The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

The first determination of Generalized Polarizabilities of the proton by a Virtual Compton Scattering experiment

Absolute differential cross sections for the reaction (e+p -> e+p+gamma) have been measured at a four-momentum transfer with virtuality Q^2=0.33 GeV^2 and polarization \epsilon = 0.62 in the range 33.6 to 111.5 MeV/c for the momentum of the outgoing photon in the photon-proton center of mass frame. The experiment has been performed with the high resolution spectrometers at the Mainz Microtron MAMI. From the photon angular distributions, two structure functions which are a linear combination of the generalized polarizabilities have been determined for the first time.Comment: 4 pages, 3 figure

Evidence for the Decay D0→K+π−π+π−D^0\to K^+ \pi^-\pi^+\pi^-

We present a search for the ``wrong-sign'' decay D0 -> K+ pi- pi+ pi- using 9 fb-1 of e+e- collisions on and just below the Upsilon(4S) resonance. This decay can occur either through a doubly Cabibbo-suppressed process or through mixing to a D0bar followed by a Cabibbo-favored process. Our result for the time-integrated wrong-sign rate relative to the decay D0 -> K- pi+ pi- pi+ is (0.0041 +0.0012-0.0011(stat.) +-0.0004(syst.))x(1.07 +-0.10)(phase space), which has a statistical significance of 3.9 standard deviations.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, submitted to PR

Hadronic Mass Moments in Inclusive Semileptonic B Meson Decays

We have measured the first and second moments of the hadronic mass-squared distribution in B -> X_c l nu, for P(lepton) > 1.5 GeV/c. We find <M_X^2 - M_D[Bar]^2> = 0.251 +- 0.066 GeV^2, )^2 > = 0.576 +- 0.170 GeV^4, where M_D[Bar] is the spin-averaged D meson mass. From that first moment and the first moment of the photon energy spectrum in b -> s gamma, we find the HQET parameter lambda_1 (MS[Bar], to order 1/M^3 and beta_0 alpha_s^2) to be -0.24 +- 0.11 GeV^2. Using these first moments and the B semileptonic width, and assuming parton-hadron duality, we obtain |V_cb| = 0.0404 +- 0.0013.Comment: 11 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, submitted to PR

Observation of the Ωc0\Omega_{c}^{0} Charmed Baryon at CLEO

The CLEO experiment at the CESR collider has used 13.7 fb$^{-1}$ of data to search for the production of the $\Omega_c^0$ (css-ground state) in $e^{+}e^{-}$ collisions at $\sqrt{s} \simeq 10.6$ {\rm GeV}. The modes used to study the $\Omega_c^0$ are $\Omega^- \pi^+$, $\Omega^- \pi^+ \pi^0$, $\Xi^- K^- pi^+ \pi^+$, $\Xi^0 K^- pi^+$, and $\Omega^- \pi^+ \pi^- \pi^+$. We observe a signal of 40.4$\pm$9.0(stat) events at a mass of 2694.6$\pm$2.6(stat)$\pm$1.9(syst) {\rm MeV/$c^2$}, for all modes combined.Comment: 10 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

Modulating gradients in regulatory signals within mesenchymal stem cell seeded hydrogels: a novel strategy to engineer zonal articular cartilage.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Engineering organs and tissues with the spatial composition and organisation of their native equivalents remains a major challenge. One approach to engineer such spatial complexity is to recapitulate the gradients in regulatory signals that during development and maturation are believed to drive spatial changes in stem cell differentiation. Mesenchymal stem cell (MSC) differentiation is known to be influenced by both soluble factors and mechanical cues present in the local microenvironment. The objective of this study was to engineer a cartilaginous tissue with a native zonal composition by modulating both the oxygen tension and mechanical environment thorough the depth of MSC seeded hydrogels. To this end, constructs were radially confined to half their thickness and subjected to dynamic compression (DC). Confinement reduced oxygen levels in the bottom of the construct and with the application of DC, increased strains across the top of the construct. These spatial changes correlated with increased glycosaminoglycan accumulation in the bottom of constructs, increased collagen accumulation in the top of constructs, and a suppression of hypertrophy and calcification throughout the construct. Matrix accumulation increased for higher hydrogel cell seeding densities; with DC further enhancing both glycosaminoglycan accumulation and construct stiffness. The combination of spatial confinement and DC was also found to increase proteoglycan-4 (lubricin) deposition toward the top surface of these tissues. In conclusion, by modulating the environment through the depth of developing constructs, it is possible to suppress MSC endochondral progression and to engineer tissues with zonal gradients mimicking certain aspects of articular cartilage.Funding was provided by Science Foundation Ireland (President of Ireland Young Researcher Award: 08/Y15/B1336) and the European Research Council (StemRepair – Project number 258463)

Observation of B→ϕKB\to \phi K and B→ϕK∗B\to \phi K^{*}

We have studied two-body charmless hadronic decays of $B$ mesons into the final states phi K and phi K^*. Using 9.7 million $B\bar{B}$ pairs collected with the CLEO II detector, we observe the decays B- -> phi K- and B0 -> phi K*0 with the following branching fractions: BR(B- -> phi K-)=(5.5 +2.1-1.8 +- 0.6) x 10^{-6} and BR(B0 -> phi K*0)=(11.5 +4.5-3.7 +1.8-1.7) x 10^{-6}. We also see evidence for the decays B0 -> phi K0 and B- -> phi K*-. However, since the statistical significance is not overwhelming for these modes we determine upper limits of <12.3 x 10^{-6} and <22.5 x 10^{-6} (90% C.L.) respectively.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN