Designing Nanoconjugates to Effectively Target Pancreatic Cancer Cells In Vitro and In Vivo

Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells.The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer.Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates

The p21-Dependent Radiosensitization of Human Breast Cancer Cells by MLN4924, an Investigational Inhibitor of NEDD8 Activating Enzyme

Radiotherapy is a treatment choice for local control of breast cancer. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. We have recently validated that SCF (SKP1, Cullins, and F-box protein) E3 ubiquitin ligase is an attractive radiosensitizing target. Here we tested our hypothesis that MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 Activating Enzyme) that inactivates SCF E3 ligase, could act as a novel radiosensitizing agent in breast cancer cells. Indeed, we found that MLN4924 effectively inhibited cullin neddylation, and sensitized breast cancer cells to radiation with a sensitivity enhancement ratio (SER) of 1.75 for SK-BR-3 cells and 1.32 for MCF7 cells, respectively. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest in SK-BR-3 cells, but not in MCF7 cells at early time point, and enhanced radiation-induced apoptosis in both lines at later time point. However, blockage of apoptosis by Z-VAD failed to abrogate MLN4924 radiosensitization, suggesting that apoptosis was not causally related. We further showed that MLN4924 failed to enhance radiation-induced DNA damage response, but did cause minor delay in DNA damage repair. Among a number of tested SCF E3 substrates known to regulate growth arrest, apoptosis and DNA damage response, p21 was the only one showing an enhanced accumulation in MLN4924-radiation combination group, as compared to the single treatment groups. Importantly, p21 knockdown via siRNA partialy inhibited MLN4924-induced G2/M arrest and radiosensitization, indicating a causal role played by p21. Our study suggested that MLN4924 could be further developed as a novel class of radiosensitizer for the treatment of breast cancer

Pre-competition anxiety and its correlation with front handspring on vault table among junior gymnasts

The present study was conducted to identify the level of anxiety and its relationship with front handspring on vault table among junior gymnasts in Nasiriyah club. The study also aimed to identify the statistical differences in performing this skill according to the variables and training conditions. A total of 20 gymnasts were recruited from the junior club of Nasiriyah by random sampling method. The measurement of anxiety among the athletes was done by a questionnaire, developed by Allawi in 1998. The findings of the present study revealed a significant correlation between pre-competition anxiety and the performance of a front handspring on the vault table among gymnasts in Nasiriyah junior club

Probability distribution of arm trajectory for motion estimation and gesture recognition

In the human motion measurement, motion capture system is used to record the movement of the human body by using different types of sensors such as a magnetic position sensor, a mechanical motion detector and a vision sensor. The most challenging task in human motion measurement is to achieve the ability and reliability of a motion capture system for tracking and recognizing dynamic gestures, because human body structure has many degrees of freedom. This paper introduces a 3D motion measurement of the human upper body by using an optical motion capture system for the purpose of the estimation of human upper body motions, which is based on the probability distribution of arm trajectories. In this study, by examining the characteristic of the arm trajectory, motion features are selected and classified by using the fuzzy technique. The posture of the occluded body part is probabilistically estimated by using the aggregation of the fuzzy information of arm trajectories and the constructed human upper body model. Experimental results show that the use of the system effectively works for classifying various motion patterns and estimating the occluded posture in the motion

Probability distribution of arm trajectory for motion estimation and gesture recognition

In the human motion measurement, motion capture system is used to record the movement of the human body by using different types of sensors such as a magnetic position sensor, a mechanical motion detector and a vision sensor. The most challenging task in human motion measurement is to achieve the ability and reliability of a motion capture system for tracking and recognizing dynamic gestures, because human body structure has many degrees of freedom. This paper introduces a 3D motion measurement of the human upper body by using an optical motion capture system for the purpose of the estimation of human upper body motions, which is based on the probability distribution of arm trajectories. In this study, by examining the characteristic of the arm trajectory, motion features are selected and classified by using the fuzzy technique. The posture of the occluded body part is probabilistically estimated by using the aggregation of the fuzzy information of arm trajectories and the constructed human upper body model. Experimental results show that the use of the system effectively works for classifying various motion patterns and estimating the occluded posture in the motion

Improving Education in the Developing World: What Have We Learned from Randomized Evaluations?

Across a range of contexts, reductions in education costs and provision of subsidies can boost school participation, often dramatically. Decisions to attend school seem subject to peer effects and time-inconsistent preferences. Merit scholarships, school health programs, and information about returns to education can all cost-effectively spur school participation. However, distortions in education systems, such as weak teacher incentives and eliteoriented curricula, undermine learning in school and much of the impact of increasing existing educational spending. Pedagogical innovations designed to address these distortions (such as technology-assisted instruction, remedial education, and tracking by achievement) can raise test scores at a low cost. Merely informing parents about school conditions seems insufficient to improve teacher incentives, and evidence on merit pay is mixed, but hiring teachers locally on short-term contracts can save money and improve educational outcomes. School vouchers can cost-effectively increase both school participation and learning.school attendance, peer effects, school quality, teacher incentives