Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse

Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course

The effectiveness of flower strips and hedgerows on pest control, pollination services and crop yield: a quantitative synthesis

Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control (18 studies) and pollination services (17 studies) in adjacent crops in North America, Europe and New Zealand. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimise floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future

Nestin expression identifies ependymoma patients with poor outcome

Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low-risk tumors, whereas grade III anaplastic ependymomas are considered high-risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin-positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression-free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co-regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics