Development of Novel Cellular Assay Model and Therapeutic Deep Eutectic Solvents to Optimize the Activity of Anticancer Agents

Multidrug resistance (MDR) is the major burden behind chemotherapeutic treatment failure. It is the principal mechanism by which cancer cells evade chemotherapeutic treatment. As a result, aggressive cancer cells survive and continue uncontrolled cell division. Multidrug resistance affects survival rate of almost all types of cancer patients and death toll rises at an alarming rate. There are seven different mechanisms for evolving MDR. The most common mechanism in efflux activity of overexpressed ABC transporters. MRP1 is a prominent ABC transporter that pumps out a wide variety of anticancer drugs from the cells and thereby reduces intracellular drug concentrations and develops chemoresistance. Currently there are several protocols available to assess interaction between MRP1 and probable substrate anticancer drugs. However, these protocols have several limitations in common, such as expansive instrument set up, trained personnel, complex image analysis, separation of drugs from cell lysate, preparation of membrane vesicle, and results are based on accumulation of secondary fluorescence or radiolabeled substrates. To the best of our knowledge, there are no known protocols that can directly detect interaction between MPP1 and chemotherapeutic agents and categorize as MRP1 substrates. To solve this issue, in first project we developed an easy to follow and efficient novel mammalian cell-based efflux assaying using HPLC-UV technique to detect whether MRP1 considers anticancer drug as substrate and directly pumps the drug of the cancer cells. We chose MDCK-II parental and MDCK-II MRP1 overexpressed cells to establish the assay. To evaluate the efficacy of novel protocol, the result was compared with a known MRP1 substrate anticancer drug vincristine (positive control). To conduct the assay, we chose total seven MRP1 modulator anticancer drugs identified previously in our laboratory. We exclusively focused on extracellular media for pumped-out drugs from both cell lines. Initially, incubation (1 hour) and efflux time points (2 hours) were optimized. In the final step, parental and MRP1 overexpressed cells were incubated with drugs for 1 hour. After that, cells were washed and replaced with fresh transport buffer and waited for 2 hours to collect pumped out drugs from the cells. Then the solution was injected into HPLC for determining concentration. Our research idea is that if the drug works as MRP1 substrate, it will be pumped out directly by MRP1 and extracellular concentration will significantly increase compared to parental cells (no MRP1 overexpression). Our idea worked perfectly and we identified some anticancer drugs namely, alisertib, mesalamine and celecoxib that are highly susceptible to MRP1 mediated drug resistance. Next, we validated our novel protocol using popular MTT assay. We used same cell lines for MTT. From MTT we noticed that for these substrate drugs cell viability was high in MRP1 overexpressed cells compared to parental cells. It confirmed the outcome of the novel efflux assay. The novel protocol will pioneer direct and rapid detection of new MRP1 substrates with accuracy. It could also be applied to other prominent ABC transporters to identify specific substrates. The novel assay will also promote development of ABC transporter specific inhibitors to inhibit activity of transporters and restore the pharmacological potential of chemotherapeutic agents

Optimal Row-Column Designs for Correlated Errors and Nested Row-Column Designs for Uncorrelated Errors

In this dissertation the design problems are considered in the row-column setting for second order autonormal errors when the treatment effects are estimated by generalized least squares, and in the nested row-column setting for uncorrelated errors when the treatment effects are estimated by ordinary least squares. In the former case, universal optimality conditions are derived separately for designs in the plane and on the torus using more general linear models than those considered elsewhere in the literature. Examples of universally optimum planar designs are given, and a method is developed for the construction of optimum and near optimum designs, that produces several infinite series of universally optimum designs on the torus and near optimum designs in the plane. Efficiencies are calculated for planar versions of the torus designs, which are found to be highly efficient with respect to some commonly used optimality criterion. In the nested row-column setting, several methods of construction of balanced and partially balanced incomplete block designs with nested rows and columns are developed, from which many infinite series of designs are obtained. In particular, 149 balanced incomplete block designs with nested rows and columns are listed (80 appear to be new) for the number of treatments, v \u3c 101, a prime power

Yet Another Symbian Vulnerability Update

The more the mobile devices are approaching to advance their security, the numbers of vulnerabilities are also becoming more astonishing. The number of mobile phones including smart phones is rising vertically, and so has the amount of malware activity. This report documents the latest threats in Symbian mobile industry and analyses the consequence. In addition, it will suggest the possible solution that may help individuals to protect their device & ultimately maintain the privacy

Data-driven insights: Assessment of airline ancillary services

Airlines increasingly rely on ancillary service fees for revenue generation. As a result, many ancillary services have been conceived and implemented. However, each customer does not desire to purchase every ancillary service. This research examines the heterogeneity among U.S. international airline passengers and their willingness to pay for assorted ancillary services. Antecedents to purchase intention and actual purchase behavior were evaluated using Amazon Mechanical Turk for data collection. Our results show that there are differences in airline passenger preferences when purchasing ancillary services on international flights. The number of times a passenger flies in a year and the reason for travel are found to be consistently significant. Occasionally, age and income are found to be significant. These findings will be very useful to airline marketing executives and could help to assure consumers receive the services they want at the price levels they are willing to pay

Revisiting Alu of The Swamp Dwellers by Soyinka and Views by Beauvoir in The Second Sex: Unifying Humanity Versus Feminist Separatism

This paper concentrates on a comparative study between Alu of the drama The Swamp Dwellers by Soyinka and the Feminist views of Beauvoir in The Second Sex while the areas of the drama so far explored and discussed are native narrative, political views, decline through modernization, moral-spiritual standpoint, family bonding and human-nature tie. In the drama, if the vital role played by Alu is construed, she appears as a woman figure of infinite capaciousness with her duties, responsibilities, feelings, commitments, rights and privileges in family and society. Alu succeeds because her human-centric Yoruba tradition gives support to her family-centric biology and psychology. But contrary to Alu, Feminist views disseminated by Beauvoir in The Second Sex embark on the estrangement of women from family and humanity. Thus, the paper seeks to unearth how Alu of Yoruba tradition harmonizes and unifies humanity through her role in family and society while Feminism of Beauvoir opposes them and wishes women to be separated. In this qualitative research of thematic analysis method, Family Systems Theory and Religious Humanism Theory were applied. By recommending for women the re-introduction of traditional human-centric life in family and society, this research may contribute to women’s emancipation from misery.    

From home to homelessness: A reflection on Nora’s possible post-departure feminist life in A Doll’s House by Henrik Ibsen

In Henrik Ibsen’s A Doll’s House, Nora’s departure from home being hurt by her husband’s behavior appears to be the most important event of the drama igniting so far a wide critical parlances of Feminist array that appreciate the departure as Nora’s freedom from male-dominated society. But Nora’s success in having a home of comfort and happiness in her post-departure future life in Feminist world deserves critical attention too. We may posit Nora will shift to a Feminist world considering the departure as the manifestation of her newly imbibed Feminist spirit because the first wave Feminism of her time is either indifferent about or antagonistic to family life by being politics-centric. However, when Nora has within her a woman’s indispensable family-centric female construction to face nonfamilial politics-centric first wave feminism, she is sure to find no home in that Feminist world. Thus, this paper aims at examining how Nora, with her declared departure from home, is going to shift to the world of first wave Feminism which, by being nonfamilial and politics-centric, works against the very family-centric construction of Nora’s female construction and offers homelessness to her.

Hydrostatic pressure effect on the Gunn threshold electric effect in n-InSb

The Gunn effect as a function of pressure has been studied in n~type InSb. The Gunn threshold field is found to decrease with increasing pressure reaching a minimum at P ~ 9 kbars. It then increases while the oscillations weaken with increasing pressure up to 12 kbars. Low field Hall and conductivity measurements have also been made in an attempt to obtain a possible explanation for the threshold minimum. It is observed that the impurity level moves away from the conduction band approximately exponentially with increasing pressure. By 9 kbars the donor ionization energy is large enough that considerable freeze-out or deionization of donor states occurs. The reduction in carrier number is unfavourable to the Gunn process and hence leads to an increase in the threshold field for pressures above 9 kbars