Induzione di microparticelle procoagulanti da parte di una adipochina, la leptina, su cellule mononucleate umane

Le microparticelle, chiamate anche ectosomi e microvescicole, sono frammenti di membrana liberati virtualmente da tutte le cellule eucariote a seguito di attivazione o durante apoptosi. Considerate originariamente artefatti legati alla manipolazione in vitro delle cellule o, al più, frammenti cellulari liberati durante la necrosi e privi di significato fisiologico, le microparticelle sono state recentemente coinvolte in vari processi tra cui l'infiammazione e la coagulazione del sangue. E' stato dimostrato che microparticelle di derivazione piastrinica legano il fattore VIII della coagulazione e pertanto possono rappresentare una superficie ideale per l'assemblaggio del complesso enzimatico denominato tenasi per l'attivazione del fattore X. Questa osservazione conferma che le microparticelle sono, almeno potenzialmente, capaci di svolgere attività biologicamente rilevanti come l’infiammazione e la coagulazione. La leptina, prodotta dal gene Ob (Lep), è un ormone proteico di 16 kDa, e rappresenta uno dei principali ormoni prodotti dal tessuto adiposo. Studi recenti hanno dimostrato che la leptina è coinvolta in vari processi tra cui la proliferazione e la migrazione di cellule endoteliali, l’aumento dell’aggregazione piastrinica, l’angiogenesi e l’induzione di fattore tissutale in cellule mononucleate umane isolate da sangue periferico. Lo scopo del mio lavoro è stato quello di valutare l’ipotesi che uno dei meccanismi attraverso i quali la leptina induce aumento del rischio cardiovascolare, fosse legato all’induzione di MP pro-coagulanti da parte di cellule mononucleate umane e valutare successivamente alcuni meccanismi intracellulari che portano al rilascio di microparticelle da parte di cellule mononucleate umane dopo stimolazione con leptina. La generazione delle microparticelle è stata valutata attraverso l’utilizzo di una metodica: il test della protrombinasi, che misura la concentrazione di fosfatidilserina basandosi sulla quantita’ di trombina generata a partire dalla protrombina in una reazione fosfatidilserina dipendente. I risultati ottenuti mostrano che la leptina e’ in grado di indurre la liberazione di microparticelle procoagulanti da parte di cellule mononucleate umane in modo dose-dipendente. Per meglio capire i possibili meccanismi intracellulari che portano al rilascio di microparticelle da parte di cellule mononucleate umane dopo stimolazione con leptina, sono stati usati sia inibitori delle mitogen-activated protein kinase, per i quali e’ gia’ stato dimostrato in letteratura il loro coinvolgimento in altre condizioni sperimentali, che inibitori della via del calcio, in quanto e’ noto che l’aumento di calcio intracellulare porta alla liberazione delle microparticelle. I dati ottenuti con tre diversi inibitori di tre diverse chinasi (ERK, JNK e p38) appartenenti alla famiglia delle mitogen-activated protein kinase mostrano che la liberazione delle microparticelle, da parte di cellule mononucleate umane ottenute dopo stimolazione con la leptina, avviene attraverso un meccanismo mitogen-activated protein kinase indipendente. I dati ottenuti con gli inibitori della via del calcio mostrano invece un’inibizione della liberazione delle microparticelle, da parte di cellule mononucleate umane, ottenute dopo stimolazione con la leptina. Questi dati mostrano che la leptina e’ in grado di far rilasciare microparticelle da parte di cellule mononucleate umane e che tale rilascio e’ dovuto principalmente ad una mobilizzazione del calcio intracellulare. E’ plausibile, quindi, pensare che bloccando alcuni step di rilascio delle microparticelle si possa in qualche modo diminuire il rischio cardiovascolare nell’ obesità

An Unsupervised Method for Suspicious Regions Detection in Mammogram Images

Over the past years many researchers proposed biomedical imaging methods for computer-aided detection and classification of suspicious regions in mammograms. Mammogram interpretation is performed by radiologists by visual inspection. The large volume of mammograms to be analyzed makes such readings labour intensive and often inaccurate. For this purpose, in this paper we propose a new unsupervised method to automatically detect suspicious regions in mammogram images. The method consists mainly of two steps: preprocessing; feature extraction and selection. Preprocessing steps allow to separate background region from the breast profile region. In greater detail, gray levels mapping transform and histogram specifications are used to enhance the visual representation of mammogram details. Then, local keypoints and descriptors such as SURF have been extracted in breast profile region. The extracted keypoints are filtered by proper parameters tuning to detect suspicious regions. The results, in terms of sensitivity and confidence interval are very encouraging

A case of severe osteomalacia secondary to phosphate diabetes in a renal transplant recipient

Transient hypophosphatemia is frequently observed during the first months after renal transplantation and is usually asymptomatic. Phosphate diabetes is defined as inadequate tubular phosphorus reabsorption leading to persistent renal phosphorus wasting, which is an important but overlooked cause of osteodystrophy in the post-renal transplantation population. We report the case of a 58-year-old male who presented with severe multiple osteoarticular pains within 3 months after successful first kidney transplantation. Bone disease was attributed initially to mild hyperparathyroidism secondary to vitamin D deficiency. Despite the correction of the hyperparathyroidism, the withdrawal of corticosteroids, and the reduction of immunosuppressive treatment to tacrolimus-based monotherapy, the osteoarticular pains persisted. Skeletal investigations at month 9 post-transplantation demonstrated a significant bone mineral density loss associated with osteomalacia and osteoporosis on the bone biopsy. Laboratory data showed persistent hypophosphatemia, and phosphate diabetes was then diagnosed explaining the post-transplant bone disease. A tacrolimus-induced renal tubular disorder was suspected to contribute to the excessive renal phosphorus wasting. The replacement of tacrolimus by sirolimus, in addition to oral phosphorus and vitamin D supplementations, led to the disappearance of pains, the normalization of urinary and plasma phosphate level, and a significant improvement of bone mineralization

MicroRNAs in colorectal cancer stem cells: new regulators of cancer stemness?

Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called 'cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy

Analysis of molecular mechanisms and anti-tumoural effects of zoledronic acid in breast cancer cells

Zoledronic acid (ZOL) is the most potent nitrogen-containing bisphosphonate (N-BPs) that strongly binds to bone mineral and acts as a powerful inhibitor of bone resorption, already clinically available for the treatment of patients with osteolytic metastases. Recent data also suggest that ZOL, used in breast cancer, may provide more than just supportive care modifying the course of the disease, though the possible molecular mechanism of action is still unclear. As breast cancer is one of the primary tumours with high propensity to metastasize to the bone, we investigated, for the first time, differential gene expression profile on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells treated with low doses of ZOL (10 lM). Microarrays analysis was used to identify, describe and summarize evidence regarding the molecular basis of actions of ZOL and of their possible direct anti-tumour effects. We validated gene expression results of specific transcripts involved in major cellular process by Real Time and Western Blot analysis and we observed inhibition of proliferation and migration through 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) and Matrigel assay. We then focused on changes in the cytoskeletal components as fibronectin 1 (FN1), actin, and anti angiogenic compounds as transforming growth factor-b1 (TGF-b1) and thrombospondin 1 (THBS1). The up-regulation of these products may have an important role in inhibiting proliferation, invasion and angiogenesis mediated by ZOL

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Identification of misbehavior detection solutions and risk scenarios in advanced connected and automated driving scenarios

The inclusion of 5G cellular communication system into vehicles, combined with other connected-vehicle technology, such as sensors and cameras, makes connected and advanced vehicles a promising application in the Cooperative Intelligent Transport Systems. One of the most challenging task is to provide resilience against misbehavior i.e., against vehicles that intentionally disseminate false information to deceive receivers and induce them to manoeuvre incorrectly or even dangerously. This calls for misbehaviour detection mechanisms, whose purpose is to analyze information semantics to detect and filter attacks. As a result, data correctness and integrity are ensured. Misbehaviour and its detection are rather new concepts in the literature; there is a lack of methods that leverage the available information to prove its trustworthiness. This is mainly because misbehaviour techniques come with several flavours and have different unpredictable purposes, therefore providing precise guidelines is rather ambitious. Moreover, dataset to test detection schemes are rare to find and inconvenient to customize and adapt according to needs. This work presents a misbehaviour detection scheme that exploits information shared between vehicles and received signal properties to investigate the behaviour of transmitters. Differently from most available solutions, this is based on the data of the on-board own resources of the vehicle. Computational effort and resources required are minor concerns, and concurrently time efficiency is gained. Also, the project addresses three different types of attack to show that detecting misbehaviour methods are more vulnerable to some profile of attacker than others. Moreover, a rich dataset was set up to test the scheme. The dataset was created according to the latest standardised evaluation methodologies and provides a valuable starting point for any further development and research