American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.

SummaryBackgroundCancer is a major cause of death in children worldwide, and the recorded incidence tends to increase with time. Internationally comparable data on childhood cancer incidence in the past two decades are scarce. This study aimed to provide internationally comparable local data on the incidence of childhood cancer to promote research of causes and implementation of childhood cancer control.MethodsThis population-based registry study, devised by the International Agency for Research on Cancer in collaboration with the International Association of Cancer Registries, collected data on all malignancies and non-malignant neoplasms of the CNS diagnosed before age 20 years in populations covered by high-quality cancer registries with complete data for 2001–10. Incidence rates per million person-years for the 0–14 years and 0–19 years age groups were age-adjusted using the world standard population to provide age-standardised incidence rates (WSRs), using the age-specific incidence rates (ASR) for individual age groups (0–4 years, 5–9 years, 10–14 years, and 15–19 years). All rates were reported for 19 geographical areas or ethnicities by sex, age group, and cancer type. The regional WSRs for children aged 0–14 years were compared with comparable data obtained in the 1980s.FindingsOf 532 invited cancer registries, 153 registries from 62 countries, departments, and territories met quality standards, and contributed data for the entire decade of 2001–10. 385 509 incident cases in children aged 0–19 years occurring in 2·64 billion person-years were included. The overall WSR was 140·6 per million person-years in children aged 0–14 years (based on 284 649 cases), and the most common cancers were leukaemia (WSR 46·4), followed by CNS tumours (WSR 28·2), and lymphomas (WSR 15·2). In children aged 15–19 years (based on 100 860 cases), the ASR was 185·3 per million person-years, the most common being lymphomas (ASR 41·8) and the group of epithelial tumours and melanoma (ASR 39·5). Incidence varied considerably between and within the described regions, and by cancer type, sex, age, and racial and ethnic group. Since the 1980s, the global WSR of registered cancers in children aged 0–14 years has increased from 124·0 (95% CI 123·3–124·7) to 140·6 (140·1–141·1) per million person-years.InterpretationThis unique global source of childhood cancer incidence will be used for aetiological research and to inform public health policy, potentially contributing towards attaining several targets of the Sustainable Development Goals. The observed geographical, racial and ethnic, age, sex, and temporal variations require constant monitoring and research.FundingInternational Agency for Research on Cancer and the Union for International Cancer Control.

It is well established that multiple microtubule-based motors contribute to the formation and function of the mitotic spindle, but how the activities of these motors interrelate remains unclear.Here we visualize spindle formation in living Drosophila embryos to show that spindle pole movements are directed by a temporally coordinated balance of forces generated by three mitotic motors, cytoplasmic dynein, KLP61F, and Ncd. Specifically, our findings suggest that dynein acts to move the poles apart throughout mitosis and that this activity is augmented by KLP61F after the fenestration of the nuclear envelope, a process analogous to nuclear envelope breakdown, which occurs at the onset of prometaphase. Conversely, we find that Ncd generates forces that pull the poles together between interphase and metaphase, antagonizing the activity of both dynein and KLP61F and serving as a brake for spindle assembly. During anaphase, however, Ncd appears to have no effect on spindle pole movements, suggesting that its activity is downregulated at this time, allowing dynein and KLP61F to drive spindle elongation during anaphase B. INTRODUCTIONThe segregation of chromosomes during mitosis depends on the action of a self-organizing, bipolar machine called the mitotic spindle. It is now established that the formation and function of the mitotic spindle requires numerous microtubule (MT)-based motor proteins (Hoyt and Geiser, 1996;Vale and Fletterick, 1997). Although the identities of many of these mitotic motors are becoming clear, their specific functional interrelationships have been extremely difficult to ascertain.Among all mitotic movements, the positioning of spindle poles during the assembly and elongation of the bipolar mitotic spindle may require the greatest degree of cooperation between different motors. This process is particularly complex because it occurs in a pathway consisting of several, temporally distinct stages, during which the organization of spindle microtubules and the general environment of the cell change dramatically (McIntosh and McDonald, 1989). The members of at least three families of MT motors are thought to play important roles in this pathway. These are the bipolar kinesins, the C-terminal kinesins, and cytoplasmic dynein.The bipolar (or BimC) kinesins (Vale and Fletterick, 1997) comprise a family of plus-end-directed motors, which have a bipolar morphology with motor domains at both ends of a central rod (Cole et al., 1994; Kashina et al., 1996a,b; Gordon and Roof, 2000). Functionally, these motors are thought to play a role in either the assembly or maintenance of spindle bipolarity, because their inhibition results in the formation of monopolar mitotic spindles (Enos and Morris, 1990;Hagan and Yanagida, 1990;Roof et al., 1991;Hoyt et al., 1992;Sawin et al., 1992;Heck et al., 1993;Blangy et al., 1995;Sharp et al., 1999b). Support for a role for bipolar kinesins in spindle maintenance but not assembly comes from the recent findings that inhibiting the Drosophila bipolar kinesin KLP61F does not pr...

Previous genetic and biochemical studies have led to the hypothesis that the essential mitotic bipolar kinesin, KLP61F, cross-links and slides microtubules (MTs) during spindle assembly and function. Here, we have tested this hypothesis by immunofluorescence and immunoelectron microscopy (immunoEM). We show that Drosophila embryonic spindles at metaphase and anaphase contain abundant bundles of MTs running between the spindle poles. These interpolar MT bundles are parallel near the poles and antiparallel in the midzone. We have observed that KLP61F motors, phosphorylated at a cdk1/cyclin B consensus domain within the BimC box (BCB), localize along the length of these interpolar MT bundles, being concentrated in the midzone region. Nonphosphorylated KLP61F motors, in contrast, are excluded from the spindle and display a cytoplasmic localization. Immunoelectron microscopy further suggested that phospho-KLP61F motors form cross-links between MTs within interpolar MT bundles. These bipolar KLP61F MT-MT cross-links should be capable of organizing parallel MTs into bundles within half spindles and sliding antiparallel MTs apart in the spindle midzone. Thus we propose that bipolar kinesin motors and MTs interact by a “sliding filament mechanism” during the formation and function of the mitotic spindle.