The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers

Càncer de mama; Genòmica del càncer; Biomarcadors tumoralsCáncer de mama; Genómica del cáncer; Biomarcadores tumoralesBreast cancer; Cancer genomics; Tumour biomarkersThe biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.This work was supported by Cancer Research UK. L.D.M.A. was partly funded by Spanish Association against cancer

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers.

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = 2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment

Hierarchical chromatin organization detected by TADpole

Mètodes computacionals; GenòmicaMétodos computacionales; GenómicaComputational Methods; GenomicsThe rapid development of Chromosome Conformation Capture (3C-based techniques), as well as imaging together with bioinformatics analyses, has been fundamental for unveiling that chromosomes are organized into the so-called topologically associating domains or TADs. While TADs appear as nested patterns in the 3C-based interaction matrices, the vast majority of available TAD callers are based on the hypothesis that TADs are individual and unrelated chromatin structures. Here we introduce TADpole, a computational tool designed to identify and analyze the entire hierarchy of TADs in intra-chromosomal interaction matrices. TADpole combines principal component analysis and constrained hierarchical clustering to provide a set of significant hierarchical chromatin levels in a genomic region of interest. TADpole is robust to data resolution, normalization strategy and sequencing depth. Domain borders defined by TADpole are enriched in main architectural proteins (CTCF and cohesin complex subunits) and in the histone mark H3K4me3, while their domain bodies, depending on their activation-state, are enriched in either H3K36me3 or H3K27me3, highlighting that TADpole is able to distinguish functional TAD units. Additionally, we demonstrate that TADpole's hierarchical annotation, together with the new DiffT score, allows for detecting significant topological differences on Capture Hi-C maps between wild-type and genetically engineered mouse.European Research Council under the Seventh Framework Program FP7/2007-2013 [609989, in part]; European Union's Horizon 2020 Research and Innovation Programme [676556]; Spanish Ministry of Science and Innovation [BFU2013-47736-P, BFU2017-85926-P to M.A.M-R., IJCI-2015-23352 to I.F., BES-2014-070327 to P.S-V.]; ‘Centro de Excelencia Severo Ochoa 2013–2017’, SEV-2012-0208; CERCA Programme/Generalitat de Catalunya (to C.R.G.). Funding for open access charge: European Research Council under the Seventh Framework Program FP7/2007-2013 [609989]. We also acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208, the CERCA Programme/Generalitat de Catalunya, Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program to the CRG

Long-term corrosion behavior and biocompatibility testing of titanium-based alloy covered with nano-crystalline hydroxyapatite

In this paper, we applied on the surface of the new Ti%20Nb%10Zr%5Ta alloy nano-crystalline hydroxyapatite (HA) coating by the method of the chemical deposition in a solution supersaturated with Ca2+ and inline image ions. The composition and crystallinity of the obtained coating was determined by X-ray diffraction, micro-Raman, infrared, and energy dispersive X-ray spectroscopies and its morphology and porosity by scanning electron microscopy. The coating long-term corrosion behavior for 3000 soaking hours in simulated human fluids (Ringer\u27s solutions of different pH values) was studied by cyclic potentiodynamic and linear polarization, electrochemical impedance spectroscopy and monitoring of the open circuit potentials and corresponding open circuit potential gradient due to the pH non-uniformity of the biofluid. Also, the coating biocompatibility was performed by cells (human osteoblast % HOS and human immortalized pulmonary fibroblast % Wi-38) adhesion and proliferation testing in the HA coated bioalloy extract compared to respective effects of the un-coated bioalloy extract. The initial HA nano-coating promoted the deposition of new HA layers, thickening itself and showing its ability to induce the formation of this main inorganic component of the human bone, therefore denoting bioactivity of the HA nano-coated alloy