Multivariate modulation of the Zr MOF UiO-66 for defect-controlled multimodal anticancer drug delivery

Metal‐organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO‐66 by defect‐loading. The drugs are added to one‐pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination at the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF‐7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis

Inducing Visuomotor Adaptation Using Virtual Reality Gaming with a Virtual Shift as a Treatment for Unilateral Spatial Neglect

Unilateral spatial neglect after stroke is characterized by reduced responses to stimuli on the contralesional side, causing significant impairments in self-care and safety. Conventional visuomotor adaptation (VMA) with prisms that cause a lateral shift of the visual scene can decrease neglect symptoms but is not engaging according to patients. Performing VMA within a virtual reality (VR) environment may be more engaging but has never been tested. To determine if VMA can be elicited in a VR environment, healthy subjects (n=7) underwent VMA that was elicited by either wearing prisms that caused an optical shift, or by application of a virtual shift of the hand cursor within the VR environment. A low cost VR system was developed by coupling the Kinect v2 gaming sensor to online games via the Flexible Action and Articulated Skeleton Toolkit (FAAST) software. The adaptation phase of training consisted of a reaching task in online games or in a custom target pointing program. Following the adaptation phase the optical or virtual shift was removed and participants were assessed during the initial portion of the de-adaptation phase for the presence of an after-effect on their reaching movements, with lateral reaching errors indicating the successful induction of VMA. Results show that practicing reaching in a VR environment with a virtual shift lead to a horizontal after-effect similar to conventional prism adaptation. The results demonstrate that VMA can be elicited in a VR environment and suggest that VR gaming therapy could be used to improve recovery from unilateral spatial neglect

Reduction in the structural changes of experimental osteoarthritis by a nitric oxide inhibitor

AbstractObjectiveTo evaluate the in-vivo therapeutic efficacy ofN-iminoethyl-L-Lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS) in a dose response study, on the progression of lesions in the experimental osteoarthritic (OA) dog model.DesignThe sectioning of the anterior cruciate ligament of the right stifle joint of mongrel dogs was done by a stab wound. Dogs were separated into experimental groups: Group 1 received no treatment, Groups 2, 3, and 4 received oral L-NIL (0.3, 1 or 10mg/kg/day, respectively) starting immediately after surgery. The OA dogs were killed at 12 weeks after surgery.ResultsMacroscopically, L-NIL decreased the size of the cartilage lesions on condyles and plateaus. The histologic severity of the cartilage lesions was decreased in the L-NIL-treated dogs. This effect was more pronounced at the highest dosage tested (3 and 10mg/kg/day).ConclusionsThis study confirms the effectiveness of L-NIL, a selective inhibitor of iNOS, in attenuating the progression of experimental OA. It also clearly shows that the effect is dose-dependent

Improved Nearside-Farside Decomposition of Elastic Scattering Amplitudes

A simple technique is described, that provides improved nearside-farside (NF) decompositions of elastic scattering amplitudes. The technique, involving the resummation of a Legendre partial wave series, reduces the importance of unphysical contributions to NF subamplitudes, which can arise in more conventional NF decompositions. Applications are made to a strong absorption model and to a $^{16}$O + $^{12}$C optical potential at $E_{\text{lab}} = 132$ MeV.Comment: 5 pages, 2 figure

A straw drift chamber spectrometer for studies of rare kaon decays

We describe the design, construction, readout, tests, and performance of planar drift chambers, based on 5 mm diameter copperized Mylar and Kapton straws, used in an experimental search for rare kaon decays. The experiment took place in the high-intensity neutral beam at the Alternating Gradient Synchrotron of Brookhaven National Laboratory, using a neutral beam stop, two analyzing dipoles, and redundant particle identification to remove backgrounds

Shapes, contact angles, and line tensions of droplets on cylinders

Using an interface displacement model we calculate the shapes of nanometer-size liquid droplets on homogeneous cylindrical surfaces. We determine effective contact angles and line tensions, the latter defined as excess free energies per unit length associated with the two contact lines at the ends of the droplet. The dependences of these quantities on the cylinder radius and on the volume of the droplets are analyzed.Comment: 26 pages, RevTeX, 10 Figure

H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Altres ajuts: Acknowledgements TAM, LG, NTC, I-JL, RT, JRH, and SR were funded by Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6, MC_UU_00016/6, and MR/ M003221/1. AR was supported by a Bloodwise Clinician Scientist Fellowship (grants: 14041 and 17001), Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z), Lady Tata Memorial International Fellowship, and EHA-ASH Translational Research Training in Hematology Fellowship. SOB was funded by the Department of Paediatrics and Alexander Thatte Fund, University of Oxford. DJHFK is funded by a CIHR Postdoctoral Fellowship. IR is supported by the NIHR Oxford BRC, by a Bloodwise Program Grant (13001) and by the MRC Molecular Haematology Unit (MC_UU_12009/14). PV via the Molecular Haematology Unit (MC_UU_12009) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme. We would like to acknowledge the WIMM Flow Cytometry Facility which is supported by the MRC HIU, MRC MHU (MC_UU_12009), NIHR Oxford BRC, Kay Kendall Leukemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170), and by the WIMM Strategic Alliance awards G0902418 and MC_UU_12025. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z); the MRC WIMM Centre for Computational Biology (CCB), Radcliffe Department of Medicine, University of Oxford; and Jelena Telenius for the use of her pipelines. B-ALL work in PM's lab is financially supported by [...], the Fundación Uno entre Cienmil, the Fundación Leo Messi. PM also acknowledges structural support from the Obra Social La Caixa-Fundaciò Josep Carreras. The human fetal material was provided by the Joint MRC/ Wellcome Trust Grant 099175/Z/ 12/Z Human Developmental Biology Resource (http://hdbr.org). We gratefully acknowledge the kind generosity of patients, their parents, and staff at Great Ormond Street Hospital, London.MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL

Increased bone mineral density in Aboriginal and Torres Strait Islander Australians: Impact of body composition differences

Bone mineral density (BMD) has been reported to be both higher and lower in Indigenous women from different populations. Body composition data have been reported for Indigenous Australians, but there are few published BMD data in this population. We assessed BMD in 161 Indigenous Australians, identified as Aboriginal (n = 70), Torres Strait Islander (n = 68) or both (n = 23). BMD measurements were made on Norland-XR46 (n = 107) and Hologic (n = 90) dual-energy X-ray absorptiometry (DXA) machines. Norland BMD and body composition measurements in these individuals, and also in 36 Caucasian Australians, were converted to equivalent Hologic BMD (BMDH) and body composition measurements for comparison