Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

The Roles of ‘Conventional’ and Demand-Responsive Bus Services

Purpose - The roles of ‘conventional’ (fixed-route and fixed-timetable) bus services is examined and compared to demand-responsive services, taking rural areas in England as the basis for comparison. It adopts a ‘rural’ definition of settlements under a population of 10,000. Design/methodology/approach - Evidence from the National Travel Survey, technical press reports and academic work is brought together to examine the overall picture. Findings - Inter-urban services between towns can provide a cost-effective way of serving rural areas where smaller settlements are suitably located. The cost structures of both fixed-route and demand-responsive services indicate that staff time and cost associated with vehicle provision are the main elements. Demand-responsive services may enable larger areas to be covered, to meet planning objectives of ensuring a minimum of level of service, but experience often shows high unit cost and public expenditure per passenger trip. Economic evaluation indicates user benefits per passenger trip of similar magnitude to existing average public expenditure per trip on fixed-route services. Considerable scope exists for improvements to conventional services through better marketing and service reliability. Practical implications - The main issue in England is the level of funding for rural services in general, and the importance attached to serving those without access to cars in such areas. Social implications - The boundary between fixed-route and demand-responsive operation may lie at relatively low population densities. Originality/value - The chapter uses statistical data, academic research and operator experience of enhanced conventional bus services to provide a synthesis of outcomes in rural areas.