Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

Angiogenesis critically sustains the progression of both physiological and pathological processes. Copper behaves as an obligatory co-factor throughout the angiogenic signalling cascades, so much so that a deficiency causes neovascularization to abate. Moreover, the progress of several angiogenic pathologies (e.g. diabetes, cardiac hypertrophy and ischaemia) can be tracked by measuring serum copper levels, which are being increasingly investigated as a useful prognostic marker. Accordingly, the therapeutic modulation of body copper has been proven effective in rescuing the pathological angiogenic dysfunctions underlying several disease states. Vascular copper transport systems profoundly influence the activation and execution of angiogenesis, acting as multi-functional regulators of apparently discrete pro-angiogenic pathways. This review concerns the complex relationship among copper-dependent angiogenic factors, copper transporters and common pathological conditions, with an unusual accent on the multi-faceted involvement of the proteins handling vascular copper. Functions regulated by the major copper transport proteins (CTR1 importer, ATP7A efflux pump and metallo-chaperones) include the modulation of endothelial migration and vascular superoxide, known to activate angiogenesis within a narrow concentration range. The potential contribution of prion protein, a controversial regulator of copper homeostasis, is discussed, even though its angiogenic involvement seems to be mainly associated with the modulation of endothelial motility and permeability

The mechanobiology of the nucleus

In addition to biochemical and molecular signals coming from the microenvironment, cells are able to sense and integrate mechanical stresses, additional fundamental regulators of cell behaviour. Emerging demonstrations indicate that mechanical cues go far beyond the plasma membrane and the cytoskeleton, since, exerting tension on the outside local microenvironment via adhesions, cells develop an equal cytoskeletal stress on the nucleus inside, leading to 3D nuclear modifications. In this context, dynamic changes in nuclear lamina and the surrounding cytoskeleton modify mechanical properties of the nucleus affecting its structural arrangement, chromatin anchoring, 3D chromosome conformation and gene expression. Here we discuss findings supporting the role of the nucleus in cellular mechanosensing, ranging from how mechanical cues are transduced to the nucleus to how genome organization is influenced by cell mechanics

Copper as a Target for Treatment of Neuroblastoma: Molecular and Cellular Mechanisms

none2Urso E; Maffia MUrso, Emanuela; Maffia, Michel

The role of Autophagy in Hepatocellular Carcinoma

Autophagy is a cellular catabolic process in which cytoplasmic material is delivered to lysosomes for degradation. The autophagy process is regulated by highly conserved autophagy-related genes (ATGs) via different signalling pathways. Among the various biological functions of autophagy, the link between autophagy and cancer has been extensively studied, demonstrating its dual role, of tumor suppressor or promoter in cancer development. Hepatocellular carcinoma (HCC) is one of the most lethal cancers that affects most of the world's population and it is caused by different etiological factors: HBV and HCV viral infections, heavy alcohol consumption, NAFLD (non-alcoholic fatty liver disease), aflatoxin B1 contaminated food. In recent years, the involvement of autophagy in both prevention and promotion of liver cancer has been increasingly studied. Here, we summarize molecular mechanisms and physiological function of liver autophagy, its dual role and its therapeutic potential in HCC

IgA and IgG antibodies in SARS-CoV-2 vaccinated health workers by a homemade ELISA diagnostic test

Abstract The SARS-CoV-2 pandemic has accelerated vaccine development and testing, an important step in its eradication. Health workers were included among the first subjects to be vaccinated, therefore it was necessary to check their immunological status after the first and second dose of vaccine. Serum samples belonging to 24 health workers undergoing vaccination for SARS-CoV-2 (Pfizer-BioNTech) were analysed: for 2 of them it was also possible to obtain a serum sample prior to the first dose of vaccine (zero time); antibody dosing was performed in 18 out of 24 after the first and second vaccination dose; in the remaining 6 healthcare workers a serum sample was obtained only after the second dose. In each serum sample, IgA and IgG antibodies to "Spike Receptor Binding Domain" (RBD) and "Nucleocapsid" (N) proteins were searched by ELISA test. Except for the two subjects for whom it was possible to have a serum sample before vaccination, the others were collected on day 18 from the first dose of vaccine and on day 8 from the second dose. Serum samples collected after the first dose of vaccine showed reactivity to anti-RBD IgG in 11 out of 18 healthcare workers and to IgA in 2 subjects. After the second dose all 24 samples showed the presence of anti-S IgG, while 5 revealed a reactivity for anti-S IgA. Three samples showed reactivity towards anti-N IgG. The ELISA test has shown all its effectiveness in controlling post vaccine immunity and in discriminating natural immunity from vaccine induced immunity

Obstructive Sleep Apnea (OSA), an emerging health problem

Obstructive Sleep Apnea (OSA) is the most common respiratory disorder in Western societies: according to a first recent worldwide epidemiological study, it was estimated that 936 million patients aged 30-69 years with mild to moderate OSA and 425 million patients aged 30-69 years with severe OSA requiring CPAP treatment. Recently, the Centre for Research on Health and Social Care Management (CERGAS) at the Bocconi University of Milan has estimated that in Italy, the prevalence of moderate to severe OSA occurs in the 27% of the general population, with an overall prevalence of mild to medium-severe OSA of more than 24 million people aged between 15 and 74 years (54% of the adult population), while from a practical point of view, Italian doctors diagnosed only 460.000 moderate-severe patients (4 per cent of the estimated prevalence) and 230,000 patients were treated (2 per cent of the estimated prevalence), highlighting a substantial gap between diagnosis and treatment. In addition, OSA patients are often obese and the close correlation between the two conditions suggests that the prevalence of OSA will increase in the short term as obesity increases. At the individual level, OSA leads to a significant decrease in quality of life (HRQoL) and intellectual and mechanical/functional capacities with reduced physical activity, as well as a marked increase in sudden death and risk of cardiovascular and metabolic diseases. Emerging epidemiological data also suggest that the severity of OSA associated with the severity of chronic nocturnal hypoxemia (CIH) correlates with an increased risk of diabetes mellitus, metabolic syndrome (MS) and cancer. OSA is also an important risk factor for high blood pressure, acute and chronic atrial fibrillation (FAC), chronic coronary artery disease (CAD) and stroke. It is therefore intuitive that at the social level, OSA also leads to a decline in economic productivity. This article addresses OSA from a new epidemiological perspective, according to the latest prevalence studies, and addresses emerging problems related to the diagnosis

Physiological role of Prion Protein in Copper homeostasis and angiogenic mechanisms of endothelial cells

Abstract The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such as the bovine spongiform encephalopathy and human Creutzfeldt–Jakob disease. Physiologically, PrP is involved in several processes including adhesion, proliferation, differentiation and angiogenesis, but the molecular mechanisms behind its role remain unclear. PrP, due to its well-described structure, is known to be able to regulate copper homeostasis; however, copper dyshomeostasis can lead to developmental defects. We investigated PrP-dependent regulation of copper homeostasis in human endothelial cells (HUVEC) using an RNA-interference protocol. PrP knockdown did not influence cell viability in silenced HUVEC (PrPKD) compared to control cells, but significantly increased PrPKD HUVEC cells sensitivity to cytotoxic copper concentrations. A reduction of PrPKD cells reductase activity and copper ions transport capacity was observed. Furthermore, PrPKD-derived spheroids exhibited altered morphogenesis and their derived cells showed a decreased vitality 24 and 48 hours after seeding. PrPKD spheroid-derived cells also showed disrupted tubulogenesis in terms of decreased coverage area, tubule length and total nodes number on matrigel, preserving unaltered VEGF receptors expression levels. Our results highlight PrP physiological role in cellular copper homeostasis and in the angiogenesis of endothelial cells

Infra-hissian Wenckebach phenomenon. A case report, with some reflection about slow conduction

We describe a case of Wenckebach periodicity in the distal conduction system. Our observation strengthens the concept that Wenckebach type block in surface ECG may reflect block in infra-hissian tissues, especially if there is a wide QRS complex in the conducted beats

Artificial Neural Networks (ANN) for automatic detection of dendritic-shaped cancer cells of cutaneous melanoma in Reflectance Confocal Microscopy (RCM) images

Melanoma (MM) is one of the tumors with the highest incidence. In Italy, MM affected about 13,700 patients out of 373,000 new cases of cancer in 2018, with prognosis dependent on the degree of tumor invasion and presence of metastasis at diagnosis: only an early detection can lead to a better prognosis. Recent evidence suggests that MM is a family of different tumors with varying abilities to grow and metastasize: dendritic-shaped tumor cells were typically found in thin MM in situ. Reflectance Confocal Microscopy (RCM) is a non-invasive imaging tool that enables in vivo observation of the skin at a quasi-histological resolution, providing transverse-section grayscale images related to refractive index of different tissues. In this work, a dataset of RCM images, from 13 healthy subjects and 22 patients affected by MM in situ, were used to train a Multi-Layer Perceptron (MLP) artificial neural network. Each image was subdivided into sub-blocks, labeled as positive if containing significant clusters of dendritic-shaped tumour cells. In each block, various standard features were calculated, e.g. Haralick's and features from the run-length matrices. The MLP was trained to recognize the presence of clusters of dendritic-shaped cancer cells. The preliminary results are encouraging, giving AUC=0.81 with about 73% accuracy. Tests are currently underway to improve quality