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1.
Cell ; 155(1): 242-56, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074872

RESUMO

The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.


Assuntos
Citometria de Fluxo/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/genética , Polimorfismo de Nucleotídeo Único , Humanos , Fenótipo
2.
Liver Int ; 41(10): 2358-2370, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33966337

RESUMO

BACKGROUND & AIMS: Cirrhosis disrupts the hypothalamic-pituitary-gonadal axis causing low testosterone. Testosterone deficiency is associated with sarcopenia and osteopenia, leading to a state of frailty and worse clinical outcomes, morbidity and mortality. We aimed to conduct a systematic review on the relationship between serum testosterone and laboratory, anthropometric and clinical outcomes in observational and interventional studies in cirrhosis. METHODS: PubMed and EMBASE were searched from inception through 27 August 2020 and reviewed independently by two investigators; a third reviewer solved disagreement. A qualitative summary of relevant findings was done. Methodological quality was assessed using the Newcastle Ottawa Scale for non-interventional studies and the Cochrane Risk of Bias for interventional studies. RESULTS: Out of 3569 articles, 15 met inclusion criteria with six observational studies of 1267 patients and nine interventional studies of 580 patients. In observational studies, low serum testosterone level was associated with sarcopenia, shorter median time to hepatic decompensation, transplant requirement, higher model for end-stage liver disease (MELD) scores, and death in cirrhotic patients. Nine interventional studies (361 treated with testosterone vs 219 placebo, 1-36 months) showed that testosterone supplementation improved serum testosterone, appendicular mass and bone mineral density. However, no trial reported improvement in liver-related scores, complications, readmission rates or death. CONCLUSIONS: Low serum testosterone is associated with increased morbidity and mortality in cirrhosis patients. Testosterone supplementation improved intermediate endpoints, but there was no conclusive data on clinical outcomes. Testosterone supplementation may be a promising strategy to improve frailty and decrease significant clinical complications in cirrhosis.


Assuntos
Doença Hepática Terminal , Testosterona , Suplementos Nutricionais , Humanos , Cirrose Hepática/tratamento farmacológico , Índice de Gravidade de Doença
3.
BMC Neurol ; 21(1): 254, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193065

RESUMO

BACKGROUND: Effective inclusion in society for young people with disabilities is increasingly seen as generating opportunities for self-development, and improving well-being. However, significant barriers remain in the vast majority of activities meaningful for young adults. Research argues that various personal (disabilities, health) and environmental (access to the resources needed, accessible environment, discrimination, lack of personal economic independence) factors contribute to limited participation. However, previous studies conducted in young people with cerebral palsy (CP) mainly investigated the transition period to adulthood, and did not fully consider the whole range of impairment severity profiles or environmental barriers. In this study, we will use the follow-up of the SPARCLE cohort and a comparison group from the general population (1) to investigate the impact of the environment on participation and quality of life of young adults with CP, (2) to determine predictors of a successful young adulthood in educational, professional, health and social fields, (3) to compare quality of life and frequency of participation in social, work and recreational activities with the general population, (4) to document on participation and quality of life in those with severe disabilities. METHODS: The SPARCLE3 study has a combined longitudinal and cross-sectional design. Young adults with CP aged 22 to 27 years in 6 European regions previously enrolled in the SPARCLE cohort or newly recruited will be invited to self-complete a comprehensive set of questionnaires exploring participation (daily life and discretionary activities), health-related quality of life, body function, personal factors (health, personal resources), and contextual factors (availability of needed environmental items, family environment, services provision) during home visits supervised by trained researchers. Proxy-reports or adapted questionnaires will be used for those with the most severe impairments. The recruitment of a large group from the general population (online survey) will enable to identify life areas where the discrepancies between young people with CP and their able-bodied peers are the most significant. DISCUSSION: This study will help identify to what extent disabilities and barriers in environment negatively affect participation and quality of life, and how previous valued experiences during childhood or adolescence might modulate these effects.


Assuntos
Paralisia Cerebral/epidemiologia , Qualidade de Vida , Adulto , Estudos Transversais , Atividades Humanas/estatística & dados numéricos , Humanos , Estudos Longitudinais , Adulto Jovem
4.
Bull Environ Contam Toxicol ; 104(3): 345-350, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31993677

RESUMO

Harbor basins are strategically important and heavily impacted water bodies according to the water framework directive. Due to constant traffic, variety of activities, and low-energy hydrodynamics, these areas can have high degrees of water pollution. This study reports the results of the preliminary investigation of anthropogenic microlitter (AM) pollution in a semi-enclosed basin (Civitavecchia harbor; northern Tyrrhenian Sea, Italy) using the tubes built by the polychaete Sabella spallanzanii. The visual inspection showed AM particles within the tube structure as a result of its building process. The total average AM abundance was 20.8 ± 3.7 AM g-1. AM abundances and flushing time as the hydrodynamic parameter of water renewal highlight the homogeneity of the sampling area. The suitability of S. spallanzanii tubes as a potential tool to investigate the AM pollution level in sheltered and polluted environments is highlighted.


Assuntos
Monitoramento Ambiental/métodos , Poliquetos/crescimento & desenvolvimento , Água do Mar/química , Resíduos Sólidos/análise , Poluentes Químicos da Água/análise , Animais , Hidrodinâmica , Itália , Mar Mediterrâneo , Poluentes Químicos da Água/química
5.
Bioinformatics ; 33(19): 3065-3071, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28549079

RESUMO

MOTIVATION: A computational model equipped with the main immunological features of the sea bass (Dicentrarchus labrax L.) immune system was used to predict more effective vaccination in fish. The performance of the model was evaluated by using the results of two in vivo vaccinations trials against L. anguillarum and P. damselae. RESULTS: Tests were performed to select the appropriate doses of vaccine and infectious bacteria to set up the model. Simulation outputs were compared with the specific antibody production and the expression of BcR and TcR gene transcripts in spleen. The model has shown a good ability to be used in sea bass and could be implemented for different routes of vaccine administration even with more than two pathogens. The model confirms the suitability of in silico methods to optimize vaccine doses and the immune response to them. This model could be applied to other species to optimize the design of new vaccination treatments of fish in aquaculture. AVAILABILITY AND IMPLEMENTATION: The method is available at http://www.iac.cnr.it/∼filippo/c-immsim/. CONTACT: nromano@unitus.it. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Aquicultura , Bass/imunologia , Doenças dos Peixes/imunologia , Animais , Simulação por Computador , Doenças dos Peixes/microbiologia , Sistema Imunitário/imunologia , Vacinação/veterinária
6.
Sensors (Basel) ; 18(7)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30011806

RESUMO

The Arctic region is known to be severely affected by climate change, with evident alterations in both physical and biological processes. Monitoring the Arctic Ocean ecosystem is key to understanding the impact of natural and human-induced change on the environment. Large data sets are required to monitor the Arctic marine ecosystem and validate high-resolution satellite observations (e.g., Sentinel), which are necessary to feed climatic and biogeochemical forecasting models. However, the Global Observing System needs to complete its geographic coverage, particularly for the harsh, extreme environment of the Arctic Region. In this scenario, autonomous systems are proving to be valuable tools for increasing the resolution of existing data. To this end, a low-cost, miniaturized and flexible probe, ArLoC (Arctic Low-Cost probe), was designed, built and installed on an innovative unmanned marine vehicle, the PROTEUS (Portable RObotic TEchnology for Unmanned Surveys), during a preliminary scientific campaign in the Svalbard Archipelago within the UVASS project. This study outlines the instrumentation used and its design features, its preliminary integration on PROTEUS and its test results.

7.
Prostate ; 77(1): 82-93, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27699828

RESUMO

BACKGROUND: AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood. Therefore, we aimed to explore existing classes of small molecules that may regulate AR-V7 expression and intracellular localization and their potential therapeutic role in CRPC. METHODS: We used AR high-content analysis (AR-HCA) to characterize the effects of a focused library of well-characterized clinical compounds on AR-V7 expression at the single-cell level in PC3 prostate cancer cells stably expressing green fluorescent protein (GFP)-AR-V7 (GFP-AR-V7:PC3). In parallel, an orthogonal AR-HCA screen of a small interfering (si)RNA library targeting 635 protein kinases was performed in GFP-AR-V7:PC3. The effect of the Src-Abl inhibitor PD 180970 was further characterized using cell-proliferation assays, quantitative PCR, and western blot analysis in multiple hormone-sensitive and CRPC cell lines. RESULTS: Compounds that tended to target Akt, Abl, and Src family kinases (SFKs) decreased overall AR-V7 expression, nuclear translocation, absolute nuclear level, and/or altered nuclear distribution. We identified 20 protein kinases that, when knocked down, either decreased nuclear GFP-AR-V7 levels or altered AR-V7 nuclear distribution, a set that included the SFKs Src and Fyn. The Src-Abl dual kinase inhibitor PD180970 decreased expression of AR-V7 by greater than 46% and decreased ligand-independent transcription of AR target genes in the 22RV1 human prostate carcinoma cell line. Further, PD180970 inhibited androgen-independent cell proliferation in endogenous-AR-V7-expressing prostate cancer cell lines and also overcame bicalutamide resistance observed in the 22RV1 cell line. CONCLUSIONS: SFKs, especially Src and Fyn, may be important upstream regulators of AR-V7 expression and represent promising targets in a subset of CRPCs expressing high levels of AR-V7. Prostate 77:82-93, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Androgênios/metabolismo , Proliferação de Células/fisiologia , Variação Genética/fisiologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Quinases da Família src/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Ensaios de Triagem em Larga Escala/métodos , Humanos , Células MCF-7 , Masculino , Neoplasias da Próstata/patologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Receptores Androgênicos/genética , Quinases da Família src/antagonistas & inibidores
8.
Lancet ; 385(9969): 705-16, 2015 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-25301503

RESUMO

BACKGROUND: Children with cerebral palsy who can self-report have similar quality of life (QoL) to their able-bodied peers. Is this similarity also found in adolescence? We examined how self-reported QoL of adolescents with cerebral palsy varies with impairment and compares with the general population, and how factors in childhood predict adolescent QoL. METHODS: We report QoL outcomes in a longitudinal follow-up and cross-sectional analysis of individuals included in the SPARCLE1 (childhood) and SPARCLE2 (adolescent) studies. In 2004 (SPARCLE1), a cohort of 818 children aged 8-12 years were randomly selected from population-based cerebral palsy registers in nine European regions. We gathered data from 500 participants about QoL with KIDSCREEN (ten domains); frequency of pain; child psychological problems (Strengths and Difficulties Questionnaire); and parenting stress (Parenting Stress Index). At follow-up in 2009 (SPARCLE2), 355 (71%) adolescents aged 13-17 years remained in the study and self-reported QoL (longitudinal sample). 76 additional adolescents self-reported QoL in 2009, providing data for 431 adolescents in the cross-sectional sample. Researchers gathered data at home visits. We compared QoL against matched controls in the general population. We used multivariable regression to relate QoL of adolescents with cerebral palsy to impairments (cross-sectional analysis) and to childhood QoL, pain, psychological problems, and parenting stress (longitudinal analysis). FINDINGS: Severity of impairment was significantly associated (p<0·01) with reduced adolescent QoL on only three domains (Moods and emotions, Autonomy, and Social support and peers); average differences in QoL between the least and most able groups were generally less than 0·5 SD. Adolescents with cerebral palsy had significantly lower QoL than did those in the general population in only one domain (Social support and peers; mean difference -2·7 [0·25 SD], 95% CI -4·3 to -1·4). Pain in childhood or adolescence was strongly associated with low adolescent QoL on eight domains. Childhood QoL was a consistent predictor of adolescent QoL. Child psychological problems and parenting stress in childhood or their worsening between childhood and adolescence predicted only small reductions in adolescent QoL. INTERPRETATION: Individual and societal attitudes should be affected by the similarity of the QoL of adolescents with and without cerebral palsy. Adolescents with cerebral palsy need particular help to maintain and develop peer relationships. Interventions in childhood to alleviate psychological difficulties, parenting stress, and especially pain, are justified for their intrinsic value and for their longer term effect on adolescent QoL. FUNDING: SPARCLE1 was funded by the European Union Research Framework 5 Program (grant number QLG5-CT-2002-00636), the German Ministry of Health GRR-58640-2/14, and the German Foundation for the Disabled Child. SPARCLE2 was funded by: Wellcome Trust WT086315 A1A (UK and Ireland); Medical Faculty of the University of Lübeck E40-2009 and E26-2010 (Germany); CNSA, INSERM, MiRe-DREES, and IRESP (France); Ludvig and Sara Elsass Foundation, The Spastics Society and Vanforefonden (Denmark); Cooperativa Sociale "Gli Anni in Tasca" and Fondazione Carivit, Viterbo (Italy); Göteborg University-Riksforbundet for Rorelsehindrade Barn och Ungdomar and the Folke Bernadotte Foundation (Sweden).


Assuntos
Paralisia Cerebral/psicologia , Dor/psicologia , Qualidade de Vida , Estresse Psicológico , Adolescente , Criança , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , Pais/psicologia , Autorrelato
9.
Bull Environ Contam Toxicol ; 96(5): 630-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26994618

RESUMO

The purpose of this study was to evaluate the extent of the Hg geochemical anomaly arising in the Amiata and Tolfa complex to the coastal area of northern Latium and to examine the possible influence on this area by the Mignone River, and by the small coastal basins, which are characterized by both previous mining activities and decades of past industrial impact. The results confirm the extension of the anomaly of concentrations of Hg in the coastal area of northern Latium, with the northern sector influenced by the contributions of the Fiora and Mignone Rivers and the southern sector influenced by the contributions of minor basins. The results show high values of the Adverse Effect Index throughout the considered area and highlight the need for further investigation in order to assess the impact of human activities on the present and past values of Hg in marine sediments.


Assuntos
Sedimentos Geológicos/análise , Mercúrio/análise , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Itália , Mineração , Rios/química
10.
Arch Environ Contam Toxicol ; 69(4): 470-81, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26033264

RESUMO

This study evaluated the distribution pattern and pollution of chromium, arsenic (As), manganese (Mn), nickel, lead, and copper in surface sediments along the northern Latium coast of the Tyrrhenian Sea in Italy. The enrichment factor, geoaccumulation index, and potential toxicity response index were used to evaluate the degree of contamination. These results show As and Mn contamination. The high enrichment and contamination levels of As and Mn are located in two hot spots. These elevations are due to naturally high levels of As and Mn in the Mignone River and the Marangone Stream as well as the intense human activity in the area including the largest energy production site in Europe (Torrevaldaliga Nord coal-fired power plant) and of one of the most important ports for cruise traffic in the Mediterranean Sea.


Assuntos
Monitoramento Ambiental , Metais Pesados/análise , Poluentes Químicos da Água/análise , Sedimentos Geológicos/química , Itália , Mar Mediterrâneo
11.
Sensors (Basel) ; 14(12): 23348-64, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25490594

RESUMO

The development of low-cost instrumentation plays a key role in marine environmental studies and represents one of the most innovative aspects of current oceanographic research. These kinds of devices can be used for several applications, ranging from vertical profilers to stand-alone systems, and can be installed on different platforms (buoys, Voluntary Observing Ships, underwater vehicles, etc.). The availability of low-cost technologies enables the realization of extended observatory networks for the study of marine physical and biological processes through an integrated approach merging in situ observations, forecasting models and remotely sensed data. We present new low-cost sensors and probes developed to measure marine temperature, conductivity, chlorophyll a and Chromophoric Dissolved Organic Matter fluorescence, focusing on sensing strategies, general architecture, laboratory trials, in situ tests and comparison with standard instruments. Furthermore, we report the expendable (New T-FLaP), vertical profiler (T-FLaPpro) and stand-alone (Spectra) applications of these technological developments that were tested during several oceanographic surveys in the Mediterranean Sea.


Assuntos
Técnicas Biossensoriais/instrumentação , Monitoramento Ambiental/instrumentação , Biologia Marinha/instrumentação , Tecnologia de Sensoriamento Remoto/instrumentação , Técnicas Biossensoriais/economia , Análise Custo-Benefício , Monitoramento Ambiental/economia , Desenho de Equipamento/economia , Análise de Falha de Equipamento , Biologia Marinha/economia , Tecnologia de Sensoriamento Remoto/economia , Avaliação da Tecnologia Biomédica
12.
Hypertension ; 81(10): 2072-2081, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39041222

RESUMO

BACKGROUND: In many practices, the screening for primary aldosteronism relies on a single-blood draw for plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to establish an aldosterone-to-renin ratio (ARR). ARR levels vary between expert centers and repeated assays in the same individual, emphasizing the potential variability of this screening approach. A suppressed PRA to <1 ng/mL per h has been proposed as an alternative test to the ARR. METHODS: We compared 2 potential screening approaches to identify probable primary aldosteronism (ARR≥30 or ARR≥20 versus PRA suppressed below 1 ng/mL per h) in a cohort of 94 829 paired PRA and PAC samples submitted by clinicians to evaluate the presence of primary aldosteronism. RESULTS: Of 94 829 patients, 20.3% tested positive based on ARR≥20 (95% CI, 20.0%-20.5%), 13.9% based on ARR≥30 (95% CI, 13.6%-14.1%), versus 45.9% based on suppressed PRA (<1 ng/mL per minute [95% CI, 45.5%-46.2%]). In the PRA group, a range of aldosterone levels was observed: 5.5% had PAC >15 ng/dL, 25.2% had PAC 5 to 15 ng/dL, and 15.2% had PAC <5 ng/dL, compared with 6%, 12.7%, and 1.6% in the ARR≥20 group and 4.7%, 8.5%, and 0.7% in the ARR≥30 group. CONCLUSIONS: In this cohort of individuals being screened for primary aldosteronism, substantially more individuals were identified using criteria focused on suppression of renin activity compared with using the aldosterone renin ratio as a screening tool.


Assuntos
Aldosterona , Hiperaldosteronismo , Programas de Rastreamento , Renina , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/sangue , Humanos , Renina/sangue , Aldosterona/sangue , Feminino , Pessoa de Meia-Idade , Masculino , Programas de Rastreamento/métodos , Adulto , Idoso
13.
Front Med (Lausanne) ; 11: 1306504, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38352143

RESUMO

Background: Young people with chronic health conditions and disabilities rely on the healthcare system to maintain their best possible health. The appropriate delivery and utilization of healthcare services are key to improve their autonomy, self-efficacy and employment outcomes. The research question of our study is directed toward investigating if poor availability and accessibility of healthcare services in general, as identified by unmet needs in healthcare, are associated with dissatisfaction with healthcare. Methods: Within a European multicenter observational study, 357 young adults with cerebral palsy aged 19-28 were included. We assessed special healthcare needs, utilization of healthcare services, and satisfaction with healthcare applying the short-form of the YHC-SUN-SF, environmental and social variables (EAEQ) as well as indicators for severity of condition and functionality (e.g., GMFCS) of these participants based on a self-, assisted self- or proxy-reports. We used correlation analyses to explore associations between satisfaction with healthcare and respective indicators related to availability and accessibility of healthcare services as well as severity of the condition. In addition, we included reference values for satisfaction with heath care from young adults with various chronic conditions assessed within population-based surveys from some of the European countries included in the study. Results: We identified several unmet healthcare needs, especially for widely used and established services (e.g., physical therapy). Satisfaction with healthcare (YHC-SUN-SF general and subscale scores) was moderate to high and almost consistently better for the sample of young adults with cerebral palsy as compared to reference values for young adults with various chronic conditions assessed within general population surveys). Correlation coefficients between satisfaction with healthcare and utilization of services and (unmet) healthcare needs were low, also with different indicators for severity of the condition or functionality. Conclusion: Young adults with cerebral palsy reports of unmet healthcare needs varied largely but showed substantial deficits in some aspects. This seems to have no impact on the satisfaction with healthcare those patients currently receive. We conclude that these are two different constructs and somewhat independent indicators to evaluate the quality of healthcare. Clinicians and other practitioners should consider this distinction when monitoring patient needs in their daily practice.

14.
Sci Rep ; 14(1): 5888, 2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467723

RESUMO

Among marine ecosystems globally, those in the Mediterranean Sea, are facing many threats. New technologies are crucial for enhancing our understanding of marine habitats and ecosystems, which can be complex and resource-intensive to analyse using traditional techniques. We tested, for the first time, an integrated multi-platform approach for mapping the coastal benthic habitat in the Civitavecchia (northern Latium, Italy) coastal area. This approach includes the use of an Unmanned Surface Vehicle (USV), a Remote Operated Vehicle (ROV), and in situ measurements of ecosystem functionality. The echosounder data allowed us to reconstruct the distribution of bottom types, as well as the canopy height and coverage of the seagrass Posidonia oceanica. Our study further involved assessing the respiration (Rd) and net primary production (NCP) rates of P. oceanica and its associated community through in situ benthic chamber incubation. By combining these findings with the results of USV surveys, we were able to develop a preliminary spatial distribution model for P. oceanica primary production (PP-SDM). The P. oceanica PP-SDM was applied between the depths of 8 and 10 m in the studied area and the obtained results showed similarities with other sites in the Mediterranean Sea. Though in the early stages, our results highlight the significance of multi-platform observation data for a thorough exploration of marine ecosystems, emphasizing their utility in forecasting biogeochemical processes in the marine environment.


Assuntos
Alismatales , Ecossistema , Mar Mediterrâneo , Itália
15.
Prostate ; 73(3): 267-77, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22821817

RESUMO

BACKGROUND: The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known. METHODS: We analyzed potential signaling pathways associated with AR-V7 constitutive activation in PTEN (-) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway. RESULTS: In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation. CONCLUSIONS: Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration-resistant PC.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/fisiologia , Androstadienos/farmacologia , Castração , Linhagem Celular Tumoral , Cromonas/farmacologia , Progressão da Doença , Proteína Forkhead Box O1 , Variação Genética/genética , Humanos , Masculino , Morfolinas/farmacologia , Fenótipo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transcrição Gênica/efeitos dos fármacos , Wortmanina
16.
Genes (Basel) ; 14(9)2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37761937

RESUMO

We report the optimization of a high-throughput, compliant DNA extraction method that uses standard format 96-well plates and a commercial automated DNA purification system (ABI PRISM® 6100 Nucleic Acid PrepStation). The procedure was set up for maize and soybean, the most common GMO crops and the main ingredients of several foodstuffs, and compared with an EU-validated CTAB-based method. Optimization of the DNA extraction was achieved by applying self-prepared buffers (for DNA extraction, binding, and washing) on the PrepStation loaded with proprietary glass-fiber-coated purification plates. Quantification of extracted DNA was performed by real-time PCR using previously reported endogenous soybean lectin and maize starch synthase genes and a novel plant-specific universal TaqMan MGB probe that targets the 18S rRNA multiple copy gene. Using serial dilutions of both maize and soybean genomic DNAs, we show low PCR sensitivity and efficiency for the official TransPrep DNA extraction protocol compared to the CTAB-based one. On the other hand, using serial dilutions of a standard reference plasmid containing a 137 bp sequence cloned from the 18S rRNA plant-specific ribosomal gene, we demonstrate the high PCR sensitivity and efficiency of the optimized DNA extraction protocol setup with self-prepared buffers. The limits of detection and quantification of the 18S rDNA reiteration were consistent with the calculated values, supporting the suitability of the DNA extraction procedure for high-throughput analyses of large populations and small amounts of tissue.


Assuntos
Glycine max , Zea mays , Glycine max/genética , Zea mays/genética , Cetrimônio , RNA Ribossômico 18S/genética , DNA , Reação em Cadeia da Polimerase em Tempo Real
17.
Life Sci ; 328: 121908, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37406768

RESUMO

AIMS: Gulf War Illness (GWI) is a multi-system condition of complex etiology and pathophysiology without specific treatment. There is an overlap between the symptoms of GWI and endocrinopathies. This study aimed to identify hormonal alterations in 1990-91 Gulf War (GW) veterans and the relationship between GWI and hormonal dysregulation. MAIN METHODS: Data from 81 GW veterans (54 with GWI and 27 controls without GWI) was analyzed in a cross-sectional, case-control observational study. Participants completed multiple questionnaires, neuropsychiatric assessments, and a comprehensive set of hormone assays including a glucagon stimulation test (GST) for adult growth hormone deficiency (AGHD) and a high-dose adrenocorticotropic hormone (ACTH) stimulation test for adrenal insufficiency. KEY FINDINGS: The GWI group had lower quality of life and greater severity of all symptoms compared to controls. Pain intensity and pain-related interference with general activity were also higher in the GWI group. AGHD was observed in 18 of 51 veterans with GWI (35.3 %) and 2 of 26 veterans without GWI (7.7 %) (p = 0.012 for interaction). Veterans with GWI also exhibited reduced insulin-like growth factor 1 (IGF-1) levels and IGF-1 Z-scores compared to controls. One participant with GWI met the criteria for adrenal insufficiency. No significant changes were observed in other hormonal axes. SIGNIFICANCE: The frequency of AGHD was significantly higher in veterans with GWI compared to controls. Recombinant human growth hormone replacement therapy (GHRT) may become a breakthrough therapeutic option for this subgroup. A large clinical trial is needed to evaluate the efficacy of GHRT in patients with GWI and AGHD.


Assuntos
Síndrome do Golfo Pérsico , Veteranos , Adulto , Humanos , Fator de Crescimento Insulin-Like I , Guerra do Golfo , Estudos Transversais , Qualidade de Vida
18.
J Cachexia Sarcopenia Muscle ; 14(2): 835-846, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36860137

RESUMO

BACKGROUND: Cancer cachexia is associated with reduced body weight, appetite and quality of life (QOL) with no approved treatments. Growth hormone secretagogues like macimorelin have potential to mitigate these effects. METHODS: This pilot study assessed the safety and efficacy of macimorelin for 1 week. Efficacy was defined a priori as 1-week change in body weight (≥0.8 kg), plasma insulin-like growth factor (IGF)-1 (≥50 ng/mL) or QOL (≥15%). Secondary outcomes included food intake, appetite, functional performance, energy expenditure and safety laboratory parameters. Patients with cancer cachexia were randomized to 0.5 or 1.0 mg/kg macimorelin or placebo; outcomes were assessed non-parametrically. RESULTS: Participants receiving at least one of either macimorelin dose were combined (N = 10; 100% male; median age = 65.50 ± 2.12) and compared with placebo (N = 5; 80% male; median age = 68.00 ± 6.19). Efficacy criteria achieved: body weight (macimorelin N = 2; placebo N = 0; P = 0.92); IGF-1 (macimorelin N = 0; placebo N = 0); QOL by Anderson Symptom Assessment Scale (macimorelin N = 4; placebo N = 1; P = 1.00) or Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; macimorelin N = 3; placebo N = 0; P = 0.50). No related serious or non-serious adverse events were reported. In macimorelin recipients, change in FACIT-F was directly associated with change in body weight (r = 0.92, P = 0.001), IGF-1 (r = 0.80, P = 0.01), and caloric intake (r = 0.83, P = 0.005), and inversely associated with change in energy expenditure (r = -0.67, P = 0.05). CONCLUSIONS: Daily oral macimorelin for 1 week was safe and numerically improved body weight and QOL in patients with cancer cachexia compared with placebo. Longer term administration should be evaluated for mitigation of cancer-induced reductions in body weight, appetite and QOL in larger studies.


Assuntos
Caquexia , Neoplasias , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Caquexia/etiologia , Caquexia/complicações , Fator de Crescimento Insulin-Like I , Qualidade de Vida , Projetos Piloto , Neoplasias/complicações , Peso Corporal
19.
Neurology ; 101(24): e2509-e2521, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37857495

RESUMO

BACKGROUND AND OBJECTIVES: To report on prevalence, associated impairments, severity, and neuroimaging findings in children with ataxic cerebral palsy (CP). METHODS: In children coded as having ataxic CP in the Central database of Joint Research Center-Surveillance of Cerebral Palsy in Europe (JRC-SCPE) and born during 1980-2010, birth characteristics, severity profiles including associated impairments, neuroimaging patterns, and the presence of syndromes were analyzed. Definitions were according to validated SCPE guidelines. Prevalence over time was estimated using Poisson regression. RESULTS: In total, 679 children with ataxic CP were identified in 20 European CP registers. The proportion with ataxic CP was 3.8% and varied from 0% to 12.9%. Prevalence over time showed no significant trend. Approximately 70% of children with ataxic CP were able to walk, and 40% had severe intellectual impairment and a high impairment index. Children with ataxic CP were mostly born at term (79%) and with normal birth weight (77%). Neuroimaging patterns revealed normal findings in 29%, brain maldevelopments in 28.5%, miscellaneous findings in 23.5%, and brain injuries in 19%, according to the SCPE classification. Genetic syndromes were described in 9%. DISCUSSION: This register-based multicenter study on children with ataxic CP provides a large sample size for the analysis of prevalence, severity, and origin of this rare CP subtype. Even with strict inclusion and classification criteria, there is variation between registers on how to deal with this subtype, and diagnosis of ataxic CP remains a challenge. Ataxic cerebral palsy differs from other CP subtypes: children with ataxic CP have a disability profile that is more pronounced in terms of cognitive than gross motor dysfunction. They are mostly term born and the origin rarely suggests acquired injuries. In addition to neuroimaging, a comprehensive genetic workup is particularly recommended for children with this CP type.


Assuntos
Paralisia Cerebral , Criança , Humanos , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/epidemiologia , Paralisia Cerebral/genética , Prevalência , Europa (Continente)/epidemiologia , Neuroimagem , Sistema de Registros
20.
Arch Phys Med Rehabil ; 93(12): 2154-64, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22846455

RESUMO

OBJECTIVE: To evaluate how participation of children with cerebral palsy (CP) varied with their environment. DESIGN: Home visits to children. Administration of Assessment of Life Habits and European Child Environment Questionnaires. Structural equation modeling of putative associations between specific domains of participation and environment, while allowing for severity of child's impairments and pain. SETTING: European regions with population-based registries of children with CP. PARTICIPANTS: Children (n=1174) aged 8 to 12 years were randomly selected from 8 population-based registries of children with CP in 6 European countries. Of these, 743 (63%) agreed to participate; 1 further region recruited 75 children from multiple sources. Thus, there were 818 children in the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Participation in life situations. RESULTS: For the hypothesized associations, the models confirmed that higher participation was associated with better availability of environmental items. Higher participation in daily activities-mealtimes, health hygiene, personal care, and home life-was significantly associated with a better physical environment at home (P<.01). Mobility was associated with transport and physical environment in the community. Participation in social roles (responsibilities, relationships, recreation) was associated with attitudes of classmates and social support at home. School participation was associated with attitudes of teachers and therapists. Environment explained between 14% and 52% of the variation in participation. CONCLUSIONS: The findings confirmed the social model of disability. The physical, social, and attitudinal environment of disabled children influences their participation in everyday activities and social roles.


Assuntos
Atitude , Paralisia Cerebral/psicologia , Paralisia Cerebral/reabilitação , Meio Ambiente , Meio Social , Atividades Cotidianas , Adolescente , Criança , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Masculino , Limitação da Mobilidade , Características de Residência , Instituições Acadêmicas , Índice de Gravidade de Doença
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