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1.
Am J Med Genet A ; 170(9): 2400-3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27273837

RESUMO

Chronic intestinal pseudo obstruction (CIPO) is a rare clinical entity characterized by symptoms and signs of intestinal obstruction without either recognizable anatomical abnormalities or intestinal aganglionosis. A Chinese female infant presented to our institution with a clinical diagnosis of CIPO. Aganglionosis was ruled out by full thickness colonic and ileal biopsies and by rectal suction biopsies. Unexpectedly, direct sequencing and PCR amplification of RET proto-oncogene from peripheral blood extracted DNA identified a RET R114H mutation. This mutation has already been reported as strongly associated with Asian patients affected by Hirschsprung's disease (HSCR) and is considered a founder mutation in Asia. The same mutation has never been reported in patients with CIPO, so far. These findings support the role of RET in the development of the enteric nervous system but underline the importance of other genetic or environmental factors contributing to the gastrointestinal phenotype of the disease. Somehow, this RET R114H mutation proved to have a role in the etiology of both CIPO and HSCR and could contribute to a more diffuse imbalance of gut dysmotility. © 2016 Wiley Periodicals, Inc.


Assuntos
Efeito Fundador , Estudos de Associação Genética , Doença de Hirschsprung/genética , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Biópsia , Feminino , Doença de Hirschsprung/diagnóstico , Humanos , Recém-Nascido , Fenótipo , Proto-Oncogene Mas
2.
Hum Vaccin Immunother ; 19(2): 2258632, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37724517

RESUMO

SARS-CoV-2 anti-spike IgG production and protection from severe respiratory illness should be explored in greater depth after COVID-19 booster vaccination. This longitudinal observational retrospective study investigated the anti-spike IgG response elicited by the first, second and booster doses of BNT162b2 mRNA vaccine in healthcare workers (HCW) at San Martino IRCCS Policlinico Hospital (Genoa) up to the 12th month. Sequential blood sampling was performed at T0 (prior to vaccination), T1 (21 days after the 1st dose of vaccine), T2, T3, T4, T5, T6 (7 days and 1, 3, 6 and 9 months after the 2nd dose, respectively), T7 and T8 (1 and 3 months after a booster dose). A SARS-CoV-2 IgG panel (Bio-Rad, Marnes-la-Coquette, France) was used to determine levels of receptor-binding domain (RBD), spike-1 (S1), spike-2 and nucleocapsid structural proteins of SARS-CoV-2. In the 51 HCWs evaluated, seroprevalence was 96% (49/51) at T1 and 100% (51/51) from T2 to T5 for RBD and S1. At T6, only one HCW was negative. T2 [RBD = 2945 (IQR:1693-5364); S1 = 1574 (IQR:833-3256) U/mL], and T7 [RBD = 8204 (IQR:4129-11,912); S1 = 4124 (IQR:2124-6326) U/mL] were characterized by the highest antibody values. Significant humoral increases in RBD and S1 were documented at T7 and T8 compared to T2 and T4, respectively (p-value < .001). Following vaccination with BNT162b2 and a booster dose in the 9th month, naïve and healthy subjects show high antibody titers up to 12 months and a protective humoral response against COVID-19 disease lasting up to 20 months after the last booster.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Estudos Retrospectivos , Vacina BNT162 , COVID-19/prevenção & controle , Seguimentos , Estudos Soroepidemiológicos , Anticorpos Antivirais , Pessoal de Saúde , Imunoglobulina G , Vacinas de mRNA
3.
Cancer Res ; 75(20): 4265-71, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26294210

RESUMO

Neuronal pentraxins (NPTX) and their corresponding receptors (NPTXR) have been studied as synapse-associated proteins in the nervous system, but their role in cancer is largely unknown. By applying a multidisciplinary, high-throughput proteomic approach, we have recently identified a peptide ligand motif for targeted drug delivery to neuroblastoma. Here, we report the sequence similarity between this peptide and a conserved portion of the pentraxin domain that is involved in the homo- and hetero-oligomerization of NPTX2 and NPTXR. We show that, in comparison with normal tissues, NPTX2 and NPTXR are overexpressed in vivo in mouse models, as well as in human Schwannian stroma-poor, stage IV neuroblastoma. Both proteins are concentrated in the vicinity of tumor blood vessels, with NPTXR also present on neuroblastic tumor cells. In vivo targeting of NPTX2 and NPTXR with the selected peptide or with specific antibodies reduces tumor burden in orthotopic mouse models of human neuroblastoma. In vitro interference with this ligand/receptor system inhibits the organization of neuroblastoma cells in tumor-like masses in close contact with vascular cells, as well as their adhesion to normal microenvironment-derived cells, suggesting a role in the cross-talk between tumor and normal cells in the early steps of neuroblastoma development. Finally, we show that NPTX2 is a marker of poor prognosis for neuroblastoma patients.


Assuntos
Proteína C-Reativa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroblastoma/metabolismo , Transdução de Sinais , Animais , Anticorpos Monoclonais/farmacologia , Proteína C-Reativa/química , Proteína C-Reativa/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Ligantes , Camundongos , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/mortalidade , Peptídeos/química , Peptídeos/farmacologia , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Biomaterials ; 68: 89-99, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26276694

RESUMO

Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.


Assuntos
Doxorrubicina/administração & dosagem , Nanocápsulas/administração & dosagem , Metástase Neoplásica/prevenção & controle , Neuroblastoma/química , Neuroblastoma/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Difusão , Doxorrubicina/química , Sinergismo Farmacológico , Feminino , Camundongos , Camundongos Nus , Nanocápsulas/química , Invasividade Neoplásica , Metástase Neoplásica/patologia , Neuroblastoma/patologia
5.
Dis Model Mech ; 7(9): 1083-91, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25147298

RESUMO

Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc(-/-)) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS­G6pc(-/-)) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS­G6pc(-/-) mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS­G6pc(-/-) mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10-20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS­G6pc(-/-) mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.


Assuntos
Adenoma/patologia , Carcinoma Hepatocelular/patologia , Glucosefosfato Desidrogenase/genética , Neoplasias Hepáticas/patologia , Adenoma/enzimologia , Animais , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Camundongos
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