Regulation of PPARγ2 Stability and Activity by SHP-1.

The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) plays an important role in modulating glucose and lipid homeostasis. We previously suggested a potential role of SHP-1 in the regulation of peroxisome proliferator-activated receptor γ2 (PPARγ2) expression and activity but the mechanisms were unexplored. PPARγ2 is the master regulator of adipogenesis, but how its activity is regulated by tyrosine phosphorylation is largely unknown. Here, we found that SHP-1 binds to PPARγ2 primarily via its N-terminal SH2-domain. We confirmed the phosphorylation of PPARγ2 on tyrosine-residue 78 (Y78), which was reduced by SHP-1 in vitro resulting in decreased PPARγ2 stability. Loss of SHP-1 led to elevated, agonist-induced expression of the classical PPARγ2 targets FABP4 and CD36, concomitant with increased lipid content in cells expressing PPARγ2, an effect blunted by abrogation of PPARγ2 phosphorylation. Collectively, we discovered that SHP-1 affects the stability of PPARγ2 through dephosphorylation thereby influencing adipogenesis.

Microscopy-BIDS: An Extension to the Brain Imaging Data Structure for Microscopy Data.

The Brain Imaging Data Structure (BIDS) is a specification for organizing, sharing, and archiving neuroimaging data and metadata in a reusable way. First developed for magnetic resonance imaging (MRI) datasets, the community-led specification evolved rapidly to include other modalities such as magnetoencephalography, positron emission tomography, and quantitative MRI (qMRI). In this work, we present an extension to BIDS for microscopy imaging data, along with example datasets. Microscopy-BIDS supports common imaging methods, including 2D/3D, ex/in vivo, micro-CT, and optical and electron microscopy. Microscopy-BIDS also includes comprehensible metadata definitions for hardware, image acquisition, and sample properties. This extension will facilitate future harmonization efforts in the context of multi-modal, multi-scale imaging such as the characterization of tissue microstructure with qMRI.

The use of a three-dimensional dynamic arm support prevents the development of muscle fatigue during repetitive manual tasks in healthy individuals.

Work-related upper extremity disorders are costly to society due to resulting medical costs, presenteeism and absenteeism. Although their aetiology is likely multifactorial, physical workplace factors are known to play an important role in their development. Promising options for preventing work-related upper extremity disorders include assistive technologies such as dynamic arm supports designed to follow the movement of the arm while compensating for its weight. The objective of this study was to assess the effects of a dynamic arm support on perceived exertion, muscle activity and movement patterns of the upper limb during repetitive manual tasks in healthy individuals. Thirty healthy right-handed individuals were allocated either a static or a dynamic task to perform with and without a dynamic arm support. During the task, surface electromyographic activity (anterior and middle deltoid, upper trapezius) and upper limb kinematics (elbow, shoulder, sternoclavicular) were measured using surface EMG and inertial sensors. Results showed that the dynamic arm support significantly reduced perceived exertion during the tasks and limited the development of muscular fatigue of the anterior and middle deltoid as demonstrated by EMG signal mean epoch amplitudes and median frequency of the EMG power spectrum. The dynamic arm support also prevented a decrease in shoulder elevation and an increase in total shoulder joint excursion during static and dynamic task, respectively. These results denote the potential benefits of dynamic arm supports in work environments. Further studies should focus on their efficacy, acceptability and implementability in work settings.

Rapid, automated nerve histomorphometry through open-source artificial intelligence.

We aimed to develop and validate a deep learning model for automated segmentation and histomorphometry of myelinated peripheral nerve fibers from light microscopic images. A convolutional neural network integrated in the AxonDeepSeg framework was trained for automated axon/myelin segmentation using a dataset of light-microscopic cross-sectional images of osmium tetroxide-stained rat nerves including various axonal regeneration stages. In a second dataset, accuracy of automated segmentation was determined against manual axon/myelin labels. Automated morphometry results, including axon diameter, myelin sheath thickness and g-ratio were compared against manual straight-line measurements and morphometrics extracted from manual labels with AxonDeepSeg as a reference standard. The neural network achieved high pixel-wise accuracy for nerve fiber segmentations with a mean (± standard deviation) ground truth overlap of 0.93 (± 0.03) for axons and 0.99 (± 0.01) for myelin sheaths, respectively. Nerve fibers were identified with a sensitivity of 0.99 and a precision of 0.97. For each nerve fiber, the myelin thickness, axon diameter, g-ratio, solidity, eccentricity, orientation, and individual x -and y-coordinates were determined automatically. Compared to manual morphometry, automated histomorphometry showed superior agreement with the reference standard while reducing the analysis time to below 2.5% of the time needed for manual morphometry. This open-source convolutional neural network provides rapid and accurate morphometry of entire peripheral nerve cross-sections. Given its easy applicability, it could contribute to significant time savings in biomedical research while extracting unprecedented amounts of objective morphologic information from large image datasets.

Comparable clinical course between coagulase-negative staphylococcal and Staphylococcus aureus endocarditis.

PURPOSE: Staphylococcus aureus (SA) is involved in almost one-third of endocarditis events (known as E-SA) and is frequently associated with unfavorable outcomes compared to infectious endocarditis (IE) caused by other pathogens including coagulase-negative staphylococci (CNS). The aim of this study was to compare the morbidity and mortality of patients with E-SA and endocarditis due to CNS (known as E-CNS). METHODS: A monocentric retrospective cohort analysis was conducted including all patients admitted with IE from January 2010 to December 2017. Lengths of stay, complications, in-hospital and 1-year mortality were described from medical records and compared between E-SA and E-CNS. RESULTS: Among the 428 patients included, 102 had staphylococcus (50 E-SA and 52 E-CNS). Half of the IE events due to staphylococcus occurred in the year following a cardiac procedure [p = 0.029]. A septic embolism occurred in 41% and 48% of patients with E-CNS and E-SA, respectively [p = 0.439]. Cardiac surgery was indicated in 50% of E-SA and 48% of E-CNS cases [p = 0.846]. The intra-hospital and 1-year mortality rates were 25% and 31% for E-CNS and 34% and 45% for E-SA [p = 0.699, p = 0.234]. CONCLUSION: Embolic complications, surgical management rate and mortality rates of E-SA and E-CNS were comparable, which may suggest a similar morbidity and mortality irrespective of the pathogen involved in IE.

Impact of telemedicine on diagnosis, clinical management and outcomes in rural trauma patients: A rapid review.

INTRODUCTION: Rural trauma patients are at increased risk of morbidity and mortality compared to trauma patients treated in urban facilities. Factors contributing to this disparity include differences in resource availability and increased time to definitive treatment for rural patients. Telemedicine can improve the early management of these patients by enabling rural providers to consult with trauma specialists at urban centres. The purpose of this study was to assess the impact of telemedicine utilisation on the diagnosis, clinical management and outcomes of rural trauma patients. MATERIALS AND METHODS: A rapid review of the literature was performed using the concepts 'trauma', 'rural' and 'telemedicine'. Fifteen electronic databases were searched from inception to 29th June 2018. Manual searches were also conducted in relevant systematic reviews, key journals and bibliographies of included studies. RESULTS: The literature search identified 187 articles, of which 8 articles were included in the review. All 8 studies reported on clinical management, while the impact of telemedicine use on diagnosis and outcomes was reported in 4 and 5 studies, respectively. Study findings suggest that the use of telemedicine may improve patient diagnosis, streamline the process of transferring patients and reduce length of stay. Use of telemedicine had minimal impact on mortality and complications in rural trauma patients. CONCLUSIONS: The evidence identified by this rapid review suggests that telemedicine may improve the diagnosis, management and outcomes of rural trauma patients. Further research is required to validate these findings by performing large and well-designed studies in rural areas, ideally as randomised clinical trials.

Résumé Introduction: Les traumatisés en région rurale présentent un risque accru de morbidité et de mortalité comparativement aux traumatisés des établissements en région urbaine. Les facteurs qui contribuent à cette disparité sont les différences quant à la disponibilité des ressources et un délai prolongé avant d'accéder au traitement définitif chez les patients des régions rurales. La télémédecine améliore la prise en charge précoce de ces patients en permettant aux fournisseurs en milieu rural de consulter des spécialistes en traumatologie des centres urbains. Cette étude avait pour but d'évaluer l'impact de la télémédecine sur le diagnostic, la prise en charge clinique et les résultats chez les patients traumatisés en milieu rural. Méthodologie: Un examen rapide de la littérature a été effectué à l'aide des mots-clés anglais "trauma", " rural " et "telemedicine". La recherche a eu lieu dans 15 banques de données électroniques à compter de leur lancement jusqu'au 29 juin 2018. Des recherches manuelles ont également été effectuées dans les revues systématiques et publications scientifiques pertinentes et dans les bibliographies des études incluses. Résultats: La recherche de la littérature a donné lieu à 187 articles, dont 8 ont été inclus dans la revue. Les 8 études portaient sur la prise en charge clinique, alors que l'impact de la télémédecine sur le diagnostic et les résultats a fait l'objet de 4 et de 5 études, respectivement. Les résultats des études laissent croire que la télémédecine améliorerait le diagnostic, simplifierait le processus de transfert des patients et raccourcirait le séjour. La télémédecine a eu un effet minime sur la mortalité et les complications chez les patients traumatisés en milieu rural. Conclusions: Les données probantes relevées par cet examen rapide laissent croire que la télémédecine améliorerait le diagnostic, la prise en charge et les résultats chez les patients traumatisés en milieu rural. D'autres recherches sont nécessaires pour valider ces conclusions par l'entremise d'études d'envergure bien conçues menées en régions rurales, idéalement sous forme d'études cliniques à répartition aléatoire. Mots-clés: rural, télémédecine, patients traumatisés en milieu rural, diagnostic des patients en milieu rural.

Coregistered optical coherence tomography and frequency-encoded multispectral imaging for spectrally sparse color imaging.

We present a system combining optical coherence tomography (OCT) and multispectral imaging (MSI) for coregistered structural imaging and surface color imaging. We first describe and numerically validate an optimization model to guide the selection of the MSI wavelengths and their relative intensities. We then demonstrate the integration of this model into an all-fiber bench-top system. We implement frequency-domain multiplexing for the MSI to enable concurrent acquisition of both OCT and MSI at OCT acquisition rates. Such a system could be implemented in endoscopic practices to provide multimodal, high-resolution imaging of deep organ structures that are currently inaccessible to standard video endoscopes.

Characterization of indoor diesel exhaust emissions from the parking garage of a school.

Diesel exhaust (DE) emissions from a parking garage located in the basement of a school were characterized during spring and winter using direct reading devices and integrated sampling methods. Concentrations of CO and NO2 were evaluated using electrochemical sensors and passive colorimetric tubes, respectively. Elemental and total carbon concentrations were measured using the NIOSH 5040 method. Particle number concentrations (PNCs), respirable particulate matter (PMresp) mass concentrations, and size distributions were evaluated using direct reading devices. Indoor concentrations of elemental carbon, PNC, CO, and NO2 showed significant seasonal variation; concentrations were much higher during winter (p < 0.01). Concentrations of the PMresp and total carbon did not show significant seasonal variation. Pearson correlation coefficients were 0.9 (p < 0.01) and 0.94 (p < 0.01) between the parking garage and ground floor average daily PNCs, and between the parking garage and first floor average daily PNCs, respectively. Since DE is the main identified source of fine and ultrafine particles in the school, these results suggest that DE emissions migrate from the parking garage into the school. Our results highlight the relevance of direct reading instruments in identifying migration of contaminants and suggest that monitoring PNC is a more specific way of assessing exposure to DE than monitoring the common PMresp fraction.

SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.

Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.

4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors.

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.

Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]-N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors.

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.

N-(2-Amino-phenyl)-4-(heteroarylmethyl)-benzamides as new histone deacetylase inhibitors.

A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.

Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.

Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.

Substituted N-(2-aminophenyl)-benzamides, (E)-N-(2-aminophenyl)-acrylamides and their analogues: novel classes of histone deacetylase inhibitors.

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.

(2-amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors.

A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.

Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors.

A series of sulfonamide hydroxamic acids and anilides have been synthesized and studied as histone deacetylase (HDAC) inhibitors that can induce hyperacetylation of histones in human cancer cells. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation. The lead candidates were screened in a panel of human tumor and normal cell lines. They selectively inhibit proliferation, cause cell cycle blocks, and induce apoptosis in human cancer cells but not in normal cells. The structure-activity relationships, the antiproliferative activity, and the in vivo efficacy are described.

Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors.

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.

Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors.

A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.