36 research outputs found
Myasthenia Gravis Treatment: From Old Drugs to Innovative Therapies with a Glimpse into the Future
No full text: Myasthenia gravis (MG) is a rare autoimmune disease that causes debilitating muscle weakness due to impaired neuromuscular transmission. Since most (about 80-90%) MG patients present autoantibodies against the acetylcholine receptor, standard medical therapy consists of symptomatic treatment with acetylcholinesterase inhibitors (e.g., pyridostigmine). In addition, considering the autoimmune basis of MG, standard therapy includes immunomodulating agents, such as corticosteroids, azathioprine, cyclosporine A, and cyclophosphamide. New strategies have been proposed for the treatment of MG and include complement blockade (i.e., eculizumab, ravulizumab, and zilucoplan) and neonatal Fc receptor antagonism (i.e., efgartigimod and rozanolixizumab). The aim of this review is to provide a detailed overview of the pre- and post-marketing evidence on the five pharmacological treatments most recently approved for the treatment of MG, by identifying both preclinical and clinical studies registered in clinicaltrials.gov. A description of the molecules currently under evaluation for the treatment of MG is also provided
Infrastructural Projects and Territorial Development in Veneto Dolomites: Evaluation of Performances through AHP
No full textAbstractThe ensemble of European traffic roads is changing in relation to the economic geography that has been developing these recent years and also to the localisation of production centres, logistics and the demand linked to the transportation of goods. The development of communication has been defined through the project of the Trans-European Transport Network (TEN-T). This network has been progressively defined until it has reached the present architecture in which Italy is crossed by four of the nine total corridors that compose the whole network - which means by almost half of the main traffic roads at European level -. Undoubtedly this new geography of European communication offers member States new development opportunities, but it is also true that the distance of the different territories from the major traffic roads can be a disparity factor. In fact, this phenomenon can worsen the marginalisation processes of some European territories, contrary to the objective of the interconnection policy of the EU territories. In front of these possible territorial disparities, the Planning discipline in Italy has not been adequately questioned, aiming instead at the research of the “territorial patching up”, progressively decreasing, rather than at the exploration of new development forms. As a consequence, mobility planning becomes strategic for Italy, especially for its Alpine area. Hence the need to set up valid tools for the environmental evaluation as regards planning and programmes, such as the Strategic Environmental Assessment (SEA), but also projects, as the Environmental Impact Assessment (EIA). The idea to realise an important road infrastructure, which may connect Belluno directly with Austria, is presented in this paper as an emblematic case, in which the application of the Analytic Hierarchy Process (AHP) permits to verify the best performing infrastructure on a territorial scale
A Figbash is Not a Fantod: Preparing the John A. Carollo Edward Gorey Collection for Exhibit at the University of Hawai‘i at Mānoa
No full textA Figbash is Not a Fantod: Preparing the John A. Carollo Edward Gorey Collection for Exhibit at the University of Hawai‘i at Mānoa
Marguerite Simpson, December 10, 2010. LIS 653 / Seminar in Archival Studies; Supervisor: Deborah Dunn; Instructor: Dr. Andrew Wertheimer.
Collection Overview: Donated incrementally to Hamilton Library by passionate Gorey collector John A. Carollo, beginning in 1998. Currently managed by the Special Research Collections (SRC), a new entity dedicated to making the treasures of the library available to student, faculty, and public researchers. Carollo’s gift to Hamilton constitutes the most comprehensive public collection of the prolific author/artist’s work in the world. Materials include: Monographs; Coffee mugs; A fur coat; Postcards; Books arts materials; Hand sewn stuffed animals; Serials; LPs; Fine art prints; Original cover art; Calendars; Jewelry; An umbrella; And more!
The Exhibit; Preliminary Preparation: Reconciling the inventory, Condition reports, Controlled vocabulary; Exhibit Preparation: During Selection, After Selection – Organization, Preparation.
Cooperation as Our Key to Success: Preparation of this collection for exhibit would have been impossible without Hamilton’s dedicated staff and willing volunteers coming together in a library-wide effort. For example, cataloging graciously rushed many items to ensure that they were properly catalogued before being loaned, and the University Archives allowed us use of their facilities for selection and treatment activities
Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes
No full textBackground: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication has only been focused on soluble factors, although increasing evidence highlights the key role of extracellular vesicles (EVs) in the modulation of tumor progression. Methods and Results: In the present study, we found that EVs derived from 3T3-L1 adipocytes could affect PC3 and DU145 PCa cell traits, inducing increased proliferation, migration and invasion. Furthermore, conditioning of both PCa cell lines with adipocyte-released EVs resulted in lower sensitivity to docetaxel, with reduced phosphatidylserine externalization and decreased caspase 3 and PARP cleavage. In particular, these alterations were paralleled by an Akt/HIF-1α axis-related Warburg effect, characterized by enhanced glucose consumption, lactate release and ATP production. Conclusions: Collectively, these findings demonstrate that EV-mediated crosstalk exists between adipocytes and PCa, driving tumor aggressiveness
Investigations into the roles of Histamine Receptor H1 and extracellular vesicles in ovarian cancer cell behaviour
No full textOvarian cancer (OC) diagnosis usually occurs very late, when metastatic spread has already started and patient’s survival is very low. One of the many soluble factors that can promote cancer metastasis is histamine, a compound involved in a plethora of physiological and pathological processes, including cancer. Indeed, activation of histamine receptor H1 (HRH1) by histamine stimulates growth of OC cells in vitro and promotes the release of extracellular vesicles (EVs) in different cell lines. EVs are heterogeneous small vesicles involved in intracellular communication, which also modulate various steps of the metastatic process.
The main hypothesis of this thesis is that HRH1 mediates several cancerous behaviours associated with OC metastatic spread, by regulating EV release. The specific aims were 1) to analyse the correlation of histamine receptors gene expression with invasion and migration rates of OC cell lines in vitro and with tumour stage of OC clinical samples; 2) to study the involvement of HRH1 in different cellular behaviours associated with cancer metastasis; 3) to investigate the involvement of HRH1 in EV release and how they affect OC cell invasion in vitro.
The results show that the level of HRH1 mRNA positively correlates with in vitro migration and invasion rate of OC cells lines and higher expression was found in stage IV of OC clinical samples compared to stage II/III. Low HRH1 correlates with increased disease free survival, although no correlation was found with overall survival. HRH1 expression was modulated in three OC cell lines (SKOV3, OVCAR3 and OVCAR5), via siRNA transfection, chemical activation (via histamine) or inhibition (via chlorpheniramine) and its effect on cellular behaviour was evaluated through different in vitro assays. Results showed that HRH1: 1) does not modulate gene expression of EMT-related genes; 2) does not influence adhesion of OC cells to endothelial cells; 3) reduces cell invasion through a Matrigel®️ layer and 4) reduces their movement from the edge of a simulated ‘wound’. Histamine increases the number of EVs released from SKOV3 cells and their ability to degrade a collagen substrate but did not modify EV protein contents compared to control EVs. EVs were able to rescue the reduction of invasion caused by HRH1 knockdown, while histamine failed to rescue the invasion of cells knocked down for Rab27a (a major regulator of EV production), suggesting a potential interplay between HRH1 and Rab27a in modulating EV release and cell invasion.
Overall, these results suggest that HRH1, via modulation of EV biogenesis, can impair OC cells invasion and migration in vitro
Extracellular Vesicles: Emerging Modulators of Cancer Drug Resistance
No full textDrug resistance still represents the main reason for therapy failure in cancer patients. In the last decade, extracellular vesicles (EVs), a heterogeneous group of particles implicated in cell-to-cell communication, have been shown to substantially contribute to this phenomenon. This review summarizes the molecular mechanisms underlying the EV-mediated development of chemoresistance, shedding light on the potential role of these vesicles as both diagnostic/prognostic markers and therapeutic targets.
Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able to regulate proliferative, apoptotic, and stemness programs in recipient cells, potentially conferring a resistant phenotype to drug-sensitive cancer cells. Finally, EVs can mediate the communication between the tumor and both stromal and immune cells within the microenvironment, promoting treatment escape. In this context, clarifying the EV-driven resistance mechanisms might improve not only tumor diagnosis and prognosis but also therapeutic outcomes. Detailed cellular and molecular events occurring during the development of EV-mediated cancer drug resistance are described in this review article
Standardizing and Comparing Management Recommendations for Potential Drug-Drug Interactions Across Different Interaction Checkers
No full textBackground: Potential drug-drug interactions (pDDIs) are frequent in clinical care, particularly among older patients. Accurate identification and management of pDDIs are essential for patient safety. Prescribers often rely on interaction checkers (ICs) to screen for pDDIs. However, these tools may provide inconsistent recommendations, potentially leading to suboptimal clinical decisions. Objective: This study aimed to develop a standardized approach for classifying and prioritizing pDDIs based on the clinical relevance of their management recommendations and to compare how these pDDIs are categorized across ICs. Methods: A scale was developed through a structured iterative process to classify pDDIs into four management categories (high priority, intermediate priority, low priority, data unavailable), based on the management recommendations extracted from six ICs. This scale was applied to 218 real-world pDDIs identified from 1923 patients, and the agreement was primarily assessed using Gwet's AC1. Main results: Overall agreement among the ICs was moderate (Gwet's AC1 = 0.44; 95% CI 0.39-0.50), with values ranging from 0.58 (0.51, 0.65) to 0.38 (0.31, 0.44) in leave-one-out analyses. The agreement was higher in binary analyses dichotomizing the scale into high- and intermediate-priority versus low-priority pDDIs (AC1 = 0.72; 95% CI 0.65-0.79), and in the classification of high-priority versus all other pDDIs (AC1 = 0.62; 95% CI 0.54-0.69). Conclusion: This study developed and tested a structured approach to systematically compare pDDI management across ICs and prioritize clinically relevant interactions. Its application revealed a generally limited agreement between ICs, pointing to the need for harmonized approaches and further studies to support more consistent, evidence-aligned pDDI management
Medication review and deprescribing in different healthcare settings: a position statement from an Italian scientific consortium
No full text: Recent medical advancements have increased life expectancy, leading to a surge in patients affected by multiple chronic diseases and consequent polypharmacy, especially among older adults. This scenario increases the risk of drug interactions and adverse drug reactions, highlighting the need for medication review and deprescribing to reduce inappropriate medications and optimize therapeutic regimens, with the ultimate goal to improving patients' health and quality of life. This position statement from the Italian Scientific Consortium on medication review and deprescribing aims to describe key elements, strategies, tools, timing, and healthcare professionals to be involved, for the implementation of medication review and deprescribing in different healthcare settings (i.e., primary care, hospital, long-term care facilities, and palliative care). Challenges and potential solutions for the implementation of medication review and deprescribing are also discussed
Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer’s disease
No full textPharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and-D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD. (C) 2020 The Authors. Published by Elsevier Inc.This work was financially supported by grants from ISAO/Alzheimer Nederland WE.03-2016-07, Young European Research Universities Network (YERUN), and the Baeter Laeve foundation. Additional funds have been provided by the Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Netherlands (Award #11532; Funded by the Dorpmans-Wigmans Foundation) (DvdH), and by the Joint ProgrammeeNeurodegenerative Disease Research (JPND) for the EPI-AD consortium (http://www.neurodegenerationresearch.eu/wp-content/uploads/2015/10/Factsheet_EPI-AD.pdf).The project is supported through the following funding organizations under the aegis of JPND; The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw); United Kingdom, Medical Research Council; Germany, German Federal Ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 643417.Prickaerts, J (corresponding author), Maastricht Univ, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands.
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On the universal completion of pointfree function spaces
No full textThis paper approaches the construction of the universal completion of the Riesz space C(L) of continuous real functions on a completely regular frame L in two different ways. Firstly as the space of continuous real functions on the Booleanization of L. Secondly as the space of nearly finite Hausdorff continuous functions on L. The former has no counterpart in the classical theory, as the Booleanization of a spatial frame is not spatial in general, and it offers a lucid way of representing the universal completion as a space of continuous real functions. As a corollary weobtain that C(L) and C(M ) have isomorphic universal completions if and only if the Booleanization of L and M are isomorphic and we characterize frames L such that C(L) is universally complete as almost Boolean frames. The application of this last result to the classical case C(X) of the space of continuous real functions on a topological space X characterizes those spaces X for which C(X) is universally complete. Finally, we present a pointfree version of the Maeda-Ogasawara-Vulikh
representation theorem and use it to represent the universal completion of an Archimedean Riesz space with weak unit as a space of continuous real functions on a Boolean frame.The author wishes to thank Frederick Dashiell for his many helpful suggestions during the preparation of the paper. The author gratefully acknowledges support from the Spanish Ministry of Science, Innovation and Universities, reference code PID2019-103838GB-100 (MCIU/AEI/FEDER, UE) and from the Basque Government (Postdoctoral Fellowship POS_2017_2_0042 and grant IT974-16)
