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Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.
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Malária Cerebral , Camundongos , Humanos , Animais , Malária Cerebral/patologia , Malária Cerebral/prevenção & controle , Células Endoteliais/patologia , Encéfalo/patologia , Barreira Hematoencefálica/patologia , Linfócitos T CD8-Positivos , Endotélio/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
The objective of this study was to examine the impact of methodological changes to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score on associations with risk for all-cause mortality, cancer mortality, and cancer risk jointly among older adults in the National Institutes of Health (NIH)-AARP Diet and Health Study. Weights were incorporated for each score component; a continuous point scale was developed in place of the score's fully discrete cut points; and cut-point values were changed for physical activity and red meat based on evidence-based recommendations. Exploratory aims also examined the impact of separating components with more than one subcomponent and whether all components were necessary to retain within this population utilizing a penalized scoring approach. Findings suggested weighting the original 2018 WCRF/AICR Score improved its predictive performance in association with all-cause mortality and provided more precise estimates in relation to cancer risk and mortality outcomes. The importance of healthy weight, physical activity, and plant-based foods in relation to cancer and overall mortality risk were highlighted in this population of older adults. Further studies are needed to better understand the consistency and generalizability of these findings across other populations.
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Exercício Físico , Neoplasias , Humanos , Neoplasias/mortalidade , Neoplasias/epidemiologia , Masculino , Estados Unidos/epidemiologia , Feminino , Idoso , Pessoa de Meia-Idade , Fatores de Risco , Dieta/estatística & dados numéricos , Medição de Risco/métodos , Causas de MorteRESUMO
BACKGROUND: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. PATIENTS AND METHODS: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. RESULTS: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. CONCLUSIONS: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. CLINICALTRIALS: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).
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Nuclear Factor of Activated T cells 5 (NFAT5) is a transcription factor (TF) that mediates protection from adverse effects of hypertonicity by increasing transcription of genes, including those that lead to cellular accumulation of protective organic osmolytes. NFAT5 has three intrinsically ordered (ID) activation domains (ADs). Using the NFAT5 N-terminal domain (NTD), which contains AD1, as a model, we demonstrate by biophysical methods that the NTD senses osmolytes and hypertonicity, resulting in stabilization of its ID regions. In the presence of sufficient NaCl or osmolytes, trehalose and sorbitol, the NFAT5 NTD undergoes a disorder-to-order shift, adopting higher average secondary and tertiary structure. Thus, NFAT5 is activated by the stress that it protects against. In its salt and/or osmolyte-induced more ordered conformation, the NTD interacts with several proteins, including HMGI-C, which is known to protect against apoptosis. These findings raise the possibility that the increased intracellular ionic strength and elevated osmolytes caused by hypertonicity activate and stabilize NFAT5.
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Proteínas Intrinsicamente Desordenadas/química , Fatores de Transcrição/química , Escherichia coli/metabolismo , Pressão Osmótica , Ligação Proteica , Dobramento de Proteína , Cloreto de Sódio , Sorbitol , Fatores de Transcrição/metabolismo , TrealoseRESUMO
BACKGROUND: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. METHODS: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. RESULTS: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. CONCLUSIONS: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.
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Neoplasias da Mama , Glândulas Mamárias Humanas , Inteligência Artificial , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Glândulas Mamárias Humanas/patologia , Paridade , GravidezRESUMO
We develop a generalized partially additive model to build a single semiparametric risk scoring system for physical activity across multiple populations. A score comprised of distinct and objective physical activity measures is a new concept that offers challenges due to the nonlinear relationship between physical behaviors and various health outcomes. We overcome these challenges by modeling each score component as a smooth term, an extension of generalized partially linear single-index models. We use penalized splines and propose two inferential methods, one using profile likelihood and a nonparametric bootstrap, the other using a full Bayesian model, to solve additional computational problems. Both methods exhibit similar and accurate performance in simulations. These models are applied to the National Health and Nutrition Examination Survey and quantify nonlinear and interpretable shapes of score components for all-cause mortality.
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Exercício Físico , Modelos Estatísticos , Teorema de Bayes , Humanos , Modelos Lineares , Inquéritos Nutricionais , Fatores de RiscoRESUMO
Tumor susceptibility gene 101 (TSG101) is involved in endosomal maturation and has been implicated in the transcriptional regulation of several steroid hormone receptors, although a detailed characterization of such regulation has yet to be conducted. Here we directly measure binding of TSG101 to one steroid hormone receptor, the glucocorticoid receptor (GR). Using biophysical and cellular assays, we show that the coiled-coil domain of TSG101 (1) binds and folds the disordered N-terminal domain of the GR, (2) upon binding improves the DNA binding of the GR in vitro, and (3) enhances the transcriptional activity of the GR in vivo. Our findings suggest that TSG101 is a bona fide transcriptional co-regulator of the GR and reveal how the underlying thermodynamics affect the function of the GR.
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Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/fisiologia , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Proteínas de Ligação a DNA/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Endossomos/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Células HeLa , Humanos , Ligação Proteica , Domínios Proteicos/fisiologia , Elementos Reguladores de Transcrição/fisiologia , Fatores de Transcrição/genética , Transcrição Gênica/genética , Ativação Transcricional/genéticaRESUMO
Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias de Mama Triplo Negativas/patologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Gestão de Riscos , Neoplasias de Mama Triplo Negativas/imunologiaRESUMO
OBJECTIVES: Systems leadership is widely acknowledged to be needed to address the many 'wicked issues' challenging public health systems. However, there is a lack of evidence on how to develop public health professionals into effective systems leaders. This study scoped the possibilities for developing the systems leadership capacity of public health specialists in England. STUDY DESIGN: This was a mixed-methods qualitative scoping study design. METHODS: The study involved three stages. In the first, a rapid literature review mapped key documents in three relevant areas: systems leadership theory and practice, the changing context of public health in the UK, and training and development for UK public health professionals. In the second, 29 stakeholders were consulted to understand the context and needs for systems leadership development in public health. A third phase involved stakeholders codesigning a potential development framework for the project commissioners. RESULTS: Four main themes were identified: the nature and purpose of systems leadership; development needs and opportunities for public health specialists; the enabling environment; and wider contextual factors impacting public health. CONCLUSIONS: Key principles of, and a framework for, a systems leadership development approach are identified, which could be applied to any public health system.
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Liderança , Saúde Pública , Inglaterra , Pessoal de Saúde , HumanosRESUMO
OBJECTIVES: Although general principles related to vaccination hesitancy have been well researched, reports on reluctance to be vaccinated for coronavirus disease 2019 (COVID-19) in the United States are somewhat surprising, given the disease's substantive disruption of everyday life. However, the landscape in which people are making COVID-19 vaccination decisions has recently evolved with releases of encouraging vaccine-related data and changes to official messaging about the virus. Therefore, this study sought to identify factors associated with reported likelihood to get vaccinated for COVID-19 among US adults in late January 2021. STUDY DESIGN: We used the Prolific online research panel to survey a nationally representative sample of 1017 US adults. METHODS: Respondents were asked about their behavioral intentions toward COVID-19 vaccination, trust in science, perceptions related to COVID-19, and selected sociodemographic factors. We computed associations between those 11 independent variables and likelihood to get vaccinated for COVID-19 using multiple linear regression. RESULTS: Around 73.9% of respondents indicated at least some likelihood to get vaccinated for COVID-19. Trust in science and perceived seriousness of COVID-19 were positively associated with intention to get vaccinated, and identifying as Black or African American was negatively associated with intention to get vaccinated. Other factors were moderately, weakly, or not at all associated with intention. CONCLUSIONS: Building trust in science and truthfully emphasizing the seriousness of catching COVID-19 should be further researched for their potential to support campaigns to encourage COVID-19 vaccination. Data continue to suggest the importance of dialogue with Black communities about COVID-19 vaccination.
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Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Intenção , SARS-CoV-2 , Inquéritos e Questionários , Estados Unidos , VacinaçãoRESUMO
Mapping connections in the neonatal brain can provide insight into the crucial early stages of neurodevelopment that shape brain organisation and lay the foundations for cognition and behaviour. Diffusion MRI and tractography provide unique opportunities for such explorations, through estimation of white matter bundles and brain connectivity. Atlas-based tractography protocols, i.e. a priori defined sets of masks and logical operations in a template space, have been commonly used in the adult brain to drive such explorations. However, rapid growth and maturation of the brain during early development make it challenging to ensure correspondence and validity of such atlas-based tractography approaches in the developing brain. An alternative can be provided by data-driven methods, which do not depend on predefined regions of interest. Here, we develop a novel data-driven framework to extract white matter bundles and their associated grey matter networks from neonatal tractography data, based on non-negative matrix factorisation that is inherently suited to the non-negative nature of structural connectivity data. We also develop a non-negative dual regression framework to map group-level components to individual subjects. Using in-silico simulations, we evaluate the accuracy of our approach in extracting connectivity components and compare with an alternative data-driven method, independent component analysis. We apply non-negative matrix factorisation to whole-brain connectivity obtained from publicly available datasets from the Developing Human Connectome Project, yielding grey matter components and their corresponding white matter bundles. We assess the validity and interpretability of these components against traditional tractography results and grey matter networks obtained from resting-state fMRI in the same subjects. We subsequently use them to generate a parcellation of the neonatal cortex using data from 323 new-born babies and we assess the robustness and reproducibility of this connectivity-driven parcellation.
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Mapeamento Encefálico , Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Algoritmos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Recém-Nascido , Masculino , Reprodutibilidade dos Testes , Substância Branca/crescimento & desenvolvimentoRESUMO
Increasing data support the importance of preexisting host immune response and neoantigen burden for determining response to immune checkpoint inhibitors (ICIs). In lung cancer and melanoma, tumor mutational burden (TMB) has emerged as an independent biomarker for ICI response. However, the significance of TMB in breast cancer, particularly in the context of PD-L1 negativity, remains unclear. This report describes a patient with HER2-negative breast cancer with high TMB and an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) trinucleotide signature; her disease was refractory to multiple lines of treatments but achieved durable complete response using ICIs and capecitabine. Additional analysis of the tumor revealed a low amount of stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 negativity, reflecting a poor preexisting host immune response. In collaboration with Foundation Medicine, comprehensive genomic profiling from 14,867 patients with breast cancer with the FoundationOne test was evaluated. Using the cutoff of ≥10 mutations/megabase (mut/Mb) for high TMB, PD-L1 positivity and TMB-high populations were not significantly overlapping (odds ratio, 1.02; P=.87). Up to 79% of TMB-high tumors with >20 mut/Mb were PD-L1-negative. Our study highlights that despite having low TILs and PD-L1 negativity, some patients may still experience response to ICIs.
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Neoplasias da Mama/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , MutaçãoRESUMO
Convective transport is an important phenomenon for nanomedicine delivery. We present an imaging-based approach to recover tissue properties that are significant in the accumulation of nanoparticles delivered via systemic methods. The classical pharmacokinetic analysis develops governing equations for the particle transport from a first principle mass balance. Fundamentally, the governing equations for compartmental mass balance represent a spatially invariant mass transport between compartments and do not capture spatially variant convection phenomena. Further, the parameters recovered from this approach do not necessarily have direct meaning with respect to the governing equations for convective transport. In our approach, a framework is presented for directly measuring permeability in the sense of Darcy flow through porous tissue. Measurements from our approach are compared to an extended Tofts model as a control. We demonstrate that a pixel-wise iterative clustering algorithm may be applied to reduce the parameter space of the measurements. We show that measurements obtained from our approach are correlated with measurements obtained from the extended Tofts model control. These correlations demonstrate that the proposed approach contains similar information to an established compartmental model and may be useful in providing an alternative theoretical framework for parameterizing mathematical models for treatment planning and diagnostic studies involving nanomedicine where convection dominated effects are important.
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Convecção , Nanopartículas , Algoritmos , Modelos Teóricos , PorosidadeRESUMO
Aureobasidium pullulans is used as a biocontrol agent for fire blight protection in organic apple and pear production. We assessed colonization of pome flowers by A. pullulans in orchards located near Corvallis, OR and Wenatchee, WA. Blossom Protect, a mix of A. pullulans strains CF10 and CF40, and its citrate-based companion, Buffer Protect, were sprayed at 70% bloom. Later in bloom, the population size of putative A. pullulans on flowers was estimated by dilution plating; plate scrapings of putative A. pullulans were then sampled and subjected to a PCR analysis. Sequenced PCR amplicons of the internal transcribed spacer region and the elongase gene confirmed the presence of A. pullulans, whereas a multiplex PCR with primers specific to CF10 and CF40 was used to determine the presence of the introduced strains. At Corvallis, a wet spring environment, A. pullulans, was recovered from most (>90%) Bartlett pear and Golden Delicious apple flowers sampled from experimental trees, regardless of whether the trees were treated with Blossom Protect. Nevertheless, population size estimates of A. pullulans on the flowers were correlated with the number of times Blossom Protect was sprayed on the trees. At Wenatchee, an arid spring environment, A. pullulans was detected on most flowers from trees treated with Blossom Protect, but only on a minority of flowers from nontreated controls. In both locations, the combined incidence of strains CF10 and CF40 on flowers averaged 89% on Blossom Protect-treated trees, but only 27% on adjacent, nontreated trees. During subsequent trials, the efficacy of Blossom Protect for fire blight control was compared with alternative yeast isolates, with each applied with Buffer Protect; local isolates of A. pullulans and Cryptococcus neoformans and a postharvest biocontrol strain of Cystofilobasidium infirmominiatum were used All yeast strains suppressed fire blight to a degree; however, in each of four trials, the level of suppression was highest with Blossom Protect, and it was significantly superior (P ≤ 0.05) to other yeast isolates in two of the trials. Because A. pullulans strains CF10 and CF40 were detected primarily on flowers on trees treated with Blossom Protect, and because they were detected much less frequently on nearby nontreated tress, we recommend treating every tree row with Blossom Protect at least once for organic fire blight suppression.
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Ascomicetos , Frutas , Malus , Pyrus , Ascomicetos/genética , Ascomicetos/crescimento & desenvolvimento , DNA Fúngico/genética , Frutas/microbiologia , Malus/microbiologia , Interações Microbianas , Doenças das Plantas/microbiologia , Reação em Cadeia da Polimerase , Pyrus/microbiologiaRESUMO
Aims To investigate whether pathological fractures impact on osteosarcoma patient prognosis in Ireland. Methods This was a retrospective study over 22 years in a National Orthopaedic Oncology Centre. There were 117 nonfracture cases and 15 fracture cases. Outcome measures included 5 and 10 year event-free (EFS) and overall survival (OS). Kaplan-Meier curves assessed length of survival and time to death. Results Pathological fracture has no significant effect on 10 year EFS or 10 year OS. 3 factors strongly associate with 10 year OS rates: American Joint Committee on Cancer (AJCC) classification (p<0.001), Metastases site (p<0.001) and Distant recurrence (p<0.001). Fractures had poorer post-chemotherapeutic necrosis rates (p=0.005). Conclusion Pathological fractures have no significant effect on survival rates or length of survival in an Irish population. The effect of pathological fractures on necrosis rates must be explored in future research.
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Neoplasias Ósseas/complicações , Neoplasias Ósseas/mortalidade , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/mortalidade , Osteossarcoma/complicações , Osteossarcoma/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Criança , Estudos de Coortes , Feminino , Humanos , Irlanda/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/epidemiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
One-Session Treatment is a well-established evidence-based treatment for specific phobias in youths that incorporates reinforcement, cognitive challenges, participant modeling, psychoeducation, and skills training into a single, massed session of graduated exposure. This review begins by briefly examining the phenomenology, etiology, epidemiology, and assessment of specific phobias and then pivots to a description of One-Session Treatment. We examine the use of One-Session Treatment with children and adolescents, briefly discussing its components and application, and subsequently review almost two decades of research supporting its efficacy. Finally, we propose future directions for research and practice.
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Terapia Cognitivo-Comportamental , Terapia Implosiva , Avaliação de Processos e Resultados em Cuidados de Saúde , Transtornos Fóbicos/terapia , Psicoterapia Breve , Adolescente , Criança , Humanos , Transtornos Fóbicos/diagnóstico , Transtornos Fóbicos/etiologia , Transtornos Fóbicos/fisiopatologiaRESUMO
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
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Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Pulmão/patologia , Adulto , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Viabilidade , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Pulmão/imunologia , Pulmão/cirurgia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante/métodos , Neoplasia Residual , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Pneumonectomia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
BACKGROUND: A significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation. METHODS: In phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1-5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them. RESULTS: In phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1-3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function. CONCLUSION: NMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.
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Seleção do Doador , Transplante de Rim , Rim/irrigação sanguínea , Preservação de Órgãos/métodos , Perfusão/métodos , Adulto , Idoso , Morte , Feminino , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , TemperaturaRESUMO
BACKGROUND: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events. METHODS: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information. RESULTS: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation. CONCLUSION: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events.
Assuntos
Neoplasias da Mama/genética , Cromotripsia , Amplificação de Genes , Receptor ErbB-2/genética , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Cromossomos Humanos Par 17 , Estudos de Coortes , Feminino , Humanos , Estadiamento de Neoplasias , Receptor ErbB-2/análiseRESUMO
BACKGROUND: Self-report instruments are commonly used to assess for childhood depressive symptoms. Historically, clinicians have relied heavily on parent-reports due to concerns about childrens' cognitive abilities to understand diagnostic questions. However, parents may also be unreliable reporters due to a lack of understanding of their child's symptomatology, overshadowing by their own problems, and tendencies to promote themselves more favourably in order to achieve desired assessment goals. One such variable that can lead to unreliable reporting is impression management, which is a goal-directed response in which an individual (e.g. mother or father) attempts to represent themselves, or their child, in a socially desirable way to the observer. AIMS: This study examined the relationship between mothers who engage in impression management, as measured by the Parenting Stress Index-Short Form defensive responding subscale, and parent-/child-self-reports of depressive symptomatology in 106 mother-child dyads. METHODS: 106 clinic-referred children (mean child age = 10.06 years, range 7-16 years) were administered the Child Depression Inventory, and mothers (mean mother age = 40.80 years, range 27-57 years) were administered the Child-Behavior Checklist, Parenting Stress Index-Short Form, and Symptom Checklist-90-Revised. RESULTS: As predicted, mothers who engaged in impression management under-reported their child's symptomatology on the anxious/depressed and withdrawn subscales of the Child Behavior Checklist. Moreover, the relationship between maternal-reported child depressive symptoms and child-reported depressive symptoms was moderated by impression management. CONCLUSIONS: These results suggest that children may be more reliable reporters of their own depressive symptomatology when mothers are highly defensive or stressed.