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1.
J Neurointerv Surg ; 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071557

RESUMO

BACKGROUND: The Pipeline Vantage Embolization Device (PEDV) is the fourth-generation pipeline flow diverter for intracranial aneurysm treatment. There are no outcome studies for the second PEDV version. We aimed to evaluate safety and efficacy outcomes. Primary and secondary objectives were to determine outcomes for unruptured and ruptured cohorts, respectively. METHODS: In this multicenter retrospective and prospective study, we analyzed outcome data from eight centers using core laboratory assessments. We determined 30-day and ≥3-month mortality and morbidity rates, and 6- and 18-month radiographic aneurysm occlusion rates for procedures performed during the period July 2021-March 2023. RESULTS: We included 121 consecutive patients with 131 aneurysms. The adequate occlusion rate for the unruptured cohort at short-term and medium-term follow up, and also for the ruptured cohort at short-term follow up, was >90%. Two aneurysms (1.5%) underwent retreatment. When mortality attributed to a palliative case in the unruptured cohort, or subarachnoid hemorrhage in the ruptured cohort, was excluded then the overall major adverse event rate in respective cohorts was 7.5% and 23.5%, with 0% mortality rates for each. When all event causes were included on an intention-to-treat basis, the major adverse event rates in respective cohorts were 8.3% and 40.9%, with 0.9% and 22.7% mortality rates. CONCLUSIONS: For unruptured aneurysm treatment, the second PEDV version appears to have a superior efficacy and similar safety profile to previous-generation PEDs. These are acceptable outcomes in this pragmatic and non-industry-sponsored study. Analysis of ruptured aneurysm outcomes is limited by cohort size. Further prospective studies, particularly for ruptured aneurysms, are needed.

2.
PLoS One ; 3(8): e2998, 2008 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-18714386

RESUMO

Viruses induce signaling and host defense during infection. Employing these natural trigger mechanisms to combat organ or tissue failure is hampered by harmful effects of most viruses. Here we demonstrate that SV40 empty capsids (Virus Like Particles-VLPs), with no DNA, induce host Hsp/c70 and Akt-1 survival pathways, key players in cellular survival mechanisms. We postulated that this signaling might protect against organ damage in vivo. Acute kidney injury (AKI) was chosen as target. AKI is critical, prevalent disorder in humans, caused by nephrotoxic agents, sepsis or ischemia, via apoptosis/necrosis of renal tubular cells, with high morbidity and mortality. Systemic administration of VLPs activated Akt-1 and upregulated Hsp/c70 in vivo. Experiments in mercury-induced AKI mouse model demonstrated that apoptosis, oxidative stress and toxic renal failure were significantly attenuated by pretreatment with capsids prior to the mercury insult. Survival rate increased from 12% to >60%, with wide dose response. This study demonstrates that SV40 VLPs, devoid of DNA, may potentially be used as prophylactic agent for AKI. We anticipate that these finding may be projected to a wide range of organ failure, using empty capsids of SV40 as well as other viruses.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Proteínas do Capsídeo/genética , DNA Viral/genética , Vírus 40 dos Símios/genética , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/fisiopatologia , Animais , Apoptose , Proteínas do Capsídeo/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Haplorrinos , Humanos , Rim , Camundongos , Necrose
3.
Pancreas ; 36(4): 411-6, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18437088

RESUMO

OBJECTIVES: Viral vector uptake into the pancreas is rare. The few viral vectors reported to transduce in vivo pancreatic islets after systemic injection required additional physical measures, such as direct pancreatic injection or hepatic vessel clamping. Because pancreatic islet uptake of the human polyomavirus family member BK virus was previously reported in hamsters after systemic administration, we hypothesized that SV40, a polyomavirus member remarkably similar to BK virus, may also infect the pancreas. METHODS: We injected intravenously a low dose of SV40, unaided by any other physical or chemical means, and evaluated viral uptake by pancreatic islets and pancreatic exocrine tissue via polymerase chain reaction, Western blot, electron microscopy, immunofluorescent microscopy, and protein A-gold immunocytochemistry. RESULTS: Pancreatic uptake of SV40 was comparable to other major organs (ie, liver and spleen). SV40 viral particles were detected in both pancreatic islets and acini. In pancreatic islets, all islet cell types were infected by SV40, albeit the infection rate of glucagon-producing alpha cells surpassed beta- and delta-islet cells. Low-dose SV40 administration was not sufficient to induce heterologous gene expression in the pancreas. CONCLUSIONS: Our study shows that pancreatic islet and acinar cell uptake of SV40 is feasible with a single, low-dose intravenous injection. However, this dose did not result in gene delivery into the murine pancreas.


Assuntos
Ilhotas Pancreáticas/virologia , Pancreatopatias/virologia , Vírus 40 dos Símios/patogenicidade , Animais , Diabetes Mellitus Tipo 1/virologia , Feminino , Regulação da Expressão Gênica , Ilhotas Pancreáticas/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pancreatopatias/patologia , Reação em Cadeia da Polimerase , Vírus 40 dos Símios/isolamento & purificação , Vírus 40 dos Símios/ultraestrutura
4.
PLoS One ; 2(8): e765, 2007 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-17712413

RESUMO

SV40 is a small, non enveloped DNA virus with an icosahedral capsid of 45 nm. The outer shell is composed of pentamers of the major capsid protein, VP1, linked via their flexible carboxy-terminal arms. Its morphogenesis occurs by assembly of capsomers around the viral minichromosome. However the steps leading to the formation of mature virus are poorly understood. Intermediates of the assembly reaction could not be isolated from cells infected with wt SV40. Here we have used recombinant VP1 produced in insect cells for in vitro assembly studies around supercoiled heterologous plasmid DNA carrying a reporter gene. This strategy yields infective nanoparticles, affording a simple quantitative transduction assay. We show that VP1 assembles under physiological conditions into uniform nanoparticles of the same shape, size and CsCl density as the wild type virus. The stoichiometry is one DNA molecule per capsid. VP1 deleted in the C-arm, which is unable to assemble but can bind DNA, was inactive indicating genuine assembly rather than non-specific DNA-binding. The reaction requires host enzymatic activities, consistent with the participation of chaperones, as recently shown. Our results demonstrate dramatic cooperativity of VP1, with a Hill coefficient of approximately 6. These findings suggest that assembly may be a concerted reaction. We propose that concerted assembly is facilitated by simultaneous binding of multiple capsomers to a single DNA molecule, as we have recently reported, thus increasing their local concentration. Emerging principles of SV40 assembly may help understanding assembly of other complex systems. In addition, the SV40-based nanoparticles described here are potential gene therapy vectors that combine efficient gene delivery with safety and flexibility.


Assuntos
Proteínas do Capsídeo/metabolismo , Vírus 40 dos Símios/metabolismo , Montagem de Vírus , Animais , Capsídeo/química , Capsídeo/metabolismo , Capsídeo/ultraestrutura , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/ultraestrutura , DNA Viral/genética , DNA Viral/metabolismo , Terapia Genética , Vetores Genéticos , Humanos , Nanopartículas , Vírus 40 dos Símios/química , Vírus 40 dos Símios/genética
5.
J Virol ; 77(7): 4273-82, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12634384

RESUMO

The abundant nuclear enzyme poly(ADP-ribose) polymerase (PARP) functions in DNA damage surveillance and repair and at the decision between apoptosis and necrosis. Here we show that PARP binds to simian virus 40 (SV40) capsid proteins VP1 and VP3. Furthermore, its enzymatic activity is stimulated by VP3 but not by VP1. Experiments with purified mutant proteins demonstrated that the PARP binding domain in VP3 is localized to the 35 carboxy-terminal amino acids, while a larger peptide of 49 amino acids was required for full stimulation of its activity. The addition of 3-aminobenzamide (3-AB), a known competitive inhibitor of PARP, demonstrated that PARP participates in the SV40 life cycle. The titer of SV40 propagated on CV-1 cells was reduced by 3-AB in a dose-dependent manner. Additional experiments showed that 3-AB did not affect viral DNA replication or capsid protein production. PARP did not modify the viral capsid proteins in in vitro poly(ADP-ribosylation) assays, implying that it does not affect SV40 infectivity. On the other hand, it greatly reduced the magnitude of the host cytopathic effects, a hallmark of SV40 infection. Additional experiments suggested that the stimulation of PARP activity by VP3 leads the infected cell to a necrotic pathway, characterized by the loss of membrane integrity, thus facilitating the release of mature SV40 virions from the cells. Our studies identified a novel function of the minor capsid protein VP3 in the recruitment of PARP for the SV40 lytic process.


Assuntos
Capsídeo/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Vírus 40 dos Símios/crescimento & desenvolvimento , Vírus 40 dos Símios/metabolismo , Animais , Apoptose , Sítios de Ligação , Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Humanos , Células K562 , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Vírus 40 dos Símios/genética
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