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1.
Nature ; 606(7916): 976-983, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35705807

RESUMO

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.


Assuntos
Instabilidade Cromossômica , Neoplasias , Instabilidade Cromossômica/genética , Recombinação Homóloga/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo
2.
Exp Dermatol ; 33(1): e15003, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38284189

RESUMO

Biological therapies are safer and more effective against psoriasis than conventional treatments. Even so, 30-50% of psoriatic patients show an inadequate response, which is associated with individual genetic heterogeneity. Pharmacogenetic studies have identified several single nucleotide polymorphisms (SNPs) as possible predictive and prognostic biomarkers for psoriasis treatment response. The objective of this study was to determine the link between several SNPs and the clinical response to biological therapies in patients with moderate-severe psoriasis. A set of 21 SNPs related to psoriasis and/or other immunological diseases were selected and analysed from salivary samples of patients (n = 88). Treatment effectiveness and patient improvement was assessed clinically through Relative Psoriasis Area and Severity Index (PASI), also called 'PASI response', as well as absolute PASI. Associations between SNPs and PASI factors were assessed at 3 and 12 months for every treatment category of IL-17, IL-23, IL-12&23 and TNF-α inhibitors. Multivariate correlation analysis and Fisher's exact test were used to analyse the relationship between SNPs and therapy outcomes. Several SNPs located in the TLR2, TLR5, TIRAP, HLA-C, IL12B, SLC12A8, TNFAIP3 and PGLYRP4 genes demonstrated association with increased short and long-term therapy-effectiveness rates. Most patients achieved values of PASI response ≥75 or absolute PASI<1, regardless of the biological treatment administered. In conclusion, we demonstrate a relationship between different SNPs and both short- and especially long-term effectiveness of biological treatment in terms of PASI. These polymorphisms may be used as predictive markers of treatment response in patients with moderate-to-severe psoriasis, providing personalized treatment.


Assuntos
Psoríase , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/genética , Interleucina-12/genética , Polimorfismo de Nucleotídeo Único , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Resultado do Tratamento , Psoríase/tratamento farmacológico , Psoríase/genética , Imunidade , Índice de Gravidade de Doença
3.
Bioinformatics ; 38(14): 3638-3641, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35640971

RESUMO

SUMMARY: Selecting the optimal cancer cell line for an experiment can be challenging given the diversity of lines available. Here, we present CNpare, which identifies similar cell line models based on genome-wide DNA copy number. AVAILABILITY AND IMPLEMENTATION: CNpare is available as an R package at https://github.com/macintyrelab/CNpare. All analysis performed in the manuscript can be reproduced via the code found at https://github.com/macintyrelab/CNpare_analyses. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Neoplasias , Software , Humanos , Variações do Número de Cópias de DNA , DNA , Neoplasias/genética
4.
Int J Gynecol Cancer ; 32(8): 1009-1016, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35437272

RESUMO

OBJECTIVES: Cancer-related systemic inflammation has been associated with prognosis in multiple cancer types. Conversely, local inflammation, which is characterized by dense intratumoral immune infiltrates, is a favorable predictor of survival outcome. However, these survival associations are not well established in ovarian cancer, particularly in the less frequent endometrioid and clear cell endometriosis associated histotypes. METHODS: This retrospective study included 119 patients (63 endometrioid and 56 clear cell ovarian carcinomas). We performed a comprehensive survival association analysis of both systemic (neutrophil-to-lymphocyte ratio or presence of endometriosis) and local inflammation markers (CD3+ and CD8+ tumor infiltrating lymphocytes) using multivariate Cox proportional hazards models that account for confounding factors. RESULTS: Medium to high levels of intraepithelial CD8+ tumor infiltrating lymphocytes are associated with longer survival in endometrioid ovarian cancer (p=0.04). In addition, we found that intraepithelial CD8+ tumor infiltrating lymphocytes are prognostic in clear cell ovarian cancer (p=0.02), and that intraepithelial CD3+ tumor infiltrating lymphocytes are also associated with improved outcome (p=0.02). Furthermore, intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes showed improved prognosis in the endometrioid subtype (p<0.1). No prognostic value was observed for systemic immune markers. CONCLUSIONS: In this study, patients with endometrioid and clear cell ovarian cancer with moderate to high CD8+ and CD3+ intraepithelial tumor infiltrating lymphocytes had longer overall survival. Higher expression of intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes also showed an improved outcome in endometrioid ovarian cancer. In contrast, systemic inflammation, evaluated by neutrophil-to-lymphocyte ratio or presence of endometriosis, did not have a prognostic impact in these histologic subtypes.


Assuntos
Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Endometriose , Neoplasias Ovarianas , Adenocarcinoma de Células Claras/patologia , Linfócitos T CD8-Positivos , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/patologia , Endometriose/patologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Linfócitos do Interstício Tumoral , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos
5.
Int J Sports Med ; 43(7): 600-607, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33017851

RESUMO

The study aimed to assess the relationship between peak oxygen uptake, ventilatory thresholds and maximal fat oxidation with ultra trail male and female performance. 47 athletes (29 men and 18 women) completed a cardiopulmonary exercise test between 2 to 4 weeks before a 107-km ultra trail. Body composition was also analyzed using a bioelectrical impedance weight scale. Exploratory correlation analyses showed that peak oxygen uptake (men: r=-0.63, p=0.004; women: r=-0.85, p < 0.001), peak speed (men: r=-0.74, p < 0.001; women: r=-0.69, p=0.009), speed at first (men: r=-0.49, p=0.035; women: r=-0.76, p=0.003) and second (men: r=-0.73, p < 0.001; women: r=-0.76, p=0.003) ventilatory threshold, and maximal fat oxidation (men: r=-0.53, p=0.019; women: r=-0.59, p=0.033) were linked to race time in male and female athletes. Percentage of fat mass (men: r=0.58, p=0.010; women: r=0.62, p= 0.024) and lean body mass (men: r=-0.61, p=0.006; women: r=-0.61, p=0.026) were also associated with performance in both sexes. Subsequent multiple regression analyses revealed that peak speed and maximal fat oxidation together were able to predict 66% of male performance; while peak oxygen uptake was the only statistically significant variable explaining 69% of the variation in women's race time. These results, although exploratory in nature, suggest that ultra trail performance is differently predicted by endurance variables in men and women.


Assuntos
Consumo de Oxigênio , Resistência Física , Atletas , Teste de Esforço , Feminino , Humanos , Masculino , Oxigênio
6.
J Strength Cond Res ; 36(6): 1629-1635, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32796418

RESUMO

ABSTRACT: Martínez-Navarro, I, Montoya-Vieco, A, Collado, E, Hernando, B, Panizo, N, and Hernando, C. Muscle Cramping in the marathon: Dehydration and electrolyte depletion vs. muscle damage. J Strength Cond Res 36(6): 1629-1635, 2022-Our aim was to compare dehydration variables, serum electrolytes, and muscle damage serum markers between runners who suffered exercise-associated muscle cramps (EAMC) and runners who did not suffer EAMC in a road marathon. We were also interested in analyzing race pacing and training background. Nighty-eight marathoners took part in the study. Subjects were subjected to a cardiopulmonary exercise test. Before and after the race, blood and urine samples were collected and body mass (BM) was measured. Immediately after the race EAMC were diagnosed. Eighty-eight runners finished the marathon, and 20 of them developed EAMC (24%) during or immediately after the race. Body mass change, post-race urine specific gravity, and serum sodium and potassium concentrations were not different between crampers and noncrampers. Conversely, runners who suffered EAMC exhibited significantly greater post-race creatine kinase (464.17 ± 220.47 vs. 383.04 ± 253.41 UI/L, p = 0.034) and lactate dehydrogenase (LDH) (362.27 ± 72.10 vs. 307.87 ± 52.42 UI/L, p = 0.002). Twenty-four hours post-race also values of both biomarkers were higher among crampers (CK: 2,438.59 ± 2,625.24 vs. 1,166.66 ± 910.71 UI/L, p = 0.014; LDH: 277.05 ± 89.74 vs. 227.07 ± 37.15 UI/L, p = 0.021). The difference in the percentage of runners who included strength conditioning in their race training approached statistical significance (EAMC: 25%, non-EAMC: 47.6%; p = 0.074). Eventually, relative speed between crampers and noncrampers only differed from the 25th km onward (p < 0.05). Therefore, runners who suffered EAMC did not exhibit a greater degree of dehydration and electrolyte depletion after the marathon but displayed significantly higher concentrations of muscle damage biomarkers.


Assuntos
Corrida de Maratona , Cãibra Muscular , Biomarcadores , Creatina Quinase , Desidratação , Eletrólitos , Humanos , Cãibra Muscular/etiologia , Músculos
7.
J Sports Sci Med ; 20(4): 706-713, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-35321133

RESUMO

The study aimed to provide within-race data on the time course of pulmonary function during a mountain ultramarathon (MUM). Additionally, we wanted to assess possible sex differences regarding pre- to post-race change in pulmonary and inspiratory muscle function. Lastly, we were interested in evaluating whether changes in respiratory function were associated with relative running speed and due to general or specific fatigue. 47 athletes (29 males and 18 females; 41 ± 5 years) were submitted to a cardiopulmonary exercise test (CPET) before a 107-km MUM. Spirometric variables: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC and peak expiratory flow (PEF); maximal inspiratory pressure (MIP); squat jump (SJ) and handgrip strength (HG) were assessed before and after the race. Additionally PEF was measured at three aid stations (33rd, 66th and 84th km) during the race. PEF declined from the 33rd to the 66th km (p = 0.004; d = 0.72) and from the 84th km to the finish line (p = 0.003; d = 0.90), while relative running speed dropped from the first (0-33 km) to the second (33-66 km) race section (p < 0.001; d = 1.81) and from the third (66-84 km) to the last race section (p < 0.001; d = 1.61). Post-race, a moderate reduction was noted in FVC (-13%; p < 0.001; d = 0.52), FEV1 (-19.5%; p < 0.001; d = 0.65), FEV1/FVC (-8.4%; p = 0.030; d = 0.59), PEF (-20.3%; p < 0.001; d = 0.58), MIP (-25.3%; p < 0.001; d = 0.79) and SJ (-31.6%; p < 0.001; d = 1.42). Conversely, HG did not change from pre- to post-race (-1.4%; p = 0.56; d = 0.05). PEF declined during the race in parallel with running speed drop. No sex differences were noted regarding post-race respiratory function, except that FEV1/FVC decay was significantly greater among women. The magnitude of pre- to post-race respiratory function decline was uncorrelated with relative running speed.


Assuntos
Força da Mão , Pulmão , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiologia , Masculino , Músculos , Capacidade Vital/fisiologia
8.
J Sports Sci Med ; 18(4): 615-622, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31827345

RESUMO

This study aimed to assess the release of cardiac damage biomarkers jointly with cardiac autonomic modulation after a mountain ultramarathon. Such knowledge and the possible relationship of these markers with race time is of primary interest to establish possible recommendations upon athletes' recovery and return to training following these competitions. Forty six athletes enrolled in the Penyagolosa Trails CSP115 race (118 km and a total positive elevation of 5439 m) took part in the study. N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin T (hs-TNT) concentrations as well as linear and nonlinear heart rate variability (HRV) were evaluated before and after the race. NT-proBNP and hs-TNT significantly increased post-race; fifty percent of the finishers surpassed the Upper Reference Limit (URL) for hs-TNT while 87% exceeded the URL for NT-proBNP. Overall and vagally-mediated HRV were diminished and cardiac autonomic modulation became less complex and more predictable following the race. More pronounced vagal modulation decreases were associated with higher levels of postexertional NT-proBNP. Moreover, rise in hs-TNT and NT-proBNP was greater among faster runners, while pre-race overall and vagally-mediated HRV were correlated with finishing time. Participation in a 118-km ultratrail induces an acute release of cardiac damage biomarkers and a large alteration of cardiac autonomic modulation. Furthermore, faster runners were those who exhibited a greater rise in those cardiac damage biomarkers. In light of these findings, an appropriate recovery period after ultraendurance races appears prudent and particularly important among better performing athletes. At the same time, HRV analysis is shown as a promising tool to assess athletes' readiness to perform at their maximum level in an ultraendurance race.


Assuntos
Frequência Cardíaca/fisiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Resistência Física/fisiologia , Corrida/fisiologia , Troponina T/sangue , Adulto , Biomarcadores/sangue , Humanos , Masculino , Nervo Vago/fisiologia
9.
Photodermatol Photoimmunol Photomed ; 34(6): 415-422, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29974532

RESUMO

BACKGROUND/PURPOSE: Recent GWAS studies, mostly performed in populations of North European origin, have identified the genetic loci associated with pigmentation, sun sensitivity, freckling and skin cancer susceptibility. Here, we aimed at addressing the genetic determinants of sunlight sensitivity in Spain, a southern European population. METHODS: Nine SNPs located in 8 pigmentation-related genes (IRF4, TYR, ASP, HERC2, OCA2, BNC2, SLC24A4 and SLC45A2) were genotyped in 456 Spaniards. Additionally, the complete sequence of the MC1R gene was obtained, testing each nonsynonymous mutation supported by the classification as R or r alleles. A standardised questionnaire was used to collect demographic characteristics, pigmentation and sun sensitivity traits, as well as sun exposure habits. RESULTS: MC1R R alleles and IRF4 rs12203592 were significantly associated with sunlight sensitivity at the Bonferroni-corrected level (P-value < 4.54 × 10-3 ). Genetic variants in SLC45A2 (rs16891982) and HERC2 (rs12913832) were also found to be significantly associated with skin photosensitivity in our Spanish sample. Interaction analysis using the MDR method revealed epistatic effects when these four variants were considered together. CONCLUSION: MC1R, IRF4, HERC2 and SLC45A2 play a significant role in skin sensitivity to sunlight in the Spanish population. Moreover, interaction among these four loci seems to modulate the ability of the skin to respond to UV radiation.


Assuntos
Alelos , Frequência do Gene , Transtornos de Fotossensibilidade/genética , Polimorfismo de Nucleotídeo Único , Pigmentação da Pele/genética , Pele , Raios Ultravioleta/efeitos adversos , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Espanha
10.
J Strength Cond Res ; 32(2): 441-449, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27548786

RESUMO

Martínez-Navarro, I, Chiva-Bartoll, O, Hernando, B, Collado, E, Porcar, V, and Hernando, C. Hydration status, executive function and response to orthostatism after a 118-km mountain race: are they interrelated? J Strength Cond Res 32(2): 441-449, 2018-The present study aimed to explore whether blood pressure (BP) and heart rate (HR) variability (HRV) responsiveness to orthostatism, jointly with executive function (EF) performance, was diminished after an ultra-endurance mountain race. Besides, we wanted to assess whether hydration status was related to either performance or the abovementioned alterations. Fifty recreational ultra-endurance athletes participating in the Penyagolosa Trails CSP115 race (118 km and a total positive elevation of 5,439 m) were evaluated before and after the competition. The HRV and BP were measured in response to an orthostatic challenge. The EF was evaluated using the color-word interference task of the Stroop test. Body mass (BM) and urine specific gravity (USG) changes were used to assess hydration status. The HRV and BP responsiveness to orthostatism was diminished after the race. Besides, a significant BM loss of 3.51 ± 2.03% was recorded. Conversely, EF and USG showed no significant changes from prerace to postrace. Eventually, BM loss was inversely related to finishing time (r = -0.34) and postrace orthostatic HR and EF were positively associated (r = 0.60). The USG and BM loss appear to provide different insights into hydration status, and our results challenge the well-established criteria that BM losses >2% are detrimental to performance. Coaches are advised to consider athletes' performance level when interpreting their BM changes during an ultra-endurance competition. Similarly, coaches should be aware that increased vulnerability to orthostatism is a common phenomenon after ultra-endurance races, and diminished HR responsiveness to orthostatism could constitute a practical indicator of EF worsening.


Assuntos
Altitude , Tontura/fisiopatologia , Função Executiva/fisiologia , Estado de Hidratação do Organismo/fisiologia , Corrida/fisiologia , Adulto , Atletas , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Adulto Jovem
11.
Exp Dermatol ; 26(10): 896-903, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28266728

RESUMO

Sunlight exposure induces signalling pathways leading to the activation of melanin synthesis and tanning response. MicroRNAs (miRNAs) can regulate the expression of genes involved in pigmentation pathways by binding to the complementary sequence in their 3'untranslated regions (3'UTRs). Therefore, 3'UTR SNPs are predicted to modify the ability of miRNAs to target genes, resulting in differential gene expression. In this study, we investigated the role in pigmentation and sun-sensitivity traits, as well as in melanoma susceptibility, of 38 different 3'UTR SNPs from 38 pigmentation-related genes. A total of 869 individuals of Spanish origin (526 melanoma cases and 343 controls) were analysed. The association of genotypic data with pigmentation traits was analysed via logistic regression. Web-based tools for predicting the effect of genetic variants in microRNA-binding sites in 3'UTR gene regions were also used. Seven 3'UTR SNPs showed a potential implication in melanoma risk phenotypes. This association is especially noticeable for two of them, rs2325813 in the MLPH gene and rs752107 in the WNT3A gene. These two SNPs were predicted to disrupt a miRNA-binding site and to impact on miRNA-mRNA interaction. To our knowledge, this is the first time that these two 3'UTR SNPs have been associated with sun-sensitivity traits. We state the potential implication of these SNPs in human pigmentation and sensitivity to sunlight, possibly as a result of changes in the level of gene expression through the disruption of putative miRNA-binding sites.


Assuntos
Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Melanoma/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Cutâneas/genética , Pigmentação da Pele/genética , Proteína Wnt3A/genética , Sítios de Ligação , Estudos de Casos e Controles , Cor de Olho/genética , Frequência do Gene , Predisposição Genética para Doença , Cor de Cabelo/genética , Humanos , Lentigo/genética , MicroRNAs/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , RNA Mensageiro/genética , Fatores de Risco , Espanha , População Branca/genética
13.
Physiol Plant ; 147(3): 296-306, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22671923

RESUMO

Phytohormones are central players in sensing and signaling numerous environmental conditions like drought stress. In this work, an experimental system based on severe drought was established and hormone profiling together with gene expression of key enzymes involved in abscisic acid (ABA) and jasmonic acid (JA) biosynthesis was studied in roots of citrumelo CPB 4475 (a commercial citrus rootstock) plants. JA concentration transiently increased after a few hours of stress, returning to control levels 30 h after the onset of the condition. A more progressive ABA accumulation was observed, with the onset of this increase at the same time or right after the JA transient accumulation. Molecular data suggested that, at least, part of the hormonal regulation takes place at the biosynthetic level. These observations also pointed to a possible involvement of JA on ABA biosynthesis under stress. To test this hypothesis, JA and ABA biosynthesis were chemically inhibited and subsequently phenotypes rescued by the addition of exogenous hormones. Results showed that the early JA accumulation was necessary for the subsequent ABA increase in roots under stress whereas the opposite could not be stated. The model includes a burst of JA in roots of citrus under severe drought stress conditions that leads to a more progressive ABA accumulation that will induce later plant responses. The present work adds a new level of interaction between JA and ABA at the biosynthetic level that together with the previously described interaction between signal transduction cascades of the two hormones would allow plants to fine-tune specific responses to different stimuli.


Assuntos
Ácido Abscísico/metabolismo , Citrus/metabolismo , Ciclopentanos/metabolismo , Regulação da Expressão Gênica de Plantas , Oxilipinas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Ácido Abscísico/análise , Vias Biossintéticas , Citrus/fisiologia , Ciclopentanos/análise , DNA Complementar/genética , Secas , Genótipo , Modelos Biológicos , Oxilipinas/análise , Fenótipo , Reguladores de Crescimento de Plantas/análise , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/fisiologia , RNA de Plantas/genética , Distribuição Aleatória , Plântula/metabolismo , Plântula/fisiologia , Transdução de Sinais
14.
Elife ; 122023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37166279

RESUMO

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Genômica , Instabilidade Cromossômica , Organoides
15.
Nat Commun ; 14(1): 1122, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36854674

RESUMO

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.


Assuntos
Neoplasias das Glândulas Suprarrenais , Segunda Neoplasia Primária , Paraganglioma , Feocromocitoma , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Genômica , Paraganglioma/genética , Paraganglioma/imunologia , Feocromocitoma/genética , Feocromocitoma/imunologia , Microambiente Tumoral/genética
16.
Front Physiol ; 13: 812237, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295572

RESUMO

Long distance races have a physiological impact on runners. Up to now, studies analyzing these physiological repercussions have been mainly focused on muscle and cardiac damage, as well as on its recovery. Therefore, a limited number of studies have been done to explore acute kidney failure and recovery after performing extreme exercises. Here, we monitored renal function in 76 marathon finishers (14 females) from the day before participating in a marathon until 192 h after crossing the finish line (FL). Renal function was evaluated by measuring serum creatinine (sCr) and the glomerular filtration rate (GFR). We randomly grouped our cohort into three intervention groups to compare three different strategies for marathon recovery: total rest (REST), continuous running at their ventilatory threshold 1 (VT1) intensity (RUN), and elliptical workout at their VT1 intensity (ELLIPTICAL). Interventions in the RUN and ELLIPTICAL groups were performed at 48, 96, and 144 h after marathon running. Seven blood samples (at the day before the marathon, at the FL, and at 24, 48, 96, 144, and 192 h post-marathon) and three urine samples (at the day before the marathon, at the finish line, and at 48 h post-marathon) were collected per participant. Both heart rate monitors and triaxial accelerometers were used to control the intensity effort during both the marathon race and the recovery period. Contrary to our expectations, the use of elliptical machines for marathon recovery delays renal function recovery. Specifically, the ELLIPTICAL group showed a significantly lower ∆GFR compared to both the RUN group (p = 4.5 × 10-4) and the REST group (p = 0.003). Hence, we encourage runners to carry out an active recovery based on light-intensity continuous running from 48 h after finishing the marathon. In addition, full resting seems to be a better strategy than performing elliptical workouts.

17.
J Sports Med Phys Fitness ; 61(12): 1668-1674, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33555667

RESUMO

BACKGROUND: The study aimed at exploring whether muscle membrane disruption, as a surrogate for muscle damage, and inflammation recovery following a mountain ultramarathon (MUM) was related with race performance and postrace physical activity. METHODS: Blood samples were obtained from thirty-four athletes (29 men and 5 women) before a 118-km MUM, immediately after and three- and seven-days postrace. Creatine kinase (CK), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were compared between faster (FR) and slower (SR) runners. Physical activity performed during the week following the MUM was objectively analyzed using accelerometers and compared between FR and SR. RESULTS: CK was significantly higher in FR at 3 days postrace (P<0.012, d=1.17) and LDH was significantly higher in FR at 3- and 7-days postrace (P=0.005, d=1.01; P<0.015, d=1.05 respectively), as compared to SR. No significant differences were identified in postrace physical activity levels between FR and SR. Significant relationships were found between race time and CK and LDH concentrations at 3 days postrace (rs=-0.41, P=0.017; rs=-0.52, P=0.002 respectively) and 7 days postrace (rs=-0.36, P=0.039; rs=-0.46. P=0.007 respectively). However, postrace physical activity was not associated with muscle damage and inflammation recovery, except for light intensity and CRP at 3 days postrace (rs=-0.40, P=0.025). CONCLUSIONS: Race time appeared to have a higher influence on muscle damage recovery than the intensity of physical activities performed in the week after running a MUM. Inflammatory activity takes longer to normalize than muscle damage following a MUM, it is not related with race time and lightly related with postrace physical activity.


Assuntos
Creatina Quinase , Inflamação , Corrida de Maratona , Músculos/lesões , Resistência Física , Atletas , Exercício Físico , Feminino , Humanos , Masculino
18.
J Hum Kinet ; 80: 71-82, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34868418

RESUMO

The study was aimed at comparing pacing adopted by males and females in a 107-km mountain ultramarathon and assessing whether pacing-related variables were associated with intracompetition body weight changes and performance. Forty-seven athletes (29 males; 18 females) were submitted to a cardiopulmonary exercise test before the race. Athletes were also weighted before the start of the race, at three midpoints (33 km, 66 km and 84 km) and after the race. Pacing was analyzed using absolute and relative speeds and accelerometry-derived sedentary time spent during the race. Results showed that females spent less sedentary time (4.72 ± 2.91 vs. 2.62 ± 2.14%; p = 0.035; d = 0.83) and displayed a smaller body weight loss (3.01 ± 1.96 vs. 4.37 ± 1.77%; p = 0.048; d = 0.77) than males. No significant sex differences were revealed for speed variability, absolute and relative speed. In addition, finishing time was correlated with: speed variability (r = 0.45; p = 0.010), index of pacing (r = -0.63; p < 0.001) and sedentary time (r = 0.64; p < 0.001). Meanwhile, intracompetition body weight changes were related with both the absolute and relative speed in the first and the last race section. These results suggest that females, as compared with males, take advantage of shorter time breaks at aid stations. Moreover, performing a more even pacing pattern may be positively associated with performance in mountain ultramarathons. Finally, intracompetition body weight changes in those races should be considered in conjunction with running speed fluctuations.

19.
Eur J Sport Sci ; 21(6): 811-818, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32538286

RESUMO

In sport disciplines with high levels of muscle damage such as an ultra-trail competition, full body compression garments (FBCG) may have an ergogenic effect during the recovery process. The aim of the study was to assess the influence of FBCG worn for 24 h immediately after a 107-km ultra-trail on delayed onset muscle soreness (DOMS), muscle damage, inflammatory and renal response. Thirty-two athletes (19 males and 13 females; VO2peak: 54.1 ± 5.2 ml O2/kg/min) participated in the study. The following blood markers were analysed before, immediately after, at 24 and 48 h post-race: lactate dehydrogenase, creatine kinase, C-reactive protein and creatinine. The glomerular filtration rate was also calculated. Delayed onset muscle soreness was evaluated before, immediately after and at 24 h post-race. On arrival at the finishing line, athletes were randomised into one of two recovery groups (FBCG and control group). The results showed that wearing FBCG did not influence the evolution of any of the blood markers up to 48 h after the race (p > .05). However, FBCG group presented a lower increase in posterior leg DOMS (11.0 ± 46.2% vs 112.3 ± 170.4%, p = .03, d = 0.8). Therefore, although FBCG is not useful for reducing muscle damage and inflammatory response after an ultra-trail race, its use may still be recommended as a recovery method to reduce muscle soreness.Trial registration: ClinicalTrials.gov identifier: NCT03990259.


Assuntos
Desempenho Atlético/fisiologia , Vestuário , Corrida de Maratona/fisiologia , Mialgia/prevenção & controle , Adulto , Análise de Variância , Biomarcadores/sangue , Proteína C-Reativa/análise , Creatina Quinase/sangue , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , L-Lactato Desidrogenase , Masculino , Músculos/lesões , Mialgia/diagnóstico , Consumo de Oxigênio , Fatores de Tempo
20.
Artigo em Inglês | MEDLINE | ID: mdl-34639701

RESUMO

In recent years, increasing numbers of women have participated in extremely long races. In adult males, there is a clear association between physiological levels of endogenous sex hormones and physical performance. However, the influence of plasmatic sex hormones and the effects of different types of hormonal contraception (HC) on the modulation of physical performance in adult females remain to be fully clarified. Eighteen female ultra-endurance athletes were recruited to participate in the study. Different variables were studied, including hematological parameters, body mass index, and body composition. Strength measurements were obtained using the squat-jump and hand-grip test. A repeated-measures analysis demonstrated significant differences in hematological values of CK and LDH pre-race as compared to immediately post-race and after 24/48 h. Furthermore, statistical differences were found in squat-jump and hand-grip test results after the ultramarathon. Testosterone, estradiol, and the testosterone/estrogen ratio were significantly correlated with muscle fatigue and were found to be indirect markers of muscle damage. A multivariate analysis demonstrated the protective role of testosterone against muscle damage and severe fatigue. Fluctuations in endogenous testosterone levels were correlated with greater fatigability and muscle damage after the competition. Adjusting the menstrual cycle with HC would not provide any further benefit to the athlete's competitive capacity.


Assuntos
Corrida , Testosterona , Adulto , Atletas , Biomarcadores , Feminino , Humanos , Masculino , Resistência Física
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