Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance

Autophagy is an ancient, intracellular degradative system which plays important roles in regulating protein homeostasis and which is essential for survival when cells are faced with metabolic stress. Increasing evidence suggests that autophagy also functions as a tumor suppressor mechanism that harnesses the growth and/or survival of cells as they transition towards a rapidly dividing malignant state. However, the impact of autophagy on cancer progression and on the efficacy of cancer therapeutics is controversial. In particular, although the induction of autophagy has been reported after treatment with a number of therapeutic agents, including imatinib, this response has variously been suggested to either impair or contribute to the effects of anticancer agents. More recent studies support the notion that autophagy compromises the efficacy of anticancer agents, where agents such as chloroquine (CQ) that impair autophagy augment the anticancer activity of histone deacetylase (HDAC) inhibitors and alkylating agents. Inhibition of autophagy is a particularly attractive strategy for the treatment of imatinib-refractory chronic myelogenous leukemia (CML) since a combination of CQ with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) compromises the survival of even BCR-ABL-T315I+ imatinib-resistant CML. Additional studies are clearly needed to establish the clinical utility of autophagy inhibitors and to identify patients most likely to benefit from this novel therapeutic approach

Predictors of negative beliefs toward the sexual rights and perceived sexual healthcare needs of people with physical disabilities in South Africa

Background: Although sexuality is a ubiquitous human need, recent empirical research has shown that people without disabilities attribute fewer sexual rights and perceive sexual healthcare to benefit fewer people with disabilities, compared to non-disabled people. Within a global context, such misperceptions have tangible, deleterious consequences for people with disabilities (e.g., exclusion from sexual healthcare), creating an urgent need for effective strategies to change misperceptions. Methods: To lay the groundwork for developing such strategies, we examined predictors of the recognition of sexual rights of people with physical disabilities within the South African context, derived from three key social psychological literatures (prejudice, social dominance orientation and intergroup contact), as well as the relationship between sexual rights and beliefs about sexual healthcare. Data were obtained through a cross-sectional survey, given to non-disabled South Africans (N = 1989). Results: Findings indicated that lack of recognition of the sexual rights for physically disabled people predicted less positive beliefs about the benefits of sexual healthcare. In turn, high levels of prejudice (both cognitive and affective) toward disabled sexuality predicted less recognition of their sexual rights, while prejudice (both forms) was predicted by prior contact with disabled people and possessing a social dominance orientation (cognitive prejudice only). Evidence was also obtained for an indirect relationship of contact and social dominance orientation on sexual healthcare beliefs through prejudice, although these effects were extremely small. Conclusion: Results are discussed in terms of their implications for rehabilitation, as well as national-level strategies to tackle negative perceptions of disabled sexuality, particularly in contexts affected by HIV.Implications for rehabilitation Findings demonstrate an empirical link between prejudice toward disabled sexuality, lack of recognition of sexual rights and viewing sexual healthcare of less benefit for disabled people. Consequently, there is need for increased attention to these dimensions within the rehabilitative context. Contact with disabled people, including dedicated interventions, is unlikely to meaningfully impact beliefs about the benefits of sexual healthcare

Inter- and Intra-household Perceived Relative Inequality Among Disabled and Non-disabled People in Liberia

Evidence suggests that people with disabilities are the most marginalised and vulnerable group within any population. However, little is known about the extent of inequality between people with and without disabilities in contexts where the majority of persons experience extreme poverty and hardship. This includes in Liberia, where very little is understood about the lives of disabled people in general. This study uses a multidimensional wellbeing framework to understand perceived relative inequality associated with disability by assessing several facets of wellbeing across and within households containing disabled members (N = 485) or households with no disabled members (N = 538) in Liberian communities (Total individuals surveyed, N = 2020). Statistical comparisons (adjusted for age, sex, education and wealth differences and clustered at the household, village and county level) reveal that disabled Liberians are managing similarly to non-disabled Liberians in terms of income and education, but experience many perceived relative inequalities including in life satisfaction, transport access, political participation and social inclusion. Our results further suggest that disability may lead to perceived relative inequality at the household level in terms of trust held in neighbours. However, they also show that being the head of a household may protect against perceived relative inequality in certain dimensions (e.g. healthcare and transport access, political participation) irrespective of disability status. Results are discussed in terms of practical implications for development efforts in Liberia and for disabled people in other low- and middle-income settings

The Ebola crisis and people with disabilities' access to healthcare and government services in Liberia

BACKGROUND: There has been little research on the impact of the 2014-2015 West African Ebola crisis on people with disabilities. This paper outlines the way in which the Ebola Virus Disease (EVD) outbreak in Liberia in 2015 highlighted existing inequalities and exclusion of people with disabilities and their households. METHODS: The results presented here are part of a larger ESRC/DFID-funded mixed methods research project in Liberia (2014-2017) which included a quantitative household survey undertaken in five counties, complemented by qualitative focus group discussions and interviews with people with disabilities and other key stakeholders. Uniquely, this research gathered information about people with disabilities' experience of the EVD outbreak, as well as additional socioeconomic and inclusion data, that compared their experience with non-disabled community members. RESULTS: Reflections by people with disabilities themselves show knowledge, preparation, and responses to the EVD epidemic was often markedly different among people with disabilities due to limited resources, lack of inclusion by many mainstream public health and medical interventions and pre-existing discrimination, marginalisation and exclusion. Interviews with other key stakeholder revealed a lack of awareness of disability issues or sufficient training to include this population systematically in both Ebola response activities and general health services. Key findings include the need to understand and mitigate direct and indirect health consequences of unequal responses to the epidemic, as well as the limited capacity of healthcare and social services to respond to people with disabilities. CONCLUSION: There are lessons to be learned from Ebola outbreak around inclusion of people with disabilities, relevant to the current COVID-19 pandemic. Now is the time to undertake measures to ensure that people with disabilities do not continue to be marginalised and excluded during global public health emergencies

Digital Dilemma 2018

In October 2018 a one-day conference was held at the UCL Institute of Archaeology focussing on the ‘Digital Dilemma’ in biological archaeology —specifically human remains research where the use of digitisation methods have increased exponentially over the last decade while comparatively little discussion of the ethical and legal considerations of these data has taken place. Papers presented at Digital Dilemma 2018 explored the use of digital data in human remains research, discussing both the benefits provided by these data, areas of ethical or methodological concern and suggestions for future research. This paper and the following conference proceedings will discuss this research demonstrating the importance that this Digital Dilemma in archaeology continues to be discussed and considered in future research

Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity

Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity. We used genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD138+ cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.National Institutes of Health, National Cancer Institute [R01CA190789, R01CA172443]; University of Arizona Cancer Center Support Grant [P30CA023074]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Counting who makes the grade: Updated estimates of the share of over-age for grade learners in sub-Saharan Africa using MICS6 data

Many education systems within sub-Saharan Africa are affected by the problem of over-aged learners. Children who are above the expected age for their grade experience poorer outcomes relative to other learners and it is therefore of interest to policymakers to accurately identify them for the purposes of informing effective remedial interventions. UNICEF's sixth round of Multiple Indicator Cluster Survey's [MICS6] are among the relatively few robust nationally representative data sources that can be used to calculate the share of over-age for grade learners within education systems. This paper identifies variability in the estimation method used to identify the same target over-age population (i.e. learners who are older than the official age for the grade they are currently attending) across MICS6 country reports in 14 countries in sub-Saharan Africa. Nine countries utilise a different method which captures only part of the desired target population. This approach fails to identify at least 50% of learners who are over-age for grade by two years in their primary education system and up to 57% of over-age for grade learners in lower secondary. Results are discussed in terms of their implications for supporting policymakers to plan and implement effective school-based education and health interventions, using Comprehensive Sexuality Education as an example

Exploring Partnerships between Academia and Disabled Persons’ Organisations: Lessons Learned from Collaborative Research in Africa

In this article, we discuss how our academic research on disability and international development in five African countries has benefited hugely from active collaboration with advocates, practitioners, and policymakers, ultimately ensuring that research evidence is used to inform policy and practice. Whilst building such partnerships is seen as good practice, it is particularly important when working on disability issues, as the clarion call of the disability movement, ‘nothing about us without us’, attests. This is not just a slogan. Without the active and critical engagement of disabled people – as researchers, participants, advocates – the evidence gathered would not have the same impact. This article discusses experiences from research in Liberia, Kenya, Uganda, Sierra Leone, and Zambia. It highlights the challenges and opportunities such partnerships can bring in achieving the goals of leaving no one behind and doing nothing without the active engagement and inclusion of persons with disabilities.Department for International Development (DFID)Economic and Social Research Council (ESRC

"When They See a Wheelchair, They've Not Even Seen Me"-Factors Shaping the Experience of Disability Stigma and Discrimination in Kenya.

Disability stigma in many low- and middle-income countries represents one of the most pervasive barriers preventing people with disabilities from accessing equal rights and opportunities, including the uptake of available assistive technology (AT). Previous studies have rarely examined how disability stigma may be shaped through factors endemic to social interactions, including how the use of assistive technology itself may precipitate or alleviate disability stigma. Through two strands of work, we address this gap. Via a series of focus groups with Kenyans without disabilities (Study 1) and secondary data analysis of consultations with Kenyans with disabilities and their allies (Study 2), we identify shared and divergent understandings of what shapes disability stigma and discrimination. Specifically, Kenyans with and without disabilities were cognizant of how religious/spiritual interpretations of disability, conceptions of impairments as "different" from the norm, and social stereotypes about (dis)ability shaped the experience of stigma and discrimination. Moreover, both groups highlighted assistive technology as an influential factor that served to identify or "mark" someone as having a disability. However, whereas participants without disabilities saw assistive technology purely as an enabler to overcome stigma, participants with disabilities also noted that, in some cases, use of assistive technologies would attract stigma from others

ELR510444 Inhibits Tumor Growth and Angiogenesis by Abrogating HIF Activity and Disrupting Microtubules in Renal Cell Carcinoma

Background: Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC. Principal Findings: ELR510444 decreased HIF-1a and HIF-2a levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis. Conclusions: ELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascula