A risk assessment-driven quantitative comparison of gene expression profiles in PBMCs and white adipose tissue of humans and rats after isoflavone supplementation

Quantitative insight into species differences in risk assessment is expected to reduce uncertainty and variability related to extrapolation from animals to humans. This paper explores quantification and comparison of gene expression data between tissues and species from intervention studies with isoflavones. Gene expression data from peripheral blood mononuclear cells (PBMCs) and white adipose tissue (WAT) after 8wk isoflavone interventions in postmenopausal women and ovariectomized F344 rats were used. A multivariate model was applied to quantify gene expression effects, which showed 3–5-fold larger effect sizes in rats compared to humans. For estrogen responsive genes, a 5-fold greater effect size was found in rats than in humans. For these genes, intertissue correlations (r = 0.23 in humans, r = 0.22 in rats) and interspecies correlation in WAT (r = 0.31) were statistically significant. Effect sizes, intertissue and interspecies correlations for some groups of genes within energy metabolism, inflammation and cell cycle processes were significant, but weak. Quantification of gene expression data reveals differences between rats and women in effect magnitude after isoflavone supplementation. For risk assessment, quantification of gene expression data and subsequent calculation of intertissue and interspecies correlations within biological pathways will further strengthen knowledge on comparability between tissues and species

Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background Rheumatoid arthritis is a chronic autoimmune inflammatory disease associated with disability and premature death. Up-to-date estimates of the burden of rheumatoid arthritis are required for health-care planning, resource allocation, and prevention. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, we provide updated estimates of the prevalence of rheumatoid arthritis and its associated deaths and disability-adjusted life-years (DALYs) by age, sex, year, and location, with forecasted prevalence to 2050. Methods Rheumatoid arthritis prevalence was estimated in 204 countries and territories from 1990 to 2020 using Bayesian meta-regression models and data from population-based studies and medical claims data (98 prevalence and 25 incidence studies). Mortality was estimated from vital registration data with the Cause of Death Ensemble model (CODEm). Years of life lost (YLL) were calculated with use of standard GBD lifetables, and years lived with disability (YLDs) were estimated from prevalence, a meta-analysed distribution of rheumatoid arthritis severity, and disability weights. DALYs were calculated by summing YLLs and YLDs. Smoking was the only risk factor analysed. Rheumatoid arthritis prevalence was forecast to 2050 by logistic regression with Socio-Demographic Index as a predictor, then multiplying by projected population estimates. Findings In 2020, an estimated 17·6 million (95% uncertainty interval 15·8–20·3) people had rheumatoid arthritis worldwide. The age-standardised global prevalence rate was 208·8 cases (186·8–241·1) per 100 000 population, representing a 14·1% (12·7–15·4) increase since 1990. Prevalence was higher in females (age-standardised female-to-male prevalence ratio 2·45 [2·40–2·47]). The age-standardised death rate was 0·47 (0·41–0·54) per 100 000 population (38 300 global deaths [33 500–44 000]), a 23·8% (17·5–29·3) decrease from 1990 to 2020. The 2020 DALY count was 3 060 000 (2 320 000–3 860 000), with an age-standardised DALY rate of 36·4 (27·6–45·9) per 100 000 population. YLDs accounted for 76·4% (68·3–81·0) of DALYs. Smoking risk attribution for rheumatoid arthritis DALYs was 7·1% (3·6–10·3). We forecast that 31·7 million (25·8–39·0) individuals will be living with rheumatoid arthritis worldwide by 2050. Interpretation Rheumatoid arthritis mortality has decreased globally over the past three decades. Global age-standardised prevalence rate and YLDs have increased over the same period, and the number of cases is projected to continue to increase to the year 2050. Improved access to early diagnosis and treatment of rheumatoid arthritis globally is required to reduce the future burden of the disease.publishedVersio

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei‐like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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