-0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive.

Conclusions

Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation.

Keywords: apixaban, atrial fibrillation, dabigatran, meta-analysis, rivaroxaban, systematic review, warfarin

SOURCE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670724/

Source: Google images

Source: Google images

SOURCE: Google Images

SOURCE

Google Images

SOURCE

Google Images

SOURCE

Google Images

SOURCE

Google Images

REFERENCES

1.	Clinical trials with new direct oral anticoagulants Additive value of indirect comparisons (network meta-analyses)
	Free download of English version J. Harenberg (1), C. Weiss (2), S. Marx (1), S. Zolfaghari (1) Phlebologie 2013 42 3: 139-148 http://dx.doi.org/10.12687/phleb2146-3-2013
	2.	Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation An indirect comparison analysis
		Online Supplementary Material F. Skjøth (1, 2), T. B. Larsen (1, 2), L. H. Rasmussen (1, 2), G. Y. H. Lip (1, 3) Thromb Haemost 2014 111 5: 981-988 http://dx.doi.org/10.1160/TH14-02-0118
	3.	Vitamin K antagonists Ready to be replaced?
		J. Steffel (1), T. F. Luscher (1) Hämostaseologie 2012 32 4: 249-257 http://dx.doi.org/10.5482/ha-12050008

1. Roskell NS, Lip GY, Noack H et al. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate. Thromb Haemost 2010; 104: 1106-1115.DOI:10.1160/TH10-10-0642
2. Hart RG, Pearce LA, Aguilar MI. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med 2007; 147: 590-592.
3. Lip GY, Andreotti F, Fauchier L et al. Bleeding risk assessment and management in atrial fibrillation patients. Thromb Haemost 2011; 106: 997-1011. DOI:10.1160/TH11-10-0690
4. Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 th ed). Chest 2008; 133 (6 Suppl): 160S-198S. DOI:10.1378/chest.08-0670
5. Ogilvie IM, Newton N, Welner SA et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 638-645.DOI:10.1016/j.amjmed.2009.11.025
6. Tasker A, Harbord R, Bannister GC. Meta-analysis of low molecular weight heparin versus placebo in patients undergoing total hip replacement and post-operative morbidity and mortality since their introduction. Hip Int 2010; 20: 64-74.
7. Falck-Ytter Y, Francis CW, Johanson NA et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e278S-325S. DOI:10.1378/chest.11-2404
8. Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e495S-530S. DOI:10.1378/chest.11-2303
9. Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Hemost 2008; 34: 39-57. DOI:10.1055/s-2008-1066023
10. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.DOI:10.1056/NEJMoa0905561
11. Connolly SJ, Ezekowitz MD, Yusuf S et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363: 1875-1876.DOI:10.1056/NEJMc1007378
12. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.DOI:10.1056/NEJMoa1009638
13. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.DOI:10.1056/NEJMoa1107039
14. Glenny AM, Altman DG, Song F et al. Indirect comparisons of competing interventions. Health Technol Assess 2005; 9: 1-134.
15. Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med 2002; 21: 2313-2324. DOI:10.1002/sim.1201
16. Ades AE, Madan J, Welton NJ. Indirect and mixed treatment comparisons in arthritis research. Rheumatology 2011; 50 (Suppl 4): iv5-9.DOI:10.1093/rheumatology/ker241
17. Cooper NJ, Sutton AJ, Morris D et al. Addressing between-study heterogeneity and inconsistency in mixed treatment comparisons: application to stroke prevention treatments in individuals with nonrheumatic atrial fibrillation. Stat Med 2009; 28: 1861-1881.DOI:10.1002/sim.3594
18. Salanti G, Higgins JP, Ades AE, Ioannidis JP. Evaluation of networks of randomized trials. Stat Methods Med Res 2008; 17: 279-301.DOI:10.1177/0962280207080643
19. Jansen JP, Fleurence R, Devine B et al. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. Value Health. 2011; 14: 417-428.DOI:10.1016/j.jval.2011.04.002
20. Hoaglin DC, Hawkins N, Jansen JP et al. Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. Value Health 2011; 14: 429-437. DOI:10.1016/j.jval.2011.01.011
21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151: 264-269.
22. Harenberg J, Marx S, Diener HC et al. Comparison of efficacy and safety of dabigatran, rivaroxaban and apixaban in patients with atrial fibrillation using network meta-analysis. Int Angiol 2012; 31: 330-339.
23. Lip GY, Larsen TB, Skjøth F et al. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012; 60: 738-746.DOI:10.1016/j.jacc.2012.03.019
24. Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost 2012; 108: 476-484.DOI:10.1160/TH12-02-0093
25. Wells GA, Coyle D, Cameron C et al. Safety, effectiveness, and cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation. http://www.cadth.ca/media/pdf/NOAC_Therapeutic_Review_final_report.pdf (assessed Dec 22, 2012)
26. Harenberg J, Marx S, Wehling M. Head-to-head or indirect comparisons of the novel oral anticoagulants in atrial fibrillation: what’s next? Thromb Haemost 2012; 108: 407-409. DOI:10.1160/TH12-07-0463
27. Schneeweiss S, Gagne JJ, Patrick AR et al. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012; 5: 480-486.DOI:10.1161/CIRCOUTCOMES.112.965988
28. Camm AJ, Kirchhof P, Lip GY et al. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the European Society of Cardiology. Europace 2010; 12: 1360-1420.DOI:10.1093/europace/euq160
29. You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141: e531S-575S. DOI:10.1378/chest.11-2304
30. Harenberg J, Lip GY. Differences between indirect comparison studies of the oral anticoagulants for stroke prevention in atrial fibrillation: where do we go next? QJM 2013; 106: 95-96. DOI:10.1093/qjmed/hcs224
31. Testa L, Agnifili M, Latini RA et al. Adjusted indirect comparison of new oral anticoagulants for stroke prevention in atrial fibrillation. QJM 2012; 105: 949-957. DOI:10.1093/qjmed/hcs114
32. Miller CS, Grandi SM, Shimony A et al. Meta-analysis ofefficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012; 110: 453-460. DOI:10.1016/j.amjcard.2012.03.049
33. Dentali F, Riva N, Crowther M et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126: 2381-2391.DOI:10.1161/CIRCULATIONAHA.112.115410
34. Rasmussen LH, Larsen TB, Graungaard T et al. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis. BMJ 2012; 345: e7097.DOI:10.1136/bmj.e7097
35. Alonso-Coello P, Zhou Q, Guyatt G. Home-monitoring of oral anticoagulation vs. dabigatran. An indirect comparison. Thromb Haemost 2012; 108: 647-653. DOI:10.1160/TH12-01-0027
36. Trkulja V, Kolundzic R. Rivaroxaban vs dabigatran for thromboprophylaxis after joint-replacement surgery: exploratory indirect comparison based on meta-analysis of pivotal clinical trials. Croat Med J 2010; 51: 113-123.DOI:10.3325/cmj.2010.51.113
37. Lereun C, Wells P, Diamantopoulos A et al. An indirect comparison, via enoxaparin, of rivaroxaban with dabigatran in the prevention of venous thromboembolism after hip or knee replacement. J Med Econ 2011; 14: 238-244. DOI:10.3111/13696998.2011.564699
38. Loke YK, Kwok CS. Dabigatran and rivaroxaban for prevention of venous thromboembolism–systematic review and adjusted indirect comparison. J Clin Pharm Ther 2011; 36: 111-124. DOI:10.1111/j.1365-2710.2010.01162.x
39. Cohen A, Drost P, Marchant N et al. The Efficacy and Safety of Pharmacological Prophylaxis of Venous Thromboembolism Following Elective Knee or Hip Replacement: Systematic Review and Network Meta-Analysis. Clin Appl Thromb Hemost 2012; 18: 611-627.DOI:10.1177/1076029612437579
40. Dahl OE, Quinlan DJ, Bergqvist D et al. A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty. J Thromb Haemost 2010; 8: 1966-1975. DOI:10.1111/j.1538-7836.2010.03965.x
41. Maratea D, Fadda V, Trippoli S, Messori A. Prevention of venous thromboembolism after major orthopedic surgery: indirect comparison of three new oral anticoagulants. J Thromb Haemost 2011; 9: 1868-1870.DOI:10.1111/j.1538-7836.2011.04421.x
42. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ 2012; 344: e3675. DOI:10.1136/bmj.e3675
43. Harenberg J, Marx S, Dahl OE et al. Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery. Thromb Haemost 2012; 108: 903-912.DOI:10.1160/TH12-07-0482
44. Hamid JS, Meaney C, Crowcroft NS, Granerod J, Beyene J; UK Etiology of Encephalitis Study Group. Cluster analysis for identifying sub-groups and selecting potential discriminatory variables in human encephalitis. BMC Infect Dis 2010; 10: 364-374. DOI:10.1186/1471-2334-10-364
45. Song EK, Moser DK, Rayens MK, Lennie TA. Symptom clusters predict event-free survival in patients with heart failure. J Cardiovasc Nurs 2010; 25: 284-291.
46. McLachlan GJ. Cluster analysis and related techniques in medical research. Stat Methods Med Res 1992; 1: 27-48.DOI:10.1177/096228029200100103
47. Schulman S. Is the network meta-analysis (NETMA) bringing us closer to the truth? Insights from recent antithrombotic drug data. Thromb Haemost 2012; 108: 872-875. DOI:10.1160/TH12-10-0730
48. Fox BD, Kahn SR, Langleben D et al. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ 2012; 345: e7498. DOI:10.1136/bmj.e7498
49. Freeman JV, Zhu RP, Owens DK et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Int Med 2011; 154: 1-11.
50. Kansal AR, Sorensen SV, Gani R et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation. Heart 2012; 98: 573-578.DOI:10.1136/heartjnl-2011-300646
51. Lee S, Anglade MW, Pham D et al. Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol 2012; 110: 845-851. DOI:10.1016/j.amjcard.2012.05.011
52. Deitelzweig S, Amin A, Jing Y et al. Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Med Econ 2012; 15: 776-785.DOI:10.3111/13696998.2012.680555
53. Krejczy M, Harenberg J, Marx S et al. Comparison of cost-effectiveness of anticoagulation with dabigatran, rivaroxaban and apixaban in patients with non-valvular atrial fibrillation across countries. Blood 2012; 120 (Suppl): P1164.

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

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

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

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

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

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

WordCloud Image Produced by Adam Tubman

 

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

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

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

 

Summary Table for TM – Part 1

 

 

 

There are some developments that deserve additional development:

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

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

 

Electron Transport and Bioenergetics

Deferred for metabolomics topic

Synthetic Biology

Introduction to Synthetic Biology and Metabolic Engineering

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

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

http://synthetic_biology/Introduction_to_Synthetic_Biology_and_Metabolic_Engineering/Kristala_ L.J._Prather/E2/iBiology.htm#/sthash.71kZ0ofr.dpuf

Dr. Prather has received numerous awards both for her innovative research and for excellence in teaching.  Learn more about how Kris became a scientist at

http://science360.gov/obj/video/753bb4fa-aafb-4315-848e-51066ed9799a/finding-way-kristala-l-jones-prather-phd 

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

VIEW VIDEOS

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

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

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

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

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

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

 

David Bartel: micro-RNAs

 

I. Introduction to microRNAs

https://www.youtube.com/watch?feature=player_embedded&v=dupzE66J8u4#t=0

– See more at: http://www.ibiology.org/ibioseminars/genetics-gene-regulation/david-bartel-part-1.html#sthash.nGGr1tIt.dpuf

II. Regulatory Effects of Mammalian microRNAs

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

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

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

in INTECH
Current Basic and Pathological Approaches to
the Function of Muscle Cells and Tissues – From Molecules to HumansLarissa Lipskaia, Isabelle Limon, Regis Bobe and Roger Hajjar
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48240

1. Introduction
Calcium ions (Ca ) are present in low concentrations in the cytosol (~100 nM) and in high concentrations (in mM range) in both the extracellular medium and intracellular stores (mainly sarco/endo/plasmic reticulum, SR). This differential allows the calcium ion messenger that carries information
as diverse as contraction, metabolism, apoptosis, proliferation and/or hypertrophic growth. The mechanisms responsible for generating a Ca signal greatly differ from one cell type to another.

In the different types of vascular smooth muscle cells (VSMC), enormous variations do exist with regard to the mechanisms responsible for generating Ca signal. In each VSMC phenotype (synthetic/proliferating and contractile [1], tonic or phasic), the Ca signaling system is adapted to its particular function and is due to the specific patterns of expression and regulation of Ca.
For instance, in contractile VSMCs, the initiation of contractile events is driven by mem- brane depolarization; and the principal entry-point for extracellular Ca is the voltage-operated L-type calcium channel (LTCC). In contrast, in synthetic/proliferating VSMCs, the principal way-in for extracellular Ca is the store-operated calcium (SOC) channel.
Whatever the cell type, the calcium signal consists of  limited elevations of cytosolic free calcium ions in time and space. The calcium pump, sarco/endoplasmic reticulum Ca ATPase (SERCA), has a critical role in determining the frequency of SR Ca release by upload into the sarcoplasmic
sensitivity of  SR calcium channels, Ryanodin Receptor, RyR and Inositol tri-Phosphate Receptor, IP3R.
Synthetic VSMCs have a fibroblast appearance, proliferate readily, and synthesize increased levels of various extracellular matrix components, particularly fibronectin, collagen types I and III, and tropoelastin [1].
Contractile VSMCs have a muscle-like or spindle-shaped appearance and well-developed contractile apparatus resulting from the expression and intracellular accumulation of thick and thin muscle filaments [1].

Schematic representation of Calcium Cycling in Contractile and Proliferating VSMCs

 

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

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

 

Time for New DNA Synthesis and Sequencing Cost Curves

By Rob Carlson

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

 

cost-of-oligo-and-gene-synthesis

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

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

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

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

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

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

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

 

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

28 Nov 2013 | PR Web

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

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

 

Life at the Speed of Light

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

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

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

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

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

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

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

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

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

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

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

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

 

 

Where Will the Century of Biology Lead Us?

By Randall Mayes

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

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

Biology + Engineering = Synthetic Biology

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

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

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

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

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

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

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

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

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

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

Synthesizing Synthetic Biology: PLOS Collections

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

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

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

Silencing Cancers with Synthetic siRNAs

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

Genomics Now—and Beyond the Bubble

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

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

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

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

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

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

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

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

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

 

Stepping into DIYbio and Synthetic Biology at ScienceHack

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

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

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

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

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

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

 

 

Share this:

• X
• LinkedIn
• Facebook
• Print
• Email

Like this:

Like Loading…

Read Full Post »

« Newer Posts - Older Posts »

• Follow Blog via Email

  Enter your email address to follow this blog and receive notifications of new posts by email.

  Email Address

  Follow

  Join 2,037 other subscribers

• Recent Posts

  • Novartis and Bristol Myers Squibb halt CAR-T trial for autoimmune diseases over patient deaths: a potential issue with cell-based manufacturing September 15, 2026
  • FDA Contemplates Changes in Trial Design, Drug Development, and Use of AI in Clinical Trials September 15, 2026
  • FDA Moves Forward With Its Guidance Framework for Rare Disease Trials: 2026 August 3, 2026
  • Artificial Intelligence TRANSFORMS Medicine, Biotech and Healthcare, How? August 3, 2026
  • In Memoriam: Nobel Laureate J. Michael Bishop for discovery of Retroviral Oncogenes July 31, 2026
  • Companies Actively Engaging Artificial Intellegence for Drug Design: 2026 July 31, 2026
  • AI-Native Drug Discovery Landscape 2026 – How LPBI Group Differentiates in the New Era of Foundation Models July 19, 2026
  • In Memoriam: In Remembrance of Cancer Researchers who passed in 2026 July 13, 2026
  • Urgent Request for Action on Proposed Rule Affecting Federal Funding Grant Review July 7, 2026
  • 2026 Tang Prize in Biopharmaceutical Science Awarded to Three Pioneers of Cellular Immunotherapy Revolutionizing Treatments for Blood Cancers and Solid Tumors July 5, 2026

• Archives

  Archives Select Month September 2026  (2) August 2026  (2) July 2026  (6) June 2026  (4) May 2026  (1) January 2026  (10) December 2025  (8) November 2025  (8) October 2025  (12) September 2025  (2) July 2025  (4) June 2025  (8) May 2025  (4) April 2025  (2) March 2025  (1) February 2025  (2) January 2025  (3) December 2024  (1) November 2024  (5) October 2024  (7) September 2024  (7) August 2024  (1) June 2024  (1) May 2024  (2) April 2024  (2) January 2024  (1) November 2023  (1) October 2023  (3) September 2023  (3) August 2023  (2) July 2023  (2) June 2023  (7) May 2023  (4) April 2023  (2) March 2023  (5) February 2023  (2) January 2023  (3) December 2022  (2) October 2022  (6) September 2022  (2) August 2022  (1) July 2022  (3) June 2022  (3) May 2022  (8) April 2022  (10) March 2022  (7) February 2022  (7) January 2022  (3) December 2021  (3) November 2021  (4) October 2021  (11) September 2021  (5) August 2021  (8) July 2021  (21) June 2021  (8) May 2021  (10) April 2021  (8) March 2021  (15) February 2021  (17) January 2021  (20) December 2020  (10) November 2020  (12) October 2020  (26) September 2020  (17) August 2020  (22) July 2020  (27) June 2020  (33) May 2020  (26) April 2020  (42) March 2020  (22) February 2020  (11) January 2020  (7) December 2019  (20) November 2019  (13) October 2019  (11) September 2019  (3) August 2019  (8) July 2019  (25) June 2019  (47) May 2019  (40) April 2019  (27) March 2019  (29) February 2019  (17) January 2019  (50) December 2018  (14) November 2018  (17) October 2018  (18) September 2018  (17) August 2018  (8) July 2018  (20) June 2018  (22) May 2018  (17) April 2018  (12) March 2018  (20) February 2018  (26) January 2018  (16) December 2017  (6) November 2017  (20) October 2017  (13) September 2017  (16) August 2017  (16) July 2017  (19) June 2017  (20) May 2017  (32) April 2017  (21) March 2017  (10) February 2017  (24) January 2017  (21) December 2016  (43) November 2016  (8) October 2016  (40) September 2016  (67) August 2016  (59) July 2016  (75) June 2016  (37) May 2016  (95) April 2016  (152) March 2016  (175) February 2016  (196) January 2016  (139) December 2015  (90) November 2015  (287) October 2015  (237) September 2015  (115) August 2015  (96) July 2015  (63) June 2015  (44) May 2015  (53) April 2015  (76) March 2015  (95) February 2015  (83) January 2015  (75) December 2014  (75) November 2014  (88) October 2014  (135) September 2014  (117) August 2014  (88) July 2014  (88) June 2014  (109) May 2014  (60) April 2014  (85) March 2014  (58) February 2014  (72) January 2014  (107) December 2013  (104) November 2013  (136) October 2013  (62) September 2013  (32) August 2013  (46) July 2013  (74) June 2013  (110) May 2013  (112) April 2013  (86) March 2013  (92) February 2013  (63) January 2013  (63) December 2012  (46) November 2012  (71) October 2012  (84) September 2012  (82) August 2012  (122) July 2012  (59) June 2012  (34) May 2012  (46) April 2012  (2)

• Categories

  Categories Select Category 3D Printing for Medical Application  (240)    3D Plotting Scaffolds  (44)    BioInks  (34)       Biopolymer Blend Open Porous  (18)       Dental Applications  (10)    BioPrinting in Regenerative Medicine  (77)       Cell Level  (16)       MicroEngineering Cell-Tissue & Systems  (31)       Tissue Engineering  (37)    Cardiovascular and Vascular Systems  (30)       Artificial Vascular Structures  (9)       Cardiovascular Tissue  (8)    Drug Development using MultiOrgan Chip  (12)    Drug Development/Formulation using 3D Printing  (10)    MEMS  (16)       Bio-MEMS  (12)    Organ-on-a-Chip  (11)    Programmable Sensors (Carbon Nano Tubes)  (5) 3rd Party IP: Drug DIscovery  (1) 4D Printing and Meta Materials  (10) Academic Publishing  (223)    Key Opinion Leaders in eScientific Publishing – Interviews with  (8) Advanced Drug Manufacturing Technology  (97)    Antimalarial Preparation  (8)    Autologous Cell Therapy  (14)    Automated Cell Processing  (13) Allergy and Infectious Diseases  (12) Alzheimer’s Disease  (163)    Etiology  (77)    Medical Device Therapies for Altzheimer’s Disease  (15)    Pharmacotherapy and Cell Activity  (51) Anticancer Resistance  (31) Art Exhibits on the Human Condition  (1) Art Inspires Science  (4) Article Type  (2)    Authored  (1)    Curated  (2)    Scientific report  (1) Artificial Heart  (2) Artificial Intelligence – General  (240)    An executive’s guide to AI  (11)    Artificial Intelligence – Breakthroughs in Theories and Technologies  (119)    Artificial Intelligence Applications in Health Care  (131)       Artificial Intelligence in CANCER  (42)       Artificial Intelligence in Health Care – Tools & Innovations  (77)    Artificial Intelligence in Medicine – Application for Diagnosis  (72)       Artificial intelligence applications for cardiology  (33)          AI-assisted Cardiac MRI  (10)       Artificial Intelligence in Psychiatry  (7)       Deep Learning in Pathology  (19)    Artificial Intelligence in Medicine – Applications in Therapeutics  (71)    ChatGPT, GPT-4  (7)       ChatGPT at LPBI Group  (3)       ChatGPT in Academic Education  (3)    Machine Learning  (73)       Deep Learning  (26)       Natural Language Processing (NLP)  (45)    Machine learning in predicting type 2 diabetes  (6) Auditory and vision  (13) Autism Spectrum Disorders  (10) Autoimmune Inflammatory DIseases  (25)    Crohn’s disease  (5)    Tolerance-inducing Autoimmune Disease Therapeutics  (7)    Ulcerative Colitis  (3) Autophagosome  (4) Bacterial Resistance  (25) Behavior  (26) Behavioral Genetics  (21) Big Data  (88)    Intelligent Information Systems  (51) Bio Instrumentation in Experimental Life Sciences Research  (368)    Analytical Instruments Industry  (5)    Microfuidics  (8) Bio-Ethics  (16) BioBanking  (36) Biodegradable Drug-eluting Material  (8) Bioengineering & reverse engineering design  (43) BioIT: BioInformatics  (147) BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics  (135)    Advanced Computing Platform  (32)       Blockchain Transactions System  (6)          Platform for Content Monetization embedded Content Promotion  (1)    Pancreatic adenocarcinoma classifier  (4)    Simulation Modeling in NGS  (5) Biological Engineering  (43) Biological Networks  (193) Biological Networks, Gene Regulation and Evolution  (479)    Virology  (10) Biomarkers & Medical Diagnostics  (572)    VOC – Volatile Organic Compounds as BioMarkers  (2) Biomedical Measurement Science  (173) BioSimilars  (112) BioTechnology – Venture Creation  (133)    Foundations for supporting Science and Education  (14)    Philanthropy to Academic Institution  (3) BioTechnology – Venture Creation, Venture Capital  (110)    Seeking Talent  (3) BiVAD  (1) Blindness  (6) Bone Disease and Musculoskeletal Disease  (82) Brain Basis of Emotion  (5) Business Career Consideration  (1) Ca2+ triggered activation  (61) Calcium  (21) Calcium Signaling  (71) Calmodulin Kinase and Contraction  (36) Cancer – General  (186) Cancer and Current Therapeutics  (412)    interventional oncology  (49)       Breast Cancer – impalpable breast lesions  (20)       Prostate Cancer: Monitoring vs Treatment  (9) CANCER BIOLOGY & Innovations in Cancer Therapy  (1,127)    Anaerobic Glycolysis  (51)    Cachexia  (18)    Cancer Genomics  (85)       Circulating Tumor Cells (CTC)  (27)          Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood  (17)             mRNA  (6)          MagSifter chip  (1)       KRAS Mutation  (9)       Li-fraumeni syndrome.  (4)       TP53 – Germline mutations  (9)    cancer metabolism  (28)    Funding Opportunities for Cancer Research  (13)    Genomic Expression  (150)    Glioblastoma  (7)    Hexokinase  (14)    Loss of function gene  (18)    Metabolic Immuno-Oncology  (21)    Metastasis Process  (15)    Methylation  (33)    Microbiome and Responses to Cancer Therapy  (10)    Monoclonal Immunotherapy  (29)    mtDNA  (13)    Oxidative phosphorylation  (56)    Pancreatic cancer  (10)    Pyruvate Kinase  (27)    The NCI Formulary  (1)    tumor microenvironment  (16)    Warburg effect  (50) Cancer Informatics  (104) Cancer Prevention: Research & Programs  (132) Cancer Screening  (108) Cancer Vaccines: Targeting Cancer Genes for Immunotherapy  (30)    Engineering Enhanced Cancer Vaccines  (3) cancer-general  (7) Cardiac and Cardiovascular Surgical Procedures  (328)    Aortic Valve: TAVR, TAVI vs Open Heart Surgery  (91)       Prosthesis-Patient Mismatch (PPM) in TAVI vs SAVR  (2)       TAVI vs Open Heart Surgery  (6)       Transcatheter Aortic Valve Replacement via the Transcarotid Access  (3)       Transcaval TAVR Procedure  (3)       Valve-in-Valve Procedure  (5)    Atrial Fibrilation (a-Fib), Cardiac Pacing and Arrhythmias  (18)    BackBeat’s Cardiac Neuromodulation Therapy (CNT) bioelectronic therapy  (1)    CABG  (47)    Cancer Surgery of the Heart  (10)    Cardiovascular Fluid Management: algorithms  (1)    Heart Transplant  (16)    Heart-Lung Transplant  (11)    Implantation  (3)    Left Main Coronary Artery Disease (LMCAD)  (3)    Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart  (22)    Mitral Valve: Repair and Replacement  (64)       TMVR – Transcatheter Mitral Valve Repair  (5)    PCI  (108)       Bioresorbable Vascular Scaffold (BVS)  (4)       Invasive FFR for PCI  (2)       Multivessel PCI FFR Guidance  (1)       Robotic-assisted percutaneous coronary intervention  (2)       Stent Retriever in endovascular thrombectomy  (3)    Peripheral Arterial Disease & Peripheral Vascular Surgery  (65)       Abdominal Aorta  (20)       Carotid Artery  (15)       Limb ischemia  (4)       Thoracic Aorta  (16)    Pulmonary Valve Replacement and Repair  (3)    Renal Denervation  (20)    Replacement  (1)    Robotically assisted Cardiothoracic Surgery  (2)    Tricuspid Valve Repair  (7)    Vena Caval Filters: Device for Prevention of Pulmonary Embolism and Thrombosis  (2) Cardiovascular Pharmacogenomics  (171) Cargo  (3) Cell Biology  (323) Cell Biology, Signaling & Cell Circuits  (673)    Apoptosis  (17)    Autophagy-Modulating Proteins  (6)    “Antibody–enzyme conjugates”  (6)    Cell Processing System in Cell Therapy Process Development  (28)    Endoplasmic reticulum  (3)    Enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)  (3)    Ubiquitin  (11) Cerebrovascular and Neurodegenerative Diseases  (123)    Stroke  (9) Chemical Biology and its relations to Metabolic Disease  (464)    #BIGAxisSummit  (1)    Gut Microbiome and Obesity  (8) Chemical Genetics  (350) Child and Adolescent Psychiatry  (13) Childhood cancer  (17) Childhood malnutrition  (3) children  (4) Circulating Progenitor Cells  (27)    Bone marrow derived cells  (17)    Endothelial cells  (7)    Umbilical cord cells  (6) Clinical & Translational  (239) Clinical Diagnostics  (220)    Mass automation of plasma proteins  (13) Clinical Genomics  (144) Coagulation Therapy and Internal Bleeding  (83) Cognition  (47) Commercialization  (20) Components and IRB related issues  (4) Computational Biology/Systems and Bioinformatics  (471)    Computational Histopathology  (3)    Meta-analysis of transcriptome data  (10) Conference Coverage with Social Media  (494)    MassBio  (3) coronavirus  (18) COVID-19  (20) CRISPR/Cas9 & Gene Editing  (192)    CRISPR alternative for editing genes without cutting  (14)       CAST – Alternative to CRISPR/Cas9  (3)       Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration  (4)    CRISPR applied to Human Germ Line  (13)       Gene Editing Impact on Longevity  (6) CT  (20) Cytokines  (21) Cytoskeleton  (85) Developmental biology  (107) Diabetes Mellitus  (146)    Artificial Pancreas for Type 2 Diabetes  (4)    Artificial Pancreas for Type1 Diabetes  (8)    Gestational diabetes  (5) Diagnostic Immunology  (61) Diagnostics and Lab Tests  (128)    Liquid Biopsy: Circulating Tumor Cells in Urine and Blood  (9) Digital HealthCare – biotech & internet joint ventures  (47) Disease Biology  (334) Disease Biology, Small Molecules in Development of Therapeutic Drugs  (488) DNA repair  (73)    Apoptosis  (13)    Autophagy  (13)    Cell death pathways  (19)    Proteolysis  (8)    Proteosome  (8) Drug Delivery Platform Technology  (159)    Drug Carrier Design  (21)       Medication Remote Compliance Monitoring  (3)    Exosomes: Natural Carriers for siRNA Delivery  (9) Drug Toxicity  (74) Ecosystems & Industrial Concentration in the Medical Device Sector  (172)    Cardiac & Vascular Repair Tools Subsegment  (128)    Exec Compensation in the Cardiac & Vascular Repair Tools Subsegment  (14)    Massachusetts Niche Suppliers and National Leaders  (20) Electronic Health Record  (10) Embryology  (24) Empathy  (6) Endocrine Diseases  (60) Enzyme Induction  (46)    ion-transporting enzyme  (2)    K + -ATPase.  (1)    Na +  (2) Epigenetics and Environmental Factors  (35) Ethics and Leadership  (10) Executive Compensation – Big Pharma  (3) Fat soluble vitamins  (4) FDA  (73) FDA Regulatory Affairs  (360)    FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP, GLP, ISO 14155  (52)    ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics  (30) Fetal Ultrasound  (2) Fiction and medicine  (5) Frontiers in Cardiology and Cardiovascular Disorders  (929)    Acute Myocardial Infarction  (63)       Cardiogenic Shock  (5)    Anemia in CVD Patients  (6)    Cardio-Oncology  (4)    Cardiomyopathy  (57)    Cardiovascular Research  (187)       Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism  (64)       Pre-Clinical Animal Model Development  (23)    Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH)  (20)    Cost of Inpatient Stay for Cardiovascular Diagnosis for Admission  (1)    Electrophysiology  (111)       Ablation Procedure vs Drug Therapy  (2)       Arrhythmia Detection with Machine Learning Algorithms  (7)       Cardiotoxic Risks of Immune Checkpoint Inhibitors  (1)       Genomic Analysis of EKG Electrophysiology Genomics  (3)       implantable cardioverter defibrillator (ICD) and External Defibrillation  (1)       implantable pacemaker  (2)       Rare heart rhythm disorders and Long QT syndrome (LQTS)  (7)    Epigenetics and Cardiovascular Risks  (57)    Heart Failure (HF)  (51)       Acute coronary syndrome  (7)       congestive heart failure  (19)       Hypertensive Disorders of Pregnancy  (1)    Medical Devices R&D and Inventions  (212)       Assist Devices: LV  (3)       RV  (1)       Stents & Tools  (90)       Valves & Tools  (67)    Origins of Cardiovascular Disease  (422)       Atherogenic Processes & Pathology  (180)       Congenital Heart Disease  (34)          Genetic Mutations in Congenital Heart Disease  (4)       inflammation independent of lipid levels  (13)       Systemic Inflammatory Diseases as CVD Risk  (12)    Pharmacotherapy of Cardiovascular Disease  (356)       HTN  (176)       HTN in Youth  (8)       Resident-cell-based  (43)       Subarachnoid Hemorrhage (SAH)  (1)       Transthyretin amyloid cardiomyopathy (ATTR-CM)  (1)    Spontaneous Coronary Artery Dissection (SCAD)  (6)    Stroke  (15)       endovascular thrombectomy  (6)    Vascular Diseases  (21)       mesenteric ischemia  (3) Future Pandemics Inform-graphics  (1) Gastroenterology  (38) Gene Regulation  (233) Gene Regulation and Evolution  (137) Genetics & Innovations in Treatment  (176) Genetics & Pharmaceutical  (204) Genome Biology  (967)    Exosomes  (25)    Gene Therapy & Gene Editing Development  (42)    mRNA Therapeutics  (20)    Mutagenesis  (27)    Single Cell Genomics  (25)    Single-cell sequencing  (20)    Variation in human protein-coding regions  (35) Genomic Endocrinology  (42) Genomic Testing: Methodology for Diagnosis  (416) Genomics Pharmacy  (40) Global Market of Medical Devices Technology  (3) Global Medical Publishers by Country  (3) Global Partnering & Biotech Investment  (48) GLP  (4) Glycobiology: Biopharmaceutical Production  (16) Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics  (28) Health Care System by Country  (58)    AI Models in Healthcare  (12)    Centers for Medicare & Medicaid Services  (8)    Health in Israel  (2)    India  (1)    United States  (27)       Hospital-based Medical Innovations  (10)       Medical Recertification and Maintenance of Certification (MOC)  (1) Health Economics and Outcomes Research  (384)    Women Health  (18)       Heart and Brain Disease in Women  (3) Health Law & Patient Safety  (165)    and Bioethics  (14)    Biotechnology  (12)    Health Law Policy  (13) HealthCare IT  (139) Healthcare Reform  (118)    Accountable Care Organizations  (26)    Affordable Care Act  (29)       Repair  (1)       Repeal ACA  (1)       Replace  (1)    Federal Budget Appropriations  (27)    Healthcare costs and reimbursement  (59)    Indigent Nutrition  (14)    Medicare and Medicaid  (20)    Prescription Drugs Costs  (21)    Skilled Nursing Facilities  (6)    Technology Capital Expenses  (15)    Uninsured and Underinsured  (20) Hematology  (100)    Acute lymphocytic leukemia  (18)    Acute myelocytic leukemia  (21)    Hematopoiesis  (48)    Lymphoma  (21) History and physical exam  (6) Human aging  (27) Human Immune System in Health and in Disease  (246) Human Sensation and Cellular Transduction: Physiology and Therapeutics  (21) Image Processing/Computing  (41) Imaging-based Cancer Patient Management  (116) Immuno-Oncology & Genomics  (133)    mRNA platform in Drug DIscovery  (6) Immunodiagnostics  (141)    Cancer-Immune Interactions  (31)    CNS-Immune Interface  (5)    Neuronal Circuits  (4) Immunology  (123)    Adaptive Immune Response to Biomaterials and Tissue Repair  (13)    Antibody Responses Predict Antigen Exposure  (17)    Cytokine Receptor Structure  (8)    Human Antibody Response  (18)    Human Circulating Antibody Repertoire  (11)    Human Naive B Cell Repertoire  (8)    MHC Repertoires for Antigen Prediction  (8)    Protection Against Autoimmune Disease  (11)    Synthetic Immunology: Hacking Immune Cells  (15) Immunotherapy  (137)    CAR-T  (16)    combination immunotherapies.  (15)    Efficacy of Anti-Tumor T Cells  (15)    Engineering Better T Cells  (11)    Immune Engineering  (18)    Immune Modulatory  (16)    Integrin-targeted Combination Immunotherapy  (6)    Modulating Macrophages in Cancer Immunotherapy  (17)    NK Cell-Based Cancer Immunotherapy  (20)    Synergistic Innate and Adaptive Immunotherapy  (14) Income Disparity  (2) Infectious Disease & New Antibiotic Targets  (162)    Antibiotic resistance  (7)    Viral diseases  (37)       Myocarditis  (1) Infectious Disease Immunodiagnostics  (58)    Virology – Vector-borne DIsease  (17) Inflammasome  (29)    Anti-tumor necrosis factor drugs (TNF inhibitors)  (3) Innovation in Immunology Diagnostics  (111)    Universal Immune Cell Therapies (uICT)  (11) Innovations  (186)    R&D Expenditure  (8) Innovations in Neurophysiology & Neuropsychology  (145)    Age and Life Expectancy  (3)    autism spectrum disorder  (1)    Circadian Rhythm and Sleep  (6)    hNPCs  (1)    Nervous System Function  (2)    Relapsing Multiple Sclerosis  (1) Intellectual Property  (85)    Disputes and Settlements  (9)    IP Valuation Models – Pricing Intangible Assets  (7)    Patent Law in Biotech  (12) Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough  (121) International Global Work in Pharmaceutical  (191) Interventional Oncology: Radiofrequency Ablation, Transarterial Chemoembolization, Microwave Ablation and Irreversible Electroporation (IRE)  (12) Interviews with Scientific Leaders  (319)    Albany Medical Center Prize in Medicine and Biomedical Research  (3)    Annual Breakthrough Prize  (4)    Annual Lewis S. Rosenstiel Award  (2)    Awards in Cardiology and Cardiovascular Medicine  (6)    CEOs of Biotech Companies  (3)    Gerald D Aurbach Award for Outstanding Translational Research  (2)    Interviews with Key Opinion Leaders (KOLs)  (11)    James Prize in Science and Technology Integration  (2)    Jessie Stevenson Kovalenko Medal – Medical Sciences  (2)    Lemelson-MIT Prize  (2)    Life Sciences Breakthrough Prize  (6)    Mosteller Statistician of the Year Award  (2)    Mourning the Loss of a Scientific Leader  (6)    National Academy of Sciences AWARDS  (4)    Nobel Prize Winners  (30)    Noble Prize (Not Nobel Prize)  (2)    Paul Marks Prize for Cancer Research  (2)    Russ Prize recognizes bioengineering achievements worldwide  (2)    The Dan David Prize  (6)    Warren Alpert Foundation Prize Recipients  (4)    Wolf Prize  (2)    Wolf Prize in Medicine  (2)    women in science  (5) Investment in Technological Breakthrough  (60) Ionic Transporters Na+  (25) IP Development by LPBI Group Team  (14) IP Development by LPBI Group Team & Other Organizations  (8) ISO 14155  (3) Joint Venture – SBH & M3DP: SOP and Arrangements  (1) Justice & Law  (1) K  (15) Lab-on-a-chip  (2) Landscape  (1) Lasers and photonics  (18)    Midrange IR spectroscopy  (1) Law and Medicine Conflicts  (15) Leadership, Power, Social Interlocking Connections  (13) Lipid metabolism  (109)    Fatty acids  (38)    Lipids  (38)    PCSK9 Inhibitor Therapy  (19) Lipidomics  (11) Liposome  (4) Liver & Digestive Diseases Research  (122) LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management  (143)    Award Nominations  (5)    BioMed e-Books e-Series by LPBI Group  (9)    Feedback from Investors: LPBI Portfolio of Five Businesses  (2)    LPBI Group Founder – Aviva Lev-Ari  (27)    PhD  (1)    RN  (1) LPBI Management  (23) Massachusetts Academy of Sciences (MAS)    (2) Materials Science & Engineering  (37)    Organic BioElectronics  (2) Math  (13)    Great Discoveries  (7) Mechanical Assist Devices: LVAD  (4) Medical and Population Genetics  (193) Medical Devices R&D Investment  (242)    21st Century Cures Act  (2)    CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP  (14)    Rhythm management device hardware: dual-chamber pacemakers  (1)       Systolic HTN  (1) Medical Imaging Technology  (59) Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound  (164)    Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI)  (3)    Echocardiography  (3)    MRI  (18)    Noninvasive Diagnostic Fractional Flow Reserve (FFR) CT  (6)    Ultra Sound  (10) Melatonin & Circadian Regulation  (9) memory loss  (1) Metabolism  (239)    Biochemical pathways  (144)       Enzymes and isoenzymes  (73)          Dehydrogenase  (16)          Kinase  (28)          Phosphatase  (9)          Phosphorylase  (22)          tyrosine decarboxylases  (3)    Inosine nucleotides  (9)    Leloir pathway  (6)    microbiome  (7)    Pentose monophosphate shunt  (14)    Pyridine nucleotides  (28)       Pyridine nucleotide transhydrogenase  (7) Metabolomics  (321) Methods  (37) Mg++  (10) Microbiologial genetics  (36) Microbiology  (68)    Virology  (14) Micronutrients  (16) Microvesicle  (7) Microwave Ablation and Irreversible Electroporation (IRE)  (1) Mobile Healthcare  (5) Molecular Genetics & Pharmaceutical  (377)    Organoids  (3) Monoclonal antibody therapy  (14) Mutant Gene Expression  (42) Myocardial adenine nucleotide metabolism  (6) Myocardial Ischemia  (26) Myocardial Metabolism  (36) Na-K transport  (40) Na-K-ATPase  (27) Nanotechnology for Drug Delivery  (99) Nephrology  (46) Nephrology & Regenerative medicine  (9) Neurodegenerative Diseases  (89)    hNPCs  (3)    MS  (5) Neurohumoral Transmission  (68)    Ca2+ triggered activation  (21)    Calmodulin  (13)    Parkinson’s disease dyskinesia levodopa  (3)    PKC  (13)    Synaptic vesicle  (20) Neurological Diseases  (121) Neuroscience  (126) Next Generation Sequencing (NGS)  (27)    Nanopore sequencing  (1) NIH Common Fund  (1) Nitric Oxide in Health and Disease  (136) Nuclear Medicine  (11) Nutrigenomics  (68) Nutrition  (195)    Nutritional Supplements: Atherogenesis, lipid metabolism  (50) Nutrition and Phytochemistry  (62)    Minerals in Medicine  (4)    Plant extract  (22) Nutrition Disorders  (31) Nutritional Supplements: Atherogenesis  (31) Obesity  (19) Oligonucleotide Therapeutics & Delivery  (7) Oncolytic virus & OncoViro-Therapy  (23)    Synthetic Virology  (1) Organ-on-a-Chip & 3D Printing in Life Sciences  (7) Pain: Etiology, Genetics & Innovations in Treatment  (24) Parasitology  (5)    Malaria  (4)    Tropical diseases  (1) Patents  (35) Patient Experience  (66)    Art therapy  (1)    Hospital reputation  (7)    Humor  (1)    Music therapy  (2)    Pain Alleviation  (7)    Patient Outlook  (28)    Reputation of Interventionist  (4)    Support Staff  (13)    Supportive therapies  (6)       laughfter  (1)    Surgical Procedure  (9) Patient Experience: Personal Memories of Invasive Medical Intervantion  (30) Patient’s Voice: Personal Experience with Invasive Medical Procedures  (18) Perioperative Statins at Noncardiac Surgery  (2) Personal Health Applications: Tech Innovations serves HealhCare  (43) Personalized and Precision Medicine & Genomic Research  (740)    Longevity  (3)    New Drug Approval  (7)    Patient-centered Medicine  (39)       cell-based therapy  (9)       stem cell biology and patient-specific  (7)    Personalized Medicine Coalition  (10)    Precision Cancer Medicine  (33) Phagophore  (2) Pharmaceutical Analytics  (262)    Pharmacologic toxicities  (63) Pharmaceutical Discovery  (112)    Rapid automation of plasma protein pools  (18) Pharmaceutical Drug Discovery  (207)    Drug Development Process  (62)       Drug Discovery Chemistry  (33)    drug repurposing  (11) Pharmaceutical Industry Competitive Intelligence  (347)    Pharmacovigilance  (8)    Value-based Drug Pricing  (8) Pharmaceutical R&D Informatics  (45) Pharmaceutical R&D Investment  (301) Pharmacodynamics and Pharmacokinetics  (24) Pharmacogenomics  (161) Photography Collection  (1) Physics  (12) Placenta  (7) Population genetics  (27) Population Health Management  (205)    Evolution of Biology Through Culture  (14)    U.S. Employment-to-Population Ratio  (8) Population Health Management, Genetics & Pharmaceutical  (643)    COVID-19  (157)       Biomarkers: Inflammation  (37)       Cancer Researchers Fighting COVID-19  (14)       COVID-19 effects on Human Heart  (15)       COVID-19: Pandemic Surgery Guidance  (19)       Economic Impact of Coronavirus Pandemic  (41)       number of asymptomatic infections  (27)       Treatment Protocols for COVID-19  (62)    SARS-CoV-2  (141)       Coronavirus Gene Expression  (66)          SARS-CoV-2 circulating variants   (14)          SARS-CoV-2 Viral Variants  (19)       Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis  (2)       Immune-Mediation (independent immunopathology: lung and reticuloendothelial system)  (30)       Mechanisms of infection by SARS-CoV-2  (21)       SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus  (35)          SARS-COV2 Hijacking the Complement and Coagulation Systems  (19)       Seasonality & Environmental Factors in Resurgence  (26)       Serology tests for coronavirus antibodies  (44)       T-cell response to SARS-CoV-2 infection  (14)       Vaccinology  (51)          Mechanism of Thrombosis with AZ & J&J COVID-19 Vaccines  (5)       Virtual Drug Molecule Screening targeting SAR-CoV-2 proteins  (8)    Virus Infective Acute Respiratory Syndrome: SARS-CoV  (92) Population Health Management, Nutrition and Phytochemistry  (162) Preimplantation Genetic Diagnosis and Reproductive Genomics  (13) Protein-energy malnutrition  (12) Proteomics  (367)    Amino acids  (54)    Proteins  (138) Pulmonary diseases  (16)    Lung and pulmonology  (15) Pulmonary pathology  (8) Radio Frequency (RF)-based Surgical Solutions  (2) REAL TIME Conference Coverage Twitter’s Hashtags and Handles per Presentation/session  (50) Regenerative Biology and Medicine  (92) Regulated Clinical Trials: Design, Methods, Components and IRB related issues  (265) Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics  (113) Reproductive Biology & Bio Instrumentation  (78) RNA Biology  (81)    RNA interference (RNAi) therapeutic  (4) RNA Biology, Cancer and Therapeutics  (64) RVAD  (1) SBIR, SBA, NIH, NSF  (3) Schizophrenia  (16) Scientific & Biotech Conferences: Press Coverage  (182) Scientific Publishing  (609)    Curation  (585)       Curation methodology  (40)       De novo synthesis  (16)       Dialectic  (17)       Discovery process  (72)       Evolutionary cognition  (52)       Experimental validation  (91)       Explanatory  (91)       Historical relevance  (71)       Technology Advance Assessment of  (69)       Theoretic convergence  (27)    Open Access Journals  (37) Scientist: Career considerations  (198)    Big Data & Analytics  (17)    Data Science  (13)    Women in Life Sciences  (12) Scoop.it  (19) Sensors & Analytics  (18) Sepsis  (2) Severe Autism  (3) Signaling  (102)    Phosphorylation  (43)    S-nitrosylation  (13)    Ubiquitinylation  (34) Signaling & Cell Circuits  (130) single cell sequencing  (3) Small Molecules in Development of Therapeutic Drugs  (71) Social Development  (15) Specialized 3D BioPrinters (Cornea  (1) Statistical Methods for Research Evaluation  (137) Stem Cells for Regenerative Medicine  (177)    Cardiac muscle regeneration  (19)    Competition in regenerative stem cell science  (18)    Human neural progenitor cells  (8)    Skeletal muscle regeneration  (9) STORM  (2) Stress Disorders  (19) Substance Abuse  (4) Systemic Inflammatory Response Related Disorders  (161)    Inflammatory Pathophysiology  (9) Technology Transfer: Biotech and Pharmaceutical  (354) therapeutics  (3) Tissue Engineering and Regenerative Medicine  (22) Tissue Microenvironment  (5) Transarterial Chemoembolization  (2) Transcriptomics  (47) Transformative Technologies in Healthcare  (23) Translational Science  (230)    Best evidence  (52)    Bias measurement tools  (2)    Evidence-based decision-making  (29)    Inferential analysis  (25)    Intra-rater error  (1)    Quality Assurance  (8)    Random Error  (2)    Systematic Error (Bias)  (6)    Total error  (2)    Translational Effectiveness  (49)    Translational Research  (92) Trends in Global Economy  (6) Uncategorized  (1,019) Unfolded Protein Response (UPR)  (6) US and Global Economy: Trends and Findings  (9) Venture Capital  (47)    Income Geographic Distribution  (3)    Institutional Capital Raised by Female Founders  (6) virology  (10) Vision  (7) Voices of Patients and Healthcare Providers  (22) Water Transporters  (8) Wearable Tech + Digital Health  (5) Anemia  (22) Neutropenia  (8) Neutrophilia  (9) Platelet count disorder  (9) Folate and B12  (7) Iron deficiency  (5) Myelodysplasia  (13) Myelofibrosis  (10)

• Meta

  • Log in
  • Entries feed
  • Comments feed
  • WordPress.org

• • 2012pharmaceutical
  • sjwilliamspa