Peptide stapling by late-stage Suzuki-Miyaura cross-coupling

The development of peptide stapling techniques to stabilise alpha-helical secondary structure motifs of peptides led to the design of modulators of protein-protein interactions, which had been considered undruggable for a long time. We disclose a novel approach towards peptide stapling utilising macrocyclisation by late-stage Suzuki-Miyaura cross-coupling of bromotryptophan-containing peptides of the catenin-binding domain of axin. Optimisation of the linker length in order to find a compromise between both sufficient linker rigidity and flexibility resulted in a peptide with an increased alpha-helicity and enhanced binding affinity to its native binding partner beta-catenin. An increased proteolytic stability against proteinase K has been demonstrated

A cross-country comparison of intensive care physicians' beliefs about their transfusion behaviour : a qualitative study using the theoretical domains framework

Pub Med ID 22999460 PMCID: PMC3527303Peer reviewedPublisher PD

Construction of realistic hybrid computational fetal phantoms from radiological images in three gestational ages for radiation dosimetry applications

Radiation exposure and associated radiation risks are major concerns for fetal development for pregnant patients who undergo radiation therapy or diagnostic imaging procedures. In order to accurately estimate the radiation dose to the fetus and assess the uncertainty of fetal position and rotation, three hybrid computational fetus phantoms were constructed using magnetic resonance imaging (MRI) for each fetus model as a starting point to construct a complete anatomically accurate fetus, gravid uterus, and placenta. A total of 27 fetal organs were outlined from radiological images via the Velocity Treatment Planning System. The DICOM-Structure set was imported to Rhinoceros software for further reconstruction of 3D fetus phantom model sets. All fetal organ masses were compared with ICRP-89 reference data. Our fetal model series corresponds to 20, 31, and 35 weeks of pregnancy, thus covering the second and third trimester. Fetal positions and locations were carefully adapted to represent the real fetus locations inside the uterus for each trimester of pregnancy. The new series of hybrid computational fetus models together with pregnant female models can be used in evaluating fetal radiation doses in diagnostic imaging and radiotherapy procedures

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib–lenalidomide–dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study

Objectives: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib–lenalidomide–dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). Methods: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA‐IXA, and REMIX. Results: Overall, 391/100/68 were lenalidomide‐naïve/−exposed/−refractory and 37/411/110 were PI‐naïve/−exposed/−refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression‐free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide‐naïve/exposed/refractory patients. Median DOT and PFS in PI‐naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. Conclusion: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide‐ and/or PI‐nonrefractory versus refractory patients

Magnetoliposomas multifuncionales como vehículos de administración de fármacos para el tratamiento potencial de la enfermedad de Parkinson

La enfermedad de Parkinson (EP) es el segundo trastorno neurodegenerativo más frecuente después de la enfermedad de Alzheimer. Por ello, el desarrollo de nuevas tecnologías y estrategias para tratarla es una prioridad sanitaria mundial. Los tratamientos actuales incluyen la administración de levodopa, inhibidores de la monoaminooxidasa, inhibidores de la catecol-O-metiltransferasa y fármacos anticolinérgicos. Sin embargo, la liberación efectiva de estas moléculas, debido a la limitada biodisponibilidad, es un reto importante para el tratamiento de la EP. Como estrategia para resolver este desafío, en este estudio desarrollamos un novedoso sistema de liberación de fármacos multifuncional magnético y sensible a estímulos redox, basado en nanopartículas de magnetita funcionalizadas con la proteína translocadora de alto rendimiento OmpA y encapsuladas en liposomas de lecitina de soja. Los magnetoliposomas multifuncionales (MLP) obtenidos se ensayaron en neuroblastoma, glioblastoma, astrocitos primarios humanos y de rata, células endoteliales de rata de barrera hematoencefálica, células endoteliales microvasculares primarias de ratón y en un modelo celular inducido por EP. Los MLP demostraron un excelente rendimiento en ensayos de biocompatibilidad, incluyendo hemocompatibilidad (porcentajes de hemólisis por debajo del 1%), agregación plaquetaria, citocompatibilidad (viabilidad celular por encima del 80% en todas las líneas celulares probadas), potencial de membrana mitocondrial (alteraciones no observadas) y producción intracelular de ROS (impacto insignificante en comparación con los controles). Además, las nanovehículas mostraron una aceptable internalización celular (área cubierta cercana al 100% a los 30 min y a las 4 h) y capacidad de escape endosomal (disminución significativa de la colocalización lisosomal tras 4 h de exposición). Además, se emplearon simulaciones de dinámica molecular para comprender mejor el mecanismo de translocación subyacente de la proteína OmpA, mostrando hallazgos clave relativos a interacciones específicas con fosfolípidos. En general, la versatilidad y el notable rendimiento in vitro de este novedoso nanovehículo lo convierten en una tecnología de administración de fármacos adecuada y prometedora para el tratamiento potencial de la EP.Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Therefore, development of novel technologies and strategies to treat PD is a global health priority. Current treatments include administration of Levodopa, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, and anticholinergic drugs. However, the effective release of these molecules, due to the limited bioavailability, is a major challenge for the treatment of PD. As a strategy to solve this challenge, in this study we developed a novel multifunctional magnetic and redox-stimuli responsive drug delivery system, based on the magnetite nanoparticles functionalized with the high-performance translocating protein OmpA and encapsulated into soy lecithin liposomes. The obtained multifunctional magnetoliposomes (MLPs) were tested in neuroblastoma, glioblastoma, primary human and rat astrocytes, blood brain barrier rat endothelial cells, primary mouse microvascular endothelial cells, and in a PD-induced cellular model. MLPs demonstrated excellent performance in biocompatibility assays, including hemocompatibility (hemolysis percentages below 1%), platelet aggregation, cytocompatibility (cell viability above 80% in all tested cell lines), mitochondrial membrane potential (non-observed alterations) and intracellular ROS production (negligible impact compared to controls). Additionally, the nanovehicles showed acceptable cell internalization (covered area close to 100% at 30 min and 4 h) and endosomal escape abilities (significant decrease in lysosomal colocalization after 4 h of exposure). Moreover, molecular dynamics simulations were employed to better understand the underlying translocating mechanism of the OmpA protein, showing key findings regarding specific interactions with phospholipids. Overall, the versatility and the notable in vitro performance of this novel nanovehicle make it a suitable and promising drug delivery technology for the potential treatment of PD

Controlling the 3D architecture of Self-Lifting Auto-generated Tissue Equivalents (SLATEs) for optimized corneal graft composition and stability

Ideally, biomaterials designed to play specific physical and physiological roles in vivo should comprise components and microarchitectures analogous to those of the native tissues they intend to replace. For that, implantable biomaterials need to be carefully designed to have the correct structural and compositional properties, which consequently impart their bio-function. In this study, we showed that the control of such properties can be defined from the bottom-up, using smart surface templates to modulate the structure, composition, and bio-mechanics of human transplantable tissues. Using multi-functional peptide amphiphile-coated surfaces with different anisotropies, we were able to control the phenotype of corneal stromal cells and instruct them to fabricate self-lifting tissues that closely emulated the native stromal lamellae of the human cornea. The type and arrangement of the extracellular matrix comprising these corneal stromal Self-Lifting Analogous Tissue Equivalents (SLATEs) were then evaluated in detail, and was shown to correlate with tissue function. Specifically, SLATEs comprising aligned collagen fibrils were shown to be significantly thicker, denser, and more resistant to proteolytic degradation compared to SLATEs formed with randomly-oriented constituents. In addition, SLATEs were highly transparent while providing increased absorption to near-UV radiation. Importantly, corneal stromal SLATEs were capable of constituting tissues with a higher-order complexity, either by creating thicker tissues through stacking or by serving as substrate to support a fully-differentiated, stratified corneal epithelium. SLATEs were also deemed safe as implants in a rabbit corneal model, being capable of integrating with the surrounding host tissue without provoking inflammation, neo-vascularization, or any other signs of rejection after a 9-months follow-up. This work thus paves the way for the de novo biofabrication of easy-retrievable, scaffold-free human tissues with controlled structural, compositional, and functional properties to replace corneal, as well as other, tissuesThis study was supported by the Medical Research Council grant MR/ K017217/1, the Biotechnology and Biological Sciences Research Council, grant BB/I008187/1 and the Spanish Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I) from the Spanish Ministry of Economy and Competitiveness (Instituto de Salud Carlos III), grant FIS PI14/0955 (cofinanced by FEDER funds, European Union)

The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome

<p>Abstract</p> <p>Background</p> <p>To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles.</p> <p>Methods</p> <p>A retrospective cohort study including all patients who had IVF-ET from January 2003–December 2005 conducted at a tertiary center.</p> <p>Results</p> <p>A total of 2464 cycles were analysed. Pregnancy rate (PR) was 35.8%. PR increased linearly (r = 0.864) from 29.4% among patients with a lining of less than or equal to 6 mm, to 44.4% among patients with a lining of greater than or equal to 17 mm. ROC showed that endometrial thickness is not a good predictor of PR, so a definite cut-off value could not be established (AUC = 0.55).</p> <p>Conclusion</p> <p>There is a positive linear relationship between the endometrial thickness measured on the day of hCG injection and PR, and is independent of other variables. Hence aiming for a thicker endometrium should be considered.</p

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: Effectiveness in relapsed/refractory multiple myeloma

[Aim]: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed.[Results]: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events.[Conclusion]: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1.This work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited