Late Holocene Aleppo pine (Pinus halepensis Miller) woodlands in Mallorca (Balearic Islands, Western Mediterranean): Investigation of their distribution and the role of human management based on anthracological, dendro-anthracological and archaeopalynological data

The pioneering nature of Mediterranean pines and their phytosociological role have been largely discussed in relation to different agents (e.g., edaphic, climatic or anthropogenic). In this context, Aleppo pine is one of the most widespread pine species in the Mediterranean basin, as it is especially adapted to climatic constraints, such as drought and high seasonality, and has a high tolerance for salinity and strong coastal winds. It is also well adapted to regeneration after anthropogenic landscape disturbances, highlighting its important after-fire regeneration rates. In this sense, phytosociological studies conducted in Mediterranean landscapes have found that this species'' wide distribution is mostly due to its rapid regeneration after human landscape transformation, including fire, and the abandonment of agricultural lands. Aleppo pine is considered to broadly develop after human action in sclerophyllous formation, in which it would be scarce or absent without human intervention. Parallel, paleoenvironmental and archaeobotanical studies have attempted to trace these trends back to prehistoric times to investigate this species'' role in Late Pleistocene and Holocene vegetation and evaluate the role of climate and human action in its diachronic dynamics. In this study, we present a compendium of anthracological, dendro-anthracological and archaeopalyonological data with the objective of (i) investigating the nature and distribution of Aleppo pine on the island of Mallorca and (ii) evaluating the possibility that human action could have resulted in the spread of this pine species during the first two millennia of permanent human occupation of the island (c. 2300 cal. BCE–1st-century ACE). Investigating these archaeobotanical datasets, as well as making comparisons with anthracological and paleoenvironmental studies in neighbouring Mediterranean zones (Iberia), allowed us to attest that Aleppo pine is a natural, pre-human component of the Holocene vegetation of the island, and it is especially well-adapted to coastal environments. Moreover, we describe the trends and characteristics of the human management of pine woodlands through anthracology and dendro-anthracology, suggesting that human action did not provoke widespread growth of Aleppo pine in Mallorca at the expense of other vegetation types during prehistory. Such processes, well-documented by current phytosociological studies, probably began at some unknown point after the Romanisation of the island

Breast cancer PAM50 signature: Correlation and concordance between RNA-Seq and digital multiplexed gene expression technologies in a triple negative breast cancer series

Background: Full RNA-Seq is a fundamental research tool for whole transcriptome analysis. However, it is too costly and time consuming to be used in routine clinical practice. We evaluated the transcript quantification agreement between RNA-Seq and a digital multiplexed gene expression platform, and the subtype call after running the PAM50 assay in a series of breast cancer patients classified as triple negative by IHC/FISH. The goal of this study is to analyze the concordance between both expression platforms overall, and for calling PAM50 triple negative breast cancer intrinsic subtypes in particular. Results: The analyses were performed in paraffin-embedded tissues from 96 patients recruited in a multicenter, prospective, non-randomized neoadjuvant triple negative breast cancer trial (NCT01560663). Pre-treatment core biopsies were obtained following clinical practice guidelines and conserved as FFPE for further RNA extraction. PAM50 was performed on both digital multiplexed gene expression and RNA-Seq platforms. Subtype assignment was based on the nearest centroid classification following this procedure for both platforms and it was concordant on 96% of the cases (N = 96). In four cases, digital multiplexed gene expression analysis and RNA-Seq were discordant. The Spearman correlation to each of the centroids and the risk of recurrence were above 0.89 in both platforms while the agreement on Proliferation Score reached up to 0.97. In addition, 82% of the individual PAM50 genes showed a correlation coefficient > 0.80. Conclusions: In our analysis, the subtype calling in most of the samples was concordant in both platforms and the potential discordances had reduced clinical implications in terms of prognosis. If speed and cost are the main driving forces then the preferred technique is the digital multiplexed platform, while if whole genome patterns and subtype are the driving forces, then RNA-Seq is the preferred method

Breast cancer PAM50 signature: correlation and concordance between RNA-Seq and digital multiplexed gene expression technologies in a triple negative breast cancer series

[Background]: Full RNA-Seq is a fundamental research tool for whole transcriptome analysis. However, it is too costly and time consuming to be used in routine clinical practice. We evaluated the transcript quantification agreement between RNA-Seq and a digital multiplexed gene expression platform, and the subtype call after running the PAM50 assay in a series of breast cancer patients classified as triple negative by IHC/FISH. The goal of this study is to analyze the concordance between both expression platforms overall, and for calling PAM50 triple negative breast cancer intrinsic subtypes in particular.[Results]: The analyses were performed in paraffin-embedded tissues from 96 patients recruited in a multicenter, prospective, non-randomized neoadjuvant triple negative breast cancer trial (NCT01560663). Pre-treatment core biopsies were obtained following clinical practice guidelines and conserved as FFPE for further RNA extraction. PAM50 was performed on both digital multiplexed gene expression and RNA-Seq platforms. Subtype assignment was based on the nearest centroid classification following this procedure for both platforms and it was concordant on 96% of the cases (N = 96). In four cases, digital multiplexed gene expression analysis and RNA-Seq were discordant. The Spearman correlation to each of the centroids and the risk of recurrence were above 0.89 in both platforms while the agreement on Proliferation Score reached up to 0.97. In addition, 82% of the individual PAM50 genes showed a correlation coefficient > 0.80.[Conclusions]: In our analysis, the subtype calling in most of the samples was concordant in both platforms and the potential discordances had reduced clinical implications in terms of prognosis. If speed and cost are the main driving forces then the preferred technique is the digital multiplexed platform, while if whole genome patterns and subtype are the driving forces, then RNA-Seq is the preferred method.M.M was supported by two research grants from Ministry of Economy and Competitiveness ISCIII-FIS grants (PI 12/02684): “Predictores genómicos de respuesta a la quimioterapia neoadyuvante con docetaxel-carboplatino en pacientes con cáncer de mama triple negativo”/“Genomic predictors of response to neoadjuvant chemotherapy with docetaxel-carboplatin in patients with triple negative breast cancer”; and (PI 15/00117): “Cáncer de mama triple negative: Predicción de respuesta a docetaxel-carboplatino neoadyuvante mediante caracterización de TILs y firmas inmunes basadas en secuenciación masiva de RNA”/” Triple negative breast cancer: Prediction of response to neoadjuvant docetaxel-carboplatin by characterization of TILs and immune signatures based on massive RNA sequencing”. C.M.P was supported by funds from the NCI Breast SPORE program (P50-CA58223).Peer reviewe

Fine-scale detection of population-specific linkage disequilibrium using haplotype entropy in the human genome

<p>Abstract</p> <p>Background</p> <p>The creation of a coherent genomic map of recent selection is one of the greatest challenges towards a better understanding of human evolution and the identification of functional genetic variants. Several methods have been proposed to detect linkage disequilibrium (LD), which is indicative of natural selection, from genome-wide profiles of common genetic variations but are designed for large regions.</p> <p>Results</p> <p>To find population-specific LD within small regions, we have devised an entropy-based method that utilizes differences in haplotype frequency between populations. The method has the advantages of incorporating multilocus association, conciliation with low allele frequencies, and independence from allele polarity, which are ideal for short haplotype analysis. The comparison of HapMap SNPs data from African and Caucasian populations with a median resolution size of ~23 kb gave us novel candidates as well as known selection targets. Enrichment analysis for the yielded genes showed associations with diverse diseases such as cardiovascular, immunological, neurological, and skeletal and muscular diseases. A possible scenario for a selective force is discussed. In addition, we have developed a web interface (ENIGMA, available at <url>http://gibk21.bse.kyutech.ac.jp/ENIGMA/index.html</url>), which allows researchers to query their regions of interest for population-specific LD.</p> <p>Conclusion</p> <p>The haplotype entropy method is powerful for detecting population-specific LD embedded in short regions and should contribute to further studies aiming to decipher the evolutionary histories of modern humans.</p

Constitutive TL1A (TNFSF15) Expression on Lymphoid or Myeloid Cells Leads to Mild Intestinal Inflammation and Fibrosis

TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohn's disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis

Pathological response in a triple-negative breast cancer cohort treated with neoadjuvant carboplatin and docetaxel according to Lehmann's refined classification

Purpose: Triple-negative breast cancer (TNBC) requires the identification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of patients with TNBC treated with neoadjuvant carboplatin and docetaxel (TCb). Methods: Patients with TNBC were accrued in a nonrandomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 for six cycles. Response was evaluated in terms of pathologic complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans and colleagues. Lehmann's subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of seven DNA damage repair genes was conducted. Results: Ninety-four out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR, and 7.4% were classified as ERþ. Response to NACT with TCb was significantly associated with Lehmann subtype (P ¼ 0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%), and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2, and 30% were M. Conclusions: TNBCtype-4 is associated with significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT, respectively

Investigation of Multiple Susceptibility Loci for Inflammatory Bowel Disease in an Italian Cohort of Patients

BACKGROUND: Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort. METHODS: Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated. RESULTS: The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10(-6)). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10(-5)). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P  =  0.038), and with HLA and steroid-responsiveness (P  =  0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P  =  0.021), and with ZNF365 and ileal location (P  =  0.024) was demonstrated. CONCLUSIONS: We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes

Plan de comunicación interna y externa de la Facultad de Ciencias Sociales. Programa de Actividades Complementarias y de Difusión Cultural de la Facultad II

Memoria ID-0258. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2014-2015