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1.
J Exp Clin Cancer Res ; 40(1): 319, 2021 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-34645505

RESUMEN

BACKGROUND: Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. METHODS: The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. RESULTS: We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. CONCLUSIONS: Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

2.
Health Policy ; 125(12): 1580-1586, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34649753

RESUMEN

Although COVID-19 affects older people more severely, health policies during the first wave of the pandemic often prioritized younger individuals. We investigated whether age had influenced the access to a diagnostic test for SARS-CoV-2 infection and whether clinical complexity and healthcare resources availability could have impacted such differences. This work included 126,741 Italian participants in the EPICOVID19 web-based survey, who reported having had contacts with known/suspected COVID-19 cases (epidemiological criterion) and/or COVID-19-like signs/symptoms (clinical criterion) from February to June 2020. Data on sociodemographic, medical history and access to SARS-CoV-2 nasopharyngeal swab (NPS) were collected. Logistic regressions estimated the probability of accessing NPS as a function of age and the possible modifying effect of chronic diseases' number and residential areas in such association. A total of 6136 (4.8%) participants had undergone an NPS. Older participants had lower NPS frequencies than the younger ones when reporting epidemiological (14.9% vs. 8.8%) or both epidemiological and clinical criteria (17.5% vs. 13.7%). After adjustment for potential confounders, including epidemiological and clinical criteria, the chance of NPS access decreased by 29% (OR=0.71, 95%CI:0.63-0.79) in older vs. younger individuals. Such disparity was accentuated in areas with greater healthcare resources. In conclusion, in the first wave of the pandemic, age may have affected the access to COVID-19 diagnostic testing, disadvantaging older people.

3.
Artículo en Inglés | MEDLINE | ID: mdl-34682362

RESUMEN

Risk perception (RP) evaluation during pregnancy and its relationship with lifestyles are considered useful tools for understanding communities living in high-risk areas and preventing dangerous exposure. It is well known that exposure to pollutants and less-healthy lifestyles may result in increased disease occurrence during life. Our work investigated environmental RP through ad hoc questionnaires administered to 611 mothers within the NEHO birth cohort, recruited in three heavily contaminated areas of Southern Italy. Four different RP indices, an exploratory factorial analysis (EFA), and a latent class analysis were evaluated from questionnaires. The highest values of risk perception index were observed in the Milazzo site (0.64 ± 0.16) and the lowest in the Crotone site (0.5 ± 0.18). EFA revealed four latent factors, including different items describing environmental pollution, and subjects were classified into four latent classes with different RP indices. Significant RP profiles were different among the sites (p < 0.001). Our results did not demonstrate any association between RP and lifestyles during pregnancy. Improving healthy lifestyle behaviours, particularly in polluted areas, would generate co-benefits by preventing further risk factors. As remediation interventions can take a long time, it needs to improve healthy lifestyles in residents until remediation is completed.


Asunto(s)
Contaminantes Ambientales , Mujeres Embarazadas , Contaminación Ambiental , Femenino , Humanos , Percepción , Embarazo , Factores de Riesgo
4.
Cancers (Basel) ; 13(15)2021 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-34359818

RESUMEN

Lung cancer burden is increasing, with 2 million deaths/year worldwide. Current limitations in early detection impede lung cancer diagnosis when the disease is still localized and thus more curable by surgery or multimodality treatment. Liquid biopsy is emerging as an important tool for lung cancer early detection and for monitoring therapy response. Here, we reviewed recent advances in liquid biopsy for early diagnosis of lung cancer. We summarized DNA- or RNA-based biomarkers, proteins, autoantibodies circulating in the blood, as well as circulating tumor cells (CTCs), and compared the most promising studies in terms of biomarkers prediction performance. While we observed an overall good performance for the proposed biomarkers, we noticed some critical aspects which may complicate the successful translation of these biomarkers into the clinical setting. We, therefore, proposed a roadmap for successful development of lung cancer biomarkers during the discovery, prioritization, and clinical validation phase. The integration of innovative minimally invasive biomarkers in screening programs is highly demanded to augment lung cancer early detection.

5.
Epidemiol Prev ; 45(3): 155-163, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34212696

RESUMEN

BACKGROUND: the exposure to a coal-fired power plant has been shown to increase mortality both for cardiovascular and respiratory causes among an exposed cohort in comparison with a cohort of unexposed. Hazard ratios between 1.30 and 1.90 were found for cardiovascular and respiratory mortality. OBJECTIVES: to estimate the individual life shortening among the exposed due to power plant emissions. DESIGN: survival for cardiovascular and respiratory disease in the exposed vs unexposed groups was estimated by the Kaplan-Meier method. For each gender and exposure, a fictitious cohort with a cumulative 30-year follow up was built combining three subcohorts of age at entry of 55-64, 65-74, and 75-84 years, with 10 years of follow up each. Survivals at 10 years in the 55-64-year subcohort were used as initial risks for 65-74-year subcohort; then, survivals at 10 years of the 65-74-year subcohort were used as initial risk in the 75-84-year subcohort. Eventually, 30-years cumulative follow up cohorts were obtained by gender and exposure. Individual life-shortening in people exposed was estimated as time from death of an exposed subject to the subsequent time when the unexposed cohort reached the same risk of the exposed subject at that time of the death. Here, it is proposed a method to take into account causes other than those considered. SETTING AND PARTICIPANTS: 144,018 subjects aged 55-74 years at entry of both genders belonging to the open cohort of residents of 12 municipalities (including Savona) from 2001 to 2013 in the area where the coal-fired power plant of Vado-Quiliano (Liguria Region, Northern Italy) is located. MAIN OUTCOME MEASURES: individual life shortening. RESULTS: after 5 years of follow up, the individual life shortening due to cardiorespiratory causes varied between 972 and 1,822 days for males and from 612 and 1,578 days among females. Taking into account other causes of death, reduces slightly (3% for males of 75 years at death) the estimate of life shortening found in this study. The comparison between the cohorts requires that the exposed and unexposed groups are comparable, except for the exposure, and that causes other than those considered are taken into account. Socioeconomic status had been found to have little effect on cause-specific death risk indicating that, at least in terms of socioeconomic status, the exposed and unexposed groups were similar. Taking into account causes other than those considered slightly reduced the found estimates (3% at age 75 in males). According to the proposal, the life-shortening for the considered causes is easy to calculate and provides an individual indicator of damage. Inferring from group statistics individual estimates could be the most controversial point of this approach. The proposed estimates are the most credible estimate of individual damage for each occurred death among the exposed people. CONCLUSIONS: an increased hazard ratio for a wide series of causes is equivalent to a life shortening among the exposed. A method to produce reasonable estimates of life-shortening is proposed as the effect of exposure at individual level. This approach is simple and do not require sophisticated statistical tools. It appears a promising approach for other settings.


Asunto(s)
Carbono , Enfermedades Cardiovasculares , Exposición a Riesgos Ambientales , Centrales Eléctricas , Enfermedades Respiratorias , Anciano , Anciano de 80 o más Años , Carbono/envenenamiento , Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Ciudades/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades Respiratorias/mortalidad
6.
Oncogene ; 40(31): 4980-4991, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34172935

RESUMEN

Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40-50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD.

7.
Epidemiol Prev ; 45(1-2): 117-121, 2021.
Artículo en Italiano | MEDLINE | ID: mdl-33884850

RESUMEN

Environmental Impact Assessments (EIAs) often conclude with a "low" or at least "negligible" final health impact assessment (HIA) of the industrial plant under assessment. We explore the reasons for this - often simplistic - conclusion and offer suggestions on how to extend the assessment focus from just the plant to an appropriate impact area. For many assessments, the conclusions are easily predictable: the application of available risk functions to modest increases in pollution, in the presence of numerically small populations in the areas of greatest fallout and considering rather rare health outcomes, can only result in quantitatively modest health impacts. This is the classic situation of low sensitivity of the observation system due to the impossibility of containing the type II error (false negatives) since we cannot increase the exposed population at will. The risk is to give the green light to an industrial plant in which the apparently null or very limited damage is simply not properly detectable. There is hardly any trace of these elements in the HIA scoping phase. In environmental complex territories, the renewal or authorization of a new plant should consider not only the impact of the individual plant, but also the health profile of the population concerned and the context in which the industrial project is located. An 'HIA area' is therefore configured, aimed at the complex of environmental pressure factors that insist on the same area of impact of the plant. Epidemiology focuses on the exposed population, considers the 'current' state of health, hazard, and risk information from toxicology, and estimates individual exposure and the effects of exposure. The 'HIA area' can assess the impact of the complex of persistent emission sources, considering in the analysis the health status of the exposed population and the presence of specific vulnerabilities. The proposal is in line with what is already foreseen in the Essential levels of care and Environmental technical performance of the National Health Service.A basic condition is the establishment of functions dedicated to integrated environmental and health surveillance to update the health profile and carry out the 'HIA area' as an accompanying tool for local strategic planning. On these issues, the Italian Environment and Health Network (RIAS) has opened a discussion within the network and with any Italian regions.


Asunto(s)
Evaluación del Impacto en la Salud , Medicina Estatal , Ambiente , Contaminación Ambiental/efectos adversos , Humanos , Italia/epidemiología
8.
Artículo en Inglés | MEDLINE | ID: mdl-33801074

RESUMEN

The study analyzed the association of the fear of contagion for oneself and for family members (FMs) during the first wave of the COVID-19 pandemic, with demographic and socioeconomic status (SES) and health factors. The study was performed within the EPICOVID19 web-based Italian survey, involving adults from April-June 2020. Out of 207,341 respondents, 95.9% completed the questionnaire (60% women with an average age of 47.3 vs. 48.9 years among men). The association between fear and demographic and SES characteristics, contacts with COVID-19 cases, nasopharyngeal swab, self-perceived health, flu vaccination, chronic diseases and specific symptoms was analyzed by logistic regression model; odds ratios adjusted for sex, age, education and occupation were calculated (aORs). Fear for FMs prevailed over fear for oneself and was higher among women than men. Fear for oneself decreased with higher levels of education and in those who perceived good health. Among those vaccinated for the flu, 40.8% responded they had feelings of fear for themselves vs. 34.2% of the not vaccinated. Fear increased when diseases were declared and it was higher when associated with symptoms such as chest pain, olfactory/taste disorders, heart palpitations (aORs > 1.5), lung or kidney diseases, hypertension, depression and/or anxiety. Trends in fear by region showed the highest percentage of positive responses in the southern regions. The knowledge gained from these results should be used to produce tailored messages and shared public health decisions.


Asunto(s)
COVID-19 , Pandemias , Adulto , Ansiedad , Estudios Transversales , Familia , Miedo , Femenino , Humanos , Internet , Italia/epidemiología , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Encuestas y Cuestionarios
10.
Semin Diagn Pathol ; 38(5): 90-97, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33810912

RESUMEN

In the lung, neuroendocrine tumors (NETs), namely typical and atypical carcinoids, and neuroendocrine carcinomas (NECs), grouping small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), make up for distinct tumor entities according to epidemiological, genetic, pathologic and clinical data. The proper classification is essential in clinical practice for diagnosis, prognosis and therapy purposes. Through an extensive literature survey, three perspectives on lung NENs have been revised: i) criteria and terminology on biopsy or cytology samples of primaries or metastases; ii) carcinoids with elevated mitotic counts and/or Ki-67 proliferation rates; iii) relevance of molecular landscape to identify new tumor entities and therapeutic targets. Furthermore, a dispute about lung NEN development has been raised according to emerging molecular models. We herein provide a pathology update on practical topics in the setting of lung NENs according to the current classification (recent advances). We have also reappraised the development of these tumors by modeling risk factors and natural history of disease (recent controversies). Combining recent advances and controversies may help clarify our biological understanding of lung NENs and give practical information for the clinical decision-making process.


Asunto(s)
Tumor Carcinoide , Carcinoma de Células Grandes , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Tumores Neuroendocrinos , Tumor Carcinoide/terapia , Humanos , Pulmón , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/terapia
11.
JMIR Public Health Surveill ; 7(4): e27091, 2021 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-33668011

RESUMEN

BACKGROUND: Several studies have reported a low prevalence of current smoking among hospitalized COVID-19 cases; however, no definitive conclusions can be drawn. OBJECTIVE: We investigated the association of tobacco smoke exposure with nasopharyngeal swab (NPS) test results for SARS-CoV-2 infection and disease severity accounting for possible confounders. METHODS: The nationwide, self-administered, cross-sectional web-based Italian National Epidemiological Survey on COVID-19 (EPICOVID19) was administered to an Italian population of 198,822 adult volunteers who filled in an online questionnaire between April 13 and June 2, 2020. For this study, we analyzed 6857 individuals with known NPS test results. The associations of smoking status and the dose-response relationship with a positive NPS test result and infection severity were calculated as odds ratios (ORs) with 95% CIs by means of logistic and multinomial regression models adjusting for sociodemographic, clinical, and behavioral characteristics. RESULTS: Out of the 6857 individuals (mean age 47.9 years, SD 14.1; 4516/6857, 65.9% female), 63.2% (4334/6857) had never smoked, 21.3% (1463/6857) were former smokers, and 15.5% (1060/6857) were current smokers. Compared to nonsmokers, current smokers were younger, were more educated, were less affected by chronic diseases, reported COVID-19-like symptoms less frequently, were less frequently hospitalized, and less frequently tested positive for COVID-19. In multivariate analysis, current smokers had almost half the odds of a positive NPS test result (OR 0.54, 95% CI 0.45-0.65) compared to nonsmokers. We also found a dose-dependent relationship with tobacco smoke: mild smokers (adjusted OR [aOR] 0.76, 95% CI 0.55-1.05), moderate smokers (aOR 0.56, 95% CI 0.42-0.73), and heavy smokers (aOR 0.38, 95% CI 0.27-0.53). This inverse association also persisted when considering the severity of the infection. Current smokers had a statistically significantly lower probability of having asymptomatic (aOR 0.50, 95% CI 0.27-0.92), mild (aOR 0.65, 95% CI 0.53-0.81), and severe infections (aOR 0.27, 95% CI 0.17-0.42) compared to those who never smoked. CONCLUSIONS: Current smoking was negatively associated with SARS-CoV-2 infection with a dose-dependent relationship. Ad hoc experimental studies are needed to elucidate the mechanisms underlying this association. TRIAL REGISTRATION: ClinicalTrials.gov NCT04471701; https://clinicaltrials.gov/ct2/show/NCT04471701.


Asunto(s)
COVID-19/epidemiología , Fumar/epidemiología , Adulto , Estudios Transversales , Femenino , Humanos , Internet , Italia/epidemiología , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios
12.
BMJ Glob Health ; 6(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33692145

RESUMEN

In the course of the COVID-19 pandemic, it has become clear that primary healthcare systems play a critical role in clinical care, such as patient screening, triage, physical and psychological support and also in promoting good community advice and awareness in coordination with secondary healthcare and preventive care. Because of the role of social and environmental factors in COVID-19 transmission and burden of disease, it is essential to ensure that there is adequate coordination of population-based health services and public health interventions. The COVID-19 pandemic has shown the primary and community healthcare (P&CHC) system's weaknesses worldwide. In many instances, P&CHC played only a minor role, the emphasis being on hospital and intensive care beds. This was compounded by political failures, in supporting local community resilience. Placing community building, social cohesion and resilience at the forefront of dealing with the COVID-19 crisis can help align solutions that provide a vision of 'planetary health'. This can be achieved by involving local well-being and participation in the face of any pervasive health and environmental crisis, including other epidemics and large-scale ecological crises. This paper proposes that P&CHC should take on two critical roles: first, to support local problem-solving efforts and to serve as a partner in innovative approaches to safeguarding community well-being; and second, to understand the local environment and health risks in the context of the global health perspective. We see this as an opportunity of immediate value and broad consequence beyond the control of the COVID-19 pandemic.


Asunto(s)
COVID-19/epidemiología , Servicios de Salud Comunitaria , Salud Pública , Cambio Climático , Educación , Salud Global , Humanos , Política , SARS-CoV-2 , Factores Socioeconómicos
13.
Orphanet J Rare Dis ; 16(1): 90, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33596949

RESUMEN

BACKGROUND: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions. RESULTS: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period. CONCLUSIONS: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.


Asunto(s)
Neoplasias , Esclerodermia Sistémica , Femenino , Humanos , Incidencia , Italia/epidemiología , Masculino , Prevalencia , Esclerodermia Sistémica/epidemiología
14.
Sci Rep ; 11(1): 2980, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536459

RESUMEN

While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538-0.754).


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/mortalidad , MicroARNs/análisis , MicroARNs/genética , Recurrencia Local de Neoplasia/epidemiología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Estudios de Cohortes , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/metabolismo , Persona de Mediana Edad , Familia de Multigenes/genética , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Medición de Riesgo/métodos , Regulación hacia Arriba
15.
Virchows Arch ; 478(1): 5-19, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33474631

RESUMEN

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.


Asunto(s)
Carcinoma Neuroendocrino/patología , Neoplasias Pulmonares/patología , Pulmón/patología , Tumores Neuroendocrinos/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo
16.
Endocr Pathol ; 32(3): 396-407, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33433886

RESUMEN

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.

17.
J Med Internet Res ; 23(1): e23897, 2021 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-33320825

RESUMEN

BACKGROUND: Confirmed COVID-19 cases have been registered in more than 200 countries, and as of July 28, 2020, over 16 million cases have been reported to the World Health Organization. This study was conducted during the epidemic peak of COVID-19 in Italy. The early identification of individuals with suspected COVID-19 is critical in immediately quarantining such individuals. Although surveys are widely used for identifying COVID-19 cases, outcomes, and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the general population. OBJECTIVE: We evaluated the capability of self-reported symptoms in discriminating COVID-19 to identify individuals who need to undergo instrumental measurements. We defined and validated a method for identifying a cutoff score. METHODS: Our study is phase II of the EPICOVID19 Italian national survey, which launched in April 2020 and included a convenience sample of 201,121 adults who completed the EPICOVID19 questionnaire. The Phase II questionnaire, which focused on the results of nasopharyngeal swab (NPS) and serological tests, was mailed to all subjects who previously underwent NPS tests. RESULTS: Of 2703 subjects who completed the Phase II questionnaire, 694 (25.7%) were NPS positive. Of the 472 subjects who underwent the immunoglobulin G (IgG) test and 421 who underwent the immunoglobulin M test, 22.9% (108/472) and 11.6% (49/421) tested positive, respectively. Compared to NPS-negative subjects, NPS-positive subjects had a higher incidence of fever (421/694, 60.7% vs 391/2009, 19.5%; P<.001), loss of taste and smell (365/694, 52.6% vs 239/2009, 11.9%; P<.001), and cough (352/694, 50.7% vs 580/2009, 28.9%; P<.001). With regard to subjects who underwent serological tests, IgG-positive subjects had a higher incidence of fever (65/108, 60.2% vs 43/364, 11.8%; P<.001) and pain in muscles/bones/joints (73/108, 67.6% vs 71/364, 19.5%; P<.001) than IgG-negative subjects. An analysis of self-reported COVID-19 symptom items revealed a 1-factor solution, the EPICOVID19 diagnostic scale. The following optimal scores were identified: 1.03 for respiratory problems, 1.07 for chest pain, 0.97 for loss of taste and smell 0.97, and 1.05 for tachycardia (ie, heart palpitations). These were the most important symptoms. For adults aged 18-84 years, the cutoff score was 2.56 (sensitivity: 76.56%; specificity: 68.24%) for NPS-positive subjects and 2.59 (sensitivity: 80.37%; specificity: 80.17%) for IgG-positive subjects. For subjects aged ≥60 years, the cutoff score was 1.28, and accuracy based on the presence of IgG antibodies improved (sensitivity: 88.00%; specificity: 89.58%). CONCLUSIONS: We developed a short diagnostic scale to detect subjects with symptoms that were potentially associated with COVID-19 from a wide population. Our results support the potential of self-reported symptoms in identifying individuals who require immediate clinical evaluations. Although these results come from the Italian pandemic period, this short diagnostic scale could be optimized and tested as a screening tool for future similar pandemics.


Asunto(s)
COVID-19/diagnóstico , COVID-19/psicología , Encuestas Epidemiológicas , Tamizaje Masivo/normas , Psicometría , Autoinforme , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/inmunología , COVID-19/fisiopatología , Femenino , Fiebre/epidemiología , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Italia/epidemiología , Masculino , Persona de Mediana Edad , Pandemias , Reproducibilidad de los Resultados , SARS-CoV-2/patogenicidad , Adulto Joven
18.
Cancers (Basel) ; 12(12)2020 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-33352737

RESUMEN

Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17ß-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as 'anti-estrogen'-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

19.
Noncoding RNA ; 6(4)2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-33333738

RESUMEN

Lung cancer burden can be reduced by adopting primary and secondary prevention strategies such as anti-smoking campaigns and low-dose CT screening for high risk subjects (aged >50 and smokers >30 packs/year). Recent CT screening trials demonstrated a stage-shift towards earlier stage lung cancer and reduction of mortality (~20%). However, a sizable fraction of patients (30-50%) with early stage disease still experience relapse and an adverse prognosis. Thus, the identification of effective prognostic biomarkers in stage I lung cancer is nowadays paramount. Here, we applied a multi-tiered approach relying on coupled RNA-seq and miRNA-seq data analysis of a large cohort of lung cancer patients (TCGA-LUAD, n = 510), which enabled us to identify prognostic miRNA signatures in stage I lung adenocarcinoma. Such signatures showed high accuracy (AUC ranging between 0.79 and 0.85) in scoring aggressive disease. Importantly, using a network-based approach we rewired miRNA-mRNA regulatory networks, identifying a minimal signature of 7 miRNAs, which was validated in a cohort of FFPE lung adenocarcinoma samples (CSS, n = 44) and controls a variety of genes overlapping with cancer relevant pathways. Our results further demonstrate the reliability of miRNA-based biomarkers for lung cancer prognostication and make a step forward to the application of miRNA biomarkers in the clinical routine.

20.
Cells ; 9(11)2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33167477

RESUMEN

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular "portfolio" pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.


Asunto(s)
Diferenciación Celular/genética , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Transcripción Genética , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Estudios de Cohortes , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Glucólisis/efectos de los fármacos , Glucólisis/genética , Humanos , Leucemia Promielocítica Aguda/patología , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Células Mieloides/patología , Fosforilación Oxidativa/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos
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