Search results for "RIMI"
showing 10 items of 3981 documents
In silico discovery of substituted pyrido[2,3-d]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models
2016
Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant DMPK (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1). Disruption of the CUG repeats and the MBNL1 protein complex has been established as the best therapeutic approach for DM1, hence two main strategies have been proposed: targeted degradation of mutant DMPK transcripts and the development of CUG-binding molecules that prevent MBNL1 sequestration. Herein, suitable CUG-binding small molecules were selected using in silico approach…
2020
Background Small sample sizes combined with multiple correlated endpoints pose a major challenge in the statistical analysis of preclinical neurotrauma studies. The standard approach of applying univariate tests on individual response variables has the advantage of simplicity of interpretation, but it fails to account for the covariance/correlation in the data. In contrast, multivariate statistical techniques might more adequately capture the multi-dimensional pathophysiological pattern of neurotrauma and therefore provide increased sensitivity to detect treatment effects. Results We systematically evaluated the performance of univariate ANOVA, Welch’s ANOVA and linear mixed effects models …
The Effects of Static and Dynamic Visual Representations as Aids for Primary School Children in Tasks of Auditory Discrimination of Sound Patterns. A…
2018
It has been proposed that non-conventional presentations of visual information could be very useful as a scaffolding strategy in the learning of Western music notation. As a result, this study has attempted to determine if there is any effect of static and dynamic presentation modes of visual information in the recognition of sound patterns. An intervention-based quasi-experimental design was adopted with two groups of fifth-grade students in a Spanish city. Students did tasks involving discrimination, auditory recognition and symbolic association of the sound patterns with non-musical representations, either static images (S group), or dynamic images (D group). The results showed neither s…
Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling
2016
Summary Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both in PRG-2 full knockout (KO) and in thalamus-specific KO mice prematurely entered the cortical plate, eventually innervating non-corresponding barrels. This misrouting relied on lost axonal sensitivity toward lysophosphatidic acid (LPA), which failed to repel PRG-2-deficient thalamocortical fibers. PRG-2 electroporation in the PRG-2−/− thalamus restored the aberrant cortical innervation. We ide…
Pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant, recurrent, pre-treated ovarian cancer - Results of the PACOVAR-trial.
2017
Abstract Purpose The prognosis is poor for patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). Evidence suggests that antiangiogenic treatment modalities could play a major role in EOC. A combined therapy consisting of the investigational oral antiangiogenic agent pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, previously treated EOC. Patients and methods This study was designed as a multicenter phase I trial evaluating the optimal dose as well as activity and tolerability of pazopanib with metronomic cyclophosphamide in the treatment of patients with recurrent, platinum-resistant, previously tre…
Ewing's Sarcoma and Peripheral Primitive Neuroectodermal Tumor of Bone and Soft Tissue
1999
The histological diagnosis of Ewing's sarcoma (Es) continues to be a difficult task for pathologists. A number of new Es varieties has been described, leading to further complexity. Conventional Es, atypical Es, and peripheral neuroectodermal tumor (pPNET), including peripheral neuroepithelioma, belong genetically to the same family of neoplasms, displaying common chromosomal rearrangements and analogous gene reorganizations. The main translocations are t(11;22) and t(21;22), with genes EWS, FLI-1 and ERG being involved, as well as other members of the ETS family of transcription factors. The prevalence of morphology should be maintained with the use of conventional histological techniques…
Violent offending in borderline personality disorder and attention deficit/hyperactivity disorder.
2018
Abstract The prevalence of borderline personality disorder (BPD) and attention deficit/hyperactivity disorder (ADHD) is significantly higher among offenders compared to the prevalence found in the general population. Both disorders share important diagnostic characteristics and thus it has been suggested that they might follow a common developmental pathway. In this narrative review, we first discuss the potential links of disorder inherent symptoms such as impulsivity and emotion regulation difficulties and how they might elevate the risk of violent delinquency. We continue with highlighting that comorbidities particularly from the antisocial spectrum as well as comorbid substance use diso…
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
2017
Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of …
Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro-inflammatory environment even in presence of glioblastoma cells
2020
Tumor-associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro-inflammatory switch in primary human monocyte-derived macrophages that reactivates their antitumor activities, thus enhancing the onco-toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages re…
Synthesis of Novel Polyazinyl-Substituted Triazolopyridines from [1,2,3]Triazolo[1,5-a]pyridines
2017
A series of 7-azinyl-substituted triazolopyridines and 3-(6-azinyl-substituted 2-pyridyl)triazolopyridines were synthesized by addition of the corresponding 3-substituted 7-lithiotriazolopyridine to pyrimidine, pyrazine, pyridazine, and 1,3,5-triazine respectively, followed by hydrolysis and oxidation.