Autonomy, information and paternalism in clinical communication

While their paper does not explicitly define the concept of autonomy, the way Ubel et al describe clinicians’ failures to enhance their patients’ autonomy reflects a broader understanding of autonomy than the default account as free and informed choice. In this OPC I would demonstrate that the communication strategies the authors recommend reflects a more sophisticated conception of autonomy than the understanding that typically prevails in bioethics. I will also distinguish between weak and strong forms of paternalism, and argue that a weak paternalistic approach is not only defensible but also aligns with the strategies the authors propose. Thus, by clarifying the concept of autonomy we can show how it can be enhanced in practice

An Epistemic Structuralist Account of Mathematical Knowledge

This thesis aims to explain the nature and justification of mathematical knowledge using an epistemic version of mathematical structuralism, that is a hybrid of Aristotelian structuralism and Hellman’s modal structuralism. Structuralism, the theory that mathematical entities are recurring structures or patterns, has become an increasingly prominent theory of mathematical ontology in the later decades of the twentieth century. The epistemically driven version of structuralism that is advocated in this thesis takes structures to be primarily physical, rather than Platonically abstract entities. A fundamental benefit of epistemic structuralism is that this account, unlike other accounts, can be integrated into a naturalistic epistemology, as well as being congruent with mathematical practice. In justifying mathematical knowledge, two levels of abstraction are introduced. Abstraction by simplification is how we extract mathematical structures from our experience of the physical world. Then, abstraction by extension, simplification or recombination are used to acquire concepts of derivative mathematical structures. It is argued that mathematical theories, like all other formal systems, do not completely capture everything about those aspects of the world they describe. This is made evident by exploring the implications of Skolem’s paradox, Gödel’s second incompleteness theorem and other limitative results. It is argued that these results demonstrate the relativity and theory-dependence of mathematical truths, rather than posing a serious threat to moderate realism. Since mathematics studies structures that originate in the physical world, mathematical knowledge is not significantly distinct from other kinds of scientific knowledge. A consequence of this view about mathematical knowledge is that we can never have absolute certainty, even in mathematics. Even so, by refining and improving mathematical concepts, our knowledge of mathematics becomes increasingly powerful and accurate

Reconceptualizing Autonomy for Bioethics

Autonomy plays a central role in bioethics, but there is no consensus as to how we should understand this concept. This paper critically considers three different conceptions of autonomy: the default conception prevalent in bioethics literature; a broader procedural account of autonomy drawing moral philosophical approaches; and a substantive, perfectionist account. Building on Rebecca Walker’s critique of the default conception of autonomy, we will argue that a substantive, perfectionist approach both fulfils Walker’s criteria for a conception of autonomy in bioethics and lends itself to application in practical scenarios. In so doing, we draw on scenarios from genomic medicine to show that a substantive, perfectionist approach not only offers a more conceptually adequate understanding of autonomy in more complex cases, but also lends itself to practical application by helping health professionals identify how they can maximize people’s capacity to exercise their autonomy

Globalisation and the ethics of transnational biobank networks

Biobanks are increasingly being linked together into global networks in order to maximise their capacity to identify causes of and treatments for disease. While there is great optimism about the potential of these biobank networks to contribute to personalised and data-driven medicine, there are also ethical concerns about, among other things, risks to personal privacy and exploitation of vulnerable populations. Concepts drawn from theories of globalisation can assist with the characterisation of the ethical implications of biobank networking across borders, which can, in turn, inform more ethically sophisticated responses. Using the China Kadoorie Biobank as a case study, we show how distinguishing between the subnational, transnational, supranational and extranational spheres of operation and influence can help researchers, institutions and regulators to understand and manage the ethical issues raised by the globalisation of biobanking.National Health and Medical Research Council (Australia

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response