Towards the PET radiotracer for p75 neurotrophin receptor: [11C]LM11A-24 shows biological activity in vitro,but unfavorable ex vivo and in vivo profile

Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75^NTR) and sortilin. Aberrant expression of p75^NTR in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease. The goal of this work was to evaluate one of the very few reported p75^NTR small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75^NTR imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75^NTR. Based on this electrophysiological assay, the compound has very high potency with an EC₅₀ <10 nM. We optimized the radiosynthesis of [¹¹C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75^NTR. Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity.     

Chemical probes for tagging mycobacterial lipids

Mycobacteria, which cause tuberculosis and related diseases, possess a diverse set of complex envelope lipids that provide remarkable tolerance to antibiotics and are major virulence factors that drive pathogenesis. Recently, metabolic labeling and bio-orthogonal chemistry have been harnessed to develop chemical probes for tagging specific lipids in live mycobacteria, enabling a range of new basic and translational research avenues. A toolbox of probes has been developed for labeling mycolic acids and their derivatives, including trehalose-, arabinogalactan-, and protein-linked mycolates, as well as newer probes for labeling phthiocerol dimycocerosates (PDIMs) and potentially other envelope lipids. These lipid-centric tools have yielded fresh insights into mycobacterial growth and host interactions, provided new avenues for drug target discovery and characterization, and inspired innovative diagnostic and therapeutic strategies.     

Integral dose based inverse optimization objective function promises lower toxicity in head-and-neck

PurposeThe voxels in a CT data sets contain density information. Besides its use in dose calculation density has no other application in modern radiotherapy treatment planning. This work introduces the use of density information by integral dose minimization in radiotherapy treatment planning for head-and-neck squamous cell carcinoma (HNSCC).Materials and methodsEighteen HNSCC cases were studied. For each case two intensity modulated radiotherapy (IMRT) plans were created: one based on dose-volume (DV) optimization, and one based on integral dose minimization (Energy hereafter) inverse optimization. The target objective functions in both optimization schemes were specified in terms of minimum, maximum, and uniform doses, while the organs at risk (OAR) objectives were specified in terms of DV- and Energy-objectives respectively. Commonly used dosimetric measures were applied to assess the performance of Energy-based optimization. In addition, generalized equivalent uniform doses (gEUDs) were evaluated. Statistical analyses were performed to estimate the performance of this novel inverse optimization paradigm.ResultsEnergy-based inverse optimization resulted in lower OAR doses for equivalent target doses and isodose coverage. The statistical tests showed dose reduction to the OARs with Energy-based optimization ranging from ∼2% to ∼15%.ConclusionsIntegral dose minimization based inverse optimization for HNSCC promises lower doses to nearby OARs. For comparable therapeutic effect the incorporation of density information into the optimization cost function allows reduction in the normal tissue doses and possibly in the risk and the severity of treatment related toxicities.     

Human gastric carcinoma cells targeting peptide-functionalized iron oxide nanoparticles delivery for magnetic resonance imaging

Iron oxide nanoparticles (IONPs) are broadly examined nanomaterials for their promising engagement of the progressive in biomedical application, for intense selective drug delivery and multimodal imaging. IONPs are commonly less price, and enhanced biocompatibility can be effectively functionalized with a broad range of functioning ligand, and have established to be active in improving clinical diagnostics tools and magnetic resonance imaging contrast agents. Consequently, IONPs could be used as a promising magnetic resonance imaging contrast. In this context, we have established an IONPs based framework for the multimodal in vitro imaging approach of gastric cancer cell lines that fast high level of glypican-3 protein (GLY-3) on the superficial. In this regards, a new GLY-3 peptide targeting model established and fabricated to IONPs. The aqueous property, biocompatibility profile and physical-chemical properties of the functionalized IONPs were characterised with various spectroscopical methods. The viability of the gastric SGC-7901 cells was examined by MTT assay. Further, the viability of the cells was evidenced through fluorescence staining methods. The binding ability and cellular uptake properties of naked IONPs and functionalized IONPs (GPC3@IONPs) were examined via laser scanning confocal microscopy (CLSM) in GLY-3 positive gastric cells (SGC-7901 cells). The obtained outcomes displayed that the GLY-3 functionalized IONPs remarkably improved the magnetic resonance imaging contrasts and were actively assured and occupied up by gastric cell lines without damaging the non-cancerous cells.     

Chromobodies to Quantify Changes of Endogenous Protein Concentration in Living Cells

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Highlights

• •Chromobodies are stabilized by antigen binding in live cells.
• •Monitoring changes of endogenous protein levels in living cells with chromobodies.
• •Broadly applicable system to generate turnover-accelerated chromobodies.
• •Quantification of time- and dose-dependent compound effects.

     

An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay

The proteins Orai1 and STIM1 control store-operated Ca²⁺ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca²⁺ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.     

Diagnosis of Distant Metastasis of Lung Cancer: Based on Clinical and Radiomic Features

OBJECTIVES: To analyze the distant metastasis possibility based on computed tomography (CT) radiomic features in patients with lung cancer. METHODS: This was a retrospective analysis of 348 patients with lung cancer enrolled between 2014 and February 2015. A feature set containing clinical features and 485 radiomic features was extracted from the pretherapy CT images. Feature selection via concave minimization (FSV) was used to select effective features. A support vector machine (SVM) was used to evaluate the predictive ability of each feature. RESULTS: Four radiomic features and three clinical features were obtained by FSV feature selection. Classification accuracy by the proposed SVM with SGD method was 71.02%, and the area under the curve was 72.84% with only the radiomic features extracted from CT. After the addition of clinical features, 89.09% can be achieved. CONCLUSION: The radiomic features of the pretherapy CT images may be used as predictors of distant metastasis. And it also can be used in combination with the patient's gender and tumor T and N phase information to diagnose the possibility of distant metastasis in lung cancer.     

Correlation between semitendinosus and gracilis tendon cross-sectional area determined using ultrasound,magnetic resonance imaging and intraoperative tendon measurements

The purpose of this study was to examine the correlation in semitendinosus (ST) and gracilis (GT) tendon cross-sectional area (CSA) evaluated directly during anterior cruciate ligament (ACL) surgery and pre-operatively using ultrasound (US) and magnetic resonance imaging (MRI). A total of 14 patients undergoing ACL reconstruction with a quadruple ST–GT graft by the same orthopaedic surgeon participated in this study. Pre-operative evaluation included determination of ST and GT CSA area using US and MRI. Intraoperative measurement of the diameters of the ST, GT and the final ACL graft using a closed-hole sizing block with 0.5-mm increments was made and this diameter was used to estimate tendon CSA. The correlation between graft diameter and CSA were 0.563 (GT) and 0.807 (ST) for MRI and 0.498 (GT) and 0.612 (ST) for US. The final ACL graft diameter displayed a correlation coefficient of 0.813 with MRI CSA and 0.518 with US CSA. No differences in CSA were observed between intraoperative, MRI and US methods (p > 0.05). The intraclass correlation coefficients between the US, MRI and intraoperative graft methods for the ST and GT data ranged from 0.502 to 0.903 with an estimation error ranging from 1.41% to 2.26%. These results indicate that in clinical situations where MRI is contra-indicated or not accessible, US can provide measurable values which could predict sufficient diameter of the ACL graft. In addition, determination of tendon CSA using US displays errors less than 2% which is similar to that observed using MRI. This suggests that the application of US can be applied to in vivo examination of the ST and GT CSA.