The Marmara Sea Gateway since ~16 ky BP: non-catastrophic causes of paleoceanographic events in the Black Sea at 8.4 and 7.15 ky BP

The Late Quaternary history of connection of the Black Sea to the Eastern Mediterranean has been intensely debated. Ryan, Pitman and coworkers advocate two pulses of outflow from the Black Sea to the world ocean at ~16–14.7 ky BP and ~11–10 ky BP. From ~14.7–11 ky BP and from ~10–8.4 ky BP, they suggest that the level of the Black Sea fell to ~ -100 m. At 8.4 ky BP, they further claim that a catastrophic flood occurred in a geological instant, refilling the Black Sea with saline waters from the Mediterranean. In contrast, we continue to gather evidence from seismic profiles and dated cores in the Marmara Sea which demonstrate conclusively that the proposed flood did not occur. Instead, the Black Sea has been at or above the Bosphorus sill depth and flowing into the world ocean unabated since ~10.5 ky BP. This conclusion is based on continuous Holocene water-column stratification (leading to sapropel deposition in the Marmara Sea and the Aegean Sea), proxy indicators of sea-surface salinity, and migration of endemic species across the Bosphorus in both directions whenever appropriate hydrographic conditions existed in the strait. The two pulses of outflow documented by Ryan, Pitman and coworkers find support in our data, and we have modified our earlier interpretations so that these pulses now coincide with the development of mid-shelf deltas: \Delta 2 (16–14.7 ky BP) and \Delta 1 (10.5–9 ky BP) at the southern end of the Bosphorus Strait. However, continued Black Sea outflow after 9 ky BP prevented the northward advection of Mediterranean water and the entry of open-marine species into the Black Sea for more than 1000 years. Sufficient Mediterranean water to change the Sr-isotopic composition of slope and shelf water masses was not available until ~8.4 ky BP (along with the first arrival of many varieties of marine fauna and flora), whereas euryhaline molluscs did not successfully populate the Black Sea shelves until ~7.15 ky BP. Instead of relying on catastrophic events, we recognize a slow, progressive reconnection of the Black Sea to the world ocean, accompanied by significant time lags

Mutational processes molding the genomes of 21 breast cancers

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed

Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups

In multiple myeloma, next-generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number abnormalities (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case. Known and novel independent prognostic markers were identified in our cohort of proteasome inhibitor and immunomodulatory drug-treated patients with long follow-up, including events with context-specific prognostic value, such as deletions of the PRDM1 gene. Taking advantage of the comprehensive genomic annotation of each case, we used innovative statistical approaches to identify potential novel myeloma subgroups. We observed clusters of patients stratified based on the overall number of mutations and number/type of CNAs, with distinct effects on survival, suggesting that extended genotype of multiple myeloma at diagnosis may lead to improved disease classification and prognostication

Genomic classification and prognosis in acute myeloid leukemia

BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTS: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNAsplicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2R172 mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONS: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification

The dinoflagellate cyst genera <i>Achomosphaera</i> Evitt 1963 and <i>Spiniferites</i> Mantell 1850 in Pliocene to modern sediments: a summary of round table discussions

We present a summary of two round-table discussions held during two subsequent workshops in Montreal (Canada) on 16 April 2014 and Ostend (Belgium) on 8 July 2015. Five species of the genus Achomosphaera Evitt 1963 and 33 of the genus Spiniferites Mantell 1850 emend. Sarjeant 1970 occuring in Pliocene to modern sediments are listed and briefly described along with remarks made by workshop participants. In addition, several holotypes and topotypes are reillustrated. Three species previously assigned to Spiniferites are here considered/accepted as belonging to other genera: Impagidinium inaequalis (Wall and Dale in Wall et al. 1973) Londeix et al. 2009, Spiniferites rubinus (Rossignol 1962 ex Rossignol 1964) Sarjeant 1970, and Thalassiphora balcanica Baltes & 1971. This summary forms the basis for a set of papers that follows, where points raised during the workshops are explored in greater detail

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment

Late Holocene benthic formainifera beneath perennial sea ice on an Arctic continental shelf

The Canadian Ice Island Project allows geological, biological and oceanographic studies of regions on the Arctic margin that are beneath the perennial pack ice. High-resolution seismic profiles, grab sampling and bottom photography resulted in the discovery of siliceous sponge reefs on the Axel Heiberg Shelf. Sponge colonies interspersed with mudflats form a variety of biotopes for a rich benthic life. The formainifera assemblage is characterized by large numbers of specimens, high species diversity, predominance of calcareous specimens, and a nearly complete lack of living fauna. The perennial sea ice cover is the main controlling factor of the environment. Low regional runoff and rapid freezing of leads in the ice may explain periodic high bottom salinity, reduced detrital deposition, and low organic matter production. The surface foraminifera assemblage is of a subfossiliferous nature which represents an accumulation of dead tests over approximately 1000 years. Small-scale biotope differences and the resulting patchy distribution of species evolved from the environmental stability of the area. The species composition is unique when compared with other known shallow-water Arctic regions and shows a slight affinity with the Pacific fauna, suggesting a migration through the Bering Strait