Autonomy, Trust, and Respect.

This article seeks to explore and analyze the relationship between autonomy and trust, and to show how these findings could be relevant to medical ethics. First, I will argue that the way in which so-called "relational autonomy theories" tie the notions of autonomy and trust together is not entirely satisfying Then, I will introduce the so-called Encapsulated Interest Account as developed by Russell Hardin. This will bring out the importance of the reasons for trust. What good reasons do we have for trusting someone? I will criticize Hardin's business model as insufficiently robust, especially in the context of health care, and then turn to another source of trust, namely, love. It may seem that trust-through-love is much better suited for the vulnerability that is often involved in health care, but I will also show that it has its own deficiencies. Good health care should therefore pay attention to both models of trust, and I will offer some tentative remarks on how to do this.

On the Authority of Advance Euthanasia Directives for People with Severe Dementia: Reflections on a Dutch Case.

In 2016, a Dutch physician complied with the advance euthanasia directive of a patient with severe dementia. In the ensuing lawsuit, the physician was charged principally with termination of life on request, with euthanasia, that is, and alternatively with murder. A district court acquitted her of both charges, a decision later upheld by the Dutch Supreme Court. Euthanasia is still a criminal offense in the Netherlands, but in 2002, a new euthanasia act came into effect allowing a physician to perform euthanasia if she has fulfilled six due-care criteria, the two most important of which are that she must be satisfied that the patient's request is voluntary and well considered and that the patient's suffering is unbearable, with no prospect of improvement. Neither of these two criteria is controversial; particular cases are controversial when it is disputed that these criteria were fulfilled. Other euthanasia cases, however, are controversial because they belong to a category that is contentious for independent reasons. One such disputed category is euthanasia performed on incompetent patients with an advance directive. Since determining whether these criteria are fulfilled in a particular case depends on the particular circumstances, we describe this 2016 case in detail. We then focus on three general philosophical reasons for doubting the validity of advance euthanasia directives for incompetent patients: the someone else problem, the problem of response shift, and the problem of normative authority. These problems have been discussed before, but our primary aim is to show how they are connected. Taken together, we believe that our two lines of argument make a strong moral case for supporting the Dutch Supreme Court's decision.

Validation of the monocyte activation test with three therapeutic monoclonal antibodies.

Pharmaceutical products intended for parenteral use must be free from pyrogenic (fever-inducing) contamination. Pyrogens comprise endotoxins from Gram-negative bacteria and non-endotoxin pyrogens from Gram-positive bacteria, viruses, and fungi. The longstanding compendial test for pyrogens is the rabbit pyrogen test, but in 2010 the monocyte acti-vation test (MAT) for pyrogenic and pro-inflammatory contaminants was introduced into the European Pharmacopoeia (Ph. Eur.) as a non-animal replacement for the rabbit pyrogen test. The present study describes the first product-specific Good Manufacturing Practice validation of Ph. Eur. MAT, Quantitative Test, Method A for the testing of three therapeutic monoclonal antibodies. The study used the MAT version with cryo-preserved peripheral blood mononuclear cells and interleukin-6 as the readout. Much of the data presented here for one of the antibodies was included in a successful product license application to the European Medicines Agency.

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity.

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.

A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.

Comparative peptidomics of Caenorhabditis elegans versus C. briggsae by LC-MALDI-TOF MS.

Neuropeptides are important signaling molecules that function in cell-cell communication as neurotransmitters or hormones to orchestrate a wide variety of physiological conditions and behaviors. These endogenous peptides can be monitored by high throughput peptidomics technologies from virtually any tissue or organism. The neuropeptide complement of the soil nematode Caenorhabditis elegans has been characterized by on-line two-dimensional liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (2D-nanoLC Q-TOF MS/MS). Here, we use an alternative peptidomics approach combining liquid chromatography (LC) with matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry to map the peptide content of C. elegans and another Caenorhabditis species, Caenorhabditis briggsae. This study allows a better annotation of neuropeptide-encoding genes from the C. briggsae genome and provides a promising basis for further evolutionary comparisons.

Psychiatry under pressure: reflections on psychiatry's drift towards a reductionist biomedical conception of mental illness.

We argue that contemporary psychiatry adopts a defensive strategy vis-à-vis various external sources of pressure. We will identify two of these sources--the plea for individual autonomy and the idea of Managed Care--and explain how they have promoted a strict biomedical conception of disease. The demand for objectivity, however, does not take into account the complexity of mental illness. It ignores that the psychiatrist's profession is essentially characterized by fragility: fluctuating between scientific reduction and the irreducible complexity of reality. Therefore, the psychiatrist is not in need of hard and fast rules, but of judgment. At the end, we suggest that philosophy could inject some healthy uncertainty within psychiatry in order to restore its fragile identity. Our examples are drawn from the Dutch situation but we are confident that they apply to other countries as well.