RESUMO
BACKGROUND: Whether there is a difference in harvesting the semitendinosus tendon alone (S) or in combination with the gracilis tendon (SG) for the recovery of knee flexor strength after anterior cruciate ligament (ACL) reconstruction remains inconclusive. Therefore, this study aimed to assess the recovery of knee flexor strength based on the autograft composition, S or SG autograft at 6, 12, and ≥ 24 months after ACL reconstruction. METHODS: A systematic review and meta-analysis was conducted following the PRISMA guidelines. A comprehensive search was performed encompassing the Cochrane Library, Embase, Medline, PEDRo and AMED databases from inception to January 2023. Inclusion criteria were human clinical trials published in English, comprised of randomized controlled trials (RCTs), longitudinal cohort-, cross-sectional and case-control studies that compared knee flexor strength recovery between S and SG autografts in patients undergoing primary ACL reconstruction. Isokinetic peak torques were summarized for angular velocities of 60°/s, 180°/s, and across all angular velocities, assessed at 6, 12, and ≥ 24 months after ACL reconstruction. A random-effects model was used with standardized mean differences and 95% confidence intervals. Risk of bias was assessed with the RoBANS for non-randomized studies and the Cochrane RoB 2 tool for RCTs. Certainty of evidence was appraised using the GRADE working group methodology. RESULTS: Among the 1,227 patients from the 15 included studies, 604 patients received treatment with S autograft (49%), and 623 received SG autograft (51%). Patients treated with S autograft displayed lesser strength deficits at 6 months across all angular velocities d = -0.25, (95% CI -0.40; -0.10, p = 0.001). Beyond 6 months after ACL reconstruction, no significant difference was observed between autograft compositions. CONCLUSION: The harvest of S autograft for ACL reconstruction yields superior knee flexor strength recovery compared to SG autograft 6 months after ACL reconstruction, irrespective of angular velocity at isokinetic testing. However, the clinical significance of the observed difference in knee flexor strength between autograft compositions at 6 months is questionable, given the very low certainty of evidence and small effect size. There was no significant difference in knee flexor strength recovery between autograft compositions beyond 6 months after ACL reconstruction. TRIAL REGISTRATION: CRD42022286773.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Autoenxertos , Tendões dos Músculos Isquiotibiais , Força Muscular , Recuperação de Função Fisiológica , Humanos , Reconstrução do Ligamento Cruzado Anterior/métodos , Reconstrução do Ligamento Cruzado Anterior/efeitos adversos , Tendões dos Músculos Isquiotibiais/transplante , Força Muscular/fisiologia , Lesões do Ligamento Cruzado Anterior/cirurgia , Articulação do Joelho/cirurgia , Articulação do Joelho/fisiopatologia , Músculo Grácil/transplante , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
This article addresses issues of importance for occupational exposure limits (OELs) and chemical carcinogens with a focus on non-threshold carcinogens. It comprises scientific as well as regulatory issues. It is an overview, not a comprehensive review. A central topic is mechanistic research and insights, and its implications for cancer risk assessment. Alongside scientific advancements, the approaches of hazard identification and qualitative and quantitative risk assessment have developed over the years. The key steps in a quantitative risk assessment are outlined, with special attention given to the dose-response assessment and the derivation of an OEL using risk calculations or default assessment factors. The work procedures of several bodies performing cancer hazard identifications and quantitative risk assessments, as well as regulatory procedures to derive OELs for non-threshold carcinogens, are presented. Non-threshold carcinogens for which the European Union (EU) introduced binding OELs in 2017-2019 serve as illustrations together with some currently used strategies in the EU and elsewhere. Available knowledge supports the derivation of health-based OELs (Hb-OELs) for non-threshold carcinogens, and the use of a risk-based approach with low-dose linear extrapolation (linear non-threshold, LNT) as the default for non-threshold carcinogens. However, there is a need to develop methods that allow recent years' advances in cancer research to be used for improving risk estimates. It is recommended that defined risk levels (terminology and numerical values) are harmonised, and that both collective and individual risks are considered and clearly communicated. Socioeconomic aspects should be dealt with transparently and separated from the scientific health risk assessment.
Assuntos
Neoplasias , Exposição Ocupacional , Saúde Ocupacional , Humanos , Carcinógenos/toxicidade , Níveis Máximos Permitidos , Neoplasias/induzido quimicamente , Medição de RiscoRESUMO
Autotaxin (ATX) and its product lysophosphatidic acid (LPA) have been implicated in lung fibrosis and cancer. We have studied their roles in DNA damage induced by carcinogenic crystalline silica particles (CSi). In an earlier study on bronchial epithelia, we concluded that ATX, via paracrine signaling, amplifies DNA damage. This effect was seen at 6-16 h. A succeeding study showed that CSi induced NLRP3 phosphorylation, mitochondrial depolarization, double strand breaks (DSBs), and NHEJ repair enzymes within minutes. In the current study we hypothesized a role for the ATX-LPA axis also in this rapid DNA damage. Using 16HBE human bronchial epithelial cells, we show ATX secretion at 3 min, and that ATX inhibitors (HA130 and PF8380) prevented both CSi-induced mitochondrial depolarization and DNA damage (detected by γH2AX and Comet assay analysis). Experiments with added LPA gave similar rapid effects as CSi. Furthermore, Rac1 was activated at 3 min, and a Rac1 inhibitor (NSC23766) prevented mitochondrial depolarization and genotoxicity. In mice the bronchial epithelia exhibited histological signs of ATX activation and signs of DSBs (53BP1 positive nuclei) minutes after a single inhalation of CSi. Our data indicate that CSi rapidly activate the ATX-LPA axis and within minutes this leads to DNA damage in bronchial epithelial cells. Thus, ATX mediates very rapid DNA damaging effects of inhaled particles.
Assuntos
Dano ao DNA , Diester Fosfórico Hidrolases/metabolismo , Mucosa Respiratória/patologia , Dióxido de Silício/química , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Cristalização , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/farmacologia , Lisofosfolipídeos/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Propionatos/farmacologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidoresRESUMO
MOTIVATION: The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-based discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD. RESULTS: We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections. AVAILABILITY AND IMPLEMENTATION: The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page http://lbd.lionproject.net. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Neoplasias , Algoritmos , Bases de Dados Factuais , Humanos , Processamento de Linguagem Natural , PublicaçõesRESUMO
BACKGROUND: Respirable crystalline silica causes lung carcinomas and many thousand future cancer cases are expected in e.g. Europe. Critical questions are how silica causes genotoxicity in the respiratory epithelium and if new cases can be avoided by lowered permissible exposure levels. In this study we investigate early DNA damaging effects of low doses of silica particles in respiratory epithelial cells in vitro and in vivo in an effort to understand low-dose carcinogenic effects of silica particles. RESULTS: We find DNA damage accumulation already after 5-10 min exposure to low doses (5 µg/cm2) of silica particles (Min-U-Sil 5) in vitro. DNA damage was documented as increased levels of γH2AX, pCHK2, by Comet assay, AIM2 induction, and by increased DNA repair (non-homologous end joining) signaling. The DNA damage response (DDR) was not related to increased ROS levels, but to a NLRP3-dependent mitochondrial depolarization. Particles in contact with the plasma membrane elicited a Ser198 phosphorylation of NLRP3, co-localization of NLRP3 to mitochondria and depolarization. FCCP, a mitochondrial uncoupler, as well as overexpressed NLRP3 mimicked the silica-induced depolarization and the DNA damage response. A single inhalation of 25 µg silica particles gave a similar rapid DDR in mouse lung. Biomarkers (CC10 and GPRC5A) indicated an involvement of respiratory epithelial cells. CONCLUSIONS: Our findings demonstrate a novel mode of action (MOA) for silica-induced DNA damage and mutagenic double strand breaks in airway epithelial cells. This MOA seems independent of particle uptake and of an involvement of macrophages. Our study might help defining models for estimating exposure levels without DNA damaging effects.
Assuntos
Dano ao DNA , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Material Particulado/toxicidade , Dióxido de Silício/toxicidade , Animais , Linhagem Celular , Ensaio Cometa , Células Epiteliais , Inflamassomos , Pulmão , Macrófagos , Camundongos , Mutagênicos , Receptores Acoplados a Proteínas G , Mucosa RespiratóriaRESUMO
MOTIVATION: To understand the molecular mechanisms involved in cancer development, significant efforts are being invested in cancer research. This has resulted in millions of scientific articles. An efficient and thorough review of the existing literature is crucially important to drive new research. This time-demanding task can be supported by emerging computational approaches based on text mining which offer a great opportunity to organize and retrieve the desired information efficiently from sizable databases. One way to organize existing knowledge on cancer is to utilize the widely accepted framework of the Hallmarks of Cancer. These hallmarks refer to the alterations in cell behaviour that characterize the cancer cell. RESULTS: We created an extensive Hallmarks of Cancer taxonomy and developed automatic text mining methodology and a tool (CHAT) capable of retrieving and organizing millions of cancer-related references from PubMed into the taxonomy. The efficiency and accuracy of the tool was evaluated intrinsically as well as extrinsically by case studies. The correlations identified by the tool show that it offers a great potential to organize and correctly classify cancer-related literature. Furthermore, the tool can be useful, for example, in identifying hallmarks associated with extrinsic factors, biomarkers and therapeutics targets. AVAILABILITY AND IMPLEMENTATION: CHAT can be accessed at: http://chat.lionproject.net. The corpus of hallmark-annotated PubMed abstracts and the software are available at: http://chat.lionproject.net/about. CONTACT: simon.baker@cl.cam.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Neoplasias/classificação , Publicações/classificação , Software , Biomarcadores , Bases de Dados Factuais , Humanos , Reprodutibilidade dos Testes , Literatura de Revisão como AssuntoRESUMO
Toluene diisocyanate (TDI) is a reactive chemical used in manufacturing plastics. TDI exposure adversely affects workers' health, causing occupational asthma, but individuals differ in susceptibility. We recently suggested a role for signalling mediated by the enzyme autotaxin (ATX) and its product, lysophosphatidic acid (LPA), in TDI toxicity. Here we genotyped 118 TDI-exposed workers for six single-nucleotide polymorphisms (SNPs) in genes encoding proteins implicated in ATX-LPA signalling: purinergic receptor P2X7 (P2RX7), CC motif chemokine ligand 2 (CCL2), interleukin 1ß (IL1B), and caveolin 1 (CAV1). Two P2RX7 SNPs (rs208294 and rs2230911) significantly modified the associations between a biomarker of TDI exposure (urinary 2,4-toluene diamine) and plasma LPA; two IL1B SNPs (rs16944 and rs1143634) did not. CAV1 rs3807989 modified the associations, but the effect was not statistically significant (pâ¯=â¯0.05-0.09). In vitro, TDI-exposed bronchial epithelial cells (16HBE14o-) rapidly released ATX and IL-1ß. P2X7 inhibitors attenuated both responses, but confocal microscopy showed non-overlapping localizations of ATX and IL-1ß, and down-regulation of CAV1 inhibited the ATX response but not the IL-1ß response. This study indicates that P2X7 is pivotal for TDI-induced ATX-LPA signalling, which was modified by genetic variation in P2RX7. Furthermore, our data suggest that the TDI-induced ATX and IL-1ß responses occur independently.
Assuntos
Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/toxicidade , Adolescente , Adulto , Biomarcadores , Caveolina 1/efeitos dos fármacos , Caveolina 1/genética , Linhagem Celular , Indústria Química , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Interferente Pequeno/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/genética , Adulto JovemRESUMO
Silica exposure is a common risk factor for lung cancer. It has been claimed that key elements in cancer development are activation of inflammatory cells that indirectly induce DNA damage and proliferative stimuli in respiratory epithelial cells. We studied DNA damage induced by silica particles in respiratory epithelial cells and focused the role of the signaling enzyme autotaxin (ATX). A549 and 16 bronchial epithelial cells (16HBE) lung epithelial cells were exposed to silica particles. Reactive oxygen species (ROS), NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activation, ATX, ataxia telangiectasia mutated (ATM), and DNA damage (γH2AX, pCHK1, pCHK2, comet assay) were end points. Low doses of silica induced NLRP3 activation, DNA damage accumulation, and ATM phosphorylation. A novel finding was that ATM induced ATX generation and secretion. Not only silica but also rotenone, camptothecin and H2O2 activated ATX via ATM, suggesting that ATX is part of a generalized ATM response to double-strand breaks (DSBs). Surprisingly, ATX inhibition mitigated DNA damage accumulation at later time points (6-16 h), and ATX transfection caused NLRP3 activation and DNA damage. Furthermore, the product of ATX enzymatic activity, lysophosphatidic acid, recapitulated the effects of ATX transfection. These data indicate an ATM-ATX-dependent loop that propagates inflammation and DSB accumulation, making low doses of silica effective inducers of DSBs in epithelial cells. We conclude that an ATM-ATX axis interconnects DSBs with silica-induced inflammation and propagates these effects in epithelial cells. Further studies of this adverse outcome pathway may give an accurate assessment of the lowest doses of silica that causes cancer.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Inflamação/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Mucosa Respiratória/patologia , Dióxido de Silício/toxicidade , Linhagem Celular , Humanos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismoRESUMO
MOTIVATION: The hallmarks of cancer have become highly influential in cancer research. They reduce the complexity of cancer into 10 principles (e.g. resisting cell death and sustaining proliferative signaling) that explain the biological capabilities acquired during the development of human tumors. Since new research depends crucially on existing knowledge, technology for semantic classification of scientific literature according to the hallmarks of cancer could greatly support literature review, knowledge discovery and applications in cancer research. RESULTS: We present the first step toward the development of such technology. We introduce a corpus of 1499 PubMed abstracts annotated according to the scientific evidence they provide for the 10 currently known hallmarks of cancer. We use this corpus to train a system that classifies PubMed literature according to the hallmarks. The system uses supervised machine learning and rich features largely based on biomedical text mining. We report good performance in both intrinsic and extrinsic evaluations, demonstrating both the accuracy of the methodology and its potential in supporting practical cancer research. We discuss how this approach could be developed and applied further in the future. AVAILABILITY AND IMPLEMENTATION: The corpus of hallmark-annotated PubMed abstracts and the software for classification are available at: http://www.cl.cam.ac.uk/â¼sb895/HoC.html. CONTACT: simon.baker@cl.cam.ac.uk.
Assuntos
Indexação e Redação de Resumos/métodos , Algoritmos , Mineração de Dados/métodos , Neoplasias/classificação , Publicações Periódicas como Assunto , Semântica , Software , Pesquisa Biomédica , Biologia Computacional , Humanos , Neoplasias/patologia , PubMedRESUMO
Cancer is a leading cause of death worldwide and environmental factors, including chemicals, have been suggested as major etiological incitements. Cancer statistics indicates that men get more cancer than women. However, differences in the known risk factors including life style or occupational exposure only offer partial explanation. Using a text mining tool, we have investigated the scientific literature concerning male- and female-specific rat carcinogens that induced tumors only in one gender in NTP 2-year cancer bioassay. Our evaluation shows that oxidative stress, although frequently reported for both male- and female-specific rat carcinogens, was mentioned significantly more in literature concerning male-specific rat carcinogens. Literature analysis of testosterone and estradiol showed the same pattern. Tox21 high-throughput assay results, although showing only weak association of oxidative stress-related processes for male- and female-specific rat carcinogens, provide additional support. We also analyzed the literature concerning 26 established human carcinogens (IARC group 1). Oxidative stress was more frequently reported for the majority of these carcinogens, and the Tox21 data resembled that of male-specific rat carcinogens. Thus, our data, based on about 600000 scientific abstracts and Tox21 screening assays, suggest a link between male-specific carcinogens, testosterone and oxidative stress. This implies that a different cellular response to oxidative stress in men and women may be a critical factor in explaining the greater cancer susceptibility observed in men. Although the IARC carcinogens are classified as human carcinogens, their classification largely based on epidemiological evidence from male cohorts, which raises the question whether carcinogen classifications should be gender specific.
Assuntos
Carcinógenos/toxicidade , Neoplasias/genética , Estresse Oxidativo/efeitos dos fármacos , Caracteres Sexuais , Animais , Exposição Ambiental , Feminino , Humanos , Masculino , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Exposição Ocupacional , Ratos , Fatores de RiscoRESUMO
Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.
Assuntos
Carcinógenos/toxicidade , Dieta/efeitos adversos , Bifenilos Policlorados/toxicidade , Neoplasias da Próstata/genética , Idoso , Linhagem Celular Tumoral , Estudos de Coortes , Poluentes Ambientais/toxicidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Suécia/epidemiologiaRESUMO
Akt kinase controls cell survival, proliferation, and invasive growth and is a critical factor for cancer development. Here we describe a cross-talk between phosphatases that may preserve levels of activated/phosphorylated Akt and confer aggressive growth of cancer cells. In prostatic cancer cells, but not in non-transformed cells or in prostate stem cells, we found that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) overexpression down-regulated PH domain and leucine-rich repeat phosphatase (PHLPP) and that PHLPP overexpression down-regulated PTEN. We also show that silencing PTEN by siRNA increased the levels of PHLPPs. This cross-talk facilitated invasive migration and was mediated by epigenetic alterations, including activation of miR-190, miR-214, polycomb group of proteins, as well as DNA methylation. A role for the purinergic receptor P2X4, previously associated with wound healing, was indicated. We also show that TGF-ß1 induced cross-talk concomitant with epithelial-mesenchymal transition in stem cells. The cross-talk emerged as an integrated part of epithelial-mesenchymal transition. We conclude that cross-talk between PTEN and PHLPPs is silenced in normal prostate cells but activated in TGF-ß1 transformed prostate stem and cancer cells and facilitates invasive growth.
Assuntos
Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Neoplasias da Próstata/metabolismo , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Epigênese Genética , Humanos , Masculino , Neoplasias da Próstata/patologia , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo Real , Transcrição GênicaRESUMO
Diisocyanates are industrial chemicals which have a wide range of applications in developed and developing countries. They are notorious lung toxicants and respiratory sensitizers. However, the mechanisms behind their adverse effects are not adequately characterized. Autotaxin (ATX) is an enzyme producing lysophosphatidic acid (LPA), and the ATX-LPA axis has been implicated in lung related inflammatory conditions and diseases, including allergic asthma, but not to toxicity of environmental low-molecular-weight chemicals. We investigated effects of toluene diisocyanate (TDI) on ATX induction in human lung epithelial cell models, and we correlated LPA-levels in plasma to biomarkers of TDI exposure in urine collected from workers exposed to <5ppb (parts per billion). Information on workers' symptoms was collected through interviews. One nanomolar TDI robustly induced ATX release within 10min in vitro. A P2X7- and P2X4-dependent microvesicle formation was implicated in a rapid ATX release and a subsequent protein synthesis. Co-localization between purinergic receptors and ATX was documented by immunofluorescence and confocal microscopy. The release was modulated by monocyte chemoattractant protein-1 (MCP-1) and by extracellular ATP. In workers, we found a dose-response relationship between TDI exposure biomarkers in urine and LPA levels in plasma. Among symptomatic workers reporting "sneezing", the LPA levels were higher than among non-symptomatic workers. This is the first report indicating induction of the ATX-LPA axis by an environmental low-molecular-weight chemical, and our data suggest a role for the ATX-LPA axis in TDI toxicity.
Assuntos
Pneumopatias/induzido quimicamente , Pulmão/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Doenças Profissionais/induzido quimicamente , Diester Fosfórico Hidrolases/biossíntese , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Indução Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Humanos , Pulmão/enzimologia , Pulmão/fisiopatologia , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Lisofosfolipídeos/sangue , Lisofosfolipídeos/urina , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/diagnóstico , Doenças Profissionais/metabolismo , Exposição Ocupacional/efeitos adversos , Interferência de RNA , Receptores Purinérgicos P2X4/efeitos dos fármacos , Receptores Purinérgicos P2X4/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Suécia , Fatores de Tempo , Transfecção , Regulação para Cima , Adulto JovemRESUMO
Epidemiological studies indicate that statins, cholesterol-lowering drugs, prevent aggressive prostate cancer and other types of cancer. Employing essentially non-prostate cell lines, we previously showed that statins rapidly downregulate nuclear levels of phosphorylated Akt via P2X7, a purinergic receptor recently implicated in invasive growth. Here, we present studies on phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-positive prostatic cells. We document an involvement of EH domain-binding protein 1 (EHBP1), previously associated with aggressive prostate cancer and insulin-stimulated trafficking and cell migration, in P2X7 signaling. We also show that EHBP1 is essential for an anti-invasive effect of atorvastatin. Furthermore, EHBP1 interacted with P-Rex1, a guanine nucleotide exchange factor previously implicated in invasive growth. Mevalonate did not prevent this anti-invasive effect of atorvastatin. These data indicate that atorvastatin modulates invasiveness via P2X7, EHBP1 and P-Rex1. Interestingly, the interaction between EHBP1 and P-Rex1 was not induced by extracellular adenosine triphosphate (ATP), the endogenous P2X7 ligand, and statins counteracted invasiveness stimulated by extracellular ATP. In support of these experimental data, a population-based genetic analysis showed that a loss of function allele in the P2X7 gene (rs3751143) associated with non-aggressive cancer, and the common allele with aggressive cancer. Our data indicate a novel signaling pathway that inhibits invasiveness and that is druggable. Statins may reduce the risk of aggressive prostate cancer via P2X7 and by counteracting invasive effects of extracellular ATP.
Assuntos
Trifosfato de Adenosina/efeitos adversos , Proteínas de Transporte/metabolismo , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Pirróis/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Atorvastatina , Western Blotting , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Movimento Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Masculino , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Receptores Purinérgicos P2X7/química , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Rehabilitation after an anterior cruciate ligament (ACL) reconstruction requires patience, devotion, and discipline. Rehabilitation should be individualized to each patient's specific need and sport. Return to sport is a continuum throughout the rehabilitation, and patients should not return to performance before passing a battery of muscle function tests and patient-reported outcomes, as well as change of direction-specific tests. Return to full participation should be an agreement between the patient, physical therapist, surgeon, and coach. For minimal risk for second ACL injury, patients should continue with maintenance and prevention training even after returning to sport.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Traumatismos em Atletas , Volta ao Esporte , Humanos , Reconstrução do Ligamento Cruzado Anterior/reabilitação , Lesões do Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/reabilitação , Traumatismos em Atletas/cirurgia , Traumatismos em Atletas/reabilitação , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: The relationship between hamstring strength and hop performance after anterior cruciate ligament (ACL) reconstruction with hamstring tendon (HT) autografts has not been well elucidated. The aim was to investigate the relationship between eccentric hamstring strength, assessed with the NordBord, and concentric hamstring strength, assessed with the Biodex, with hop performance at 8 and 12 months after ACL reconstruction. METHODS: Registry study. Patients ≥ 16 years who had undergone primary ACL reconstruction with HT autograft, followed by muscle strength and hop tests at 8 and 12 months were included. Correlations of the relative hamstring strength (Nm/kg or N/kg) and limb symmetry index (LSI) with hop performance were analyzed. Pearson's correlation coefficient, and coefficient of determination (r2) were used for statistical analysis. RESULTS: A total of 90 patients were included, of which 48 (53%) were women. The mean age at ACL reconstruction was 27.0 ± 8.0 years. Relative hamstring strength had significant positive correlations with hop performance, ranging from r = 0.25-0.66, whereas hamstring strength LSI had significant positive correlations which ranged from r = 0.22-0.37 at 8 and 12 months after ACL reconstruction. At 12 months, the relative hamstring strength in the Biodex explained 32.5-43.6% of the hop performance in vertical hop height, hop for distance relative to height, and the total number of side hops, whereas the relative hamstring strength in the NordBord explained 15.2-23.0% of the hop performance. CONCLUSION: The relative hamstring strength in the Biodex test explained 32.5-43.6% of the hop performance, whereas the relative hamstring strength in the NordBord explained 15.2-23.0%. Thus, our findings suggest that relative hamstring strength, especially in the hip-flexed position may be a better indicator of hop performance at 8 and 12 months after ACL reconstruction in patients treated with HT autograft.
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BACKGROUND: It is unknown whether knee flexor strength recovers after anterior cruciate ligament (ACL) reconstruction with a hamstring tendon (HT) autograft and whether persistent knee flexor strength asymmetry is associated to a second ACL injury. OBJECTIVE: We aimed to systematically review (1) whether knee flexor strength recovers after ACL reconstruction with HT autografts, and (2) whether it influences the association with a second ACL injury. A third aim was to summarize the methodology used to assess knee flexor strength. DESIGN: Systematic review and meta-analysis reported according to PRISMA. METHODS: A systematic search was performed using the Cochrane Library, Embase, Medline, PEDRo, and AMED databases from inception to December 2021 and until completion in January 2023. Human clinical trials written in English and conducted as randomized controlled trials, longitudinal cohort, cross-sectional, and case-control studies on patients with index ACL reconstructions with HT autografts harvested from the ipsilateral side were considered. Knee flexor strength was measured isokinetically in both the reconstructed and uninjured limb to enable the calculation of the limb symmetry index (LSI). The Risk of Bias Assessment Tool for Non-Randomized Studies was used to assess risk of bias for non-randomized studies and the revised Cochrane Risk of Bias tool was used for randomized controlled trials. For the meta-analysis, the LSI (mean ± standard error) for concentric knee flexor strength at angular velocities of 60°/second (s) and 180°/s preoperatively and at 3 months, 6 months, 12 months, and 24 months were pooled as weighted means with standard errors. RESULTS: The search yielded 64 studies with a total of 8378 patients, which were included for the assessment of recovery of knee flexor strength LSI, and a total of 610 patients from four studies that investigated the association between knee flexor strength and second ACL injuries. At 1 year after ACL reconstruction, the knee flexor strength LSI had recovered to 89.0% (95% CI 87.3; 90.7%) and 88.3% (95% CI 85.5; 91.1%) for the velocities of 60°/s and 180°/s, respectively. At 2 years, the LSI was 91.7% (95% CI 90.8; 92.6%) and 91.2% (95% CI 88.1; 94.2%), for velocities of 60°/s and 180°/s, respectively. For the association between knee flexor strength and second ACL injuries, there was insufficient and contradictory data. CONCLUSIONS: There was low to very low certainty of evidence indicating that the recovery of knee flexor strength LSI, defined as ≥ 90% of the uninjured side, takes up to 2 years after ACL reconstruction with HT autografts. Whether knee flexor strength deficits influence the association of second ACL injuries is still uncertain. There was considerable heterogeneity in the methodology used for knee flexor strength assessment, which together with the low to very low certainty of evidence, warrants further caution in the interpretation of our results. REGISTRATION NUMBER: CRD42022286773.
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OBJECTIVE: Comparison of knee flexor strength limb symmetry index (LSI) between the NordBord-test and the Biodex-test, and to determine the relationship between knee flexor strength and function in patients 2 and 5 years after anterior cruciate ligament reconstruction (ACL-R) with hamstring tendon (HT) autografts. DESIGN: Observational registry study. SETTING: Primary care. PATIENTS: Cross-sectional data from 96 patients (55% women) participating in a rehabilitation-registry after ACL-R with HT autografts. MAIN OUTCOME MEASURES: Comparison of knee flexor strength symmetry between the Biodex-test and the NordBord-test. Secondly, the relationship between knee flexor strength test and perceived knee function, activity level, and hop performance. RESULTS: The NordBord-test demonstrated greater strength deficits compared to the Biodex-test with a mean difference of 12.5% ± 15.1% 95 % CI [8.1; 16.9%] at 2 years, and 11.1% ± 11.9% 95 % CI [7.7; 14.6 %] at 5 years after ACL-R. Relative concentric knee flexor strength (Nm/kg) in the Biodex demonstrated significant weak-to-moderate correlations with activity level and hop performance (r = 0.33-0.67) at 2 and 5 years. CONCLUSION: The NordBord-test identified deficits in knee flexor strength LSI not seen with the Biodex-test at 2 and 5 years after ACL-R. No significant correlations were found between the persistent knee flexor strength asymmetry and perceived function, activity level or hop performance.
Assuntos
Lesões do Ligamento Cruzado Anterior , Tendões dos Músculos Isquiotibiais , Humanos , Feminino , Masculino , Tendões dos Músculos Isquiotibiais/transplante , Autoenxertos , Estudos Transversais , Lesões do Ligamento Cruzado Anterior/cirurgia , Articulação do Joelho , Força MuscularRESUMO
BACKGROUND: The stress on the anterior cruciate ligament (ACL) induced by the quadriceps can be attenuated by activation of the hamstrings by exerting an opposing torque to the anterior translation of tibia. Consequently, considering the ratio between strength of the hamstrings-to-quadriceps (HQ-ratio) may be of value to reduce the odds of second ACL injuries. The objective was therefore to evaluate (1) the association between HQ-ratio and the occurrence of a second ACL injury in patients after ACL-reconstruction within 2 years of return to preinjury sport level and (2) to compare the HQ-ratio between males and females after ACL reconstruction. METHODS: Patients who had undergone primary ACL reconstruction and participated in knee-strenuous activity preinjury were included. Demographics, the occurrence of a second ACL injury, and muscle strength test results before returning to preinjury sport level were extracted from a rehabilitation registry. The endpoint was set at a second ACL injury or 2 years after return to preinjury sport level. A multivariable logistic regression was used to analyze the association between the HQ-ratio and a second ACL injury. RESULTS: A total of 574 patients (50.0% female) with a mean age of 24.0 ± 9.4 years at primary ACL reconstruction were included. In the univariable logistic regression analysis, the odds of sustaining a second ACL injury decreased by 3% for every 1% increase in the HQ-ratio (OR 0.97 [95% CI 0.95-1.00], p = 0.025). After adjusting for the time from reconstruction to return to preinjury sport level, sex, preinjury sport level, graft choice, age, and body mass index, the results were no longer significant (OR 0.98 [95% CI 0.95-1.01], p = 0.16). Females had a higher HQ-ratio compared with males for both the ACL-reconstructed and uninjured side (3.7% [95% CI 5.7; 1.8%], p = 0.0002 and 3.3% [95% CI 4.6; 2.1], p < 0.001, respectively). CONCLUSION: The HQ-ratio did not significantly affect the odds for sustaining a second ACL injury upon return to preinjury sports level after primary ACL reconstruction. Females had a significant higher HQ-ratio than males for both the ACL reconstructed and uninjured side.