A functional gene expression analysis in epithelial sinonasal cancer: Biology and clinical relevance behind three histological subtypes

Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics. We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses. The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8 + effector memory cells, in SNUC) and \u201cother cells\u201d: keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic \u3b2-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples. Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities

Modelo de Avaliação de Obras de Contenção de Pequenos Movimentos de Massa

Mass movements can be the result of elevated precipitation events and inadequate policies of land use. This study aims at diagnosing the performance of a hillside stabilization structure that suffered a landslide in the meteorological event at the Itajaí Valley in 2008, and to propose a simple method for evaluating reinforcement structures of small mass movement. The study area is located at BR”“470 ”“ km 45, near to the city limit of Gaspar and Blumenau, in Santa Catarina, South Brazil. Tests were performed to determine the infiltration rate and soil moisture, as well as a survey of the floristic composition and slope. The mass movement still takes place and the stabilization structure is compromised. The use of gabion wall and other geotechnical techniques for environmental recovery were insufficient to provide the hillside stabilization. To a greater efficiency we suggest: slope reduction; soil compaction; suitable planting species (ecologic succession); and implementation of a comprehensive drainage system.Movimentos de massa podem ser resultantes de eventos de precipitação elevada e de políticas inadequadas de uso do solo. Este estudo teve como objetivo diagnosticar o desempenho de uma obra de estabilização em uma encosta que sofreu movimentação de massa no evento meteorológico do Vale do Itajaí, em 2008, e propor um método simples de avaliação de pequenas obras de contenção. A área de estudo está localizada na BR”“470 ”“ km 45, próxima à divisa do município de Gaspar e Blumenau, em Santa Catarina. Foram realizados ensaios para determinação da taxa de infiltração e umidade do solo, além de um levantamento da composição florística e da declividade da encosta. Verificou-se que o movimento de massa não foi totalmente estabilizado e que o sistema ainda encontra-se comprometido. A utilização do muro gabião e demais medidas de geotecnia e recuperação ambiental não foram suficientes e eficazes para a estabilização da encosta. Para uma maior eficácia sugere-se: o taludamento da encosta; adensament

A multidisciplinary approach to describe population structure of Solea solea in the Mediterranean Sea

Investigating marine species population structure in a multidisciplinary framework can reveal signatures of potential local adaptation and the consequences for management and conservation. In this study we delineate the population structure of common sole (Solea solea) in the Mediterranean Sea using genomic and otolith data, based on single nucleotide polymorphism (SNPs) markers, otolith shape and otolith trace element composition data. We correlated SNPs with environmental and spatial variables to evaluate the impact of the selected features on the actual population structure. Specifically, we used a seascape genetics approach with redundancy (RDA) and genetic-environmental association (GEA) analysis to identify loci potentially involved in local adaptation. Finally, putative functional annotation was investigated to detect genes associated with the detected patterns of neutral and adaptive genetic variation. Results from both genetic and otolith data suggested significant divergence among putative populations of common sole, confirming a clear separation between the Western and Eastern Mediterranean Sea, as well as a distinct genetic cluster corresponding to the Adriatic Sea. Evidence of fine-scale population structure in the Western Mediterranean Sea was observed at outlier loci level and further differentiation in the Adriatic. Longitude and salinity variation accounted for most of the wide and fine spatial structure. The GEA detected significant associated outlier loci potentially involved in local adaptation processes under highly structured differentiation. In the RDA both spatial distribution and environmental features could partially explain the genetic structure. Our study not only indicates that separation among Mediterranean sole population is led primarily by neutral processes because of low connectivity due to spatial segregation and limited dispersal, but it also suggests the presence of local adaptation. These results should be taken into account to support and optimize the assessment of stock units, including a review and possible redefinition of fishery management units

Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

BACKGROUND: Glycogen Synthase Kinase-3 (GSK-3) \u3b1 and \u3b2 are two serine-threonine kinases controlling insulin, Wnt/\u3b2-catenin, NF-\u3baB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK-3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3\u3b1 and GSK-3\u3b2 function in multiple myeloma (MM). METHODS: GSK-3 \u3b1 and \u3b2 expression and cellular localization were investigated by Western blot (WB) and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 \u3b1 and \u3b2 isoforms. Survival signaling pathways were studied with WB analysis. RESULTS: GSK-3\u3b1 and GSK-3\u3b2 were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles: GSK-3\u3b2 knock down decreased MM cell viability, while GSK-3\u3b1 knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of \u3b2-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3\u3b1 knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself. CONCLUSIONS: These data suggest that in MM cells GSK-3\u3b1 and \u3b2 i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors

Sex differences, gender and addiction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134421/1/jnr23963_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134421/2/jnr23963.pd

Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel

Background: Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray. Methods: A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues' responses. Stata 16.1 software was used for the analyses. Results: Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement. Conclusions: This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs