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Examples of extrachromosomal circular DNAs (eccDNAs) are found in many organisms, but their impact on genetic variation at the genome scale has not been investigated. We mapped 1,756 eccDNAs in the Saccharomyces cerevisiae genome using Circle-Seq, a highly sensitive eccDNA purification method. Yeast eccDNAs ranged from an arbitrary lower limit of 1 kb up to 38 kb and covered 23% of the genome, representing thousands of genes. EccDNA arose both from genomic regions with repetitive sequences ≥15 bases long and from regions with short or no repetitive sequences. Some eccDNAs were identified in several yeast populations. These eccDNAs contained ribosomal genes, transposon remnants, and tandemly repeated genes ( HXT6/7 , ENA1/2/5 , and CUP1-1/-2 ) that were generally enriched on eccDNAs. EccDNAs seemed to be replicated and 80% contained consensus sequences for autonomous replication origins that could explain their maintenance. Our data suggest that eccDNAs are common in S. cerevisiae , where they might contribute substantially to genetic variation and evolution. Significance We performed a screen for extrachromosomal circular DNAs containing segments of genomic yeast DNA. We found 1,756 such extrachromosomal circular DNAs containing about 23% of the total yeast genomic information. The abundance of these circular forms of genomic DNA suggests that eccDNA formation might be a common mutation that can arise in any part of the genome, and not in only a few special loci. We propose that eccDNAs may be precursors to the copy number variation in eukaryotic genomes characteristic of both the evolutionary process and cancer progression.

The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing. Cancer cells carry different types of mutations that are associated with the cell starting to multiply uncontrollably. Certain changes only affect one or a few letters of the genetic code. Others, known as copy number alterations, or CNA, involve larger portions of the genome that can either be lost (deletions) or duplicated (amplifications). Tumors in different patients carry variable amounts of these deletions or amplifications, which together are known as the CNA burden. New technologies allow scientists to scan the genomes of tumors and examine the type of mutations present in each patient. The results can help to decide on the best course of action. For example, in prostate cancer, patients whose tumors have a high CNA burden are at greater risk of relapse after treatment. However, it has been unclear whether these people also have lower survival rates, and if CNA burden can predict outcome of other types of cancers. Hieronymus et al. conducted genetic analyses on over a hundred samples from prostate cancer patients who were not treated with surgery or radiation. The results showed that a higher CNA burden in the tumors is correlated with more deaths due to the disease. The findings in prostate cancer were also true across different types of cancers. These conclusions also emerged when Hieronymus et al. then looked at genomic data obtained from patients with various cancers using a different DNA sequencing test, which is certified for clinical use. This demonstrates that CNA burden could be a useful marker in clinical settings to help assess risk in cancer patients.

Background The study objectives were to assess the prognostic value of quantitative PET and to test whether combining baseline metabolic tumour burden with early PET response could improve predictive power in DLBCL. Methods A total of 147 patients with DLBCL underwent FDG-PET/CT scans before and after two cycles of RCHOP. Quantitative parameters including metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were measured, as well as the percentage change in these parameters. Cox regression analysis was used to test the relationship between progression-free survival (PFS) and the study variables. Receiver operator characteristics (ROC) analysis determined the optimal cut-off for quantitative variables, and Kaplan–Meier survival analysis was performed. Results The median follow-up was 3.8 years. As MTV and TLG measures correlated strongly, only MTV measures were used for multivariate analysis (MVA). Baseline MTV (MTV-0) was the only statistically significant predictor of PFS on MVA. The optimal cut-off for MTV-0 was 396 cm 3 . A model combing MTV-0 and Deauville score (DS) separated the population into three distinct prognostic groups: good (MTV-0 < 400; 5-year PFS > 90 %), intermediate (MTV-0 ≥ 400+ DS1-3; 5-year PFS 58.5 %) and poor (MTV-0 ≥ 400+ DS4-5; 5-year PFS 29.7 %) Conclusions MTV-0 is an important prognostic factor in DLBCL. Combining MTV-0 and early PET/CT response improves the predictive power of interim PET and defines a poor-prognosis group in whom most of the events occur.

Livestock manure is a major source of the greenhouse gases (GHGs) methane (CH4) and nitrous oxide (N2O). The emissions can be mitigated by production of biogas through anaerobic digestion (AD) of manure, mostly together with other biowastes, which can substitute fossil energy and thereby reduce CO2 emissions and postdigestion GHG emissions. This paper presents GHG balances for manure and biowaste management as affected by AD for five Danish biogas scenarios in which pig and cattle slurry were codigested with one or more of the following biomasses: deep litter, straw, energy crops, slaughterhouse waste, grass–clover green manure, and household waste. The calculated effects of AD on the GHG balance of each scenario included fossil fuel substitution, energy use for transport, leakage of CH4 from biogas production plants, CH4 emissions during storage of animal manure and biowaste, N2O emissions from stored and field applied biomass, N2O emissions related to nitrate (NO3−) leaching and ammonia (NH3) losses, N2O emissions from cultivation of energy crops, and soil C sequestration. All scenarios caused significant reductions in GHG emissions. Most of the reductions resulted from fossil fuel substitution and reduced emissions of CH4 during storage of codigestates. The total reductions in GHG emissions ranged from 65 to 105 kg CO2-eq ton−1 biomass. This wide range showed the importance of biomass composition. Reductions were highest when straw and grass–clover were used as codigestates, whereas reductions per unit energy produced were highest when deep litter or deep litter plus energy crops were used. Potential effects of iLUC were ignored but may have a negative impact on the GHG balance when using energy crops, and this may potentially exceed the calculated positive climate impacts of biogas production. The ammonia emission potential of digestate applied in the field is higher than that from cattle slurry and pig slurry because of the higher pH of the digestate. This effect, and the higher content of TAN in digestate, resulted in increasing ammonia emissions at 0.14 to 0.3 kg NH3-N ton−1 biomass. Nitrate leaching was reduced in all scenarios and ranged from 0.04 to 0.45 kg NO3-N ton−1 biomass. In the scenario in which maize silage was introduced, the maize production increased leaching and almost negated the effect of AD. Methane leakage caused a 7% reduction in the positive climate impact for each percentage point of leakage in a manure-based biogas scenario.

Anaerobic digestion is a common method for managing liquid manure and other biomasses, generating biogas as a renewable energy source. The resulting digestate can be processed into organic fertilizers to enhance nutrient recycling, but its environmental impact warrants investigation. In this study, a life cycle assessment was conducted to examine the impact of fertilizers derived from cattle slurry and grass–clover co-digestion on global warming (measured in CO2 equivalents) compared to untreated cattle slurry (CA). The different treatments analyzed include CA, digestate, liquid fractions (LFs) from digestate separation, and an enriched liquid nitrogen–sulfur product derived from post-processing of biogas and drying of the solid fraction. The functional units of this study were 100 kg of total nitrogen in the final organic fertilizer (FU1) with the cradle-to-processing gate boundary, and the harvesting of 1 ton of spring barley dry matter (FU2) with the cradle-to-field application boundary. The carbon footprint ranged from 24% to 49% of the baseline scenario for FU1, and from −6% to 177% of the baseline scenario for FU2. The main contributors to the carbon footprint of fertilizers included greenhouse gas emissions from storage and field application. However, biogas production from anaerobic digestion, together with the concurrent mitigation of CH4 emissions during storage, contributed most to a reduction in the overall global warming potential associated with anaerobic digestate and its LF. This study showed large climate prospects in replacing untreated slurry as organic fertilizer with alternatives resulting from its anaerobic digestion and post-treatment.

Worldwide, most colorectal cancer screening programmes were paused at the start of the COVID-19 pandemic, while the Danish faecal immunochemical test (FIT)-based programme continued without pausing. We examined colorectal cancer screening participation and compliance with subsequent colonoscopy in Denmark throughout the pandemic. We used data from the Danish Colorectal Cancer Screening Database among individuals aged 50-74 years old invited to participate in colorectal cancer screening from 2018 to 2021 combined with population-wide registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) of colorectal cancer screening participation within 90 days since invitation and compliance with colonoscopy within 60 days since a positive FIT test during the pandemic in comparison with the previous years adjusting for age, month and year of invitation. Altogether, 3,133,947 invitations were sent out to 1,928,725 individuals and there were 94,373 positive FIT tests (in 92,848 individuals) during the study period. Before the pandemic, 60.7% participated in screening within 90 days. A minor reduction in participation was observed at the start of the pandemic (PR = 0.95; 95% CI: 0.94-0.96 in pre-lockdown and PR = 0.85; 95% CI: 0.85-0.86 in first lockdown) corresponding to a participation rate of 54.9% during pre-lockdown and 53.0% during first lockdown. This was followed by a 5-10% increased participation in screening corresponding to a participation rate of up to 64.9%. The largest increase in participation was observed among 55-59 years old and among immigrants. The compliance with colonoscopy within 60 days was 89.9% before the pandemic. A slight reduction was observed during first lockdown (PR = 0.96; 95% CI: 0.93-0.98), where after it resumed to normal levels. Participation in the Danish FIT-based colorectal cancer screening programme and subsequent compliance to colonoscopy after a positive FIT result was only slightly affected by the COVID-19 pandemic. The study was funded by the Danish Cancer Society Scientific Committee (Grant number R321-A17417) and the Danish regions.

In contrast to most of the world, the cervical cancer screening programme continued in Denmark throughout the COVID-19 pandemic. We examined the cervical cancer screening participation during the pandemic in Denmark. We included all women aged 23-64 y old invited to participate in cervical cancer screening from 2015 to 2021 as registered in the Cervical Cancer Screening Database combined with population-wide registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% CIs of cervical cancer screening participation within 90, 180, and 365 d since invitation during the pandemic in comparison with the previous years adjusting for age, year, and month of invitation. Altogether, 2,220,000 invited women (in 1,466,353 individuals) were included in the study. Before the pandemic, 36% of invited women participated in screening within 90 d, 54% participated within 180 d, and 65% participated within 365 d. At the start of the pandemic, participation in cervical cancer screening within 90 d was lower (pre-lockdown PR = 0.58; 95% CI: 0.56-0.59 and first lockdown PR = 0.76; 95% CI: 0.75-0.77) compared with the previous years. A reduction in participation within 180 d was also seen during pre-lockdown (PR = 0.89; 95% CI: 0.88-0.90) and first lockdown (PR = 0.92; 95% CI: 0.91-0.93). Allowing for 365 d to participation, only a slight reduction (3%) in participation was seen with slightly lower participation in some groups (immigrants, low education, and low income). The overall participation in cervical cancer screening was reduced during the early phase of the pandemic. However, the decline almost diminished with longer follow-up time. The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.

Objective This study assessed the associations between hospital volume, resection rate and survival of oesophageal and gastric cancer patients in England. Design 62 811 patients diagnosed with oesophageal or gastric cancer between 2004 and 2008 were identified from a national population-based cancer registration and Hospital Episode Statistics-linked dataset. Cox regression analyses were used to assess all-cause mortality according to hospital volume and resection rate, adjusting for case-mix variables (sex, age, socioeconomic deprivation, comorbidity and type of cancer). HRs and 95% CIs, according to hospital volume, were evaluated for three predefined periods following surgery: <30, 30–365, and >365 days. Analysis of mortality in relation to resection rate was performed among all patients and among the 13 189 (21%) resected patients. Results Increasing hospital volume was associated with lower mortality (ptrend=0.0001; HR 0.87, 95% CI 0.79 to 0.95 for hospitals resecting 80+ and compared with <20 patients a year). In relative terms, the association between increasing hospital volume and lower mortality was particularly strong in the first 30 days following surgery (ptrend<0.0001; HR 0.52, (0.39 to 0.70)), but a clinically relevant association remained beyond 1 year (ptrend=0.0011; HR 0.82, (0.72 to 0.95)). Increasing resection rates were associated with lower mortality among all patients (ptrend<0.0001; HR 0.86, (0.84 to 0.89) for the highest, compared with the lowest resection quintile). Conclusions With evidence of lower short-term and longer-term mortality for patients resected in high-volume hospitals, this study supports further centralisation of oesophageal and gastric cancer surgical services in England.

Background: Gleason scoring (GS) has major deficiencies and a novel system of five grade groups (GS⩽6; 3+4; 4+3; 8; ⩾9) has been recently agreed and included in the WHO 2016 classification. Although verified in radical prostatectomies using PSA relapse for outcome, it has not been validated using prostate cancer death as an outcome in biopsy series. There is debate whether an ‘overall’ or ‘worst’ GS in biopsies series should be used. Methods: Nine hundred and eighty-eight prostate cancer biopsy cases were identified between 1990 and 2003, and treated conservatively. Diagnosis and grade was assigned to each core as well as an overall grade. Follow-up for prostate cancer death was until 31 December 2012. A log-rank test assessed univariable differences between the five grade groups based on overall and worst grade seen, and using univariable and multivariable Cox proportional hazards. Regression was used to quantify differences in outcome. Results: Using both ‘worst’ and ‘overall’ GS yielded highly significant results on univariate and multivariate analysis with overall GS slightly but insignificantly outperforming worst GS. There was a strong correlation with the five grade groups and prostate cancer death. Conclusions: This is the largest conservatively treated prostate cancer cohort with long-term follow-up and contemporary assessment of grade. It validates the formation of five grade groups and suggests that the ‘worst’ grade is a valid prognostic measure.

Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer. We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort. After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1·89; 95% CI 1·54–2·31; p=5·6×10 −9) and the best multivariate analysis (1·77, 1·40–2·22; p=4·3×10 −6). In the best predictive model (final multivariate analysis), the CCP score and prostate-specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2·92, 2·38–3·57, p=6·1×10 −22) and the final multivariate analysis (2·57, 1·93–3·43; p=8·2×10 −11), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables. The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer. Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation.