“I am not a number!” Opinions and preferences of people with intellectual disability about genetic healthcare

There is limited research exploring the knowledge and experiences of genetic healthcare from the perspective of people with intellectual disability. This study, conducted in New South Wales (Australia), addresses this gap. Eighteen adults with intellectual disability and eight support people were interviewed in this inclusive research study. The transcribed interviews were analysed using inductive content analysis. The findings were discussed in a focus group with ten adults with intellectual disability and in three multi-stakeholder advisory workshops, contributing to the validity and trustworthiness of the findings. Five main themes emerged: (i) access to genetic healthcare services is inequitable, with several barriers to the informed consent process; (ii) the experiences and opinions of people with intellectual disability are variable, including frustration, exclusion and fear; (iii) genetic counselling and diagnoses can be profoundly impactful, but translating a genetic diagnosis into tailored healthcare, appropriate support, peer connections and reproductive planning faces barriers; (iv) people with intellectual disability have a high incidence of exposure to trauma and some reported that their genetic healthcare experiences were associated with further trauma; (v) recommendations for a more respectful and inclusive model of genetic healthcare. Co-designed point-of-care educational and consent resources, accompanied by tailored professional education for healthcare providers, are required to improve the equity and appropriateness of genetic healthcare for people with intellectual disability

Rapid copper acquisition by developing murine mesothelioma: Decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an antiangiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes

Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16. OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-alpha 2, IFN-gamma, TNF-alpha, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-alpha 2, IFN-gamma and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-alpha 2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-alpha 2, IFN-gamma and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience.Peer reviewe