Role of Ezrin in Colorectal Cancer Cell Survival Regulation

Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States, mainly due to metastasis to the distant organ sites. However, the molecular basis of CRC metastasis is poorly understood. Therefore, identification and characterization of novel potential anti-cancer therapeutic targets CRC is of urgent need. Utilizing a 2D-DIGE proteomics approach ezrin was identified as a protein that is differentially expressed between primary colon tumors xenografts, orthotopically implanted in athymic nude mice, and corresponding and liver metastatic deposits. Ezrin, a cytoskeletal protein belonging to the ezrin–radixin–moesin (ERM) family plays important roles in cell motility, invasion and metastasis. However, its function in CRC is not well characterized. Increased phosphorylation of ezrin at the T567 site (termed here as p-ezrin T567) was observed in liver metastasis as compared to the primary tumors in both orthotopic xenograft mouse models and human CRC patient specimens. Inhibition of ezrin activation by siRNA, shRNA, pharmacological inhibitor or an ezrin phospho-deficient T567A mutant significantly increased cell death associated with downregulation of inhibitors of apoptosis (IAP) proteins, XIAP and survivin which have been linked to aberrant cell survival and metastasis. In addition inhibition of the IGF1R signaling pathway by the humanized recombinant IGF1R monoclonal antibody MK-0646 in subcutaneous xenografts resulted in the inhibition of p-ezrin T567. Furthermore, TGFβ/Smad3 signaling inhibits ezrin phosphorylation at T567. These results suggest that ezrin is a downstream effector of the IGF1R and TGFβ signaling pathways. Ezrin is a known cAMP dependent A-kinase Anchoring Protein (AKAP). We demonstrate that the knockdown or inhibition of ezrin activates PKA in a cAMP-independent manner leading and leads to decreased expression of XIAP and survivin and CRC cell death. Interestingly, ezrin activation by hyperphosphorylation at T567 also activates PKA, but in cAMP-dependent manner leading to CRC cell survival and upregulation of XIAP and survivin. These results were further confirmed with ezrin T567 phospho-mimetic (T567D) and phospho-deficient (T567A) mutants which demonstrated PKA activation by cAMP-dependent and independent mechanisms respectively leading to different CRC cell fates. Hence, there are two opposing pathways mediated by ezrin in which PKA is activated but results in different cell fates. Therefore, ezrin might be a novel target that could be utilized for the development of new therapeutic strategies. Further understanding of the mechanisms by which PKA is activated and its differential role in CRC cell fates could have potential impact for CRC treatment

金砖四国跨国公司如何应对国际政治风险

笔者分析了关于对巴西，俄罗斯，印度和中国（金砖四国）公司向外投资的政治风险忧患的调查报告的结果，并且将其与全球类似的风险忧患进行比较

Democracy and Emergency rule in India :

An analysis of the actions of the Emergency reveals a systematic perversion of the fundamental concepts of constitutionalism and a corresponding attempt at the institutionalization of an authoritarian political system in place of the democratic system that India had adopted at independence. The changes to the political and constitutional system made during this period are remarkable for their disregard for constitutional constraints and their deviation from accepted democratic norms. There was suspension of civil liberties, denial of due process of justice and the revocation of the rule of law. All meaningful opposition was disallowed, public dissent stifled and the freedom of the press virtually destroyed. Permanent changes to the political order were enacted through constitutional amendments which altered the distribution of power among the branches of government, reduced the scope of citizens' rights, curtailed judicial review and gave parliament absolute authority to amend the Constitution. In short, the 1975 Indian Emergency was characterized not merely by the institution of a temporary crisis government with expanded powers to meet an extraordinary situation, but by the emergence of a government which sought to institutionalize authoritarian norms and procedures in Indian politics.The study, however, is not confined to an examination of the changes made to the Indian political system during the Emergency. While these changes, no doubt, sanctioned a fundamental shift away from democratic institutions and processes, they are essentially the logical outcome of the authoritarian trend in Indian politics, which had developed under Mrs. Gandhi. The significance of the Emergency cannot be fully recognized unless the Emergency is viewed against the backdrop of the process of political change that preceded it. Therefore, this study is also concerned, as its subtitle suggests, with the larger issue of political change under Mrs. Gandhi.This is a study of political change--the Indian Emergency of June 1975 to March 1977. It examines the events that led up to it and the political and constitutional changes instituted under it, with a view to understanding the dilemma posed by the subversion of democratic political systems through ostensibly constitutional means

How BRIC MNEs Deal with International Political Risk

The author analyzes the results of a survey of political risk concerns of outward-investing Brazilian, Russian, Indian, and Chinese (BRIC) firms and compares the results to the concerns of global counterparts

The perceived influence of grandparents’ beliefs and attitudes on parents’ breastfeeding behaviour and paediatric vaccination decisions

Human infants are highly dependent on their parents for a prolonged period of time. The resources required to raise a child cannot be provided by biological parents alone and requires the assistance of others, usually relatives. Grandparents among them, have played the most significant role. With increased life expectancy in Western, educated, industrialised, rich and democratic (WEIRD) societies, grandparents have come to the forefront as informal childcare providers. Although the influence of a child’s social environment on health has been well-studied, the influence of grandparents, specifically in regard to breastfeeding remains inconclusive, while grandparental influence on paediatric vaccinations has not been investigated. Using an exploratory mixed-method research design this study investigated the perceived influence of grandparents on parents’ breastfeeding behaviour and paediatric vaccination uptake in Perth, Western Australia. Focus group discussions were conducted to collect exploratory data on the beliefs, attitudes and perceived sources of influence on parents and grandparents towards breastfeeding and paediatric vaccines. Qualitative data was collected from Australian Aboriginal (N=15) and non-Aboriginal participants (N=73). Interpretative phenomenological data analysis revealed different themes for Aboriginal and non- Aboriginal participants. Although both groups reported positive beliefs and attitudes towards breastfeeding, Aboriginal grandmothers reported having a direct and positive influence on breastfeeding behaviour in young Aboriginal mothers. The influence of grandparents on non-Aboriginal parents’ breastfeeding behaviour was not always positive. The participants also shared positive beliefs and attitudes towards paediatric vaccines. Grandparents expressed full confidence in paediatric vaccines based on their memories of the diseases. Parents who had been vaccinated as children accepted immunisation as a normal part of child rearing. This data then informed the development of a questionnaire to quantitatively assess perceived grandparental influence. Data from mothers, fathers, grandmothers and grandfathers (N=278) were analysed to test the effects of beliefs, attitudes and perceived sources of influence on breastfeeding behaviour and paediatric vaccine uptake. The study sample was typical of WEIRD societies and reported high levels of educational qualifications and income. Positive attitude scores did not have a significant effect on breastfeeding behaviour in parents or grandparents. This suggested the influence of external factors such as physiological challenges to breastfeeding, physical ecology of the mother and the attitudes towards formula feeding. Maternal grandmothers did report offering the most advice regarding breastfeeding. However, the type of advice imparted and the effect of the advice on breastfeeding behaviour could not be discerned from this data. This cohort reported good knowledge on the benefits of paediatric vaccines and positive group influences and had low scores on vaccine anxiety. This was reflected by high confidence levels on the information available to them and the protection conferred to their children by vaccines. Grandparents who had high scores on knowledge and positive group influence reported they would advise their children on vaccinations for grandchildren. Less than 2% of the study sample scored high on vaccine anxiety and reported vaccine refusal and lack of confidence, which limited the study of whether grandparents could positively influence vaccine hesitant parents. The quantitative study sample is not representative of the average population which restricts generalisation of the findings. The precise nature of grandparents’ influence on parents’ infant feeding and paediatric vaccines need further exploration among the different cultural groups. Education, income levels and cultural and traditional child care practices are likely to have the most influence on the relationship between parents and grandparents, and consequently the extent to which grandparents’ opinions are valued and accepted in relation to breastfeeding and paediatric vaccinations decision

Effects of Substrate and Temperature on Growth of Aspergillus Flavus in Peanuts from Georgia

We investigated the effects of different substrates (potato dextrose agar [PDA], nutrient agar [NA], and corn meal agar [CMA]) and temperatures on growth and aflatoxin production in Aspergillus flavus. Contaminated peanuts from retailers at different locations in Georgia were used throughout the experiment and 200 seeds were selected from each sample. PDA, NA, and CMA served as the substrate to express the mold from the contaminated seeds. Seeds were plated equidistantly on each of the media and incubated at 10° C, 27° C, 30° C, and 37° C, respectively. Seeds incubated on moist filter paper served as control. Neither growth of A. flavus nor detectable levels of aflatoxin was observed at the temperature of 10° C on any of the media. While no growth of this mold was observed at a temperature of 37° C in most media, some growth was seen in PDA media at this temperature. However, maximum growth of A. flavus, along with detectable levels of aflatoxin, was attained at the temperatures of 27° C and 30° C. Of the three media tested, PDA supported vigorous growth of A. flavus at the temperatures of 27° C and 30° C

Outward FDI from India and its policy context

India is now the world's 21st largest outward investor, which is significant given its historically miniscule foreign direct investment (FDI) outflows. Annual FDI outflows have jumped fifty-fold after 2000, and Indian firms have invested over US$ 75 billion overseas in the past decade, in some cases to attain global status by acquiring world-leading firms. Substantial improvements in the country's economic performance and the competitiveness of its firms and their strategy, resulting from ongoing liberalization in economic and outward FDI (OFDI) policies, made these developments possible. Indian firms now invest across a wide variety of sectors and countries, departing from their historical focus on trading and textile investments in developing countries. Following the 25% crisis-induced drop in Indian OFDI in 2009, Indian firms are once again increasing their overseas investment, including through mergers and acquisitions (M&As). India's OFDI should continue its rapid upward trend over the next few years, as more companies seek to transfer their products and service innovations to new markets, and acquire strategic international know-how and market shares, particularly in crisis-hit developed economies

Effect of Substrate and Temperature on Growth of Aspergillus flavus in Peanuts from Georgia

We investigated the effects of different substrates (potato dextrose agar [PDAI, nutrient agar [NA], and corn meal agar [CMA)) and temperatures on growth and aflatoxin production in Aspergillus f]avus. Contaminated peanuts from retailers at different locations in Georgia were used throughout the experiment and 200 seeds were selected from each sample. PDA, NA, and CMA served as the substrate to express the mold from the contaminated seeds. Seeds were plated equidistantly on each of the media and incubated at 10 °C, 27 °C, 30 °C, and 37 °C, respectively. Seeds incubated on moist filter paper served as control. Neither growth of A. flavus nor detectable levels of aflatoxin was observed at the temperature of 10 °C on any of the media. While no growth of this mold was observed at a temperature of 37 °C in most media, some growth was seen in PDA media at this temperature. However, maximum growth of A. flavus, along with detectable levels of aflatoxin, was attained at the temperatures of 27 °C and 30 °C. Of the three media tested, PDA supported vigorous growth of A. flavus at the temperatures of 27 °C and 30 °C

Inward FDI in India and its policy context

A minor global FDI player in 2000, India is now the world's thirteenth largest FDI host country. With 2008 inflows of US$42 billion and 2009 inflows of US$ 27 billion, it is also a global top three preferred investment destination. Notable liberalizations in FDI policy and in several economic sectors, a globally competitive workforce, and rapid GDP and market growth are the main drivers of foreign investment in India. Yet, equity caps limit the size of potential new inflows, while national security concerns might prompt more oversight of FDI approval processes

Understanding the Experience of stress on initiation of Haemodialysis: A Phenomenological Study

Background: Research evidence on stress among chronic kidney disease/end stage renal disease patients in India is sparse. Experience of stress is a subjective phenomenon. Hence qualitative research methodology helps to gain real insight about factors that cause stress among haemodialysis patients. The objective of this study was to understand the stressors experienced by patients on initiation of haemodialysis treatment.Methods: A phenomenological approach was used to gain insight into the lived experience of stressors experienced by patients’ on haemodialysis treatment. The study was conducted in outpatient haemodialysis units of two private hospitals in Bangalore, India. Participants of the study consisted of six males and four females who were on haemodialysis for between 2 months to 36 months. Individual semi-structured interviews were conducted with all participants. All interviews were audio-taped and transcribed verbatim .Results: Content analysis was used to analyze the data. Three main themes emerged namely ‘Physical stress- ors’, ‘psychological stressors’ and ‘Socioeconomic stressors’. Pain, tiredness and loss of appetite were the predominant physical stressors reported by participants. Shock and depression on diagnosis and initiation of dialysis, difficulty adhering to prescribed therapeutic regimen, feeling of being burden on family, fear of complications and uncertainty about life were the psychological stressors reported by participants. A range of socioeconomic stressors were reported by the participants which included; Loss of employment, financial problems, loss of ability to perform activities of daily living and limited social life.Conclusion: Findings of this study can be utilized to design a pre-haemodialysis preparatory program which can be implemented for stage-4 chronic kidney disease patients to prepare them for haemodialysis.Â