Role of AKT2 in Cell Survival, Establishment and/or Maintenance of Colorectal Cancer Metastasis

There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt acts as a key signaling node that bridges oncogenic receptors to many essential pro-survival cellular functions, and is perhaps the most commonly activated signaling pathway in human cancer. Akt has three isoforms, Akt1, 2 and 3. Variable phenotypic differences are observed following the genetic inactivation and/or removal of the Akt isoforms, which suggests that the isoforms have distinct non-redundant functional characteristics despite sharing a high level of structural homology and similar mechanisms of activation. The major goal of the work presented in this dissertation was to identify the role of Akt isoforms on cell survival, establishment and/or maintenance of metastasis in colorectal cancer (CRC). Although there is an increase in the 5-year survival rate of CRC during early stages, the progress in the survival rate during the metastatic stage is still dismal, suggesting the need to develop anti-metastatic therapy. The work presented in this dissertation has led to the identification of Akt2, among Akt isoforms, as a major player for establishment and/or maintenance of metastasis. shRNA-mediated knockdown of Akt2, not Akt1, causes reduction in metastatic burden in CRC. We show that loss of Akt2 upregulates Metastasis Suppressor 1 (MTSS1) and inhibits the expression of anti-apoptotic genes, XIAP and survivin thus inhibiting cell survival which in turn could lead to reduction in metastatic potential of the cells. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation, leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. Extensive drug development efforts and clinical evaluations are underway targeting the aberrant cell survival properties associated with PI3K/Akt signaling in regulating cancer progression and metastasis. Inhibition of Akt activation by small molecule kinase inhibitors is an attractive candidate for targeting aberrant cell survival associated with malignant progression and metastasis and could be effective in the treatment of CRC. In this dissertation work, we have used a kinase inhibitor of Akt, MK-2206, to inhibit phosphorylation of Akt. We provide novel mechanistic insights on MK-2206-mediated cell death. MK-2206 showed an anti-tumorigenic role and led to a dual mechanism of cell death by inhibiting XIAP and survivin and by inducing Apoptosis Inducing Factor. Additionally, strategies to inhibit Akt2 as opposed to the other two isoforms may provide a therapeutic approach for treatment of metastases. A negative correlation between Akt2 and MTSS1 in human primary colorectal cancer samples might be useful in identification of metastatic patients. The work presented in this dissertation may assist in understanding whether loss of Akt2 could be a mechanism of increasing cell death, thus leading to reduction in metastasis. Additionally, this work provides a new paradigm for MK-2206-mediated control of aberrant cell survival associated with IGF1R-dependent CRC that may offer new targets for enhancing cell death in cancer cells

Optimising nutrition in residential aged care: A narrative review

In developed countries the prevalence of protein-energy malnutrition increases with age and multi-morbidities increase nutritional risk in aged care residents in particular. This paper presents a narrative review of the current literature on the identification, prevalence, associated risk factors, consequences, and management of malnutrition in the <i>residential aged care (RAC)</i> setting. We performed searches of English-language publications on <i>Medline, PubMed, Ovid and the Cochrane Library</i> from January 1 1990 to November 25 2015. We found that, on average, half of all residents in aged care are malnourished as a result of factors affecting appetite, dietary intake and nutrient absorption. Malnutrition is associated with a multitude of adverse outcomes, including increased risk of infections, falls, pressure ulcers and hospital admissions, all of which can lead to increased health care costs and poorer quality of life. A number of food and nutrition strategies have demonstrated positive nutritional and clinical outcomes in the <i>RAC</i> setting. These strategies extend beyond simply enhancing the nutritional value of foods and hence necessitate the involvement of a range of committed stakeholders. Implementing a nutritional protocol in <i>RAC</i> facilities that comprises routine nutrition screening, assessment, appropriate nutrition intervention, including attention to food service systems, and monitoring by a multidisciplinary team can help prevent decline in residents’ nutritional status. Food and nutritional issues should be identified early and managed on admission and regularly in the <i>RAC</i> setting

Memory Access Techniques in Virtual Environment

In cloud computing, Virtualization is used to make virtual image of all resources like server, network, storage etc. This helps in sharing a single resource among multiple users. The main concept is to create and handle virtual machine on existing and available operating system but the environment of new virtual machine does not have any relation with host operating system. The virtual environment is handled by an application called Hypervisor

“I don't eat when I'm sick”: Older people's food and mealtime experiences in hospital

Background Inadequate dietary intake is a common problem amongst older acute-care patients and has been identified as an independent risk factor for in-hospital mortality. This study aimed to explore whether food and mealtime experiences contribute to inadequate dietary intake in older people during hospitalisation. Methods This was a qualitative phenomenological study, data for which were collected using semi-structured interviews over a three-week period. During this time, 26 patients aged 65 years or more, admitted to medical and surgical wards in a tertiary acute-care hospital, were asked to participate if they were observed to eat less than half of the meal offered at lunch. Participants provided their perspectives on food and mealtimes in hospital. Responses were recorded as hand-written notes, which were agreed with the interviewee, and analysed thematically using the framework method. Results Twenty-five older people were interviewed across six wards. Two main themes, ‘validating circumstances’ and ‘hospital systems’, were identified. Each theme had several sub-themes. The sub-themes within validating circumstances included ‘expectations in hospital’, ‘prioritising medical treatment’, ‘being inactive’, and ‘feeling down’. Those within ‘hospital systems’ were ‘accommodating inconvenience’, ‘inflexible systems’, and ‘motivating encouragement’. Conclusion Inadequate dietary intake by older hospital patients is complex and influenced by a range of barriers. Multilevel and multidisciplinary interventions based on a shared understanding of food and nutrition as an important component of hospital care are essential to improve dietary intake and reduce the risk of adverse clinical outcomes. Improving awareness of the importance of food for recovery amongst hospitalised older people and healthcare staff is a priority

An investigation into the nutritional status of patients receiving an Enhanced Recovery After Surgery (ERAS) protocol versus standard care following Oesophagectomy

Enhanced Recovery After Surgery (ERAS) protocols have been effectively expanded to various surgical specialities including oesophagectomy. Despite nutrition being a key component, actual nutrition outcomes and specific guidelines are lacking. This cohort comparison study aims to compare nutritional status and adherence during implementation of a standardised post-operative nutritional support protocol, as part of ERAS, compared to those who received usual care.Two groups of patients undergoing resection of oesophageal cancer were studied. Group 1 (n = 17) underwent oesophagectomy between Oct 2014 and Nov 2016 during implementation of an ERAS protocol. Patients in group 2 (n = 16) underwent oesophagectomy between Jan 2011 and Dec 2012 prior to the implementation of ERAS. Demographic, nutritional status, dietary intake and adherence data were collected. Ordinal data was analysed using independent t tests, and categorical data using chi-square tests.There was no significant difference in nutrition status, dietary intake or length of stay following implementation of an ERAS protocol. Malnutrition remained prevalent in both groups at day 42 post surgery (n = 10, 83% usual care; and n = 9, 60% ERAS). A significant difference was demonstrated in adherence with earlier initiation of oral free fluids (p

Malnutrition, poor food intake, and adverse healthcare outcomes in non-critically ill obese acute care hospital patients

Obesity, defined as a BMI\ua0≥\ua030\ua0kg/m, has demonstrated protective associations with mortality in some diseases. However, recent evidence demonstrates that poor nutritional status in critically ill obese patients confounds this relationship. The purpose of this paper is to evaluate if poor nutritional status, poor food intake and adverse health-related outcomes have a demonstrated association in non-critically ill obese acute care hospital patients.This is a secondary analysis of the Australasian Nutrition Care Day Survey dataset (N\ua0=\ua03122), a prospective cohort study conducted in hospitals from Australia and New Zealand in 2010. At baseline, hospital dietitians recorded participants' BMI, evaluated nutritional status using Subjective Global Assessment (SGA), and recorded 24-h\ua0food intake (as 0%, 25%, 50%, 75%, and 100% of the offered food). Post-three months, participants' length of stay (LOS), readmissions, and in-hospital mortality data were collected. Bivariate and regression analyses were conducted to investigate if there were an association between BMI, nutritional status, poor food intake, and health-related outcomes.Of the 3122 participants, 2889 (93%) had eligible data. Obesity was prevalent in 26% of the cohort (n\ua0=\ua0750; 75% females; 61\ua0±\ua015 years; 37\ua0±\ua07\ua0kg/m). Fourteen percent (n\ua0=\ua0105) of the obese patients were malnourished. Over a quarter of the malnourished obese patients (N\ua0=\ua030/105, 28%) consumed ≤25% of the offered meals. Most malnourished obese patients (74/105, 70%) received standard diets without additional nutritional support. After controlling for confounders (age, disease type and severity), malnutrition and intake ≤25% of the offered meals independently trebled the odds of in-hospital mortality within 90 days of hospital admission in obese patients.Although malnourished obese experienced significantly adverse health-related outcomes they were least likely to receive additional nutritional support. This study demonstrates that BMI alone cannot be used as a surrogate measure for nutritional status and warrants routine nutritional screening for all hospital patients, and subsequent nutritional assessment and support for malnourished patients