In vitro study of a selective PI3K inhibitor on brain metastases

BMED395MAMD-MEDB

Quality management systems in Aboriginal Community Controlled Health Services: a review of the literature

Background A national accreditation policy for the Australian primary healthcare (PHC) system was initiated in 2008. While certification standards are mandatory, little is known about their effects on the efficiency and sustainability of organisations, particularly in the Aboriginal Community Controlled Health Service (ACCHS) sector. Aim The literature review aims to answer the following: to what extent does the implementation of the International Organisation for Standardization 9001:2008 quality management system (QMS) facilitate efficiency and sustainability in the ACCHS sector? Methods Thematic analysis of peer-reviewed and grey literature was undertaken from Australia and New Zealand PHC sector with a focus on First Nations people. The databases searched included Medline, Scopus and three Informit sites (AHB-ATSIS, AEI-ATSIS and AGIS-ATSIS). The initial search strategy included quality improvement, continuous quality improvement, efficiency and sustainability. Results Sixteen included studies were assessed for quality using the McMaster criteria. The studies were ranked against the criteria of credibility, transferability, dependability and confirmability. Three central themes emerged: accreditation (n=4), quality improvement (n=9) and systems strengthening (n=3). The accreditation theme included effects on health service expenditure and clinical outcomes, consistency and validity of accreditation standards and linkages to clinical governance frameworks. The quality improvement theme included audit effectiveness and value for specific population health. The theme of systems strengthening included prerequisite systems and embedded clinical governance measures for innovative models of care. Conclusion The ACCHS sector warrants reliable evidence to understand the value of QMSs and enhancement tools, particularly given ACCHS (client-centric) services and their specialist status. Limited evidence exists for the value of standards on health system sustainability and efficiency in Australia. Despite a mandatory second certification standard, no studies reported on sustainability and efficiency of a QMS in PHC

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18–2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.publishedVersio

Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes

Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.publishedVersio

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/thre onine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18–2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study

Purpose: People living with cancer and haematological malignancies are at increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. Methods: This study is a population-scale real-world evaluation of the United Kingdom’s third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England’s national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. Results: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction (PCR) coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5% respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Lymphoma patients had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01 respectively. p<0.001 for both). Conclusions: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous, and lower than the general population. Many patients with cancer will remain at increased risk of coronavirus infections, even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic

Who cares? Aboriginal and Torres Strait Islander health care choices and access barriers in Mount Isa

This thesis presents an illustration of the access barriers to health care as experienced by Aboriginal and Torres Strait Islander peoples in Mount Isa, Queensland, Australia. This examination is conducted via fieldwork observations and the narratives of Aboriginal and Torres Strait Islander peoples in Mount Isa, as well as the stories of the health professionals that care for them. In particular, this thesis attempts to unpack the term 'cultural barriers' as used in health and medical literature in discussions of access.\ud \ud Stories are placed within the context of Australian rural health issues and considerations of global issues affecting rural, minority and Indigenous populations. The research represents a distinct blend of anthropology and health services research principles and practices. This perspective is developed utilising principles from the 'Mindful Bodies' approach within Critical Medical Anthropology, which seeks an understanding of human health issues via examination at three levels (or bodies): the individual body, the social body and the body politic (Scheper-Hughes and Lock 1987). Critical issues of concern with regards to health service provision in Mount Isa are examined using Penchansky and Thomas's (1981) taxonomy, the 5As of Access. This taxonomy allows for a nuanced discussion of access by unpacking the term and identifying the various aspects that create access: Availability, Accessibility, Affordability, Accommodation and Acceptance. Dedicated ethnographic fieldwork was undertaken in Mount Isa from October 2007 to August 2009.\ud \ud An examination of the ways that Aboriginal and Torres Strait Islander peoples in Mount Isa express their understandings of the barriers to health care has two advantages. First, such discussions at a local level align with and illuminate the barriers that affect Aboriginal and Torres Strait Islander populations nationally. Second, the significance assigned to such barriers, and examination of what may constitute a cultural barrier (as discussed in health literature) highlights the ways in which cultural difference becomes constructed as problematic in health system encounters.\ud \ud Culture should not be seen as a barrier to health care, but should be seen as an opportunity for increased awareness, understanding and improved personal care for patients in the health system

Royal Geographical Society (with IBG) Medals and Awards celebration 2020 and 2021

The Royal Geographical Society (with IBG) annual Medals and Awards recognise achievements in researching, communicating and teaching a wide range of geographical knowledge. The speeches and citations are a record of both the 2020 and 2021 celebrations, which were delayed and combined because of COVID-19, with contributions from Heather Viles, Andy Eavis, Rita Gardner, Jonathan Rigg, Chris Philo, Peter Kraftl, Patricia Noxolo, Emma Mawdsley and Nina Laurie. The event concluded with comments from the Society’s Patron, Her Royal Highness The Princess Royal. The speeches included comments on inspirational students and teachers; the importance of collaboration, of equity and inclusivity; understanding places, making connections and crossing boundaries; earth-writing and earth-righting

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18–2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis