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1.
Curr Cardiol Rep ; 25(12): 1769-1781, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37975970

RESUMO

PURPOSE OF REVIEW: To discuss the prevailing racial and ethnic disparities in heart failure (HF) care by identifying barriers to equitable care and proposing solutions for achieving equitable outcomes. RECENT FINDINGS: Throughout the entire spectrum of HF care, from prevention to implementation of guideline-directed medical therapy and advanced interventions, racial and ethnic disparities exist. Factors such as differential distribution of risk factors, poor access to care, inadequate representation in clinical trials, and discrimination from healthcare clinicians, among others, contribute to these disparities. Recent data suggests that despite improvements, disparities prevail in several aspects of HF care, hindering our progress towards equity in HF care. This review highlights the urgent need to address racial and ethnic disparities in HF care, emphasizing the importance of a multifaceted approach involving policy changes, quality improvement strategies, targeted interventions, and intentional community engagement. Our proposed framework was derived from existing research and emphasizes integrating equity into routine quality improvement efforts, tailoring interventions to specific populations, and advocating for policy transformation. By acknowledging these disparities, implementing evidence-based strategies, and fostering collaborative efforts, the HF community can strive to reduce disparities and achieve equity in HF care.


Assuntos
Equidade em Saúde , Insuficiência Cardíaca , Humanos , Acessibilidade aos Serviços de Saúde , Etnicidade , Melhoria de Qualidade , Insuficiência Cardíaca/terapia , Disparidades em Assistência à Saúde
2.
Sensors (Basel) ; 23(7)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37050622

RESUMO

The Sustainable Development Goals (SDGs), also known as the Global Goals, were adopted by the United Nations in 2015 as a universal call to end poverty, protect the planet and ensure peace and prosperity for all by 2030. The 17 SDGs have been designed to end poverty, hunger, AIDS and discrimination against women and girls. Despite the clear SDG framework, there is a significant gap in the literature to establish the alignment of systems, projects or tools with the SDGs. In this research work, we assess the SDG alignment of an activity recognition platform for healthcare systems, called ACTIVA. This new platform, designed to be deployed in environments inhabited by vulnerable people, is based on sensors and artificial intelligence, and includes a mobile application to report anomalous situations and ensure a rapid response from healthcare personnel. In this work, the ACTIVA platform and its compliance with each of the SDGs is assessed, providing a detailed evaluation of SDG 7-ensuring access to affordable, reliable, sustainable and modern energy for all. In addition, a website is presented where the ACTIVA platform's compliance with the 17 SDGs has been evaluated in detail. The comprehensive assessment of this novel platform's compliance with the SDGs provides a roadmap for the evaluation of future and past systems in relation to sustainability.


Assuntos
Inteligência Artificial , Desenvolvimento Sustentável , Humanos , Feminino , Atenção à Saúde , Nações Unidas
3.
Sensors (Basel) ; 23(24)2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38139505

RESUMO

In this work, a secure architecture to send data from an Internet of Things (IoT) device to a blockchain-based supply chain is presented. As is well known, blockchains can process critical information with high security, but the authenticity and accuracy of the stored and processed information depend primarily on the reliability of the information sources. When this information requires acquisition from uncontrolled environments, as is the normal situation in the real world, it may be, intentionally or unintentionally, erroneous. The entities that provide this external information, called Oracles, are critical to guarantee the quality and veracity of the information generated by them, thus affecting the subsequent blockchain-based applications. In the case of IoT devices, there are no effective single solutions in the literature for achieving a secure implementation of an Oracle that is capable of sending data generated by a sensor to a blockchain. In order to fill this gap, in this paper, we present a holistic solution that enables blockchains to verify a set of security requirements in order to accept information from an IoT Oracle. The proposed solution uses Hardware Security Modules (HSMs) to address the security requirements of integrity and device trustworthiness, as well as a novel Public Key Infrastructure (PKI) based on a blockchain for authenticity, traceability, and data freshness. The solution is then implemented on Ethereum and evaluated regarding the fulfillment of the security requirements and time response. The final design has some flexibility limitations that will be approached in future work.

4.
Biol Sport ; 40(1): 273-281, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36636186

RESUMO

This study aimed (i) to analyse the associations between serve velocity (SV) and anthropometric, ball impact and landing location parameters in total serves (TS) and fastest serves (FS) performed during an ATP Tour event; (ii) to observe differences between first (S1) and second (S2) serves, and (iii) to determine a SV prediction model based on the relationship between the observed variables. Using Foxtenn technology, 30 S1 and 15 S2 were registered in 14 matches in twenty-one male professional tennis players. Ball impact (impact height [IH], impact projection angle [IPA] and relative impact height [RIH]), bounce landing (width and depth) location parameters, S1 and S2 SV in TS (TSV1 and TSV2) and FS (FSV1 and FSV2) alongside anthropometric characteristics of tennis players (body height [BH], body mass [BM] and body mass index [BMI]) were analysed. Significant moderate to large associations were found between BH and BM and TSV1, FSV1 and FSV2 (r = 0.315 to 0.593; p < 0.001), and between IH and IPA and TSV1 and TSV2 (r = 0.294 to -0.409; p < 0.001). BH and BM were the unique significant contributors of FS explaining 22 to 35% of FSV1 and FSV2. Only BM appears in the model to predict FSV1 and FSV2 (r2 = 0.48 and 0.21). We concluded that all three anthropometric, ball impact and bounce landing location parameters small to moderately influence TSV. Anthropometric parameters show an impact on SV when tennis players serve at or near maximal speed, highlighting the influence of BM above BH.

5.
Int J Mol Sci ; 23(23)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36498916

RESUMO

26S proteasome non-ATPase subunits 1 (PSMD1) and 3 (PSMD3) were recently identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia (CML) and multiple solid tumors. In the present study, we analyzed the expression of 19S proteasome subunits in acute myeloid leukemia (AML) patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene and assessed their impact on overall survival (OS). High levels of PSMD3 but not PSMD1 expression correlated with a worse OS in FLT3-mutated AML. Consistent with an oncogenic role for PSMD3 in AML, shRNA-mediated PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines, which correlated with increased OS in xenograft models. While PSMD3 regulated nuclear factor-kappa B (NF-κB) transcriptional activity in CML, we did not observe similar effects in FLT3+ AML cells. Rather, proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism. Finally, we identified additional PSMD subunits that are upregulated in AML patients with mutated versus wild-type FLT3, which correlated with worse outcomes. These findings suggest that different components of the 19S regulatory complex of the 26S proteasome can have indications for OS and may serve as prognostic biomarkers in AML and other types of cancers.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Complexo de Endopeptidases do Proteassoma/genética , Prognóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Oncogenes
6.
J Struct Biol ; 212(1): 107595, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736071

RESUMO

Tailed bacteriophages are one of the most widespread biological entities on Earth. Their singular structures, such as spikes or fibers are of special interest given their potential use in a wide range of biotechnological applications. In particular, the long fibers present at the termini of the T4 phage tail have been studied in detail and are important for host recognition and adsorption. Although significant progress has been made in elucidating structural mechanisms of model phages, the high-resolution structural description of the vast population of marine phages is still unexplored. In this context, we present here the crystal structure of C24, a putative receptor-binding tip-like protein from Bizionia argentinensis JUB59, a psychrotolerant bacterium isolated from the marine surface waters of Potter Cove, Antarctica. The structure resembles the receptor-binding tip from the bacteriophage T4 long tail fiber yet showing marked differences in its domain organization, size, sequence identity and metal binding nature. We confirmed the viral origin of C24 by induction experiments using mitomycin C. Our results reveal the presence of a novel uncharacterized prophage in the genome of B. argentinensis JUB59, whose morphology is compatible with the order Caudovirales and that carries the nucleotide sequence of C24 in its genome. This work provides valuable information to expand our current knowledge on the viral machinery prevalent in the oceans.


Assuntos
Bacteriófagos/genética , Flavobacteriaceae/virologia , Regiões Antárticas , Genoma Bacteriano/genética , Genoma Viral/genética , Ligação Proteica/genética
7.
J Sci Food Agric ; 98(5): 1787-1793, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28862326

RESUMO

BACKGROUND: The giant squid (Dosidicus gigas) has been proposed as raw material to obtain myofibrillar protein concentrates. However, it has been observed that colloidal systems formed from squid proteins have limited stability. Therefore, the isolation and characterization of the actomyosin-paramyosin isolated (API) complex were performed, because they are the main proteins to which functionality has been attributed. RESULTS: Densitogram analysis revealed 45% of actin, 38% of myosin and 17% of paramyosin. The amino acid profile indicates a higher proportion of acidic amino acids, which gives a higher negative charge; this was supported by the zeta potential. Total sulfhydryl (TSH) content was lower compared with proteins of other aquatic species. CONCLUSION: The higher percentage of actin in relation to myosin, the presence of paramyosin, as well as the low content of sulfhydryl groups, could comprise the main causes of the low technological functional property of proteins from D. gigas mantle. © 2017 Society of Chemical Industry.


Assuntos
Actomiosina/química , Decapodiformes/química , Tropomiosina/química , Actinas/química , Actinas/metabolismo , Actomiosina/metabolismo , Animais , Decapodiformes/metabolismo , Estabilidade Proteica , Alimentos Marinhos/análise , Tropomiosina/metabolismo
8.
J Sci Food Agric ; 97(3): 802-810, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27173758

RESUMO

BACKGROUND: Some studies have reported that different parts of the pomegranate fruit, especially the peel, may act as potential antimicrobial agents and thus might be proposed as a safe natural alternative to synthetic antimicrobial agents. The high tannin content, especially punicalagin, found in pomegranate extracts, has been reported as the main compound responsible for such antimicrobial activity. Because the pomegranate peel chemical composition may vary with the type of cultivar (sweet, sour-sweet and sour), pomegranates may also differ with respect to their antimicrobial capacity. RESULTS: The extract from PTO8 pomegranate cultivar peel had the highest antimicrobial activity, as well as the highest punicalagins (α and ß) and ellagic acid concentrations. In the results obtained from both antibacterial and antifungal activity studies, the sour-sweet pomegranate cultivar PTO8 showed the best antimicrobial activity, and the highest ellagic acid concentrations. CONCLUSION: The results of the present study suggest that ellagic acid content has a significant influence on the antimicrobial activity of the pomegranate extracts investigated. The pomegranate peel of the PTO8 cultivar is a good source of antifungal and antibacterial compounds, and may represent an alternative to antimicrobial agents of synthetic origin. © 2016 Society of Chemical Industry.


Assuntos
Anti-Infecciosos/isolamento & purificação , Conservantes de Alimentos/isolamento & purificação , Frutas/química , Resíduos Industriais/análise , Lythraceae/química , Extratos Vegetais/isolamento & purificação , 1-Butanol/química , Anti-Infecciosos/análise , Anti-Infecciosos/economia , Anti-Infecciosos/metabolismo , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/metabolismo , Produtos Agrícolas/química , Produtos Agrícolas/crescimento & desenvolvimento , Produtos Agrícolas/metabolismo , Ácido Elágico/análise , Ácido Elágico/química , Ácido Elágico/isolamento & purificação , Ácido Elágico/metabolismo , Conservantes de Alimentos/análise , Conservantes de Alimentos/economia , Conservantes de Alimentos/metabolismo , Indústria de Processamento de Alimentos/economia , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/crescimento & desenvolvimento , Bactérias Gram-Positivas/metabolismo , Taninos Hidrolisáveis/análise , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/isolamento & purificação , Taninos Hidrolisáveis/metabolismo , Resíduos Industriais/economia , Lythraceae/crescimento & desenvolvimento , Lythraceae/metabolismo , Metanol/química , Viabilidade Microbiana , Fungos Mitospóricos/crescimento & desenvolvimento , Fungos Mitospóricos/metabolismo , Estrutura Molecular , Extratos Vegetais/análise , Extratos Vegetais/economia , Extratos Vegetais/metabolismo , Solventes/química , Espanha , Especificidade da Espécie , Estereoisomerismo
9.
Opt Express ; 24(15): 16499, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27464104

RESUMO

We present some comments to the paper "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: comment."

10.
Opt Express ; 24(15): 16986-7, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27464150

RESUMO

We found an error affecting the results presented in Figure 7 of our article "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces". Here we publish the revised Fig. 7.

11.
Opt Express ; 24(5): 5448-5462, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29092368

RESUMO

A rigorous and powerful theoretical framework is proposed to obtain systems of orthogonal functions (or shape modes) to represent optical surfaces. The method is general so it can be applied to different initial shapes and different polynomials. Here we present results for surfaces with circular apertures when the first basis function (mode) is a conicoid. The system for aspheres with rotational symmetry is obtained applying an appropriate change of variables to Legendre polynomials, whereas the system for general freeform case is obtained applying a similar procedure to spherical harmonics. Numerical comparisons with standard systems, such as Forbes and Zernike polynomials, are performed and discussed.

12.
Appl Opt ; 55(34): 9688-9694, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27958457

RESUMO

We propose systems of orthogonal functions qn to represent optical transfer functions (OTF) characterized by including the diffraction-limited OTF as the first basis function q0=OTFperfect. To this end, we apply a powerful and rigorous theoretical framework based on applying the appropriate change of variables to well-known orthogonal systems. Here we depart from Legendre polynomials for the particular case of rotationally symmetric OTF and from spherical harmonics for the general case. Numerical experiments with different examples show that the number of terms necessary to obtain an accurate linear expansion of the OTF mainly depends on the image quality. In the rotationally symmetric case we obtained a reasonable accuracy with approximately 10 basis functions, but in general, for cases of poor image quality, the number of basis functions may increase and hence affect the efficiency of the method. Other potential applications, such as new image quality metrics are also discussed.

13.
J Sci Food Agric ; 96(10): 3342-50, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26526074

RESUMO

BACKGROUND: Low protein digestibility and lysine content of white sorghum grain limit its use as a foodstuff. The increase in γ-kafirin cross-linking, has an important role in the reduction of protein digestibility. The objective of this study was to characterize the γ-kafirin gene in 12 Mexican tannin-free white sorghum genotypes and its relationship with protein digestibility and lysine content. RESULTS: Two alleles of γ-kafirin gene were identified: alleles 1 and 7. The predicted amino acid sequence of allele 7 showed seven point mutations; six were silent, and one missense (C235G), causing the substitution P79A in the deduced amino acid sequence. In silico analysis showed that γ-kafirin codified by allele 1 has five α-helixes without disulfide bonds, while γ-kafirin coding by allele 7 has four α-helixes and three disulfide bonds. Genotypes with allele 7 had higher lysine content than those with allele 1, showing no differences in the kafirin electrophoretic profile, neither a correlation with the protein content nor the in vitro pepsin digestibility. CONCLUSIONS: Mexican tannin-free white sorghum genotypes showed two γ-kafirin alleles, 1 and 7. Allele 7 was associated with higher lysine content; in silico analysis showed that the substitution of P79A in this allele could modify γ-kafirin secondary structure. © 2015 Society of Chemical Industry.


Assuntos
Alelos , Lisina/análise , Proteínas de Plantas/genética , Sementes/química , Sorghum/química , Sequência de Aminoácidos , Proteínas Alimentares/metabolismo , Digestão , Dissulfetos/química , Genótipo , México , Pepsina A/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Conformação Proteica em alfa-Hélice , Estrutura Secundária de Proteína
15.
J Anat ; 226(3): 289-300, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25688933

RESUMO

The year 2014 marked the 350th anniversary of the publication in London of Cerebri anatome, a ground-breaking work of neuroscience heavily influenced by the political and cultural context of Baroque Europe and mid-17th century England. This article aims to review the work of the English physician and anatomist Thomas Willis, specifically with regard to the contents of his Cerebri anatome. Willis's academic and professional career was influenced by the turbulent period of the English Civil War during which he studied medicine. Willis went from chemistry to dissection arguably because of his need to justify the body-brain-soul relationship. As a result, he became a fellow of a select club of eminent experimentalists, and afterward was a Fellow of the Royal Society. Later on, he went to London, leaving the academic life to dedicate himself fully to the profession of medicine. As a physician, Willis did not base his practice on aphorisms but on a 'bench to bedside' approach to medicine, while studying neuroanatomy--covering embryology, comparative anatomy and pathological anatomy--as a basis for the comprehension of neurological pathology. He developed innovative anatomical methods for the preservation and dissection of the brain, injection of coloured substances and illustration of his findings. In Cerebri anatome, Willis recognized the cerebral cortex as the substrate of cognition. He also claimed that the painful stimuli came from the meninges, but not from the brain itself. He explained for the first time the pathological and functional meaning of the brain's circular arterial anastomosis, which is named after him. He also specified some features of the cranial origin of the sympathetic nerves and coined the term 'neurologie'. Cerebri anatome marked the transition between the mediaeval and modern notions of brain function, and thus it is considered a cornerstone of clinical and comparative anatomy of the nervous system. The new contributions and methods employed by Willis justify his place as a father of neurology and a pioneer of translational research.


Assuntos
Neuroanatomia/história , Pesquisa Translacional Biomédica/história , Inglaterra , História do Século XVII , Relações Metafísicas Mente-Corpo
16.
Appl Opt ; 54(21): 6575-83, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26367845

RESUMO

Zernike polynomials are commonly used to represent the wavefront phase on circular optical apertures, since they form a complete and orthonormal basis on the unit disk. In [Opt. Lett.32, 74 (2007)10.1364/OL.32.000074OPLEDP0146-9592] we introduced a new Zernike basis for elliptic and annular optical apertures based on an appropriate diffeomorphism between the unit disk and the ellipse and the annulus. Here, we present a generalization of this Zernike basis for a variety of important optical apertures, paying special attention to polygons and the polygonal facets present in segmented mirror telescopes. On the contrary to ad hoc solutions, most of them based on the Gram-Smith orthonormalization method, here we consider a piecewise diffeomorphism that transforms the unit disk into the polygon under consideration. We use this mapping to define a Zernike-like orthonormal system over the polygon. We also consider ensembles of polygonal facets that are essential in the design of segmented mirror telescopes. This generalization, based on in-plane warping of the basis functions, provides a unique solution, and what is more important, it guarantees a reasonable level of invariance of the mathematical properties and the physical meaning of the initial basis functions. Both the general form and the explicit expressions for a typical example of telescope optical aperture are provided.

17.
Opt Express ; 22(18): 21263-79, 2014 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-25321506

RESUMO

Zernike polynomials are commonly used to represent the wavefront phase on circular optical apertures, since they form a complete and orthonormal basis on the unit circle. Here, we present a generalization of this Zernike basis for a variety of important optical apertures. On the contrary to ad hoc solutions, most of them based on the Gram-Schmidt orthonormalization method, here we apply the diffeomorphism (mapping that has a differentiable inverse mapping) that transforms the unit circle into an angular sector of an elliptical annulus. In this way, other apertures, such as ellipses, rings, angular sectors, etc. are also included as particular cases. This generalization, based on in-plane warping of the basis functions, provides a unique solution and what is more important, it guarantees a reasonable level of invariance of the mathematical properties and the physical meaning of the initial basis functions. Both, the general form and the explicit expressions for most common, elliptical and annular apertures are provided.

18.
J Strength Cond Res ; 28(7): 1896-905, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24276307

RESUMO

The main objective of this study was to examine the effect of different judo training loads on heart rate variability (HRV) measurements, to determine if they can be used as valid indicators in monitoring stress and recovery in judo athletes. Fourteen male national-standard judo athletes were randomly divided into 2 groups, and each group followed a different type of training, namely, a high training load (HTL) and a moderate training load program (MTL). Data collection included HRV measurements, a Recovery Stress Questionnaire for athletes (RESTQ-SPORT), and strength measurements, 4 weeks before and after the training program. The HTL group had lower square root of the mean squared difference of successive RR intervals, very low frequency, high frequency, short-term variability, short-range scaling exponents, general recovery, sport-specific recovery, general stress, maximum strength, maximum power, and higher low/high frequency ratio at posttest compared with pretest (p ≤ 0.05). The HTL group showed lower short-range and long-range scaling exponents, general recovery, sport-specific recovery, and higher general stress than the MTL group in posttest measurements (p ≤ 0.05). In conclusion, judo athletes enrolled in an HTL program showed an imbalance of the autonomic nervous system with decreased vagal modulation, together with a decrease in strength parameters, higher markers for stress, and a lower perception of recovery.


Assuntos
Frequência Cardíaca , Artes Marciais/fisiologia , Condicionamento Físico Humano/fisiologia , Recuperação de Função Fisiológica/fisiologia , Estresse Fisiológico , Força da Mão/fisiologia , Humanos , Masculino , Músculo Esquelético/fisiologia , Condicionamento Físico Humano/métodos , Inquéritos e Questionários , Adulto Jovem
19.
Rev Argent Microbiol ; 46(3): 218-30, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25444131

RESUMO

Bacterial richness in maritime Antarctica has been poorly described to date. Phylogenetic affiliation of seawater free-living microbial assemblages was studied from three locations near the Argentinean Jubany Station during two Antarctic summers. Sixty 16S RNA cloned sequences were phylogenetically affiliated to Alphaproteobacteria (30/60 clones), Gammaproteobacteria(19/60 clones), Betaproteobacteria and Cytophaga-Flavobacteriia-Bacteroides (CFB), which were (2/60) and (3/60) respectively. Furthermore, six out of 60 clones could not be classified. Both, Alphaproteobacteria and Gammaproteobacteria, showed several endemic and previously undescribed sequences. Moreover, the absence of Cyanobacteria sequences in our samples is remarkable. In conclusion, we are reporting a rich sequence assemblage composed of widely divergent isolates among themselves and distant from the most closely related sequences currently deposited in data banks.


Assuntos
Bactérias/isolamento & purificação , Água do Mar/microbiologia , Regiões Antárticas , Bactérias/classificação , Bactérias/genética , Sequência de Bases , DNA Bacteriano/genética , DNA Ribossômico/genética , Evolução Molecular , Microbiota , Dados de Sequência Molecular , Filogenia , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Ribotipagem
20.
Br J Haematol ; 162(3): 336-47, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23725219

RESUMO

Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53-CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance.


Assuntos
Biomarcadores Tumorais/genética , Doença de Hodgkin/genética , MicroRNAs/genética , RNA Neoplásico/genética , Adulto , Idoso , Antibióticos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Perfilação da Expressão Gênica/métodos , Inativação Gênica , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Células de Reed-Sternberg/metabolismo , Análise de Sobrevida , Resultado do Tratamento , Células Tumorais Cultivadas , Microambiente Tumoral , Adulto Jovem
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