Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma.

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

Of euphemisms and euthanasia: the language games of the Nazi doctors and some implications for the modern euthanasia movement.

Euphemisms are place-holders for important concepts. They may disguise a practice which one might abhor if it were given another name. In Nazi Germany during World War II, euphemisms were used to desensitize physicians and society to the horrors of a program of euthanasia. This article examines some of the euphemisms used by the Nazi physicians to redefine medicalized killing, compares the Nazi language games with those of contemporary proponents of medicalized killing, and concludes that the consistent application of euphemisms for medicalized killing significantly weakens arguments against assisted killing.

Is moral ambiguity all we have to offer?

Theology risks marginalization in the debate about ethical medicine, if theologians merely surrender to ambiguity. We live in a pluralistic society, C. Ben Mitchell points out, but Christians must not accept pluralism as an ideology. In light of our own tradition, we must speak out on ethical issues as we see them. Since "the public" is sympathetic to religious values, public policy should not be dictated by anti-religious points of view.

Mechanical assessment of polyurethane impregnated fibreglass bandages for splinting.

The introduction of polyurethane (PU) resin impregnated fibreglass bandages is likely to have a significant effect on modern orthopaedic practice. The manufacturers of these products claim many improved properties compared to plaster of Paris bandages, such as , high strength to weight ratio, rapid setting time and high radiolucency. This paper reports on a series of mechanical tests designed to assess the strength, flexibility, working time and wear properties of the current range of fibreglass bandages and to compare them with plaster of Paris bandages. The results have clearly demonstrated that the fibreglass bandages are mechanically superior and offer numerous advantages over plaster of Paris for use as the definitive casting material for both weight-bearing and non-weight-bearing casts.