Palliative care for older people with dementia — we need a paradigm shift in our approach

Older people with dementia have multiple palliative care needs, with pain, agitation, dyspnoea, aspiration and pressure ulcers being common and persistent in advanced dementia. Anticipating the person’s possible symptoms requires knowledge of the whole person, including the type of dementia, which is problematic when the dementia type is often not documented. A palliative care approach to dementia should look at symptoms across the four pillars of palliative care, but in reality, we tend to over-focus on physical and psychological symptoms, while spiritual and emotional needs can be overlooked, especially around the time of diagnosis, where such needs may be significant. Advance care planning (ACP) is a central tenet of good dementia palliative care, as the person may lose their ability to communicate and make complex decisions over time. Despite this, care planning is often approached too late, and with the person’s family rather than with the person; much of the literature on ACP in dementia is based on proxy decision-making for people in residential care. Thus, we need a paradigm shift in how we approach dementia, beginning with timely diagnosis that includes the dementia type, and with services able to assess and meet emotional and spiritual needs especially around the time of diagnosis, and with timely ACP as an integral part of our overall approach

Clofarabine Targets the Large Subunit (α) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers

Available in PMC 2013 July 27Clofarabine (ClF) is a drug used in the treatment of leukemia. One of its primary targets is human ribonucleotide reductase (hRNR), a dual-subunit, (α2)m(β2)n, regulatory enzyme indispensable in de novo dNTP synthesis. We report that, in live mammalian cells, ClF targets hRNR by converting its α-subunit into kinetically stable hexamers. We established mammalian expression platforms that enabled isolation of functional α and characterization of its altered oligomeric associations in response to ClF treatment. Size exclusion chromatography and electron microscopy documented persistence of in-cell-assembled-α6. Our data validate hRNR as an important target of ClF, provide evidence that in vivo α's quaternary structure can be perturbed by a nonnatural ligand, and suggest small-molecule-promoted, persistent hexamerization as a strategy to modulate hRNR activity. These studies lay foundations for documentation of RNR oligomeric state within a cell.Howard Hughes Medical Institute (Investigator)National Institutes of Health (U.S.) (NIH grant GM29595)National Institutes of Health (U.S.) (NIH grant GM67167)Damon Runyon Cancer Research Foundation (postdoctoral fellowship (DRG2015-09))Howard Hughes Medical Institute (International Student Fellowship

3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound

Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the β subunit houses the radical cofactor. Here, we present a 3.3-Å resolution structure by cryo-electron microscopy (EM) of a dATP-inhibited state of human RNR. This structure, which was determined in the presence of substrate CDP and allosteric regulators ATP and dATP, has three α 2 units arranged in an α 6 ring. At near-atomic resolution, these data provide insight into the molecular basis for CDP recognition by allosteric specificity effectors dATP/ATP. Additionally, we present lower-resolution EM structures of human α 6 in the presence of both the anticancer drug clofarabine triphosphate and β 2 . Together, these structures support a model for RNR inhibition in which β 2 is excluded from binding in a radical transfer competent position when α exists as a stable hexamer.National Institutes of Health (U.S.) (Grant GM29595