Anticancer Therapy SMRT-ens Up: Targeting the BCL6-SMRT Interaction in B Cell Lymphoma

Transcription factors have proven to be difficult targets for the development of small-molecule drugs. In this issue of Cancer Cell, Cerchietti et al. identify and characterize a specific, small-molecule inhibitor of BCL6, an oncogenic transcriptional repressor, that has high clinical promise for treating diffuse large B cell lymphoma

Melanoma in a patient with DNMT3A overgrowth syndrome

Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gen

Coronary vessel development is dependent on the type III transforming growth factor beta receptor

Abstract-Transforming growth factor (TGF)␤ receptor III (TGF␤R3), or ␤-glycan, binds all 3 TGF␤ ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGF␤R1, TGF␤R2). TGF␤R3 facilitates signaling via TGF␤R1/TGF␤R2 but also has been suggested to play a unique and nonredundant role in TGF␤ signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability. (Circ Res. 2007;101:000-000.) Key Words: coronary vessels Ⅲ transforming growth factor ␤ receptor Ⅲ mice, null C oronary artery disease is responsible for 54% of all cardiovascular disease in the United States. 1 Coronary vessels have a unique derivation from mesothelial cells that form a transitory structure termed the proepicardium. Proepicardial cells are transferred to the heart, form the epicardium, and give rise to endothelial cells, smooth muscle cells, and cardiac fibroblasts (reviewed elsewhere 2,3 ). Endothelial cells derived from the epicardium form a vascular plexus by the process of vasculogenesis. This vascular network attaches to the aorta and recruits epicardially derived mesenchyme to become vascular smooth muscle. The identification of the molecular and cellular processes that regulate coronary vessel development may provide insight into coronary vessel disease and reveal novel therapeutic opportunities. The transforming growth factor (TGF)␤ family of growth factors regulates cell growth and differentiation in the cardiovascular system during both development and disease. 4 -6 Three ligands, TGF␤1, TGF␤2, and TGF␤3, 7-9 bind 4 cell surface proteins. These include two transmembrane serine/ threonine kinase receptors, the type I TGF␤ receptor (TGF␤R1) and the type II TGF␤ receptor (TGF␤R2). 10 -12 Several type I receptors, termed activin receptor-like kinases (ALKs), have been described. TGF␤R2 has a constitutively active cytoplasmic kinase domain and an extracellular domain that binds TGF␤1 and TGF␤3 with high affinity. Materials and Methods Generation of Null Mice A targeting vector was made to delete exon 3 that encodes the N terminus, including a portion of the extracellular ligand binding domain. Construction and validation of the targeting vector is described in the online data supplement at http://circres.ahajournals.org (see supplemental Histology, Whole-Mount Immunohistochemistry, and ␤-Galactosidase Staining Detailed methodology is described in the online data supplement. Results Deletion of Tgfbr3 Results in Embryonic Lethality Exon 3 was targeted as depicted in the online data supplement (supplemental Tgfbr3-Null Mice Display Defects in Coronary Vasculogenesis Because embryonic death coincides temporally with the known dependency of embryo viability on the formation of the coronary circulation, we examined null embryos for the presence of coronary vessels. Whole-heart immunostaining for the vascular endothelial cell marker platelet endothelial cell adhesion molecule (PECAM) (also known as CD31) at E14.0 revealed dramatically decreased immunoreactivity in nulls Percentage of Observed Defects in Embryos Tgfbr3-Null Mice Have Abnormal Epicardium and Dysmorphic Coronary Vessels The epicardium is derived from the proepicardium and contains coronary vessel precursor cells. At E13.5, the epicardium forms a tightly apposed monolayer on the surface on the atria and ventricles. In the region of the atrioventricular groove, the epicardium is separated from the myocardium by a layer of epicardial-derived mesenchyme ( Tgfbr3-Null Mice Initiate Recruitment of Smooth Muscle to Extracardiac and Coronary Vessels TGF␤ has multiple roles during blood vessel formation, including vascular smooth muscle cell recruitment. After right and left coronary arteries attach to the systemic circulation at the aorta, smooth muscle recruitment commences at the coronary ostia and progresses distally. As noted in Discussion Disruption of Tgfbr3 revealed a requirement for coronary vessel development and embryonic viability. Null embryos die at E14.5 with defects in coronary vessel development, whereas vasculature outside of the coronary circulation appears normal. Although greatly reduced in size, nascent coronary vessels attach to the aorta and initiate smooth muscle recruitment. Coronary vessel defects are coincident with epicardial abnormalities that include increased space between the epicardium and myocardium, abundant subepi- cardial mesenchyme, and persistent blood islands. In addition to coronary vessel anomalies, null embryos have OFT abnormalities and myocardial thinning. Presumably, the greatly reduced coronary vasculature in null embryos is not sufficient to adequately perfuse the heart resulting in embryonic death. Despite the abundance of data implicating TGF␤ signaling in vasculogenesis and angiogenesis, these processes appear to occur normally outside of the coronary vessels in nulls. The localization of defects to the coronary vessels may be explained by the unique derivation of these vessels (reviewed elsewhere 2,3 ). The proepicardium, adjacent to the liver rudiment, is transferred to the heart and gives rise to the epicardium as well as coronary endothelial cells, smooth muscle cells, and cardiac fibroblasts. Although targeted gene deletion in mice has uncovered roles for several molecules in coronary vessel development, none has a phenotype similar to Tgfbr3 nulls. Deletion of vascular cell adhesion molecule-1 40 or the counter receptor ␣4 integrin Defects in coronary vasculogenesis in Tgfbr3 nulls do not appear to result from defects in angioblast or endothelial differentiation because PECAM-positive cells do appear. A failure in coronary vasculogenesis could result from an insufficient population of angioblasts or endothelial cells, a possibility we cannot exclude because the numbers of these cells was not quantitated. At E14.5, we saw fewer vessels on the heart and a complete absence of large vessels formed by remodeling of the primary vascular plexus. This observation suggests a defect in angioblast or endothelial cell assembly or remodeling. TGF␤R3 contains a cytoplasmic PDZ domain that has been shown to bind glycoinositolphosphorylceramide or synectin

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background: Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods: Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (>= 65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0-100 based on the 2.5th and 97.5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target-1 billion more people benefiting from UHC by 2023-we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings: Globally, performance on the UHC effective coverage index improved from 45.8 (95% uncertainty interval 44.2-47.5) in 1990 to 60.3 (58.7-61.9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2.6% [1.9-3.3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010-2019 relative to 1990-2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0.79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388.9 million (358.6-421.3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3.1 billion (3.0-3.2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968.1 million [903.5-1040.3]) residing in south Asia. Interpretation: The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people-the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close-or how far-all populations are in benefiting from UHC

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15–39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods: Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15–39 years to define adolescents and young adults. Findings: There were 1·19 million (95% UI 1·11–1·28) incident cancer cases and 396 000 (370 000–425 000) deaths due to cancer among people aged 15–39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59·6 [54·5–65·7] per 100 000 person-years) and high-middle SDI countries (53·2 [48·8–57·9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14·2 [12·9–15·6] per 100 000 person-years) and middle SDI (13·6 [12·6–14·8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23·5 million (21·9–25·2) DALYs to the global burden of disease, of which 2·7% (1·9–3·6) came from YLDs and 97·3% (96·4–98·1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation: Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Funding: Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St Baldrick's Foundation, and the National Cancer Institute

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe