Overlapping Effects of miR-21 Inhibition and Drugs for Idiopathic Pulmonary Fibrosis: Rationale for Repurposing Nintedanib as a Novel Treatment for Ischemia/Reperfusion Injury

ABSTRACT: A specific anti-miR-21 has emerged as an effective treatment for ischemia/reperfusion injury in a pig model of myocardial infarction (MI), but the perspectives for clinical translation are limited. Anti-miR-21 blunts profibrotic pathways, whose excessive activation is detrimental in the post-MI setting. Repurposing antifibrotic drugs approved for other indications is a possible strategy. We compared the molecular effects of anti-miR-21 and the 2 drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone) through a bioinformatic approach. We report that nintedanib and anti-miR-21 share many targets, including the proto-oncogene Rous sarcoma oncogene cellular homolog. Conversely, pirfenidone and anti-miR-21 do not have common mechanisms of action. In summary, the molecular mechanisms activated by nintedanib are partially overlapping with those elicited by anti-miR-21. Nintedanib could be evaluated in animal studies or clinical trials on MI

Prevalence and Prognostic Value of Mesenteric Artery Stenosis in Patients Undergoing Transcatheter Aortic Valve Implantation.

Data regarding the prevalence of mesenteric artery stenosis in patients undergoing transcatheter aortic valve implantation (TAVI) are scarce. Whether patients with high-risk features for acute mesenteric ischemia (AMesI) have a worse prognosis compared with those without high-risk features is unknown. We aimed to address these questions. We included 361 patients who underwent TAVI between 2015 and 2019. Using pre-TAVI computed tomography exams, the number of stenosed arteries in each patient and the degree of stenosis for the coeliac trunk (CTr), SMA and inferior mesenteric artery (IMA) were analyzed. High-risk features for AMesI were defined as the presence of ≥2 arteries presenting with ≥50% stenosis. Patient demographic and echocardiographic data were collected. Endpoints included 30-day all-cause mortality, mortality and morbidity related to mesenteric ischemia. 22.7% of patients had no arterial stenosis, while 59.3% had 1 or 2 stenosed arteries, and 18.0% presented stenoses in 3 arteries. Prevalence of significant stenosis (≥50%) in CTr, SMA, and IMA were respectively 11.9, 5.5, 10.8%. Twenty patients at high-risk for AMesI were identified: they had significantly higher all-cause mortality (15.0 vs. 1.2%, p < 0.001) and higher mortality related to AMesI (5.0 vs. 0.3%, p = 0.004), compared with non-high-risk patients. Patients at high-risk for AMesI presented with significantly higher 30-day all-cause mortality and mortality related to AMesI following TAVI. Mesenteric revascularization before TAVI interventions may be beneficial in these patients. Prospective studies are needed to clarify these questions

Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders

Biological behavior of familial papillary thyroid microcarcinoma: Spanish multicenter study

Purpose Familial papillary thyroid microcarcinoma (FPTMC) can present a more aggressive behavior than the sporadic microcarcinoma. However, few studies have analyzed this situation. The objective is to analyze the recurrence rate of FPTMC and the prognostic factors which determine that recurrence in Spain. Methods Spanish multicenter longitudinal analytical observational study was conducted. Patients with FPTMC received treatment with curative intent and presented cure criteria 6 months after treatment. Recurrence rate and disease-free survival (DFS) were analyzed. Two groups were analyzed: group A (no tumor recurrence) vs. group B (tumor recurrence). Results Ninety-four patients were analyzed. During a mean follow-up of 73.3 +/- 59.3 months, 13 recurrences of FPTMC (13.83%) were detected and mean DFS was 207.9 +/- 11.5 months. There were multifocality in 56%, bilateral thyroid involvement in 30%, and vascular invasion in 7.5%; that is to say, they are tumors with histological factors of poor prognosis in a high percentage of cases. The main risk factors for recurrence obtained in the multivariate analysis were the tumor size (OR: 2.574, 95% CI 1.210-5.473; p = 0.014) and the assessment of the risk of recurrence of the American Thyroid Association (ATA), both intermediate risk versus low risk (OR: 125, 95% CI 10.638-1000; p < 0.001) and high risk versus low risk (OR: 45.454, 95% CI 5.405-333.333; p < 0.001). Conclusion FPTMC has a recurrence rate higher than sporadic cases. Poor prognosis is mainly associated with the tumor size and the risk of recurrence of the ATA

Branch-and-lift algorithm for deterministic global optimization in nonlinear optimal control

This paper presents a branch-and-lift algorithm for solving optimal control problems with smooth nonlinear dynamics and potentially nonconvex objective and constraint functionals to guaranteed global optimality. This algorithm features a direct sequential method and builds upon a generic, spatial branch-and-bound algorithm. A new operation, called lifting, is introduced, which refines the control parameterization via a Gram-Schmidt orthogonalization process, while simultaneously eliminating control subregions that are either infeasible or that provably cannot contain any global optima. Conditions are given under which the image of the control parameterization error in the state space contracts exponentially as the parameterization order is increased, thereby making the lifting operation efficient. A computational technique based on ellipsoidal calculus is also developed that satisfies these conditions. The practical applicability of branch-and-lift is illustrated in a numerical example. © 2013 Springer Science+Business Media New York

On the treatment of soil water stress in GCM simulations of vegetation physiology

Current land surface schemes in weather and climate models make use of the so-called coupled photosynthesis–stomatal conductance (A–gs) models of plant function to determine the surface fluxes that govern the terrestrial energy, water and carbon budgets. Plant physiology is controlled by many environmental factors, and a number of complex feedbacks are involved, but soil moisture control on root water uptake is primary, particularly in sub-tropical to temperate ecosystems. Land surface models (LSMs) represent plant water stress in different ways, but most implement a water stress factor, beta, which ranges linearly (more recently also curvilinearly) between beta =1 for unstressed vegetation and beta = 0 at the wilting point, expressed in terms of volumetric water content ("θ" ). beta is most commonly used to either limit A or gs, and hence carbon and water fluxes, and a pertinent research question is whether these treatments are in fact interchangeable. Following Egea et al. (2011) and Verhoef and Egea (2014), we have implemented new beta treatments, reflecting higher levels of biophysical complexity in a state-of-the-art LSM, JULES, by allowing root zone soil moisture to limit plant function non-linearly and via individual routes (carbon assimilation, stomatal conductance, or mesophyll conductance) as well as any (non-linear) combinations thereof. The treatment of beta does matter to the prediction of water and carbon fluxes: this study demonstrates that it represents a key structural uncertainty in contemporary LSMs, in terms of predictions of GPP, energy fluxes and soil moisture evolution, both in terms of climate means and response to a number of European droughts, including the 2003 heat wave. Treatments allowing beta to act on vegetation fluxes via stomatal and mesophyll routes are able to simulate the spatiotemporal variability in water use efficiency with higher fidelity during the growing season; they also support a broader range of ecosystem responses, e.g. those observed in regions that are radiation limited or water limited. We conclude that current practice in weather and climate modelling is inconsistent, as well as too simplistic, failing to credibly simulate vegetation response to soil water stress across the typical range of variability that is encountered for current European weather and climate conditions, including extremes of land surface temperature and soil moisture drought. A generalized approach performs better in current climate conditions and promises to be, based on responses to recently observed extremes, more trustworthy for predicting the impacts of climate change

Comparative fruit quality parameters of ‘Ninfa’ apricot (Prunus armeniaca L.) grafted on two different rootstocks in a newly established organic orchard

The fruit quality parameters of Prunus armeniaca L. cv ‘Ninfa’ grafted on ‘Myrobalan 29C’ (Prunus cerasifera Ehrh.) and ‘Real Fino’ apricot seedling (Prunus armeniaca L.) were analysed in an experimental orchard under organic management. The study was performed between 2010 and 2012 in the province of Seville (SW Spain). Colour, fruit and stone weights, firmness, soluble solid concentration, and acidity were measured for fruit quality evaluation. Trunk cross-sectional area, main branches, and fruit yield were also determined. In general, ‘Myrobalan 29C’ rootstock produced fruit slightly larger in size and with a bigger weight. By contrast, apricots on ‘Myrobalan 29C’ had less firmness and a lower solid soluble concentration than on ‘Real Fino’. There was little difference in the colour, acidity, and stone dry weights. Trees on ‘Real Fino’ had larger areas of trunk and branches but no significant differences were obtained in relation to fruit yields

Hybrid optimization method with general switching strategy for parameter estimation

This article is available from: http://www.biomedcentral.com/1752-0509/2/26[Background] Modeling and simulation of cellular signaling and metabolic pathways as networks of biochemical reactions yields sets of non-linear ordinary differential equations. These models usually depend on several parameters and initial conditions. If these parameters are unknown, results from simulation studies can be misleading. Such a scenario can be avoided by fitting the model to experimental data before analyzing the system. This involves parameter estimation which is usually performed by minimizing a cost function which quantifies the difference between model predictions and measurements. Mathematically, this is formulated as a non-linear optimization problem which often results to be multi-modal (non-convex), rendering local optimization methods detrimental.[Results] In this work we propose a new hybrid global method, based on the combination of an evolutionary search strategy with a local multiple-shooting approach, which offers a reliable and efficient alternative for the solution of large scale parameter estimation problems.[Conclusion] The presented new hybrid strategy offers two main advantages over previous approaches: First, it is equipped with a switching strategy which allows the systematic determination of the transition from the local to global search. This avoids computationally expensive tests in advance. Second, using multiple-shooting as the local search procedure reduces the multi-modality of the non-linear optimization problem significantly. Because multiple-shooting avoids possible spurious solutions in the vicinity of the global optimum it often outperforms the frequently used initial value approach (single-shooting). Thereby, the use of multiple-shooting yields an enhanced robustness of the hybrid approach.This work was supported by the European Community as part of the FP6 COSBICS Project (STREP FP6-512060), the German Federal Ministry of Education and Research, BMBF-project FRISYS (grant 0313921) and Xunta de Galicia (PGIDIT05PXIC40201PM).Peer reviewe