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Adda Grimberg

Publications and source records attributed to Adda Grimberg.

14 recordsLinked to original sources
PubMed2006

Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling.

The p53 tumor suppressor induces cellular growth arrest and apoptosis in response to DNA damage by transcriptionally activating or repressing target genes and also through protein-protein interactions and direct mitochondrial activities. In 1995, insulin-like growth factor binding protein (IGFBP)-3 was identified as one of the genes transcriptionally activated by p53. IGFBP-3 is one of six closely related IGFBP's, with additional IGFBP-related proteins belonging to the IGFBP superfamily. Here we show that IGFBP-2 is also a p53 target. Like IGFBP-3, IGFBP-2 secretion is reduced when p53+/+ lung cancer cells are transfected with human papillomavirus E6, which targets p53 for degradation. IGFBP-2 mRNA is induced by irradiation in vivo in a p53-dependent manner. p53 protein binds IGFBP-2 intronic sequences in an electrophoretic mobility shift assay, and activates transcription in a luciferase assay. Loss of IGFBP-2 inhibits the ability of p53 to inhibit the activation of extracellular signal-regulated kinase (ERK)1 by IGF-I. Thus, p53 effects on the IGF axis are more complex than previously appreciated, and overall transform the axis from IGF-mediated mitogenesis to growth inhibition and apoptosis. This has significant implications for how growth hormone and IGF-I can induce growth without also inducing cancer.

Base Sequence↗
PubMed2006

PTU-associated vasculitis in a girl with Turner Syndrome and Graves' disease.

Palpable purpura is a concerning clinical finding in pediatric patients and can have many causes, including infectious and autoimmune processes. A rare cause, drug-induced vasculitis, may result from the production of antineutrophil cytoplasmic antibodies (ANCAs) in response to a medication. We report a girl with Turner syndrome and Graves' disease who presented with palpable purpuric lesions. The diagnosis of propylthiouracil (PTU)-associated vasculitis was made by observation of consistent clinical features, the detection of elevated ANA and ANCA in the blood, and the observed clinical resolution of symptoms following withdrawal of PTU. Subsequent treatment of persistent hyperthyroidism with radioablation did not result in an exacerbation of the vasculitis, a complication described in prior case reports.

Antithyroid Agents↗
PubMed2006

Reconciling diabetes management and the ketogenic diet in a child with pyruvate dehydrogenase deficiency.

A 4-year-old girl with pyruvate dehydrogenase deficiency, static encephalopathy, and seizure disorder treated with the ketogenic diet presented in severe diabetic ketoacidosis. Pyruvate dehydrogenase deficiency is a rare genetic defect of mitochondrial energy metabolism that leads to inefficient glucose use and lactic acidosis. The ketogenic diet provides the brain with an alternate fuel source, but its implementation opposes traditional diabetes management. Faced with this therapeutic dilemma, we aimed to maintain ketosis without compromising safety to optimize neurologic function and quality of life. This is the first report, to our knowledge, of a child simultaneously treated with the ketogenic diet and exogenous insulin. A 28-month follow-up revealed excellent glycemic control, improved activity level, significant developmental achievements, and, perhaps most striking, catch-up linear growth from < 5th percentile to the 50th percentile. Her progress to date indicates that diabetes does not preclude use of the ketogenic diet.

Child, Preschool↗
PubMed2006

Adrenocortical tumors and hyperplasias in childhood--etiology, genetics, clinical presentation and therapy.

Adrenocortical tumors are rare in children and are associated with a poor prognosis when malignant. The fund of knowledge regarding etiology, presentation and clinical outcomes remains limited. Evaluation of genetic disorders associated with the development of adrenocortical disorders has allowed researchers to identify a number of mutations that may be involved in tumorigenesis, including alterations in the GNAS1, PRKAR1A, TP53 and IGF2 genes. Clinical presentation in children is associated most commonly with young age, female gender and symptoms of virilization. Most children have localized disease at presentation which may be associated with a better prognosis when compared to adults. Surgical resection remains the only potentially curative treatment and mitotane, the most frequently used chemotherapeutic agent, has a poor response rate and is highly toxic. Broader participation in multi-center research, such as the International Pediatric Adrenocortical Tumor Registry, is needed to collect sufficient data to better guide our clinical management.

Adrenal Cortex↗
PubMed2005

Non-invasive fluorescence imaging of cell death in fresh human colon epithelia treated with 5-Fluorouracil, CPT-11 and/or TRAIL.

Apoptosis is instrumental in several physiological/pathophysiological processes and is a frequently used end-point in the development of anti-neoplastic compounds. Despite ample data on several colon cancer cell lines, little is known about the susceptibility of human colon to apoptosis following treatment with established chemotherapeutics. By treating fresh human colonic explants with 5-Fluorouracil (200 microg/ml), CPT-11 (100 microg/ml) and/or TRAIL (100 ng/ml) we readily detected a signal in situ using FITC-VAD-FMK at different time points, whereas labeling of colonic explants with EGFP-conjugated Annexin V proved less specific. Although TRAIL treatment alone appeared to cause little apoptosis in human colonic epithelia versus the control, we observed a greater number of cells undergoing apoptosis when a combination of CPT-11 and TRAIL was used as compared to either agent alone. This is the initial demonstration of TRAIL-induced apoptosis with or without a chemotherapeutic agent in fresh primary human colon epithelia explants. Thus, human colonic explants may provide a valuable reference point when candidate therapeutic compounds triggering apoptosis in colon cancer cell lines, xenografts or mouse models are developed. The results support the feasibility of developing non-invasive optical imaging strategies to detect apoptosis through direct visualization of injury to human colonic epithelia in vivo.

Adolescent↗
PubMed2005

p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia.

IGF binding protein (IGFBP)-3, the principal carrier of IGFs in the circulation, contributes to both endocrine and autocrine/paracrine growth control; it can be induced by GH, cytokines, retinoic acid, and tumor suppressors. Induction of IGFBP-3 by the tumor suppressor p53 has been shown in various models that directly manipulate p53 activity. However, the physiologic settings under which this induction occurs have not been established. DNA damage and hypoxia are two important physiologic activators of p53. We have demonstrated for the first time that IGFBP-3 is an in vivo target of p53 in response to ionizing radiation. This effect was tissue specific. Furthermore, we demonstrated that genotoxic drugs could increase IGFBP-3 protein levels and secretion in tumor cell lines in a p53-independent manner. Finally, we have established that IGFBP-3 induction under hypoxic conditions is independent of p53 in tumor cell lines derived form multiple tissue types. Thus, IGFBP-3 is induced by physiologic conditions that also induce p53, although p53 is not always required. Because IGFBP-3 can inhibit growth and induce apoptosis in IGF-dependent and IGF-independent manners, its induction by DNA damage and hypoxia suggest IGFBP-3 plays a role in the physiologic protection against aberrant cell growth.

Animals↗
PubMed2005

Cancer.

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Animals↗
PubMed2005

Sex differences in patients referred for evaluation of poor growth.

OBJECTIVES: The objective of this study was to compare sex differences among referrals for evaluation of poor growth. STUDY DESIGN: This study was based on chart reviews of all new-patient encounters at Children's Hospital of Philadelphia Diagnostic and Research Growth Center for short stature or poor growth evaluations during 2001. Outcome measures were patient growth characteristics, frequency of underlying pathology, and frequency of laboratory and radiologic investigations before referral. RESULTS: One hundred eighty-two boys and 96 girls were referred ( P < .0001). Girls were shorter, relative to the general population (median height z score, -2.4 vs -1.9 for boys, P = .02) and mid-parental target heights (median deficit, 1.9 vs 1.3 SD, P < .01). Differences were more pronounced starting at age 9 years. Median time to referral from initial fall-off on the growth curve was 35 months in girls and 24 months in boys (not significant). The percentage of girls (41%) with organic disease significantly exceeded that of boys (15%). Conversely, more boys (72%) than girls (48%) were of normal height or short but healthy ( P < .0001). Sex was not associated with frequency of tests before referral; neither was severity of short stature. CONCLUSIONS: Sex differences in short stature referrals may delay diagnosis of diseases in girls while promoting overzealous evaluations of healthy boys who do not appear to be tall enough.

Age Factors↗
PubMed2004

Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up-regulated gene. IGFBP-3 regulates cell proliferation through both insulin-like growth factor-dependent and independent mechanisms. We found that IGFBP-3 mRNA and protein expression was increased in EGFR-overexpressing primary and immortalized human esophageal cells. IGFBP-3 was also up-regulated in EGFR-overexpressing cells in organotypic culture and in EGFR transgenic mice. Furthermore, IGFBP-3 mRNA was overexpressed in 80% of primary esophageal squamous cell carcinomas and 60% of primary esophageal adenocarcinomas. Concomitant up-regulation of EGFR and IGFBP-3 was observed in 60% of primary esophageal squamous cell carcinomas. Immunohistochemistry revealed cytoplasmic localization of IGFBP-3 in the preponderance of preneoplastic and neoplastic esophageal lesions. IGFBP-3 was also overexpressed in esophageal cancer cell lines at both mRNA (60%) and protein (40%) levels. IGFBP-3 secreted by cancer cells was capable of binding to insulin-like growth factor I. Functionally, epidermal growth factor appeared to regulate IGFBP-3 expression in esophageal cancer cell lines. Finally, suppression of IGFBP-3 by small interfering RNA augmented cell proliferation, suggesting that IGFBP-3 may inhibit tumor cell proliferation as a negative feedback mechanism. In aggregate, we have identified for the first time that IGFBP-3 is an aberrantly regulated gene through the EGFR signaling pathway and it may modulate EGFR effects during carcinogenesis.

Animals↗
PubMed2004

Somatostatin and cancer: applying endocrinology to oncology.

Somatostatin is a peptide hormone that normally suppresses growth hormone (GH), thyrotropin (TSH), insulin and gut hormone release, as well as affecting multiple aspects of gastrointestinal function. It achieves these pleiotropic effects by binding somatostatin receptors (SSTR), a family of five G-protein coupled membrane receptors. Somatostatin analogs, such as octreotide, lanreotide and vapreotide, are well-established treatments for tumors that over secrete these hormones. Recently, use of somatostatin analogs for treating nonendocrine malignancies are being explored. Hu et al. found progressive reduction in SSTR3 expression when comparing normal gastric mucosa versus well differentiated versus poorly differentiated gastric adenocarcinomas; octreotide inhibited growth and induced apoptosis in vitro of those cells expressing SSTR3. Potential mechanisms by which somatostatin analogs may be useful in oncology include its endocrine actions, autocrine/paracrine effects, SSTR-mediated cell signaling and SSTR-mediated cell labeling.

Antineoplastic Agents, Hormonal↗
PubMed2002

Expanded spectrum of recombinant human growth hormone therapy.

The efficacy of recombinant human growth hormone in the treatment of growth hormone deficiency is well established. In recent years, the use of recombinant human growth hormone as a therapeutic modality has greatly increased and has expanded beyond the realm of replacement for growth hormone deficiency. Recombinant human growth hormone has been employed to ameliorate growth failure in multiple other disorders. For some, like Turner syndrome, recombinant human growth hormone has become the standard of care. For others, the ultimate benefit of recombinant human growth hormone remains to be determined. Although recent investigations provide encouraging short-term data, it is important to recognize that the impact of recombinant human growth hormone therapy on adult height has not been established in a number of conditions.

Adult↗
PubMed2002

IGFBP-3 mediates p53-induced apoptosis during serum starvation.

Insulin-like growth factor binding protein (IGFBP)-3, a p53-response gene, can induce apoptosis in an IGF-independent manner. Here we demonstrate that IGFBP-3 mediates p53-induced apoptosis during serum starvation using two foil neoplastic cell models: one which introduces p53 activity and one which eliminates it. We created a doxycycline-inducible p53 model from the p53-negative PC-3 prostate cancer cell line. Doxycycline treatment increased both p53 and IGFBP-3 levels. It also augmented apoptosis, but not during insulin-like growth factor-I co-treatment. In a second model, lung carcinoma H460 cells expressing fully functional p53 were stably transfected with E6, which targets p53 for degradation. H460-E6 cells contained less p53 and IGFBP-3 than control neo-transfected cells, and proteasome blockade restored both. In serum deprivation, H460-E6 cells had enhanced growth and less apoptosis than did H460-neo cells. Reductions in H460-neo apoptosis, comparable in magnitude to H460-E6, were achieved by adding anti-IGFBP-3-antibody or IGFBP-3 antisense oligomers, but not non-specific immunoglobulin or IGFBP-3 sense oligomers. In summary, turning p53 in two foil neoplastic cell models induced IGFBP-3 expression and increased apoptosis during serum starvation, an effect inhibited by insulin-like growth factor-I treatment and specific IGFBP-3 blockade. This is the first demonstration of inhibition of p53 action by antagonizing IGFBP-3.

Apoptosis↗
PubMedDate not supplied

Mechanisms by which IGF-I may promote cancer.

Multiple large case-control studies in the past five years have reported positive associations between high circulating levels of the insulin-like growth factor (IGF)-I and risk for different types of cancer. Correlations certainly do not prove causation, but the reproducibility of this finding implies this is a hypothesis worth further examination through more mechanistic studies. IGF-I binds to the IGF-I receptor, a tyrosine kinase receptor that transduces signals to the nucleus and mitochondrion primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Examples will be provided to illustrate how IGF-I signaling may contribute to each stage of cancer progression: malignant transformation, tumor growth, local invasion and distant metastases, and resistance to treatment. In addition to direct contributions to each of these stages, IGF-I may promote cancer indirectly, through interactions with oncogenes and tumor suppressors, interactions with other hormones (especially the sex steroids in breast and prostate cancers) and interactions with the IGF binding proteins (IGFBPs). Finally, circulating IGF-I may facilitate cancer development though it likely does not cause cancer to form. Prompted by the accumulating evidence, investigations are also being pursued to modulate the IGF system as a possible means of cancer prevention or treatment.

Animals↗