Gephyrin Selective Intrabodies as a New Strategy for Studying Inhibitory Receptor Clustering

The microtubule-binding protein gephyrin is known to play a pivotal role in targeting and clustering postsynaptic inhibitory receptors. Here, the Intracellular Antibodies Capture Technology (IATC) was used to select two single-chain antibody fragments or intrabodies, which, fused to nuclear localization signals (NLS), were able to efficiently and selectively remove gephyrin from glycine receptor (GlyR) clusters. Co-transfection of NLS-tagged individual intrabodies with gephyrin-enhanced green fluorescent protein (EGFP) in HEK 293 cells revealed a partial relocalization of gephyrin aggregates onto the nucleus or in the perinuclear area. When expressed in cultured neurons, these intrabodies caused a significant reduction in the number of immunoreactive GlyR clusters, which was associated with a decrease in the peak amplitude of glycine-evoked whole cell currents as assessed with electrophysiological experiments. Hampering protein function at a posttranslational level may represent an attractive alternative for interfering with gephyrin function in a more spatially localized manner

Exercise and bone health in cancer: enemy or ally?

Simple Summary Patients with cancer may face bone metastases and osteoporosis due to cancer or treatments, leading to a high risk of developing skeletal-related events. Skeletal-related events may negatively affect patients' quality and length of life. Although physical exercise has been recognized as a potential adjunctive strategy in the cancer setting, it is often not recommended to patients with bone health impairments due to safety concerns. In the present review, we explore the effects of exercise on safety profile, bone health, and the impact on functional outcomes in patients with cancer affected by bone metastasis, osteoporosis/osteopenia, or at high risk of losing bone. Moreover, the underlying mechanisms of the beneficial effect of exercise on bone are explored, and considerations about exercise prescription are discussed. Bone health is often threatened in cancer patients. Bone metastasis and osteoporosis frequently occur in patients with cancer and may lead to different skeletal-related events, which may negatively affect patients' quality of life and are associated with high mortality risk. Physical exercise has been recognized as a potential adjunctive strategy in the cancer setting to improve physical function as well as treatment-related side effects. Nevertheless, exercise is often not recommended to patients with bone health impairments due to safety concerns. In the current review, we aimed, through a comprehensive review of the evidence, to explore the impact of exercise in terms of safety profile, bone outcomes, and the effects on other outcomes in patients with cancer affected by bone metastasis or at high risk of losing bone. Additionally, we explored the potential mechanisms by which exercise may act on bone, particularly the impact of mechanical load on bone remodeling. Finally, considerations about exercise prescription and programming in these populations are also discussed

The risk of late or advanced presentation of HIV infected patients is still high, associated factors evolve but impact on overall mortality is vanishing over calendar years: Results from the Italian MASTER Cohort

BACKGROUND: We aimed at evaluating frequency and factors associated with late presentation and advanced HIV disease and excess risk of death due to these conditions from 1985 to 2013 among naïve HIV infected patients enrolled in the Italian MASTER Cohort. METHODS: All antiretroviral naive adults with available CD4+ T cell count after diagnosis of HIV infection were included. Multivariable logistic regression analysis investigated factors associated either with late presentation or advanced HIV disease. Probabilities of survival were estimated both at year-1 and at year-5 according to the Kaplan-Meier method. Flexible parametric models were used to evaluate changes in risk of death overtime according to late presentation and advanced HIV disease. The analyses were stratified for calendar periods. RESULTS: 19,391 patients were included (54 % were late presenters and 37.6 % were advanced presenters). At multivariable analysis, the following factors were positively associated with late presentation: male gender (OR = 1.29), older age (≥55 years vs. <25 years; OR = 7.45), migration (OR = 1.54), and heterosexual risk factor for HIV acquisition (OR = 1.52) or IDU (OR = 1.27) compared to homosexual risk. Survival rates at year-5 increased steadily and reached 92.1 % for late presenters vs. 97.4 % for non-late presenters enrolled in the period 2004-2009. Using flexible parametric models we found a sustained reduction of hazard ratios over time for any cause deaths between late and non-late presenters over time. Similar results were found for advanced HIV disease. CONCLUSION: Screening polices need to be urgently implemented, particularly in most-at-risk categories for late presentation, such as migrants, older patients and those with heterosexual intercourse or IDU as risk factors for HIV acquisition. Although in recent years the impact of late presentation on survival decreased, about 10 % of patients diagnosed in more recent years remains at increased risk of death over a long-term follow-up

CWC simulator (Calculus of Wrapped Compartments)

The CWC simulator is a simulation tool for the Calculus of Wrapped Compartments (CWC) that is based on Gillespie’s direct method supporting the simulation and the analysis simulating biological phenomena. The CWC simulator is parallel application able to exploit the full power of multicore platforms by way of the fastflow lock-free C++ library

Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study.

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients

The prognostic role of systemic inflammatory markers on HIV-infected patients with non-Hodgkin lymphoma, a multicenter cohort study

BACKGROUND: The systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. We aimed to assess the prognostic role of inflammatory markers on survival in HIV-infected patients with Non-Hodgkin Lymphoma (NHL), and to compute a prognostic score based on inflammatory biomarkers. METHODS: We evaluated data on HIV patients with NLH diagnosis between 1998 and 2012 in a HIV Italian Cohort. Using Cox proportional regression model, we assessed the prognostic role of Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). We also computed a risk score equation, assigning patients to a derivation and a validation sample. The area under the curve (AUC) was use to evaluate the predictive ability of this score. RESULTS: 215 non-Hodgkin lymphoma cases (80.0% males) with a mean age of 43.2 years were included. Deaths were observed in 98 (45.6%) patients during a median follow up of 5 years. GPS, mGPS, PI and PNI were independently associated with risk of death. We also computed a mortality risk score which included PNI and occurrence of an AIDS event within six months from NHL diagnosis. The AUCs were 0.69 (95% CI 0.58 to 0.81) and 0.69 (95% CI 0.57 to 0.81) at 3 and 5 years of the follow-up, respectively. CONCLUSIONS: GPS, mGPS, PI and PNI are independent prognostic factors for survival of HIV patients with NH

A ligação entre o balanced scorecard e o scenario planning em contexto empresarial

Mestrado em Controlo de Gestão e dos NegóciosCom a chegada do século XXI, estão a ocorrer no mundo diversas transformações económicas, tecnológicas e sociais, o que contribui para um aumento das incertezas. A elaboração da estratégia assume-se cada vez mais, como um fator critico de sucesso, nesse sentido o Balanced Scorecard surge como uma ferramenta de extrema importância, contudo estima-se que 70 por cento dos Balanced Scorecard implementados falharam (McCunn, 1998), seja por dificuldades na implementação por parte das organizações, seja por limitação do próprio método. Por forma a se tentar colmatar estas falhas, o presente trabalho tem por objetivo efetuar a ligação entre o Balanced Scorecard e o Scenario Planning, por forma a verificar se estas duas ferramentas se complementam e assim se consegue minimizar as limitações identificadas na implementação do Balanced Scorecard, como tal, foi efetuado um estudo de caso com a empresa Suma, onde se elaborou cenários prospetivos para o horizonte temporal 2019-2030, bem como se definiu com base nesses cenários, estratégias, objetivos e metas para o Balanced Scorecard.With the arrival of the 21st century, economic, technological and social transformations are taking place in the world, which contributes to an increase of uncertainties. The elaboration of the strategy is increasingly becoming a critical success factor. Scorecard emerges as an extremely important tool, however it is estimated that 70 percent of the Balanced Scorecard implemented has failed (McCunn, 1998), either due to difficulties in implementation by organizations, or by limitation of the method itself, the present work aims to make the connection between the Balanced Scorecard and Scenario Planning, in order to verify if these two tools complement each other and thus it is possible to minimize the limitations identified in the implementation of the Balanced Scorecard, as such, a case study was conducted with Suma company, which prepared prospective scenarios for the 2019-2030 time horizon, as well as defined based on these scenarios, objectives and goals for the Balanced Scorecard.info:eu-repo/semantics/publishedVersio

West Nile Virus Outbreak in the Lombardy Region, Northern Italy, Summer 2013

In the summer of 2013, an outbreak of West Nile virus (WNV) infection occurred in the Lombardy, a region of northern Italy to the west of districts affected by WNV in previous years. Eighteen cases of human WNV infection were diagnosed—10 cases of acute WNV neuroinvasive disease and eight of WNV fever. In the same period, WNV was detected in birds (one crow) in horses (11 cases) and from mosquitoes (six pools)