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Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Espondilartrite/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Estudo de Associação Genômica Ampla , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Espondilartrite/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system. METHODS: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel. RESULTS: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified. CONCLUSIONS: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.
Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Neoplasias/genética , Neoplasias/genética , DNA de Neoplasias/análise , Feminino , Humanos , Estudos Longitudinais , Masculino , Mutação , Estudos ProspectivosRESUMO
Polarization-resolved terahertz (THz) time-domain spectroscopy was utilized to examine the complex refractive index of lanthanum aluminate (LaAlO3), a rhombohedrally distorted perovskite that exhibits crystallographic twin domains. The uniaxial anisotropy of the refractive index was quantified. The ellipticity of THz radiation pulses after transmission through single domains indicated that LaAlO3 can be used as a quarter- or half-wave plate. The effective anisotropy of [001]-oriented LaAlO3 was found to be reduced when the material exhibited multiple, narrow twin domains.
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OBJECTIVE: Referral of movement disorder patients for deep brain stimulation surgery was examined to determine whether referred patients were representative of gender proportions in our population, and reasons why patients do not proceed to surgery. METHODS: Demographic information on referrals to the surgical program was retrospectively reviewed from our database and from a detailed chart review. RESULTS: Although almost equal numbers of movement disorder patients are male and female, of the 91 patients referred for surgery, only 31% were female. Sixty-one percent of referred patients did not undergo surgery. Of these, the majority were denied for medical reasons, including cognitive decline (21%), psychiatric concerns (5%) and neurological reasons (42%). CONCLUSIONS: Almost one-third of patients referred for movement disorder surgery were denied for medical reasons. This underscores the importance of evaluation of all potential patients by a multidisiplinary team to fully assess suitablity for stereotactic surgery. Interestingly, women were under-represented in those referred. In order that all appropriate patients have the opportunity to consider surgery, education of both physicians and patients, and different strategies to approach females regarding surgery may allow more patients to benefit from this treatment.
Assuntos
Estimulação Encefálica Profunda , Transtornos dos Movimentos/terapia , Preconceito , Encaminhamento e Consulta , Recusa em Tratar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Prática Profissional , Encaminhamento e Consulta/normas , Sistema de Registros , Fatores SexuaisRESUMO
OBJECTIVE: To examine the validity of the Child Development Inventory (CDI) compared with other commonly used measures of developmental outcomes in high-risk infants. STUDY DESIGN: Primary caregivers of 63 toddlers and preschoolers enrolled at a routine neonatal high-risk follow-up clinic completed a CDI describing their children. Only those with successfully completed CDIs were included in the analysis (n = 43). The CDI General Development Developmental Quotient was compared with the Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS) and the Bayley Scales of Infant Development, 2nd Edition (BSID-II). RESULTS: Significant correlations were found between the CDI, the CAT/CLAMS (r =.87, P <.001), and the BSID-II (r =.86, P <.001). There were no significant correlations between the CDI and parent education and income. Findings revealed high sensitivity (80% to 100%) and specificity (94% to 96%) for the CDI. CONCLUSION: The CDI appears to be a useful and cost-effective screening measure for determining developmental outcomes among high-risk infants.