13 research outputs found
Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease
Abstract Defects of the angiogenic process occur in the
brain of twitcher mouse, an authentic model of human
Krabbe disease caused by genetic deficiency of lysosomal
b-galactosylceramidase (GALC), leading to lethal neurological
dysfunctions and accumulation of neurotoxic psychosine
in the central nervous system. Here, quantitative
computational analysis was used to explore the alterations
of brain angioarchitecture in twitcher mice. To this aim,
customized ImageJ routines were used to assess calibers,
amounts, lengths and spatial dispersion of CD31? vessels
in 3D volumes from the postnatal frontal cortex of twitcher
animals. The results showed a decrease in CD31
immunoreactivity in twitcher brain with a marked reduction
in total vessel lengths coupled with increased vessel
fragmentation. No significant changes were instead
observed for the spatial dispersion of brain vessels
throughout volumes or in vascular calibers. Notably, no
CD31? vessel changes were detected in twitcher kidneys in
which psychosine accumulates at very low levels, thus
confirming the specificity of the effect. Microvascular
corrosion casting followed by scanning electron microscopy
morphometry confirmed the presence of significant
alterations of the functional angioarchitecture of the brain
cortex of twitcher mice with reduction in microvascular
density, vascular branch remodeling and intussusceptive
angiogenesis. Intussusceptive microvascular growth, con-
firmed by histological analysis, was paralleled by alterations
of the expression of intussusception-related genes in
twitcher brain. Our data support the hypothesis that a
marked decrease in vascular development concurs to the
onset of neuropathological lesions in twitcher brain and
suggest that neuroinflammation-driven intussusceptive
responses may represent an attempt to compensate
impaired sprouting angiogenesis
Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells
Inhibitory effect by new monocyclic 4-alkyliden-beta-lactam compounds on human platelet activation
Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease
Antiangiogenic effects of N6-isopentenyladenosine, an endogenous isoprenoid end product, mediated by AMPK activation.
N6-isopentenyladenosine (iPA), an end product of the mevalonate pathway with an isopentenyl chain, is already known to exert a suppressor effect against various tumors. In this work, we investigated whether iPA also directly interferes with the angiogenic process, which is fundamental to tumor growth and progression. To this end, using human umbilical vein endothelial cells (HUVECs) as a suitable in vitro model of angiogenesis, we evaluated their viability, proliferation, migration, invasion, tube formation in response to iPA, and molecular mechanisms involved. Data were corroborated in mice by using a gel plug assay. iPA dose- and time-dependently inhibited all the neoangiogenesis stages, with an IC50 of 0.98 ÎĽM. We demonstrated for the first time, by liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS), that iPA was monophosphorylated into 5'-iPA-monophosphate (iPAMP) by the adenosine kinase (ADK) inside the cells. iPAMP is the active form that inhibits angiogenesis through the direct activation of AMP-kinase (AMPK). Indeed, all effects were completely reversed by pretreatment with 5-iodotubercidin (5-Itu), an ADK inhibitor. The isoprenoid intermediate isopentenyl pyrophosphate (IPP), which shares the isopentenyl moiety with iPA, was ineffective in the inhibition of angiogenesis, thus showing that the iPA structure is specific for the observed effects. In conclusion, iPA is a novel AMPK activator and could represent a useful tool for the treatment of diseases where excessive neoangiogenesis is the underlying pathology.- Pisanti, S., Picardi, P., Ciaglia, E., Margarucci, L., Ronca, R., Giacomini, A., Malfitano, A. M., Casapullo, A., Laezza, C., Gazzerro, P., Bifulco, M. Anti-angiogenic effects of N6-isopentenyladenosine, an endogenous isoprenoid end-product, mediated by AMPK activation
Qualit\ue0 della vita correlata alla salute in pazienti HIV+. Analisi del campione dello studio I.A.N.U,A
Circulating microRNAs and their role in multiple myeloma
Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow infiltration
of clonal plasma cells. The recent literature has clearly demonstrated clonal heterogeneity in terms
of both the genomic and transcriptomic signature of the tumor. Of note, novel studies have also
highlighted the importance of the functional cross-talk between the tumor clone and the surrounding
bone marrow milieu, as a relevant player of MM pathogenesis. These findings have certainly
enhanced our understanding of the underlying mechanisms supporting MM pathogenesis and
disease progression. Within the specific field of small non-coding RNA-research, recent studies have
provided evidence for considering microRNAs as a crucial regulator of MM biology and, in this
context, circulating microRNAs have been shown to potentially contribute to prognostic stratification
of MM patients. The present review will summarize the most recent studies within the specific topic
of microRNAs and circulating microRNAs in MM
The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis
Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited anti-tumor activity
34siThe multiple myeloma (MM) mutational landscape has identified alterations in KRAS as the most recurring somatic variant. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying that KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We have used AZD4785, a potent and selective antisense oligonucleotide (ASO) which selectively targets and down-regulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche; and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, confirming KRAS as a driver and a therapeutic target in MM.reservedmixedSacco, Antonio; Federico, Cinzia; Todoerti, Katia; Ziccheddu, Bachisio; Palermo, Valentina; Giacomini, Arianna; Ravelli, Cosetta; Maccarinelli, Federica; Bianchi, Giada; Belotti, Angelo; Ribolla, Rossella; Favasuli, Vanessa; Revenko, Alexey S; MacLeod, Robert A; Willis, Brandon Stephen; Cai, Hongbo; Hauser, Joana; Rooney, Claire; Willis, Sophie Elizabeth; Martin, Philip L; Staniszewska, Anna Dominika; Ambrose, Helen; Hanson, Lyndsey; Cattaneo, Chiara; Tucci, Alessandra; Rossi, Giuseppe; Ronca, Roberto; Neri, Antonino; Mitola, Stefania; Bolli, Niccolo; Presta, Marco; Moschetta, Michele; Ross, Sarah; Roccaro, Aldo MSacco, Antonio; Federico, Cinzia; Todoerti, Katia; Ziccheddu, Bachisio; Palermo, Valentina; Giacomini, Arianna; Ravelli, Cosetta; Maccarinelli, Federica; Bianchi, Giada; Belotti, Angelo; Ribolla, Rossella; Favasuli, Vanessa; Revenko, Alexey S; Macleod, Robert A; Willis, Brandon Stephen; Cai, Hongbo; Hauser, Joana; Rooney, Claire; Willis, Sophie Elizabeth; Martin, Philip L; Staniszewska, Anna Dominika; Ambrose, Helen; Hanson, Lyndsey; Cattaneo, Chiara; Tucci, Alessandra; Rossi, Giuseppe; Ronca, Roberto; Neri, Antonino; Mitola, Stefania; Bolli, Niccolo; Presta, Marco; Moschetta, Michele; Ross, Sarah; Roccaro, Aldo