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Jennifer J Clark

Publications and source records attributed to Jennifer J Clark.

13 recordsLinked to original sources
PubMed2006

Early childhood externalising behaviour problems: child, parenting, and family-related predictors over time.

This study examined the dynamic relationships between child, parenting, and family-related predictor variables and early childhood externalising behaviour problems. A community sample of 395 Australian children was followed longitudinally, and assessed at 4 and 6 years with the Child Behavior Checklist, Teacher Report Form, and standard measures of parenting, temperament, and familial adversity. Variables based on the average scores across the two assessments and the change in scores between assessments were utilised as predictors of parent-reported and teacher-reported externalising behaviour problems at age 6. It was hypothesised that both higher average scores and more detrimental changes in scores, would independently predict externalising problems at age 6. Multivariable analyses found that the presence of parent-reported child externalising problems in six-year-olds were predicted by: (i) the presence of parent-reported child externalising problems at age 4, (ii) higher average "teacher-reported child externalising behaviour," "inflexible temperament," "non-persistent temperament," and "over-reactive parenting," and (iii) an increased "inflexible temperament" score between age 4 and age 6. The presence of teacher-reported child externalising problems at age 6 was predicted by higher average "parent-reported child externalising behaviour," and "over-reactive parenting." The results provide further evidence of the adverse impact of continuing high levels of temperament difficulties and over-reactive parenting on externalising behaviour in early childhood. However, contrary to expectations, the contribution of including the dynamic change scores was limited.

Child Behavior Disorders↗
PubMed2006

Treatment burden and health-related quality of life of children with diabetes, cystic fibrosis and asthma.

AIM: To identify the time required by children with cystic fibrosis (CF), diabetes or asthma to complete daily treatment tasks and the hassle they experienced when completing these tasks. To compare parent and child reports of daily treatment time and hassle. To investigate the relationship between treatment time and hassle, and (i) children's health-related quality of life (HRQL); and (ii) disease severity. METHODS: 160 children aged 10-16 years with CF, type 1 diabetes, or asthma were followed over a 2-year period. Information about children's treatment time and hassle, and their HRQL was obtained from parents and children at baseline, 1-year and 2-year follow-up assessments. RESULTS: On average, children with CF reported spending 74.6 +/- 57.0 min completing treatment tasks, children with diabetes spent 56.9 +/- 27.8 min and children with asthma spent 6.4 +/- 9.3 min. Parents reported that children spent less time that was reported by their children. Over the two years, parent and child reports describing treatment time for children with CF did not vary significantly (P = 0.3). Treatment time for children with diabetes increased (P = 0.02) whereas that for children with asthma reduced (P = 0.001). The level of hassle experienced by children when completing individual treatment tasks was low for all three conditions. There was no significant relationship between treatment time and children's HRQL. CONCLUSION: Children with CF or diabetes spent a substantial amount of time each day completing the treatment tasks. Although this was not related to HRQL, it could impact the ability to comply with complex and all home-based-therapies for some children.

Adolescent↗
PubMed2006

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

BACKGROUND: The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). METHODS AND FINDINGS: DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. CONCLUSIONS: Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF, including extramedullary hematopoiesis, splenomegaly, and megakaryocytic proliferation. Further analysis of positive and negative regulators of the JAK-STAT pathway is warranted in JAK2V617F-negative MPD.

Amino Acid Substitution↗
PubMed2005

The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.

Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies.

Aged↗
PubMed2005

Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412.

Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib mesylate. In these cells, PKC412, but not imatinib mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib mesylate-resistant D816V or D816Y activation mutations.

Animals↗
PubMed2005

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.

Adult↗
PubMed2004

Hemoglobin Jamaica plain--a sickling hemoglobin with reduced oxygen affinity.

A baby girl presented with symptomatic sickle cell disease exacerbated by mild hypoxemia, despite a newborn-screening diagnosis of sickle cell trait. DNA sequencing of the beta globin gene revealed that her maternal beta globin allele was normal. Her paternal allele had not only the expected sickle-trait mutation, betaGlu6Val, but also a second, charge-neutral mutation, betaLeu68Phe. Analysis of the patient's hemoglobin revealed that the double-mutant protein, which we called "hemoglobin Jamaica Plain," had severely reduced oxygen affinity. Structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at an ambient partial pressure of oxygen.

Altitude↗
PubMed2004

Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia.

Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AML patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors.

Acute Disease↗
PubMed2004

Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518.

FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in acute myeloid leukemia (AML). We tested the sensitivity of 8 activation loop mutations to the small molecule FLT3 inhibitor, MLN518. Each FLT3 activation loop mutant, including D835Y, D835A, D835E, D835H, D835N, D835V, D835del, and I836del, transformed Ba/F3 cells to factor-independent proliferation and had constitutive tyrosine kinase activation, as assessed by FLT3 autophosphorylation and activation of downstream effectors, including STAT5 and ERK. MLN518 inhibited FLT3 autophosphorylation and phosphorylation of STAT5 and ERK in FLT3-ITD-transformed Ba/F3 cells with an IC(50) (50% inhibition of cell viability) of approximately 500 nM. However, there was a broad spectrum of sensitivity among the 8 activation loop mutants, with IC(50) ranging from approximately 500 nM to more than 10 microM for the inhibition of phosphorylation of FLT3, STAT5, and ERK. The relative sensitivity of the mutants to MLN518 in biochemical assays correlated with the cellular IC(50) for cytokine-independent proliferation of FLT3-transformed Ba/F3 cells in the presence of MLN518. Thus, certain activation loop mutations in FLT3 simultaneously confer resistance to small molecule inhibitors. These findings have implications for the evaluation of responses in clinical trials with FLT3 inhibitors and provide a strategy to screen for compounds that can overcome resistance.

Animals↗
PubMed2003

Update in childhood acute myeloid leukemia: recent developments in the molecular basis of disease and novel therapies.

Childhood acute myeloid leukemia is a heterogeneous group of disorders that remains challenging to treat. There are multiple common genetic alterations in childhood acute myeloid leukemia. These include chromosomal translocations affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these abnormalities are better understood, they are providing important insights into the pathogenesis of disease as well as information about prognosis. Although intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy, long-term cure rates with chemotherapy alone remain approximately 50%, creating an urgent need for better therapies. Multiple avenues are being explored in the design of new treatments for pediatric acute myeloid leukemia. Targeted therapies include targeted antibody therapy; inhibitors of FLT3, KIT, and farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage colony-stimulating factor; and antisense oligonucleotides. Another area of interest is chromatin remodeling and differentiation therapy, including agents such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation and histone deacetylation. There are also ongoing trials of antiangiogenesis agents. Another avenue for novel therapies is immunotherapy with agents such as interleukin-2 and tumor vaccines. This article reviews recent advances in understanding of the molecular basis for childhood acute myeloid leukemia and the design of novel therapies for the treatment of childhood acute myeloid leukemia.

Acute Disease↗
PubMed2003

Socio-economic differentials in the health-related quality of life of Australian children: results of a national study.

OBJECTIVE: To examine differences in health-related quality of life (HRQL) of children living in different socio-economic contexts in Australia. METHODS: Parental reports describing the HRQL and socio-economic status of a random national sample of 3,597 school-age children were obtained using the Child Health Questionnaire (CHQ) and a standardised socio-economic interview. Response rate was 70%. RESULTS: Children in families of higher income, whose parents had more years of schooling and were employed and children who lived in two-parent, original families had significantly higher HRQL across a range of domains assessed by the CHQ. CONCLUSION: Children from lower socio-economic backgrounds in Australia have a significantly more negative experience of health and wellness. Such differences may well increase unless deliberate political attention is given to addressing the widening differences in relative wealth in Australia.

Adolescent↗
PubMed2002

Use of medication by young people with attention-deficit/hyperactivity disorder.

OBJECTIVES: To examine the prevalence of psychotropic medication use by children with attention-deficit/hyperactivity disorder (ADHD) and children without ADHD. To identify factors associated with stimulant use by children in the community. DESIGN: A representative, multistage probability sample of Australian households was conducted in 1998. Parents completed questionnaires assessing children's mental health problems and health-related quality of life. They also completed a structured interview to identify children's psychiatric disorders and their use of medications during the previous six months. PARTICIPANTS: Parent or main caregiver of 3597 children aged 6-17 years. MAIN OUTCOME MEASURES: Rates of use of stimulants (dexamphetamine and methylphenidate), antidepressants and clonidine by children. RESULTS: Overall, 1.8% of children (95% CI, 1.5%-2.3%) were receiving stimulant medication. Of those with ADHD, 12.6% (95% CI, 9.8%-16.1%) were being treated with stimulants, 2.3% (95% CI, 1.3%-4.3%) with antidepressants, and 1.9% (95% CI, 1.0%-3.7%) with clonidine. Among children without ADHD, 0.5% (95% CI, 0.3%-0.8%) were receiving stimulant medication. This represented 22.9% (95% CI, 14.6%-34.0%) of all the children who were receiving stimulants. Variables significantly associated with stimulant use were being male, having ADHD, attending a paediatrician, and having higher scores on the Aggressive Behaviour and Attention Problems scales on the Child Behaviour Checklist. CONCLUSIONS: About 13% of Australian children with ADHD, and a substantial number of children without ADHD, are taking stimulants. The question of whether Australian children are being undertreated or overtreated with stimulant medication depends on the criteria used to assess the appropriateness of stimulant use. Additional information is needed to clarify when stimulants should be used to treat ADHD.

Adolescent↗