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1.
Brain ; 146(3): 850-857, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36315647

RESUMO

Early infantile developmental and epileptic encephalopathies are devastating conditions, generally of genetic origin, but the pathological mechanisms often remain obscure. A major obstacle in this field of research is the difficulty of studying cortical brain development in humans, at the relevant time period in utero. To address this, we established an in vitro assay to study the impact of gene variants on the developing human brain by using living organotypic cultures of the human subplate and neighbouring cortical regions, prepared from ethically sourced, 14-17 post-conception week brain tissue (www.hdbr.org). We were able to maintain cultures for several months, during which time the gross anatomical structures of the cortical plate, subplate and marginal zone persisted, while neurons continued to develop morphologically and form new synaptic networks. This preparation thus permits the study of genetic manipulations and their downstream effects on an intact developing human cortical network. We focused on STXBP1 haploinsufficiency, which is among the most common genetic causes of developmental and epileptic encephalopathy. This was induced using shRNA interference, leading to impaired synaptic function and a reduced density of glutamatergic synapses. We thereby provide a critical proof-of-principle for how to study the impact of any gene of interest on the development of the human cortex.


Assuntos
Encefalopatias , Epilepsia Generalizada , Humanos , Neurônios/metabolismo , Sinapses/metabolismo , Encéfalo/metabolismo , Proteínas Munc18/genética
2.
BMC Pregnancy Childbirth ; 23(1): 444, 2023 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-37316792

RESUMO

BACKGROUND: Disrespect and abuse violates women's basic human rights and autonomy and can traumatize women who are already in a vulnerable position during childbirth and deter them from utilizing skilled care for future childbirth. This study explored women's perspectives on the acceptability of disrespect and abuse during facility-based childbirth in Ethiopia. METHODS: A qualitative descriptive design using five focus group discussions and fifteen in-depth, semi-structured, interviews was conducted with women between October 2019 to January 2020 in north Showa zone of Oromia region, central Ethiopia. Using purposive sampling, women who had given birth at public health facilities of North Showa zone during the twelve months preceding data collection were recruited, regardless of birth outcome. Inductive thematic analysis using Open Code software was used to explore the perspectives of participants. RESULTS: While women reject disrespectful and abusive acts during childbirth generally, they may consider some disrespectful acts as acceptable and or necessary under certain circumstances. Four emerging themes were identified. (1) Disrespect and abuse is not acceptable, (2) Disrespectful and abusive actions are acceptable only if intended to save lives, (3) Disrespectful and abusive actions are an accepted part of everyday practice to prevent complications and adverse outcomes, (4) Disrespectful and abusive actions are necessary to discipline disobedient women. CONCLUSION: Women's perceptions of disrespectful and abusive acts of care providers is deeply rooted within the context of violence in Ethiopia and the societal hierarchies that have systematically disempowered women. Given the pervasiveness of disrespect and abusive actions during childbirth, policymakers, clinical managers and care providers must take these essential contextual and societal norms into account and devise comprehensive clinical interventions that addresses the root causes.


Assuntos
Atitude do Pessoal de Saúde , Parto Obstétrico , Abuso Emocional , Parto , Relações Profissional-Paciente , Feminino , Humanos , Gravidez , Etiópia , Grupos Focais , Parto/psicologia , Pesquisa Qualitativa , Abuso Emocional/psicologia , Serviços de Saúde Materna/ética , Características Culturais
3.
Aggress Behav ; 49(1): 33-48, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36037395

RESUMO

Research with military veterans has established that distress may arise in response to perpetrating violent behaviors that violate individuals' moral beliefs. To date, no studies have similarly examined morally-related cognitive and emotional responses specifically among intimate partner violence (IPV) perpetrators. However, research on moral cognitions and emotions in response to IPV perpetration may inform understanding of the behavior and potential mechanisms for intervention. In the current series of four studies, we used classical test theory to develop a measure of moral distress following IPV perpetration that focuses on thoughts about the actions (assimilated cognitions), thoughts about the self due to one's actions (accommodated cognitions), and emotions experienced due to one's actions (moral emotions). Items were developed and tested among two samples of undergraduate students, and psychometric properties of the final measure were confirmed among two community samples. The final measure consists of three subscales consisting of five items each. Results demonstrate support for internal consistency and test-retest reliability, convergent, discriminant, and incremental validity, and factor structure. This measure can be used in future research designed to examine how individuals respond to their IPV perpetration, and to study the implications this may have for long-term outcomes and behavioral change.


Assuntos
Violência por Parceiro Íntimo , Humanos , Reprodutibilidade dos Testes , Violência por Parceiro Íntimo/psicologia , Emoções , Agressão/psicologia , Princípios Morais
4.
AIDS Care ; 34(12): 1595-1601, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-34851784

RESUMO

Previous research has identified that self-efficacy is an essential factor in the process of self-management; however, the evidence is lacking concerning factors influencing self-efficacy in low-income countries. Therefore, this study examined factors influencing self-efficacy. A validated survey tool was orally administered to 415 adults living with HIV. Many of the respondents, 82.4%, do not have a regular job while one-fourth (25.5%) of the respondents were from a rural area. A mean self-efficacy score, 19.76 ± 0.12 out of a maximum of 24 was identified. This self-efficacy score was positively correlated with age, educational level, income and job status, but negatively correlated with gender, residency and drug side effects. Income, residency in rural, and experiencing drug side effects were significant predictors of self-efficacy and explained 5.4% of the variance. Better income (ß = 0.514, p = 0.029) was associated with a higher self-efficacy score but living in rural areas (ß = -0.520, p = 0.043) and experiencing drug side effects (ß = -1.246, p = 0.001) were associated with a lower self-efficacy score. The use of Individual and Family Self-Management Theory helps clinician and patients to work together to identify factors influencing self-efficacy and to intervene.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV , Autogestão , Adulto , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Autoeficácia , Etiópia
5.
Fam Process ; 61(2): 823-840, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34355392

RESUMO

Early childhood is critical to the development of children's social-emotional competence, which predicts peer relations and school adjustment in later periods of childhood. The effects of experiencing or witnessing aggression on children's social-emotional development are well known, yet the role of conflict resolution within the family has not been sufficiently studied. Social information processing models suggests that children who experience positive forms of conflict resolution within the family are likely to generalize these experiences and related skills outside the family, and thus develop greater social-emotional competence. In this longitudinal study, 128 parents (representing 79 families) participated in four quarterly telephone interviews in which they described aggressive conflicts that occurred in their family for which their children were present, including the degree to which each conflict was resolved. They also reported on the frequency of intimate partner aggression (IPA) and parent-to-child aggression (PCA) that occurred while the child was in toddlerhood and preschool as well as children's social-emotional competence at the end of the study. Multi-level models reveal that parents' reports of positive conflict resolution mitigated the concurrent and longitudinal negative effects of children's exposure to both IPA and PCA on their social-emotional competence. These findings reinforce prevention scientists' emphasis on conflict resolution skills as an essential component of parent education programs.


La primera infancia es fundamental para el desarrollo de la competencia socioemocional de los niños, la cual predice las relaciones entre pares y la adaptación escolar en periodos posteriores de la niñez. Se conocen muy bien los efectos que producen el sufrir o ser testigos de agresión en el desarrollo socioemocional de los niños, sin embargo, aún no se ha estudiado de manera suficiente el papel que desempeña la resolución de conflictos dentro de la familia. Los modelos de procesamiento de la información social sugieren que los niños que viven formas positivas de resolución de conflictos dentro de la familia son propensos a generalizar estas experiencias y las habilidades afines fuera de la familia y, por lo tanto, a desarrollar una mayor competencia socioemocional. En este estudio longitudinal, 128 padres (que representaban 79 familias) participaron en cuatro entrevistas telefónicas cada tres meses en las cuales describieron conflictos agresivos que hubo en su familia en los cuales sus hijos estuvieron presentes, incluido el grado en el cual se resolvió cada conflicto. También informaron la frecuencia de agresión en la pareja y de agresión de padres a hijos que tuvo lugar durante sus primeros años de vida y en la etapa del preescolar, así como la competencia socioemocional de los niños al final del estudio. Los modelos multinivel indican que los informes de los padres sobre la resolución positiva de los conflictos mitigaron los efectos negativos longitudinales y simultáneos de la exposición de los niños a la agresión en la pareja y a la agresión de padres a hijos en su competencia socioemocional. Estos resultados refuerzan el énfasis en las habilidades de resolución de conflictos de los científicos de la prevención como componente esencial de los programas de educación para padres.


Assuntos
Agressão , Negociação , Agressão/psicologia , Pré-Escolar , Conflito Familiar/psicologia , Humanos , Estudos Longitudinais , Relações Pais-Filho , Pais/psicologia , Habilidades Sociais
6.
RNA Biol ; 18(1): 93-103, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32816606

RESUMO

CTCF is a master regulator of gene transcription and chromatin organisation with occupancy at thousands of DNA target sites genome-wide. While CTCF is essential for cell survival, CTCF haploinsufficiency is associated with tumour development and hypermethylation. Increasing evidence demonstrates CTCF as a key player in several mechanisms regulating alternative splicing (AS), however, the genome-wide impact of Ctcf dosage on AS has not been investigated. We examined the effect of Ctcf haploinsufficiency on gene expression and AS in five tissues from Ctcf hemizygous (Ctcf+/-) mice. Reduced Ctcf levels caused distinct tissue-specific differences in gene expression and AS in all tissues. An increase in intron retention (IR) was observed in Ctcf+/- liver and kidney. In liver, this specifically impacted genes associated with cytoskeletal organisation, splicing and metabolism. Strikingly, most differentially retained introns were short, with a high GC content and enriched in Ctcf binding sites in their proximal upstream genomic region. This study provides new insights into the effects of CTCF haploinsufficiency on organ transcriptomes and the role of CTCF in AS regulation.


Assuntos
Processamento Alternativo , Fator de Ligação a CCCTC/genética , Regulação da Expressão Gênica , Haploinsuficiência , Íntrons , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/metabolismo , Genótipo , Camundongos , Camundongos Knockout , Modelos Biológicos , Especificidade de Órgãos , Ligação Proteica , Transcriptoma
7.
BMC Infect Dis ; 20(1): 879, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228546

RESUMO

BACKGROUND: Effective self-management is an important consideration for adults living with HIV on therapy to enable people to maintain their health and well-being whilst living with chronic HIV. Although numerous attempts have been made to implement and improve HIV self-management practice, there is limited evidence on effective self-management strategies, particularly in sub-Saharan Africa. This study aimed to identify the level and factors influencing the self-management practice of adults living with HIV on antiretroviral therapy. METHODS: A cross-sectional survey was conducted on a sample of 415 adults living with HIV on antiretroviral therapy at a major referral hospital in Northwest Ethiopia using convenience sampling. A theory of self-management - the Individual and Family Self-Management Theory - guided the study design, analysis and presentation of the data. A face-to-face survey tool was administered for data collection, and the data were entered and analyzed using SPSS version 25.0. RESULTS: Over half (58.1%) of the respondents were female. Many of the respondents did not know their HIV stage (76.9%) but reported adequate knowledge of their treatment (79.5%). The mean self-management score was 1.94+ 0.22 out of a total score of 3. Female gender was associated with decreased self-management. Contextual factors (gender, educational level, job status, income, living in a rural area, and awareness of HIV stage) explained 8.2% of the variance in self-management. The explanatory power increased by 9.2% when self-management process variables (self-efficacy, setting a goal, knowledge of antiretroviral therapy, HIV disclosure, and use of reminders) were added. Intervention-focused variables (encouraging disclosure and adherence support) increased the proportion of explained variance by 2.3%. CONCLUSIONS: The findings of the study indicate that the level of self-management practice amongst the population studied was low compared to international literature. Our study findings support the theoretical model and previously identified factors influencing HIV self-management. The most important predictors of lower self-management practice in Ethiopia were female gender, illiteracy, lack of awareness of HIV stage, low self-efficacy, absence of reminders, lack of encouragement to disclose and absence of adherence support. HIV care providers should seek ways to empower and support adults living with HIV to self-manage, particularly through enhancing self-efficacy and encouraging the use of reminders.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Autogestão , Adulto , Conscientização , Estudos Transversais , Etiópia/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Renda , Alfabetização , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Fatores Sexuais , Inquéritos e Questionários
8.
J Trauma Stress ; 31(3): 352-361, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29870079

RESUMO

Impaired emotional processes are related to posttraumatic stress disorder (PTSD) and are implicated in intimate partner violence (IPV) perpetration. To address the interpersonal context of PTSD, emotion, and IPV, we examined interactions among one's own and one's partner's emotional expressivity and PTSD symptom severity in association with IPV perpetration. Heterosexual couples (N = 56) in which at least one partner met screening criteria for PTSD engaged in two video-recorded discussions about negative and positive aspects of their relationships. Videos were coded for observed emotional expressiveness during moments participants reported experiencing significant emotions. Actor-partner interdependence models revealed few main effects of emotional expressivity, except that women's expressivity of positive emotions was positively associated with men's IPV perpetration, r2adj = .14. Emotional expressivity played a larger role among couples managing PTSD symptoms; that is, the association between one's own PTSD symptom severity and more IPV perpetration was stronger among men who expressed more negative emotions, r2adj = .19, and women who expressed fewer negative emotions, r2adj = .21. Several partner effects suggested the importance of understanding the dyadic nature of these constructs. For example, men's PTSD symptom severity was differentially associated with each partners' IPV perpetration based on women's expressivity of positive emotion, r2adj = .22-.27. Understanding of emotional expressivity in the link between PTSD and IPV must include consideration of gender differences in how these constructs operate interpersonally. Strategies to promote moderate and safe communication of positive and negative emotions may prevent IPV escalation, particularly among couples managing PTSD symptoms.


Assuntos
Emoções Manifestas , Relações Interpessoais , Violência por Parceiro Íntimo/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Adolescente , Adulto , Características da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores Sexuais , Gravação em Vídeo , Adulto Jovem
9.
Am J Occup Ther ; 71(1): 7101100030p1-7101100030p10, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28027034

RESUMO

In this article, we describe the use of the objects and spaces of the physical environment by occupational therapy practitioners in the United States over the profession's first 100 years. Using professional literature selected by decade from the years 1917 through 2016 to obtain data, we applied grounded theory methods to complete a detailed description. Team-based analysis over four coding schemes yielded a theoretical description of the profession's therapeutic use of the physical environment. Study findings included descriptions across occupational therapy's history of (1) treatment spaces, (2) the concepts of adapting and grading, and (3) a typology of constructive and nonconstructive applications of objects and activities by occupational therapy clients and practitioners. This extended historical perspective on trajectories of change in intervention space, the role of physical products in intervention, therapist repertoire, and the enduring role of adaptation suggests how the physical environment may be used in future practice.

10.
Int J Cancer ; 139(11): 2529-39, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27486861

RESUMO

l-type amino acid transporters (LAT1-4) are expressed in various cancer types and are involved in the uptake of essential amino acids such as leucine. Here we investigated the expression of LAT1-4 in endometrial adenocarcinoma and evaluated the contribution of LATs to endometrial cancer cell growth. Analysis of human gene expression data showed that all four LAT family members are expressed in endometrial adenocarcinomas. LAT1 was the most highly expressed, and showed a significant increase in both serous and endometrioid subtypes compared to normal endometrium. Endometrioid patients with the highest LAT1 levels exhibited the lowest disease-free survival. The pan-LAT inhibitor BCH led to a significant decrease in cell growth and spheroid area in four endometrial cancer cell lines tested in vitro. Knockdown of LAT1 by shRNA inhibited cell growth in HEC1A and Ishikawa cells, as well as inhibiting spheroid area in HEC1A cells. These data show that LAT1 plays an important role in regulating the uptake of essential amino acids such as leucine into endometrial cancer cells. Increased ability of BCH compared to LAT1 shRNA at inhibiting Ishikawa spheroid area suggests that other LAT family members may also contribute to cell growth. LAT1 inhibition may offer an effective therapeutic strategy in endometrial cancer patients whose tumours exhibit high LAT1 expression.


Assuntos
Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Transportador 1 de Aminoácidos Neutros Grandes/biossíntese , Aminoácidos Cíclicos/farmacologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Terapia de Alvo Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Esferoides Celulares
11.
JBI Evid Implement ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39291725

RESUMO

OBJECTIVES: The objective of this study was to identify the key characteristics of leaders that support the implementation of innovations in aged care settings. METHODS: We conducted a secondary analysis of papers from a large scoping review that identified how leaders supported the implementation of innovations in aged care. Once imported into NVivo12, the findings were deductively coded using the domains of Bloom's taxonomy of learning. Each parent code was then inductively analyzed to identify key characteristics within each domain. RESULTS: Our review identified four types of knowledge, five skills, and six attitudes that leaders should exhibit to better support the implementation of innovations within aged care settings. In addition to our findings regarding Bloom's learning domains, we identified nine leadership behaviors that participants in the included papers perceived as valuable for enhancing the implementation process. Furthermore, we identified four key organizational elements that support leaders in navigating and facilitating the implementation of innovations within aged care settings. CONCLUSION: Our review identified the characteristics that leaders should demonstrate when supporting the implementation of innovations in aged care. Importantly, our findings also emphasized the changing role of leadership from a hierarchical approach to a more collaborative, supportive, and empowering style. The insights identified in this review will help to guide aged care leaders, stressing the significance of adaptable and relational leadership styles that will guide the implementation of innovations within the aged care sector. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A271.

12.
J Neurotrauma ; 41(19-20): 2219-2237, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38323539

RESUMO

Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.


Assuntos
Violência por Parceiro Íntimo , Humanos , Violência por Parceiro Íntimo/psicologia , Lesões Encefálicas/psicologia , Feminino
13.
J Affect Disord ; 361: 768-777, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38897303

RESUMO

BACKGROUND: Military veterans with posttraumatic stress disorder (PTSD) commonly experience posttraumatic guilt. Guilt over commission or omission evolves when responsibility is assumed for an unfortunate outcome (e.g., the death of a fellow combatant). Survivor guilt is a state of intense emotional distress experienced by the weight of knowing that one survived while others did not. METHODS: This study of the Translational Research Center for TBI and Stress Disorders (TRACTS) analyzed structural and diffusion-weighted magnetic resonance imaging data from 132 male Iraq/Afghanistan veterans with PTSD. The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) was employed to classify guilt. Thirty (22.7 %) veterans experienced guilt over acts of commission or omission, 34 (25.8 %) experienced survivor guilt, and 68 (51.5 %) had no posttraumatic guilt. White matter microstructure (fractional anisotropy, FA), cortical thickness, and cortical volume were compared between veterans with guilt over acts of commission or omission, veterans with survivor guilt, and veterans without guilt. RESULTS: Veterans with survivor guilt had significantly lower white matter FA compared to veterans who did not experience guilt (p < .001), affecting several regions of major white matter fiber bundles. There were no significant differences in white matter FA, cortical thickness, or volumes between veterans with guilt over acts of commission or omission and veterans without guilt (p > .050). LIMITATIONS: This cross-sectional study with exclusively male veterans precludes inferences of causality between the studied variables and generalizability to the larger veteran population that includes women. CONCLUSION: Survivor guilt may be a particularly impactful form of posttraumatic guilt that requires specific treatment efforts targeting brain health.


Assuntos
Culpa , Transtornos de Estresse Pós-Traumáticos , Sobreviventes , Veteranos , Substância Branca , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/patologia , Veteranos/psicologia , Adulto , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Sobreviventes/psicologia , Campanha Afegã de 2001- , Guerra do Iraque 2003-2011 , Imagem de Difusão por Ressonância Magnética , Pessoa de Meia-Idade
14.
Nat Med ; 30(5): 1320-1329, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38480922

RESUMO

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .


Assuntos
Receptores ErbB , Glioblastoma , Imunoterapia Adotiva , Subunidade alfa2 de Receptor de Interleucina-13 , Receptores de Antígenos Quiméricos , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Subunidade alfa2 de Receptor de Interleucina-13/imunologia , Pessoa de Meia-Idade , Masculino , Receptores de Antígenos Quiméricos/imunologia , Feminino , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Injeções Espinhais , Dose Máxima Tolerável
15.
Nat Cancer ; 5(3): 517-531, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38216766

RESUMO

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.


Assuntos
Anticorpos Monoclonais Humanizados , Glioblastoma , Humanos , Glioblastoma/terapia , Receptores ErbB , Recidiva Local de Neoplasia/metabolismo , Linfócitos T , Microambiente Tumoral
16.
Int J Cancer ; 133(7): 1603-13, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23553099

RESUMO

BORIS and CTCF are paralogous, multivalent 11-zinc finger transcription factors that play important roles in organizing higher-order chromatin architecture. BORIS is a cancer-testis antigen with a poorly defined function in cancer, although it has been hypothesized to exhibit oncogenic properties. CTCF, however, has been postulated as a candidate tumor suppressor. We collated the genetic lesions in BORIS and CTCF from multiple cancers identified using high-throughput genomics. In BORIS, nonsense and missense mutations are evenly distributed. In CTCF, recurrent mutations are mostly clustered in the conserved zinc finger domain and at residues critical for contacting DNA and zinc ion co-ordination. Three missense mutations are common to both proteins. We used an inducible lentivector to express wildtype BORIS or CTCF in primary cells and cancer cell lines in order to define their functional differences. Both BORIS and CTCF caused a significant decrease in cell proliferation and clonogenic capacity, without alteration of specific cell cycle phases. Both BORIS and CTCF conferred protective effects in primary cells and some cancer cells during UV damage-induced apoptosis. Using a bioluminescent MCF-7 orthotopic breast cancer model in vivo, we demonstrated that CTCF and BORIS suppressed breast cancer growth. These findings provide further evidence that CTCF behaves as a tumor suppressor, and show BORIS has a similar growth inhibitory effect in vitro and in vivo. Hence, acquired zinc finger mutations may disrupt these functions, thereby contributing to tumor growth and development.


Assuntos
Antígenos de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Proteínas Repressoras/genética , Sequência de Aminoácidos , Animais , Antígenos de Neoplasias/metabolismo , Apoptose/genética , Sequência de Bases , Fator de Ligação a CCCTC , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Códon sem Sentido , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Mutação de Sentido Incorreto , Regiões Promotoras Genéticas , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Análise de Sequência de DNA , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/genética , Dedos de Zinco
17.
J Trauma Stress ; 26(3): 397-400, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23606358

RESUMO

Individuals with posttraumatic stress disorder (PTSD) experience elevated concerns about their capacity to control, and the consequences of, strong emotions that occur in response to trauma reminders. Anxiety is theorized to compromise attentional control (Eysenck, Derakshan, Santos, & Calvo, 2007). In turn, diminished attentional control may increase vulnerability to threat cues and emotional reactivity (Ehlers & Clark, 2001). Consequently, attentional control may play a role in the fear of emotions frequently experienced by individuals with PTSD. Study participants included 64 men and 64 women with a mean age of 37 years, 86% of whom were White, non-Hispanic. Participants experienced an average of 7.68 types of traumatic events, most commonly including motor vehicle accidents and intimate partner violence. PTSD symptoms positively correlated with fear of emotions (r = .53) and negatively correlated with attentional control (r = -.38). Attentional control was negatively correlated with fear emotions (r = -.77) and partially mediated the link between PTSD and fear of emotions (R(2) = .22). Given the findings regarding top-down attentional control, these results have implications for cognitive and emotional processing theories of PTSD and emphasize the importance of clinical consideration of fear of emotions and attentional control in the treatment of PTSD.


Assuntos
Inteligência Emocional , Emoções Manifestas , Transtornos de Estresse Pós-Traumáticos/psicologia , Acidentes/psicologia , Adulto , Atenção , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Maus-Tratos Conjugais/psicologia , Adulto Jovem
18.
J Adv Nurs ; 69(1): 4-15, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22709336

RESUMO

AIM: To identify the common, core elements of patient-centred care in the health policy, medical and nursing literature. BACKGROUND: Healthcare reform is being driven by the rhetoric around patient-centred care yet no common definition exists and few integrated reviews undertaken. DESIGN: Narrative review and synthesis. DATA SOURCES: Key seminal texts and papers from patient organizations, policy documents, and medical and nursing studies which looked at patient-centred care in the acute care setting. Search sources included Medline, CINHAL, SCOPUS, and primary policy documents and texts covering the period from 1990-March 2010. REVIEW METHODS: A narrative review and synthesis was undertaken including empirical, descriptive, and discursive papers. Initially, generic search terms were used to capture relevant literature; the selection process was narrowed to seminal texts (Stage 1 of the review) and papers from three key areas (in Stage 2). RESULTS: In total, 60 papers were included in the review and synthesis. Seven were from health policy, 22 from medicine, and 31 from nursing literature. Few common definitions were found across the literature. Three core themes, however, were identified: patient participation and involvement, the relationship between the patient and the healthcare professional, and the context where care is delivered. CONCLUSION: Three core themes describing patient-centred care have emerged from the health policy, medical, and nursing literature. This may indicate a common conceptual source. Different professional groups tend to focus on or emphasize different elements within the themes. This may affect the success of implementing patient-centred care in practice.


Assuntos
Atenção à Saúde , Política de Saúde , Enfermagem , Assistência Centrada no Paciente , Austrália , Reforma dos Serviços de Saúde
19.
Child Maltreat ; : 10775595231210017, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37917022

RESUMO

Youth suicidal ideation is a prevalent experience, particularly among youth exposed to maltreatment, with a variety of indicators such as youth statements of ideation. To better understand suicidal ideation, and the associations with youth mental health outcomes, a fruitful path may be through the study of the dimensions (e.g., severity, frequency) of maltreatment exposure. While there exists extensive work on methods to best operationalize casefile records of maltreatment, such work has not been undertaken for youth self-reports, which are an important indicator of youth functioning following exposure. To address the lack of clarity of how to best operationalize youth self-reports of maltreatment, a multiverse analytic approach was taken to operationalize severity and frequency in a sample of 471 8- to 17-year-old children in foster care. We examined differences across measurement models and the models' associations with caregiver reports of youth suicidal ideation statements. Results indicate that the operationalizations used to define maltreatment resulted in differing measurement models that further differed in their associations with reports of youth suicidal ideation. This study highlights the importance of how researchers operationalize their data and the role dimensions of maltreatment have in further elucidating differential outcomes for youth exposed to maltreatment.

20.
J Fam Violence ; : 1-14, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36743687

RESUMO

Purpose: The perspectives of children and young people with disability who experience domestic and family violence are under-researched, impeding the development of approaches that meet their needs. Knowledge gaps stem from the layered discursive positioning of disability, childhood/youth, or domestic and family violence in addition to the methodological, ethical and pragmatic complexity of research needed to understand their priorities and be attuned to their lived experience. This article explores methodological, ethical and practical challenges to centring their voices in research about domestic and family violence. Method: A conceptual framework of feminist disability theory and intersectionality informed our co-designed research, across three phases: (1) quantitative large-scale data linkage and case file analysis; (2) qualitative research with children and young people, their families and service providers and (3) stakeholder engagement workshops. Results: We reflect on how our research was able to prioritise the contextual agency of children and young people with disability, ways it could not, and other constraints. Conclusion: Children and young people with disability experiencing domestic and family violence hold an expert and unique vantage point on what happens to them. Amplifying their priorities for directing policy and organisational change requires more of researchers in terms of methods, but also more flexibility in how projects are funded to enable creativity and innovation. We call for collective attention to frameworks for supported decision-making and child ethics to progress inclusive research which recognises the importance of participation for children and young people with disability.

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