Biology subjects

Marini, L.

Publications and source records attributed to Marini, L..

3 recordsLinked to original sources

bioRxiv2019

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer

BackgroundLittle is known about mechanisms of resistance to PARP inhibitors and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. Patients and MethodsWe obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARP inhibitor or platinum chemotherapy. Whole exome sequencing was performed on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was performed for functional assessment of intact homologous recombination. ResultsPre- and post-resistance tumor samples were sequenced from 8 patients (4 with BRCA1 and 4 with BRCA2 mutation; 4 treated with PARP inhibitor and 4 with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore homologous recombination through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of homologous recombination. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. ConclusionsGenomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in 4 of 8 patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

cancer biology↗

bioRxiv2019

A global synthesis reveals biodiversity-mediated benefits for crop production

Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by few abundant species or rely on high richness remains unclear. Using a global database from 89 crop systems, we partition the relative importance of abundance and species richness for pollination, biological pest control and final yields in the context of on-going land-use change. Pollinator and enemy richness directly supported ecosystem services independent of abundance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society.

ecology↗

bioRxiv2018

Species-habitat networks: Bridging applied ecology and network theory

Land-use change is massively reshaping terrestrial ecosystems worldwide, and is recognized as a key driver of biodiversity loss with negative consequences on ecosystem functioning. Understanding how species use resources across landscapes is essential for the design of effective management strategies. Despite recent advances in theoretical ecology, there is still a gap between theory and applied ecological science and we lack the tools to manage entire landscapes to maximize biodiversity conservation and ecosystem service delivery. Here, we propose a new approach that uses existing bipartite networks to create species-habitat networks. Networks enable powerful visualizations via a common language that defines most processes in terms of nodes and links. This approach explicitly links multiple species and habitat resources, provides tools to estimate the importance of particular species in a given landscape, and quantifies emerging properties of entire habitat networks. Most existing metrics used to study properties of bipartite ecological networks can easily be adapted to investigate species-habitat relationships. One key advantage of this approach is that the scale of the derived ecological information will match the scale of management interventions. The flexibility of the proposed approach is that it can be easily applied across a range of ecological fields such as species conservation, habitat restoration, ecosystem services management, or invasion ecology. Network emerging properties could also be used to test the effects of large scale drivers of global change upon ecosystem structure and stability.

ecology↗