Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter
Article selection: Aviva Lev-Ari, PhD, RN
#1 – February 20, 2016
Contributions to Personalized and Precision Medicine & Genomic Research
ClotTriever XL catheter for large blood vessels, i.e., inferior vena ceva on FDA Recall
Reporter: Aviva Lev-Ari, PhD, RN
The ClotTriever XL catheter, like Inari Medical’s other ClotTriever devices, was designed to treat deep vein thrombosis. Marketed as “a large device for the largest vein,” it was built specifically to target issues found in the vena cava.
The clinical advantage of the ClotTriever system
The CLOUT registry (NCT03575364) is a prospective, single-arm study evaluating outcomes of all-comer patients with proximal lower extremity DVT after thrombectomy with the ClotTriever system. CLOUT enrolled 500 patients from 43 US clinical sites. In-hospital results demonstrated safe and effective thrombus removal with immediate symptom relief. https://www.inarimedical.com/clottriever-system
“Operation of a thrombectomy catheter may cause embolization of some thrombus and/or thrombotic particulate, physician discretion advised,” according to another new warning. “The potential for extensive and/or difficult to treat pulmonary thromboembolism should be carefully considered when ClotTriever XL catheter is used to engage and remove thrombus from large vessels such as the inferior vena cava.”
The news comes after the FDA received several reports of “serious adverse events” due to the device becoming entrapped or blocking arteries in the patient’s lungs. Six deaths and four other patient injuries have been associated with the issue so far.
Inari Medical has published updated instructions for use (IFU) that include additional warnings.
For example, the new IFU tell users to avoid pulling the ClotTriever XL “caudal to cranial” through upper extremity access or jugular vein access. In addition, users should ensure the device is “slowly retracted distally away from the heart” while still tracking sheath position and visualization under fluoroscopy.
SOURCE for Clinical Trials on the device
Dexter D, Kado H, Shaikh A, et al. Safety and effectiveness of mechanical thrombectomy from the fully enrolled multicenter, prospective CLOUT registry. J Soc Cardiovasc Angiog Interv. 2023;2(2):100585.
Shaikh A, et al. Six-month outcomes of mechanical thrombectomy for treating deep vein thrombosis: analysis from the 500-patient CLOUT registry. Cardiovasc Intervent Radiol. 2023; 46(11):1571-1580.
W. Gerald “Jerry” Austen, MD influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump at MGH as renowned cardiac surgeon
Curator and reporter: Aviva Lev-Ari, PhD, RN
This article is classified in the ontology of LPBI Group’s Journal PharmaceuticalIntelligence.com under the Category of Research
Interviews with Scientific Leaders
This category includes 300 articles. LPBI Group’s will publish in July 2023 its Library of Audio Podcasts on “Interviews with Scientific Leaders.”
The presentations in the video below, about W. Gerald “Jerry” Austen, MD contributions to cardiac surgery are considered to be testimonials as well as qualify as “Interviews with a Scientific Leader” in the domains of cardiac surgery and cardiac repair medical devices with a special focus on:
cardiopulmonary (heart-lung) bypass machine, and
the intra-aortic balloon pump
On these two domains, LPBI Group had published extensively as the sources cited, below: Articles, e-Books in English and Spanish and Chapters in these book on the very specialty of Dr. Austen as included in the title of this article.
Recently, Mass General celebrated the life and legacy of W. Gerald “Jerry” Austen, MD — a renowned cardiac surgeon, beloved family man and visionary leader.
SOURCE
In Memoriam: W. Gerald Austen, MD – Mass General Giving
For 70 years, Dr. Austen was part of the Mass General community, having completed his residency at the hospital and continuing to become one of the most distinguished and well-regarded physicians in the hospital’s more than 200-year history. At 39 years old, he was named Mass General’s chief of surgical services — a position he held for nearly 29 years. Under his leadership, the Department of Surgery became one of the greatest academic departments of surgery in the country. Among his many contributions, he was influential in the design and creation of a cardiopulmonary (heart-lung) bypass machine and the intra-aortic balloon pump.
Hundreds of Dr. Austen’s closest friends, colleagues and family members gathered at Boston Symphony Hall to commemorate his legacy. A variety of speakers — from current Mass General President David F. M. Brown, MD, to former hospital President Peter Slavin, MD, and retired Chairman, President and CEO of Abiomed Mike Minogue — shared fond memories of Dr. Austen, further illustrating his unmatched and lasting impact on others.
The Mass General community will continue to mourn the loss of such a giant in the medical world and will carry on Dr. Austen’s legacy through compassionate care and an unparalleled commitment to all patients.
Susan Hockfield, ex-President of MIT delivered a speech about mechanical engineering and biomedicine, medical devices and cardiac repair devices. How proud Dr. Austen was about his MIT education and functions he fulfilled for this institutions and others.
Other related contributions on the specialty of Dr.W. Gerald “Jerry” Austen, MD – cardiac surgery are covered in e-books and articles on this Open Access Online Scientific Journal, include the following:
Articles
319 articles in the Cardiac and Cardiovascular Surgical Procedures Category
98 articles in the Aortic Valve Category
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement
Chapter 13: Valve Replacement, Valve Implantation and Valve Repair
13.2 Aortic Valve
13.2.1 New method for performing Aortic Valve Replacement: Transmural catheter procedure developed at NIH, Minimally-invasive tissue-crossing – Transcaval access, abdominal aorta and the inferior vena cava
13.2.4 Surgical Aortic Valve Replacement (SAVR) vs Transcatheter Aortic Valve Implantation (TAVI): Results Comparison for Prosthesis-Patient Mismatch (PPM) – adjusted outcomes, including mortality, heart failure (HF) rehospitalization, stroke, and quality of life, at 1 year
13.2.6 Off-Label TAVR Procedures: 1 in 10 associated with higher in-hospital 30-day mortality, 1-year mortality was similar in the Off-Label and the On-Label groups
13.2.11 One year Post-Intervention Mortality Rate: TAVR and AVR – Aortic Valve Procedures 6.7% in AVR, 11.0% in AVR with CABG, 20.7 in Transvascular (TV-TAVR) and 28.0% in Transapical (TA-TAVR) Patients
13.2.16 The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement (TAVR) under Coverage with Evidence Development (CED)
Chapter 7: Ventricular Failure: Assist Devices, Surgical and Non-Surgical
7.1 Trends in the Industry
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In addition to minimally invasive treatments for coronary disease and valve disease, there are minimally invasive alternatives to heart transplant for the dangerously weak heart (extreme heart failure) which can otherwise result in Cardiogenic Shock. These involve various means to augment or complement the pumping function of the heart, such as a Ventricular Assist Device (VAD) .
With respect to the performance of Mitral Valve Replacement, the current practice favors bioprosthetic valves over mechanical valve replacement for most patients, initially just used for elderly to avoid need for coumadin, but now used at younger ages due to improvements in longevity of the bioprosthetic valves, plus less damage to red cells.
7.1.2 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia
7.2.4 Experimental Therapy (Left inter-atrial shunt implant device) for Heart Failure: Expert Opinion on a Preliminary Study on Heart Failure with preserved Ejection Fraction
7.3.1 Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Chapter 11: Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty
11.1 Hybrid Cath Lab/OR Suite
The Voice of Series A Content Consultant: Justin D. Pearlman, MD, PhD, FACC
In an uncommon reversal of opinion, the combined forces of the American Heart Association (AHA) and the American College of Cardiology (ACC) reviewed compelling data and reversed a prior assessment on the need for an on-site cardiovascular surgery support for sites offering interventional cardiac catheterization. The data show that sites offering the intervention without a surgeon achieve better results that sites that ship patients out for the interventions, and that the risk without on-site thoracic surgery backup is negligible.
AHA, ACC Change in requirement for surgical support: Class IIb -> Class IIa Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, level of Evidence B).
Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC
11.1.2 Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
11.1.6 Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes
11.2.8 CABG: a Superior Revascularization Modality to PCI in Patients with poor LVF, Multivessel disease and Diabetes, Similar Risk of Stroke between 31 days and 5 years, post intervention
Bioresorbable Stent Clinical Trials with New Esprit Below-the-knee Scaffold
Reporter: Irina Robu, PhD
Abbott announced on September 3, 2020, the beginning of the LIFE-BTK clinical trial to evaluate effectiveness and safety of the Esprit BTK Everolimus Eluting Resorbable Scaffold System. The Esprit BTK System consists of a thin strutted scaffold made of poly-L-lactide, a semi-crystalline bioresorbable polymer engineered to resist vessel recoil and provide a platform for drug delivery. The scaffold is coated with poly-D, L-lactide (PDLLA) and the cytostatic drug, everolimus.
This trial is the first Investigational Device Exemption in the US to assess a fully bioresorbable stent to treat blocked arteries below the knees, also known as critical limb ischemia in people battling advanced stages of peripheral artery disease. For people with CLI, blocked vessels weaken blood flow to the lower extremities, which can lead to severe pain, wounds, and in severe cases, limb amputation.
At this time, the standard of care for patients battling critical limb ischemia is balloon angioplasty, which depend on on a small balloon delivered via a catheter to the blockage to compress it against the arterial wall, opening the vessel and restoring blood flow. Yet, blockages treated only with balloon angioplasty have poor short- and long-term results, and in many cases the vessels become blocked again, lacking additional treatment.
Patients treated with balloon angioplasty often require several procedures on treated arteries, and a drug eluting resorbable device is if at all possible suited to provide mechanical support, decrease the chance of the vessel re-narrowing and then slowly disappear over time. At this time, there are no drug eluding stents, drug coated balloons or bare metal stents approved for use below the knee. Since, there is a limited number of options for stents below the knee, the FDA has granted Esprit BTK breakthrough device designation, which simplifies review and pre-market approval timelines.
According to Abbott, Espirit BTK System is not a permanent implant, but it does provide support to an artery right after a balloon angioplasty, stopping the vessel from reclosing. As soon as it is implanted, the scaffold distributes a drug over a few months that encourages healing and keeps the artery open. The scaffold is naturally resorbed into the body over time, like dissolving sutures, and eventually leaves only a healed artery behind.
The LIFE-BTK trial is the first Investigational Device Exemption trial in the U.S. to evaluate a fully dissoluble device to treat critical limb ischemia in people battling advanced stages of peripheral artery disease (PAD). The trial will be run by principal investigators Brian DeRubertis, M.D. (vascular surgeon, UCLA), Sahil Parikh M.D., (interventional cardiologist, New York-Presbyterian/Columbia University Irving Medical Center.
Targeting Atherosclerotic Plaques with Stents made of Drug-eluting Biomaterials
Reporter: Daniel Menzin, BSc BioMedical Engineering, expected, May 2021, Research Assistant 4, Core Applications Developer and Acting CTO
Atherosclerosis is a chronic cardiovascular disease with a multitude of different implications. A coronary artery plaque may lead to congestive heart failure while an aortic plaque may cause angina. Both can quite possibly lead to a heart attack unless properly managed. One way to manage this condition is through the use of stents made of a mesh that is expanded following placement into the diseased vessel.
Unfortunately, stents are oftentimes initially effective but eventually restenosis occurs. Restenosis is a condition in which the affected vessel becomes blocked again. Cholesterol-rich blood vessel environments oftentimes lead to an irritation that results in white blood cells aggregating in the area and releasing proinflammatory chemokines and cytokines, which cause fibrosis. To make matters worse, the cholesterol plaques undergo compression against the vessel wall which causes vessel injury and further inflammation. This leads to thrombus formation and may potentiate neointimal hyperplasia, an abnormal proliferation and migration of smooth muscle cells in the tunica intima. Neointimal hyperplasia plays a major role in restenosis.
Recent research has found that interfacing drug eluting biomaterials with stents may help prevent restenosis. One study showed that rapamycin delivered with acid labile and ROS-sensitive forms of Beta-cyclodextrin produced promising results when treating atherosclerosis in rat models (Dou, et al). In this promising new paradigm of treatment, non-proinflammatory biomaterials are interfaced with stents. Once inflammation appears the biomaterial will begin to degrade, slowly releasing the drug which suppresses the underlying immune reaction and the resulting inflammation.
SOURCE
Dou Y;Chen Y;Zhang X;Xu X;Chen Y;Guo J;Zhang D;Wang R;Li X;Zhang J; “Non-Proinflammatory and Responsive Nanoplatforms for Targeted Treatment of Atherosclerosis.” Biomaterials, U.S. National Library of Medicine, 29 July 2017, pubmed.ncbi.nlm.nih.gov/28778000/.
Other related articles published in this Open Access Online Scientific Journal include:
Risks from Dual Antiplatelet Therapy (DAPT) may be reduced by Genotyping Guidance of Cardiac Patients
Reporter: Aviva Lev-Ari, PhD, RN
Genotyping Cardiac Patients May Reduce Risks From DAPT
-STEMI patient study reaches noninferiority mark for adverse cardiac events
by Vicki Brower,CME Writer, MedPage Today September 7, 2019
In the investigational arm, all 1,242 patients were tested for CYP2C19 loss-of-function alleles *2 or *3. Carriers received ticagrelor or prasugrel, while noncarriers received clopidogrel, considered to be less powerful.
No genetic testing was performed in the standard treatment arm (n=1,246), in which patients largely went on to receive ticagrelor or prasugrel. Nearly all patients in both cohorts received dual antiplatelet therapy (DAPT) with aspirin.
Following primary PCI, patients went on to the P2Y12 inhibitor for at least 12 months, with drug adherence similar between the genotype-guided (84.5%) and standard groups (82.0%).
For patients with CYP2C19 loss-of-function alleles in the genotype-guided arm, 38% received ticagrelor and 1% received prasugrel. The remaining 61% of patients — the noncarriers — received clopidogrel. In the control arm, 91% were treated with ticagrelor, 2% with prasugrel, and 7% with clopidogrel, according to local protocol.
Ten Berg said that prasugrel is not typically used in the Netherlands, where eight of the centers in the trial were located, but that this might change given that the drug lowered rates of ischemic events versus ticagrelor in the head-to-head ISAR REACT 5 trial, which was also presented at ESC.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
The removal of thrombus under the image guidance, endovascular thrombectomy is preferred for an arterial embolism which is characteristic for an arterial blockage frequently caused by atrial fibrillation, a heart rhythm disorder. An arterial embolism causes restricted blood supply which leads to pain in the affected area. A thrombectomy can too be used to treat conditions in your organs which is usually associated with less benefit and more risk, a large retrospective study found.
Alejandro Spiotta, MD from Medical University of South Carolina in Charleston stated that functional independence rates were 45% for those treated in less than 30 minutes, 33% with procedures 30 to 60 minutes long, and 27% when procedures took more than 60 minutes. The results indicate that complications double after 50 minutes and the mortality risk is significantly for the over 60-minute group than in those treated in 30 to 60 minutes.
Earlier research has shown that when it comes to mechanical thrombectomy, procedure time has a noteworthy effect on patient outcomes. Based on these findings, it seems reasonable to conclude that at 60 minutes, one should consider the futility of continuing the procedure. However, procedures that last longer were connected with increased cost, worse outcomes, and increased incidence of complications, the investigators noted. Yet, the findings underscore the importance of timely recanalization and suggest there’s a point at which continuing to manipulate the intracranial artery may not be helpful for the patient.
Spiotta’s group evaluated 1,357 participants at seven U.S. medical centers, but only 12% out of the patients showed signs of posterior circulation stroke and 46% of cases received IV tissue-type plasminogen activator. The scientists use a prospectively-maintained database which consists of clinical and technical outcomes and baseline variables and can evaluate patients that underwent endovascular thrombectomy with direct aspiration as first pass technique or a stent retriever.
They collected their experience with the benefit of hindsight and joint it together, so there’s always a chance of case ascertain bias or other bias in the collection of the cases. One limitation is the fact that these are quality, busy centers, and the results might even worse if less experienced centers were included. It’s a little bit like getting the cream of the crop and analyzing their data. Upcoming studies should gather data on the relationship between specific thrombectomy devices and techniques and the success of recanalization procedures for patients with AIS.
Today’s lesson 3 explains how extracellular signals are transduced (transmitted) into the cell through receptors to produce an agonist-driven event (effect). This lesson focused on signal transduction from agonist through G proteins (GTPases), and eventually to the effectors of the signal transduction process. Agonists such as small molecules like neurotransmitters, hormones, nitric oxide were discussed however later lectures will discuss more in detail the large growth factor signalings which occur through receptor tyrosine kinases and the Ras family of G proteins as well as mechanosignaling through Rho and Rac family of G proteins.
Transducers: The Heterotrimeric G Proteins (GTPases)
An excellent review of heterotrimeric G Proteins found in the brain is given by
Cyclic AMP is an important second messenger. It forms, as shown, when the membrane enzyme adenylyl cyclase is activated (as indicated, by the alpha subunit of a G protein).
The cyclic AMP then goes on the activate specific proteins. Some ion channels, for example, are gated by cyclic AMP. But an especially important protein activated by cyclic AMP is protein kinase A, which goes on the phosphorylate certain cellular proteins. The scheme below shows how cyclic AMP activates protein kinase A.
Updated 7/15/2019
Additional New Studies on Regulation of the Beta 2 Adrenergic Receptor
We had discussed regulation of the G protein coupled beta 2 adrenergic receptor by the B-AR receptor kinase (BARK)/B arrestin system which uncouples and desensitizes the receptor from its G protein system. In an article by Xiangyu Liu in Science in 2019, the authors describe another type of allosteric modulation (this time a POSITIVE allosteric modulation) in the intracellular loop 2. See below:
Mechanism of β2AR regulation by an intracellular positive allosteric modulator
Xiangyu Liu1,*, Ali Masoudi2,*, Alem W. Kahsai2,*, Li-Yin Huang2, Biswaranjan Pani2, Dean P. Staus2, Paul J. Shim2, Kunio Hirata3,4, Rishabh K. Simhal2, Allison M. Schwalb2, Paula K. Rambarat2, Seungkirl Ahn2, Robert J. Lefkowitz2,5,6,†, Brian Kobilka1
Positive reinforcement in a GPCR
Many drug discovery efforts focus on G protein–coupled receptors (GPCRs), a class of receptors that regulate many physiological processes. An exemplar is the β2-adrenergic receptor (β2AR), which is targeted by both blockers and agonists to treat cardiovascular and respiratory diseases. Most GPCR drugs target the primary (orthosteric) ligand binding site, but binding at allosteric sites can modulate activation. Because such allosteric sites are less conserved, they could possibly be targeted more specifically. Liu et al. report the crystal structure of β2AR bound to both an orthosteric agonist and a positive allosteric modulator that increases receptor activity. The structure suggests why the modulator compound is selective for β2AR over the closely related β1AR. Furthermore, the structure reveals that the modulator acts by enhancing orthosteric agonist binding and stabilizing the active conformation of the receptor.
Abstract
Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2– over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
Recent structures of GPCRs bound to allosteric modulators have revealed that receptor surfaces are decorated with diverse cavities and crevices that may serve as allosteric modulatory sites (1). This substantiates the notion that GPCRs are structurally plastic and can be modulated by a variety of allosteric ligands through distinct mechanisms (2-7). Most of these structures have been solved with negative allosteric modulators (NAMs), which stabilize receptors in their inactive states (1). To date, only a single structure of an active GPCR bound to a small-molecule positive allosteric modulator (PAM) has been reported, namely, the M2 muscarinic acetylcholine receptor with LY2119620 (8). Thus, mechanisms of PAMs and their potential binding sites remain largely unexplored.
Fig 1. Structure of the active state T4L-B2AR in complex with the orthosteric agonist BI-167107, nanobody 689, and compound 6FA. (A) The chemical structure of compound-6FA (Cmpd-6FA). (B) Isoproterenol (ISO) competition binding with 125I-cyanopindolol (CYP) to the β2AR reconstituted in nanodisks in the presence of vehicle (0.32% dimethylsulfoxide; DMSO), Cmpd-6, or Cmpd-6FA at 32 μM. Values were normalized to percentages of the maximal 125I-CYP binding level obtained from a one-site competition binding–log IC50 (median inhibitory concentration) curve fit. Binding curves were generated by GraphPad Prism. Points on curves represent mean ± SEM obtained from five independent experiments performed in duplicate. (C) Analysis of Cmpd-6FA interaction with the BI-167107–bound β2AR by ITC. Representative thermogram (inset) and binding isotherm, of three independent experiments, with the best titration curve fit are shown. Summary of thermodynamic parameters obtained by ITC: binding affinity (KD = 1.2 ± 0.1 μM), stoichiometry (N = 0.9 ± 0.1 sites), enthalpy (ΔH = 5.0 ± 1.2 kcal mol−1), and entropy (ΔS =13 ± 2.0 cal mol−1 deg−1). (D) Side view of T4L-β2AR bound to the orthosteric agonist BI-167107, nanobody 6B9 (Nb6B9), and Cmpd-6FA. The gray box indicates the membrane layer as defined by the OPM database. (E) Close-up view of Cmpd-6FA binding site. Covering Cmpd-6FA is 2Fo– Fc electron density contoured at 1.0 σ (green mesh).From Science 28 Jun 2019:
Vol. 364, Issue 6447, pp. 1283-1287
Fig 3. Fig. 3Mechanism of allosteric activation of the β2AR by Cmpd-6FA.
(A) Superposition of the inactive β2AR bound to the antagonist carazolol (PDB code: 2RH1) and the active β2AR bound to the agonist BI-167107, Cmpd-6FA, and Nb6B9. Close-up view of the Cmpd-6FA binding site is shown. The residues of the inactive (yellow) and active (blue) β2AR are depicted, and the hydrogen bond formed between Asp1303.49and Tyr141ICL2 in the active state is indicated by a black dashed line. (B) Topography of Cmpd-6FA binding surface on the active β2AR (left, blue) and the corresponding surface of the inactive β2AR (right, yellow) with Cmpd-6FA (orange sticks) docked on top. Molecular surfaces are of only those residues involved in interaction with Cmpd-6FA. Steric clash between Cmpd-6FA and the surface of inactive β2AR is represented by a purple asterisk. (C) Overlay of the β2AR bound to BI-167107, Nb6B9, and Cmpd-6FA with the β2AR–Gscomplex (PDB code: 3SN6). The inset shows the position of Phe139ICL2 relative to the α subunit of Gs. (D) Superposition of the active β2AR bound to the agonist BI-167107, Nb6B9, and Cmpd-6FA (blue) with the inactive β2AR bound to carazolol (yellow) (PDB code: 2RH1) as viewed from the cytoplasm. For clarity, Nb6B9 and the orthosteric ligands are omitted. The arrows indicate shifts in the intracellular ends of the TM helices 3, 5, and 6 upon activation and their relative distances.
Allosteric sites may not face the same evolutionary pressure as do orthosteric sites, and thus are more divergent across subtypes within a receptor family (24–26). Therefore, allosteric sites may provide a greater source of specificity for targeting GPCRs.
D. M. Thal, A. Glukhova, P. M. Sexton, A. Christopoulos, Structural insights into G-protein-coupled receptor allostery. Nature 559, 45–53 (2018). doi:10.1038/s41586-018-0259-zpmid:29973731CrossRefPubMedGoogle Scholar
D. Wacker, R. C. Stevens, B. L. Roth, How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170, 414–427 (2017).
D. P. Staus, R. T. Strachan, A. Manglik, B. Pani, A. W. Kahsai, T. H. Kim, L. M. Wingler, S. Ahn, A. Chatterjee, A. Masoudi, A. C. Kruse, E. Pardon, J. Steyaert, W. I. Weis, R. S. Prosser, B. K. Kobilka, T. Costa, R. J. Lefkowitz, Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation. Nature 535, 448–452 (2016). doi:10.1038/nature18636pmid:27409812CrossRefPubMedGoogle Scholar
A. Manglik, T. H. Kim, M. Masureel, C. Altenbach, Z. Yang, D. Hilger, M. T. Lerch, T. S. Kobilka, F. S. Thian, W. L. Hubbell, R. S. Prosser, B. K. Kobilka, Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling. Cell 161, 1101–1111 (2015). doi:10.1016/j.cell.2015.04.043pmid:25981665CrossRefPubMedGoogle Scholar
5, L. Ye, N. Van Eps, M. Zimmer, O. P. Ernst, R. S. Prosser, Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533, 265–268 (2016). doi:10.1038/nature17668pmid:27144352CrossRefPubMedGoogle Scholar
N. Van Eps, L. N. Caro, T. Morizumi, A. K. Kusnetzow, M. Szczepek, K. P. Hofmann, T. H. Bayburt, S. G. Sligar, O. P. Ernst, W. L. Hubbell, Conformational equilibria of light-activated rhodopsin in nanodiscs. Proc. Natl. Acad. Sci. U.S.A. 114, E3268–E3275 (2017). doi:10.1073/pnas.1620405114pmid:28373559Abstract/FREE Full TextGoogle Scholar
R. O. Dror, H. F. Green, C. Valant, D. W. Borhani, J. R. Valcourt, A. C. Pan, D. H. Arlow, M. Canals, J. R. Lane, R. Rahmani, J. B. Baell, P. M. Sexton, A. Christopoulos, D. E. Shaw, Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature 503, 295–299 (2013). doi:10.1038/nature12595pmid:24121438CrossRefPubMedWeb of ScienceGoogle Scholar
A. C. Kruse, A. M. Ring, A. Manglik, J. Hu, K. Hu, K. Eitel, H. Hübner, E. Pardon, C. Valant, P. M. Sexton, A. Christopoulos, C. C. Felder, P. Gmeiner, J. Steyaert, W. I. Weis, K. C. Garcia, J. Wess, B. K. Kobilka, Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101–106 (2013). doi:10.1038/nature12735pmid:24256733
Additional information on Nitric Oxide as a Cellular Signal
Nitric oxide is actually a free radical and can react with other free radicals, resulting in a very short half life (only a few seconds) and so in the body is produced locally to its site of action (i.e. in endothelial cells surrounding the vascular smooth muscle, in nerve cells). In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980s he and others identified this substance as being NO.
Nitric oxide is implicated in many pathologic processes as well. Nitric oxide post translational modifications have been attributed to nitric oxide’s role in pathology however, although the general mechanism by which nitric oxide exerts its physiological effects is by stimulation of soluble guanylate cyclase to produce cGMP, these post translational modifications can act as a cellular signal as well. For more information of NO pathologic effects and how NO induced post translational modifications can act as a cellular signal see the following:
Spectranetics, a Technology Leader in Medical Devices for Coronary Intervention, Peripheral Intervention, Lead Management to be acquired by Philips for 1.9 Billion Euros
Dutch healthcare company Philips (PHG.AS) has agreed to buy U.S.-based Spectranetics Corp (SPNC.O), a maker of devices to treat heart disease, for 1.9 billion euros (£1.68 billion) including debt, as it expands its image-guided therapy business.
Spectranetics uses techniques including lasers and tiny drug-covered balloons to clean the insides of veins and arteries that have become clogged due to heart disease.
Philips will pay Spectranetics shareholders $38.50 per share, a 27 percent premium to their closing price on June 27.
Philips Chief Executive Frans van Houten has transformed the former conglomerate into a focused maker of healthcare equipment over the past five years, spinning off its lighting division (LIGHT.AS) and selling most of its remaining consumer products business.
Philips said Spectranetics, which expects sales of around $300 million this year, will continue to grow revenues at double-digit rates and will begin adding to Philips’ earnings in 2018.
Coronary Artery Disease (CAD) is the leading cause of death among men and women. Each year, one in four deaths are attributed to CAD in the United States, accounting for over a half million lives lost. From scoring balloon technology to laser atherectomy to thrombus aspiration and removal, Spectranetics offers a comprehensive portfolio of solutions to cross, prep and treat compromised vessels. Learn more about CAD by navigating through the tile grid below and exploring the products that are saving lives.
Spectranetics is dedicated to helping physicians cross, prep and treat complex clinical challenges of Peripheral Artery Disease, such as Critical Limb Ischemia, Chronic Total Occlusions and In-Stent Restenosis. We provide expert tools, training, ongoing support and patient education so that you can help eradicate restenosis, and amputation and modify all plaque. Explore the tile grid below to learn more about Peripheral Artery Disease and Spectranetics’ comprehensive portfolio of products to successfully treat this challenging cardiovascular condition at every stage.
Managing cardiac implantable electronic device (CIED) leads has never been more important. Patients with CIEDs are on a lifelong journey, and Spectranetics is there to make sure it’s a healthy one. Making the right decision at the right time, for every patient, is critical. Lives depend on it. Explore the tile grid below to learn more about Lead Management and the products that ensure lead extraction is done safely, responsibly and predictably.
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