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The transcription factors that regulate differentiation into the monocyte subset in bone marrow have not yet been identified. Here we found that the orphan nuclear receptor NR4A1 controlled the differentiation of Ly6C- monocytes. Ly6C- monocytes, which function in a surveillance role in circulation, were absent from Nr4a1-/- mice. Normal numbers of myeloid progenitor cells were present in Nr4a1-/- mice, which indicated that the defect occurred during later stages of monocyte development. The defect was cell intrinsic, as wild-type mice that received bone marrow from Nr4a1-/- mice developed fewer patrolling monocytes than did recipients of wild-type bone marrow. The Ly6C- monocytes remaining in the bone marrow of Nr4a1-/- mice were arrested in S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of the differentiation and survival of 'patrolling' Ly6C- monocytes.
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Antígenos Ly/imunologia , Apoptose/imunologia , Medula Óssea/imunologia , Diferenciação Celular/imunologia , Monócitos/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Animais , Ciclo Celular/imunologia , Dano ao DNA/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Organismos Livres de Patógenos EspecíficosRESUMO
OBJECTIVE: To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. METHODS: We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. RESULTS: Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. CONCLUSION: In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.
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Neoplasias do Endométrio , Recidiva Local de Neoplasia , Feminino , Humanos , Idoso , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/etiologia , Compostos de Fenilureia/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide increasing incidence and disease-associated mortality. Although most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified 4 distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This review describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The NCCN Guidelines for Uterine Neoplasms provide detailed recommendations regarding the diagnosis, workup, and management of EC.
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Neoplasias do Endométrio , Neoplasias dos Genitais Femininos , Neoplasias Uterinas , Humanos , Feminino , Medicina de Precisão , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/genéticaRESUMO
We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.
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Deficiências do Desenvolvimento/etiologia , Holoprosencefalia/etiologia , Doenças do Recém-Nascido/etiologia , Mutação , Doenças do Sistema Nervoso/etiologia , Pâncreas/anormalidades , Pancreatopatias/congênito , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Holoprosencefalia/patologia , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/patologia , Masculino , Camundongos , Camundongos Knockout , Doenças do Sistema Nervoso/patologia , Pâncreas/patologia , Pancreatopatias/etiologia , Pancreatopatias/patologia , Linhagem , Fenótipo , Homologia de Sequência , SíndromeRESUMO
PURPOSE: Despite growing evidence supporting the benefits of yoga for cancer-related symptom management, yoga usage among cancer survivors is low. To translate the evidence of yoga benefits into community practice, it is critical to understand interest in yoga as well as barriers and preferences that influence yoga usage among cancer survivors. METHOD: We conducted a cross-sectional survey study among cancer survivors, 18 years or older, with a primary diagnosis of cancer, and receiving treatment or follow-up care at outpatient clinics at five regional academic cancer center sites. We collected data and performed bivariate and multivariable analyses on self-reported yoga usage and interest in and barriers to practicing yoga, as well as preferred location and time for yoga practice. RESULTS: Of 857 participants, 70.0% had never practiced yoga and 52.3% were interested in practicing yoga. Among those interested, 52.5% had never practiced yoga. Lower interest was independently associated with being male (odds ratio [OR] = 0.30, 95% confidence interval [CI] = 0.20-0.44, p < 0.001), unemployed (OR = 0.60, 95% CI = 0.39-0.91, p = 0.016), and white (OR = 0.42, 95% CI = 0.23-0.78, p = 0.005). Commonly cited barriers among those who were interested but had never practiced were not aware of yoga benefits (36.3%), difficulty motivating (28.7%), experiencing symptoms (22.9%), and not enough time (22.0%). Participants indicated "on-site and at a studio near home" (41.5%) as preferred location and evenings (3-8 pm, 34.0%) as preferred time for yoga practice. CONCLUSION: Although more than 50% of patients indicated interest in practicing yoga, use of yoga is low among cancer survivors. Barriers and patient preferences for yoga practice need to be addressed to design effective yoga programs for this population.
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Sobreviventes de Câncer , Neoplasias , Yoga , Estudos Transversais , Humanos , Masculino , Meditação , Neoplasias/terapia , AutorrelatoRESUMO
PURPOSE: Early recognition and response to clinical deterioration is critical to patient safety. Failures or delays in recognition and response often manifest as emergency transfers to the intensive care unit (ICU). We describe implementation of a program to improve recognition and response to clinical deterioration within the pediatric inpatient acute care setting (i.e., medical-surgical, hematology-oncology, and intermediate care units). DESIGN AND METHODS: We assembled an inter-professional team including nurses, physicians, and hospital leaders to evaluate preventable patient harm events associated with failures in identifying and responding to clinical deterioration and resultant emergency transfers to the intensive care unit (ICU). We evaluated an existing situational awareness framework incorporating principles of high-reliability organizations, refined the framework utilizing internal event analyses data, and subsequently implemented a program reducing emergency transfers. RESULTS: Emergency transfers to the ICU from acute care settings decreased by more than 70%, and to date, this improvement has sustained. Nurses report increased satisfaction and empowerment to proactively escalate their concerns, respond to changes in a patient's condition, and reduce uncertainty about the plan of care. CONCLUSIONS: The program has enhanced situational awareness, reduced emergency transfers, and fostered a culture of accountability and collaboration in alignment with the organizational core value of safety. PRACTICE IMPLICATIONS: Developing a reliable system to support the healthcare team in recognizing and responding to clinical deterioration reduces the risk of care delays. Applying situational awareness to other high-risk situations, additional areas for program expansion were identified, to include emergency department admissions and behavioral health patients.
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Criança Hospitalizada , Unidades de Terapia Intensiva , Criança , Hospitalização , Humanos , Segurança do Paciente , Reprodutibilidade dos TestesRESUMO
PURPOSE: We sought to evaluate whether provider volume or other factors are associated with chemotherapy guideline compliance in elderly patients with epithelial ovarian cancer (EOC). METHODS: We queried the SEER-Medicare database for patients ≥66 years, diagnosed with FIGO stage II-IV EOC from 2004 to 2013 who underwent surgery and received chemotherapy within 7 months of diagnosis. We compared NCCN guideline compliance (6 cycles of platinum-based doublet) and chemotherapy-related toxicities across provider volume tertiles. Factors associated with guideline compliance and chemotherapy-related toxicities were assessed using logistic regression. Overall survival (OS) was compared across volume tertiles and Cox proportional-hazards model was created to adjust for case-mix. RESULTS: 1924 patients met inclusion criteria. The overall rate of guideline compliance was 70.3% with a significant association between provider volume and compliance (64.5% for low-volume, 72.2% for medium-volume, 71.7% for high-volume, p = .02). In the multivariate model, treatment by low-volume providers and patient age ≥ 80 years were independently associated with worse chemotherapy-guideline compliance. In the survival analysis, there was a significant difference in median OS across provider volume tertiles with median survival of 32.8 months (95%CI 29.6, 36.4) low-volume, 41.9 months (95%CI 37.5, 46.7) medium-volume, 42.1 months (95%CI 38.8, 44.2) high-volume providers, respectively (p < .01). After adjusting for case-mix, low-volume providers were independently associated with higher rates of mortality (aHR 1.25, 95%CI: 1.08, 1.43). CONCLUSIONS: In a modern cohort of elderly Medicare patients with advanced EOC, we found higher rates of non-compliant care and worse survival associated with treatment by low-volume Medicare providers. Urgent efforts are needed to address this volume-outcomes disparity.
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Carcinoma Epitelial do Ovário/terapia , Fidelidade a Diretrizes/estatística & dados numéricos , Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Hospitais com Baixo Volume de Atendimentos/estatística & dados numéricos , Neoplasias Ovarianas/terapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/mortalidade , Terapia Combinada/métodos , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Ovarianas/mortalidade , Estados UnidosRESUMO
BACKGROUND: NCCN produces highly influential disease-specific oncology clinical practice guidelines. Because the number of women in academic oncology has increased, we assessed whether the composition of NCCN Guidelines Panels reflected this trend. METHODS: Using historical guidelines requested from NCCN, we investigated time trends for female representation on 21 NCCN Guidelines Panels and analyzed the trends for female-predominant cancers (breast, ovarian, uterine, and cervical) compared with all cancers. RESULTS: From 2013 to 2019, there was an increase from 123 women of 541 total panelists (22.7%) to 175 women of 542 panelists (32.3%). Within the 4 female-predominant cancers, the increase was more rapid: from 30 of 101 total panelists (29.7%) to 66 of 118 panelists (56.4%). Excluding female-predominant cancers, increases were minimal. CONCLUSIONS: There could be multiple explanations for these differing trends, including the possibility of more rapid increases in the underlying pool of female physician-scientists in female-predominant specialties or more efforts to increase the representation of women in decisions about the standard of care in cancers predominantly affecting women.
Assuntos
Equidade de Gênero , Oncologia , Neoplasias , Feminino , Humanos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: This study sought to describe how high- versus low-frequency surveillance imaging practices among providers at Memorial Sloan Kettering Cancer Center (MSKCC) impact overall survival (OS) and time to recurrence of patients with advanced epithelial ovarian cancer in first remission. METHODS: The study cohort included patients with stage II-IV high-grade epithelial ovarian cancer diagnosed in January 2001 through January 2017 who experienced recurrence after initial platinum-based chemotherapy. To determine usual imaging practices for providers at MSKCC, median frequency of CT or MRI of the abdomen/pelvis was calculated among patients with a long-term remission (defined as at least 1 year) treated by each provider. Cox proportional hazards models were used to examine differences in OS and time to recurrence among patients treated by providers with high versus low imaging frequency practices, with additional subgroup analysis among patients with elevated CA-125 levels >35 U/mL at diagnosis. Chi-square tests were used to examine differences in the proportion of patients who enrolled in clinical trials or underwent secondary cytoreductive surgery (SCS) by imaging frequency. RESULTS: A total of 543 patients were treated by providers with high imaging frequency (>1 scan every 12 months) and 141 were treated by providers with low imaging frequency (≤1 scan every 12 months). Time to recurrence was shorter among patients treated by providers with high versus low imaging frequency (18.0 vs 19.2 months; hazard ratio, 1.33; P=.003). Results were similar when restricted to patients with elevated CA-125 levels at diagnosis. There was no significant difference in OS, clinical trial enrollment, or SCS by imaging practice. CONCLUSIONS: Within the limitations of this retrospective analysis, patients with advanced ovarian cancer treated by high-frequency-imaging providers had earlier detection of recurrence. Future analyses in a larger population are warranted to elucidate the risks versus benefits of surveillance imaging.
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Diagnóstico por Imagem , Pessoal de Saúde , Neoplasias Ovarianas/epidemiologia , Padrões de Prática Médica , Adulto , Idoso , Biomarcadores Tumorais , Diagnóstico por Imagem/métodos , Gerenciamento Clínico , Feminino , Avaliação do Impacto na Saúde , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Prognóstico , Vigilância em Saúde PúblicaRESUMO
BACKGROUND: Adults with congenital heart disease (CHD) are an emerging adult heart disease subset, now outnumbering the pediatric population with CHD. OBJECTIVE: We aimed to gain understanding and knowledge of what adults with CHD perceive as important for self-management and describe these needs across demographic factors, developmental characteristics, lesion severity, and quality of life. METHODS: We used a descriptive mixed-methods online survey merging 4 instruments: Adult CHD Self-management Experience Questionnaire; Adult CHD Demographic Questionnaire; Adaptive Behavior Assessment System, Third Edition; and Stanford Quality of Life Visual Numeric. Participants with CHD 18 to 30 years of age with initial defect repair before 12 months of age were recruited through support from the Adult Congenital Heart Association, clinic adult CHD support groups, and newspaper advertising. Thematic analysis for short-answer questions, descriptive analysis for demographic data and the visual numeric, and intrument-specific scoring assistant software for the Adaptive Behavior Assessment System were used. RESULTS: We received 22 responses from 13 women and 9 men. These individuals represented 15 different heart defect diagnoses, mostly of moderate or complex lesion severity. Most had postsecondary education and were employed. Four prominent themes emerged related to self-management: desire for connectivity-psychological support; a plan for the future-education about health and life expectations; coping needs-skills for mental stress; and access to care-navigation of healthcare systems. CONCLUSIONS: Future longitudinal research and replication studies with larger samples are needed. Educational materials and targeted interventions that promote self-management benefit the aging adult with CHD population.
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Necessidades e Demandas de Serviços de Saúde , Cardiopatias Congênitas/psicologia , Cardiopatias Congênitas/terapia , Autogestão/psicologia , Adaptação Psicológica , Adulto , Feminino , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Qualidade de Vida , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVE: To determine the validity of the ActiGraph GT3X accelerometer in step count quantification when compared to observed step count in hospitalised adults recovering from critical illness. SETTING: Large National Health Service (NHS) Hospitals Trust. SUBJECTS: In total, 20 hospital ward-based adults (age: mean 62.3, SD 11.5) who had required greater than 48 hours of mechanical ventilation in the intensive care unit. MAIN MEASURES: Participants walked self-selected distances and speeds as part of a semi-structured movement protocol not exceeding 3 hours. Two ActiGraph GT3X accelerometers were worn, one on the thigh and one on the ankle of the non-dominant leg. Accelerometer-recorded step counts were compared against observed step counts. RESULTS: In total, 31 separate walking episodes were analysed. A mean (SD) of 45.87 (±19.72) steps was calculated for observed step count (range 15-90). Mean differences (95% limits of agreement) of -0.84 steps (-3.88 to 2.2) for the ankle placement and -17.7 steps (-40.63 to 5.25) for the thigh were calculated. Intraclass correlation coefficients (95% confidence intervals) of 0.99 (0.99 to 1.0) and 0.46 (-0.1 to 0.78) were determined for the ankle and thigh, respectively. Placement sites were well tolerated by 95% of participants. CONCLUSION: An ankle-mounted ActiGraph GT3X accelerometer demonstrates validity in quantification of step count in hospitalised adults recovering from critical illness. A thigh placement was not considered valid.
Assuntos
Acelerometria/instrumentação , Estado Terminal , Recuperação de Função Fisiológica , Caminhada , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
PURPOSE: We conducted a systematic review and meta-analysis to measure the extent to which race is associated with delayed initiation or receipt of inadequate chemotherapy among women with early-stage breast cancer. METHODS: We performed a systematic search of all articles published from January 1987 until June 2017 within four databases: PubMed/Medline, EMBASE, CINAHL, and Cochrane CENTRAL. Eligible studies were US-based and examined the influence of race on chemotherapy delays, cessation, or dose reductions among women with stage I, II, or III breast cancer. Data were pooled using a random effects model. RESULTS: A total of twelve studies were included in the quantitative analysis. Blacks were significantly more likely than whites to have delays to initiation of adjuvant therapy of 90 days or more (OR 1.41, 95% CI 1.06-1.87; X² = 31.05, p < 0.00001; I² = 90%). There was no significant association between race and chemotherapy dosing. Due to overlap between studies assessing the relationship between race and completion of chemotherapy, we conducted two separate analyses. Black patients were significantly more likely to discontinue chemotherapy, however, this was no longer statistically significant when larger numbers of patients with more advanced (stage III) breast cancer were included. CONCLUSIONS: These results suggest that black breast cancer patients experience clinically relevant delays in the initiation of adjuvant chemotherapy more often than white patients, which may in part explain the increased mortality observed among black patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Negro ou Afro-Americano , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Estadiamento de Neoplasias , Grupos Raciais , População BrancaRESUMO
OBJECTIVE: To investigate the validity and reliability of accelerometers to detect lying, sitting and standing postures or purposeful activity in hospitalized adults recovering from acute or critical illness. DATA SOURCES: CINAHL, MEDLINE, EMBASE, AMED, Cochrane Library, PEDro, PsycINFO and SPORTDiscuss were searched from inception to June 2017. Professional networks and reference lists of relevant articles were also searched. The main selection criteria were hospitalized adults with acute or critical illness and studies investigating the validity or reliability of accelerometers to identify body position or purposeful activity. REVIEW METHODS: Two authors individually assessed study eligibility and independently undertook methodological quality assessment and data extraction from selected articles. A narrative synthesis of the data was undertaken. RESULTS: Fifteen studies, collectively enrolling 385 hospitalized participants, were identified. Populations included stroke, the elderly, acute exacerbation of chronic respiratory disease, abdominal surgery and those recovering from critical illness. Correlations of r = 0.36 to 0.98 and levels of agreement of κ = 0.28 to 0.98 were reported for identification of lying, sitting or standing postures. Correlations of r = 0.4 to 0.8 with general activity were found, with r = 0.94 and 0.96 reported for step count. The reliability of accelerometry measurement was investigated in one study evaluating step count quantification (intraclass correlation coefficient (ICC) = 0.99, 95% confidence interval (CI) = 0.99-1.00). CONCLUSION: The validity of accelerometers to determine lying, sitting and standing postures or quantify purposeful activity within hospitalized acute or critically ill populations is variable. The reliability of accelerometry measurement within this setting remains largely unexplored.
Assuntos
Acelerometria , Estado Terminal/reabilitação , Imobilização/efeitos adversos , Pacientes Internados , Postura/fisiologia , Atividades Cotidianas , Doença Aguda , Adulto , Idoso , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Equilíbrio Postural/fisiologia , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: This study examined the prevalence of compassion fatigue and life stress of pediatric nurses. BACKGROUND: Distressing patient situations over time may affect nurses' professional quality of life and result in compassion fatigue. If not addressed, compassion fatigue may have personal and organizational consequences. METHODS: Using a descriptive, correlational design, a convenience sample of 268 nurses completed a web-based survey. RESULTS: High compassion satisfaction and moderate to low burnout and secondary traumatic stress were described by 49% of participants. Education was statistically associated with burnout and secondary traumatic stress. Life stress scores were significantly associated with age, experience, organizational tenure, and professional engagement. Narrative commentary yielded 5 themes: staffing, recognition, boundaries, expectations, and hopelessness. Organizational initiatives to prevent or mitigate compassion fatigue focused on awareness, balance, and connections. CONCLUSIONS: Nurses are negatively impacted by the emotional cost of caring. Future studies need to identify interventions to minimize compassion fatigue.
RESUMO
The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Ceramidase Alcalina/metabolismo , Alopecia/enzimologia , Ceramidas/metabolismo , Metabolismo Energético , Homeostase , Ceramidase Alcalina/genética , Alopecia/fisiopatologia , Animais , Diferenciação Celular , Epiderme/anormalidades , Epiderme/enzimologia , Feminino , Folículo Piloso/anormalidades , Folículo Piloso/enzimologia , Humanos , Queratinócitos/enzimologia , Queratinócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipófise/anormalidades , Hipófise/enzimologia , Glândulas Sebáceas/anormalidades , Glândulas Sebáceas/enzimologia , Pele/enzimologia , Anormalidades da Pele , Esfingolipídeos/metabolismoRESUMO
Dengue is a major public health problem globally. It is caused by four antigenically distinct serotypes of dengue virus (DENV1-4), and although serotype-specific and strongly neutralizing cross-reactive immune responses against the four DENV serotypes are thought to be protective, subneutralizing Abs can contribute to increased disease severity upon secondary infection with a different DENV serotype. Understanding the breadth of the immune response in natural DENV infections and in vaccinees is crucial for determining the correlates of protection or disease severity. Transformation of B cell populations to generate mAbs and ELISPOT assays have been used to determine B cell and Ab specificity to DENV; however, both methods have technical limitations. We therefore modified the conventional ELISPOT to develop a Quad-Color FluoroSpot to provide a means of examining B cell/Ab serotype specificity and cross-reactivity on a single-cell basis. Abs secreted by B cells are captured by an Fc-specific Ab on a filter plate. Subsequently, standardized concentrations of all four DENV serotypes are added to allow equal stoichiometry for Ag binding. After washing, the spots, representing individual B cells, are visualized using four fluorescently labeled DENV serotype-specific detection mAbs. This method can be used to better understand the breadth and magnitude of B cell responses following primary and secondary DENV infection or vaccination and their role as immune correlates of protection from subsequent DENV infections. Furthermore, the Quad-Color FluoroSpot assay can be applied to other diseases caused by multiple pathogen serotypes in which determining the serotype or subtype-specific B cell response is important.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos Virais/imunologia , Vírus da Dengue/classificação , Vírus da Dengue/imunologia , ELISPOT/métodos , Aedes , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/análise , Linfócitos B/imunologia , Células Cultivadas , Reações Cruzadas/imunologia , Dengue/imunologia , Dengue/virologia , Vacinas contra Dengue/imunologia , Vírus da Dengue/genética , Humanos , Análise de Célula Única , Vacinação , Proteínas do Envelope Viral/imunologiaRESUMO
Pediatric heart transplant recipients are scarce and widely dispersed. Previous studies of adolescents in this population were limited to small homogenous samples. Although online focus groups are an emerging data collection method, its use in pediatric populations has not been fully realized. The purpose of this study was to explore the feasibility of using online focus groups with pediatric populations. Adolescents (aged 13 to 21 years) at least 6 months post-heart transplant and their parents were recruited from two children's hospitals. An online discussion forum (iTracks) was used to conduct asynchronous focus groups with separate parent and adolescent groups. Six parents and four adolescents participated in the discussions. iTracks provided a framework for conducting focus groups in dispersed populations. Access to the discussion transcripts enhanced data analysis and eliminated transcription costs. Overall, online discussion forums were a feasible and cost-effective option to conduct online focus groups in this pediatric population.
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Transplante de Coração , Adolescente , Adulto , Grupos Focais , Humanos , Projetos PilotoRESUMO
BACKGROUND: In this paper, we provide background and context regarding the potential for a new data-sharing platform, the Project Data Sphere (PDS) initiative, funded by financial and in-kind contributions from the CEO Roundtable on Cancer, to transform cancer research and improve patient outcomes. Given the relatively modest decline in cancer death rates over the past several years, a new research paradigm is needed to accelerate therapeutic approaches for oncologic diseases. Phase III clinical trials generate large volumes of potentially usable information, often on hundreds of patients, including patients treated with standard of care therapies (i.e., controls). Both nationally and internationally, a variety of stakeholders have pursued data-sharing efforts to make individual patient-level clinical trial data available to the scientific research community. POTENTIAL BENEFITS AND RISKS OF DATA SHARING: For researchers, shared data have the potential to foster a more collaborative environment, to answer research questions in a shorter time frame than traditional randomized control trials, to reduce duplication of effort, and to improve efficiency. For industry participants, use of trial data to answer additional clinical questions could increase research and development efficiency and guide future projects through validation of surrogate end points, development of prognostic or predictive models, selection of patients for phase II trials, stratification in phase III studies, and identification of patient subgroups for development of novel therapies. Data transparency also helps promote a public image of collaboration and altruism among industry participants. For patient participants, data sharing maximizes their contribution to public health and increases access to information that may be used to develop better treatments. Concerns about data-sharing efforts include protection of patient privacy and confidentiality. To alleviate these concerns, data sets are deidentified to maintain anonymity. To address industry concerns about protection of intellectual property and competitiveness, we illustrate several models for data sharing with varying levels of access to the data and varying relationships between trial sponsors and data access sponsors. THE PROJECT DATA SPHERE INITIATIVE: PDS is an independent initiative of the CEO Roundtable on Cancer Life Sciences Consortium, built to voluntarily share, integrate, and analyze comparator arms of historical cancer clinical trial data sets to advance future cancer research. The aim is to provide a neutral, broad-access platform for industry and academia to share raw, deidentified data from late-phase oncology clinical trials using comparator-arm data sets. These data are likely to be hypothesis generating or hypothesis confirming but, notably, do not take the place of performing a well-designed trial to address a specific hypothesis. Prospective providers of data to PDS complete and sign a data sharing agreement that includes a description of the data they propose to upload, and then they follow easy instructions on the website for uploading their deidentified data. The SAS Institute has also collaborated with the initiative to provide intrinsic analytic tools accessible within the website itself. As of October 2014, the PDS website has available data from 14 cancer clinical trials covering 9,000 subjects, with hopes to further expand the database to include more than 25,000 subject accruals within the next year. PDS differentiates itself from other data-sharing initiatives by its degree of openness, requiring submission of only a brief application with background information of the individual requesting access and agreement to terms of use. Data from several different sponsors may be pooled to develop a comprehensive cohort for analysis. In order to protect patient privacy, data providers in the U.S. are responsible for deidentifying data according to standards set forth by the Privacy Rule of the U.S. Health Insurance Portability and Accountability Act of 1996. USING DATA SHARING TO IMPROVE OUTCOMES IN CANCER THE "PROSTATE CANCER CHALLENGE": Control-arm data of several studies among patients with metastatic castration-resistant prostate cancer (mCRPC) are currently available through PDS. These data sets have multiple potential uses. The "Prostate Cancer Challenge" will ask the cancer research community to use clinical trial data deposited in the PDS website to address key research questions regarding mCRPC. General themes that could be explored by the cancer community are described in this article: prognostic models evaluating the influence of pretreatment factors on survival and patient-reported outcomes; comparative effectiveness research evaluating the efficacy of standard of care therapies, as illustrated in our companion article comparing mitoxantrone plus prednisone with prednisone alone; effects of practice variation in dose, frequency, and duration of therapy; level of patient adherence to elements of trial protocols to inform the design of future clinical trials; and age of subjects, regional differences in health care, and other confounding factors that might affect outcomes. POTENTIAL LIMITATIONS AND METHODOLOGICAL CHALLENGES: The number of data sets available and the lack of experimental-arm data limit the potential scope of research using the current PDS. The number of trials is expected to grow exponentially over the next year and may include multiple cancer settings, such as breast, colorectal, lung, hematologic malignancy, and bone marrow transplantation. Other potential limitations include the retrospective nature of the data analyses performed using PDS and its generalizability, given that clinical trials are often conducted among younger, healthier, and less racially diverse patient populations. Methodological challenges exist when combining individual patient data from multiple clinical trials; however, advancements in statistical methods for secondary database analysis offer many tools for reanalyzing data arising from disparate trials, such as propensity score matching. Despite these concerns, few if any comparable data sets include this level of detail across multiple clinical trials and populations. CONCLUSION: Access to large, late-phase, cancer-trial data sets has the potential to transform cancer research by optimizing research efficiency and accelerating progress toward meaningful improvements in cancer care. This type of platform provides opportunities for unique research projects that can examine relatively neglected areas and that can construct models necessitating large amounts of detailed data. The full potential of PDS will be realized only when multiple tumor types and larger numbers of data sets are available through the website.