The evaluation criteria used by venture capitalists:evidence from a UK fund

GRAHAM BOOCOCK AND MARGARET WOODS are Lecturers in Banking and Finance, and Financial Management, respectively, at Loughborough University Business School, England. The paper examines how venture fund managers select their investee companies, by exploring the evaluation criteria and the decision-making process adopted at one United Kingdom regional venture fund (henceforth referred to as the Fund). The analysis confirms that relatively consistent evaluation criteria are applied across the industry and corroborates previous models which suggest that the venture capitalist's decision-making consists of several stages. With the benefit of access to the Fund's internal records, however, this paper adds to the current literature by differentiating the evaluation criteria used at each successive stage of the decision-making process. The paper presents a model of the Fund's activities which demonstrates that the relative importance attached to the evaluation criteria changes as applications are systematically processed. Proposals have to satsfy different criteria at each stage of the decision-making process before they receive funding. In the vast majority of cases, applications are rejected by the fund managers. In addition, the length of time taken by the fund managers in appraising propositions can lead to withdrawal of applications at an advanced stage

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

The vitamin D binding protein axis modifies disease severity in Lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM. Methods: 101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM (Nottingham, UK). 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the NHLBI LAM Registry (USA). Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control sera using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and SNPs in GC encoding Vitamin D Binding Protein (VTDB) genotyped. Results: Proteomic analysis showed VTDB was 2.6 fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A containing haplotypes at rs7041/4588 (p=0.014 and 0.008 respectively). Conclusions: The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant free survival in LAM

Complex history of dog (Canis familiaris) origins and translocations in the Pacific revealed by ancient mitogenomes

Archaeological evidence suggests that dogs were introduced to the islands of Oceania via Island Southeast Asia around 3,300 years ago, and reached the eastern islands of Polynesia by the fourteenth century AD. This dispersal is intimately tied to human expansion, but the involvement of dogs in Pacific migrations is not well understood. Our analyses of seven new complete ancient mitogenomes and five partial mtDNA sequences from archaeological dog specimens from Mainland and Island Southeast Asia and the Pacific suggests at least three dog dispersal events into the region, in addition to the introduction of dingoes to Australia. We see an early introduction of dogs to Island Southeast Asia, which does not appear to extend into the islands of Oceania. A shared haplogroup identified between Iron Age Taiwanese dogs, terminal- Lapita and post-Lapita dogs suggests that at least one dog lineage was introduced to Near Oceania by or as the result of interactions with Austronesian language speakers associated with the Lapita Cultural Complex. We did not find any evidence that these dogs were successfully transported beyond New Guinea. Finally, we identify a widespread dog clade found across the Pacific, including the islands of Polynesia, which likely suggests a post-Lapita dog introduction from southern Island Southeast Asia

How child‐centred education favours some learners more than others

Debates on how best to educate young children have been raging over the last 100 years—more often fuelled by ideological preferences rather than empirical evidence. To some extent this is hardly surprising given the difficulty of examining pupil progress in a systematic and comparative way. However, the introduction of a new child‐centred curriculum in Wales provides the opportunity to undertake just such an examination. The Foundation Phase curriculum, introduced in 2008, is designed to provide all 3‐ to 7‐year‐olds with a developmental, experiential, play‐based approach to learning. Evidence from a major 3‐year evaluation of this intervention finds that, overall, pupil progress and well‐being is fostered in those settings where the principles of the Foundation Phase have been most closely followed. However, the evidence also suggests that even within these contexts, progress is uneven and that some kinds of children seem to gain more from this approach than others. The ‘losers’ appear to be boys and those living in poverty. Drawing on the theories of Basil Bernstein, the paper explores why this may be the case and examines the relative significance of teacher dispositions, teacher–learner dynamics and the availability of resources. The paper concludes by arguing that these issues will need to be addressed if the benefits of child‐centred approaches are to benefit all

The vitamin D binding protein axis modifies disease severity in Lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM. Methods: 101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM (Nottingham, UK). 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the NHLBI LAM Registry (USA). Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control sera using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and SNPs in GC encoding Vitamin D Binding Protein (VTDB) genotyped. Results: Proteomic analysis showed VTDB was 2.6 fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A containing haplotypes at rs7041/4588 (p=0.014 and 0.008 respectively). Conclusions: The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant free survival in LAM

The vitamin D binding protein axis modifies disease severity in lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM.Methods: 101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM (Nottingham, UK). 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the NHLBI LAM Registry (USA). Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control sera using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and SNPs in GC encoding Vitamin D Binding Protein (VTDB) genotyped.Results: Proteomic analysis showed VTDB was 2.6 fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity (p=0.01). Median time to death or lung transplant was reduced by 46?months in those with CC genotypes at rs4588 and 38?months in those with non-A containing haplotypes at rs7041/4588 (p=0.014 and 0.008 respectively).Conclusions: The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant free survival in LAM

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

PYK2 promotes HER2-positive breast cancer invasion

Background: Metformin, a biguanide, is one of the most commonly prescribed treatments for type 2 diabetes and has recently been recommended as a potential drug candidate for advanced cancer therapy. Although Metformin has antiproliferative and proapoptotic effects on breast cancer, the heterogenous nature of this disease affects the response to metformin leading to the activation of pro-invasive signalling pathways that are mediated by the focal adhesion kinase PYK2 in pure HER2 phenotype breast cancer. Methods: The effect of metformin on different breast cancer cell lines, representing the molecular heterogenicity of the disease was investigated using in vitro proliferation and apoptosis assays. The activation of PYK2 by metformin in pure HER2 phenotype (HER2+/ER−/PR-) cell lines was investigated by microarrays, quantitative real time PCR and immunoblotting. Cell migration and invasion PYK2-mediated and in response to metformin were determined by wound healing and invasion assays using HER2+/ER−/PR- PYK2 knockdown cell lines. Proteomic analyses were used to determine the role of PYK2 in HER2+/ER−/PR- proliferative, migratory and invasive cellular pathways and in response to metformin. The association between PYK2 expression and HER2+/ER−/PR- patients’ cancer-specific survival was investigated using bioinformatic analysis of PYK2 expression from patient gene expression profiles generated by the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) study. The effect of PYK2 and metformin on tumour initiation and invasion of HER2+/ER−/PR- breast cancer stem-like cells was performed using the in vitro stem cell proliferation and invasion assays. Results: Our study showed for the first time that pure HER2 breast cancer cells are more resistant to metformin treatment when compared with the other breast cancer phenotypes. This drug resistance was associated with the activation of PTK2B/PYK2, a well-known mediator of signalling pathways involved in cell proliferation, migration and invasion. The role of PYK2 in promoting invasion of metformin resistant HER2 breast cancer cells was confirmed through investigating the effect of PYK2 knockdown and metformin on cell invasion and by proteomic analysis of associated cellular pathways. We also reveal a correlation between high level of expression of PYK2 and reduced survival in pure HER2 breast cancer patients. Moreover, we also report a role of PYK2 in tumour initiation and invasion-mediated by pure HER2 breast cancer stem-like cells. This was further confirmed by demonstrating a correlation between reduced survival in pure HER2 breast cancer patients and expression of PYK2 and the stem cell marker CD44. Conclusions: We provide evidence of a PYK2-driven pro-invasive potential of metformin in pure HER2 cancer therapy and propose that metformin-based therapy should consider the molecular heterogeneity of breast cancer to prevent complications associated with cancer chemoresistance, invasion and recurrence in treated patients

Using behavioural theories to optimise shared haemodialysis care: a qualitative intervention development study of patient and professional experience

Background Patients in control of their own haemodialysis report better outcomes than those receiving professional controlled care in a hospital setting, even though home and hospital haemodialysis are largely equivalent from mechanical and physiological perspectives. Shared Haemodialysis Care (SHC) describes an initiative in which hospital haemodialysis patients are supported by dialysis staff to become as involved as they wish in their own care; and can improve patient safety, satisfaction and may reduce costs. We do not understand why interventions to support self-management in other conditions have variable effects or how to optimise the delivery of SHC. The purpose of this study was to identify perceived patient and professional (nurses and healthcare assistants) barriers to the uptake of SHC, and to use these data to identify intervention components to optimise care. Methods Individual semi-structured interviews with patients and professionals were conducted to identify barriers and facilitators. Data were coded to behavioural theory to identify solutions. A national UK learning event with multiple stakeholders (patients, carers, commissioners and professionals) explored the salience of these barriers and the acceptability of solutions. Results A complex intervention strategy was designed to optimise SHC for patients and professionals. Interviews were conducted with patients (n = 15) and professionals (n = 7) in two hospitals and three satellite units piloting SHC. Data from patient and professional interviews could be coded to behavioural theory. Analyses identified key barriers (knowledge, beliefs about capabilities, skills and environmental context and resources). An intervention strategy that focuses on providing, first, patients with information about the shared nature of care, how to read prescriptions and use machines, and second, providing professionals with skills and protected time to teach both professionals/patients, as well as providing continual review, may improve the implementation of SHC and be acceptable to stakeholders. Conclusions We have developed an intervention strategy to improve the implementation of SHC for patients and professionals. While this intervention strategy has been systematically developed using behavioural theory, it should be rigorously tested in a subsequent effectiveness evaluation study prior to implementation to ensure that shared haemodialysis care can be delivered equitably, efficiently and safely for all patients