Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner

Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non–growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor–induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15, known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen. Mol Cancer Ther; 15(3); 379–91. ©2016 AACR

PCR-Independent Detection of Bacterial Species-Specific 16S rRNA at 10 fM by a Pore-Blockage Sensor.

A PCR-free, optics-free device is used for the detection of Escherichia coli (E. coli) 16S rRNA at 10 fM, which corresponds to ~100-1000 colony forming units/mL (CFU/mL) depending on cellular rRNA levels. The development of a rapid, sensitive, and cost-effective nucleic acid detection platform is sought for the detection of pathogenic microbes in food, water and body fluids. Since 16S rRNA sequences are species specific and are present at high copy number in viable cells, these nucleic acids offer an attractive target for microbial pathogen detection schemes. Here, target 16S rRNA of E. coli at 10 fM concentration was detected against a total RNA background using a conceptually simple approach based on electromechanical signal transduction, whereby a step change reduction in ionic current through a pore indicates blockage by an electrophoretically mobilized bead-peptide nucleic acid probe conjugate hybridized to target nucleic acid. We investigated the concentration detection limit for bacterial species-specific 16S rRNA at 1 pM to 1 fM and found a limit of detection of 10 fM for our device, which is consistent with our previous finding with single-stranded DNA of similar length. In addition, no false positive responses were obtained with control RNA and no false negatives with target 16S rRNA present down to the limit of detection (LOD) of 10 fM. Thus, this detection scheme shows promise for integration into portable, low-cost systems for rapid detection of pathogenic microbes in food, water and body fluids

Pultrusion and compression moulding of thermoplastic pre-impregnated materials reinforced by continuous glass fibres

Four different pre-impregnated materials were used in this study: towpregs and tapes (PCT´s), both produced in our manufacturing lines and commingled fibres (TWINTEX®)) and tapes (CompTape®) supplied by external companies. The laboratory made pre-impregnated materials consisted of carbon and glass fibres and a polypropylene thermoplastic matrix. Pultrusion and heated compression moulding processes were used to obtain composite profiles and plates and were described in this paper. The optimization of those processes was made by studying the influence of the most relevant processing parameters – preheating, heating and cooling inside the die and speed for the pultrusion, and heating temperature, pressure and time for compression moulding - in the final properties of the produced carbon and glass fibres thermoplastic matrix pre-impregnated materials and composites. One interesting target to be achieved was the increase of pultrusion speeds to meet the industrial needs. This was possible particularly with the thermoplastic composite Tape due to its consistency. The composite relevant mechanical properties were determined and the final composites had optical microscopy and calcination tests.Programa Operacional Regional do Norte (NORTE2020), projeto NORTE-01-0145-FEDER-000022 - SciTech - Science and Technology for Competitive and Sustainable Industrie

Production and processing of pre-impregnated thermoplastic tapes by pultrusion and compression moulding

Although there is no doubt that composite materials are the future of lightweight structures and components, most of composites currently produced are made from thermoset polymers, which are not able to be recycled or reprocessed. In contrast, thermoplastic polymers offer the possibility to recycle and reprocess and when combined with a fibrous reinforcement, provide interesting mechanical properties. This work reviews the production of two thermoplastic preimpregnated materials in a tape form, one of which is produced on new prototype equipment developed in our laboratories. The method for the production of tape is described, and the prepregs presented here were subjected to two processing techniques. The first processing method, pultrusion, is an efficient and autonomous method to produce composite profiles, marking itself as a continuous and cost-effective way to produce these materials. Pultrusion bars were then subjected to heated compression moulding, a process that allows to obtain more complex-shaped parts. The second method, heated compression moulding, is a relatively simple process which was used to obtain composite laminates. The pultrusion bars and composite laminates were then subjected to mechanical testing to evaluate the levels of consolidation of the final material. A microscope testing was also carried out to analyse the dispersion of fibres and polymer, as well as the amount of voids present in the composite.Agência Nacional para a Inovação - ANI, Projeto ADD.CompFiber 6960

Classification on imbalanced data sets, taking advantage of errors to improve performance

Classification methods usually exhibit a poor performance when they are applied on imbalanced data sets. In order to overcome this problem, some algorithms have been proposed in the last decade. Most of them generate synthetic instances in order to balance data sets, regardless the classification algorithm. These methods work reasonably well in most cases; however, they tend to cause over-fitting. In this paper, we propose a method to face the imbalance problem. Our approach, which is very simple to implement, works in two phases; the first one detects instances that are difficult to predict correctly for classification methods. These instances are then categorized into “noisy” and “secure”, where the former refers to those instances whose most of their nearest neighbors belong to the opposite class. The second phase of our method, consists in generating a number of synthetic instances for each one of those that are difficult to predict correctly. After applying our method to data sets, the AUC area of classifiers is improved dramatically. We compare our method with others of the state-of-the-art, using more than 10 data sets

Intraoperative tissue classification methods in orthopedic and neurological surgeries: A systematic review

Accurate tissue differentiation during orthopedic and neurological surgeries is critical, given that such surgeries involve operations on or in the vicinity of vital neurovascular structures and erroneous surgical maneuvers can lead to surgical complications. By now, the number of emerging technologies tackling the problem of intraoperative tissue classification methods is increasing. Therefore, this systematic review paper intends to give a general overview of existing technologies. The review was done based on the PRISMA principle and two databases: PubMed and IEEE Xplore. The screening process resulted in 60 full-text papers. The general characteristics of the methodology from extracted papers included data processing pipeline, machine learning methods if applicable, types of tissues that can be identified with them, phantom used to conduct the experiment, and evaluation results. This paper can be useful in identifying the problems in the current status of the state-of-the-art intraoperative tissue classification methods and designing new enhanced techniques

Recovering Nimbus Era Observations at the NASA GES DISC

Between 1964 and 1978, NASA launched a series of seven Nimbus meteorological satellites which provided Earth observations for 30 years. These satellites, carrying a total of 33 instruments to observe the Earth at visible, infrared, ultraviolet, and microwave wavelengths, revolutionized weather forecasting, provided early observations of ocean color and atmospheric ozone, and prototyped location-based search and rescue capabilities. The Nimbus series paved the way for a number of currently operational systems such as the EOS (Earth Observation System) Terra, Aqua, and Aura platforms. The original data archive includes both magnetic tapes and film media. These media are well past their expected end of life, placing at risk valuable data that are critical to extending the history of Earth observations back in time. GES DISC (Goddard Earth Sciences Data and Information Services Center) has been incorporating these data into a modern online archive by recovering the digital data files from the tapes, and scanning images of the data from film strips. The digital data products were written on obsolete hardware systems in outdated file formats, and in the absence of metadata standards at that time, were often written in proprietary file structures. Through a tedious and laborious process, oft-corrupted data are recovered, and incomplete metadata and documentation are reconstructed

Diagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin

Abstract Background Metreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy. Case presentation A 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL. Conclusions Causal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.https://deepblue.lib.umich.edu/bitstream/2027.42/148289/1/40842_2019_Article_76.pd

Sarcopenic Obesity and Myosteatosis Are Associated with Higher Mortality in Patients with Cirrhosis

Background and aims Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients. Methods We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using previously validated gender-and body mass index-specific cutoffs. Results Patients were predominately men (n = 457, 67%), and cirrhosis aetiology was hepatitis C virus in 269 patients (40%), alcohol in 153 (23%), non-alcoholic steatohepatitis/cryptogenic in 96 (14%), autoimmune liver disease in 55 (8%), hepatitis B virus in 43 (6%), and others in 5 patients (1%). Sarcopenia was present in 292 (43%), 135 had sarcopenic obesity (20%) and 353 had myosteatosis (52%). Patients with sarcopenia (22 ± 3 vs. 95 ± 22 months, P = 0.04) were associated with mortality. Conclusions Sarcopenia, sarcopenic obesity and myosteatosis are often present in patients with cirrhosis, and sarcopenia and myosteatosis are independently associated with a higher long-term mortality in cirrhosis