Growth factor concentrations and their placental mRNA expression are modulated in gestational diabetes mellitus: possible interactions with macrosomia

<p>Abstract</p> <p>Background</p> <p>Gestational diabetes mellitus (GDM) is a form of diabetes that occurs during pregnancy. GDM is a well known risk factor for foetal overgrowth, termed macrosomia which is influenced by maternal hypergycemia and endocrine status through placental circulation. The study was undertaken to investigate the implication of growth factors and their receptors in GDM and macrosomia, and to discuss the role of the materno-foeto-placental axis in the <it>in-utero </it>regulation of foetal growth.</p> <p>Methods</p> <p>30 women with GDM and their 30 macrosomic babies (4.75 ± 0.15 kg), and 30 healthy age-matched pregnant women and their 30 newborns (3.50 ± 0.10 kg) were recruited in the present study. Serum concentrations of GH and growth factors, <it>i.e</it>., IGF-I, IGF-BP3, FGF-2, EGF and PDGF-B were determined by ELISA. The expression of mRNA encoding for GH, IGF-I, IGF-BP3, FGF-2, PDGF-B and EGF, and their receptors, <it>i.e</it>., GHR, IGF-IR, FGF-2R, EGFR and PDGFR-β were quantified by using RT-qPCR.</p> <p>Results</p> <p>The serum concentrations of IGF-I, IGF-BP3, EGF, FGF-2 and PDGF-B were higher in GDM women and their macrosomic babies as compared to their respective controls. The placental mRNA expression of the growth factors was either upregulated (FGF-2 or PDGF-B) or remained unaltered (IGF-I and EGF) in the placenta of GDM women. The mRNA expression of three growth factor receptors, <it>i.e</it>., IGF-IR, EGFR and PDGFR-β, was upregulated in the placenta of GDM women. Interestingly, serum concentrations of GH were downregulated in the GDM women and their macrosomic offspring. Besides, the expression of mRNAs encoding for GHR was higher, but that encoding for GH was lower, in the placenta of GDM women than control women.</p> <p>Conclusions</p> <p>Our results demonstrate that growth factors might be implicated in GDM and, in part, in the pathology of macrosomia via materno-foeto-placental axis.</p

Low adipocyte IRS-1 protein expression is associated with an increased arterial stiffness in non-diabetic males

Objective: Low adipocyte IRS-1 protein expression is a biomarker for insulin resistance and early atherosclerosis. However, whether IRS-1 protein expression is related to systemic arterial stiffness, is unknown. Methods and results: Ten non-diabetic male subjects with low adipocyte IRS-1 protein expression (NIRS) were matched with 10 non-diabetic males with normal IRS-1 protein expression (NIRS). Augmentation index (AIx) and time for reflection of pulse wave (Tr) were studied with pulse wave analysis, both in the fasting state and during a euglycemic hyperinsulinemic clamp. The LIRS-group showed an increased fasting insulin concentration (fP-insulin 71 +/- 4 pmol/L versus 58 +/- 5 pmol/L;p = 0.02 (mean +/- S.E.)), whereas glucose disposal rate during the clamp (8.7 +/- 0.8 mg/kg LBM/min versus 10.3 +/- 1.3 mg/kg LBM/min; n.s.) did not differ significantly. Blood pressure, lipid parameters, adiponectin, endothelin-1 and CRP concentrations were similar. However, in the basal state, AIx was increased (129 +/- 4% versus 116 +/- 2%; p < 0.02) and Tr was decreased (150 +/- 3 ms versus 171 +/- 5 ms; P < 0.01), suggesting stiffer vessels in the LIRS-group. The LIRS-group exhibited an attenuated AIx response to hyperinsulinemia compared to the NIRS-group. Conclusions: The data suggest that non-obese non-diabetic men with a low adipocyte IRS-1 protein expression have an increased systemic arterial stiffness

J. Pathol.

With the appearance of defect-targeted therapies, the definition of tumour protein expression profiles has gained increasing importance. Two lung carcinoma tissue microarrays, one including 75 primary adenocarcinomas (ACs) and the other comprising 67 primary squamous cell carcinomas (SQCCs), were generated in the present study. On both arrays, each tumour was represented by an average of five cores. In addition, one punch of normal lung parenchyma adjacent to each tumour was included in the array. Immunohistochemical expression of 86 proteins was evaluated and the results were analysed by non-parametric tests, hierarchical clustering, and principal component analysis. In both tumour entities, parenchyma and tumours were clearly separated by hierarchical clustering. By the same statistical approach, it was possible to distinguish ACs from SQCCs with 98% accuracy and to distinguish parenchyma adjacent to ACs from that adjacent to SQCCs with 96% accuracy. It was also possible to separate ACs into three groups that significantly differed in survival. Cathepsin E and hsp105 were identified as previously unknown predictors of survival in lung AC. In summary, this study has shown that protein profiles are feasible tools for anticipating biological behaviour. Copyright © 2004 Pathological Society of Great Britain and Ireland

Protein expression profiles in adenocarcinomas and squamous cell carcinomas of the lung generated using tissue microarrays.

With the appearance of defect-targeted therapies, the definition of tumour protein expression profiles has gained increasing importance. Two lung carcinoma tissue microarrays, one including 75 primary adenocarcinomas (ACs) and the other comprising 67 primary squamous cell carcinomas (SQCCs), were generated in the present study. On both arrays, each tumour was represented by an average of five cores. In addition, one punch of normal lung parenchyma adjacent to each tumour was included in the array. Immunohistochemical expression of 86 proteins was evaluated and the results were analysed by non-parametric tests, hierarchical clustering, and principal component analysis. In both tumour entities, parenchyma and tumours were clearly separated by hierarchical clustering. By the same statistical approach, it was possible to distinguish ACs from SQCCs with 98% accuracy and to distinguish parenchyma adjacent to ACs from that adjacent to SQCCs with 96% accuracy. It was also possible to separate ACs into three groups that significantly differed in survival. Cathepsin E and hsp105 were identified as previously unknown predictors of survival in lung AC. In summary, this study has shown that protein profiles are feasible tools for anticipating biological behaviour

Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6

Colorectal cancer (CRC) is the third most common cause of cancer related death worldwide. Furthermore, with more than 1.2 million cases registered per year, it constitutes the third most frequent diagnosed cancer entity worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Eukaryotic translation initiation factors (eIFs) are involved in the regulation of protein synthesis and are functionally linked to the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. The identification of factors accounting for colorectal carcinoma (CRC) development is a major gap in the field. Besides the importance of eIF3 subunits and the eIF4 complex, eIF1, eIF5 and eIF6 were found to be altered in primary and metastatic CRC. We observed significant difference in the expression profile between low and high grade CRC. eIF1, eIF5 and eIF6 are involved in translational control in CRC. Our findings also indicate a probable clinical impact when separating them into low and high grade colon and rectum carcinoma. eIF and mTOR expression were analysed on protein and mRNA level in primary low and high grade colon carcinoma (CC) and rectum carcinoma (RC) samples in comparison to non-neoplastic tissue without any disease-related pathology. To assess the therapeutic potential of targeting eIF1, eIF5 and eIF6 siRNA knockdown in HCT116 and HT29 cells was performed. We evaluated the eIF knockdown efficacy on protein and mRNA level and investigated proliferation, apoptosis, invasion, as well as colony forming and polysome associated fractions. These results indicate that eIFs, in particular eIF1, eIF5 and eIF6 play a major role in translational control in colon and rectum cancer