The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by ...appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma.
A total of 183 samples from appendiceal adenocarcinoma 46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR), 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC.
We observed high mutation rates in appendiceal adenocarcinoma samples for
(55%),
(40%),
(31%),
(16%), and
(10%). Appendiceal adenocarcinoma exhibited higher mutation rates in
and
, and lower mutation rates in
, and
(6%) than colorectal cancers. PMP exhibited much higher mutation rates in
(74%) and
63%), and much lower mutation rates in
(23%),
(2%), and
(2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC.
Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment.
Recent mass mortalities of bats, birds and even humans highlight the substantial threats that rising global temperatures pose for endotherms. Although less dramatic, sublethal fitness costs of high ...temperatures may be considerable and result in changing population demographics. Endothermic animals exposed to high environmental temperatures can adjust their behaviour (e.g. reducing activity) or physiology (e.g. elevating rates of evaporative water loss) to maintain body temperatures within tolerable limits. The fitness consequences of these adjustments, in terms of the ability to balance water and energy budgets and therefore maintain body condition, are poorly known. We investigated the effects of daily maximum temperature on foraging and thermoregulatory behaviour as well as maintenance of body condition in a wild, habituated population of Southern Pied Babblers Turdoides bicolor. These birds inhabit a hot, arid area of southern Africa where they commonly experience environmental temperatures exceeding optimal body temperatures. Repeated measurements of individual behaviour and body mass were taken across days varying in maximum air temperature. Contrary to expectations, foraging effort was unaffected by daily maximum temperature. Foraging efficiency, however, was lower on hotter days and this was reflected in a drop in body mass on hotter days. When maximum air temperatures exceeded 35.5 °C, individuals no longer gained sufficient weight to counter typical overnight weight loss. This reduction in foraging efficiency is likely driven, in part, by a trade‐off with the need to engage in heat‐dissipation behaviours. When we controlled for temperature, individuals that actively dissipated heat while continuing to forage experienced a dramatic decrease in their foraging efficiency. This study demonstrates the value of investigations of temperature‐dependent behaviour in the context of impacts on body condition, and suggests that increasingly high temperatures will have negative implications for the fitness of these arid‐zone birds.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Why do some winning rebel groups build obedient and effective state militaries after civil war, while others suffer military defections? When winning rebels face intense security threats during civil ...wars, rebel field commanders are more likely to remain obedient during war-to-peace transitions. Intense security threats incentivize militants to create more inclusive leadership structures, reducing field commanders’ incentives to defect in the postwar period. Intense security threats also reduce commanders’ capacity for postwar resistance by forcing insurgents to remain mobile and adopt shorter time horizons in rebel-governed territory, reducing the likelihood that field commanders will develop local ties and independent support bases. The plausibility of the argument is examined using a new list of winning rebel groups since 1946. Two case studies—Zimbabwe and Côte d'Ivoire—probe the causal mechanisms of the theory. The study contributes to debates about the consequences of
military victory in civil war, the postwar trajectories of armed groups, and the conditions necessary for civil-military cohesion in fragile states.
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IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
Although increasing efforts are being made to restore tropical forests, little information is available regarding the time scales required for carbon and plant biodiversity to recover to the values ...associated with undisturbed forests. To address this knowledge gap, we carried out a meta-analysis comparing data from more than 600 secondary tropical forest sites with nearby undisturbed reference forests. Above-ground biomass approached equivalence to reference values within 80 years since last disturbance, whereas below-ground biomass took longer to recover. Soil carbon content showed little relationship with time since disturbance. Tree species richness recovered after about 50 years. By contrast, epiphyte richness did not reach equivalence to undisturbed forests. The proportion of undisturbed forest trees and epiphyte species found in secondary forests was low and changed little over time. Our results indicate that carbon pools and biodiversity show different recovery rates under passive, secondary succession and that colonization by undisturbed forest plant species is slow. Initiatives such as the Convention on Biological Diversity and REDD+ should therefore encourage active management to help to achieve their aims of restoring both carbon and biodiversity in tropical forests.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Ex-rebel military commanders play a central role in peacebuilding after civil war. Yet the influence and mobilization power of these actors is not uniform: in some areas commanders retain strong ties ...to civilian populations after war’s end, while in other areas such ties wither away. This article analyses a novel dataset of former rebel-occupied localities in Côte d’Ivoire to investigate why commander–community linkages endure or decline after post-conflict transitions. The findings support a theory of political accountability: commanders retained political capital and access to networks of supporters in areas where insurgents provided essential goods to civilians during war. By contrast, where insurgents’ wartime rule involved abuse and coercion, commanders were less likely to sustain strong ties. These findings challenge the conventional wisdom that violent warlordism explains the persistence of rebel commanders’ power in peacetime. Rather, effective wartime governance may create regionally embedded strongmen who can in turn disrupt postwar state-building.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Monitoring the impacts of anthropogenic threats and interventions to mitigate these threats is key to understanding how to best conserve biodiversity. Ecologists use many different study designs to ...monitor such impacts. Simpler designs lacking controls (e.g. Before–After (BA) and After) or pre‐impact data (e.g. Control–Impact (CI)) are considered to be less robust than more complex designs (e.g. Before–After Control‐Impact (BACI) or Randomized Controlled Trials (RCTs)). However, we lack quantitative estimates of how much less accurate simpler study designs are in ecology. Understanding this could help prioritize research and weight studies by their design's accuracy in meta‐analysis and evidence assessment.
We compared how accurately five study designs estimated the true effect of a simulated environmental impact that caused a step‐change response in a population's density. We derived empirical estimates of several simulation parameters from 47 ecological datasets to ensure our simulations were realistic. We measured design performance by determining the percentage of simulations where: (a) the true effect fell within the 95% Confidence Intervals of effect size estimates, and (b) each design correctly estimated the true effect's direction and magnitude. We also considered how sample size affected their performance.
We demonstrated that BACI designs performed: 1.3–1.8 times better than RCTs; 2.9–4.2 times versus BA; 3.2–4.6 times versus CI; and 7.1–10.1 times versus After designs (depending on sample size), when correctly estimating true effect's direction and magnitude to within ±30%. Although BACI designs suffered from low power at small sample sizes, they outperformed other designs for almost all performance measures. Increasing sample size improved BACI design accuracy, but only increased the precision of simpler designs around biased estimates.
Synthesis and applications. We suggest that more investment in more robust designs is needed in ecology since inferences from simpler designs, even with large sample sizes may be misleading. Facilitating this requires longer‐term funding and stronger research–practice partnerships. We also propose ‘accuracy weights’ and demonstrate how they can weight studies in three recent meta‐analyses by accounting for study design and sample size. We hope these help decision‐makers and meta‐analysts better account for study design when assessing evidence.
Foreign Language Japanese
生物多様性の保全を効果的に行うためには、人為的脅威の影響や保全対策の効果を適切に評価することが重要となる。生態学ではこのような評価を行うために、様々な研究デザインが用いられている。対照区が存在しないBefore‐After (BA)デザインやAfterデザイン、また処理以前のデータが存在しないControl‐Impact (CI)デザインなど簡素な研究デザインは、Before‐After Control‐Impact (BACI)デザインやランダム化比較試験（RCTs: Randomized Controlled Trials)などの複雑なデザインよりも頑健さに劣ると考えられている。しかしながら、生態学においてこれら簡素な研究デザインがどれだけ正確度に劣るのか、定量的な評価はこれまで行われていない。研究デザインの正確度を定量的に評価することで、メタ解析やエビデンスの評価を行う際に、用いられた研究デザインの正確度に基づいて各研究の優先順位付けや重み付けを行うことが可能になるだろう。
本研究では、環境変化が個体群密度に及ぼす影響を、5種類の研究デザインがどれだけ正確に推定することができるのか、シミュレーションを用いて検討した。より現実に即した状況を再現するため、シミュレーションで用いたパラメータは、47の生態学的データから抽出した。各研究デザインの正確度は、シミュレーションにおいて、（１）推定された効果サイズの95％信頼区間に真の効果が含まれる割合、（２）推定された効果が真の効果の方向・程度と一致した割合、を算出することによって評価した。またサンプルサイズの違いが各研究デザインの正確度に及ぼす影響も検討した。
シミュレーションの結果、BACIデザインはランダム化比較試験に対して1.3–1.8倍、BAデザインに対して2.9–4.2倍、CIデザインに対して3.2–4.6倍、Afterデザインに比較すると7.1–10.1倍も正確に真の効果を推定できる（推定された効果が真の効果の方向と一致し、且つ真の効果の ± 30%内に含まれる）ことが明らかになった（比較値のばらつきはサンプルサイズによる）。BACIデザインの正確度はサンプルサイズが小さい場合には低下したが、それでもほとんどの指標において他のデザインよりも高い正確度を示していた。サンプルサイズを増やすことでBACIデザインの正確度は向上したが、他の研究デザインでは偏った推定値の精度が向上するだけであった。
Synthesis and applications. 例えサンプルサイズが十分であったとしても、簡素なデザインに基づいた推論は正確でない可能性があるため、生態学においてもより頑健な研究デザインの利用を推進していく必要があると考えられる。頑健な研究デザインの利用を推進するためには、長期に渡る研究資金の確保や、研究と実践の間でのより強固な連携が必要となるだろう。本研究では更にこれらの結果に基づいて、メタ解析において研究デザインとサンプルサイズに基づいて各研究の重み付けをする手法を提案し、近年行われた３つのメタ解析を用いてその実用例を提示した。これらの結果は、意思決定者やメタ解析を行う研究者が、研究デザインを考慮したエビデンスの評価を行うために有用となるだろう。
We suggest that more investment in more robust designs is needed in ecology since inferences from simpler designs, even with large sample sizes may be misleading. Facilitating this requires longer‐term funding and stronger research–practice partnerships. We also propose ‘accuracy weights’ and demonstrate how they can weight studies in three recent meta‐analyses by accounting for study design and sample size. We hope these help decision‐makers and meta‐analysts better account for study design when assessing evidence.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the ...role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC.
We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments CLIA-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability MSI, tumour mutational burden TMB, programmed death ligand 1 PD-L1 and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry.
ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell–inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes CTLs) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples.
Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
•The impact of ARID1A mutations was analysed using 7978 colorectal cancer samples.•ARID1A mutation was linked to immune activation, right-sided tumour and early stage.•ARID1A mutation may be a biomarker for chemotherapy/radiotherapy and targeted therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Frequency, duration, and intensity of hot-weather events are all predicted to increase with climate warming. Despite this, mechanisms by which temperature increases affect individual fitness and ...drive population-level changes are poorly understood. We investigated the link between daily maximum air temperature (tmax) and breeding success of Kalahari common fiscals (Lanius collaris) in terms of the daily effect on nestling body-mass gain, and the cumulative effect on size and age of fledglings. High tmax reduced mass gain of younger, but not older nestlings and average nestling-period tmax did not affect fledgling size. Instead, the frequency with which tmax exceeded critical thresholds (tcrits) significantly reduced fledging body mass (tcrit = 33°C) and tarsus length (tcrit= 37°C), as well as delaying fledging (tcrit= 35°C). Nest failure risk was 4.2% per day therefore delays reduced fledging probability. Smaller size at fledging often correlates with reduced lifetime fitness and might also underlie documented adult body-size reductions in desert birds in relation to climate warming. Temperature thresholds above which organisms incur fitness costs are probably common, as physiological responses to temperature are non-linear. Understanding the shape of the relationship between temperature and fitness has implications for our ability to predict species' responses to climate change.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, ...histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification.
Summary Background Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years. ...Methods We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958–67, 1968–77, 1978–87, 1988–97, and 1998–2007), stratified by sex. Findings During 50 years of observation (202 417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 47% were women). Between 1958–67 and 1998–2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20·4 to 96·2 cases per 1000 person-years in men and from 13·7 to 49·4 cases per 1000 person-years in women; age-adjusted incidence increased from 3·7 to 13·4 new cases per 1000 person-years in men and from 2·5 to 8·6 new cases per 1000 person-years in women (ptrend <0·0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12·6 in 1958–67 to 25·7 in 1998–2007 in men, ptrend =0·0007; 8·1 to 11·8 in women, ptrend =0·009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50–86%) decrease in stroke (hazards ratio HR 3·77, 95% CI 1·98–7·20 in 1958–1967 compared with 1998–2007; ptrend =0·0001) and a 25% (95% CI −3–46%) decrease in mortality (HR 1·34, 95% CI 0·97–1·86 in 1958–1967 compared with 1998–2007; ptrend =0·003) in 20 years following atrial fibrillation onset. Interpretation Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention. Funding NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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