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The tumor suppressor Annexin A6 increases the sensitivity towards anti-cancer drugs targeting the EGFR/Ras/MAPK pathway

Sustained EGFR/Ras/MAPK signaling is associated with various cancers. Hence, blocking EGFR and its downstream effectors has become an established target in anti-cancer therapeutics. However, targeted agents face several challenges which limit their clinical use such as inter-patient variation, mutation, and resistance. Therefore, the identification of biomarkers that could predict the treatment outcome in cancer patients is crucial. Annexin A6 (AnxA6) is a calcium-dependent membrane binding protein with potential tumor suppressor properties. It was shown to bind and promote the involvement of p120GAP and protein kinase Cα (PKCα), two negative regulators of the EGFR/Ras/MAPK pathway, in the signal termination of this cascade. Increasing evidence points at the involvement of scaffold proteins, like AnxA6, in the sensitivity of cancer cells towards anti-cancer drugs. In this study, we examined the influence of single and combinatorial treatments targeting the EGFR/Ras/MAPK signaling cascade on the oncogenic proliferation of A431 cells in the presence and absence of AnxA6. Using A431wt cells, which lack endogenous AnxA6, and A431-A6 cells, a well characterized cell line which stably overexpress AnxA6, we investigated clonogenic growth in the presence of the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, the EGFR-targeted monoclonal antibody cetuximab, the MEK1/2 inhibitor PD98059, and the PKCα inhibitors BIM-I and Gö 6976 via clonogenic and MTS assays. We found that treating the cells with TKIs, MEK1/2 or PKCα inhibitors was able to effectively reduce colony and cell growth more than the individual drugs, and this inhibition was more pronounced in AnxA6 overexpressing cells. Furthermore, combinatorial treatment of A431 cancer cells with TKIs together with MEK1/2 inhibitors was more effective in cells expressing AnxA6. The data presented here suggest AnxA6 as a possible biomarker that could predict treatment outcome in EGFR-related cancers

Significance of Bcl-2 and Bcl-6 immunostaining in B-Non Hodgkin's lymphoma

The determination of prognosis for B-Non-Hodgkin's lymphoma (NHL) is known to be related to the multiple differences in tumor cell biology. Bcl-2 and Bcl-6 are two markers linked to germinal center B cells. Both markers are thought to have an effect on prognosis of mature B-cell neoplasms. Forty-four patients with chronic B-cell neoplasm were included; Bcl-2 and Bcl-6 expression by immunohistochemistry was examined. Bcl-2 protein was positive in 36.4% (16 of 44) of cases (62.5% of follicular lymphoma, 16.7% of mantle cell lymphoma and 30% of diffuse large B-cell lymphoma); the positive group implying a bad prognostic effect of the marker in NHL. Bcl-6 was positive in 13.6% (6 of 44) of cases (11.1% of mantle cell lymphoma and 40% of diffuse large B-cell lymphoma) and its positivity implies a better disease course. Bcl-2 and Bcl-6 can be used as prognostic marker in NHL

The profile of chronic pain patients attending the Helen Joseph Hospital Pain Management Unit

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Master of Science in Medicine in the branch of Anaesthesiology Johannesburg, 2014BACKGROUND: Chronic pain is a biopsychosocial phenomenon that can have a profound impact on people’s lives. Internationally, chronic pain is being recognised as a health priority. South Africa is a developing country with limited resources that are directed at catering for a growing population where life threatening conditions like Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS), violent crimes, and poverty predominate. Auditing the Helen Joseph Hospital Pain Management Unit (HJHPMU) is a step towards addressing the paucity of epidemiological data on chronic pain in South Africa. Clinical records are a basic clinical tool that also serves as a medicolegal document. It is essential that these records are legible and complete. AIM: The aim of this study was to describe the profile of chronic pain patients at the HJHPMU for 2011 and to determine the adequacy of record keeping. METHODOLOGY: A retrospective, contextual, descriptive study design was utilised. A consecutive sampling method was used and the study sample included the HJHPMU database and all files of adult patients that attended the HJHPMU during the period January 2011 to December 2011. Patient files were excluded from the audit if insufficient data were found. Descriptive statistics were used to analyse the data obtained during the study. Frequencies and percentages have been reported. A Chi-­‐squared test was utilised to analyse any association between gender and type of pain. RESULTS: There were 475 patients in the HJHPMU database for the year 2011 and 190 of these patients were excluded from the study due to illegible handwriting, duplication in the HJHPMU database, missing data such as no hospital number recorded, no initials to a surname, or the file not found. This resulted in a study sample of 285 patients. The HJHPMU had 215 (75,44%) pre-­‐existing patients and 70 (24,56%) new patients during the year 2011. The preponderance of patients were in the 41-­‐60 year age group, with 146 (51,23%) patients presenting in this age group. Of the 285 patients in the study, 91 (31,93%) patients were male and 194 (68,07%) were female. The most common complaint was of lower back pain (LBP). There were 97 (34,04%) patients with a diagnosis of spinal pain and 59 (20,70%) with Failed Back Surgery Syndrome (FBSS). There were 164 patients with a relevant surgical history. This included 46 (28,05%) patients that had been involved in a traumatic event, 47 (16,49%) patients that had surgery other than spinal surgery that was relevant to their pain diagnosis, and 71 patients (43,29%) that 4 had spinal surgery that was relevant to their diagnosis. A Chi-­‐squared test was performed on the relationship between gender and the type of pain, and a p value of 0.001 was found. When relating the type of pain with age, mixed pain and nociceptive pain was found to be most common in those aged >60 years (n=26), whereas neuropathic pain was found to be most common in the 41-­‐60 year age group (n=43). CONCLUSION: With the limited data from this study, the profile of patients with chronic pain in South Africa seems to not differ grossly from data collected internationally. The most pertinent finding of this study is the inadequacy of record keeping

A multi-criteria framework for office tenants' preferences at office buildings

In order to mitigate the anticipated oversupply of office space, it is necessary to gauge the preference of office occupiers, namely tenants of purpose built office buildings, since these tenants form the indicator of demand for space. In this study, a multi-criteria decision making method (MCDM) – the Analytic Hierarchy Process (AHP) procedure was employed to analyse the relative importance of the main factors chosen by the main sectors of tenants at top grade office buildings in Kuala Lumpur city centre. This study had identified the elicitation of experts’ opinion and tenants’ selection comprises twenty-six important factors for office occupation in Kuala Lumpur city centre, grouped under four main categories: Location, Lease, Building and Financial/Cost. This study then employed AHP to assess the relative importance placed on each category, revealing the varying patterns of preferences when tested on tenants from three main business sectors occupying top grade office buildings. The findings showed that, between the three sectors (Finance/Banking, ICT & Media and Oil & Gas), differences in preference were only slight for most factors but were significant for a few. The findings from this study are insightful in informing decisions on future office provision, particularly in the context of working towards satisfying office tenants’ requirements

General risks for tunnelling projects: an overview

Tunnels are indispensable when installing new infrastructure as well as when enhancing the quality of existing urban living due to their unique characteristics and potential applications. Over the past few decades, there has been a significant increase in the building of tunnels, world-wide. Tunnelling projects are complex endeavors, and risk assessment for tunnelling projects is likewise a complex process. Risk events are often interrelated. Occurrence of a technical risk usually carries cost and schedule consequences. Schedule risks typically impact cost escalation and project overhead. One must carefully consider the likelihood of a risk’s occurrence and its impact in the context of a specific set of project conditions and circumstances. A project’s goals, organization, and environment impacts in the context of a specific set of project conditions and circumstances. Some projects are primarily schedule driven; other projects are primarily cost or quality driven. Whether a specific risk event is perceived fundamentally as a cost risk or a schedule risk is governed by the project-specific context. Many researchers have pointed out the significance of recognition and control of the complexity, and risks of tunnelling projects. Although all general information on a project such as estimated duration, estimated cost, and stakeholders can be obtained, it is still quite difficult to accurately understand, predict and control the overall situation and development trends of the project, leading to the risks of tunnelling projects. This paper reviews all the key risks for tunnelling projects from several case studies that have been carried out by other researchers. These risks have been identified and reviewed in this paper. As a result, the current risk management plan in tunnelling projects can be enhanced by including all these reviewed risks as key information

Comparative study of the resolution efficiency of HPLC and HPTLC-densitometric methods for the analysis of mebeverine hydrochloride and chlordiazepoxide in their binary mixture

Accurate, rapid, and selective reversed phase HPLC and HPTLC-densitometric methods with UV detection have been developed and validated for simultaneous determination of a binary mixture of mebeverine hydrochloride (MVH) and chlordiazepoxide (CDZ) in their Co-formulation. For the HPLC method, ACE-126-2546 AQ C-18 column, (250×4.6 mm i.d., 5 μm particle size) in isocratic mode, with mobile phase containing 25 mM ammonium acetate buffer: acetonitrile in the ratio of (60:40, v:v), pH adjusted to 3±0.2 by using hydrochloric acid, the flow rate of 1.0 mL/min and detection was performed at 260 nm. The retention times were 7.23±0.01 and 3.85±0.01 min for MVH and CDZ, respectively. For the HPTLC-densitometric method, the separation was performed using stationary phase pre-coated silica gel 60F254 and mobile phase ethyl acetate: methanol (8:4, v:v) were used and scanned at 222 nm with Camag TLC scanner controlled by Wincats Software. The Rf values were 0.26±0.02 and 0.73±0.01 for MVH and CDZ, respectively. The linearity graphs for MVH and CDZ, respectively, were found to be linear over 1-50 μg/mL and 0.5-40.0 μg/mL with mean percentage recoveries 100.14±0.354 and 99.70±0.764 for HPLC method and 0.5-30.0 μg/band and 1-14 μg/band with mean percentage recoveries 100.29±0.665 and 99.68±0.987 for HPTLC-densitometric method. A comparative study of different analytical validation parameters such as accuracy, precision, specificity, robustness was conducted. The obtained results were statistically compared with those of the official methods; using student t-test, F-test, and one way ANOVA, showing no significant difference with respect to accuracy and precision