Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer

Angiogenesis and lymphangiogenesis are considered to play key roles in tumour growth, progression and metastasis. However, targeting tumour angiogenesis in clinical trials showed only modest efficacy. We therefore scrutinised the concept of tumour angiogenesis and lymphangiogenesis by analysing the expression of crucial markers involved in these processes in primary breast cancer. Methods: We analysed the expression of angiogenic, lymphangiogenic or antiangiogenic factors, their respective receptors and specific markers for endothelial and lymphendothelial cells by quantitative real-time RT-PCR in primary breast cancer and compared the expression profiles to non-cancerous, tumour-adjacent tissues and breast tissues from healthy women. Results: We found decreased mRNA amounts of major angiogenic and lymphangiogenic factors in tumour compared to healthy tissues, whereas antiangiogenic factors were upregulated. Concomitantly, angiogenic and lymphangiogenic receptors were downregulated in breast tumours. This antiangiogenic, antilymphangiogenic microenvironment was even more pronounced in aggressive tumours and accompanied by reduced amounts of endothelial and lymphatic endothelial cell markers. Conclusion: Primary breast tumours are not a site of highly active angiogenesis and lymphangiogenesis. Selection for tumour cells that survive with minimal vascular supply may account for this observation in clinical apparent tumours

BH3-only proteins BIM and PUMA in the regulation of survival and neuronal differentiation of newly generated cells in the adult mouse hippocampus

Neurogenesis persists in the adult hippocampus, where several thousand neurons are born every day. Most of the newly generated cells are eliminated by apoptosis, possibly because of their failure to integrate properly into neural networks. The BH3-only proteins Bim and Puma have been shown to mediate trophic factor withdrawal- and anoikis-induced apoptosis in various systems. We therefore determined their impact on proliferation, survival, and differentiation of adult-generated cells in the mouse hippocampus using gene-deficient mice. Wild-type, bim-, and puma-deficient mice showed similar rates of precursor cell proliferation, as evidenced by 5-bromo-2-deoxyuridine (BrdU)-incorporation. Deficiency in either bim or puma significantly increased the survival of adult-born cells in the dentate gyrus (DG) after 7 days. Consistently, we detected increased numbers of doublecortin (DCX)-positive and fewer terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelled-positive cells in the DG of bim- and puma-deficient mice. Bim and puma deficiency did not change early markers of neuronal differentiation, as evidenced by BrdU/DCX double-labelling. However, BrdU/NeuN double-labelling revealed that deficiency of bim, but not puma, accelerated the differentiation of newly generated cells into a neuronal phenotype. Our data show that Bim and Puma are prominently involved in the regulation of neuronal progenitor cell survival in the adult DG, but also suggest that Bim has an additional role in neuronal differentiation of adult-born neural precursor cells

Care planning for consumers on community treatment orders: an integrative literature review

Background Case management is the established model for care provision in mental health and is delivered within current care philosophies of person-centred and recovery-oriented care. The fact that people with a mental illness may be forced to receive care and treatment in the community poses challenges for clinicians aiming to engage in approaches that promote shared decision-making and self-determination. This review sought to gain an in-depth understanding of stakeholders’ perspectives and experiences of care planning for consumers’ on CTOs. Methods An integrative review method allowed for inclusion of a broad range of studies from diverse empirical sources. Systematic searches were conducted across six databases. Following appraisal, findings from included papers were coded into groups and presented against a framework of case management. Results Forty-eight papers were included in the review. Empirical studies came from seven countries, with the majority reporting on qualitative methods. Many similarities were reported across studies. Positive gains from CTOs were usually associated with the nature of support received, highlighting the importance of the therapeutic relationship in care planning. Key gaps in care planning included a lack of connection between CTO, treatment and consumer goals and lack of implementation of focussed interventions. Conclusions Current case management processes could be better utilised for consumers on CTOs, with exploration of how this could be achieved warranted. Workers need to be sensitive to the ‘control and care’ dynamic in the care planning relationship, with person-centred approaches requiring core and advanced practitioner and communication skills, including empathy and trust

Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide

BACKGROUND:Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America), Guadeloupe islands (Lesser Antilles) as well as New Caledonia (Pacific Ocean), have encountered such resistance. METHODOLOGY/PRINCIPAL FINDINGS:We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534. CONCLUSION /SIGNIFICANCE:This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence

Building International Business Theory: A Grounded Theory Approach

The field of international business (IB) is in need of more theory development (Morck & Yeung, 2007). As such, the main focus of our manuscript was to provide guidance on how to build IB specific theory using grounded theory (GT). Moreover, we contribute to future theory development by identifying areas within IB where GT can be applied and the type of research issues that can be addressed using this methodology. Finally, we make a noteworthy contribution by discussing some of GT’s caveats and limitations, particularly those relevant to IB. This effort is intended to spur further interest in the development of IB theory

Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical signal transduction pathway that regulates multiple cellular functions. Aberrant activation of this pathway has been identified in a wide range of cancers. Several pathway components including AKT, PI3K and mTOR represent potential therapeutic targets and many small molecule inhibitors are in development or early clinical trials. The complex regulation of the pathway, together with the multiple mechanisms by which it can be activated, make this a highly challenging pathway to target. For successful inhibition, detailed molecular information on individual tumours will be required and it is already clear that different tumour types show distinct combinations of alterations. Recent results have identified alterations in pathway components PIK3CA, PTEN, AKT1 and TSC1 in bladder cancer, some of which are significantly related to tumour phenotype and clinical behaviour. Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway

Development and validation of self-reported line drawings of the modified Beighton score for the assessment of generalised joint hypermobility

Background: The impracticalities and comparative expense of carrying out a clinical assessment is an obstacle in many large epidemiological studies. The purpose of this study was to develop and validate a series of electronic self-reported line drawing instruments based on the modified Beighton scoring system for the assessment of selfreported generalised joint hypermobility.Methods: Five sets of line drawings were created to depict the 9-point Beighton score criteria. Each instrument consisted of an explanatory question whereby participants were asked to select the line drawing which best represented their joints. Fifty participants completed the self-report online instrument on two occasions, before attending a clinical assessment. A blinded expert clinical observer then assessed participants’ on two occasions,using a standardised goniometry measurement protocol. Validity of the instrument was assessed by participant observeragreement and reliability by participant repeatability and observer repeatability using unweighted Cohen’s kappa (k). Validity and reliability were assessed for each item in the self-reported instrument separately, and for the sum of the total scores. An aggregate score for generalised joint hypermobility was determined based on a Beighton score of 4 or more out of 9.Results: Observer-repeatability between the two clinical assessments demonstrated perfect agreement (k 1.00; 95%CI 1.00, 1.00). Self-reported participant-repeatability was lower but it was still excellent (k 0.91; 95% CI 0.74, 1.00). Theparticipant-observer agreement was excellent (k 0.96; 95% CI 0.87, 1.00). Validity was excellent for the self-report instrument, with a good sensitivity of 0.87 (95% CI 0.81, 0.91) and excellent specificity of 0.99 (95% CI 0.98, 1.00).Conclusions: The self-reported instrument provides a valid and reliable assessment of the presence of generalisedjoint hypermobility and may have practical use in epidemiological studie