Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.     

Rome and Theistic Evolutionism: The Hidden Strategies behind the ‘Dorlodot Affair’, 1920–1926

In 1918, Henry de Dorlodot—priest, theologian, and professor of geology at the University of Louvain (Belgium)—published Le Darwinisme au point de vue de l'Orthodoxie Catholique (translated as Darwinism and Catholic Thought) in which he defended a reconciliation between evolutionary theory and Catholicism with his own particular kind of theistic evolutionism. He subsequently announced a second volume in which he would extend his conclusions to the origin of Man. Traditionalist circles in Rome reacted vehemently. Operating through the Pontifical Biblical Commission, they tried to force Dorlodot to withdraw his book and to publicly disown his ideas by threatening him with an official condemnation, a strategy that had been used against Catholic evolutionists since the late nineteenth century. The archival material on the ‘Dorlodot affair’ shows how this policy ‘worked’ in the early stages of the twentieth century but also how it would eventually reach the end of its logic. The growing popularity of theistic evolutionism among Catholic intellectuals, combined with Dorlodot's refusal to pull back amidst threats, made certain that the traditionalists did not get their way completely, and the affair ended in an uncomfortable status quo. Dorlodot did not receive the official condemnation that had been threatened, nor did he withdraw his theories, although he stopped short on publishing on the subject. With the decline of the traditionalists’ power and authority, the policy of denunciation towards evolutionists made way for a growing tolerance. The ‘Dorlodot affair’—which occurred in a pivotal era in the history of the Church—can be seen as exemplary with regards to the changing attitude of the Roman authorities towards evolutionism in the first half of the twentieth century.     

Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.