A calibrated mammal scale for the Neogene of Western Europe. State of the art

A magnetobiostratigraphically calibrated mammal scale for the Neogene of Western Europe is presented in this paper. The Mammal Neogene MN units originally proposed by Mein [Report on activity RCMNS-Working groups] 1975 have been re-defined here on the basis of first appearances of selected small and large mammal taxa. The chronology of the lower boundaries of each unit had been established mostly after the significant magnetobiostratigraphic framework developed in the last decade in a number of Spanish basins: Ebro, Calatayud-Daroca, Vallès-Penedès, Teruel, Fortuna, Cabriel and Guadix-Baza. In the case of the early and middle Miocene particularly, MN 1, MN 2 and MN 3 , the authors have also taken into account the magnetobiostratigraphic framework developed in the North Alpine Foreland Basin. Some alternative correlations of the magnetostratigraphic data from this last basin are proposed in order to achieve a higher degree of consistence with the data from the Iberian basins. A quite well established magnetostratigraphic calibration of the MN boundaries can be proposed for most of the Neogene, from Middle Miocene to Late Pliocene. On the other hand, the chronological boundaries of the Early Miocene MN units are still poorly constrained due to: (1) scarcity of well-studied, continuous, thick magnetostratigraphic sections; (2) the difficulty in defining the boundaries of the MN zones for this time-span due to the relative homogeneity and persistence of the fossil rodent faunas and the absence of significant large mammal dispersal events. Some of the troubles which arise with the application of the MN units strengthen the need to take into account the palaeobiogeographical meaning of these units and their real suitability to date and correlate through extensive geographic areas

Mercury-DPM: Fast particle simulations in complex geometries

Mercury-DPM is a code for performing discrete particle simulations. That is to say, it simulates the motion of particles, or atoms, by applying forces and torques that stem either from external body forces, (e.g. gravity, magnetic fields, etc…) or from particle interactions. For granular particles, these are typically contact forces (elastic, viscous, frictional, plastic, cohesive), while for molecular simulations, forces typically stem from interaction potentials (e.g. Lennard-Jones). Often the method used in these packages is referred to as the discrete element method (DEM), which was originally designed for geotechnical applications. However, as Mercury-DPM is designed for simulating particles with emphasis on contact models, optimized contact detection for highly different particle sizes, and in-code coarse graining (in contrast to post-processing), we prefer the more general name discrete particle simulation. The code was originally developed for granular chute flows, and has since been extended to many other granular applications, including the geophysical modeling of cinder cone creation. Despite its granular heritage it is designed in a flexible way so it can be adapted to include other features such as long-range interactions and non-spherical particles, etc

Chronology and integrated stratigraphy of the Miocene Sinj Basin (Dinaride Lake System, Croatia)

a b s t r a c t a r t i c l e i n f o In the Miocene, the intra-montane basins of the Dinaric Mountain Chain harbored a series of long-lived lakes constituting the so-called Dinaride Lake System. The thick lacustrine sedimentary records of these lakes provide an excellent opportunity to study evolution and radiation of mollusks in an isolated environment. The 500 m thick infill that accumulated in the Sinj Basin is one of the key records because of its excellent mollusk preservation. Recent studies on the depositional history, pollen assemblages and large mammals have enhanced the understanding not only of Lake Sinj, but also of the regional climatic developments and faunal migratory patterns. A reliable chronology of the development of Lake Sinj, which is crucial for global correlation of its endemic realm, was still lacking. In this paper we present a detailed time-frame for the Miocene Sinj basin based on palaeomagnetic and 40 Ar/ 39 Ar data. We conclude that deposition took place between 18.0 to 15.0 Ma, a time span that correlates with the upper Burdigalian and lower Langhian Mediterranean stages and Ottnangian, Karpatian and lowermost Badenian Paratethys stages. Furthermore, we determined the timing of several events in mollusk evolution, important for correlation across the Dinarides. An age of 15.0 Ma is attributed to the large mammals Conohyus and Gomphotherium, preserved in the upper part of the basin stratigraphy

High fidelity copy number analysis of formalin-fixed and paraffin-embedded tissues using affymetrix cytoscan HD chip

Detection of human genome copy number variation (CNV) is one of the most important analyses in diagnosing human malignancies. Genome CNV detection in formalin-fixed and paraffin-embedded (FFPE) tissues remains challenging due to suboptimal DNA quality and failure to use appropriate baseline controls for such tissues. Here, we report a modified method in analyzing CNV in FFPE tissues using microarray with Affymetrix Cytoscan HD chips. Gel purification was applied to select DNA with good quality and data of fresh frozen and FFPE tissues from healthy individuals were included as baseline controls in our data analysis. Our analysis showed a 91% overlap between CNV detection by microarray with FFPE tissues and chromosomal abnormality detection by karyotyping with fresh tissues on 8 cases of lymphoma samples. The CNV overlap between matched frozen and FFPE tissues reached 93.8%. When the analyses were restricted to regions containing genes, 87.1% concordance between FFPE and fresh frozen tissues was found. The analysis was further validated by Fluorescence In Situ Hybridization on these samples using probes specific for BRAF and CITED2. The results suggested that the modified method using Affymetrix Cytoscan HD chip gave rise to a significant improvement over most of the previous methods in terms of accuracy in detecting CNV in FFPE tissues. This FFPE microarray methodology may hold promise for broad application of CNV analysis on clinical samples. © 2014 Yu et al

Neoadjuvant nivolumab and nivolumab plus ipilimumab induce (near-) complete responses in patients with head and neck squamous cell carcinoma:The IMCISION trial

BackgroundNivolumab (NIVO) alone or with ipilimumab (COMBO) immune checkpoint blockade (ICB) prior to curative surgery has shown promising results in multiple tumor types. We completed a phase Ib/II study with neoadjuvant NIVO or COMBO in resectable head and neck squamous cell carcinoma (HNSCC) and show safety, efficacy and correlative biomarker results.Methods32 stage II-IVB HNSCC patients indicated for curative (salvage) surgery were treated with NIVO (240mg, weeks 1&3, N=6) or NIVO (240mg, weeks 1&3) + IPI (1mg/kg, week 1, N=26) prior to surgery in week 5. Imaging was performed at baseline and week 4. AEs were reported in terms of CTCAE. Pathological response (pR) was defined as % change in viable tumor cells from baseline to on-treatment; ≥90% pR was considered (near-) complete response (pCR). WES and RNAseq were performed on paired tumor biopsies.Results32 (31 HPV-negative) patients started treatment (stage II n=3, III n=8, IVA-B n=11, recurrent disease n=10). 6 patients included with recurrent disease had had previous (C)RT. 1 patient discontinued ICB after one course due to patient’s preference. Surgery was not postponed in any patient. 3/32 patients did not undergo surgery: 1 due to unresectable PD and 2 due to reasons unrelated to ICB or disease. Grade 3-4 irAEs in 11/32 patients were well manageable. (Near-)pCR in the primary tumor was seen in 9/29 evaluable patients (31%). Another 31% of patients had 20-89% pR. At 14 months median FU, RFS for patients with (near-)pCR was 100%, significantly better than patients with <90% pR (p=<0.05). Metabolic response assessment with FDG-PET (week 4) was able to identify (near-)pCRs. A baseline AID/APOBEC-associated tumor mutational profile was correlated with (near)pCR (p=<0.05). Finally, (near)pCR tumors were characterized by a decrease in hypoxia gene expression after ICB.ConclusionsNeoadjuvant ICB was feasible in HNSCC and induced (near)pCR in 31% of evaluable patients at time of surgery, which was accompanied by 100% RFS. Baseline AID/APOBEC-related mutations, on-treatment FDG-PET and resolution of hypoxia need future validation to discover their potential role as biomarkers for (near)pCR after ICB in HNSCC

PRAME expression and clinical outcome of breast cancer

The tumour antigen PReferentially expressed Antigen of MElanoma (PRAME) is expressed in a variety of malignancies, including breast cancer. We have analysed PRAME gene expression in relation to clinical outcome for 295 primary breast cancer patients. Kaplan–Meier survival curves show a correlation of PRAME expression levels with increased rates of distant metastases and decreased overall patient survival. This correlation existed both for the entire patient group (n=295) and for the subgroup of patients (n=185) who did not receive adjuvant chemotherapy. Multivariable analysis indicated that PRAME is an independent marker of shortened metastasis-free interval in patients who did not receive adjuvant chemotherapy. PRAME expression was associated with tumour grade and negative oestrogen receptor status. We conclude that PRAME expression is a prognostic marker for clinical outcome of breast cancer, independent of traditional clinicopathological markers

Quaternary time scales for the Pontocaspian domain: interbasinal connectivity and faunal evolution

The Pontocaspian (Black Sea - Caspian Sea) region has a very dynamic history of basin development and biotic evolution. The region is the remnant of a once vast Paratethys Sea. It contains some of the best Eurasian geological records of tectonic, climatic and paleoenvironmental change. The Pliocene-Quaternary co-evolution of the Black Sea-Caspian Sea is dominated by major changes in water (lake and sea) levels resulting in a pulsating system of connected and isolated basins. Understanding the history of the region, including the drivers of lake level and faunal evolution, is hampered by indistinct stratigraphic nomenclature and contradicting time constraints for regional sedimentary successions. In this paper we review and update the late Pliocene to Quaternary stratigraphic framework of the Pontocaspian domain, focusing on the Black Sea Basin, Caspian Basin, Marmara Sea and the terrestrial environments surrounding these large, mostly endorheic lake-sea systems

The contribution of 7q33 copy number variations for intellectual disability

Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition. One family presents a small duplication in cis affecting CALD1 and AGBL3 genes, while the other four patients carry two larger deletions encompassing EXOC4, CALD1, AGBL3, and CNOT4. This work helps to refine the phenotype and narrow the minimal critical region involved in 7q33 CNVs. Comparison with similar cases and functional studies should help us clarify the relevance of the deleted genes for ID and behavioral alterations.FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the projects PIC/IC/83026/2007, PIC/IC/83013/2007, and POCI-01-0145-FEDER-007038. This work has also been funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER)info:eu-repo/semantics/publishedVersio