Will “opt out” implementation save more lives; view of the South Asians’ in the UK

Organ transplantation is the gold standard treatment of choice for many patients with organ failure and has undoubtedly improved both the quality and longevity of life for the majority of patients. The success of human organ transplantation relies on the willingness of the public to donate their organs, either during their lifetime or after death. In the United Kingdom (UK), transplantation is limited by a shortage of donated organs, especially in the South Asian community. This leads to a disproportionate number of Asians waiting for transplants longer than the average waiting time, as often, most suitable matches are found between people of the same ethnic group. This disparity costs lives, and many who are waiting count down their days on the list and lead an agonizing life due to the scarcity of matching organ donors. This article is derived from a two phased study that sought to explore possible methods to increase the number of registered organ donors and cadaver organ retrieval in the South Asian community in the North West of England. A total of 907 participants completed the questionnaire and 10 semi structured interviews with individuals who declined to join the organ donor register were undertaken to understand the in-depth details of their negative attitude towards organ donation. This paper reflects on one of the focus areas of the study - the views of South Asians on the implementation of an opt-out system in the UK and to understand if the community will challenge or support such a donor recruitment method. This study was funded by the British Renal Society and supported by the Central Manchester Foundation Trust, University of Salford and National Health Service Blood and Transplant (NHSBT). Keywords: South Asian, Knowledge, Survey, Organ donation, Opt out, Opt in, Religio

Identifying information needs of patients with IgA Nephropathy, using an innovative social media stepped analytical approach

Introduction Increasingly people with kidney disease are using social media to search for medical information and to find peer-support. IgA nephropathy (IgAN) predominantly affects young adults, demographically the biggest users of social media. This paper presents an innovative analysis of social media interactions to identify unmet education and information needs of IgAN patients. Methods Following ethical approval for the study, the IgA Nephropathy Support UK Facebook group (https://www.facebook.com/groups/915274415226674) granted us permission to anonymously collect and analyse 1959 posts and comments from 498 group users. An initial patient focus group and quantitative word frequency analysis created an initial categorisation matrix which was iteratively refined following serial analyses of the social media database to generate a final categorisation matrix of needs. We examined narrative data relating to each identified category to define patient narratives relating to each area. Results A large number of information gaps and unanswered questions were identified relating to: diet, symptoms, diagnosis, treatment and patient co-morbidities. Additionally, patient-clinician communication and the presentation of information were drawn out as cross-cutting issues. These themes differed significantly from those identified from the traditional patient focus group highlighting the value of this novel method for interrogating social media data to understand unmet patient need. Conclusions Social media data is an untapped and valuable resource which can be used to better understand patient information gaps, leading to the generation of targeted materials to address unmet educational needs. This innovative approach could be replicated across other health conditions

Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer

Extending conceptual understanding : how interprofessional education influences affective domain development

Background: Interprofessional learning (IPL) can influence affective domain development of students, through teaching activities that facilitate learning with, from and about other professions. Current quantitative evidence offers limited explanation of how this learning is achieved within IPL programmes. This original paper tests a conceptual framework drawn from theories on IPL and affective domain development (attitudes, values and behaviours) to explain what works for whom, when and in what circumstances. Methods: The objectives of the study were twofold: to evaluate the impact of the IPL programme on the student’s attitudes and values, and identify behaviour changes in clinical practice towards interprofessional working. Using an action research approach, based in practice, an IPL programme was delivered over six weeks. Students from five professional disciplines: nursing, radiography, physiotherapy, social work, and podiatry (n=63) participated over the two action research cycles and in semi structured focus groups (n=37). Results: The recorded personal experiences of the IPL activities on the students were examined in relation to the: type of activity; impact on the affective domain of learning (attitude, value, or behaviour) and self-reported outcome on application to their practice. Modification in affective domain development was measured to identification or internalisation stage for 30 of the students. Self-reported outcomes on application to practice included direct impact on patient care, personal resilience building, improved communication and ability to challenge practice. Conclusion: This paper presents a conceptual framework not evident in current research, in regards to what IPL works for whom, in what circumstances and when. IPL Activities that address a personal reward or incentive and are delivered over 4 weeks, imitating ‘circles of care,’ that explore self-assessment, team building and reflection can lead to sustained change in values, attitudes and behaviours. Keywords: Action Research, Interprofessional Education, Interprofessional learning, Health and Social care, Collaboration

Researchers’ attitudes to the 3Rs - An upturned hierarchy?

Animal use in biomedical research is generally justified by its potential benefits to the health of humans, or other animals, or the environment. However, ethical acceptability also requires scientists to limit harm to animals in their research. Training in laboratory animal science (LAS) helps scientists to do this by promoting best practice and the 3Rs. This study evaluated scientists’ awareness and application of the 3Rs, and their approach to other ethical issues in animal research. It was based on an online survey of participants in LAS courses held in eight venues in four European countries: Portugal (Porto, Braga), Germany (Munich, Heidelberg), Switzerland (Basel, Lausanne, Zurich), and Denmark (Copenhagen). The survey questions were designed to assess general attitudes to animal use in biomedical research, Replacement alternatives, Reduction and Refinement conflicts, and harm-benefit analysis. The survey was conducted twice: immediately before the course (‘BC’, N = 310) and as a follow-up six months after the course (‘AC’, N = 127). While courses do appear to raise awareness of the 3Rs, they had no measurable effect on the existing low level of belief that animal experimentation can be fully replaced by non-animal methods. Most researchers acknowledged ethical issues with their work and reported that they discussed these with their peers. The level of an animal’s welfare, and especially the prevention of pain, was regarded as the most pressing ethical issue, and as more important than the number of animals used or the use of animals as such. Refinement was considered more feasible than Replacement, as well as more urgent, and was also favoured over Reduction. Respondents in the survey reversed the ‘hierarchy’ of the 3Rs proposed by their architects, Russell and Burch, prioritizing Refinement over Reduction, and Reduction over Replacement. This ordering may conflict with the expectations of the public and regulators.</div

Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma

BACKGROUND: Osteosarcoma is the most common type of primary bone tumor. The use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, however the prognosis of the patients with metastasis is still very poor. Then, new and more effective treatments for curing osteosarcoma, such as immunotherapy are needed. Tumor-infiltrating lymphocytes (TIL) have been involved in the control of tumor development and already assessed with success for the treatment of several cancers including melanoma. While TIL represent a fascinating therapeutic approach in numerous malignant pathologies, there is few report concerning adult bone-associated tumors including osteosarcoma. METHODS: Human TIL were isolated and characterized (phenotype, lytic activity) from twenty-seven patients with bone-associated tumors (osteosarcoma, Ewing's sarcoma, giant cell tumor, chondrosarcoma, plasmocytoma and bone metastases). Similar experiments were performed using rat osteosarcoma model. RESULTS: While TIL with a main CD4(+ )profile were easily isolated from most of the tumor samples, only TIL extracted from osteosarcoma were cytotoxic against allogeneic tumor cells. In all cases, TIL lytic activity was significantly higher compared to autologous peripheral blood leukocytes. Similar data were observed in rat osteosarcoma model where TIL were characterized by a main CD4(+ )profile and high lytic activity against allogeneic and autologous tumor cells. Moreover, rat TIL expansion was not accompanied by refractoriness to further activation stimulus mainly by tumor antigens. CONCLUSION: These results demonstrated that TIL therapy could be a very efficient strategy for the treatment of adult osteosarcoma

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy

Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy

Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer

Introduction: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, namely CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Over-expression of cyclin D-1 protein, however, confers tamoxifen resistance but not a tamoxifen-induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein over-expression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we examined a selected marker for this event. Method: Array comparative genomic hybridization analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients who were randomly assigned to either tamoxifen or no adjuvant treatment. The protein expression was also compared with gene expression data in a subset of 56 breast cancer samples. Results: Cortactin and FADD (Fas-associated death domain) over-expression was linked to CCND1 amplification, determined by fluorescence in situ hybridization, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1 (checkpoint kinase 1), was associated with an impaired tamoxifen response, and interestingly with low proliferative breast cancer of low grade. For Pak1 (p21-activated kinase 1) and cyclin D-1 the protein expression corresponded to the gene expression data. Conclusions: The results indicate that many 11q13 associated gene products are over-expressed in conjunction with cyclin D-1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer