The Effect of the Pressure Exerted on the Maternal Abdominal Wall by the US Probe on Fetal MCA Peak Systolic Velocity.

Purpose To quantify the pressure exerted on the maternal abdominal wall during ultrasound examination and evaluate its effect on the fetal middle cerebral artery (MCA) peak systolic velocity (PSV). Materials and Method Gravid women with singleton pregnancies in their 2nd-3 rd trimester undergoing fetal sonographic evaluation for various indications were recruited. Each subject underwent transabdominal US measuring fetal distance from the probe, abdominal thickness, amniotic fluid index and biophysical profile. The applied pressure was measured simultaneously using an electronic pressure sensor attached directly to the US probe. For each subject baseline values of the pressure required for proper visualization were obtained. Fetal MCA was then demonstrated using color Doppler US. The PSV was measured at different pressure ranges with each subject used as her own control. Care was taken not to exceed the baseline pressure for each subject. Results 29 women were recruited. 24 subjects (82.7 %) demonstrated a statistically significant positive correlation between the pressure exerted and MCA-PSV (R-0.37, p < 0.0001). Of these, 4 subjects (13.8 % of study population) demonstrated elevation of PSV values above 1.29 MOM and 5 subjects (17.2 %) demonstrated elevation of PSV values above 1.5 MOM for gestational age with increasing pressure. In total, 9 subjects (31 %) demonstrated significant changes in the MCA-PSV measurements (owing to increase in pressure applied) that could potentially falsely influence clinical obstetric diagnosis and management. Conclusion The pressure exerted on the maternal abdominal wall during US examination is an important parameter, producing clinically significant measurable changes in fetal MCA hemodynamics. Further study is needed in order to demonstrate the potential effect of pressure as a parameter influencing the diagnostic accuracy of the MCA-PSV in the setting of fetal anemia.

Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells.

Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser(789), a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser(789) phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.

Loss of function of PTEN alters the relationship between glucose concentration and cell proliferation, increases glycolysis, and sensitizes cells to 2-deoxyglucose.

PTEN loss of function enhances proliferation, but effects on cellular energy metabolism are less well characterized. We used an inducible PTEN expression vector in a PTEN-null glioma cell line to examine this issue. While proliferation of PTEN-positive cells was insensitive to increases in glucose concentration beyond 2.5mM, PTEN-null cells significantly increased proliferation with increasing glucose concentration across the normal physiologic range to approximately 10mM, coinciding with a shift to glycolysis and "glucose addiction". This demonstrates that the impact of loss of function of PTEN is modified by glucose concentration, and may be relevant to epidemiologic results linking hyperglycemia to cancer risk and cancer mortality.

Insulin receptor expression by human prostate cancers.

BACKGROUND: Although recent laboratory and population studies suggest that prostate cancer may be responsive to insulin, there is a gap in knowledge concerning the expression of insulin receptors on benign or malignant prostate tissue. METHODS: We immunostained 644 cores on tissue microarrays prepared from 29 prostate tissue samples without malignancies, 78 Gleason grade 3 cancers, 21 Gleason grade 4 cancers and 33 Gleason grade 5 cancers with antibodies against the insulin-like growth factor I receptor and the insulin receptor. RESULTS: We observed immunoreactivity with both antibodies, which implies the presence of hybrid receptors as well as IGF-I receptors and insulin receptors. Insulin receptor staining intensity was significantly (P < 0.001) higher on malignant than benign prostate epithelial cells. Analysis of information from public gene expression databases confirmed that co-expression of insulin receptor mRNA and IGF-I receptor mRNA is common in prostate cancer specimens. RT-PCR methods provided evidence for the presence of mRNA for both IR-A and IR-B insulin receptor isoforms. CONCLUSION: These observations document the presence of insulin receptors on primary human prostate cancers. The findings are relevant not only to ongoing clinical trials of drug candidates that target IGF-I and/or insulin receptors, but also to the hypothesis that obesity-associated hyperinsulinemia mediates the adverse effect of obesity on prostate cancer prognosis.