NEOGENE HISTORY OF INTRAMONTANE BASINS IN THE WESTERN PART OF THE CARPATHIANS

Neogene collision of the Carpathians with the European Platform resulted in flysch nappes overthrust in frontal part of the orogene. Tectonic activation of the Paleoalpine-consolidated Centrai Western Carpathians led to modification of their structural pattern. Axis of the main compression rotated from NW-SE to NE-SW. Thrust-reverse faults and ENE-WSW dextral strike- slips were dominant in the Lower Miocene. Movement of the Western Carpathians north-eastward during the Middle and Upper Miocene caused activation of ENE-WSW sinistrai strike-slips and NE-SW normai faults. Pliocene regional extension was manifested mainly by NE-SW normai faults which controlled the sedimentation and form of the basins

Late Miocene sedimentary record of the Danube / Kisalföld Basin: interregional correlation of depositional systems, stratigraphy and structural evolution

The Danube / Kisalföld Basin is the north-western sub-basin of the Pannonian Basin System. The lithostratigraphic subdivision of the several-km-thick Upper Miocene to Pliocene sedimentary succession related to Lake Pannon has been developed independently in Slovakia and Hungary. A study of the sedimentary formations across the entire basin led us to claim that these formations are identical or similar between the two basin parts to such an extent that their correlation is indeed a matter of nomenclature only. Nemčiňany corresponds to the Kálla Formation, representing locally derived coarse clastics along the basin margins (11– 9.5 Ma). The deep lacustrine sediments are collectively designated the Ivanka Formation in Slovakia, while in Hungary they are subdivided into Szák (fine-grained transgressive deposits above basement highs, 10.5 – 8.9 Ma), Endrőd (deep lacustrine marls, 11.6 –10 Ma), Szolnok (turbidites, 10.5 – 9.2 Ma) and Algyő Formations (fine-grained slope deposits, 10 – 9 Ma). The Beladice Formation represents shallow lacustrine deltaic deposits, fully corresponding to Újfalu (10.5 – 8.7 Ma). The overlying fluvial deposits are the Volkovce and Zagyva Formations (10 – 6 Ma). The synoptic description and characterization of these sediments offer a basin-wide insight into the development of the basin during the Late Miocene. The turbidite systems, the slope, the overlying deltaic and fluvial systems are all genetically related and are coeval at any time slice after the regression of Lake Pannon initiated about 10 Ma ago. All these formations get younger towards the S, SE as the progradation of the shelf-slope went on. The basin got filled up to lake level by 8.7 Ma, since then fluvial deposition dominated

The early evolutionary landscape of osteosarcoma provides clues for targeted treatment strategies

Osteosarcomas are aggressive primary tumors of bone that are typically detected in locally advanced stages; however, which genetic mutations drive the cancer before its clinical detection remain unknown. To identify these events, we performed longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. Phylogenetic and molecular clock analyses were carried out next to identify actionable mutations, and these were validated by integrating data from additional 153 osteosarcomas and pre-existing functional evidence from mouse PDX models. We found that the earliest and thus clinically most promising mutations affect the cell cycle G1 transition, which is guarded by cyclins D3, E1, and cyclin-dependent kinases 2, 4, and 6. Cell cycle G1 alterations originate no more than a year before the primary tumor is clinically detected and occur in >90% and 50% of patients of the discovery and validation cohorts, respectively. In comparison, other cancer driver mutations could be acquired at any evolutionary stage and often do not become pervasive. Consequently, our data support that the repertoire of actionable mutations present in every osteosarcoma cell is largely limited to cell cycle G1 mutations. Since they occur in mutually exclusive combinations favoring either CDK2 or CDK4/6 pathway activation, we propose a new genomically-based algorithm to direct patients to correct clinical trial options

Convergent Evolution of Copy Number Alterations in Multi-Centric Hepatocellular Carcinoma

In the recent years, new molecular methods have been proposed to discriminate multicentric hepatocellular carcinomas (HCC) from intrahepatic metastases. Some of these methods utilize sequencing data to assess similarities between cancer genomes, whilst other achieved the same results with transcriptome and methylome data. Here, we attempt to classify two HCC patients with multi-centric disease using the recall-rates of somatic mutations but find that difficult because their tumors share some chromosome-scale copy-number alterations (CNAs) but little-to-no single-nucleotide variants. To resolve the apparent conundrum, we apply a phasing strategy to test if those shared CNAs are identical by descent. Our findings suggest that the conflicting alterations occur on different homologous chromosomes, which argues for multi-centric origin of respective HCCs

A non-linear SVR-based cascade model for improving prediction accuracy of biomedical data analysis

Biomedical data analysis is essential in current diagnosis, treatment, and patient condition monitoring. The large volumes of data that characterize this area require simple but accurate and fast methods of intellectual analysis to improve the level of medical services. Existing machine learning (ML) methods require many resources (time, memory, energy) when processing large datasets. Or they demonstrate a level of accuracy that is insufficient for solving a specific application task. In this paper, we developed a new ensemble model of increased accuracy for solving approximation problems of large biomedical data sets. The model is based on cascading of the ML methods and response surface linearization principles. In addition, we used Ito decomposition as a means of nonlinearly expanding the inputs at each level of the model. As weak learners, Support Vector Regression (SVR) with linear kernel was used due to many significant advantages demonstrated by this method among the existing ones. The training and application procedures of the developed SVR-based cascade model are described, and a flow chart of its implementation is presented. The modeling was carried out on a real-world tabular set of biomedical data of a large volume. The task of predicting the heart rate of individuals was solved, which provides the possibility of determining the level of human stress, and is an essential indicator in various applied fields. The optimal parameters of the SVR-based cascade model operating were selected experimentally. The authors shown that the developed model provides more than 20 times higher accuracy (according to Mean Squared Error (MSE)), as well as a significant reduction in the duration of the training procedure compared to the existing method, which provided the highest accuracy of work among those considered

Expression of OCT4 isoforms is reduced in primary colorectal cancer

IntroductionColorectal cancer (CRC) is one of the most common types of cancer worldwide. The carcinogenesis of CRC is indeed complex, and there are many different mechanisms and pathways that contribute to the development of malignancy and the progression from primary to metastatic tumors. The OCT4A, encoded by the POU5F1 gene, is a transcription factor responsible for the phenotype of stem cells, maintaining pluripotency and regulation of differentiation. The POU5F1 gene is made up of five exons that can create numerous isoforms through alternative promoter or alternative splicing. In addition to OCT4A, other isoforms called OCT4B are also translated into protein; however, their role in cells has been unclear. The aim of our work was to investigate the expression patterns of OCT4 isoforms in primary and metastatic CRC, providing us with useful information about their role in the development and progression of CRC.MethodsSurgical specimens from a total of 78 patients were collected and isolated from primary tumors (n = 47) and metastases (n = 31). The relative gene expression of OCT4 isoforms was investigated using the RT-qPCR method together with the TaqMan probes for particular OCT4 isoforms.ResultsOur results suggest significantly downregulated expression of the OCT4A and OCT4Bs isoforms in both primary (p = 0.0002 and p < 0.0001, respectively) and metastatic tumors (p = 0.0006 and p = 0.00051, respectively) when compared with the control samples. We also observed a correlation between reduced expression of all OCT4 isoforms and both primary and left-sided tumors (p = 0.001 and p = 0.030, respectively). On the other hand, the expression of all OCT4 isoforms was significantly upregulated in metastases compared with primary tumors (p < 0.0001).DiscussionUnlike previous reports, we found out that the expression of OCT4A, OCT4Bs, and all OCT4 isoforms was significantly reduced in primary tumors and metastases compared with control samples. On the other hand, we supposed that the expression rate of all OCT4 isoforms may be related to the cancer type and side, as well as to liver metastases. However, further studies are required to investigate the detailed expression patterns and significance of individual OCT4 isoforms in carcinogenesis

<i>BCL9L</i> dysfunction impairs caspase-2 expression permitting aneuploidy tolerance in colorectal cancer

Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution

3'-UTR Poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers

The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers. Cancer Res; 74(1); 224-34. ©2013 AACR