VARIABILITY OF DEPOSITIONAL SETTING ALONG THE NORTH-WESTERN SICILY CONTINENTAL SHELF (ITALY) DURING LATE QUATERNARY: EFFECTS OF SEA LEVEL CHANGES AND TECTONIC EVOLUTION

The geological, geomorphological and sedimentological features of the north-western Sicily continental shelf are here illustrated with the aim to propose a geological model able to explain the Neogene-Quaternary evolution of the Sicilian continental margin in the context of the central Mediterranean region. Above the continental shelf and upper slope the sedimentary succession, showing along the different sectors of the margin considerably variable internal geometry and stratigraphic relationships with the underlying units, is interpreted as a IV order depositional sequence (Late Quaternary Depositional Sequence, LQDS) deposited during the last eustatic change (last 125 ky). The lower boundary of the LQDS is represented by a subaerial erosional surface formed during the last eustatic sea level fall ended in the LGM (20-18 ka). This unconformity lies above a seaward dipping Pleistocene succession whose depositional architecture is in turn controlled by Quaternary eustatic sea-level fluctuations. A dense dataset of morphobathymetric and high resolution seismic data allowed to recognize along the continental shelf to bathyal plain system different types of continental shelf with different stratigraphic and morphostructural settings, associated to both large-scale processes and specific factors related to more local control: a) predominantly rocky shelves, both accompanied by a moderate frontal sedimentary prism and with a structural edge, in the structural highs of the Monti di Palermo offshore and around the main rocky headlands (Capo San Vito, Monte Catalfano); b), depositional shelves, in the Castellammare, Palermo and Termini Imerese gulfs, both with a regular seaward deepening of the substrate and with a substrate uplift at the shelf break. We confirm that depositional sequences in this margin are the result of the interaction between sea level changes and sedimentation, but demonstrate that the tectonic activity has played a key role, not only in the creation of different types of continental shelves, but also to determine the different characters of each sequence in different areas. The general tectonic uplift during the Pleistocene, together with the episodic alternation of extensional and compressional events, often with strike-slip component, is responsible for the thickness and facies variation both onland, where residual Pleistocene marine deposits today outcrops, and in the continental shelf, where most of the depositional sequences developed and are now recognized. As well tectonic activity exerted a control on the geomorphological features (e.g. pockmarks and mounds) of the present day coastal areas and shelf-slope system, as well as for the submarine canyons and the mass failure processes

Ruolo della chirurgia endovascolare nelle rotture aortiche del politraumatizzato con lesioni polidistrettuali di pertinenza chirurgica

Nel politraumatizzato con gravi lesioni polidistrettuali di interesse chirurgico il trattamento endovascolare (TEV) della rottura posttraumatica dell’ aorta toracica (RPAT) rappresenta oggi una valida alternativa terapeutica al trattamento chirurgico convenzionale. Nella nostra esperienza (ottobre 2001-novembre 2004) abbiamo osservato 5 casi di RPAT (3 rotture istmiche, 2 rotture aorta toracica discendente) in gravi politraumatizzati, tutti di sesso maschile, di età compresa fra i 23 ed i 42 anni (media 32,4), trattate con successo con TEV. Il Glasgow Coma Score (GCS) era compreso fra 5 e 13. Tutti i pazienti sono stati sottoposti, dopo adeguata stabilizzazione del quadro clinico-emodinamico, ad angio-TC total body al fine di valutare la lesione aortica ed identificare le altre lesioni associate. In 4 casi erano coinvolti più distretti corporei di pertinenza chirurgica (3 casi: trauma osseo, addominale e neurochirurgico; 1 caso: trauma osseo, addominale, neurochirurgico e toracico). Il TEV è stato eseguito sempre in sala operatoria previa arteriografia digitale. La durata media della procedura angio-radiologica è stata di 105 minuti (range 80 - 125). Non si è verificata nessuna complicanza né immediata né a distanza (follow-up = medio 24 mesi; range 12-36). In conclusione il TEV delle RPAT offre in pazienti ‘critici’ una valida opzione terapeutica alla chirurgia tradizionale in grado di stabilizzare il quadro clinico e trattare successivamente ‘in sicurezza’ le altre gravi lesioni chirurgiche associate

3D CT scan for perioperative identification of anatomical variations of lungs

Aim: The aim of this study is to investigate anatomical lung variations and vascular patterns using volumetric 3D computed tomography (CT) representations. Methods & results: We considered 24 major thoracic surgery performed in our ward. In these, we discovered some interesting anatomical variations of the main pulmonary fissures. These findings were not visible on the plain x-ray or during routine examination of a preoperative CT scan. After re-examination of 3D CT scan reconstruction the anatomical variations were detected. Discussion: General thoracic surgeons must familiarize themselves with anatomical variations in lungs. 3D images may aid the general thoracic surgeon in performing safer surgeries. Conclusion: 3D CT scan should be performed before surgery if possible

Substantial Histone Reduction Modulates Genomewide Nucleosomal Occupancy and Global Transcriptional Output

The basic unit of genome packaging is the nucleosome, and nucleosomes have long been proposed to restrict DNA accessibility both to damage and to transcription. Nucleosome number in cells was considered fixed, but recently aging yeast and mammalian cells were shown to contain fewer nucleosomes. We show here that mammalian cells lacking High Mobility Group Box 1 protein (HMGB1) contain a reduced amount of core, linker, and variant histones, and a correspondingly reduced number of nucleosomes, possibly because HMGB1 facilitates nucleosome assembly. Yeast nhp6 mutants lacking Nhp6a and -b proteins, which are related to HMGB1, also have a reduced amount of histones and fewer nucleosomes. Nucleosome limitation in both mammalian and yeast cells increases the sensitivity of DNA to damage, increases transcription globally, and affects the relative expression of about 10% of genes. In yeast nhp6 cells the loss of more than one nucleosome in four does not affect the location of nucleosomes and their spacing, but nucleosomal occupancy. The decrease in nucleosomal occupancy is non-uniform and can be modelled assuming that different nucleosomal sites compete for available histones. Sites with a high propensity to occupation are almost always packaged into nucleosomes both in wild type and nucleosome-depleted cells; nucleosomes on sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells. We suggest that variation in nucleosome number, by affecting nucleosomal occupancy both genomewide and gene-specifically, constitutes a novel layer of epigenetic regulation

Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation

Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8.38 [7.07] mm 3, n = 3; HSP90i 4.18 [1.93] mm 3, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm 3, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm 3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA- mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i

Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors

[Background] Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.[Methods] We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).[Results] We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.[Conclusions] ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.This research is supported by a Fero Fellowship Award (C.S.), Asociación Española Contra el Cáncer (J.P. Barcelona) (C.S.), and ISCIII PI16/01371 (C.S.). C.S. and A.V. acknowledge to the Cellex Foundation for providing facilities and equipment

HumMeth27QCReport: an R package for quality control and primary analysis of Illumina Infinium methylation data

<p>Abstract</p> <p>Background</p> <p>The study of the human DNA methylome has gained particular interest in the last few years. Researchers can nowadays investigate the potential role of DNA methylation in common disorders by taking advantage of new high-throughput technologies. Among these, Illumina Infinium assays can interrogate the methylation levels of hundreds of thousands of CpG sites, offering an ideal solution for genome-wide methylation profiling. However, like for other high-throughput technologies, the main bottleneck remains at the stage of data analysis rather than data production.</p> <p>Findings</p> <p>We have developed <it>HumMeth27QCReport</it>, an R package devoted to researchers wanting to quickly analyse their Illumina Infinium methylation arrays. This package automates quality control steps by generating a report including sample-independent and sample-dependent quality plots, and performs primary analysis of raw methylation calls by computing data normalization, statistics, and sample similarities. This package is available at CRAN repository, and can be integrated in any Galaxy instance through the implementation of ad-hoc scripts accessible at Galaxy Tool Shed.</p> <p>Conclusions</p> <p>Our package provides users of the Illumina Infinium Methylation assays with a simplified, automated, open-source quality control and primary analysis of their methylation data. Moreover, to enhance its use by experimental researchers, the tool is being distributed along with the scripts necessary for its implementation in the Galaxy workbench. Finally, although it was originally developed for HumanMethylation27, we proved its compatibility with data generated with the HumanMethylation450 Bead Chip.</p

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer

Altres ajuts: This work was supported by the Fundacion Cientifica Asociación Española Contra el Cancer-AECC [grant number GCB14142170 to LMM, MS-C, and EF].Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs

Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS -mutant metastatic colorectal cancer

Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS -mutant allele fraction (MAF) in plasma in mCRC. Forty-seven plasma samples from 37 RAS -mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first- and/or second-line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19-9 levels, primary site location, and treatment line) and clinical outcome [progression-free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI-GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first-line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRI-GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5-9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07-5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice