RESUMO
Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
Assuntos
Neoplasias Hematológicas , Leucemia , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Neoplasias Hematológicas/genética , Mutação em Linhagem Germinativa , RNA Helicases DEAD-box/genética , Carcinogênese , Células Germinativas , Fator de Transcrição GATA2/genéticaRESUMO
Unstable gamma globin variants can cause transient neonatal hemolytic anemia. We have identified a novel variant in a newborn who presented with jaundice and anemia requiring phototherapy and red blood cell transfusion. The patient was found to be heterozygous for the mutation HGB2:c.290T>C, p.Leu97Pro, which we have termed hemoglobin (Hb) Wareham. This substitution is expected to generate an unstable hemoglobin with increased oxygen affinity based on the homologous mutation previously described in the beta globin gene, which is termed as Hb Debrousse. The patient fully recovered by 9 months of age as expected with the transition from fetal to adult hemoglobin.
Assuntos
Anemia Hemolítica , Hemoglobinas Anormais , gama-Globinas , Humanos , Recém-Nascido , Anemia Hemolítica/genética , Globinas beta/genética , gama-Globinas/genética , Hemoglobinas Anormais/genética , Heterozigoto , Mutação , LactenteRESUMO
Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
Assuntos
Síndrome de Down , Fator de Transcrição GATA1 , Leucemia Megacarioblástica Aguda , Leucemia Mieloide , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Mutação em Linhagem Germinativa , Humanos , Leucemia Megacarioblástica Aguda/complicações , Leucemia Megacarioblástica Aguda/genética , Leucemia Mieloide/complicações , Masculino , Mutação , Fenótipo , TrissomiaRESUMO
Definitive long-term hematopoietic stem cells (LT-HSCs) arise during embryogenesis in a process termed endothelial-to-hematopoietic transition (EHT), in which specialized hemogenic endothelial cells (HECs) transform into hematopoietic cells. The transcription factor RUNX1 marks HECs and is essential for EHT. Ectopic RUNX1 expression in non-HECs is sufficient to convert them into HECs. However, the conversion efficiency depends on the developmental timing of expression. In this issue of Genes & Development, Howell and colleagues (pp. 1475-1489) leverage this observation to further understand how RUNX1 mediates EHT. They engineered mice that ectopically express RUNX1 in endothelial cells at different developmental time points and doses. They then performed chromatin accessibility and other analyses and correlate this with hemogenic potential. They found that RUNX1 collaborates with TGFß signaling transcription factors to drive chromatin accessibility changes that specify HECs. They also highlight interesting parallels between EHT and endothelial-to-mesenchymal transition (EndoMT), which occurs during cardiac development. The results of Howell and colleagues provide new mechanistic insights into EHT and take us one step closer to generating patient-specific LT-HSCs from induced pluripotent stem cells.
Assuntos
Hemangioblastos , Hematopoese , Animais , Adesão Celular , Diferenciação Celular/genética , Hemangioblastos/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , CamundongosRESUMO
Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C>T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic sample. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.
Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células Germinativas , Humanos , MutaçãoAssuntos
Infecções por Clostridium/patologia , Enterocolite Necrosante/patologia , Hemólise , Doenças do Recém-Nascido/patologia , Sepse/patologia , Infecções por Clostridium/complicações , Clostridium perfringens/isolamento & purificação , Enterocolite Necrosante/etiologia , Humanos , Recém-Nascido , Masculino , Sepse/etiologiaRESUMO
Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Polimorfismo de Nucleotídeo Único/genética , Trombocitopenia/genética , Adolescente , Adulto , Idoso , Linhagem Celular , Linhagem Celular Tumoral , Criança , Quebra Cromossômica , Transtornos Cromossômicos/genética , Exoma/genética , Feminino , Células HEK293 , Células HeLa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Trombocitopenia/congênitoRESUMO
Genome-wide association studies identify genomic variants associated with human traits and diseases. Most trait-associated variants are located within cell-type-specific enhancers, but the molecular mechanisms governing phenotypic variation are less well understood. Here, we show that many enhancer variants associated with red blood cell (RBC) traits map to enhancers that are co-bound by lineage-specific master transcription factors (MTFs) and signaling transcription factors (STFs) responsive to extracellular signals. The majority of enhancer variants reside on STF and not MTF motifs, perturbing DNA binding by various STFs (BMP/TGF-ß-directed SMADs or WNT-induced TCFs) and affecting target gene expression. Analyses of engineered human blood cells and expression quantitative trait loci verify that disrupted STF binding leads to altered gene expression. Our results propose that the majority of the RBC-trait-associated variants that reside on transcription-factor-binding sequences fall in STF target sequences, suggesting that the phenotypic variation of RBC traits could stem from altered responsiveness to extracellular stimuli.
Assuntos
Eritrócitos/fisiologia , Regulação da Expressão Gênica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos/genética , Eritrócitos/citologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas/genética , Proteína Smad1/genética , Proteína Smad1/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica/genéticaRESUMO
Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Hematopoese , Animais , Diferenciação Celular , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/química , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Baço/citologia , Peixe-ZebraRESUMO
Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.
Assuntos
Mutação/genética , Mielofibrose Primária/diagnóstico , Proteína cdc42 de Ligação ao GTP/genética , Ciclo Celular , Microambiente Celular , Células HEK293 , Hematopoese/genética , Humanos , Lactente , Recém-Nascido , Mielofibrose Primária/genética , Irmãos , Sequenciamento do ExomaRESUMO
Cells are constantly exposed to endogenous and exogenous stresses that can result in DNA damage. In response, they have evolved complex pathways to maintain genomic integrity. RUNX family transcription factors (RUNX1, RUNX2, and RUNX3 in mammals) are master regulators of development and differentiation, and are frequently dysregulated in cancer. A growing body of research also implicates RUNX proteins as regulators of the DNA damage response, often acting in conjunction with the p53 and Fanconi anemia pathways. In this review, we discuss the functional role and mechanisms involved in RUNX factor mediated response to DNA damage and other cellular stresses. We highlight the impact of these new findings on our understanding of cancer predisposition associated with RUNX factor dysregulation and their implications for designing novel approaches to prevent cancer formation in affected individuals.
Assuntos
Subunidades alfa de Fatores de Ligação ao Core/genética , Dano ao DNA/genética , Anemia de Fanconi/genética , Genômica/métodos , Fatores de Transcrição/genética , Anemia de Fanconi/patologia , HumanosRESUMO
Erythroid maturation requires the concerted action of a core set of transcription factors. We previously identified the Krüppel-type zinc finger transcription factor Zfp148 (also called ZBP-89) as an interacting partner of the master erythroid transcription factor GATA1. Here we report the conditional knockout of Zfp148 in mice. Global loss of Zfp148 results in perinatal lethality from nonhematologic causes. Selective Zfp148 loss within the hematopoietic system results in a mild microcytic and hypochromic anemia, mildly impaired erythroid maturation, and delayed recovery from phenylhydrazine-induced hemolysis. Based on the mild erythroid phenotype of these mice compared with GATA1-deficient mice, we hypothesized that additional factor(s) may complement Zfp148 function during erythropoiesis. We show that Zfp281 (also called ZBP-99), another member of the Zfp148 transcription factor family, is highly expressed in murine and human erythroid cells. Zfp281 knockdown by itself results in partial erythroid defects. However, combined deficiency of Zfp148 and Zfp281 causes a marked erythroid maturation block. Zfp281 physically associates with GATA1, occupies many common chromatin sites with GATA1 and Zfp148, and regulates a common set of genes required for erythroid cell differentiation. These findings uncover a previously unknown role for Zfp281 in erythroid development and suggest that it functionally overlaps with that of Zfp148 during erythropoiesis.
Assuntos
Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Células Eritroides/citologia , Células Eritroides/metabolismo , Eritropoese/genética , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição GATA1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Humanos , Camundongos , Camundongos Knockout , Ligação Proteica , Fatores de Transcrição/metabolismo , gama-Globinas/genética , gama-Globinas/metabolismoRESUMO
Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Plaquetas/patologia , Medula Óssea/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Progressão da Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Masculino , Megacariócitos/patologia , Isoformas de Proteínas , Adulto JovemRESUMO
BACKGROUND: The current study assessed the feasibility of a mentored home-based vegetable gardening intervention and examined changes in health-related outcomes among breast cancer survivors (BCS). METHODS: BCS were randomized to either a year-long vegetable gardening intervention to begin immediately or a wait-list control. Master Gardeners mentored participants in planning, planting, and maintaining 3 seasonal gardens over the course of 1 year. Participant accrual, retention, and satisfaction rates of ≥80% served as feasibility (primary outcome) benchmarks. Secondary outcomes (ie, vegetable consumption, physical activity, performance and function, anthropometrics, biomarkers, and health-related quality of life) were collected at baseline and post-intervention (1-year follow-up) using subjective and objective measures. RESULTS: The trial surpassed all feasibility benchmarks at 82% of targeted accrual, 95% retention, and 100% satisfaction (ie, experience ratings of "good to excellent" and willingness to "do it again"). Compared with the controls, intervention participants reported significantly greater improvements in moderate physical activity (+14 vs -17 minutes/week) and demonstrated improvements in the 2-Minute Step Test (+22 vs + 10 steps), and Arm Curl (+2.7 vs + 0.1 repetitions) (P values < .05). A trend toward improved vegetable consumption was observed (+0.9 vs + 0.2 servings/day; P = .06). Approximately 86% of participants were continuing to garden at the 2-year follow-up. CONCLUSIONS: The results of the current study suggest that a mentored, home-based vegetable gardening intervention is feasible and offers an integrative and durable approach with which to improve health behaviors and outcomes among BCS. Harvest for Health led to the establishment of a group of trained Master Gardeners and gave rise to local and global community-based programs. Larger studies are needed to confirm the results presented herein and to define applicability across broader populations of survivors.
Assuntos
Neoplasias da Mama/reabilitação , Sobreviventes de Câncer , Exercício Físico/fisiologia , Jardinagem , Serviços de Assistência Domiciliar , Tutoria , Desempenho Físico Funcional , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobreviventes de Câncer/educação , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Jardinagem/métodos , Comportamentos Relacionados com a Saúde/fisiologia , Humanos , Tutoria/métodos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Qualidade de Vida , VerdurasRESUMO
BACKGROUND: Holistic approaches are sought to improve lifestyle behaviors and health of cancer survivors long term. OBJECTIVE: Our aim was to explore whether a home-based vegetable gardening intervention is feasible and whether it improves diet and other health-related outcomes among older cancer survivors. DESIGN: We conducted a feasibility trial in which cancer survivors were randomized to receive a year-long gardening intervention immediately or to a wait-list control arm. Home visits at baseline and 1 year assessed physical performance, anthropometric indices, behavioral and psychosocial outcomes, and biomarkers. PARTICIPANTS/SETTING: Participants included 46 older (aged 60+ years) survivors of locoregionally staged cancers across Alabama from 2014 to 2016. Forty-two completed 1-year follow-up. INTERVENTION: Cooperative extension master gardeners delivered guidance to establish three seasonal vegetable gardens at survivors' homes. Plants, seeds, and gardening supplies were provided. OUTCOMES: Primary outcomes were feasibility targets of 80% accrual and retention, and an absence of serious adverse events; other outcomes were secondary and explored potential benefits. STATISTICAL ANALYSES: Baseline to follow-up changes were assessed within and between arms using paired t, McNemar's, and χ2 tests. RESULTS: This trial proved to be safe and demonstrated 91.3% retention; 70% of intervention participants rated their experience as "excellent," and 85% would "do it again." Data suggest significantly increased reassurance of worth (+0.49 vs -0.45) and attenuated increases in waist circumference (+2.30 cm vs +7.96 cm) in the gardening vs control arms (P=0.02). Vegetable and fruit consumption increased by approximately 1 serving/day within the gardening arm from baseline to follow-up (mean [standard error]=1.34 [1.2] to 2.25 [1.9] servings/day; P=0.02)] compared to controls (1.22 [1.1] to 1.12 [0.7]; P=0.77; between-arm P=0.06). CONCLUSIONS: The home vegetable gardening intervention among older cancer survivors was feasible and suggested improvements in vegetable and fruit consumption and reassurance of worth; data also suggest attenuated increases in waist circumference. Continued study of vegetable gardening interventions is warranted to improve health, health behaviors, and well-being of older cancer survivors.
Assuntos
Sobreviventes de Câncer/psicologia , Dieta/métodos , Frutas , Jardinagem/métodos , Verduras , Adiposidade , Alabama , Dieta/psicologia , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Estudos de Viabilidade , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente , Projetos Piloto , Qualidade de Vida , Desejabilidade Social , Circunferência da CinturaRESUMO
Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development.
Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Eritropoetina/metabolismo , Fator de Transcrição GATA1/metabolismo , Heme/biossíntese , Transdução de Sinais , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Camundongos , Membranas Mitocondriais/metabolismo , Peixe-ZebraRESUMO
BACKGROUND: Cancer survivors suffer from long-term adverse effects that reduce health-related quality of life (QOL) and physical functioning, creating an urgent need to develop effective, durable, and disseminable interventions. Harvest for Health, a home-based vegetable gardening intervention, holds promise for these domains. METHODS: This report describes the methods and recruitment experiences from two randomized controlled feasibility trials that employ a waitlist-controlled design. Delivered in partnership with Cooperative Extension Master Gardeners, this intervention provides one-on-one mentorship of cancer survivors in planning and maintaining three seasonal vegetable gardens over 12months. The primary aim is to determine intervention feasibility and acceptability; secondary aims are to explore effects on objective and subjective measures of diet, physical activity and function, and QOL and examine participant factors associated with potential effects. One trial is conducted exclusively among 82 female breast cancer survivors residing in the Birmingham, AL metropolitan area (BBCS); another broadly throughout Alabama among 46 older cancer survivors aged >60 (ASCS). RESULTS: Response rates were 32.6% (BBCS) and 52.3% (ASCS). Both trials exceeded 80% of their accrual target. Leading reasons for ineligibility were removal of >10 lymph nodes (lymphedema risk factor), lack of physician approval, and unwillingness to be randomized to the waitlist. CONCLUSION: To date, recruitment and implementation of Harvest for Health appears feasible. DISCUSSION: Although both studies encountered recruitment challenges, lessons learned can inform future larger-scale studies. Vegetable gardening interventions are of interest to cancer survivors and may provide opportunities to gain life skills leading to improvements in overall health and QOL.
Assuntos
Sobreviventes de Câncer , Exercício Físico , Jardinagem/organização & administração , Projetos de Pesquisa , Verduras , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
OBJECTIVE: To examine pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura (ITP) or chronic ITP (cITP) diagnosed before or during pregnancy. METHODS: A linkage of mothers and babies within a large U.S. health insurance database that combines enrollment data, pharmacy claims, and medical claims was carried out to identify pregnancies in women with ITP or cITP. Outcomes included preterm birth, elective and spontaneous loss, and major congenital anomalies. RESULTS: Results suggest that women diagnosed with ITP or cITP prior to their estimated date of conception may be at higher risk for stillbirth, fetal loss, and premature delivery. Among 446 pregnancies in women with ITP, 346 resulted in live births. Women with cITP experienced more adverse outcomes than those with a pregnancy-related diagnosis of ITP. Although 7.8% of all live births had major congenital anomalies, the majority were isolated heart defects. Among deliveries in women with cITP, 15.2% of live births were preterm. CONCLUSIONS: The results of this study provide further evidence that cause and duration of maternal ITP are important determinants of the outcomes of pregnancy.
Assuntos
Anormalidades Congênitas/epidemiologia , Nascido Vivo/epidemiologia , Complicações Hematológicas na Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Púrpura Trombocitopênica Idiopática/epidemiologia , Natimorto/epidemiologia , Adolescente , Adulto , Doença Crônica , Estudos de Coortes , Bases de Dados Factuais , Feminino , Morte Fetal , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Src phosphorylates Runx1 on one central and four C-terminal tyrosines. We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter. Mutation of the four Runx1 C-terminal tyrosines to aspartate or glutamate to mimic phosphorylation increases trans-activation of the reporter in 293T cells and allows induction of Cebpa or Pu.1 mRNAs in 32Dcl3 myeloid cells, whereas mutation of these residues to phenylalanine to prevent phosphorylation obviates these effects. Three mechanisms contribute to increased Runx1 activity upon tyrosine modification as follows: increased stability, reduced histone deacetylase (HDAC) interaction, and increased DNA binding. Mutation of the five modified Runx1 tyrosines to aspartate markedly reduced co-immunoprecipitation with HDAC1 and HDAC3, markedly increased stability in cycloheximide or in the presence of co-expressed Cdh1, an E3 ubiquitin ligase coactivator, with reduced ubiquitination, and allowed DNA-binding in gel shift assay similar to wild-type Runx1. In contrast, mutation of these residues to phenylalanine modestly increased HDAC interaction, modestly reduced stability, and markedly reduced DNA binding in gel shift assays and as assessed by chromatin immunoprecipitation with the -14-kb Pu.1 or +37-kb Cebpa enhancers after stable expression in 32Dcl3 cells. Affinity for CBFß, the Runx1 DNA-binding partner, was not affected by these tyrosine modifications, and in vitro translated CBFß markedly increased DNA affinity of both the translated phenylalanine and aspartate Runx1 variants. Finally, further supporting a positive role for Runx1 tyrosine phosphorylation during granulopoiesis, mutation of the five Src-modified residues to aspartate but not phenylalanine allows Runx1 to increase Cebpa and granulocyte colony formation by Runx1-deleted murine marrow.