29 research outputs found
Meniscal ossicles as micro-CT imaging biomarker in a rodent model of antigen-induced arthritis: A synchrotron-based x-ray pilot study
It is increasingly recognized that early detection of bone erosion plays an important role in the overall evaluation of rheumatoid arthritis and in the choice of the correct treatment approach. Since an appropriate use of imaging biomarkers in preclinical settings offers the prospect of smaller and optimized sample size, in the present study we define an anatomical imaging biomarker that could be objectively measured from micro-CT imaging data as an indicator of bone erosion in arthritis process. The well-characterized antigen-induced arthritis (AIA) model in rats was used. The animals were divided into 2 groups: arthritic disease control and arthritic having been administrated with the tumor necrosis factor alpha-blocking agent (Humira). Rats were sacrificed in the acute phase of AIA; peripheral blood and synovial tissue were collected for assessment of arthritis. Ex vivo micro-CT tomography of knee joints was performed at the Elettra synchrotron light source (Trieste, Italy). Overall, results from this study suggest that use of high-resolution micro-CT analysis coupled with meniscal ossicles bone parameters quantification provide a powerful combination to enhance data interpretation and assessment of disease-modifying drugs in an animal model of arthritis
Targeted delivery of neutralizing anti-C5 antibody to renal endothelium prevents complement- dependent tissue damage
Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI). As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney
Beta 2 glycoprotein I and neutrophil extracellular traps: Potential bridge between innate and adaptive immunity in anti-phospholipid syndrome
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS
The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis
Copyright © 2021 Agostinis, Zorzet, Balduit, Zito, Mangogna, Macor, Romano, Toffoli, Belmonte, Morello, Martorana, Borelli, Ricci, Kishore and Bulla. The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.Ministry of Health: Project code: ENDO-2020-23670288 “Pathogenesis of endometriosis: the role of genes, inflammation and environment”; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy (RC20/16, RC23/18; 5MILLE15D; PORFESR 2014/2020 FVG (“TiCheP” project)
Indici per la valutazione della qualit? ecologica dei laghi
Collection of methods to evaluate lake quality using biological element
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Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom
The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency
Possible Ways of Extending the Biogas Plants Lifespan after the Feed-In Tariff Expiration
Energy production from biogas can play a pivotal role in many European countries, and specifically in Italy, for three main reasons: (i) fossil fuels are scarce, (ii) imports cover large shares of internal demand, and (iii) electricity and heat production from biogas is already a consolidated business. Nonetheless, in Italy, current legislation and incentive policies on electricity generation from biogas are causing a stagnation of the entire sector, which may lead to the shutting down of many in-operation plants in the years 2027–2028 and the consequent loss of 573 MWel over a total of 1400 MWel. This work aims to investigate the potential of revamping biogas power plants in prolonging operation until the end of the plants’ useful life, regardless of the implementation of a new government’s incentive schemes. Based on the time-series analysis of electricity prices in Italy and a case study representative of the vast set of in-operation power plants, our findings show that 700 plants will likely shut down between 2027 and 2028 unless the government adequately rewards electricity produced and fed into the grid via incentive schemes. In detail, our results show that the investment to revamp the plant exhibits a highly negative Net Present Value
Diagnostic and prognostic role of eEF1A in chronic lymphocytic leukaemia
Background. Chronic lymphocytic leukaemia (CLL), the most common form of leukaemia in adults in Western countries, is characterized by the clonal expansion of B cells. Despite major advances in CLL therapy/diagnosis, the medical approach to CLL can be further improved. Here we explore the potential diagnostic/therapeutic role of the elongation factor 1 A (eEF1A) in CLL. Two major isoforms of eEF1A proteins exist: the ubiquitous eEF1A1 and the tissue-specialized eEF1A2. Beside their role in the elongation step of translation, both isoforms are involved in different cellular processes such as cell proliferation and apoptosis. Whereas both eEF1A isoforms play a role in solid and hematologic human tumors, nothing is known in CLL. Methods. eEF1A1/eEF1A2 amounts were quantitated by quantitative real time PCR and western blotting in the lymphocytes of 46 CLL patients vs 26 normal control. eEF1A1 functional role in CLL was investigated in a cellular (MEC-1) and in a subcutaneous xenograft animal model of CLL via its targeting by an aptamer (GT75) or a siRNA (siA1), we previously developed. As control molecules an inactive aptamer (CT75) or siRNA (siGL2) were used. Results. At the mRNA level, eEF1A1 but not eEF1A2 was significantly (p=0,0081) more elevated in CLL lymphocytes compared to control. At the protein level, both eEF1A1 and eEF1A2 were more elevated (p=0,028) in CLL lymphocytes compared to control. Moreover, eEF1A1 but not eEF1A2 protein levels were higher (p=0,0042) in patient which died during the study compared to those surviving. Finally, eEF1A1 targeting by either GT75 or siA1 resulted in MEC-1 viability down regulation (p=0,04) mostly due to autophagy stimulation. In vivo, GT75 or siA1 resulted in tumor growth down-regulation (p=0.014) and extension of animal survival (p=0.014), demonstrating the functional role of eEF1A1 in CLL. Conclusions. The increase of eEF1A1/eEF1A2 protein in lymphocytes of CLL patient cells suggests a role as possible novel CLL markers. The increase of eEF1A1 protein in dead vs surviving patients may confer to eEF1A1 also the role of a novel prognostic marker. This, together with the involvement of eEF1A1 in MEC-1 survival in vitro and in vivo, opens the possibility to consider eEF1A1 also as a novel therapeutic target in CLL