RESUMO
Xeroderma pigmentosum group D (XPD) helicase is a component of the transcription factor IIH (TFIIH) transcription complex and plays essential roles in transcription and nucleotide excision repair. Although iron-sulfur (Fe-S) cluster binding by XPD is required for activity, the process mediating Fe-S cluster assembly remains poorly understood. We recently identified a cytoplasmic Fe-S cluster assembly (CIA) targeting complex composed of MMS19, CIAO1, and FAM96B that is required for the biogenesis of extramitochondrial Fe-S proteins including XPD. Here, we use XPD as a prototypical Fe-S protein to further characterize how Fe-S assembly is facilitated by the CIA targeting complex. Multiple lines of evidence indicate that this process occurs in a stepwise fashion in which XPD acquires a Fe-S cluster from the CIA targeting complex before assembling into TFIIH. First, XPD was found to associate in a mutually exclusive fashion with either TFIIH or the CIA targeting complex. Second, disrupting Fe-S cluster assembly on XPD by either 1) depleting cellular iron levels or 2) utilizing XPD mutants defective in either Fe-S cluster or CIA targeting complex binding blocks Fe-S cluster assembly and prevents XPD incorporation into TFIIH. Finally, subcellular fractionation studies indicate that the association of XPD with the CIA targeting complex occurs in the cytoplasm, whereas its association with TFIIH occurs largely in the nucleus where TFIIH functions. Together, these data establish a sequential assembly process for Fe-S assembly on XPD and highlight the existence of quality control mechanisms that prevent the incorporation of immature apoproteins into their cellular complexes.
Assuntos
Proteínas Ferro-Enxofre/metabolismo , Fator de Transcrição TFIIH/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo , Sítios de Ligação , Núcleo Celular/metabolismo , Citoplasma/metabolismo , DNA/química , DNA Helicases/metabolismo , Reparo do DNA , Células HeLa , Humanos , Ferro/química , Mitocôndrias/metabolismo , Ligação Proteica , Proteômica , Frações Subcelulares/metabolismo , Enxofre/químicaRESUMO
Play spaces are important components of paediatric healthcare environments. They provide children with critical opportunities to experience the social, emotional, and developmental benefits of play while in healthcare settings for appointments or hospitalizations. These spaces can help to mitigate stress, provide a sense of normalcy in unfamiliar environments, and facilitate social engagement for children and their families. Given the benefits of play spaces in paediatric healthcare settings, it is important to understand how these spaces can be designed to enhance children's inclusion and quality of care. The aim of this scoping review was to explore the current understanding of paediatric play space design. Using search terms related to children, health care, and play space, six interdisciplinary databases were searched over a 30-year period. The search found 2,533 records from which eighteen were included for review. Findings suggest that although it is well-documented that play spaces offer valuable social and emotional benefits, little is known about the specific design features that can and should be incorporated to enhance play opportunities and ensure that they benefit all children and families. Further, the literature mostly considers play spaces in the context of designated play or recreational rooms. Scholars are encouraged to consider how play opportunities can be incorporated into the designs of paediatric healthcare environments beyond the boundaries of these rooms. Future studies should also consider the diversity of play space users, including children of varying ages and abilities, to create more accessible and inclusive paediatric play spaces for children and their families. Advancing knowledge on play space design can help to optimize the quality of these important spaces and to ensure their designs meaningfully enhance children's play experiences and quality of care.
RESUMO
BACKGROUND: Some children with disabilities (CWD) frequently visit pediatric healthcare settings for appointments. Their age, disability, and regular visits mean that they have unique experiences in healthcare settings. While previous research has explored the clinical experiences of CWD, little is known about their experiences of pediatric healthcare built environments, even though these environments may play an important role in shaping their perceptions of care. Given the significant time that some CWD and chronic illnesses (e.g., cancer) spend in healthcare environments and the impact that these settings can have on their experiences, the knowledge gap concerning how they view, and experience healthcare built environments demands attention. OBJECTIVE: To explore how CWD and their families experience pediatric healthcare built environments. METHODS: A scoping review was conducted by searching five health science and interdisciplinary literature databases using terms related to children, disability, healthcare, and built environment. The search identified 5,397 records that were screened independently by three reviewers. RESULTS: Nineteen studies met inclusion criteria and were considered in the final review. Findings indicate that CWD and their families value healthcare built environment features that support social engagement, patient privacy, and parental presence. Further, the age of a child was highlighted as an important factor that influences the built environment preferences of CWD. CONCLUSIONS: CWD and their families prefer certain healthcare built environment features to optimize their experiences in these settings. Healthcare designers can leverage these findings to advance more inclusive pediatric healthcare spaces to improve care and the quality of life for CWD and their families.
Assuntos
Ambiente Construído , Crianças com Deficiência , Humanos , Crianças com Deficiência/psicologia , Criança , Família/psicologia , Pais/psicologia , Privacidade , Preferência do PacienteRESUMO
BACKGROUND: Heart failure (HF) readmission rates are low in some jurisdictions. However, international comparisons are lacking and could serve as a foundation for identifying regional patient management strategies that could be shared to improve outcomes. OBJECTIVES: This study sought to summarize 30-day and 1-year all-cause readmission and mortality rates of hospitalized HF patients across countries and to explore potential differences in rates globally. METHODS: We performed a systematic review and meta-analysis using MEDLINE, Embase, and CENTRAL for observational reports on hospitalized adult HF patients at risk for readmission or mortality published between January 2010 and March 2021. We conducted a meta-analysis of proportions using a random-effects model, and sources of heterogeneity were evaluated with meta-regression. RESULTS: In total, 24 papers reporting on 30-day and 23 papers on 1-year readmission were included. Of the 1.5 million individuals at risk, 13.2% (95% CI: 10.5%-16.1%) were readmitted within 30 days and 35.7% (95% CI: 27.1%-44.9%) within 1 year. A total of 33 papers reported on 30-day and 45 papers on 1-year mortality. Of the 1.5 million individuals hospitalized for HF, 7.6% (95% CI: 6.1%-9.3%) died within 30 days and 23.3% (95% CI: 20.8%-25.9%) died within 1 year. Substantial variation in risk across countries was unexplained by countries' gross domestic product, proportion of gross domestic product spent on health care, and Gini coefficient. CONCLUSIONS: Globally, hospitalized HF patients exhibit high rates of readmission and mortality, and the variability in readmission rates was not explained by health care expenditure, risk of mortality, or comorbidities.
Assuntos
Insuficiência Cardíaca , Readmissão do Paciente , Adulto , Humanos , Comorbidade , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Morte , HospitalizaçãoRESUMO
Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell-inflamed, stromal adaptations, many of which are tumor cell-driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248-65. ©2017 AACR.See related commentary by Haq, p. 1216This article is highlighted in the In This Issue feature, p. 1201.
Assuntos
Melanoma Experimental/tratamento farmacológico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Transcriptoma/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indóis/administração & dosagem , Antígenos Comuns de Leucócito/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , Melanoma/genética , Melanoma/patologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Transcriptoma/efeitos dos fármacosRESUMO
Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. (V600E)BRAF, expressed at supraphysiological levels because of (V600E)BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed (V600E)BRAF via a regulatory interface at R662 of (V600E)BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/patologia , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRß), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.