ABSTRACT
BACKGROUND: TACE/ADAM17 is a transmembranous protease that cleaves membrane-bound growth factors like EGFR ligands. TACE-dependent proteolysis is regulated by its inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP3). This study analyses the role of TACE and TIMP3 mRNA expression in squamous cell carcinomas of the head and neck (HNSCCs). METHODS: We analysed TACE and TIMP3 mRNA expression in HNSCCs from 106 patients by RNA in situ hybridisation. RESULTS: TACE mRNA was upregulated in HNSCCs compared with dysplastic (P<0.05) and normal epithelia (P<0.001), with strong hybridisation signals in 21.9% of invasive tumour tissues and 4.5% of dysplasia. Elevated mRNA levels were accompanied by increased amounts of TACE protein in HNSCCs. TIMP3 mRNA expression in HNSCC-associated stroma was significantly higher than in the stroma adjacent to dysplastic or normal epithelia. Expression of TACE mRNA in HNSCCs was associated with tumour stage (P=0.019) and regional lymph node metastasis (P=0.009). Furthermore, levels of TACE mRNA in HNSCCs correlated with the expression of TIMP3 mRNA in HNSCC-associated stroma. Concomitantly, patients expressing high levels of TACE and TIMP3 mRNA showed significantly reduced overall survival compared with those with low mRNA levels. CONCLUSION: Our results indicate an important role of TACE and TIMP3 during development and progression of HNSCCs.
Subject(s)
ADAM Proteins/genetics , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , RNA, Messenger/genetics , Tissue Inhibitor of Metalloproteinase-3/genetics , ADAM Proteins/metabolism , ADAM17 Protein , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , Carcinoma, Squamous Cell , Disease Progression , Female , Follow-Up Studies , Head and Neck Neoplasms/metabolism , Humans , Immunoenzyme Techniques , In Situ Hybridization , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Neoplasms, Squamous Cell/genetics , Neoplasms, Squamous Cell/metabolism , Neoplasms, Squamous Cell/pathology , Prognosis , RNA Probes , RNA, Messenger/metabolism , Squamous Cell Carcinoma of Head and Neck , Survival Rate , Tissue Inhibitor of Metalloproteinase-3/metabolism , Tumor Cells, CulturedABSTRACT
Putative transmembrane helices of membrane proteins in general and channel proteins in particular often contain proline residues which may induce a bend into an otherwise regular helical structure. Here we show by fluorescence-energy-transfer measurements and molecular-dynamics calculations that, in the case of synthetic bilayer-spanning helical polypeptides, a proline-induced bend in a helix acts as a flexible element mediating rigid body motions of the helical segments. Most important, such structural fluctuations in the transmembrane helices seem to play a functional role in the formation of ionic channels in planar lipid bilayers and biological membranes.
Subject(s)
Ion Channels/chemistry , Membrane Lipids/chemistry , Membrane Proteins/chemistry , Protein Structure, Secondary , Amino Acid Sequence , Molecular Sequence Data , Protein ConformationABSTRACT
In a prospective study the psychomotor development up to the end of the second year of life of 409 preterm and term newborn infants was examined in order to identify which optimality score might be associated with disturbances of normal childlike development. Significant connections between 24 and 55 risk factors and the mortality could be demonstrated, but only 3 factors (sex, apgar, acidosis) exert influence on psychomotor development. The risk loading of the collective was high, not one of the children showed an optimal score. Decreased patients possessed a stronger reduced optimality than survivors. The optimality concept is not suitable for the prediction of later disturbed development of children, because the items are unspecific. The marker of hypoxia, the erythrocytic-density-test, as well as the neuron-specific enolase showed better diagnostic values than the optimality concept.
Subject(s)
Brain Damage, Chronic/etiology , Developmental Disabilities/etiology , Psychomotor Disorders/etiology , Brain Damage, Chronic/prevention & control , Child, Preschool , Developmental Disabilities/prevention & control , Disabled Persons , Erythrocyte Indices , Female , Humans , Infant , Infant, Newborn , Male , Neurologic Examination , Phosphopyruvate Hydratase/analysis , Prospective Studies , Psychomotor Disorders/prevention & control , Risk FactorsABSTRACT
In a prospective study 306 high-risk infants with a birth-weight between 890 to 4900 gm were examined by means of cerebral ultrasound scanning and about a time of two years the psychomotor development was evaluated. 145 patients (47.4%) were classified as intracerebral haemorrhages. The strongest relation with the event of bleeding was found for the high level of PCO2. With increased severity of the intracranial haemorrhage was associated a worse prognosis of development in the first two years of life. The type I-haemorrhage showed in 72.2%, the types III/IV in yet only 42.9% a development without psychomotor disorders.
