Influence of Surfactants on Lipase Fat Digestion in a Model Gastro-intestinal System

In the present study, we use a model gastro-intestinal system to study the influence of different food-grade surface-active molecules (Sn-2 monopalmitin, β-lactoglobulin, or lysophosphatodylcholine) on lipase activity. The interfacial activity of lipase and surfactants are assessed with the pendant drop technique, a commonly used tensiometry instrument. A mathematical model is adopted which enables quantitative determination of the composition of the water–oil interface as a function of bulk surfactant concentration in the water–oil mixtures. Our results show a decrease in gastric lipolysis when interfacially active molecules are incorporated into a food matrix. However, only the Sn-2 monopalmitin caused a systematic decrease in triglyceride hydrolysis throughout the gastro-intestinal tract. This effect is most likely due to exclusion of both lipase and triglyceride from the water–oil interface together with a probable saturation of the solubilization capacity of bile with monoglycerides. Addition of β-lactoglobulin or lysophopholipids increased the hydrolysis of fat after the gastric phase. These results can be attributed to an increasing interfacial area with lipase and substrate present at the interface. Otherwise, β-lactoglobulin, or lysophopholipids reduced fat hydrolysis in the stomach. From the mathematical modeling of the interface composition, we can conclude that Sn-2 monopalmitin can desorb lipase from the interface, which, together with exclusion of substrate from the interface, explains the gradually decreased triglyceride hydrolysis that occurs during the digestion. Our results provide a biophysics approach on lipolysis that can bring new insights into the problem of fat uptake

Doxorubicin induces caspase-mediated proteolysis of KV7.1

Strigli A, Raab C, Hessler S, et al. Doxorubicin induces caspase-mediated proteolysis of KV7.1. Communications Biology. 2018;1(1): 155.Kv7.1 (KCNQ1) coassembles with KCNE1 to generate the cardiac IKs-channel. Gain- and loss-of-function mutations in KCNQ1 are associated with cardiac arrhthymias, highlighting the importance of modulating IKs activity for cardiac function. Here, we report proteolysis of Kv7.1 as an irreversible posttranslational modification. The identification of two C-terminal fragments of Kv7.1 led us to identify an aspartate critical for the generation of one of the fragments and caspases as responsible for mediating proteolysis. Activating caspases reduces Kv7.1/KCNE1 currents, which is abrogated in cells expressing caspase-resistant channels. Enhanced cleavage of Kv7.1 can be detected for the LQT mutation G460S, which is located adjacent to the cleavage site, whereas a calmodulin-binding-deficient mutation impairs cleavage. Application of apoptotic stimuli or doxorubicin-induced cardiotoxicity provokes caspase-mediated cleavage of endogenous IKs in human cardiomyocytes. In summary, caspases are novel regulatory components of IKs channels that may have important implications for the molecular mechanism of doxorubicin-induced cardiotoxicity

an interim analysis from the prospective GMMG-MM5 trial

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16

Atomic Resonance and Scattering

Contains reports on nine research projects.National Science Foundation (Grant PHY79-09743)National Science Foundation (Grant PHY82-10486)Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0183)National Bureau of Standards (Grant NB83-NAHA-4058)National Science Foundation (Grant CHE79-02967-A04)National Science Foundation (Grant PHY83-07172)Joint Services Electronics Program (Grant DAAG29-83-K-0003

Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY83-06273)National Bureau of Standards (Grant NB83-NAHA-4058)National Science Foundation (Grant PHY84-11483)Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract NO0014-79-C-0183)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant PHY83-07172-A01

a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24)

Atomic Resonance and Scattering

Contains reports on six research projects.National Science Foundation (Grant PHY 83-06273)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0183)Joint Services Electronics Program (Contract DAALO03-86-K-0002)National Science Foundation (Grant PHY 84-11483)National Science Foundation (Grant PHY 86-05893)National Science Foundation (Grant ECS 84-21392)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant CHE 84-21392

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi