GSK-3 as potential target for therapeutic intervention in cancer

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others

Scheduling M2M traffic over LTE uplink of a dense small cell network

We present an approach to schedule Long Term Evolution (LTE) uplink (UL) Machine-to-Machine (M2M) traffic in a densely deployed heterogeneous network, over the street lights of a big boulevard for smart city applications. The small cells operate with frequency reuse 1, and inter-cell interference (ICI) is a critical issue to manage. We consider a 3rd Generation Partnership Project (3GPP) compliant scenario, where single-carrier frequency-division multiple access (SC-FDMA) is selected as the multiple access scheme, which requires that all resource blocks (RBs) allocated to a single user have to be contiguous in the frequency within each time slot. This adjacency constraint limits the flexibility of the frequency-domain packet scheduling (FDPS) and inter-cell interference coordination (ICIC), when trying to maximize the scheduling objectives, and this makes the problem NP-hard. We aim to solve a multi-objective optimization problem, to maximize the overall throughput, maximize the radio resource usage and minimize the ICI. This can be modelled through a mixed-integer linear programming (MILP) and solved through a heuristic implementable in the standards. We propose two models. The first one allocates resources based on the three optimization criteria, while the second model is more compact and is demonstrated through numerical evaluation in CPLEX, to be equivalent in the complexity, while it performs better and executes faster. We present simulation results in a 3GPP compliant network simulator, implementing the overall protocol stack, which support the effectiveness of our algorithm, for different M2M applications, with respect to the state-of-the-art approaches

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19

Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19

Objective: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. // Methods: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. // Results: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). // Conclusion: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD

Theorising age and generation in development: A relational approach

This introduction outlines the analytical approach informing the articles presented in this special issue. The project of ‘generationing’ development involves re-thinking development as distinctly generational in its dynamics. For this, we adopt a relational approach to the study of young people in development, which overcomes the limitations inherent to common categorising approaches. Concepts of age and generation are employed to conceptualise young people as social actors and life phases such as childhood and youth in relational terms. Acknowledging the centrality of young people in social reproduction puts them at the heart of development studies and leads the articles comprising this special issue to explore how young people’s agency shapes and is shaped by the changing terms of social reproduction brought about by development

Novel Combination of Sorafenib and Celecoxib Provides Synergistic Anti-Proliferative and Pro-Apoptotic Effects in Human Liver Cancer Cells

Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies

Application of frequency ratio, statistical index, and weights-of-evidence models and their comparison in landslide susceptibility mapping in Central Nepal Himalaya

The Mugling–Narayanghat road section falls within the Lesser Himalaya and Siwalik zones of Central Nepal Himalaya and is highly deformed by the presence of numerous faults and folds. Over the years, this road section and its surrounding area have experienced repeated landslide activities. For that reason, landslide susceptibility zonation is essential for roadside slope disaster management and for planning further development activities. The main goal of this study was to investigate the application of the frequency ratio (FR), statistical index (SI), and weights-of-evidence (WoE) approaches for landslide susceptibility mapping of this road section and its surrounding area. For this purpose, the input layers of the landslide conditioning factors were prepared in the first stage. A landslide inventory map was prepared using earlier reports, aerial photographs interpretation, and multiple field surveys. A total of 438 landslide locations were detected. Out these, 295 (67 %) landslides were randomly selected as training data for the modeling using FR, SI, and WoE models and the remaining 143 (33 %) were used for the validation purposes. The landslide conditioning factors considered for the study area are slope gradient, slope aspect, plan curvature, altitude, stream power index, topographic wetness index, lithology, land use, distance from faults, distance from rivers, and distance from highway. The results were validated using area under the curve (AUC) analysis. From the analysis, it is seen that the FR model with a success rate of 76.8 % and predictive accuracy of 75.4 % performs better than WoE (success rate, 75.6 %; predictive accuracy, 74.9 %) and SI (success rate, 75.5 %; predictive accuracy, 74.6 %) models. Overall, all the models showed almost similar results. The resultant susceptibility maps can be useful for general land use planning

Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)haloimines

Highly optically enriched, protected, nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines, and azepanes bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.This work was generously supported by the Spanish Ministerio de Ciencia e Innovación (MICINN; grant no. CONSOLIDER INGENIO 2010, CSD2007-00006, CTQ2007-65218 and CTQ2011-24151) and the Generalitat Valenciana (PROMETEO/2009/039 and FEDER). O.P. thanks the Spanish Ministerio de Educación for a predoctoral fellowship (grant no. AP-2008-00989)

A point mutation in cpsE renders Streptococcus pneumoniae nonencapsulated and enhances its growth, adherence and competence.

BACKGROUND: The polysaccharide capsule is a major virulence factor of the important human pathogen Streptococcus pneumoniae. However, S. pneumoniae strains lacking capsule do occur. RESULTS: Here, we report a nasopharyngeal isolate of Streptococcus pneumoniae composed of a mixture of two phenotypes; one encapsulated (serotype 18C) and the other nonencapsulated, determined by serotyping, electron microscopy and fluorescence isothiocyanate dextran exclusion assay.By whole genome sequencing, we demonstrated that the phenotypes differ by a single nucleotide base pair in capsular gene cpsE (C to G change at gene position 1135) predicted to result in amino acid change from arginine to glycine at position 379, located in the cytoplasmic, enzymatically active, region of this transmembrane protein. This SNP is responsible for loss of capsule production as the phenotype is transferred with the capsule operon. The nonencapsulated variant is superior in growth in vitro and is also 117-fold more adherent to and more invasive into Detroit 562 human epithelial cells than the encapsulated variant.Expression of six competence pathway genes and one competence-associated gene was 11 to 34-fold higher in the nonencapsulated variant than the encapsulated and transformation frequency was 3.7-fold greater. CONCLUSIONS: We identified a new single point mutation in capsule gene cpsE of a clinical S. pneumoniae serotype 18C isolate sufficient to cause loss of capsule expression resulting in the co-existence of the encapsulated and nonencapsulated phenotype. The mutation caused phenotypic changes in growth, adherence to epithelial cells and transformability. Mutation in capsule gene cpsE may be a way for S. pneumoniae to lose its capsule and increase its colonization potential