Locally applied Simvastatin improves fracture healing in mice

<p>Abstract</p> <p>Background</p> <p>HMG-CoA reductase inhibitors, statins, are widely prescribed to lower cholesterol. High doses of orally administered simvastatin has previously been shown to improve fracture healing in a mouse femur fracture model. In this study, simvastatin was administered either subcutaneously or directly to the fracture area, with the goal of stimulating fracture repair at acceptable doses.</p> <p>Methods</p> <p>Femur fractures were produced in 70 mature male Balb-C mice and stabilized with marrow-nailing. Three experiments were performed. Firstly, 20 mice received subcutaneous injections of either simvastatin (20 mg) or vehicle. Secondly, 30 mice were divided into three groups of 10 mice receiving continuous subcutaneous delivery of the vehicle substance, the vehicle with 5 mg or with 10 mg of simvastatin per kg bodyweight per day. Finally, in 20 mice, a silicone tube was led from an osmotic mini-pump to the fracture area. In this way, 10 mice received an approximate local dose of simvastatin of 0.1 mg per kg per day for the duration of the experiment and 10 mice received the vehicle compound. All treatments lasted until the end of the experiment. Bilateral femurs were harvested 14 days post-operative. Biomechanical tests were performed by way of three-point bending. Data was analysed with ANOVA, Scheffé's post-hoc test and Student's unpaired t-test.</p> <p>Results</p> <p>With daily simvastatin injections, no effects could be demonstrated for any of the parameters examined. Continuous systemic delivery resulted in a 160% larger force at failure. Continuous local delivery of simvastatin resulted in a 170% larger force at failure as well as a twofold larger energy uptake.</p> <p>Conclusion</p> <p>This study found a dramatic positive effect on biomechanical parameters of fracture healing by simvastatin treatment directly applied to the fracture area.</p

Método automático de clasificación de color en dientes humanos usando aprendizaje de máquina

Trabajo de InvestigaciónActualmente el proceso de identificación del color de los dientes para la fabricación de prótesis dentales es realizado manualmente por un experto que, utilizando un método de identificación visual, determina el color de las piezas dentales en la boca del paciente, usando guías de color como la VITA®. A pesar de que el método visual es el más utilizado para la identificación del color de dientes, este se ve afectado por distintas variables tales como: el cansancio del experto, la luminosidad en el ambiente, salud visual del especialista, entre otras que influyen en la identificación del color en los dientes. Los errores en la clasificación del color de los dientes pueden generar pérdidas de tiempo lo que implicaría en consecuencia sobrecostos que afectarían directamente al fabricante y la satisfacción final del cliente.1. Planteamiento del problema 2. Pregunta de investigación 3. Objetivos 4. Estado del arte 5. Marco de referencia 6. Alcances y limitaciones 7. Metodología 8. Diseño metodológico 9. Discusión y resultados 10. Conclusiones 11. Trabajos futuros 12. Bibliografía 13. ANEXOSPregradoIngeniero de Sistema

Chemotherapy Synergizes with Radioimmunotherapy Targeting La Autoantigen in Tumors

To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 (90Y)-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment. Methodology/Principal Findings: Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-​tetraacetic acid (DOTA), and then radiolabeled with 90Y. Mice bearing established subcutaneous tumors were treated with 90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2) model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of 90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants. Conclusions/Significance: We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death, which further augments DAB4 binding to produce a tumor-lethal ‘genotoxic chain reaction’. Clinically, this approach may be useful as consolidation treatment after a drug-induced cell death among (small-volume) metastatic deposits, the commonest cause of cancer death. This article is part II of a two-part series providing proof-of-concept for the diagnostic and therapeutic use of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®.Fares Al-Ejeh, Jocelyn M. Darby and Michael P. Brow

APOMAB®, a La-Specific Monoclonal Antibody, Detects the Apoptotic Tumor Response to Life-Prolonging and DNA-Damaging Chemotherapy

Background: Antineoplastic therapy may impair the survival of malignant cells to produce cell death. Consequently, direct measurement of tumor cell death in vivo is a highly desirable component of therapy response monitoring. We have previously shown that APOMAB® representing the DAB4 clone of a La/SSB-specific murine monoclonal autoantibody is a malignant cell-death ligand, which accumulates preferentially in tumors in an antigen-specific and dose-dependent manner after DNA-damaging chemotherapy. Here, we aim to image tumor uptake of APOMAB® (DAB4) and to define its biological correlates. Methodology/Principal Findings: Brisk tumor cell apoptosis is induced in the syngeneic EL4 lymphoma model after treatment of tumor-bearing mice with DNA-damaging cyclophosphamide/etoposide chemotherapy. Tumor and normal organ accumulation of Indium 111 (111In)-labeled La-specific DAB4 mAb as whole IgG or IgG fragments was quantified by whole-body static imaging and organ assay in tumor-bearing mice. Immunohistochemical measurements of tumor caspase-3 activation and PARP-1 cleavage, which are indicators of early and late apoptosis, respectively, were correlated with tumor accumulation of DAB4. Increased tumor accumulation of DAB4 was associated directly with both the extent of chemotherapy-induced tumor cell death and DAB4 binding per dead tumor cell. Tumor DAB4 accumulation correlated with cumulative caspase-3 activation and PARP-1 cleavage as tumor biomarkers of apoptosis and was directly related to the extended median survival time of tumor-bearing mice. Conclusions/Significance: Radiolabeled La-specific monoclonal antibody, DAB4, detected dead tumor cells after chemotherapy, rather than chemosensitive normal tissues of gut and bone marrow. DAB4 identified late apoptotic tumor cells in vivo. Hence, radiolabeled DAB4 may usefully image responses to human carcinoma therapy because DAB4 would capture the protracted cell death of carcinoma. We believe that the ability of radiolabeled DAB4 to rapidly assess the apoptotic tumor response and, consequently, to potentially predict extended survival justifies its future clinical development as a radioimmunoscintigraphic agent. This article is part I of a two-part series providing proof-of-concept for the the diagnostic and therapeutic use of a La-specific monoclonal antibody, the DAB4 clone of which is represented by the registered trademark, APOMAB®.Fares Al-Ejeh, Jocelyn M. Darby, Chris Tsopelas, Douglas Smyth, Jim Manavis and Michael P. Brow

Analysis of Crystallographic Structure of a Japanese Sword by the Pulsed Neutron Transmission Method

AbstractWe measured two-dimensional transmission spectra of pulsed neutron beams for a Japanese sword sample. Atom density, crystalline size, and preferred orientation of crystals were obtained using the RITS code. The position dependence of the atomic density is consistent with the shape of the sample. The crystalline size is very small and shows position dependence, which is understood by the unique structure of Japanese swords. The preferred orientation has strong position dependence. Our study shows the usefulness of the pulsed neutron transmission method for cultural metal artifacts