Problematising the Problem: Exploring How Hearing Privilege Fosters Employment Inequality for Deaf People

Employment inequality is recognised as a problem for deaf people. What is rarely understood is that what often lies behind that inequality is less a “deaf-centered” problem, but rather the issue of “hearing privilege”. Hearing privilege refers to the unearned advantage granted to hearing people on the basis of their hearing identity in a society characterised by ableism. Despite a proliferation of research on the employment disadvantage experienced by deaf people, hearing people continue to dominate in leadership positions in deaf community voluntary organisations. By drawing upon scholarship from Privilege Studies and social justice education, this article “problematises the problem” by discussing the importance of viewing deaf people’s experience of disadvantage through the prism of hearing privilege. The article offers insight into how privilege awareness workshops can be hugely influential in educating hearing people about their privilege and encouraging them to take responsibility for challenging their unearned advantage

1,4-dihydroxy quininib modulates the secretome of uveal melanoma tumour explants and a marker of oxidative phosphorylation in a metastatic xenograft model

Uveal melanoma (UM) is an intraocular cancer with propensity for liver metastases. The median overall survival (OS) for metastatic UM (MUM) is 1.07 years, with a reported range of 0.84-1.34. In primary UM, high cysteinyl leukotriene receptor 1 (CysLT(1)) expression associates with poor outcomes. CysLT(1) antagonists, quininib and 1,4-dihydroxy quininib, alter cancer hallmarks of primary and metastatic UM cell lines in vitro. Here, the clinical relevance of CysLT receptors and therapeutic potential of quininib analogs is elaborated in UM using preclinical in vivo orthotopic xenograft models and ex vivo patient samples. Immunohistochemical staining of an independent cohort (n = 64) of primary UM patients confirmed high CysLT(1) expression significantly associates with death from metastatic disease (p = 0.02; HR 2.28; 95% CI 1.08-4.78), solidifying the disease relevance of CysLT(1) in UM. In primary UM samples (n = 11) cultured as ex vivo explants, 1,4-dihydroxy quininib significantly alters the secretion of IL-13, IL-2, and TNF-alpha. In an orthotopic, cell line-derived xenograft model of MUM, 1,4-dihydroxy quininib administered intraperitoneally at 25 mg/kg significantly decreases ATP5B expression (p = 0.03), a marker of oxidative phosphorylation. In UM, high ATP5F1B is a poor prognostic indicator, whereas low ATP5F1B, in combination with disomy 3, correlates with an absence of metastatic disease in the TCGA-UM dataset. These preclinical data highlight the diagnostic potential of CysLT(1) and ATP5F1B in UM, and the therapeutic potential of 1,4-dihydroxy quininib with ATP5F1B as a companion diagnostic to treat MUM

Metformin is a metabolic modulator and radiosensitiser in rectal cancer

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer

Automated tests for diagnosing and monitoring cognitive impairment: a diagnostic accuracy review

Background Cognitive impairment is a growing public health concern, and is one of the most distinctive characteristics of all dementias. The timely recognition of dementia syndromes can be beneficial, as some causes of dementia are treatable and are fully or partially reversible. Several automated cognitive assessment tools for assessing mild cognitive impairment (MCI) and early dementia are now available. Proponents of these tests cite as benefits the tests’ repeatability and robustness and the saving of clinicians’ time. However, the use of these tools to diagnose and/or monitor progressive cognitive impairment or response to treatment has not yet been evaluated. Objectives The aim of this review was to determine whether or not automated computerised tests could accurately identify patients with progressive cognitive impairment in MCI and dementia and, if so, to investigate their role in monitoring disease progression and/or response to treatment. Data sources Five electronic databases (MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science and PsycINFO), plus ProQuest, were searched from 2005 to August 2015. The bibliographies of retrieved citations were also examined. Trial and research registers were searched for ongoing studies and reviews. A second search was run to identify individual test costs and acquisition costs for the various tools identified in the review. Review methods Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. The results of the data extraction and quality assessment for each study are presented in structured tables and as a narrative summary. Results The electronic searching of databases, including ProQuest, resulted in 13,542 unique citations. The titles and abstracts of these were screened and 399 articles were shortlisted for full-text assessment. Sixteen studies were included in the diagnostic accuracy review. No studies were eligible for inclusion in the review of tools for monitoring progressive disease. Eleven automated computerised tests were assessed in the 16 included studies. The overall quality of the studies was good; however, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that meaningful synthesis or statistical analysis was not possible. Limitations The main limitation of this review is the substantial heterogeneity of the tests assessed in the included studies. As a result, no meta-analyses could be undertaken. Conclusion The quantity of information available is insufficient to be able to make recommendations on the clinical use of the computerised tests for diagnosing and monitoring MCI and early dementia progression. The value of these tests also depends on the costs of acquisition, training, administration and scoring

Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain’s innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed

The Youngest Victims: Children and Youth Affected by War

In 1989, the United Nation Convention on the Rights of the Child declared, “[state parties] shall take all feasible measures to ensure protection and care of children who are affected by an armed conflict.” In addition to attempting to secure the welfare of children in armed conflict, the Convention went on to ban the recruitment and deployment of children during armed conflict. Despite the vast majority of sovereign nations signing and ratifying this agreement, this treaty, unfortunately, has not prevented children and youth from witnessing, becoming victims of, or participating in political, ethnic, religious, and cultural violence across the past three decades. This chapter offers an “ecological perspective” on the psychosocial consequences of exposure to the trauma of war-related violence and social disruption

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

The Omentum in Obesity-Associated Cancer: A Hindrance to Effective Natural Killer Cell Migration towards Tumour Which Can Be Overcome by CX3CR1 Antagonism

Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction

Phosphorus monolayer doping (MLD) of silicon on insulator (SOI) substrates

This paper details the application of phosphorus monolayer doping of silicon on insulator substrates. There have been no previous publications dedicated to the topic of MLD on SOI, which allows for the impact of reduced substrate dimensions to be probed. The doping was done through functionalization of the substrates with chemically bound allyldiphenylphosphine dopant molecules. Following functionalization, the samples were capped and annealed to enable the diffusion of dopant atoms into the substrate and their activation. Electrical and material characterisation was carried out to determine the impact of MLD on surface quality and activation results produced by the process. MLD has proven to be highly applicable to SOI substrates producing doping levels in excess of 1 × 1019 cm−3 with minimal impact on surface quality. Hall effect data proved that reducing SOI dimensions from 66 to 13 nm lead to an increase in carrier concentration values due to the reduced volume available to the dopant for diffusion. Dopant trapping was found at both Si–SiO2 interfaces and will be problematic when attempting to reach doping levels achieved by rival techniques