Specification and survival of post-metamorphic branchiomeric neurons in a non-vertebrate chordate.

Tunicates are the sister group to the vertebrates, yet most species have a life cycle split between swimming larva and sedentary adult phases. During metamorphosis, larval neurons are replaced by adult-specific ones. The regulatory mechanisms underlying this replacement remain largely unknown. Using tissue-specific CRISPR/Cas9-mediated mutagenesis in the tunicate Ciona, we show that orthologs of conserved hindbrain and branchiomeric neuron regulatory factors Pax2/5/8 and Phox2 are required to specify the "neck", a cellular compartment set aside in the larva to give rise to cranial motor neuron-like neurons post-metamorphosis. Using bulk and single-cell RNAseq analyses, we characterize the transcriptome of the neck downstream of Pax2/5/8. We present evidence that neck-derived adult ciliomotor neurons begin to differentiate in the larva and persist through metamorphosis, contrary to the assumption that the adult nervous system is formed after settlement and the death of larval neurons during metamorphosis. Finally, we show that FGF signaling during the larval phase alters the patterning of the neck and its derivatives. Suppression of FGF converts neck cells into larval neurons that fail to survive metamorphosis, while prolonged FGF signaling promotes an adult neural stem cell-like fate.

Specification of distinct cell types in a sensory-adhesive organ important for metamorphosis in tunicate larvae.

The papillae of tunicate larvae contribute sensory, adhesive, and metamorphosis-regulating functions that are crucial for the biphasic lifestyle of these marine, non-vertebrate chordates. We have identified additional molecular markers for at least 5 distinct cell types in the papillae of the model tunicate Ciona, allowing us to further study the development of these organs. Using tissue-specific CRISPR/Cas9-mediated mutagenesis and other molecular perturbations, we reveal the roles of key transcription factors and signaling pathways that are important for patterning the papilla territory into a highly organized array of different cell types and shapes. We further test the contributions of different transcription factors and cell types to the production of the adhesive glue that allows for larval attachment during settlement, and to the processes of tail retraction and body rotation during metamorphosis. With this study, we continue working towards connecting gene regulation to cellular functions that control the developmental transition between the motile larva and sessile adult of Ciona.

Spectroscopic Studies of Clusters of Atmospheric Relevance.

Atmospheric aerosols exert a significant but highly uncertain effect on the global climate, and roughly half of these particles originate as small clusters formed by collisions between atmospheric trace vapors. These particles typically consist of acids, bases, and water, stabilized by salt bridge formation and a network of strong hydrogen bonds. We review spectroscopic studies of this process, focusing on the clusters likely to be involved in the first steps of particle formation and the intermolecular interactions governing their stability. These studies typically focus on determining structure and stability and have shown that acid-base chemistry in the cluster may violate chemical intuition derived from solution-phase behavior and that hydration of these clusters is likely to be complex to describe. We also suggest fruitful areas for extension of these studies and alternative spectroscopic techniques that have not yet been applied to this problem.

Stability and Structure of Potentially Atmospherically Relevant Glycine Ammonium Bisulfate Clusters.

New particle formation (NPF) is the process by which trace atmospheric acids and bases cluster and grow into particles that ultimately impact climate. Sulfuric acid concentration drives NPF, but nitrogen-containing bases promote the formation of more stable clusters via salt bridge formation. Recent computational efforts have suggested that amino acids can enhance NPF, predicting that they can stabilize new particles via multiple protonation sites, but there has yet to be experimental validation of these predictions. We used mass spectrometry and infrared spectroscopy to study the structure and stability of cationic clusters composed of glycine, sulfuric acid, and ammonia. When collisionally activated, clusters were significantly more likely to eliminate ammonia or sulfuric acid than glycine, while quantum chemical calculations predicted lower binding free energies for ammonia but similar binding free energies for glycine and sulfuric acid. These calculations predicted several low-energy structures, so we compared experimental and computed vibrational spectra to attempt to validate the computationally predicted minimum energy structure. Unambiguous identification of the experimental structure by comparison to these calculations was made difficult by the complexity of the experimental spectra and the fact that the identity of the computed lowest-energy structure depended strongly on temperature. If their vapors are present, amino acids are likely to be enriched in new particles by displacing more weakly bound ammonia, similar to the behavior of other atmospheric amines. The carboxylic acid groups were found to preferentially interact with other carboxylic acids, suggesting incipient organic/inorganic phase separation even at these small sizes.

The Competition between Hydrogen, Halogen, and Covalent Bonding in Atmospherically Relevant Ammonium Iodate Clusters.

Iodine-containing clusters are expected to be central to new particle formation (NPF) events in polar and midlatitude coastal regions. Iodine oxoacids and iodine oxides are observed in newly formed clusters, and in more polluted midlatitude settings, theoretical studies suggest ammonia may increase growth rates. Structural information was obtained via infrared (IR) spectroscopy and quantum chemical calculations for a series of clusters containing ammonia, iodic acid, and iodine pentoxide. Structures for five of the smallest cationic clusters present in the mass spectrum were identified, and four of the structures were found to preferentially form halogen and/or covalent bonds over hydrogen bonds. Ammonia is important in proton transfer from iodic acid components and also provides a scaffold to template the formation of a halogen and covalent bonded backbone. The calculations executed for the two largest clusters studied suggested the formation of a covalent I3O8- anion within the clusters.

Metal-Mediated, Autolytic Amide Bond Cleavage: A Strategy for the Selective, Metal Complexation-Catalyzed, Controlled Release of Metallodrugs.

Activation of metalloprodrugs or prodrug activation using transition metal catalysts represents emerging strategies for drug development; however, they are frequently hampered by poor spatiotemporal control and limited catalytic turnover. Here, we demonstrate that metal complex-mediated, autolytic release of active metallodrugs can be successfully employed to prepare clinical grade (radio-)pharmaceuticals. Optimization of the Lewis-acidic metal ion, chelate, amino acid linker, and biological targeting vector provides means to release peptide-based (radio-)metallopharmaceuticals in solution and from the solid phase using metal-mediated, autolytic amide bond cleavage (MMAAC). Our findings indicate that coordinative polarization of an amide bond by strong, trivalent Lewis acids such as Ga3+ and Sc3+ adjacent to serine results in the N, O acyl shift and hydrolysis of the corresponding ester without dissociation of the corresponding metal complex. Compound [68Ga]Ga-10, incorporating a cleavable and noncleavable functionalization, was used to demonstrate that only the amide bond-adjacent serine effectively triggered hydrolysis in solution and from the solid phase. The corresponding solid-phase released compound [68Ga]Ga-8 demonstrated superior in vivo performance in a mouse tumor model compared to [68Ga]Ga-8 produced using conventional, solution-phase radiolabeling. A second proof-of-concept system, [67Ga]Ga-17A (serine-linked) and [67Ga]Ga-17B (glycine-linked) binding to serum albumin via the incorporated ibuprofen moiety, was also synthesized. These constructs demonstrated that complete hydrolysis of the corresponding [68Ga]Ga-NOTA complex from [67Ga]Ga-17A can be achieved in naïve mice within 12 h, as traceable in urine and blood metabolites. The glycine-linked control [68Ga]Ga-17B remained intact. Conclusively, MMAAC provides an attractive tool for selective, thermal, and metal ion-mediated control of metallodrug activation compatible with biological conditions.

Bonding and Acidity of the Formal Hydride in the Prototypical Au9 (PPh3 )8 H2+ Nanocluster.

The role of hydrogen atoms as surface ligands on metal nanoclusters is of profound importance but remains difficult to directly study. While hydrogen atoms often appear to be incorporated formally as hydrides, evidence suggests that they donate electrons to the cluster's delocalized superatomic orbitals and may consequently behave as acidic protons that play key roles in synthetic or catalytic mechanisms. Here we directly test this assertion for the prototypical Au9 (PPh3 )8 H2+ nanocluster, formed by addition of a hydride to the well-characterized Au9 (PPh3 )8 3+ . Using gas-phase infrared spectroscopy, we were able to unambiguously isolate Au9 (PPh3 )8 H2+ and Au9 (PPh3 )8 D2+ , revealing an Au-H stretching mode at 1528 cm-1 that shifts to 1038 cm-1 upon deuteration. This shift is greater than the maximum expected for a typical harmonic potential, suggesting a potential governing cluster-H bonding that has some square-well character consistent with the hydrogen nucleus behaving as a metal atom in the cluster core. Complexing this cluster with very weak bases reveals a redshift of 37 cm-1 in the Au-H vibration, consistent with those typically seen for moderately acidic groups in gas phase molecules and providing an estimate of the acidity of Au9 (PPh3 )8 H2+ , at least with regard to its surface reactivity.

Excited-State Copper-Catalyzed [4 + 1] Annulation Reaction Enables Modular Synthesis of α,ß-Unsaturated-γ-Lactams.

Synthesis of α,ß-unsaturated-γ-lactams continue to attract attention due to the importance of this structural motif in organic chemistry. Herein, we report the development of a visible-light-induced excited-state copper-catalyzed [4 + 1] annulation reaction for the preparation of a wide range of γ-H, -OH, and -OR-substituted α,ß-unsaturated-γ-lactams using acrylamides as the 4-atom unit and aroyl chlorides as the 1-atom unit. This modular synthetic protocol features mild reaction conditions, broad substrate scope, and high functional group tolerance. The reaction is amenable to late-stage diversification of complex molecular architectures, including derivatives of marketed drugs. The products of the reaction can serve as versatile building blocks for further derivatization. Preliminary mechanistic studies suggest an inner-sphere catalytic cycle involving photoexcitation of the Cu(BINAP) catalyst, single-electron transfer, and capture of radical intermediates by copper species, followed by reductive elimination or protonation to give the desired γ-functionalized α,ß-unsaturated-γ-lactams.

Increased Attack Rates and Decreased Incubation Periods in Raccoons with Chronic Wasting Disease Passaged through Meadow Voles.

Chronic wasting disease (CWD) is a naturally-occurring neurodegenerative disease of cervids. Raccoons (Procyon lotor) and meadow voles (Microtus pennsylvanicus) have previously been shown to be susceptible to the CWD agent. To investigate the potential for transmission of the agent of CWD from white-tailed deer to voles and subsequently to raccoons, we intracranially inoculated raccoons with brain homogenate from a CWD-affected white-tailed deer (CWDWtd) or derivatives of this isolate after it had been passaged through voles 1 or 5 times. We found that passage of the CWDWtd isolate through voles led to a change in the biologic behavior of the CWD agent, including increased attack rates and decreased incubation periods in raccoons. A better understanding of the dynamics of cross-species transmission of CWD prions can provide insights into how these infectious proteins evolve in new hosts.

Impact of including second and later cancers in cause-specific survival estimates using population-based registry data.

BACKGROUND: Second or later primary cancers account for approximately 20% of incident cases in the United States. Currently, cause-specific survival (CSS) analyses exclude these cancers because the cause of death (COD) classification algorithm was available only for first cancers. The authors added rules for later cancers to the Surveillance, Epidemiology, and End Results cause-specific death classification algorithm and evaluated CSS to include individuals with prior tumors. METHODS: The authors constructed 2 cohorts: 1) the first ever primary cohort, including patients whose first cancer was diagnosed during 2000 through 2016) and 2) the earliest matching primary cohort, including patients with any cancer who matched the selection criteria irrespective of whether it was the first or a later cancer diagnosed during 2000 through 2016. The cohorts' CSS estimates were compared using follow-up through December 31, 2017. The new rules were used in the second cohort for patients whose first cancers during 2000 through 2016 were their second or later cancers. RESULTS: Overall, there were no statistically significant differences in CSS estimates between the 2 cohorts. Estimates were similar by age, stage, race, and time since diagnosis, except for patients with leukemia and those aged 65 to 74 years (3.4 percentage point absolute difference). CONCLUSIONS: The absolute difference in CSS estimates for the first cancer ever cohort versus earliest of any cancers cohort in the study period was small for most cancer types. As the number of newly diagnosed patients with prior cancers increases, the algorithm will make CSS more inclusive and enable estimating survival for a group of patients with cancer for whom life tables are not available or life tables are available but do not capture other-cause mortality appropriately.

Excited-State Copper Catalysis for the Synthesis of Heterocycles.

Heterocycles are one of the largest groups of organic moieties with significant medicinal, chemical, and industrial applications. Herein, we report the discovery and development of visible-light-induced, synergistic excited-state copper catalysis using a combination of Cu(IPr)I as a catalyst and rac-BINAP as a ligand, which produces more than 10 distinct classes of heterocycles. The reaction tolerates a broad array of functional groups and complex molecular scaffolds, including derivatives of peptides, natural products, and marketed drugs. Preliminary mechanistic investigation suggests in situ generations of [Cu(BINAP)2 ]+ and [Cu(IPr)2 ]+ catalysts that work cooperatively under visible-light irradiation to facilitate catalytic carbo-aroylation of unactivated alkenes, affording a wide range of useful heterocycles.

Effector gene expression underlying neuron subtype-specific traits in the Motor Ganglion of Ciona.

The central nervous system of the Ciona larva contains only 177 neurons. The precise regulation of neuron subtype-specific morphogenesis and differentiation observed during the formation of this minimal connectome offers a unique opportunity to dissect gene regulatory networks underlying chordate neurodevelopment. Here we compare the transcriptomes of two very distinct neuron types in the hindbrain/spinal cord homolog of Ciona, the Motor Ganglion (MG): the Descending decussating neuron (ddN, proposed homolog of Mauthner Cells in vertebrates) and the MG Interneuron 2 (MGIN2). Both types are invariantly represented by a single bilaterally symmetric left/right pair of cells in every larva. Supernumerary ddNs and MGIN2s were generated in synchronized embryos and isolated by fluorescence-activated cell sorting for transcriptome profiling. Differential gene expression analysis revealed ddN- and MGIN2-specific enrichment of a wide range of genes, including many encoding potential "effectors" of subtype-specific morphological and functional traits. More specifically, we identified the upregulation of centrosome-associated, microtubule-stabilizing/bundling proteins and extracellular guidance cues part of a single intrinsic regulatory program that might underlie the unique polarization of the ddNs, the only descending MG neurons that cross the midline. Consistent with our predictions, CRISPR/Cas9-mediated, tissue-specific elimination of two such candidate effectors, Efcab6-related and Netrin1, impaired ddN polarized axon outgrowth across the midline.

Time from breast cancer diagnosis to treatment among Idaho's National Breast and Cervical Cancer Early Detection Program population, 2011-2017.

PURPOSE: Idaho's Women's Health Check (WHC) Program provides breast and cervical cancer screening to under- and uninsured women via funding from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Because WHC serves populations with less access to health care, this study evaluated time from breast cancer diagnosis to treatment for women enrolled in the WHC program and linked to Cancer Data Registry of Idaho (CDRI) case data (WHC-linked) and the remainder of female Idaho resident breast cases. METHODS: Among Idaho residents aged 50-64 years diagnosed during 2011-2017 with ductal carcinoma in situ or invasive breast cancer, we assessed differences in the median time from definitive diagnosis to treatment initiation overall and by demographic and tumor characteristics, and differences in the distribution of demographic and tumor-related variables between 231 WHC-linked and 3,040 non-linked breast cancer cases. RESULTS: WHC-linked cases were significantly less likely to be non-Hispanic white, and more likely to live in poorer census tracts, be diagnosed at a later stage, and be treated with mastectomy. Most WHC-linked (92%) and non-linked women (94%) began treatment within 60 days of diagnosis; no differences in time to treatment were observed. CONCLUSION: Disparities in the interval from definitive diagnosis to breast cancer treatment initiation were not observed for women enrolled in the WHC program relative to other Idaho women.

Homologous Structural, Chemical, and Biological Behavior of Sc and Lu Complexes of the Picaga Bifunctional Chelator: Toward Development of Matched Theranostic Pairs for Radiopharmaceutical Applications.

The radioactive isotopes scandium-44/47 and lutetium-177 are gaining relevance for radioimaging and radiotherapy, resulting in a surge of studies on their coordination chemistry and subsequent applications. Although the trivalent ions of these elements are considered close homologues, dissimilar chemical behavior is observed when they are complexed by large ligand architectures due to discrepancies between Lu(III) and Sc(III) ions with respect to size, chemical hardness, and Lewis acidity. Here, we demonstrate that Lu and Sc complexes of 1,4-bis(methoxycarbonyl)-7-[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane (H3mpatcn) and its corresponding bioconjugate picaga-DUPA can be employed to promote analogous structural features and, subsequently, biological properties for coordination complexes of these ions. The close homology was evidenced using potentiometric methods, computational modeling, variable temperature mass spectrometry, and pair distribution function analysis of X-ray scattering data. Radiochemical labeling, in vitro stability, and biodistribution studies with Sc-47 and Lu-177 indicate that the 7-coordinate ligand environment of the bifunctional picaga ligand is compatible with biological applications and the future investigation of ß-emitting, picaga-chelated Sc and Lu isotopes for radiotherapy.

Hydration motifs of ammonium bisulfate clusters show complex temperature dependence.

The role of water in the formation of particles from atmospheric trace gases is not well understood, in large part due to difficulties in detecting its presence under atmospheric conditions and the variety of possible structures that must be screened computationally. Here, we use infrared spectroscopy and variable-temperature ion trap mass spectrometry to investigate the structural motifs adopted by water bound to ammonium bisulfate clusters and their temperature dependence. For clusters featuring only acid-base linkages, water adopts a bridging arrangement spanning an adjacent ammonium and bisulfate. For larger clusters, water can also insert into a bisulfate-bisulfate hydrogen bond, yielding hydration isomers with very similar binding energies. The population of these isomers shows a complex temperature evolution, as an apparent third isomer appears with a temperature dependence that is difficult to explain using simple thermodynamic arguments. These observations suggest that the thermodynamics of water binding to atmospheric clusters such as these may not be straightforward.

Toward quantitative electronic structure in small gold nanoclusters.

Ligand-protected gold nanoclusters (AuNCs) feature a dense but finite electronic structure that can be rationalized using qualitative descriptions such as the well-known superatomic model and predicted using quantum chemical calculations. However, the lack of well-resolved experimental probes of a AuNC electronic structure has made the task of evaluating the accuracy of electronic structure descriptions challenging. We compare electronic absorption spectra computed using time-dependent density functional theory to recently collected high resolution experimental spectra of Au9(PPh3)8 3+ and Au8(PPh3)7 2+ AuNCs with strikingly similar features. After applying a simple scaling correction, the computed spectrum of Au8(PPh3)7 2+ yields a suitable match, allowing us to assign low-energy metal-metal transitions in the experimental spectrum. No similar match is obtained after following the same procedure for two previously reported isomers for Au9(PPh3)8 3+, suggesting either a deficiency in the calculations or the presence of an additional isomer. Instead, we propose assignments for Au9(PPh3)8 3+ based off of similarities Au8(PPh3)7 2+. We further model these clusters using a simple particle-in-a-box analysis for an asymmetrical ellipsoidal superatomic core, which allows us to reproduce the same transitions and extract an effective core size and shape that agrees well with that expected from crystal structures. This suggests that the superatomic model, which is typically employed to explain the qualitative features of nanocluster electronic structures, remains valid even for small AuNCs with highly aspherical cores.

High Precision Electronic Spectroscopy of Ligand-Protected Gold Nanoclusters: Effects of Composition, Environment, and Ligand Chemistry.

Atomically precise gold nanoclusters (AuNCs) are a class of nanomaterials valued for their electronic properties and diverse structural features. While the advent of X-ray crystallography of AuNCs has revealed their geometric structures with high precision, detailed electronic structure analysis is challenged by environmental, compositional, and thermal averaging effects present in electronic spectra of typical samples. To circumvent these challenges, we have adapted mass spectrometer-based electronic absorption spectroscopy techniques to acquire high-resolution electronic spectra of atomically precisely defined nanoclusters separated from a synthetic mixture. Here we discuss recent results using this approach to link the surface chemistry of triphenylphosphine-protected AuNCs to their electronic structure and expand on key elements of the experiment and the link between these gas-phase measurements and solution-phase behavior of AuNCs. Chemically derivatized Au8(P(p-X-Ph)3)72+ and Au9(P(p-X-Ph)3)83+ clusters, where X = -H, -CH3, or -OCH3, are used to derive systematic trends in the response of the electronic spectrum to the electron-donating character of the ligand shell. We find a linear relationship between the substituent Hammett parameter σp and the transition energy between both sets of clusters' highest occupied and lowest unoccupied molecular orbitals, a transition that is localized in the metal core within the limits of the superatomic model. The similarity of the mass-selective and solution-phase UV/vis spectra of Au9(PPh3)83+ indicates that the interpretation of these experiments is transferable to the condensed phase. He and N2 environments are introduced to a series of isovalent clusters as a subtle probe of discrete environmental effects over electronic structure. Strikingly, select bands in the UV/vis spectrum respond strongly to the identity of the environment, which we interpret as a state-selective indicator of interfacially relevant electronic transitions. Physically predictable trends such as these will aid in building molecular design principles necessary for the development of novel materials based on nanoclusters.

Establishing the structural motifs present in small ammonium and aminium bisulfate clusters of relevance to atmospheric new particle formation.

Atmospheric new particle formation is the process by which atmospheric trace gases, typically acids and bases, cluster and grow into potentially climatically relevant particles. Here, we evaluate the structures and structural motifs present in small cationic ammonium and aminium bisulfate clusters that have been studied both experimentally and computationally as seeds for new particles. For several previously studied clusters, multiple different minimum-energy structures have been predicted. Vibrational spectra of mass-selected clusters and quantum chemical calculations allow us to assign the minimum-energy structure for the smallest cationic cluster of two ammonium ions and one bisulfate ion to a CS-symmetry structure that is persistent under amine substitution. We derive phenomenological vibrational frequency scaling factors for key bisulfate vibrations to aid in the comparison of experimental and computed spectra of larger clusters. Finally, we identify a previously unassigned spectral marker for intermolecular bisulfate-bisulfate hydrogen bonds and show that it is present in a class of structures that are all lower in energy than any previously reported structure. Tracking this marker suggests that this motif is prominent in larger clusters as well as ∼180 nm ammonium bisulfate particles. Taken together, these results establish a set of structural motifs responsible for binding of gases at the surface of growing clusters that fully explain the spectrum of large particles and provide benchmarks for efforts to improve structure predictions, which are critical for the accurate theoretical treatment of this process.

General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry.

The formation of ternary aqua complexes of metal-based diagnostics and therapeutics is closely correlated to their in vivo efficacy but approaches to quantify the presence of coordinated water ligands are limited. We introduce a general and high-throughput method for characterizing the hydration state of para- and diamagnetic coordination complexes in the gas phase based on variable-temperature ion trap tandem mass spectrometry. Ternary aqua complexes are directly observed in the mass spectrum and quantified as a function of ion trap temperature. We recover expected periodic trends for hydration across the lanthanides and distinguish complexes with several inner-sphere water ligands by inspection of temperature-dependent speciation curves. We derive gas-phase thermodynamic parameters for discernible inner- and second-sphere hydration events, and discuss their application to predict solution-phase behavior. The differences in temperature at which water binds in the inner and outer spheres arise primarily from entropic effects. The broad applicability of this method allows us to estimate the hydration states of Ga, Sc, and Zr complexes under active preclinical and clinical study with as-yet undetermined hydration number. Variable-temperature mass spectrometry emerges as a general tool to characterize and quantitate trends in inner-sphere hydration across the periodic table.

Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: 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.