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1.
BMC Public Health ; 21(1): 108, 2021 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-33422022

RESUMO

BACKGROUND: Home-based interventions have potential for improving early child development (ECD) in low-resource settings. The design of locally acceptable strategies requires an in-depth understanding of the household context. In this formative research study, we aimed to characterize the home play and learning environments of children 6-23 months of age from low-income households in peri-urban Lima, Peru. METHODS: Drawing on the developmental niche framework, we used quantitative and qualitative methods to understand children's physical and social settings, childcare practices, and caregiver perspectives. We conducted interviews, unstructured video-recorded observations, and spot-checks with 30 randomly selected caregiver-child dyads, 10 from each child age group of 6-11, 12-17, and 18-23 months of age, as well as key informant interviews with 12 daycare instructors. We analyzed the data for key trends and themes using Stata and ATLAS.ti and employed an adapted version of the Indicator of Parent-Child Interaction to evaluate the observations. RESULTS: Children's social settings were characterized by multi-generational homes and the presence of siblings and cousins as play partners. Access to books and complex hand-eye coordination toys (e.g., puzzles, building blocks) in the home was limited (30.0 and 40.0%, respectively). Caregivers generally demonstrated low or inconsistent levels of interaction with their children; they rarely communicated using descriptive language or introduced novel, stimulating activities during play. Reading and telling stories to children were uncommon, yet 93.3% of caregivers reported singing to children daily. On average, caregivers ascribed a high learning value to reading books and playing with electronic toys (rated 9.7 and 9.1 out of 10, respectively), and perceived playing with everyday objects in the home as less beneficial (rated 6.8/10). Daycare instructors reinforced the problems posed by limited caregiver-child interaction and supported the use of songs for promoting ECD. CONCLUSIONS: The features of the home learning environments highlighted here indicate several opportunities for intervention development to improve ECD. These include encouraging caregivers to communicate with children using full sentences and enhancing the use of everyday objects as toys. There is also great potential for leveraging song and music to encourage responsive caregiver-child interactions within the home setting.


Assuntos
Cuidadores , Relações Pais-Filho , Criança , Cuidado da Criança , Desenvolvimento Infantil , Humanos , Lactente , Peru
2.
Gastroenterol Nurs ; 44(4): E69-E77, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149042

RESUMO

Food-related quality of life is defined as achieving adequate nutrition, deriving pleasure, and maintaining social activities through eating and drinking. The objective of this qualitative study was to characterize the parental perspective about eating experiences and family functioning after diagnosis of inflammatory bowel disease in their child in order to describe how these experiences may impact food-related quality of life. Semistructured interviews were completed with 10 parents of a child with inflammatory bowel disease. Conventional content analysis was conducted with steps to ensure trustworthiness. Family Systems Theory was the interpretive framework. Ambiguous nutrition information emerged as the main theme. Families experienced various and conflicting viewpoints regarding the role of diet, which presented a challenge after diagnosis. Parents reported frustration regarding the lack of uniform and personalized nutrition guidance. Our results support that families desire shared decision-making in regard to medication and diet, which is an important clinical practice implication for the entire gastroenterology medical team. Understanding the challenges faced by families after a major medical diagnosis in a child provides insight into designing medical interventions that maintain optimal quality of life in families.


Assuntos
Doenças Inflamatórias Intestinais , Qualidade de Vida , Criança , Família , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Pais , Pesquisa Qualitativa
3.
Child Dev ; 84(6): 1872-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23534446

RESUMO

Shape knowledge, a key aspect of school readiness, is part of early mathematical learning. Variations in how children are exposed to shapes may affect the pace of their learning and the nature of their shape knowledge. Building on evidence suggesting that child-centered, playful learning programs facilitate learning more than other methods, 4- to 5-year-old children (N = 70) were taught the properties of four geometric shapes using guided play, free play, or didactic instruction. Results revealed that children taught shapes in the guided play condition showed improved shape knowledge compared to the other groups, an effect that was still evident after 1 week. Findings suggest that scaffolding techniques that heighten engagement, direct exploration, and facilitate "sense-making," such as guided play, undergird shape learning.


Assuntos
Percepção de Forma/fisiologia , Conhecimento , Aprendizagem/fisiologia , Jogos e Brinquedos , Análise de Variância , Pré-Escolar , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estimulação Física , Ensino/métodos
4.
Nicotine Tob Res ; 14(5): 586-95, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22140146

RESUMO

INTRODUCTION: The nicotine bolus theory states that the dependence-producing potential of cigarettes relates to a rapid increase in nicotine at brain receptor sites. It has been suggested that ammonia, a compound typically found in tobacco products, further increases the amount of nicotine absorbed and its absorption rate. The aim of this study was to determine whether different ammonia yields in cigarettes affected the rate or amount of nicotine absorption from the lungs to arterial circulation. METHODS: 34 adult smokers received 3 separate puffs from each of 2 test cigarettes with different ammonia yields (ammonia in smoke: 10.1 µg per cigarette vs. 18.9 µg per cigarette), followed by rapid radial arterial blood sampling (maximum one sample per second) with 30 min between puffs. Arterial blood samples were assayed for nicotine by liquid chromatography tandem mass spectrometry. Pharmacokinetic modeling was performed and the two test cigarettes were assessed for bioequivalence. RESULTS: No significant differences were found in area under the curve, C(max), or T((max)) and the 2 test cigarettes were found to be bioequivalent based on 2 one-sided tests at a significance level of 5%. In addition, the zero-order rate constant (k(0)) obtained from the initial slope of the curves and the model-dependent first-order rate constant (k(a)) were not significantly different. CONCLUSIONS: This study provides strong evidence that the different ammonia yields of the test cigarettes had no impact on nicotine pharmacokinetics; thus, the ammonia did not increase the rate or amount of nicotine absorption from a puff of cigarette smoke.


Assuntos
Amônia/farmacologia , Artérias/metabolismo , Nicotina/farmacocinética , Adulto , Método Duplo-Cego , Humanos , Fumar , Nicotiana
5.
Biochem J ; 436(2): 363-9, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21410436

RESUMO

The HIF (hypoxia-inducible factor) plays a central regulatory role in oxygen homoeostasis. HIF proteins are regulated by three Fe(II)- and α-KG (α-ketoglutarate)-dependent prolyl hydroxylase enzymes [PHD (prolyl hydroxylase domain) isoenzymes 1-3 or PHD1, PHD2 and PHD3] and one asparaginyl hydroxylase [FIH (factor inhibiting HIF)]. The prolyl hydroxylases control the abundance of HIF through oxygen-dependent hydroxylation of specific proline residues in HIF proteins, triggering subsequent ubiquitination and proteasomal degradation. FIH inhibits the HIF transcription activation through asparagine hydroxylation. Understanding the precise roles and regulation of these four Fe(II)- and α-KG-dependent hydroxylases is of great importance. In the present paper, we report the biochemical characterization of the first HIF protein substrates that contain the CODDD (C-terminal oxygen-dependent degradation domain), the NODDD (N-terminal oxygen-dependent degradation domain) and the CAD (C-terminal transactivation domain). Using LC-MS/MS (liquid chromatography-tandem MS) detection, we show that all three PHD isoenzymes have a strong preference for hydroxylation of the CODDD proline residue over the NODDD proline residue and the preference is observed for both HIF1α and HIF2α protein substrates. In addition, steady-state kinetic analyses show differential substrate selectivity for HIF and α-KG in reference to the three PHD isoforms and FIH.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sítios de Ligação , Humanos , Hidroxilação , Isoenzimas/química , Isoenzimas/metabolismo , Pró-Colágeno-Prolina Dioxigenase/química , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Especificidade por Substrato
6.
Front Big Data ; 5: 992620, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247972

RESUMO

This article draws upon original qualitative interview data with Norwegian male and female cyberengineer cadets at the Norwegian Cyber Defense Academy, who could in the future be working with AI-enabled systems in a variety of positions throughout the Norwegian military. The interviews explored how these cadets feel they as cyberengineers will be perceived in their future positions in the military, what challenges they feel they may face, and how gender may play a role in this. Different cyberengineers expressed concern about being able to communicate the cyber domain to their non-technology specialist colleagues due to the increasing complexity of new technologies. Gender appeared to be playing a role in this concern as the women interviewed expressed specific concerns that they feel as women, that they do not fit the stereotype of who is a cyberengineer, while some of the men felt that as cyberengineers they were seen as embodying a nerd masculinity, and that these gendered perceptions has implications for how they feel others perceive their competence levels. The findings from this article highlights gendered hierarchies in the military and the need for military institutions to focus on developing communication skills among those working with cyber operations. As the role of cyber is expected to grow in military operations, cyberengineers will need to find ways of communicating effectively with non-specialists-especially as complex AI-enabled systems are introduced. Finally, this paper argues the need for military institutions to take gender into account for this training and need for gender-sensitive policies.

7.
J Appl Gerontol ; 41(3): 855-866, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34958243

RESUMO

In order to increase the number of students entering the geriatric workforce, an understanding of factors influencing career preference and what may prevent students from pursuing geriatric careers is necessary. Using a convergent parallel mixed methods approach, the aim of this study was to provide insight for geriatric educators regarding the collective perceptions of aging and older persons held by 864 students from eight healthcare professions. Quantitative questions assessed students' attitudes (Geriatric Attitudes Scale). Student responses to four open-ended questions were assessed using conventional content analysis. Results included rich narrative examples of healthcare professions students' perceptions and understanding of the aging process, as well as myths and misconceptions of aging and older persons that can be used to inform geriatric curricula across multiple health professions training and education programs. Geriatric education is a critical avenue to correct misperceptions, quell ageism and address the current shortage in the geriatrician workforce.


Assuntos
Etarismo , Geriatria , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Atitude do Pessoal de Saúde , Currículo , Atenção à Saúde , Geriatria/educação , Humanos , Estudantes
8.
J Patient Saf ; 18(3): 152-160, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508042

RESUMO

OBJECTIVES: Inpatient falls are the most commonly reported safety incidents and are associated with serious injuries. This study aimed to use multifactorial interventions to reduce the delays to the diagnosis of serious injury in a time series analysis after serious incidents relating to falls within a central London Trust. METHODS: A multiprofessional project team undertook process mapping to identify opportunities for improvement at different stages in the management of a fall. The interventions included an educational teaching session aimed at doctors, a lanyard card designed by doctors using the plan-do-study-act methodology, a falls-specific pager for radiographers, and a new system to refer to portering. Quantitative data were obtained using an serious incident database where serious injury occurred (SI data; n = 65) and routinely collected incident reporting database on falls regardless of injury (IR data; n = 178). Qualitative questionnaire data (n = 70) were also used to evaluate doctors' confidence in falls assessment before and after interventions. RESULTS: Results in the IR data demonstrated a significant reduction in the median (interquartile range) minutes delay in the time to review a patient after a fall from 81 (43-180) to 51 (26-112; P = 0.003) and the time to order imaging from 102 (45-370) to 50 (33-96; P = 0.04). Analysis of the SI database demonstrated a nonstatistically significant reduction in the overall time taken to detect serious injury after a fall from 348 (126-756) to 192 (108-384) minutes (P = 0.070). Furthermore, analysis using statistical process control charts showed evidence of special cause variation and a shift in the process in detecting serious harm after a fall. Junior doctors' confidence in investigations improved from 53% to 76% (P = 0.04) after the intervention. CONCLUSIONS: The cumulative application of multiple interventions with small individual effects resulted in a substantial positive effect on delays and variability in diagnosis of serious harm. Given a similar institutional context, the more effective interventions in our study could be adopted elsewhere.


Assuntos
Acidentes por Quedas , Pacientes Internados , Acidentes por Quedas/prevenção & controle , Hospitais , Humanos , Medição de Risco , Gestão de Riscos
9.
J Allied Health ; 50(3): e87-e90, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495037

RESUMO

Our interprofessional team examined the mental health effects of a pilot mindfulness meditation workshop for college students (n = 39) from 4 health professions. A mixed-methods survey examined students' self-compassion (short form; SCS-sf), perceived stress (PSS-10), and self-reported mindfulness behaviors pre-workshop and at 2 months. The survey captured attitudes, beliefs, and intentions to continue mindfulness practices over time and perceived barriers to mindfulness practice. Participants (69%; 27/39) indicated significantly improved SCS-sf (p=0.016) and significantly reduced PSS (p=0.009) at 2 months post-workshop. Students reported improved mental health after 2 months, but the small sample size limits generalizability of findings. Interprofessional education promoting mindfulness skills may help prevent burnout and empathy fatigue for health professionals entering the workplace.


Assuntos
Atenção Plena , Estudantes de Ciências da Saúde , Ocupações em Saúde , Humanos , Saúde Mental , Estresse Psicológico/prevenção & controle
10.
Cogn Res Princ Implic ; 5(1): 29, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32588283

RESUMO

BACKGROUND: Spatial thinking skills are strongly correlated with achievement in Science, Technology, Engineering, and Mathematics (STEM) fields and emerging research suggests that interventions aimed at building students' skills will likely yield measurable impacts on learning across K-12 settings. The importance of spatial thinking in science has received increased attention in academic discussions; however, the intentional practice of teaching spatial thinking skills is still largely absent from K-12 education. The translation of science into educational practice is challenging for a variety of reasons, including the difficulty "translating" research findings into practical applications and limited resources to support its development, implementation, and evaluation. Given these obstacles, one may ask "can spatial thinking be brought to the classroom?" In this paper, we argue that in order to effectively move research into the classroom, we must first systematically explore how spatial thinking can be translated into practice. APPROACH: We present a use-inspired, integrative framework that draws upon planned action and translation science theories, as well as research from cognitive, developmental, educational, and implementation sciences, to guide the infusion of spatial thinking into science curricula. In the Knowledge Translation Framework (KTF), translation is conceived as a multistage process, proceeding through seven stages: (1) the identification of relevant disciplinary and contextual knowledge, (2) the synthesis and translation of knowledge into guidelines to support the infusion of knowledge into the curriculum, (3) the development of tools to support curriculum development, implementation, and track the translation process, (4) the iterative development and refinement of the spatially-enhanced curriculum, (5) the creation of an analysis plan to evaluate the impact of the spatial enhancements and other contextual features on learning, (6) the development and implementation of an intervention plan, and (7) the evaluation of the intervention. CONCLUSION: The KTF is a use-inspired, integrative framework that unpacks the translation process and offers practical guidance on how a team may synthesize scientific and contextual knowledge, infuse it into a curriculum, and evaluate its impact in ways that will yield scientific understanding and practical knowledge. We also provide illustrative examples of how this approach was used to spatially enhance an elementary science curriculum.


Assuntos
Currículo , Visualização de Dados , Gestos , Guias como Assunto , Modelos Educacionais , Ciência/educação , Percepção Espacial , Pensamento , Humanos
11.
Nutr Clin Pract ; 35(2): 231-245, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30937981

RESUMO

Irritable bowel syndrome (IBS) is classified as a functional gastrointestinal (GI) disorder characterized by abdominal pain, bloating, and changes in bowel function. Although the pathophysiology of IBS is incompletely understood, fermentable carbohydrates are implicated as a potential cause of symptoms. An elimination diet, such as a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, represents a potential intervention for reducing GI symptoms in patients with IBS. The role of fermentable carbohydrates in symptom onset is well studied in adult patients with IBS; however, less research exists in the pediatric population. This review sought to explore evidence for the role of dietary fermentable carbohydrate elimination to reduce GI symptoms (abdominal pain, stool changes, abdominal bloating) in children and adolescents (4-19 years of age) diagnosed with IBS based on Rome III or IV criteria. Five studies of neutral to positive quality rating were identified and analyzed using the Academy of Nutrition and Dietetics Evidence Analysis Process. These studies demonstrate that dietary elimination of fermentable carbohydrates, such as through a low-FODMAP diet, reduces the severity of 1 or more GI symptoms in about one-quarter to one-half of pediatric patients with IBS. Patients without improvement are considered "nonresponders" and may require an alternative intervention. More research is needed to establish the best way to identify patients who would respond to elimination diets vs other IBS treatment strategies.


Assuntos
Dieta/métodos , Carboidratos da Dieta/efeitos adversos , Alimentos Fermentados/efeitos adversos , Síndrome do Intestino Irritável/dietoterapia , Síndrome do Intestino Irritável/fisiopatologia , Adolescente , Criança , Pré-Escolar , Dissacarídeos/efeitos adversos , Feminino , Fermentação , Trato Gastrointestinal/fisiopatologia , Humanos , Masculino , Monossacarídeos/efeitos adversos , Oligossacarídeos/efeitos adversos , Adulto Jovem
12.
Lifestyle Genom ; 13(1): 43-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31786575

RESUMO

BACKGROUND: Angelman syndrome (AS) is a rare disorder of genetic imprinting which results in intellectual and developmental disability. It meets criteria of a disorder of neurologic impairment. A deletion in the long arm of chromosome 15 (del 15q11.2-q13) is responsible for about 70% of cases of AS (deletion genotype). SUMMARY: There is a paucity of evidence to allow algorithmic nutrition assessment and intervention in pediatric patients with AS. Therefore, our objective is to use a case presentation to provide an example of nutrition assessment and intervention in a pediatric patient with the deletion genotype of AS and then highlight common challenges to providing evidenced-based nutrition care. For the highlighted challenges, we suggest evidence-based solutions to provide a resource for clinicians who may encounter similar challenges in clinical practice. Key Messages: There are genotype-phenotype correlations in AS that can help guide clinicians regarding nutritionally relevant clinical characteristics and corresponding interventions that are patient specific. The deletion genotype in AS is associated with multiple characteristics that are relevant to nutrition care and may also be different and/or more severe than characteristics seen in other AS genetic mechanisms. There is also overlap in certain nutritionally relevant clinical characteristics between AS and other conditions, including Prader-Willi syndrome, autism spectrum disorders, and disorders of neurological impairment like cerebral palsy. Clinicians can utilize nutrition resources related to these conditions to expand the scope of relevant resources available.


Assuntos
Síndrome de Angelman/dietoterapia , Síndrome de Angelman/genética , Impressão Genômica , Avaliação Nutricional , Algoritmos , Antropometria , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Medicina Baseada em Evidências , Feminino , Deleção de Genes , Estudos de Associação Genética , Humanos , Inquéritos Nutricionais , Pediatria
13.
Am J Clin Pathol ; 149(5): 434-441, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29618001

RESUMO

OBJECTIVES: In a clinical laboratory, the design of the workspace directs the workflow and significantly affects the productivity of clinical laboratory scientists (CLS). With the chronic shortage of CLS, a well-designed workspace is essential to take full advantage of available staff, especially in high-volume laboratories. METHODS: Through the use of quality improvement tools, a manual body fluid testing workspace was redesigned to address weaknesses in the layout that led to excessive physical steps taken by staff. RESULTS: System engineering tools such as a fishbone diagram, spaghetti diagrams, Plan-Do-Study-Act cycles, and a counterbalance measure were all used in a CLS-led quality improvement initiative to redesign a workspace in the manual body fluid processing area of a clinical laboratory at Mayo Clinic. CONCLUSIONS: After the redesign, physical steps taken and time to process body fluids were reduced by an average of 40% and 32%, respectively, demonstrating the utility of quality improvement tools in clinical laboratory settings.


Assuntos
Serviços de Laboratório Clínico/organização & administração , Laboratórios/organização & administração , Melhoria de Qualidade , Simplificação do Trabalho , Líquidos Corporais , Eficiência , Humanos , Pessoal de Laboratório Médico , Fluxo de Trabalho
14.
Prev Med Rep ; 10: 113-116, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29850396

RESUMO

Food insecurity (FI) is common - affecting one in six American households with children. FI is defined as limited or uncertain availability of nutritionally adequate and safe foods. Awareness of food insecurity and its impact on health has increased since the American Academy of Pediatrics 2015 policy statement, "Promoting Food Security for All Children." Though FI is frequently addressed in general pediatric primary care, it is not routinely identified in patients with chronic medical problems. Patients with complex care needs, prescription medication, or restrictive nutritional requirements may be at higher risk of food insecurity. The prevalence of FI in patients with chronic disease, including pediatric patients with kidney disease, remains unknown. We sought to determine the prevalence of FI among our pediatric nephrology clinic patients with a cross-sectional screening pilot study. Nearly 35% of 118 children seen in our pediatric nephrology outpatient clinic lived in food insecure households, a prevalence rate more than double the general pediatric population (16%). Barriers to food security were variable; common themes included challenges with restricted diet and available food, identifying and accessing community resources, and not qualifying for support. For physicians, dietitians, and other health providers that counsel patients with kidney disease on dietary interventions, it is important to be aware of food security status. To our knowledge, this is the first study to assess the prevalence of food insecurity in pediatric patients with kidney disease. Further studies of food insecurity and social determinants of heath in this patient population are needed.

15.
Diabetes Educ ; 32(1): 51-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16439492

RESUMO

The purpose of this article is to share an educational strategy or tool that is relevant for use in patient and professional diabetes education. The tool offers an opportunity for diabetes educators to screen for psychosocial variables such as depression or emotional distress. A systematic review of the literature was conducted to identify psychological variables that have an impact on individuals living with diabetes and their ability to self-manage their disease. The literature revealed that both depression and emotional distress related to diabetes was experienced by individuals with diabetes along with those individuals who were unable to self-management their disease. The Accu-Check Interview is a computer software program that may assist diabetes educators to provide diabetes education. Use of the Accu-Check Interview software program has been implemented at various sites including the Joslin Clinic (Boston, Mass), Baystate Medical Center (Springfield, Mass), and Emerson Hospital (Concord, Mass). The Diabetes Self Care Profile is a Web-based version of the Accu-Check Interview and can be accessed as a demonstration in English and Spanish. These tools allow diabetes educators to screen for psychosocial variables and address issues with individuals while using a motivational interviewing approach.


Assuntos
Diabetes Mellitus/psicologia , Diabetes Mellitus/reabilitação , Computadores , Humanos , Educação de Pacientes como Assunto , Psicologia , Software
16.
Sci Transl Med ; 5(166): 166ra3, 2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23283368

RESUMO

Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.


Assuntos
Sinergismo Farmacológico , Paclitaxel/farmacologia , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Aurora Quinase A , Aurora Quinases , Ciclo Celular , Linhagem Celular Tumoral , Separação Celular , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis , Camundongos , Camundongos Nus , Mitose , Metástase Neoplásica , Transplante de Neoplasias , Proteínas Serina-Treonina Quinases/farmacologia , RNA Interferente Pequeno/metabolismo , Carcinoma Anaplásico da Tireoide , Fatores de Tempo , Moduladores de Tubulina/uso terapêutico
17.
Clin Cancer Res ; 17(5): 989-1000, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21245089

RESUMO

PURPOSE: Despite their preclinical promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize GSK1120212' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life. EXPERIMENTAL DESIGN: Enzymatic studies were conducted to determine GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models. RESULTS: In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27(Kip1/CDKN1B), and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras. CONCLUSIONS: GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors.


Assuntos
Antineoplásicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Piridonas/farmacologia , Pirimidinonas/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feminino , Genes ras , Humanos , Immunoblotting , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosforilação , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacocinética , Pirimidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chem Biol ; 18(2): 177-86, 2011 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-21338916

RESUMO

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.


Assuntos
Descoberta de Drogas , Hidantoínas/metabolismo , Hidantoínas/farmacologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Hidantoínas/química , Modelos Moleculares , Dados de Sequência Molecular , Permeabilidade , Fosforilação/efeitos dos fármacos , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-crk/metabolismo , Pirazóis/química
19.
J Med Chem ; 53(10): 3973-4001, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20420387

RESUMO

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.


Assuntos
Compostos Aza/síntese química , Indóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinase A , Aurora Quinase B , Aurora Quinases , Compostos Aza/química , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Transplante de Neoplasias , Fosforilação , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo
20.
J Sch Nurs ; 22(4): 223-8, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16856777

RESUMO

The purpose of this study was to measure school nurses' perceived self-efficacy in providing diabetes care and education to children and to identify factors that correlate with higher self-efficacy levels in the performance of these tasks. The results of this study revealed that the surveyed school nurses perceived a moderate level of self-efficacy in providing diabetes education. Significant findings in this study were positive relationships between self-efficacy and 3 variables: (a) participating in the care of children with diabetes, (b) having type 1 diabetes children in the school system, and (c) supervising children with blood glucose meter testing. There was a significant relationship between higher self-efficacy scores and having a diabetes curriculum. However, only nine school nurses reported having a diabetes curriculum. School nurses can benefit by understanding what factors increase self-efficacy related to diabetes education designed to enhance school-age children's knowledge of diabetes and its management.


Assuntos
Diabetes Mellitus/enfermagem , Diabetes Mellitus/prevenção & controle , Educação em Saúde , Serviços de Enfermagem Escolar , Autoeficácia , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/enfermagem , Humanos , Pessoa de Meia-Idade , New England
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