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Abstract Earthworms are known to stimulate soil greenhouse gas (GHG) emissions, but the majority of previous studies have used simplified model systems or lacked continuous high-frequency measurements. To address this, we conducted a 2-year study using large lysimeters (5 m2 area and 1.5 m soil depth) in an ecotron facility, continuously measuring ecosystem-level CO2, N2O, and H2O fluxes. We investigated the impact of endogeic and anecic earthworms on GHG emissions and ecosystem water use efficiency (WUE) in a simulated agricultural setting. Although we observed transient stimulations of carbon fluxes in the presence of earthworms, cumulative fluxes over the study indicated no significant increase in CO2 emissions. Endogeic earthworms reduced N2O emissions during the wheat culture (− 44.6%), but this effect was not sustained throughout the experiment. No consistent effects on ecosystem evapotranspiration or WUE were found. Our study suggests that earthworms do not significantly contribute to GHG emissions over a two-year period in experimental conditions that mimic an agricultural setting. These findings highlight the need for realistic experiments and continuous GHG measurements.

Background: Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) with a single-gene sensitive assay has never been tested in a case-control setting. Methods: We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology. Findings: In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6–93·2), and five controls (Specificity 94·7%; 95%CI 88·0–98·3), with 98·6% (95% CI 92·5–99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P

Background: Detecting pre-clinical bladder cancer (BC) using urinary biomarkers may provide a valuable opportunity for screening and management. Telomerase reverse transcriptase (TERT) promoter mutations detectable in urine have emerged as promising BC biomarkers. Methods: We performed a nested case-control study within the population-based prospective Golestan Cohort Study (50,045 participants, followed up to 14 years) and assessed TERT promoter mutations in baseline urine samples from 38 asymptomatic individuals who subsequently developed primary BC and 152 matched controls using a Next-Generation Sequencing-based single-plex assay (UroMuTERT) and droplet digital PCR assays. Findings: Results were obtained for 30 cases and 101 controls. TERT promoter mutations were detected in 14 pre-clinical cases (sensitivity 46·67%) and none of the controls (specificity 100·00%). At an estimated BC cumulative incidence of 0·09% in the cohort, the positive and negative predictive values were 100·00% and 99·95% respectively. The mutant allelic fractions decreased with the time interval from urine collection until BC diagnosis (p = 0·033) but the mutations were detectable up to 10 years prior to clinical diagnosis. Interpretation: Our results provide the first evidence from a population-based prospective cohort study of the potential of urinary TERT promoter mutations as promising non-invasive biomarkers for early detection of BC. Further studies should validate this finding and assess their clinical utility in other longitudinal cohorts. Funding: French Cancer League, World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, the International Agency for Research on Cancer, and the U.S. National Cancer Institute. Keywords: Early detection, TERT promoter mutations, Urinary biomarker, Bladder cancer, Prospective cohort

Background: Some evidence suggests environmental tobacco smoke (ETS) might cause chronic obstructive pulmonary disease (COPD). We reviewed available epidemiological data in never smokers. Methods: We identified epidemiological studies providing estimates of relative risk (RR) with 95% confidence interval (CI) for various ETS exposure indices. Confounder-adjusted RRs for COPD were extracted, or derived using standard methods. Meta-analyses were conducted for each exposure index, with tests for heterogeneity and publication bias. For the main index (spouse ever smoked or nearest equivalent), analyses investigated variation in RR by location, publication period, study type, sex, diagnosis, study size, confounder adjustment, never smoker definition, and exposure index definition. Results: Twenty-eight relevant studies were identified; nine European or Middle Eastern, nine Asian, eight American and two from multiple countries. Five were prospective, seven case-control and 16 cross-sectional. The COPD definition involved death or hospitalisation in seven studies, GOLD stage 1+ criteria in twelve, and other definitions in nine. For the main index, random-effects meta-analysis of 33 heterogeneous (p

Background: To present up-to-date meta-analyses of evidence from Japan relating smoking to major smoking-related diseases. Methods: We restricted attention to lung cancer, chronic obstructive pulmonary disease (COPD), ischemic heart disease (IHD) and stroke, considering relative risks (RRs) for current and ex-smokers relative to never smokers. Evidence by amount smoked and time quit was also considered. For IHD and stroke only, studies had to provide age-adjusted RRs, with age-specific results considered. For each disease we extended earlier published databases to include more recent studies. Meta-analyses were conducted, with random-effects RRs and tests of heterogeneity presented. Results: Of 40 studies, 26 reported results for lung cancer and 7 to 9 for each other disease. For current smoking, RRs (95%CIs) were lung cancer 3.59 (3.25-3.96), COPD 3.57 (2.72-4.70), IHD 2.21 (1.96-2.50) and stroke 1.40 (1.25-1.57). Ex-smoking RRs were lower. Data for lung cancer and IHD showed a clear tendency for RRs to rise with increasing amount smoked and decrease with increasing time quit. Dose-response data were unavailable for COPD and unclear for stroke, where the association was weaker. Conclusions: Compared to studies in other Asian and Western countries, current smoking RRs were quite similar for IHD and stroke. The comparison is not clear for COPD, where the Japanese data, mainly from cross-sectional studies, is limited. For lung cancer, the RRs are similar to those in other Asian countries, but substantially lower than in Western countries. Explanations for this are unclear, but less accurate reporting of smoking by Japanese may contribute to the difference.

Triple negative breast cancer (TNBC), defined by the lack of expression of the estrogen receptor, progesterone receptor and human epidermal receptor 2, is an aggressive form of breast cancer that is more prevalent in certain populations, in particular in low- and middle-income regions. The detailed molecular features of TNBC in these regions remain unexplored as samples are mostly accessible as formalin-fixed paraffin embedded (FFPE) archived tissues, a challenging material for advanced genomic and transcriptomic studies. Using dedicated reagents and analysis pipelines, we performed whole exome sequencing and miRNA and mRNA profiling of 12 FFPE tumor tissues collected from pathological archives in Mexico. Sequencing analyses of the tumor tissues and their blood pairs identified TP53 and RB1 genes as the most frequently mutated genes, with a somatic mutation load of 1.7 mutations/exome Mb on average. Transcriptional analyses revealed an overexpression of growth-promoting signals (EGFR, PDGFR, VEGF, PIK3CA, FOXM1), a repression of cell cycle control pathways (TP53, RB1), a deregulation of DNA-repair pathways, and alterations in epigenetic modifiers through miRNA:mRNA network de-regulation. The molecular programs identified were typical of those described in basal-like tumors in other populations. This work demonstrates the feasibility of using archived clinical samples for advanced integrated genomics analyses. It thus opens up opportunities for investigating molecular features of tumors from regions where only FFPE tissues are available, allowing retrospective studies on the search for treatment strategies or on the exploration of the geographic diversity of breast cancer.

The function of prostate-specific antigen (PSA) is to liquefy the semen coagulum so that the released sperm can fuse with the ovum. Fifteen spliced variants of the PSA gene have been reported in humans, but little is known about alternative splicing in nonhuman primates. Positive selection has been reported in sex- and reproductive-related genes from sea urchins to Drosophila to humans; however, there are few studies of adaptive evolution of the PSA gene. Here, using polymerase chain reaction (PCR) product cloning and sequencing, we study PSA transcript variant heterogeneity in the prostates of chimpanzees (Pan troglodytes), cynomolgus monkeys (Macaca fascicularis), baboons (Papio hamadryas anubis), and African green monkeys (Chlorocebus aethiops). Six PSA variants were identified in the chimpanzee prostate, but only two variants were found in cynomolgus monkeys, baboons, and African green monkeys. In the chimpanzee the full-length transcript is expressed at the same magnitude as the transcripts that retain intron 3. We have found previously unidentified splice variants of the PSA gene, some of which might be linked to disease conditions. Selection on the PSA gene was studied in 11 primate species by computational methods using the sequences reported here for African green monkey, cynomolgus monkey, baboon, and chimpanzee and other sequences available in public databases. A codon-based analysis (dN/dS) of the PSA gene identified potential adaptive evolution at five residue sites (Arg45, Lys70, Gln144, Pro189, and Thr203).

Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.