Climate sensitivity of radiative impacts from transport systems

Comparing individual components of a total climate impact is traditionally done in terms of radiative forcing. However, the climate impact of transport systems includes contributions that are likely to imply climate sensitivity parameters distinctly different from the “reference value” for a homogeneous CO2 perturbation. We propose to introduce efficacy factors for each component into the assessment. The way of proceeding is illustrated using aviation as an example, and prospects for evaluating the other transport system in the EU project QUANTIFY are given

An evaluation of the performance of chemistry transport models - Part 2: Detailed comparison with two selected campaigns

This is the second part of a rigorous model evaluation study involving five global Chemistry-Transport and two Chemistry-Climate Models operated by different groups in Europe. Simulated trace gas fields were interpolated to the exact times and positions of the observations to account for the actual weather conditions and hence for the specific histories of the sampled air masses. In this part of the study we focus on a detailed comparison with two selected campaigns, PEM-Tropics A and SONEX, contrasting the clean environment of the tropical Pacific with the more polluted North Atlantic region. The study highlights the different strengths and weaknesses of the models in accurately simulating key processes in the UT/LS region including stratosphere-troposphere-exchange, rapid convective transport, lightning emissions, radical chemistry and ozone production. Model simulated Radon, which was used as an idealized tracer for continental influence, was occasionally much better correlated with measured CO than simulated CO pointing towards deficiencies in the used biomass burning emission fields. The abundance and variability of HOx radicals is in general well represented in the models as inferred directly from the comparison with measured OH and HO2 and indirectly from the comparison with hydrogen peroxide concentrations. Components of the NOy family such as PAN, HNO3 and NO were found to compare less favorably. Interestingly, models showing good agreement with observations in the case of PEM-Tropics A often failed in the case of SONEX and vice versa. A better description of NOx and NOy emissions, chemistry and sinks is thought to be key to future model improvements with respect to the representation of chemistry in the UT/LS region

Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE):study protocol for a trial within a cohort study

BACKGROUND: Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. METHODS/DESIGN: MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. DISCUSSION: The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. TRIAL REGISTRATION: Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281

ARID1B is a specific vulnerability in ARID1A-mutant cancers

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers

Signatures of mutational processes in human cancer.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy