Development of DuoMYC: a synthetic cell penetrant miniprotein that efficiently inhibits the oncogenic transcription factor MYC.

The master regulator transcription factor MYC is implicated in numerous human cancers, and its targeting is a long-standing challenge in drug development. MYC is a typical 'undruggable' target, with no binding pockets on its DNA binding domain and extensive intrinsically disordered regions. Rather than trying to target MYC directly with classical modalities, here we engineer synthetic miniproteins that can bind to MYC's target DNA, the enhancer box (E-Box), and potently inhibit MYC-driven transcription.

Phosphinate Esters as Novel Warheads for Quenched Activity-Based Probes Targeting Serine Proteases.

Quenched activity-based probes (qABP) are invaluable tools to visualize aberrant protease activity. Unfortunately, most studies so far have only focused on cysteine proteases, and only a few studies describe the synthesis and use of serine protease qABPs. We recently used phosphinate ester electrophiles as a novel type of reactive group to construct ABPs for serine proteases.

Synthetic Peptides: Promising Modalities for the Targeting of Disease-Related Nucleic Acids.

DNA and RNA play pivotal roles in life processes by storing and transferring genetic information, modulating gene expression, and contributing to essential cellular machinery such as ribosomes. Dysregulation and mutations in nucleic acid-related processes are implicated in numerous diseases. Despite the critical impact on health of nucleic acid mutations or dysregulation, therapeutic compounds addressing these biomolecules remain limited.

Duodenal macrophages control dietary iron absorption via local degradation of transferrin.

Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin (Tf), the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood.

Clotrimazole-Based Modulators of the TRPM3 Ion Channel Reveal Narrow Structure-Activity Relationship.

TRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca signaling and opens a non-canonical pore, permeable to Na, which aggravates TRPM3-induced pain. To date, little is known about structural features that govern the Clt modulatory effect of TRPM3.

Phosphinate esters as novel warheads for activity-based probes targeting serine proteases.

Activity-based protein profiling enables the specific detection of the active fraction of an enzyme and is of particular use for the profiling of proteases. The technique relies on a mechanism-based reaction between small molecule activity-based probes (ABPs) with the active enzyme. Here we report a set of new ABPs for serine proteases, specifically neutrophil serine proteases.

Atrial natriuretic peptide (ANP) as an endogenous anxiolytic in patients with heart failure? - No replication of previous results showing an inverse association of anxiety and plasma ANP parameters.

Objective: An acute anxiolytic-like effect of atrial natriuretic peptide (ANP) has been demonstrated in several preclinical and clinical studies. In a so far singular study (Herrmann-Lingen et al., 2003), patients with congestive heart failure, who pathognomonicly display increased plasma ANP, showed a significant inverse association of anxiety symptoms and pro-ANP levels, giving rise to speculations about ANP as an endogenous anxiolytic.

Fracture of an S-ICD lead after two prior transvenous lead-related complications with conventional defibrillators.

Six months after subcutaneous implantable cardioverter defibrillator (S-ICD) implantation a 26-year-old Brugada patient presented because of a beeping tone emitted by his device. Chest X-ray displayed two functionless transvenous shock leads and the S-ICD system with a lead fracture. During lead revision procedure, extensive preparation of the lead from unexpectedly firm surrounding fibrous tissue encapsulating the lead was necessary before it could be removed, and a new shock lead could be implanted.

Feasibility, Safety, and Clinical Performance of Self-apposing Stents for Left Main Stenosis.

Drug-eluting stents (DES) are the gold standard for percutaneous coronary interventions (PCI); however, technical and anatomical challenges need to be addressed to ensure optimal apposition and prevent late adverse events. Complex vessel anatomies, including ectatic or aneurysmatic vessels, or significant differences in diameter in left main stenosis of the coronary artery, are clinical indications in which current PCI techniques attempt to shape conventional DES to follow vessel anatomy, thus modifying the original stent scaffold and its properties. However, due to their design, balloon-expandable cobalt-chromium and cobalt-nickel DES have limitations regarding their expansion capacity, which can result in undersizing and malapposition.

Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction.

Serine proteases comprise about one-third of all proteases, and defective regulation of serine proteases is involved in numerous diseases. Therefore, serine protease inhibitors are promising drug candidates. Aminomethyl diphenyl phosphonates have been regularly used as scaffolds for covalent serine protease inhibition and the design of activity-based probes.

Activity-Based Protein Profiling of Serine Proteases in Immune Cells.

Multiple types of immune cells utilize serine proteases in their mechanisms of defense against pathogens or altered host cells. Dysregulation of the serine protease activity from these cells underlies different diseases. In the past, the technique of activity-based protein profiling proved to be especially useful for the study of proteases, and various studies have used small-molecule activity-based probes to covalently label and detect serine proteases from immune cells.

ATP13A2 deficiency disrupts lysosomal polyamine export.

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome-a parkinsonism with dementia-and early-onset Parkinson's disease. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson's disease, whereas loss of ATP13A2 compromises lysosomes. However, the transport function of ATP13A2 in lysosomes remains unclear.

Recent Advances in Activity-Based Protein Profiling of Proteases.

The activity of proteases is tightly regulated, and dysregulation is linked to a variety of human diseases. For this reason, ABPP is a well-suited method to study protease biology and the design of protease probes has pushed the boundaries of ABPP. The development of highly selective protease probes is still a challenging task.

Clickable Polyamine Derivatives as Chemical Probes for the Polyamine Transport System.

Polyamines are essential for cell growth and differentiation, but their trafficking by the polyamine transport system is not fully understood. Herein, the synthesis of several azido-derivatized polyamines for easy conjugation by click chemistry is described. Attachment of a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dye gave fluorescent polyamine probes, which were tested in cell culture.

The effect of internal thoracic artery grafts on long-term clinical outcomes after coronary bypass surgery.

Objectives: We sought to compare long-term outcomes after coronary bypass surgery with and without an internal thoracic artery graft.

Methods: We analyzed clinical outcomes over a median follow-up of 6.7 years among 3,087 patients who received coronary bypass surgery as participants in one of 8 clinical trials comparing surgical intervention with angioplasty.

Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials.

Background: Coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) are alternative treatments for multivessel coronary disease. Although the procedures have been compared in several randomised trials, their long-term effects on mortality in key clinical subgroups are uncertain. We undertook a collaborative analysis of data from randomised trials to assess whether the effects of the procedures on mortality are modified by patient characteristics.

Endothelin-1 in humans is increased by oxygen-derived radicals ex vivo and in vivo.

Endothelin-1, angiotensin II, and oxygen-derived radicals are pivotal factors in the development and progression of atherosclerosis. In vitro studies suggest that generation of oxygen-derived radicals by angiotensin II is an important mechanism increasing endothelin-1 synthesis, which consecutively may trigger effects such as cell proliferation and hypertrophy. The aim of this study was to confirm our previous data in an ex vivo and an in vivo setting.

Inhibition of xanthine oxidase improves myocardial contractility in patients with ischemic cardiomyopathy.

Reactive oxygen species, in particular superoxide, have been closely linked to the underlying pathophysiology of ischemic cardiomyopathy: superoxide not only mediates mechanoenergetic uncoupling of the myocyte but also adversely impacts on myocardial perfusion by depleting endothelial-derived nitric oxide bioavailability. Xanthine oxidase generates superoxide upon oxidation of hypoxanthine and xanthine and has been detected in cardiac myocytes and coronary endothelial cells of patients with ischemic heart disease. Here we investigated the effects of oxypurinol, a xanthine oxidase inhibitor, on myocardial contractility in patients with ischemic cardiomyopathy.

Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events.

Aims: We investigated the role of asymmetric dimethylarginine (ADMA) for clinical outcome of patients with unstable angina.

Methods And Results: Forty-five patients with stable angina, 36 patients with unstable angina, and 40 healthy controls were included in this study. Coronary artery disease (CAD) patients were prospectively followed for 1 year.

Laser coronary angioplasty: history, present and future.

The efficacy of percutaneous transluminal coronary angioplasty (PTCA) is limited by remaining plaque tissue and the development of restenosis. It has been demonstrated that the restenosis rate is low if a large lumen diameter is achieved after coronary intervention. Debulking of coronary stenoses is a concept to increase the luminal diameter after intervention.