Incorporation of Sb5+ into CeO2 : local structural distortion of the fluorite structure from a pentavalent substituent

Hydrothermal crystallisation of CeO2 from aqueous sodium hydroxide solution at 240oC using CeCl3·7H2O in the presence of hydrogen peroxide with addition of either SbCl3 or SbCl5 yields polycrystalline samples of antimony-containing ceria directly from solution. Powder X-ray diffraction shows a contraction of the cubic lattice parameter with increasing Sb content, and also a broadening of Bragg peaks, from which Scherrer analysis yields crystallite domain sizes of 5 - 20 nm. Scanning transmission electron microscopy provides consistent results with observation of highly crystalline particles of a few nm in diameter. X-ray absorption near edge structure spectroscopy at the Ce LIII and Sb K edges reveals the presence of Ce4+ and Sb5+ in the solids. To balance charge the presence of co-included Na is proposed, corroborated by elemental analysis. The general chemical formula of the materials can thus be written as (Ce1 xSbx)1 yNayO2-δ (where x < 0.4 and y ≥ x/3). Sb K-edge extended X-ray absorption fine structure spectroscopy of the substituted ceria samples shows that the local structure of Sb resembles that in NaSbO3, where six-coordinate metal sites are found, but with evidence of a longer interatomic correlation due to surrounding Ce/Sb atoms in the fluorite structure; this implies that the Sb is displaced from the ideal eight-coordinate site of the fluorite structure. This structural distortion gives materials that are unstable under reducing conditions, coupled by the ease of reduction to elemental antimony, which is extruded leading to phase separation

Incorporation of square-planar Pd2+ in fluorite CeO2 : hydrothermal preparation, local structure, redox properties and stability

The direct hydrothermal crystallisation at 240 °C of Pd2+-containing ceria is investigated to study the extent to which precious metal dopants may be introduced into the cubic fluorite lattice. Samples of composition Ce1−xPdxO2−δ, where 0 ≤ x ≤ 0.15 can be produced in which Pd is included within the CeO2 structure to give a linear lattice expansion. Attempts to produce higher Pd2+-substitution result in the formation of PdO as a secondary phase. Ce and Pd were determined to be in the +4 and +2 oxidation states, respectively, by X-ray absorption near edge structure, suggesting oxide deficiency as the mechanism of charge balance. Extended X-ray absorption fine structure (EXAFS) analysis at the Pd K-edge reveals that Pd2+ has local square-planar coordination, as expected, and that a structural model can fitted in which the average fluorite structure is maintained, but with Pd2+ sitting in the square faces of oxide ions present in the local cubic geometry of Ce. This model, consistent with previous modelling studies, gives an excellent fit to the EXAFS spectra, and explains the observed lattice expansion. Transmission electron microscopy analysis shows that Pd is well dispersed in the nanocrystalline ceria particles, and in situ powder XRD shows that upon heating in air the samples remain stable up to 800 °C. H2-TPR shows that Pd-substitution leads to low temperature (<200 °C) reduction of the oxide, which increases in magnitude with increasing Pd-substitution. On prolonged heating, however, the Pd is lost from the ceria lattice to give dispersed Pd metal, suggesting an inherent instability of Pd-doped CeO2

Ba4Ru3O10.2(OH)1.8 : a new member of the layered hexagonal perovskite family crystallised from water

A new barium ruthenium oxyhydroxide Ba4Ru3O10.2(OH)1.8 crystallises under hydrothermal conditions at 200 °C: powder neutron diffraction data show it adopts an 8H hexagonal perovskite structure with a new stacking sequence, while high resolution electron microscopy reveals regions of ordered layers of vacant Ru sites, and magnetometry shows antiferromagnetism with TN = 200(5) K

Detection and Crystal Structure of Hydrogenated Bipentacene as an Intermediate in Thermally Induced Pentacene Oligomerization

6,6′,13,13′- tetrahydro-6,6′-bipentacene (HBP), the first intermediate molecule between pentacene and peripentacene and extended pentacene oligomers, is synthesised and crystallographically characterised for the first time. Heating pentacene to 300 ºC under vacuum for 200 hours results in pale golden crystals of HBP and amorphous material containing pentacene oligomers, and is the first experimental evidence that pentacene preferentially dimerises at the 6,6′- position. Continued heating of HBP results in co-crystals of 6,13-dihydrogenated pentacene (HP) and pentacene and further amorphous pentacene oligomers. The amorphous material consists of layered carbonaceous species with a graphenic nature, as determined by Raman spectroscopy and electron microscopy, and shows the importance of HBP as an intermediate to hydrogenated pentacene species and pentacene oligomers. The synthesis of HBP from pentacene could be useful as a starting material in the rational synthesis of peripentacene towards organic electronic devices

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

New oxides for catalysis from hydrothermal synthesis

In this thesis the one-pot subcritical hydrothermal synthesis of several novel complex oxides with potential applications in catalysis is reported. The hydrothermal synthesis of nanocrystalline pentavalent ion-substituted cerium dioxide is reported. The materials were all characterised by powder diffraction and a range of spectroscopic techniques in order to elucidate their structures. Up to approximately 30% pentavalent ion-substitution the mixed metal oxides continue to adopt the fluorite unit cell, and the lattice parameter decreases as substitution increases. The choice of mineraliser in the hydrothermal reaction was found to affect the composition and structure of the oxide: when prepared in NaOH, Na is incorporated into the structure as well as the pentavalent ion, and the combination of these allows charge balance to be achieved without the need for Ce reduction or the incorporation of interstitial oxygen. The inclusion of Na greatly improves both the measured oxygen storage capacity and the stability of the fluorite phases, as measured by in situ powder X-ray diffraction. Precious metals Pt and Pd have also been successfully incorporated into the fluorite ceria structure by hydrothermal synthesis, with up to 20 – 25% precious metal substitution. A study of both the average structure and local environment of the precious metals leads to the conclusion that neither precious metal sits on the same crystallographic site as the Ce. Pd adopts a square-planar geometry by shifting ¼ of a unit cell in one direction, to sit in an oxide plane, and thereby expanding the unit cell. The Pt exists a distorted octahedral environment. These oxides were found to be inherently unstable, with precious metal extruded from the fluorite under even mildly reducing conditions. The hydrothermal reaction of KRuO4 with AO2 (A = Ca, Sr, Ba) peroxides at 200 °C yields a range of previously unreported ruthenium oxides. Ca1.5Ru2O7, an A-site deficient pyrochlore containing a mixed Ru(V/VI) B-site. SrRu2O6 adopts the PbSb2O6 structure and contains antiferromagnetically ordered Ru(V) moments. In situ powder neutron diffraction shows that this ordering persists up to 563 K, an extraordinarily high temperature. Ba2Ru3O9(OH) is an example of a new structure type, which is made up of puckered layers of quasi-trimeric edge-sharing Ru(V)O6 octahedra which are corner-linked together with layers of Ba atoms separating them. Ba4Ru3O12 is an 8H hexagonal perovskite with a previously unreported stacking order, containing Ru with an average oxidation state of +5.33. Structural refinements and magnetometry of all new materials are presented

Pair distribution function analysis of structural disorder by Nb5+ inclusion in Ceria : evidence for enhanced oxygen storage capacity from under-coordinated oxide

Partial substitution of Ce4+ by Nb5+ is possible in CeO2 by coinclusion of Na+ to balance the charge, via hydrothermal synthesis in sodium hydroxide solution. Pair distribution function analysis using reverse Monte Carlo refinement reveals that the small pentavalent substituent resides in irregular coordination positions in an average fluorite lattice, displaced away from the ideal cubic coordination toward four oxygens. This results in under-coordinated oxygen, which explains significantly enhanced oxygen storage capacity of the materials of relevance to redox catalysis used in energy and environmental applications