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1.
JAMA ; 299(11): 1315-9, 2008 Mar 19.
Article in English | MEDLINE | ID: mdl-18349092

ABSTRACT

CONTEXT: Individuals with Li-Fraumeni syndrome (LFS) have an inherited cancer predisposition to a diverse array of malignancies beginning early in life; survivors of one cancer have a markedly elevated risk of additional primary tumors. The underlying genetic defect in the majority of the families is a germline mutation in the TP53 tumor suppressor gene. The diversity of tumors and rarity of families have contributed to the difficulty in devising effective screening recommendations for members of LFS kindreds. OBJECTIVE: To gather preliminary data with which to evaluate F18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging as a potential surveillance modality to detect early malignancies in asymptomatic members of LFS kindreds. DESIGN, SETTING, AND PARTICIPANTS: Members of LFS families with documented germline TP53 mutations or obligate carrier status, no history of cancer within 5 years of enrollment, and no symptoms of cancer or ill-health were offered FDG-PET/CT scanning as a screening test in a comprehensive US cancer center from 2006 to 2007. Scans were initially reviewed clinically, then centrally reviewed by an expert radiologist. MAIN OUTCOME MEASURE: The primary outcome was the detection of new primary cancers using FDG-PET/CT scanning. RESULTS: Of 15 individuals, baseline FDG-PET/CT scan identified asymptomatic cancers in 3 (20%). Two individuals had papillary thyroid cancers (stage II and stage III) and one individual had stage II esophageal adenocarcinoma. CONCLUSIONS: These preliminary data provide the first evidence for a potential cancer surveillance strategy that may be worthy of further investigation for patients with LFS. Concerns about radiation exposure and other challenges inherent in screening high-risk patients will require further consideration.


Subject(s)
Li-Fraumeni Syndrome/diagnosis , Positron-Emission Tomography , Tomography, Spiral Computed , Whole Body Imaging , Adult , Feasibility Studies , Female , Fluorodeoxyglucose F18 , Genes, p53 , Heterozygote , Humans , Li-Fraumeni Syndrome/genetics , Male , Mutation , Neoplasms/diagnosis , Neoplasms/genetics , Pilot Projects , Radiopharmaceuticals
2.
Arch Biochem Biophys ; 466(2): 242-9, 2007 Oct 15.
Article in English | MEDLINE | ID: mdl-17626781

ABSTRACT

Low levels of hydrogen peroxide (H(2)O(2)) are mitogenic to mammalian cells and stimulate the hyperphosphorylation of heterogeneous nuclear ribonucleoprotein C (hnRNP-C) by protein kinase CK1alpha. However, the mechanisms by which CK1alpha is regulated have been unclear. Here it is demonstrated that low levels of H(2)O(2) stimulate the rapid dephosphorylation of CK1alphaLS, a nuclear splice form of CK1alpha. Furthermore, it is demonstrated that either treatment of endothelial cells with H(2)O(2), or dephosphorylation of CK1alphaLS in vitro enhances the association of CK1alphaLS with hnRNP-C. In addition, dephosphorylation of CK1alphaLS in vitro enhances the kinase's ability to phosphorylate hnRNP-C. While CK1alpha appears to be present in all metazoans, analysis of CK1alpha genomic sequences from several species reveals that the alternatively spliced nuclear localizing L-insert is unique to vertebrates, as is the case for hnRNP-C. These observations indicate that CK1alphaLS and hnRNP-C represent conserved components of a vertebrate-specific H(2)O(2)-responsive nuclear signaling pathway.


Subject(s)
Casein Kinase I/metabolism , Hydrogen Peroxide/metabolism , Amino Acid Sequence , Cell Nucleus/metabolism , Cells, Cultured , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Heterogeneous-Nuclear Ribonucleoprotein Group C/metabolism , Humans , Hydrogen Peroxide/pharmacology , Molecular Sequence Data , Phosphorylation , Protein Splicing , Reactive Oxygen Species/metabolism
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