Survey of VFC provider knowledge of catch-up regimens and contraindications to vaccination in Houston, Texas

In 2004, Houston had one of the lowest childhood immunization levels among major metropolitan cities in the United States at 65% for the 4:3:1:3:3 vaccination series. Delays in the receipt of scheduled vaccinations may be related to missed opportunities due to health care provider lack of knowledge about catch-up regimens and contraindications for pediatric vaccination. The objectives of this study are to identify, measure, and report on VFC provider-practice characteristics, knowledge of catch-up regimens and contraindications, and use of Reminder recall (R/R) and moved or gone elsewhere (MOGE) practices among providers with high (>80%) and low (<70%) immunization coverage among 19-35 month old children. The sampling frame consists of 187 Vaccines for Children (VFC) providers with 2004 clinic assessment software application (CASA) scores. Data were collected by personal interview with each participating practice provider. Only ten VFC providers were successful at maximizing vaccinations for every vignette and no provider administered the maximum possible number of vaccinations at visit 2 for all six vignettes. Both coverage groups administered polio conjugate vaccine (PCV), haemophilus influenza type b (Hib), and diphtheria, tetanus and acellular pertussis (DTaP) most frequently and omitted most frequently varicella zoster vaccine (VZV) and measles, mumps, and rubella (MMR) vaccine. ^

The coordinated approach to child health in underserved population (CATCH UP) curriculum: A quantitative evaluation of an innovative preschool obesity prevention program

Obesity has been on the rise in the United States over the last 30 years for all populations, including preschoolers. The purpose of the project was to develop an observation tool to measure physical activity levels in preschool children and use the tool in a pilot test of the CATCH UP curriculum at two Head Start Centers in Houston. Pretest and posttest interobserver agreements were all above 0.60 for physical activity level and physical activity type. Preschoolers spent the majority of their time in light physical activity (75.33% pretest, 87.77% posttest), and spent little time in moderate to vigorous physical activity (MVPA) (24.67% pretest, 12.23% posttest). Percent time spent in MVPA decreased significantly pretest to posttest from (F=5.738, p=0.043). While the pilot testing of the CATCH UP curriculum did not show an increase in MVPA, the SOFIT-P tool did show promising results as being a new method for collecting physical activity level data for preschoolers. Once the new tool has undergone more reliability and validity testing, it could allow for a more convenient method of collecting physical activity levels for preschoolers. ^

GROWTH PATTERNS OF CHILDREN OF MOTHERS WITH EPILEPSY

The extent to which antiepileptic drugs (AED) in utero exposure are related to prenatal and postnatal growth is investigated in an retrospective, cohort study of children of AED treated mothers with epilepsy (N = 89) and children of women without epilepsy (N = 89). The study groups were obtained from a population based health care facility.^ Major finding was that birth head circumference of AED exposed children are significantly smaller than control children, notably male children. Other findings include birth length and weight of exposed children was slightly but not significantly smaller. Postnatal growth as measured by two velocity terms, rate of growth, and deceleration, was not significantly different between exposed and control children for height, weight, and head circumference, indicating no catch up growth. Morphologic defects, neonatal and infant mortality was more frequent in exposed children. Mothers with epilepsy reported significantly fewer spontaneous abortions. ^

Commentary on "Expanded Learning Time in Schools"

As co-founder of KIPP, I know from experience and research that more time in school works. A well-designed extended-time program can help underserved students catch up academically, and prepare them for the rigors of higher education. Implementing extended time more widely poses challenges, but there are also creative solutions to these challenges.

Body mass index trajectories and predictors among 3rd to 12th graders using growth curve mixture modeling the Child and Adolescent Trial for Cardiovascular Health (CATCH) study

This dissertation examined body mass index (BMI) growth trajectories and the effects of gender, ethnicity, dietary intake, and physical activity (PA) on BMI growth trajectories among 3rd to 12th graders (9-18 years of age). Growth curve model analysis was performed using data from The Child and Adolescent Trial for Cardiovascular Health (CATCH) study. The study population included 2909 students who were followed up from grades 3-12. The main outcome was BMI at grades 3, 4, 5, 8, and 12. ^ The results revealed that BMI growth differed across two distinct developmental periods of childhood and adolescence. Rate of BMI growth was faster in middle childhood (9-11 years old or 3rd - 5th grades) than in adolescence (11-18 years old or 5th - 12th grades). Students with higher BMI at 3rd grade (baseline) had faster rates of BMI growth. Three groups of students with distinct BMI growth trajectories were identified: high, average, and low. ^ Black and Hispanic children were more likely to be in the groups with higher baseline BMI and faster rates of BMI growth over time. The effects of gender or ethnicity on BMI growth differed across the three groups. The effects of ethnicity on BMI growth were weakened as the children aged. The effects of gender on BMI growth were attenuated in the groups with a large proportion of black and Hispanic children, i.e., “high” or “average” BMI trajectory group. After controlling for gender, ethnicity, and age at baseline, in the “high BMI trajectory”, rate of yearly BMI growth in middle childhood increased 0.102 for every 500 Kcals increase (p=0.049). No significant effects of percentage of energy from total fat and saturated fat on BMI growth were found. Baseline BMI increased 0.041 for every 30 minutes increased in moderate-to-vigorous PA (MVPA) in the “low BMI trajectory”, while Baseline BMI decreased 0.345 for every 30 minutes increased in vigorous PA (VPA) in the “high BMI trajectory”. ^ Childhood overweight and obesity interventions should start at the earliest possible ages, prior to 3rd grade and continue through grade school. Interventions should focus on all children, but specifically black and Hispanic children, who are more likely to be highest at-risk. Promoting VPA earlier in childhood is important for preventing overweight and obesity among children and adolescents. Interventions should target total energy intake, rather than only percentage of energy from total fat or saturated fat. ^

Stromal derived growth factor alpha (SDF-1α) induces the differentiation of bone marrow progenitor cells (BMCs) into pericytes by regulating platelet derived growth factor B (PDGF-B) transcription

We previously demonstrated that bone marrow cells (BMCs) migrate to TC71 and A4573 Ewing’s sarcoma tumors where they can differentiate into endothelial cells (ECs) and pericytes and, participate in the tumor vascular development. This process of neo-vascularization, known as vasculogenesis, is essential for Ewing’s sarcoma growth with the soluble vascular endothelial growth factor, VEGF165, being the chemotactic factor for BMC migration to the tumor site. Inhibiting VEGF165 in TC71 tumors (TC/siVEGF7-1) inhibited BMC infiltration to the tumor site and tumor growth. Introducing the stromal-derived growth factor (SDF-1α) into the TC/siVEGF7-1 tumors partially restored vasculogenesis with infiltration of BMCs to a perivascular area where they differentiated into pericytes and rescued tumor growth. RNA collected from the SDF-1α-treated TC/siVEGF7-1 tumors also revealed an increase in platelet-derived growth factor B (PDGF-B) mRNA levels. PDGF-B expression is elevated in several cancer types and the role of PDGF-B and its receptor, PDGFR-β, has been extensively described in the process of pericyte maturation. However, the mechanisms by which PDGF-B expression is up-regulated during vascular remodeling and the process by which BMCs differentiate into pericytes during tumor vasculogenesis remain areas of investigation. In this study, we are the first to demonstrate that SDF-1α regulates the expression of PDGF-B via a transcriptional mechanism which involves binding of the ELK-1 transcription factor to the pdgf-b promoter. We are also first to validate the critical role of the SDF-1α/PDGF-B pathway in the differentiation of BMCs into pericytes both in vitro and in vivo. SDF-1α up-regulated PDGF-B expression in both TC/siVEGF7-1 and HEK293 cells. In contrast, down-regulating SDF-1α, down-regulated PDGF-B. We cloned the 2 kb pdgf-b promoter fragment into the pGL3 reporter vector and showed that SDF-1α induced pdgf-b promoter activity. We used chromatin immunoprecipitation (ChIP) and demonstrated that the ELK-1 transcription factor bound to the pdgf-b promoter in response to SDF-1α stimulation in both TC/siVEGF7-1 and HEK293 cells. We collected BMCs from the hind femurs of mice and cultured the cells in medium containing SDF-1α and PDGF-B and found that PDGFR-β+ BMCs differentiated into NG2 and desmin positive pericytes in vitro. In contrast, inhibiting SDF-1α and PDGF-B abolished this differentiation process. In vivo, we injected TC71 or A4573 tumor-bearing mice with the SDF-1α antagonist, AMD3100 and found that inhibiting SDF-1α signaling in the tumor microenvironment decreased the tumor microvessel density, decreased the tumor blood vessel perfusion and, increased tumor cell apoptosis. We then analyzed the effect of AMD3100 on vasculogenesis of Ewing’s sarcoma and found that BMCs migrated to the tumor site where they differentiated into ECs but, they did not form thick perivascular layers of NG2 and desmin positive pericytes. Finally, we stained the AMD3100-treated tumors for PDGF-B and showed that inhibiting SDF-1α signaling also inhibited PDGF-B expression. All together, these findings demonstrated that the SDF-1α/PDGF-B pathway plays a critical role in the formation of BM-derived pericytes during vasculogenesis of Ewing’s sarcoma tumors.

Reduced vascular endothelial growth factor expression in contusive spinal cord injury.

Vascular endothelial growth factor (VEGF) is being investigated as a potential interventional therapy for spinal cord injury (SCI). In the current study, we examined SCI-induced changes in VEGF protein levels using Western blot analysis around the epicenter of injury. Our results indicate a significant decrease in the levels of VEGF(165) and other VEGF isoforms at the lesion epicenter 1 day after injury, which was maintained up to 1 month after injury. We also examined if robust VEGF(165) decrease in injured spinal cords affects neuronal survival, given that a number of reported studies show neuroprotective effect of this VEGF isoform. However, exogenously administered VEGF(165) at the time of injury did not affect the number of sparred neurons. In contrast, exogenous administration of VEGF antibody that inhibits actions of not only VEGF(165) but also of several other VEGF isoforms, significantly decreased number of sparred neurons after SCI. Together these results indicate a general reduction of VEGF isoforms following SCI and that isoforms other than VEGF(165) (e.g., VEGF(121) and/or VEGF(189)) provide neuroprotection, suggesting that VEGF(165) isoform is likely involved in other pathophysiological process after SCI.

Insulin-associated changes in carnitine palmitoyltransferase activity are mediated through the insulin-like growth factor I pathway in the cultured neonatal rat cardiac myocyte

The mitochondrial carnitine palmitoyltransferase (CPT) system is composed of two proteins, CPT-I and CPT-II, involved in the transport of fatty acids into the mitochondrial matrix to undergo $\beta$-oxidation. CPT-I is located outside the inner membrane and CPT-II is located on the inner aspect of the inner membrane. The CPT proteins are distinct with different molecular weights and activities. The malonyl-CoA sensitivity of CPT-I has been proposed as a regulatory step in $\beta$-oxidation. Using the neonatal rat cardiac myocyte, assays were designed to discriminate between these activities in situ using digitonin and Triton X-100. With this methodology, we are able to determine the involvement of the IGF-I pathway in the insulin-mediated increase in CPT activities. Concentrations of digitonin up to 25 $\mu$M fail to release citrate synthase from the mitochondrial matrix or alter the malonyl-CoA sensitivity of CPT-I. If the mitochondrial matrix was exposed, malonyl-CoA insensitive CPT-II would reduce malonyl-CoA sensitivity. In contrast to digitonin, Triton X-100 (0.15%) releases citrate synthase from the matrix and exposes CPT-II. CPT-II activity is confirmed by the absence of malonyl-CoA sensitivity. To examine the effects of various agents on the expression and/or activity of CPT, it is necessary to use serum-free medium to eliminate mitogenic effects of serum proteins. Comparison of different media to optimize CPT activity and cell viability resulted in the decision to use Dulbecco's Modified Eagle medium supplemented with transferrin. In three established models of cardiac hypertrophy using the neonatal rat cardiac myocyte there is a significant increase in CPT-I and CPT-II activity in the treated cells. Analogous to the situation seen in the hypertrophy model, insulin also significantly increases the activity of the mitochondrial proteins CPT-I, CPT-II and cytochrome oxidase with a coinciding increase the expression of CPT-II and cytochrome oxidase mRNA. The removal of serum increases the I$\sb{50}$ (concentration of inhibitor that halves enzyme activity) of CPT-I for malonyl-CoA by four-fold. Incubation with insulin returns I$\sb{50}$ values to serum levels. Incubation with insulin significantly increases malonyl-CoA and ATP levels in the cells with a resulting reduction in palmitate oxidation. Once malonyl-CoA inhibition of CPT-I is removed by permeabilizing the cells, insulin significantly increases the oxidation of palmitoyl-CoA in a manner which parallels the increase in CPT-I activity. Interestingly, CPT-II activity increases significantly only at the tissue culture concentration (1.7 $\mu$M) of insulin suggesting that the IGF-I pathway may be involved. Supporting a role for the IGF-I pathway in the insulin-induced increase in CPT activity is the significant increase in the synthesis of both cellular and mitochondrial proteins as well as increased synthesis of CPT-II. Consistent with an IGF-mediated pathway for the effect of insulin, IGF-I (10 ng/ml) significantly increases the activities of both CPT-I and -II. An IGF-I analogue which inhibits the autophosphorylation of the IGF-I receptor blunts the insulin-mediated increase in CPT-I and -II activity by greater than 70% and virtually eliminates the IGF-I response by greater than 90%. This is the first study to demonstrate the involvement of the IGF-I pathway in the regulation of mitochondrial protein expression, e.g. CPT. ^

Left ventricular growth from age 8 to 18 and its anthropometric determinants: Longitudinal results from Project Heartbeat!

Left ventricular mass (LVM) is a strong predictor of cardiovascular disease (CVD) in adults. However, normal growth of LVM in healthy children is not well understood, and previous results on independent effects of body size and body fatness on LVM have been inconsistent. The purpose of this study was (1) to establish the normal growth curve of LVM from age 8 to age 18, and evaluate the determinants of change in LVM with age, and (2) to assess the independent effects of body size and body fatness on LVM.^ In Project HeartBeat!, 678 healthy children aged 8, 11 and 14 years at baseline were enrolled and examined at 4-monthly intervals for up to 4 years. A synthetic cohort with continuous observations from age 8 to 18 years was constructed. A total of 4608 LVM measurements was made from M-mode echocardiography. The multilevel linear model was used for analysis.^ Sex-specific trajectories of normal growth of LVM from age 8 to 18 was displayed. On average, LVM was 15 g higher in males than females. Average LVM increased linearly in males from 78 g at age 8 to 145 g at age 18. For females, the trajectory was curvilinear, nearly constant after age 14. No significant racial differences were found. After adjustment for the effects of body size and body fatness, average LVM decreased slightly from age 8 to 18, and sex differences in changes of LVM remained constant.^ The impact of body size on LVM was examined by adding to a basic LVM-sex-age model one of 9 body size indicators. The impact of body fatness was tested by further introducing into each of the 9 LVM models (with one or another of the body size indicators) one of 4 body fatness indicators, yielding 36 models with different body size and body fatness combinations. The results indicated that effects of body size on LVM can be distinguished between fat-free body mass and fat body mass, both being independent, positive predictors. The former is the stronger determinant. When a non-fat-free body size indicator is used as predictor, the estimated residual effect of body fatness on LVM becomes negative. ^

CATCH across Texas: Building a model for the diffusion of effective school-based health promotion programs

The impact of health promotion programs is related to both program effectiveness and the extent to which the program is implemented among the target population. The purpose of this dissertation was to describe the development and evaluation of a school-based program diffusion intervention designed to increase the rate of dissemination and adoption of the Child and Adolescent Trial for Cardiovascular Health, or CATCH program (recently renamed the Coordinated Approach to Child Health). ^ The first study described the process by which schools across the state of Texas spontaneously began to adopt the CATCH program after it was tested and proven effective in a multi-site randomized efficacy trial. A survey of teachers and administrator representatives of all schools on record that purchased the CATCH program, but were not involved in the efficacy trial, was used to find out who brought CATCH into the schools, how they garnered support for its adoption, why they decided to adopt the program, and what was involved in deciding to adopt. ^ The second study described how the Intervention Mapping framework guided the planning, development and implementation of a program for the diffusion of CATCH. An iterative process was used to integrate theory, literature, the experience of project staff and data from the target population into a meaningful set of program determinants and performance objectives. Proximal program objectives were specified and translated into both media and interpersonal communication strategies for program diffusion. ^ The third study assessed the effectiveness of the diffusion program in a case-comparison design. Three of the twenty Education Service Center regions in Texas were chosen, selected based on similar demographic criteria, and were followed for adoption of the CATCH curriculum. One of these regions received the full media and interpersonal channel intervention; a second received a reduced media-only intervention, and a third received no intervention. Results suggested the use of the interpersonal channels with media follow-up is an effective means to facilitate program dissemination and adoption. The media-alone condition was not effective in facilitating program adoption. ^

Functional studies of insulin-like growth factor binding protein 2 pathway in glioma progression

Comparison of gene expressing profiles between gliomas with different grades revealed frequent overexpression of insulin-like growth factor binding protein 2 (IGFBP2) in glioblastomas (GBM), in which uncontrolled cell proliferation, angiogenesis, invasion and anti-apoptosis are hallmarks. Using the glia-specific gene transfer transgenic mouse and the stable LN229(BP2) GBM cell lines, we found that IGFBP2 by itself cannot transform cells in vitro and in vivo. IGFBP2 had growth inhibitory effects on mouse primary neural progenitors, but overexpression of IGFBP2 had no effect on GBM cells. ^ Although IGFBP2 does not initiate gliomagenesis, using tissue array technology, we observed strong correlation between IGFBP2 overexpression and VEGF up-regulation in human diffuse gliomas. Furthermore, overexpression of IGFBP2 in GBM cells not only enhanced VEGF expression but also increased the malignant potential of U87 MG cells in our angiogenesis xenograft animal model. ^ In parallel to these studies, using established stable SNB19 GBM cells that overexpress IGFBP2, we found that IGFBP2 significantly increased invasion by induction of matrix metalloproteinase-2 (MMP-2) as well as other invasion related genes, providing evidence that IGFBP2 contributes to glioma progression in part by enhancing MMP-2 gene transcription and in turn tumor cell invasion. ^ Finally, we found that primary filial cells infected with an anti-sense IGFBP2 construct have markedly increased sensitivity to γ irradiation and reduced Akt activation. On the other hand, SNB19(BP2) stable lines have consistently increased levels of Akt and NFkB activation, suggesting that one possible mechanism for anti-apoptosic function of IGFBP2 is through the activation of Akt and NFkB. Beside this, what is especially interesting is the finding that Akt protein was cleaved and inactivated during apoptosis by caspases, and IGFBP2 can prevent Akt cleavage, revealing another possible mechanism through it IGFBP2 exhibit strong antiapoptotic effects. Our data showed that IGFBP2 is a specific substrate for caspase-3, raising the possibility that IGFBP2 may inhibit apoptosis by a suicide mechanism. ^ In summary, using cellular, genomics, and molecular approaches, this thesis documented the potential roles of IGFBP2 in glioma progression. Our findings shed light on an important biological aspect of glioma progression and may provide new insights useful for the design of novel mechanism-based therapies for GBM. ^

A mechanism of insulin-like growth factor binding protein 2-induced cell mobility in glioma

Insulin-like growth factor binding protein 2 (IGFBP2) is a protein known to be overexpressed in a majority of glioblastoma multiforme (GBM) tumors. While it is known the IGFBP2 is involved in promoting GBM tumor cell invasion, no mechanism exists for how the protein is involved in signal transduction pathways leading to enhanced cell invasion. ^ We follow up on preliminary microarray data on IGFBP2-overexpressing GBM cells and protein sequence analysis of IGFBP2 in generating the hypothesis that IGFBP2 interacts with integnn α5 in regulating cell mobility. Microarray data showing upregulation of integrin α5 by IGFBP2 is validated and evidence of protein-protein interaction between IGFBP2 and integrin α5 is found. The exact binding domain on IGFBP2 responsible for its interaction with integrin α5 is also determined, confirming our initial findings and reaffirming that the IGFBP2/integrin α5 interaction is specific. Disruption of this interaction resulted in attenuation of IGFBP2-enhanced cell mobility. Further, we found that cell mobility is only enhanced when IGFBP2 and integrin α5 are both overexpressed and able to interact with each other. ^ We also determined fibronectin to be a critical player in the activation of the IGFBP2/integrin α5 pathway. The activation of this pathway appears to be progressive and initiates once GBM cells have sufficiently established anchorage. ^

Helicobacter pylori infection and the effect on growth in a cohort of children in the US/Mexico border

Helicobacter pylori (H. pylori) is an S-shaped or curved gram-negative bacterium that is mostly found in the human stomach. H. pylori causes gastritis in adults and children, which can lead to gastric ulcers or risk of cancer. Transmission of this bacterial infection remains to be unknown but is mostly acquired during childhood. Little is known about the effect H. pylori has on growth in children. Although some studies have reported that H. pylori is associated with subnormal growth, the association of H. pylori with growth retardation and malnutrition is poorly described. Data from this study comes from The Pasitos Cohort Study which draws its population from three border communities which include Socorro and San Elizario in Texas, as well as Ciudad Juarez, Chihuahua, Mexico. Birth documentation was obtained for 803 infants and 472 entered follow-up. This cohort study allowed us to assess the growth of children from 6 months to the seventh anniversary, and describe the prevalence of underweight, short stature and overweight in the study population. We also tested the hypothesis that children in the Pasitos Cohort Study who were ever infected with H. pylori show an increased risk of growth retardation or malnutrition at 66 months of age. Using the 2000 CDC Growth Reference, we found that the mean BMI of the study population increased as children grew older, while the mean of their height for age decreased slightly. The proportion of children who were classified as of short stature was under 5%, while those considered underweight were less than 10% at selected six-months of age intervals. Using the subset of children who were 66 months of age we found that the risk of underweight was higher among those who ever tested positive for H. pylori infection using the urea breath test; however, due to small numbers of children with 'wasting' this difference was not statistically significant. Moreover, since the six cases of under weight occurred among children of low socio-economic status we could not rule out potential confounding. The risk of developing short stature was not different among those ever infected and those who never tested positive for H. pylori infection. ^

Physical activity, body composition, exogenous estrogen use and their association with insulin-like growth factors

Obesity and physical inactivity are modifiable risk factors that are associated with several health issues; they are major factors in up to 30% of major cancers. Elevated levels of circulating insulin-like growth factor-I (IGF-I) have been associated with high body composition measurements and high cancer risk; exogenous estrogen use is associated with low circulating IGF-I levels and high cancer risk. The relationship between physical activity and circulating IGF levels is complex and findings of previous studies of their relationship remain inconsistent; however, these studies included vague definitions of physical activity. In this study, we used cross-sectional data from the Women's Health Initiative to determine the relationship between specific measures of physical activity (e.g., intensity, duration, and frequency) and circulating IGF-I levels, accounting for exogenous estrogen use and body composition. These data were collected from women enrolled at Women's Health Initiative clinical centers at Baylor College of Medicine and Wake Forest University School of Medicine. Multivariate linear regression analysis showed that circulating IGF-I and IGF-binding protein (BP) 3 levels were positively associated with frequency, duration, and intensity of physical activity. Circulating IGF-I levels and the molar IGF-I:IGF-BP3 ratio were significantly associated with frequency of walking, whereas circulating IGF-BP3 levels were significantly associated with strenuous physical activity, suggesting that different aspects of physical activity and their effects on fitness affect members of the IGF family differently. The results from our study support the recommendation of a regular exercise routine, particularly that of strenuous intensity, for postmenopausal women as a means to prevention of cancer.^

Roles of insulin-like growth factor binding protein-3 in gastrointestinal stromal tumors

Imatinib mesylate, a selective inhibitor of KIT, PDGFR, and Abl kinases, has shown significant success as a therapy for patients with advanced gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms of imatinib-induced cytotoxicity are not well understood. Using gene expression profiling and real-time PCR for target validation, we identified insulin-like growth factor binding protein-3 (IGFBP3) to be to be up-regulated after imatinib treatment in imatinib-sensitive GISTs. IGFBP3 is a multifunctional protein that regulates cell proliferation and survival and mediates the effects of a variety of anti-cancer agents through IGF-dependent and IGF-independent mechanisms. Therefore, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 protein levels in two KIT mutant, imatinib-sensitive GIST cell lines and assessed the resultant changes in cell viability, survival, and imatinib sensitivity. In GIST882 cells, endogenous IGFBP3 was required for cell viability. However, inhibiting imatinib-induced IGFBP3 up-regulation by RNA interference or neutralization resulted in reduced drug sensitivity, suggesting that IGFBP3 sensitizes GIST882 cells to imatinib. GIST-T1 cells, on the other hand, had no detectable levels of endogenous IGFBP3, nor did imatinib induce IGFBP3 up-regulation, in contrast to our previous findings. IGFBP3 overexpression in GIST-T1 cells reduced viability but did not induce cell death; rather, the cells became polyploid through a mechanism that may involve attenuated Cdc20 expression and securin degradation. Moreover, IGFBP3 overexpression resulted in a loss of KIT activation and decreased levels of mature KIT. Consistent with this, GIST-T1 cells overexpressing IGFBP3 were less sensitive to imatinib. Furthermore, as neither GIST882 cells nor GIST-T1 cells expressed detectable levels of IGF-1R, IGFBP3 is likely not exerting its effects by modulating IGF signaling through IGF-1R or IR/IGF-1R hybrid receptors in these cell lines. Collectively, these findings demonstrate that IGFBP3 has cell-dependent effects and would, therefore, not be an ideal marker for identifying imatinib response in GISTs. Nevertheless, our results provide preliminary evidence that IGFBP3 may have some therapeutic benefits in GISTs. ^