Lessons from LIMK1 enzymology and their impact on inhibitor design

LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding

Active Mass Under Pressure

After a historical introduction to Poisson's equation for Newtonian gravity, its analog for static gravitational fields in Einstein's theory is reviewed. It appears that the pressure contribution to the active mass density in Einstein's theory might also be noticeable at the Newtonian level. A form of its surprising appearance, first noticed by Richard Chase Tolman, was discussed half a century ago in the Hamburg Relativity Seminar and is resolved here.Comment: 28 pages, 4 figure

Traditional and emerging biomarkers in asymptomatic left ventricular dysfunction\u2014promising non-coding rnas and exosomes as biomarkers in early phases of cardiac damage

Heart failure (HF) is one of the major causes of morbidity and mortality worldwide and represents an escalating problem for healthcare systems. The identification of asymptomatic patients with underlying cardiac subclinical disease would create an opportunity for early intervention and prevention of symptomatic HF. Traditional biomarkers are very useful as diagnostic and prognostic tools in the cardiovascular field; however, their application is usually limited to overt cardiac disease. On the other hand, a growing number of studies is investigating the diagnostic and prognostic potential of new biomarkers, such as micro-RNAs (miRNA), long non-coding RNAs, and exosome cargo, because of their involvement in the early phases of cardiac dysfunction. Unfor-tunately, their use in asymptomatic phases remains a distant goal. The aim of this review is to gather the current knowledge of old and novel biomarkers in the early diagnosis of cardiac dysfunction in asymptomatic individuals

What the cardiologist needs to consider in the management of oncologic patients with stemi-like syndrome; A case report and literature review

In pre-hospital care, an accurate and quick diagnosis of ST-segment elevation myocardial infarction (STEMI) is imperative to promptly kick-off the STEMI network with a direct transfer to the cardiac catheterization laboratory (cath lab) in order to reduce myocardial infarction size and mortality. Aa atherosclerotic plaque rupture is the main mechanism responsible for STEMI. However, in a small percentage of patients, emergency coronarography does not reveal any significant coronary stenosis. The fluoropyrimidine agents such as 5-Fluorouracil (5-FU) and capecitabine, widely used to treat gastrointestinal, breast, head and neck cancers, either as a single agent or in combination with other chemotherapies, can cause potentially lethal cardiac side effects. Here, we present the case of a patient with 5-FU cardiotoxicity resulting in an acute coronary syndrome (ACS) with recurrent episodes of chest pain and ST-segment elevation.. Our case report highlights the importance of widening the knowledge among cardiologists of the side effects of chemotherapeutic drugs, especially considering the rising number of cancer patients around the world and that fluoropyrimidines are the main treatment for many types of cancer, both in adjuvant and advanced settings

Gradient catastrophe and flutter in vortex filament dynamics

Gradient catastrophe and flutter instability in the motion of vortex filament within the localized induction approximation are analyzed. It is shown that the origin if this phenomenon is in the gradient catastrophe for the dispersionless Da Rios system which describes motion of filament with slow varying curvature and torsion. Geometrically this catastrophe manifests as a rapid oscillation of a filament curve in a point that resembles the flutter of airfoils. Analytically it is the elliptic umbilic singularity in the terminology of the catastrophe theory. It is demonstrated that its double scaling regularization is governed by the Painlev\'e-I equation.Comment: 11 pages, 3 figures, typos corrected, references adde

Partitioning of bronchopulmonary carcinoids in two different prognostic categories by Ki-67 score

Introduction: Histological distinction between typical and atypical bronchopulmonary car- cinoids is based on mitotic activity and necrosis. Regardless of these two parameters, outcome after surgery is often unpredictable. In this study the prognostic value of different clinico-pathological factors was retrospectively analyzed in a large series of patients with bronchopulmonary carcinoid. Materials and Methods: The long-term post-surgical out- come of 106 radically treated patients affected by bronchopulmonary carcinoid from two Italian centers was correlated with tumor characteristics assessed by combining conven- tional histology with a panel of immunohistochemical markers of neuroendocrine differen- tiation (chromogranin-A, NSE) and proliferation activity (Ki-67 score). Results: Carcinoids were assessed as typical (TC = 75; 70.8%) and atypical (AC = 31; 29.2%). Mean follow-up was 8.3 years (range: 0-20; median: 8.0). All cases expressed neuroendocrine markers. At univariate analysis, tumor recurrence [14/75 TC (18.7%), 15/31 AC (48.4%)] correlated with carcinoid histotype (P = 0.003), tumor size (P = 0.012), mitotic index (P = 0.044), Ki-67 score (P < 0.0001), and synchronous node metastasis (P = 0.037). Of these, Cox multivari- ate analysis confirmed only Ki-67 score as independent predictor of disease recurrence (P = 0.009). The best cut-off for Ki-67 score (calculated by ROC curves) discriminating recurrent vs non-recurrent disease was 4% (sensitivity 79.3%; specificity 83.8%; area under the curve 0.85). By stratifying patients according to this cut-off, a significantly dif- ferent disease-free survival was found (log-rank test P < 0.0001). Conclusion: Ki-67 score accurately separates bronchopulmonary carcinoids in two well-distinct histo-prognostic categories. Ki-67 score predicts the patients outcome better than mitotic count, histotype, and tumor stage and it is therefore helpful in establishing the appropriate follow-up. © 2011 Grimaldi, Muser, Beltrami, Machin, Morelli, Pizzolitto, Talmassons, Marciello, Colao, Monaco, Monaco and Faggiano

Fourier and Gegenbauer expansions for a fundamental solution of the Laplacian in the hyperboloid model of hyperbolic geometry

Due to the isotropy $d$-dimensional hyperbolic space, there exist a spherically symmetric fundamental solution for its corresponding Laplace-Beltrami operator. On the $R$-radius hyperboloid model of $d$-dimensional hyperbolic geometry with $R>0$ and $d\ge 2$, we compute azimuthal Fourier expansions for a fundamental solution of Laplace's equation. For $d\ge 2$, we compute a Gegenbauer polynomial expansion in geodesic polar coordinates for a fundamental solution of Laplace's equation on this negative-constant sectional curvature Riemannian manifold. In three-dimensions, an addition theorem for the azimuthal Fourier coefficients of a fundamental solution for Laplace's equation is obtained through comparison with its corresponding Gegenbauer expansion.Comment: arXiv admin note: substantial text overlap with arXiv:1201.440