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1.
BMJ Open ; 11(10): e049128, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670762

RESUMO

OBJECTIVES: To measure and explain financial toxicity (FT) of cancer in Italy, where a public healthcare system exists and patients with cancer are not expected (or only marginally) to pay out-of-pocket for healthcare. SETTING: Ten clinical oncological centres, distributed across Italian macroregions (North, Centre, South and Islands), including hospitals, university hospitals and national research institutes. PARTICIPANTS: From 8 October 2019 to 11 December 2019, 184 patients, aged 18 or more, who were receiving or had received within the previous 3 months active anticancer treatment were enrolled, 108 (59%) females and 76 (41%) males. INTERVENTION: A 30-item prefinal questionnaire, previously developed within the qualitative tasks of the project, was administered, either electronically (n=115) or by paper sheet (n=69). PRIMARY AND SECONDARY OUTCOME MEASURES: According to the protocol and the International Society for Pharmacoeconomics and Outcomes Research methodology, the final questionnaire was developed by mean of explanatory factor analysis and tested for reliability, internal consistency (Cronbach's α test and item-total correlation) and stability of measurements over time (test-retest reliability by intraclass correlation coefficient and weighted Cohen's kappa coefficient). RESULTS: After exploratory factor analysis, a score measuring FT (FT score) was identified, made by seven items dealing with outcomes of FT. The Cronbach's alpha coefficient for the FT score was 0.87 and the item-total correlation coefficients ranged from 0.53 to 0.74. Further, nine single items representing possible determinants of FT were also retained in the final instrument. Test-retest analysis revealed a good internal validity of the FT score and of the 16 items retained in the final questionnaire. CONCLUSIONS: The Patient-Reported Outcome for Fighting FInancial Toxicity (PROFFIT) instrument consists of 16 items and is the first reported instrument to assess FT of cancer developed in a country with a fully public healthcare system. TRIAL REGISTRATION NUMBER: NCT03473379.


Assuntos
Neoplasias , Medidas de Resultados Relatados pelo Paciente , Estudos Transversais , Atenção à Saúde , Feminino , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários
2.
Support Care Cancer ; 29(6): 3219-3233, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33094357

RESUMO

PURPOSE: This paper illustrates a conceptual model for a new patient-reported outcome measure (PROM) aimed at measuring financial toxicity (FT) in oncological setting in Italy, where citizens are provided universal healthcare coverage. METHODS: Focus groups with overall 34 patients/caregivers in three different Italian centers (from Northern, Centre, and Southern Italy) and an open-ended survey with 97 medical oncologists were undertaken. Transcripts from focus groups and the open-ended survey were analyzed to identify themes and links between themes. Themes from the qualitative research were supplemented with those reported in the literature; concepts identified formed the basis for item development that were then tested through the importance analysis (with 45 patients) and the cognitive debriefing (with other 45 patients) to test relevance and comprehension of the first draft PRO instrument. RESULTS: Ten domains were extracted by analyzing 156 concepts generated from focus groups and the open-ended survey. After controlling for redundancy, 55 items were generated and tested through the importance analysis. After controlling comprehension and feasibility through cognitive debriefing interviews, a first version of the questionnaire consisting of 30 items was devised. CONCLUSIONS: This qualitative study represents the first part of a study conducted to develop a new PROM to assess FT in Italy, by using a bottom-up approach that makes the most of patients' experiences and the health system analysis. TRIAL REGISTRATION: clinicaltrials.gov NCT03473379 first posted on March 22, 2018.


Assuntos
Neoplasias/economia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida/psicologia , Assistência de Saúde Universal , Feminino , Grupos Focais , Humanos , Masculino , Pesquisa Qualitativa , Inquéritos e Questionários
3.
J Proteome Res ; 11(12): 6111-23, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23106691

RESUMO

Mutations in cohesin genes have been identified in Cornelia de Lange syndrome (CdLS), but its etiopathogenetic mechanisms are still poorly understood. To define biochemical pathways that are affected in CdLS, we analyzed the proteomic profile of CdLS cell lines carrying mutations in the core cohesin genes, SMC1A and SMC3. Dysregulated protein expression was found in CdLS probands compared to controls. The proteomics analysis was able to discriminate between probands harboring mutations in the different domains of the SMC proteins. In particular, proteins involved in the response to oxidative stress were specifically down-regulated in hinge mutated probands. In addition, the finding that CdLS cell lines show an increase in global oxidative stress argues that it could contribute to some CdLS phenotypic features such as premature physiological aging and genome instability. Finally, the c-MYC gene represents a convergent hub lying at the center of dysregulated pathways, and is down-regulated in CdLS. This study allowed us to highlight, for the first time, specific biochemical pathways that are affected in CdLS, providing plausible causal evidence for some of the phenotypic features seen in CdLS.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Síndrome de Cornélia de Lange/metabolismo , Mutação , Proteoma/análise , Sequência de Aminoácidos , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA , Síndrome de Cornélia de Lange/patologia , Feminino , Regulação da Expressão Gênica , Instabilidade Genômica , Humanos , Masculino , Espectrometria de Massas , Dados de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estresse Oxidativo , Fenótipo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultura Primária de Células , Mapas de Interação de Proteínas , Estrutura Terciária de Proteína , Proteoma/metabolismo , Proteômica/métodos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transcrição Genética , Eletroforese em Gel Diferencial Bidimensional
4.
J Proteomics ; 75(15): 4717-33, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22846432

RESUMO

Phenotypic variability in the presence of an identical molecular defect is a recurrent feature in heritable disorders and it was also reported in osteogenesis imperfecta (OI). OI is a prototype for skeletal dysplasias mainly caused by mutations in the two genes coding for type I collagen. No definitive cure is available for this disorder, but the understanding of molecular basis in OI phenotypic modulation will have a pivotal role in identifying possible targets to develop novel drug therapy. We used a functional proteomic approach to address the study of phenotypic variability using the skin of the OI murine model Brtl. Brtl mice reproduce the molecular defect, dominant transmission and phenotypic variability of human OI patients. In the presence of a Gly349Cys substitution in α1(I)-collagen Brtl mice can have a lethal or a moderately severe outcome. Differential expression of chaperones, proteasomal subunits, metabolic enzymes, and proteins related to cellular fate demonstrated that a different ability to adapt to cellular stress distinguished mutant from wild-type mice and mutant lethal from surviving mutant animals. Interestingly, class discovery analysis identified clusters of differentially expressed proteins associated with a specific outcome, and functional analysis contributed to a deeper investigation into biochemical and cellular pathways affected by the disease. This article is part of a Special Issue entitled: Translational Proteomics.


Assuntos
Osteogênese Imperfeita/metabolismo , Proteoma/metabolismo , Proteômica , Pele/metabolismo , Estresse Fisiológico , Substituição de Aminoácidos , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Fenótipo , Proteoma/genética , Pele/patologia
5.
Proteomics ; 12(11): 1767-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22623105

RESUMO

The Saccharomyces cerevisiae gene SCO1 has been shown to play an essential role in copper delivery to cytochrome c oxidase. Biochemical studies demonstrated specific transfer of copper from Cox17p to Sco1p, and physical interactions between the Sco1p and Cox2p. Deletion of SCO1 yeast gene results in a respiratory deficient phenotype. This study aims to gain a more detailed insight on the effects of SCO1 deletion on S. cerevisiae metabolism. We compared, using a proteomic approach, the protein pattern of SCO1 null mutant strain and wild-type BY4741 strain grown on fermentable and on nonfermentable carbon sources. The analysis showed that on nonfermentable medium, the SCO1 mutant displayed a protein profile similar to that of actively fermenting yeast cells. Indeed, on 3% glycerol, this mutant displayed an increase of some glycolytic and fermentative enzymes such as glyceraldehyde-3-phosphate dehydrogenase 1, enolase 2, pyruvate decarboxylase 1, and alcohol dehydrogenase 1. These data were supported by immunoblotting and enzyme activity assay. Moreover, the ethanol assay and the oxygen consumption measurement demonstrated a fermentative activity in SCO1 mutant on respiratory medium. Our results suggest that on nonfermentable carbon source, the lack of Sco1p causes a metabolic shift from respiration to fermentation.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Proteoma/análise , Proteínas de Saccharomyces cerevisiae/análise , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/biossíntese , Complexo IV da Cadeia de Transporte de Elétrons/genética , Fermentação/genética , Deleção de Genes , Glicólise/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Consumo de Oxigênio/genética , Proteômica , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
6.
Proteomics ; 11(18): 3725-42, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21761561

RESUMO

Several solid tumors are characterized by poor prognosis and few effective treatment options, other than palliative chemotherapy in the recurrent/metastatic setting. Epidermal growth factor receptor (EGFR) has been considered an important anticancer target because it is involved in the development and progression of several solid tumors; however, only a subset of patients show a clinically meaningful response to EGFR inhibition, particularly to EGFR tyrosine kinase inhibitors such as gefitinib. We have recently demonstrated synergistic antitumor effect of the histone deacetylase inhibitor vorinostat combined with gefitinib. To further characterize the interaction between these two agents, cellular extracts from Hep-2 cancer cells that were untreated or treated for 24 h with either vorinostat or gefitinib alone or with a vorinostat/gefitinib combination were analyzed using 2-D DIGE. Software analysis using DeCyder was performed, and numerous differentially expressed protein spots were visualized between the four examined settings. Using MALDI-TOF MS and ESI-Ion trap MS/MS, several differentially expressed proteins were identified; some of these were validated by Western blotting. Finally, a pathway analysis of experimental data performed using MetaCore highlighted a relevant relationship between the identified proteins and additional potential effectors. In conclusion, we performed a comprehensive analysis of proteins regulated by vorinostat and gefitinib, alone and in combination, providing a useful insight into their mechanisms of action as well as their synergistic interaction.


Assuntos
Receptores ErbB/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Sinergismo Farmacológico , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Espectrometria de Massas/métodos , Mapeamento de Peptídeos , Isoformas de Proteínas/química , Proteômica , Software , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Eletroforese em Gel Diferencial Bidimensional , Vorinostat
7.
Gut ; 56(4): 480-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16891357

RESUMO

BACKGROUND: Gliadins, a family of wheat proteins, are central to the pathogenesis of celiac disease (CD). In addition to 'immunogenic' effects, gliadin directly affects cultured cells and intestine preparations, and produces damage in vivo, via a separate 'toxic' peptide, such as A-gliadin p31-43 (P31-43). AIMS: Understanding the molecular mechanisms underlying direct non T-cell mediated effects of gliadin peptides, and assessing their potential role in promoting CD. METHOD: Gliadin effects were tested on a number of cell lines and on cultured mucosa samples by evaluating cytoskeleton rearrangements, endocytosis, proliferation and apoptosis. Standard biochemical methods were used to assess prolonged epidermal growth factor receptor (EGFR) activation. RESULTS: Crude gliadin peptic-tryptic peptides (PTG], or P31-43 alone, fully reproduce the effects of epidermal growth factor (EGF] on actin cytosketon, cell cycle and cell proliferation of various cell lines. Inhibitor studies demonstrate the role of EGFR in the early response to gliadin exposure, pointing to activation of the EGFR pathway. Peptide P31-43 is not similar to any EGFR ligand, but can delay inactivation of the EGFR interfering with its endocytosis. Gliadin-induced delay of EGFR endocytosis in cultured intestinal biopsies, together with S-phase entry of epithelial intestinal cells, confirm a role for EGFR activation in CD. CONCLUSION: The ability of gliadin peptides to delay EGFR inactivation through interference with the endocytic pathway suggests a model where gliadin fragments amplify the effects of trace amounts of EGF, and possibly of other growth factors, by prolonging receptor activation. The results, using cultures of coeliac intestinal biopsies, highlight the role of the EGF pathway in establishing and maintaining the typical atrophic and proliferative alterations of the small intestine in CD.


Assuntos
Doença Celíaca/metabolismo , Receptores ErbB/efeitos dos fármacos , Gliadina/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Actinas/metabolismo , Apoptose/efeitos dos fármacos , Células CACO-2 , Doença Celíaca/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/fisiologia , Gliadina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Ligantes , Técnicas de Cultura de Órgãos
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