Gender, Risk-Taking Propensity and Culture of Entrepreneurs at Small and Medium Enterprises in Gauteng

This study analyzed the risk-taking propensity amongst the four cultural groups and its impact on the business performance, from a sample of Small and Medium Enterprises (SMEs) within the Gauteng Province of South Africa. The data was collected using two sets of questionnaire measuring risk taking propensity and perceived business performance. 83 responses were returned from 400 respondents. The results indicate that male on average show higher risk taking, while difference in risk taking propensity between male and female was not statistically significant. A very weak or no correlation between risk taking and business performance scores for both the genders were found, indicating that gender and culture does not play a role in the relationship between risk taking and business performance. However study found that there was significant difference in risk taking behavior by different culture groups, Zimbabweans were the highest risk takers, while Chinese, Pakistanis and South Africans differed in their risk taking behavior

Monitoring Budget Allocation on Performance of Socio-Economic Empowerment Projects: A case of Women and Law in Southern Africa Research and Education Trust Project

This study seeks to investigate the influence of the monitoring and evaluation (M&E) budget allocation on the performance of socio-economic empowerment projects. The overarching theoretical framework is the resource-based view theory. The study adopted quantitative approaches to gather an in-depth understanding of the research variables and to allow a researcher to make informed recommendations using both words and numbers. The research site for the study is Women and Law Southern Africa -Lesotho. The target population of 68 project team members. A census method was adopted and the researcher used questionnaires to collect data from 68 respondents. To test reliability the research tools were piloted before actual data collection. Further, Cronbach’s alpha coefficient was used to estimate instrument reliability using the pilot responses and it returned 0.818 which was fairly high. Content and face validity were adopted to test instrument validity. Proper authorizations were secured from relevant bodies to conduct the study and SPSS Version 23 data analysis software was deployed to analyze the collected data. The researcher further analyzed the data through descriptive analysis with means and standard deviation to measure central tendencies and dispersion of the data. The general findings of the study indicated that the response was higher than a composite mean of 4.37 with a standard deviation of 0.745, implying that the study objective; of monitoring budget allocation positively influences the performance of the socio-economic empowerment project. Findings implied that the team should, as part of best practice, maintain the M&E budget separately and promote transparency by issuing the M&E budget performance reports. The study made recommendations for improving M&E budgeting. The study suggests comparative studies to be conducted on other socio-economic empowerment projects and the usage of hybrid approaches of qualitative and quantitative approaches to gather as much information as possible. The study findings conformed to the principles of resource-based view theory that advocates for adequate allocation of resources to enable the monitoring and evaluation team to execute the activities according to plan

Analysis of telomere dynamics in human tissues

In Barrett's oesophagus, the metaplastic tissue displayed clonal growth characterised by very short homogeneous telomere profiles compared to the adjacent normal tissue. Short telomeres and fusions were also detected in normal dermis and melanocytic naevi with evidence of clonal telomere fusion events. Such events can result in clonal expansion, which could confer selective advantage for other abnormalities that may derive neoplastic progression. These data are consistent with the view that telomere dysfunction in vivo may drive large-scale genomic instability of the type observed in early-stage neoplasi

Analysis of telomere dynamics in human tissues

In Barrett's oesophagus, the metaplastic tissue displayed clonal growth characterised by very short homogeneous telomere profiles compared to the adjacent normal tissue. Short telomeres and fusions were also detected in normal dermis and melanocytic naevi with evidence of clonal telomere fusion events. Such events can result in clonal expansion, which could confer selective advantage for other abnormalities that may derive neoplastic progression. These data are consistent with the view that telomere dysfunction in vivo may drive large-scale genomic instability of the type observed in early-stage neoplasia.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Telomere length is a critical determinant for survival in multiple myeloma

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high‐resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk‐stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS. Despite the introduction of novel therapeutic modalities, patients with multiple myeloma (MM) display a heterogeneous clinical course, with survival ranging from a few months to over 10 years. Therefore, there is a requirement for reliable prognostic and predictive markers in this disease to allow for risk stratification and rational clinical decision‐making. The most commonly used prognostic system in MM is the International Staging System (ISS) that is based on serum levels of both β2‐micoglobulin and albumin (Greipp et al, 2005). Recently the ISS has been improved upon by the inclusion of cytogenetic information to take into account the level of lactate dehydrogenase and the considerable genetic heterogeneity known to occur in this disease (Palumbo et al, 2015). Hyperdiploidy and the loss of whole chromosome arms is frequently detected in MM, which includes, amongst others, gains of 1q in 30% of cases and the loss of 17p in 7% of cases (Walker et al, 2010). Short dysfunctional telomeres are susceptible to DNA repair activities that can result in chromosomal fusion and the initiation of cycles of anaphase‐bridging, breakage and fusion that can drive genomic instability and clonal evolution (Artandi et al, 2000; Roger et al, 2013; Jones et al, 2014). Telomere dysfunction has been documented in numerous haematological malignancies (Jones et al, 2012), and is one putative mechanism that may lead to the genetic and clinical heterogeneity observed in MM (Wu et al, 2003) and may relate to changes in the 3D telomeric architecture that have been documented in MM cells (Klewes et al, 2013). Recently, we have shown that high‐resolution telomere analysis, combined with a functional definition of telomere length, can provide powerful prognostic information in several tumour types, including chronic lymphocytic leukaemia (CLL)(Lin et al, 2014), myelodysplasia (unpublished observations) and breast cancer (Simpson et al, 2015). Here we sought to apply these technologies to examine the prognostic utility of telomere length in MM

Knock-down of the 37kDa/67kDa laminin receptor LRP/LR impedes telomerase activity.

Cancer has become a major problem worldwide due to its increasing incidence and mortality rates. Both the 37kDa/67kDa laminin receptor (LRP/LR) and telomerase are overexpressed in cancer cells. LRP/LR enhances the invasiveness of cancer cells thereby promoting metastasis, supporting angiogenesis and hampering apoptosis. An essential component of telomerase, hTERT is overexpressed in 85-90% of most cancers. hTERT expression and increased telomerase activity are associated with tumor progression. As LRP/LR and hTERT both play a role in cancer progression, we investigated a possible correlation between LRP/LR and telomerase. LRP/LR and hTERT co-localized in the perinuclear compartment of tumorigenic breast cancer (MDA-MB231) cells and non-tumorigenic human embryonic kidney (HEK293) cells. FLAG® Co-immunoprecipitation assays confirmed an interaction between LRP/LR and hTERT. In addition, flow cytometry revealed that both cell lines displayed high cell surface and intracellular LRP/LR and hTERT levels. Knock-down of LRP/LR by RNAi technology significantly reduced telomerase activity. These results suggest for the first time a novel function of LRP/LR in contributing to telomerase activity. siRNAs targeting LRP/LR may act as a potential alternative therapeutic tool for cancer treatment by (i) blocking metastasis (ii) promoting angiogenesis (iii) inducing apoptosis and (iv) impeding telomerase activity.This work was supported by the National Research Foundation, the Republic of South Africa.NCS201

Mre11 modulates the fidelity of fusion between short telomeres in human cells

The loss of telomere function can result in the fusion of telomeres with other telomeric loci, or non-telomeric double-stranded DNA breaks. Sequence analysis of fusion events between short dysfunctional telomeres in human cells has revealed that fusion is characterized by a distinct molecular signature consisting of extensive deletions and micro-homology at the fusion points. This signature is consistent with alternative error-prone end-joining processes. We have examined the role that Mre11 may play in the fusion of short telomeres in human cells; to do this, we have analysed telomere fusion events in cells derived from ataxia-telangiectasia-like disorder (ATLD) patients that exhibit hypomorphic mutations in MRE11. The telomere dynamics of ATLD fibroblasts were indistinguishable from wild-type fibroblasts and they were proficient in the fusion of short telomeres. However, we observed a high frequency of insertion of DNA sequences at the fusion points that created localized sequence duplications. These data indicate that Mre11 plays a role in the fusion of short dysfunctional telomeres in human cells and are consistent with the hypothesis that as part of the MRN complex it serves to stabilize the joining complex, thereby controlling the fidelity of the fusion reaction

Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients

Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed with invasive ductal carcinoma of the breast (n = 120). The telomere fusion threshold defined a small subset of patients with an extremely poor clinical outcome, with a median survival of less than 12 months (HR = 21.4 (7.9-57.6), P < 0.0001). Furthermore, this telomere length threshold was independent of ER, PGR, HER2 status, NPI, or grade and was the dominant variable in multivariate analysis. We conclude that the fusogenic telomere length threshold provides a powerful, independent prognostic marker with clinical utility in breast cancer. Larger prospective studies are now required to determine the optimal way to incorporate high-resolution telomere length analysis into multivariate prognostic algorithms for patients diagnosed with breast cancer

Extensive telomere erosion is consistent with localised clonal expansions in Barrett’s metaplasia

Barrett’s oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett’s oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett’s oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett’s metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett’s metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett’s metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett’s metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett’s metaplasia

Fusion of short telomeres in human cells is characterized by extensive deletion and microhomology, and can result in complex rearrangements

Telomere fusion is an important mutational event that has the potential to lead to large-scale genomic rearrangements of the types frequently observed in cancer. We have developed single-molecule approaches to detect, isolate and characterize the DNA sequence of telomere fusion events in human cells. Using these assays, we have detected complex fusion events that include fusion with interstitial loci adjacent to fragile sites, intra-molecular rearrangements, and fusion events involving the telomeres of both arms of the same chromosome consistent with ring chromosome formation. All fusion events were characterized by the deletion of at least one of the telomeres extending into the sub-telomeric DNA up to 5.6 kb; close to the limit of our assays. The deletion profile indicates that deletion may extend further into the chromosome. Short patches of DNA sequence homology with a G:C bias were observed at the fusion point in 60% of events. The distinct profile that accompanies telomere fusion may be a characteristic of the end-joining processes involved in the fusion event