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1.
BJA Educ ; 24(9): 309-317, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39234155
2.
ESMO Open ; 9(9): 103689, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39265219

RESUMO

BACKGROUND: To present findings from a retrospective study conducted by the Ultra-Rare Sarcoma Working Group on metastatic low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid (H)-LGFMS/SEF across 28 global centres. METHODS: Patients treated at participating institutions from January 2000 to September 2022 were retrospectively selected. Diagnosis was confirmed by expert pathologists. Primary endpoint was progression-free survival (PFS-1) from metastasis detection to first progression or death. PFS-2 was calculated from therapy initiation. RESULTS: A total of 101 patients were identified (32 LGFMS, 50 SEF, 19 H-LGFMS/SEF). Median (m) follow-up was 62.1 months. mPFS-1 was 28.7, 11.8, and 20.3 months for LGFMS, SEF, and H-LGFMS/SEF, respectively. mOS was 145.8, 41.9, and 113.5 months, respectively. Treatments included anthracycline-based chemotherapy, gemcitabine-based chemotherapy (G), pazopanib, trabectedin, others. mPFS-2 was: 20.1, 5.5, and 3.5 months in H-LGFMS/SEF, SEF, and LGFMS, respectively, with anthracyclines; 19.5, 7.7, and 6.9 months in LGFMS, SEF, and H-LGFMS/SEF, respectively, with pazopanib; 12.0, 9.7, and 3.1 months in H-LGFMS/SEF, LGFMS, and SEF, respectively. Occasional responses occurred with ifosfamide/oral cyclophosphamide, and prolonged stable disease with immune checkpoint inhibitors. CONCLUSIONS: In this series, the largest available, metastatic LGFMS, SEF, and H-LGFMS/SEF showed different courses. Systemic agents have modest efficacy, informing future trials of novel agents for these tumours.

3.
Oncogene ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39198616

RESUMO

Trabectedin, approved for the treatment of soft tissue sarcoma (STS), interferes with cell division and genetic transcription processes. Due to its strong anti-tumor activity in only certain histotypes, several studies on trabectedin combinations are currently ongoing to improve its efficacy. In this study, we aimed to investigate novel potential therapeutic strategies to enhance the anti-tumor effect of trabectedin using integrated in silico, in vitro, and in vivo approaches. For in silico analysis, we screened two public datasets, GSEA M5190 and TCGA SARC. Fibrosarcoma, leiomyosarcoma, dedifferentiated, and myxoid liposarcoma cell lines were used for in vitro studies. For in vivo experiments, fibrosarcoma orthotopic murine model was developed. In silico analysis identified Glo1 as the only druggable target upregulated after trabectedin treatment and correlated with poor prognosis. The specific Glo1 inhibitor, S-p-bromobenzylglutathione cyclopentyl diester (BBGC), increased trabectedin cytotoxicity in STS cells, and restored drug sensitivity in myxoid liposarcoma cells resistant to trabectedin. Moreover, the combined treatment with BBGC and trabectedin had a synergistic antitumor effect in vivo without any additional toxicity to mice. Based on these results, we believe that BBGC warrants further investigation to evaluate its potential clinical use in combination with trabectedin.

4.
J Neurol Sci ; 460: 123012, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38626532

RESUMO

OBJECTIVE: Essential Tremor (ET) is one of the most common neurological disorders. In most instances ET is inherited as an autosomal dominant trait with age-related penetrance (virtually complete in advanced age); however, ET genetics remains elusive. The current study aims to identify possibly pathogenic genetic variants in a group of well-characterized ET families. METHODS: 34 individuals from 14 families with dominant ET were clinically evaluated and studied by whole exome sequencing studies (after excluding trinucleotide expansion disorders). RESULTS: Most patients had pure ET. In 4 families, exome studies could identify a genetic variant potentially able to significantly alter the protein structure (CADD >20, REVEL score > 0.25), shared by all the affected individuals (in CAMTA1, FUS, MYH14, SGCE genes). In another family there were two variants in dominant genes (PCDH9 and SQSTM1). Moreover, an interrupted "intermediate" trinucleotide expansion in ATXN1 ("SCA1") was identified in a further family with pure ET. CONCLUSION: Combining our observations together with earlier reports, we can conclude that ET genes confirmed in at least two families to date include CAMTA1 and FUS (reported here), as well as CACNA1G, NOTCH2NLC and TENM4. Most cases of familial ET, inherited with an autosomal dominant inheritance, may result from "mild" variants of many different genes that, when affected by more harmful genetic variants, lead to more severe neurological syndromes (still autosomal dominant). Thus, ET phenotype may be the "mild", incomplete manifestation of many other dominant neurogenetic diseases. These findings further support evidence of genetic heterogeneity for such disease(s). Author's keywords: cerebellar ataxias, movement disorders, neurogenetics, rare neurological disorders, tremor.


Assuntos
Ataxina-1 , Tremor Essencial , Proteína FUS de Ligação a RNA , Humanos , Feminino , Masculino , Itália , Proteína FUS de Ligação a RNA/genética , Pessoa de Meia-Idade , Tremor Essencial/genética , Idoso , Adulto , Ataxina-1/genética , Linhagem , Idoso de 80 Anos ou mais , Sequenciamento do Exoma
6.
Clin Ter ; 174(4): 322-325, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37378500

RESUMO

Abstract: Zoonotic dirofilariasis infestation, caused by Dirofilaria Repens, is described worldwide in different countries. A 31-years-old male patient presented thoracic muscle pain after growth of an ovoidal undefine cyst in left parasternal region. Patient reported several contacts with different species of animals for a familiar activity. In absence of blood inflammatory indices and systemic symptoms, imaging studies showed a suspected muscle cyst infection. Surgical excision was performed and microbiology confirmed parasite nature. Dirofilaria Repens, probably adult female, was identified. Treatment resulted to be definitive and any other clinical and surgical approach was needed. Healing time was uneventful and follow-up showed no further systemic relapses. The case highlights the effectiveness of surgical treatment in this subcutaneous infestation for an increasing number of human cases reported in endemic areas such as Central Italy.


Assuntos
Dirofilaria repens , Dirofilariose , Adulto , Animais , Humanos , Masculino , Feminino , Dirofilariose/diagnóstico , Dirofilariose/cirurgia , Dirofilariose/epidemiologia , Músculos Peitorais , Recidiva Local de Neoplasia , Itália
7.
Clin Radiol ; 77(10): 784-793, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35850865

RESUMO

AIM: To report the first UK experience of cryoablation in desmoid fibromatosis (DF) with particular focus on technique, safety, and efficacy. MATERIALS AND METHODS: Patients were selected at multidisciplinary tumour board meetings at a specialist cancer hospital. Radiation dose, procedure duration, and number of cryoprobes were compared for small versus large tumours (>10 cm long axis). Response at magnetic resonance imaging (MRI) was evaluated using different criteria, and percentage agreement with clinical response as assessed in oncology clinic calculated. RESULTS: Thirteen procedures were performed in 10 patients (eight women, median age 51 years, IQR 42-69 years) between February 2019 and August 2021. Procedures for large tumours had higher radiation dose (2,012 ± 1,012 versus 1,076 ± 519 mGy·cm, p=0.048) used more cryoprobes (13 ± 7 versus 4 ± 2, p=0.009), and were more likely to have residual unablated tumour (38 ± 37% versus 7.5 ± 10%, p=0.045). Adverse events were minor apart from one transient radial nerve palsy. Eight of 10 patients had symptomatic benefit at clinical follow-up (median 353 days, IQR 86-796 days), and three started systemic therapy mean 393 days later. All patients who had complete ablation demonstrated symptomatic response, with no instances of repeat treatment, recurrence, or need for systemic therapy during the study period. All progression occurred outside ablation zones. CONCLUSION: Cryoablation for symptomatic DF is a reproducible technique with low, transient toxicity, where one or two treatments can achieve a meaningful response. Where possible, the ablation ice ball should fully cover DF tumours.


Assuntos
Criocirurgia , Fibromatose Agressiva , Criocirurgia/métodos , Feminino , Fibromatose Agressiva/diagnóstico por imagem , Fibromatose Agressiva/patologia , Fibromatose Agressiva/cirurgia , Humanos , Gelo , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido
8.
J Matern Fetal Neonatal Med ; 35(21): 4035-4042, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33203279

RESUMO

BACKGROUND AND PURPOSE: MR imaging provides means for discriminating different patterns of Hypoxic-ischemic encephalopathy (HIE) and may distinguish most severe cases from less severe but is unable to predict long-term outcome. Diffusion tensor imaging (DTI) offers information for a more complete characterization of HIE. The purpose of this study is to compare the modifications of DTI parameters in newborns one week and six months following total-body cooling to healthy controls. METHODS: Forty-seven cooled newborns were studied with MRI, 20 underwent follow-up at 6 months. 12 healthy newborns and nine children at 6 months were enrolled as control groups (HC). Inferior Longitudinal Fasciculus (ILF), Corpus Callosum Fasciculus (CCF), Corticospinal Tract (CST), Optical Tract (OT), Optic Radiation (OR) were generated in all subjects. DTI parameters were evaluated in basal ganglia (BG), thalamus (TH) and tracks. Statistical analysis was performed with MANOVA. RESULTS: In newborns HIE versus HC, there were significantly lower fractional anisotropy (FA) on OR and CST and higher axial diffusivity (AD), apparent diffusion coefficient (ADC) and radial diffusivity (RD) values on CST, BG and TH in HIE-N. At 6 months there were no significant grouping effects. The analysis showed a significant increase of FA, decrease of ADC, AD, RD after 6 months for HIE and HC. CONCLUSIONS: We observed modifications of parameter values in HIE newborns vs HC; however normalization of values at 6 months suggests that changes of parameters cannot be considered early biomarkers for evaluation of therapeutic hypothermia in newborns with moderate HIE and normal conventional MRI.


Assuntos
Hipotermia , Hipóxia-Isquemia Encefálica , Anisotropia , Criança , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Humanos , Recém-Nascido
9.
Arch Ital Biol ; 159(1): 3-20, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-34159573

RESUMO

Cortical thickness (CT) and local gyrification index (LGI) in psychotic disorders may show modifications that relate to clinical course. This observational study aimed to analyse such variables in patients with schizophrenia, compared to healthy controls (HCs). We compared CT and LGI of 18 patients with first-episode psychosis with that of 21 with multi-episode schizophrenia and 16 HCs. CT corrected for false-positive cases (Family-Wise Error Rate) showed a reduction in the multi-episode group compared to HCs in left temporal and parietal, and right temporal, parietal, occipital, and hippocampal cortices. Family-wise corrected LGI was increased in the left inferior and middle frontal cortices, and in the right fusiform gyrus, cingulate, lingual, and parahippocampal gyri in first onset patients compared to HCs. Increased LGI was absent from later stages of psychosis, suggesting that specific CT and LGI alterations may underlie different stages of illness.


Assuntos
Transtornos Psicóticos , Esquizofrenia , Espessura Cortical do Cérebro , Córtex Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem
10.
ESMO Open ; 6(2): 100083, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33714008

RESUMO

BACKGROUND: This multicentric, retrospective study conducted within the Italian Rare Cancer Network describes clinical features and explores their possible prognostic relevance in patients with advanced epithelioid haemangioendothelioma (EHE) started on surveillance. PATIENTS AND METHODS: We collected data on adult patients with molecularly confirmed, advanced EHE consecutively referred at five sarcoma reference centres between January 2010 and June 2018, with no evidence of progressive disease (PD) and started on surveillance. Overall survival (OS) and progression-free survival (PFS) univariable and multivariable Cox analyses were performed. In the latter, due to the low number of cases and events, penalized likelihood was applied, and variable selection was performed using a random forest model. RESULTS: Sixty-seven patients were included. With a median follow-up of 50.2 months, 51 (76%) patients developed PD and 16 (24%) remained stable. PD at treatment start did not meet RECIST version 1.1 in 15/51 (29%) patients. The 3-year PFS and OS were 25.4% and 71.1%, respectively, in the whole population. Tumour-related pain (TRP) was the most common baseline symptom (32.8%), followed by temperature (20.9%), fatigue (17.9%), and weight loss (16.4%). Baseline TRP (P = 0.0002), development of TRP during follow-up (P = 0.005), baseline temperature (P = 0.002), and development of fatigue during follow-up (P = 0.007) were associated with a significantly worst PFS. An association between baseline TRP (P < 0.0001), development of TRP during follow-up (P = 0.0009), evidence of baseline serosal effusion (P = 0.121), and OS was recorded. CONCLUSION: Because of the poor outcome observed in EHE patients presenting with serosal effusion, TRP, temperature, or serosal effusion, upfront treatment in this subgroup could be considered.


Assuntos
Hemangioendotelioma Epitelioide , Adulto , Hemangioendotelioma Epitelioide/diagnóstico , Humanos , Itália/epidemiologia , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos
11.
Gynecol Endocrinol ; 35(9): 767-771, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30935252

RESUMO

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.


Assuntos
Desidroepiandrosterona/administração & dosagem , Glucose/farmacologia , Pós-Menopausa/sangue , Pós-Menopausa/efeitos dos fármacos , beta-Endorfina/metabolismo , Administração Oral , Idoso , Androgênios/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Peso Corporal Ideal/efeitos dos fármacos , Peso Corporal Ideal/fisiologia , Insulina/sangue , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Fatores de Tempo , beta-Endorfina/sangue
12.
J Endocrinol Invest ; 41(5): 583-590, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29090431

RESUMO

PURPOSE: To evaluate the efficacy of alpha-lipoic acid (ALA) administration on hormonal and metabolic parameters of obese PCOS patients. METHODS: A group of 32 obese PCOS patients were selected after informed consent. 20 patients referred to have first grade relatives with diabetes type I or II. Hormonal and metabolic parameters as well as OGTT were evaluated before and after 12 weeks of ALA integrative administration (400 mg per os every day). RESULTS: ALA administration significantly decreased insulin, glucose, BMI and HOMA index. Hyperinsulinemia and insulin response to OGTT decreased both as maximal response (Δmax) and as AUC. PCOS with diabetes relatives showed the decrease also of triglyceride and GOT. Interestingly in all PCOS no changes occurred on all hormonal parameters involved in reproduction such as LH, FSH, and androstenedione. CONCLUSIONS: ALA integrative administration at a low dosage as 400 mg daily improved the metabolic impairment of all PCOS patients especially in those PCOS with familiar diabetes who have a higher grade of risk of NAFLD and predisposition to diabetes.


Assuntos
Antioxidantes/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Resistência à Insulina , Obesidade/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Ácido Tióctico/administração & dosagem , Adulto , Índice de Massa Corporal , Diabetes Mellitus/patologia , Feminino , Seguimentos , Humanos , Obesidade/complicações , Obesidade/patologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/patologia , Prognóstico , Adulto Jovem
13.
Oncogene ; 36(46): 6501-6507, 2017 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-28759042

RESUMO

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cisplatino/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/genética , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma Maligno , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Pemetrexede/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Análise de Sobrevida
14.
Med Phys ; 43(12): 6621, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27908173

RESUMO

PURPOSE: The effect of the movement near the MRI scanner bore for people with a pacemaker (PM) or an implantable cardioverter defibrillator (ICD) is experimentally evaluated and discussed. METHODS: The authors performed in vitro measurements on a saline-filled human-shaped phantom (male, 170 cm height), equipped first with an MR-conditional PM (bicameral configuration, DDD programming), then with an MR-conditional ICD (biventricular configuration, detection algorithms enable but shock delivery disable). Both the devices were able to transmit in real-time the detected cardiac activity (electrograms) while moving the phantom around the MRI scanner. The phantom was also equipped with an accelerometer and a magnetic field probe to measure the angular velocity and the magnetic field variation during the experiment. Unipolar versus bipolar sensing mode and maximum sensitivity versus nominal settings were tested. RESULTS: The sensing functions of the PM and ICD systems began to react to motion induced electromagnetic interference starting at an angular velocity as low as 2 rad/s (|dB/dT| = 2 T/s). The motion induced EMI in PM and ICD systems was interpreted as sensed intrinsic heartbeats which resulted in inappropriate pacing inhibition and arrhythmia classification. At the maximum speed of about 6 rad/s (|dB/dT| = 3 T/s), the induced EMI affected classification of ectopic beats and two episodes of VF were inappropriately recorded. CONCLUSIONS: These results demonstrate that motion in and around an MR scanner can induce EMI significant enough to be misinterpreted by implanted PMs and ICDs leading to inappropriate changes in therapy. These findings highlight that PM or ICDs, including MR-conditional systems should not enter the MRI room, except in case of an examination under specified conditions.


Assuntos
Artefatos , Desfibriladores Implantáveis , Imageamento por Ressonância Magnética/instrumentação , Movimento , Marca-Passo Artificial , Humanos , Masculino , Imagens de Fantasmas
15.
Eur J Paediatr Neurol ; 20(1): 158-63, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26387071

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the CNS occurring in young adults and even in children in 5% of cases. Lower quality of life (QoL) and cognitive impairment (CI) (40-54%) have been reported in early-onset MS (EO-MS) patients. OBJECTIVE: To assess QoL and cognitive function in EO-MS and their relationship, also considering demographic and clinical variables. METHODS: Paediatric Quality of life inventory Version 4.0 for patients aged 13-18 and 19-25 years, Beck Depression Inventory II (BDI II) and the Rao Brief Repeatable Battery were performed in EO-MS patients (onset age ≤25years). EDSS and MSSS were performed at same time. After testing for normal distribution, group comparisons were performed through the two-tailed Student's t test, one-way analysis of variance (ANOVA) and linear or logistic regression when appropriate. The Bonferroni correction for multiple testing was used when appropriate. RESULTS: 59 patients were included (mean age: 20 ± 3.6; Female sex 52.54%). 34 patients had a paediatric onset (<18 years) while 20 patients had a juvenile onset (18 < age < 25 years) of disease. 5 patients were excluded for missing data. HR-QoL was higher in paediatric than juvenile MS patients (p = 0.02), and it was inversely related to EDSS (p = 0.0005) and Multiple Sclerosis Severity score (MSSS) (p = 0.0001). Sixtyone % of patients showed a CI at BRB. No association was found between CI and any socio-demographic and clinical data. HR-QoL total score was not related to CI status nor to any domain-specific cognitive function score, even considering BDI as possible bias. CI was related to social, physical functioning score and EDSS (p = 0.01) at a logistic regression backward stepwise estimation. CONCLUSION: HR-QoL resulted to be better in paediatric than juvenile MS onset patients and was inversely related to rapidity of disability accumulation, while cognitive impairment was influenced by physical disability and poor social involvement (school, education …). Social participation, affective relations and psychological flexibility could have a protective function on CI.


Assuntos
Transtornos Cognitivos/epidemiologia , Cognição , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idade de Início , Análise de Variância , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Feminino , Humanos , Masculino , Esclerose Múltipla/epidemiologia , Escalas de Graduação Psiquiátrica , Análise de Regressão , Fatores Sociológicos , Adulto Jovem
16.
Oncogene ; 35(15): 1996-2002, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26119930

RESUMO

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.


Assuntos
Asbesto Crocidolita/toxicidade , Mesotelioma/etiologia , Neoplasias Peritoneais/etiologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Animais , Asbesto Crocidolita/administração & dosagem , Líquido Ascítico/química , Quimiocinas/análise , Citocinas/análise , Relação Dose-Resposta a Droga , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Leucócitos/patologia , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/fisiologia , Masculino , Mesotelioma/genética , Camundongos , Camundongos Endogâmicos C57BL , Fibras Minerais/toxicidade , Neoplasias Peritoneais/genética , Peritonite/etiologia , Peritonite/genética , Distribuição Aleatória , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/fisiologia
17.
Cell Death Dis ; 6: e1786, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-26068794

RESUMO

High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Ácido Salicílico/uso terapêutico , Células 3T3 , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Proteína HMGB1/metabolismo , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Mesotelioma Maligno , Camundongos , Camundongos Knockout , Camundongos SCID , Invasividade Neoplásica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Minerva Ginecol ; 66(1): 91-102, 2014 Feb.
Artigo em Italiano | MEDLINE | ID: mdl-24569408

RESUMO

Introduction of new compounds containing natural estrogens represented a major development in the field of hormonal contraception. Micronized estradiol (E2) and its estere valerate (EV), is more easily metabolized by the liver than ethynylestradiol (EE). This causes minimal metabolic impact, but the weak estrogenic activity needs not be antagonized by androgenic progestin and requires progestin capable to stabilize the endometrium. Dienogest (DNG), an antiandrogenic progestin with a short half-life, is associated with estradiol valerate (EV) in a quadriphasic fashion. In comparison to EE/levonorgestrel (LNG), EV/DNG is more neutral on metabolism and coagulation. Furthermore, it does not seem to negatively affect the cardiovascular system and breast. Cycle control is optimal with a higher prevalence of amenorrhea and reduction of menstrual flow. For this reason EV/DNG can be tehrapeutic for heavy menstrual bleedings. Nomegestrol acetate (NOMAc), an anti-andogen progestin with a long half-life is combined in monophasic regimen with micronized E2. E2/NOMAc is more neutral than EE/LNG on metabolism and more neutral than EE/DRSP on coagulation. NOMAc reduces peripheral tissue estrogen formation, and this may be beneficial for the breast. The two formulations exert a high contraceptive efficacy similar to the ones containing EE, but with less estrogen-related side-effects. The additional benefits due to DNG and NOMAc need to be further explored.


Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Estrogênios/administração & dosagem , Animais , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Anticoncepcionais Femininos/farmacologia , Anticoncepcionais Orais/farmacocinética , Anticoncepcionais Orais/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Anticoncepcionais Orais Combinados/farmacologia , Desenho de Fármacos , Estrogênios/farmacocinética , Estrogênios/farmacologia , Feminino , Humanos
19.
Funct Neurol ; 28(2): 121-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24125562

RESUMO

The Scales for Outcomes in Parkinson's disease-Cognition (SCOPA-Cog) has been shown to be a clinimetrically rigorous and valid instrument for a disease-oriented neuropsychological assessment of Parkinson's disease (PD) patients. In the present study we evaluated the psychometric properties of the Italian version of the SCOPA-Cog in 121 PD patients. The scale explores memory, attention, and executive and visuospatial functions and takes approximately 20 minutes to administer. Data distribution (skewness= -0.23) and internal consistency (Cronbach's alpha= 0.78) were satisfactory. Standard error of measurement was 3.42. The outcome was significantly worse in patients with an abnormal Psychometric properties of the Italian version of the Scales for Outcomes in Parkinson's disease-Cognition (SCOPA-Cog) score on the Dementia Rating Scale (DRS) (SCOPACog mean score 14.6 ± 5.1 out of a total of 43) with respect to cognitively intact subjects (24.2 ± 4.3) (p<0.0001). The DRS showed good convergent validity (Spearman rho= 0.77, p<0.0001), and a high coefficient of variation (= 0.34). These findings support the goodness of the Italian SCOPA-Cog in terms of metrics and validity.


Assuntos
Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Psicometria
20.
Parkinsonism Relat Disord ; 19(12): 1160-3, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24011719

RESUMO

The detection of cognitive decline in Parkinson's disease (PD), at the Mild Cognitive Impairment (MCI) stage, has prognostic and treatment implications. The Movement Disorders Society (MDS) has recently published criteria and guidelines for the diagnosis of possible and probable PD-MCI. In the present study we assessed the ability of the Scales for Outcomes in Parkinson's disease-Cognition (SCOPA-Cog) to discriminate possible PD-MCI cases from patients with PD-dementia (PDD) and from cognitively intact PD subjects. Hundred-and-thirteen consecutive PD patients underwent the MMSE, the Dementia Rating Scale and an interview on independence in daily living, and were classified as cognitively intact (n = 49), or as possible PD-MCI (n = 33) or PDD (n = 31), according to MDS criteria. Logistic regression analysis was carried out with PD-MCI diagnosis (yes/no) as an outcome variable, and age, education and the SCOPA-Cog total score as covariates. Classification of cases according to the regression model was used for constructing Receiver Operating Characteristic (ROC) curves. Area Under the Curve (AUC) was 0.92 [95% CI 0.86-0.98], for the differential diagnosis between PD-MCI and cognitively normal patients, and 0.97 [95% CI 0.80-1.00], for the differential diagnosis between PD-MCI and PDD. Sensitivity and specificity were 90% and 73% for the PD-MCI versus no cognitive impairment differentiation, at the cutpoint ≥24, and 93% and 97% for the PD-MCI versus PDD discrimination, at the cutpoint ≥17. The SCOPA-Cog is a quick and psychometrically sound PD-specific scale. Our findings support its use for the screening of possible PD-MCI.


Assuntos
Disfunção Cognitiva/diagnóstico , Doença de Parkinson/psicologia , Idoso , Área Sob a Curva , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Curva ROC
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