Overexpressed TP73 induces apoptosis in medulloblastoma

Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. Methods We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Results Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents. Conclusion These results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells

A Primal-Dual Augmented Lagrangian Method for Optimal Control of Linear-Quadratic Problem with Time Varying Systems

In this paper we are concerned with time-varying optimal control problems whose cost is quadratic and whose state is a differential equation and with general boundary conditions. The basic new idea of this paper is to propose a primal-dual augmented Lagrangian method, embedded with a sequential quadratic programming(SQP) for the solution of such problems.The benefit of this approach is that the quality of the dual variables is monitored explicitly during the solution of the subproblem. Moreover, the formulation of a penalized matrix in the primal-dual variables with mesh-refinement strategy guarantees the reliability of the algorithm. Numerical experiments verify the efficiency of the proposed method.Keywords: Optimal control,primal-dual methods, augmented Lagrangian methods, conjugate gradient method, sequential quadratic programming

A Primal-Dual Augmented Lagrangian Method for Optimal Control of Linear-Quadratic Problem with Time Varying Systems

In this paper we are concerned with time-varying optimal control problems whose cost is quadratic and whose state is a differential equation and with general boundary conditions. The basic new idea of this paper is to propose a primal-dual augmented Lagrangian method, embedded with a sequential quadratic programming(SQP) for the solution of such problems.The benefit of this approach is that the quality of the dual variables is monitored explicitly during the solution of the subproblem. Moreover, the formulation of a penalized matrix in the primal-dual variables with mesh-refinement strategy guarantees the reliability of the algorithm. Numerical experiments verify the efficiency of the proposed method.Keywords: Optimal control,primal-dual methods, augmented Lagrangian methods, conjugate gradient method, sequential quadratic programmingJournal of the Nigerian Association of Mathematical Physics, Volume 20 (March, 2012), pp 165 – 17

Lean Distribution: Concept, Constructs, And Practices.

In today’s competitive market, applying lean thinking provides supply chain the ability to produce and deliver products in a timely and cost effective manner. To date, little research addressed lean distribution concept as an effective approach for improving supply chains. This caused a level of ambiguity regarding the concept’s dimensional structure and its practices. This paper aims to explore the antecedents of lean distribution concept and identify its constructs and practices using a data driven analytical approach (i.e. exploratory factor analysis). Findings show that enhancing communication with customers, optimising transportation activity, people participating in problem solving procedures and increasing the reliability of distribution operations are critical dimensions of lean distribution paradigm

Is Nigeria really on top of COVID-19? Message from effective reproduction number

Following the importation of coronavirus disease (COVID-19) into Nigeria on 27 February 2020 and then the outbreak, the question is: How do we anticipate the progression of the ongoing epidemic following all the intervention measures put in place? This kind of question is appropriate for public health responses and it will depend on the early estimates of the key epidemiological parameters of the virus in a defined population.In this study, we combined a likelihood-based method using a Bayesian framework and compartmental model of the epidemic of COVID-19 in Nigeria to estimate the effective reproduction number (R(t)) and basic reproduction number (R0) - this also enables us to estimate the initial daily transmission rate (β0). We further estimate the reported fraction of symptomatic cases. The models are applied to the NCDC data on COVID-19 symptomatic and death cases from 27 February 2020 and 7 May 2020.In this period, the effective reproduction number is estimated with a minimum value of 0.18 and a maximum value of 2.29. Most importantly, the R(t) is strictly greater than one from 13 April till 7 May 2020. The R0 is estimated to be 2.42 with credible interval: (2.37-2.47). Comparing this with the R(t) shows that control measures are working but not effective enough to keep R(t) below 1. Also, the estimated fraction of reported symptomatic cases is between 10 and 50%.Our analysis has shown evidence that the existing control measures are not enough to end the epidemic and more stringent measures are needed

Modeling the potential of wAu-Wolbachia strain invasion in mosquitoes to control Aedes-borne arboviral infections

Arboviral infections such as dengue, Zika and chikungunya are fast spreading diseases that pose significant health problems globally. In order to control these infections, an intracellular bacterium called Wolbachia has been introduced into wild-type mosquito populations in the hopes of replacing the vector transmitting agent, Aedes aegypti with one that is incapable of transmission. In this study, we developed a Wolbachia transmission model for the novel wAu strain which possesses several favourable traits (e.g., enhanced viral blockage and maintenance at higher temperature) but not cyctoplasmic incompatibility (CI)-when a Wolbachia-infected male mosquito mates with an uninfected female mosquito, producing no viable offspring. This model describes the competitive dynamics between wAu-Wolbachia-infected and uninfected mosquitoes and the role of imperfect maternal transmission. By analysing the system via computing the basic reproduction number(s) and stability properties, the potential of the wAu strain as a viable strategy to control arboviral infections is established. The results of this work show that enhanced maintenance of Wolbachia infection at higher temperatures can overcome the lack of CI induction to support wAu-Wolbachia infected mosquito invasion. This study will support future arboviral control programs, that rely on the introduction of new Wolbachia variants

Mathematical analysis of a two-strain disease model with amplification

We investigate a two-strain disease model with amplification to simulate the prevalence of drug-susceptible (s) and drug-resistant (m) disease strains. Drug resistance first emerges when drug-susceptible strains mutate and become drug-resistant, possibly as a consequence of inadequate treatment, i.e. amplification. In this case, the drug-susceptible and drug-resistant strains are coupled. We perform a dynamical analysis of the resulting system and find that the model contains three equilibrium points: a disease-free equilibrium; a mono-existent disease-endemic equilibrium at which only the drug-resistant strain persists; and a co-existent disease-endemic equilibrium where both the drug-susceptible and drug-resistant strains persist. We found two basic reproduction numbers: one associated with the drug-susceptible strain (R0s); the other with the drug-resistant strain (R0m), and showed that at least one of the strains can spread in a population if max[R0s,R0m]>1. Furthermore, we also showed that if R0m>max[R0s,1], the drug-susceptible strain dies out but the drug-resistant strain persists in the population (mono-existent equilibrium); however if R0s>max[R0m,1], then both the drug-susceptible and drug-resistant strains persist in the population (co-existent equilibrium). We conducted a local stability analysis of the system equilibrium points using the Routh-Hurwitz conditions and a global stability analysis using appropriate Lyapunov functions. Sensitivity analysis was used to identify the key model parameters that drive transmission through calculation of the partial rank correlation coefficients (PRCCs). We found that the contact rate of both strains had the largest influence on prevalence. We also investigated the impact of amplification and treatment/recovery rates of both strains on the equilibrium prevalence of infection; results suggest that poor quality treatment/recovery makes coexistence more likely and increases the relative abundance of resistant infections