East African coastal forest under pressure

The Arabuko Sokoke dryland coastal forest along the East African coastline provides a unique habitat for many endangered endemic animal and plant species. High demographic pressure with subsequent land-splitting, soil depletion in combination with erratic rainfalls and the collapse of the tourism industry are negatively affecting food security and human livelihood quality in this region. Food crops were originally produced by subsistence farming, but have now to be purchased at local-and super-markets, constituting a major financial burden for the local people. In consequence, overexploitation of natural resources from Arabuko Sokoke forest (illegal logging, charcoal burning, poaching of wild animals) increased during the past years. In this commentary we document ecosystem heterogeneity leading to high species richness. We discuss direct and indirect drivers of habitat degradation of the Arabuko Sokoke forest, and critically reflect current and future solutions. Key drivers of habitat destruction and biodiversity loss are (i) illegal timber logging and removal of woody biomass, (ii) poaching of bush-meat, (iii) exceeding of the carrying capacity by the local elephant population, restricted to Arabuko Sokoke by an electric fence, and (iv) weak governance structures and institutional confusion exacerbating illegal exploitation of natural resources. Potential solutions might be: Provisioning of additional income sources; reforestation of the surrounding areas in the framework of REDD+ activities to create a buffer around the remaining primary forest; improving governance structures that formulates clear guidelines on future usage and protection of natural resources within the Arabuko Sokoke forest; and family planning to counteract human demographic pressure and the exploitation of natural resources

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Added Value of Molecular Biological Analysis in Diagnosis and Clinical Management of Liposarcoma: A 30-Year Single-Institution Experience

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Towards a better future for biodiversity and people: modelling Nature Futures

The expert group on scenarios and models of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services initiated the development of the Nature Futures Framework for developing scenarios of positive futures for nature, to help inform assessments of policy options. This new scenarios and modelling Framework seeks to open up diversity and plurality of perspectives by differentiating three main value perspectives on nature – Nature for Nature (intrinsic values of nature), Nature for Society (instrumental values) and Nature as Culture (relational values). This paper describes how the Nature Futures Framework can be applied in modelling to support policy processes by identifying key interventions for change in realizing a diversity of desirable futures. First, the paper introduces and elaborates on key building blocks of the framework for developing qualitative scenarios and translating them into quantitative scenarios: i) multiple value perspectives on nature and the Nature Futures frontier representing diverse preferences, ii) incorporating mutual and key feedbacks of social-ecological systems in Nature Futures scenarios, and iii) indicators describing the evolution of social-ecological systems with complementary knowledge and data. This paper then presents three possible application approaches to modelling Nature Futures scenarios to support the i) review, ii) implementation and iii) design phases of policy processes. The main objective of this paper is to facilitate the integration of the relational values of nature in models, through improved indicators and other forms of evidence, and to strengthen modelled linkages across biodiversity, ecosystems, nature’s contributions to people, and quality of life to identify science- and knowledge-based interventions and to enhance ecological understanding for achieving sustainable futures. The paper aims at stimulating the development of new scenarios and models based on this new framework by a wide community of modelers, and the testing and possible further development of the framework, particularly in the context of future IPBES assessments

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of beta-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis