Background Rare cancers here defined as those with an annual incidence rate less than 6/100,000 in Europe, pose challenges for diagnosis, treatments, and clinical decision-making. Information on rare cancers is scant. We updated the estimates of the burden of rare cancers in Europe, their time trends in incidence and survival, and provide information on centralization of treatments in seven European countries. Methods We analysed data on more than two million rare cancer diagnoses, provided by 83 cancer registries, to estimate European incidence and survival in 2000-2007 and the corresponding time trends during 1995-2007. Incidence rates were calculated as the number of new cases divided by the corresponding total person years in the population. Five-year relative survival (RS) was calculated by the Ederer-2 method. Seven registries

Background Accurate childhood cancer burden data are crucial for resource planning and health policy prioritisation. Model-based estimates are necessary because cancer surveillance data are scarce or non-existent in many countries. Although global incidence and mortality estimates are available, there are no previous analyses of the global burden of childhood cancer represented in disability-adjusted life-years (DALYs). Methods Using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 methodology, childhood (ages 0-19 years) cancer mortality was estimated by use of vital registration system data, verbal autopsy data, and population-based cancer registry incidence data, which were transformed to mortality estimates through modelled mortality-to-incidence ratios (MIRs). Childhood cancer incidence was estimated using the mortality estimates and corresponding MIRs. Prevalence estimates were calculated by using MIR to model survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated by multiplying age-specific cancer deaths by the difference between the age of death and a reference life expectancy. DALYs were calculated as the sum of YLLs and YLDs. Final point estimates are reported with 95% uncertainty intervals. Findings Globally, in 2017, there were 11•5 million (95% uncertainty interval 10•6-12•3) DALYs due to childhood cancer, 97•3% (97•3-97•3) of which were attributable to YLLs and 2•7% (2•7-2•7) of which were attributable to YLDs. Childhood cancer was the sixth leading cause of total cancer burden globally and the ninth leading cause of childhood disease burden globally. 82•2% (82•1-82•2) of global childhood cancer DALYs occurred in low, low-middle, or middle Socio-demographic Index locations, whereas 50•3% (50•3-50•3) of adult cancer DALYs occurred in these same locations. Cancers that are uncategorised in the current GBD framework comprised 26•5% (26•5-26•5) of global childhood cancer DALYs. Interpretation The GBD 2017 results call attention to the substantial burden of childhood cancer globally, which disproportionately affects populations in resource-limited settings. The use of DALY-based estimates is crucial in demonstrating that childhood cancer burden represents an important global cancer and child health concern. Funding Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities (ALSAC), and St. Baldrick's Foundation.

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In Saccharomyces cerevisiae SIR proteins mediate transcriptional silencing, forming heterochromatin structures at repressed loci. Although recruitment of transcription initiation factors can occur even to promoters packed in heterochromatin, it is unclear whether heterochromatin inhibits RNA polymerase II (RNAPII) transcript elongation. To clarify this issue, we recruited SIR proteins to the coding region of an inducible gene and characterized the effects of the heterochromatic structure on transcription. Surprisingly, RNAPII is fully competent for transcription initiation and elongation at the locus, leading to significant loss of heterochromatin proteins from the region. A search for auxiliary factors required for transcript elongation through the heterochromatic locus revealed that two proteins involved in histone H3 lysine 56 acetylation, Rtt109 and Asf1, are needed for efficient transcript elongation by RNAPII. The efficiency of transcription through heterochromatin is also impaired in a strain carrying the K56R mutation in histone H3. Our results show that H3 K56 modification is required for efficient transcription of heterochromatic locus by RNAPII, and we propose that transcription-coupled incorporation of H3 acetylated K56 (acK56) into chromatin is needed for efficient opening of heterochromatic loci for transcription.In order to produce mRNA, RNA polymerase II (RNAPII) has to contend with chromatin in regulatory and coding regions of genes. Different modifications of histone proteins, rearrangements of nucleosome positioning, and packaging of nucleosomes into higher-order chromatin structures are used to facilitate or repress the accessibility of cellular factors to DNA. Modifications of histone proteins by acetylation and methylation are the most common ways to initiate changes in chromatin structure. In addition to several transcription-coupled modifications of chromatin in active gene loci, nucleosomes can be removed from entire transcribed regions and replaced with new histones after shutdown of transcription (14,18,21,42,49,54). A detailed study of nucleosome dynamics in budding yeast has revealed a remarkable replication-independent exchange of histones throughout the genome. While turnover of promoter nucleosomes is detectable regardless of transcriptional activity of the locus, exchange of histones in the coding regions is in good correlation with gene expression level, indicating that turnover of nucleosomes is a rather common feature of ongoing transcription, especially in highly transcribed loci (7).Gene expression in eukaryotic cells is also controlled by the formation of repressive heterochromatic domains in loci of regulated genes. There are three main regions in the genome of Saccharomyces cerevisiae that are subject to silencing by heterochromatin: telomeres, ribosomal DNA (rDNA) locus, and silent mating type loci (HML and HMR). Heterochromatin at telomeres and HM loci is formed by the complex of silent information regulator (SIR) proteins Sir2, Sir3, and Sir4, which are also required f...

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