217 MECHANISMS OF ACTION OF ESE1, A NOVEL TRANSCRIPTIONAL REGULATOR OF CARTILAGE REMODELING, IN MMP-13 REGULATION

Ischemic preconditioning (IPC) limits myocardial infarct size through the activation of the PI3K-Akt signal cascade; however, little is known about the roles of individual PI3K isoforms in cardioprotection. We aimed, therefore, to elucidate the role of the PI3K alpha isoform in cardioprotection Pharmacological PI3K alpha inhibition was assessed in isolated-perfused mouse hearts subjected to ischemia/reperfusion injury (IRI), either during the IPC procedure or at reperfusion. PI3K alpha inhibition abrogated the IPC-induced protective effect at reperfusion, but not when given only during the IPC protocol. These results were confirmed in an in vivo model. Moreover, pharmacological PI3K alpha activation by insulin at reperfusion was sufficient to confer cardioprotection against IRI. In addition, PI3K alpha was shown to be expressed and activated in mouse cardiomyocytes, mouse cardiac endothelial cells, as well as in mouse and human heart tissue. Furthermore, PI3K alpha was shown to mediate its effect though the inhibition of mitochondrial permeability transition pore opening. In conclusion, PI3K alpha activity is required during the early reperfusion phase to reduce myocardial infarct size. This suggests that strategies specifically enhancing the alpha isoform of PI3K at reperfusion promote tissue salvage and as such, and could provide a direct target for clinical treatment of IRI.Fundacion Rafael del Pino FONDECYT 3160298 British Heart Foundation Cancer Research UK C23338/A15965 UK NIHR University College London Hospitals Biomedical Research Centr

Optimization of sentinel lymph node biopsy in breast cancer using an operative gamma camera

<p>Abstract</p> <p>Background</p> <p>Sentinel lymph node (SLN) procedure is now a widely accepted method of LN staging in selected invasive breast cancers (unifocal, size ≤ 2 cm, clinically N0, without previous treatment). Complete axillary clearance is no longer needed if the SLN is negative. However, the oncological safety of this procedure remains to be addressed in randomized clinical trials. One main pitfall is the failure to visualize SLN, resulting in incorrect tumor staging, leading to suboptimal treatment or axillary recurrence. Operative gamma cameras have therefore been developed to optimize the SLN visualization and the quality control of surgery.</p> <p>Case presentation</p> <p>A 44-year-old female patient with a 14-mm infiltrative ductal carcinoma underwent the SLN procedure. An operative gamma camera was used during and after the surgery. The conventional lymphoscintigraphy showed only one SLN, which was also detected by the operative gamma camera, then removed and measured (9.6 kBq). It was analyzed by frozen sections, showing no cancer cells. During this analysis, the exploration of the axillary area with the operative gamma camera enabled the identification of a second SLN with low activity (0.5 kBq) that conventional lymphoscintigraphy, surgical probe and blue staining had failed to visualize. Histological examination revealed a macrometastasis. Axillary clearance was then performed, followed by a postoperative image proving that no SLN remained. Therefore, the use of the operative gamma camera prevented an under-estimation of staging which would have resulted in a suboptimal treatment for this patient.</p> <p>Conclusion</p> <p>This case report illustrates that an efficient operative gamma camera may be able to decrease the risk of false negative rate of the SLN procedure, and could be an additional tool to control the quality of the surgery.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00357487</p

Modulation of radial blood flow during Braille character discrimination task

Purpose: Human hands are excellent in performing sensory and motor function. We have hypothesized that blood flow of the hand is dynamically regulated by sympathetic outflow during concentrated finger perception. To identify this hypothesis, we measured radial blood flow (RBF), radial vascular conductance (RVC), heart rate (HR), and arterial blood pressure (AP) during Braille reading performed under the blind condition in nine healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 30 s by the forefinger, and to touch a blank plate as control for the Braille discrimination procedure. Results: HR and AP slightly increased during Braille reading but remained unchanged during the touching of the blank plate. RBF and RVC were reduced during the Braille character discrimination task (decreased by -46% and -49%, respectively). Furthermore, the changes in RBF and RVC were much greater during the Braille character discrimination task than during the touching of the blank plate (decreased by -20% and -20%, respectively). Conclusions: These results have suggested that the distribution of blood flow to the hand is modulated via sympathetic nerve activity during concentrated finger perception

Quantum chemical calculations of X-ray emission spectroscopy

The calculation of X-ray emission spectroscopy with equation of motion coupled cluster theory (EOM-CCSD), time dependent density functional theory (TDDFT) and resolution of the identity single excitation configuration interaction with second order perturbation theory (RI-CIS(D)) is studied. These methods can be applied to calculate X-ray emission transitions by using a reference determinant with a core-hole, and they provide a convenient approach to compute the X-ray emission spectroscopy of large systems since all of the required states can be obtained within a single calculation removing the need to perform a separate calculation for each state. For all of the methods, basis sets with the inclusion of additional basis functions to describe core orbitals are necessary, particularly when studying transitions involving the 1s or- bitals of heavier nuclei. EOM-CCSD predicts accurate transition energies when compared with experiment, however, its application to larger systems is restricted by its computational cost and difficulty in converging the CCSD equations for a core-hole reference determinant, which become increasing problematic as the size of the system studied increases. While RI-CIS(D) gives accurate transition energies for small molecules containing first row nuclei, its application to larger systems is limited by the CIS states providing a poor zeroth order reference for perturbation theory which leads to very large errors in the computed transition energies for some states. TDDFT with standard exchange-correlation functionals predicts transition energies that are much larger than experiment. Optimization of a hybrid and short-range cor- rected functional to predict the X-ray emission transitions results in much closer agreement with EOM-CCSD. The most accurate exchange-correlation functional identified is a modified B3LYP hybrid functional with 66% Hartree-Fock exchange, denoted B66LYP, which predicts X-ray emission spectra for a range of molecules including fluorobenzene, nitrobenzene, ace- tone, dimethyl sulfoxide and CF3Cl in good agreement with experiment