Structure and dynamics of deep-seated slope failures in the Magura Flysch Nappe, outer Western Carpathians (Czech Republic)

International audienceDeep-seated mass movements currently comprise one of the main morphogenetic processes in the Flysch Belt of the Western Carpathians of Central Europe. These mass movements result in a large spectrum of slope failures, depending on the type of movement and the nature of the bedrock. This paper presents the results of a detailed survey and reconstruction of three distinct deep-seated slope failures in the Raca Unit of the Magura Nappe, Flysch Belt of the Western Carpathians in the Czech Republic. An interdisciplinary approach has enabled a global view of the dynamics and development of these deep-seated slope failures. The three cases considered here have revealed a complex, poly-phase development of slope failure. They are deep-seated ones with depths to the failure surface ranging from 50 to 110m. They differ in mechanism of movement, failure structure, current activity, and total displacement. The main factors influencing their development have been flysch-bedrock structure, lithology, faulting by bedrock separation (which enabled further weakening through deep weathering), geomorphic setting, swelling of smectite-rich clays, and finally heavy rainfall. All of the slope failures considered here seem to have originated during humid phases of the Holocene or during the Late Glacial

Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma

Parallel Expansions of Sox Transcription Factor Group B Predating the Diversifications of the Arthropods and Jawed Vertebrates

Group B of the Sox transcription factor family is crucial in embryo development in the insects and vertebrates. Sox group B, unlike the other Sox groups, has an unusually enlarged functional repertoire in insects, but the timing and mechanism of the expansion of this group were unclear. We collected and analyzed data for Sox group B from 36 species of 12 phyla representing the major metazoan clades, with an emphasis on arthropods, to reconstruct the evolutionary history of SoxB in bilaterians and to date the expansion of Sox group B in insects. We found that the genome of the bilaterian last common ancestor probably contained one SoxB1 and one SoxB2 gene only and that tandem duplications of SoxB2 occurred before the arthropod diversification but after the arthropod-nematode divergence, resulting in the basal repertoire of Sox group B in diverse arthropod lineages. The arthropod Sox group B repertoire expanded differently from the vertebrate repertoire, which resulted from genome duplications. The parallel increases in the Sox group B repertoires of the arthropods and vertebrates are consistent with the parallel increases in the complexity and diversification of these two important organismal groups

Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience

We demonstrated previously that antenatal glucocorticoid treatment (AGT, gestational days 16-19) altered the size and organization of the adult rat midbrain dopaminergic (DA) populations. Here we investigated the consequences of these AGT-induced cytoarchitectural disturbances on indices of DA function in adult rats. We show that in adulthood, enrichment of striatal DA fiber density paralleled AGT-induced increases in the numbers of midbrain DA neurons, which retained normal basal electrophysiological properties. This was co-incident with changes in (i) striatal D2-type receptor levels (increased, both sexes); (ii) D1-type receptor levels (males decreased; females increased); (iii) DA transporter levels (males increased; females decreased) in striatal regions; and (iv) amphetamine-induced mesolimbic DA release (males increased; females decreased). However, despite these profound, sexually dimorphic changes in markers of DA neurotransmission, in-utero glucocorticoid overexposure had a modest or no effect on a range of conditioned and unconditioned appetitive behaviors known to depend on mesolimbic DA activity. These findings provide empirical evidence for enduring AGT-induced adaptive mechanisms within the midbrain DA circuitry, which preserve some, but not all, functions, thereby casting further light on the vulnerability of these systems to environmental perturbations. Furthermore, they demonstrate these effects are achieved by different, often opponent, adaptive mechanisms in males and females, with translational implications for sex biases commonly found in midbrain DA-associated disorders

Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer

In this study, we characterized the metabolome of the human ovary and identified metabolic alternations that coincide with primary epithelial ovarian cancer (EOC) and metastatic tumors resulting from primary ovarian cancer (MOC) using three analytical platforms: gas chromatography mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) using buffer systems and instrument settings to catalog positive or negative ions. The human ovarian metabolome was found to contain 364 biochemicals and upon transformation of the ovary caused changes in energy utilization, altering metabolites associated with glycolysis and β-oxidation of fatty acids—such as carnitine (1.79 fold in EOC, p<0.001; 1.88 fold in MOC, p<0.001), acetylcarnitine (1.75 fold in EOC, p<0.001; 2.39 fold in MOC, p<0.001), and butyrylcarnitine (3.62 fold, p<0.0094 in EOC; 7.88 fold, p<0.001 in MOC). There were also significant changes in phenylalanine catabolism marked by increases in phenylpyruvate (4.21 fold; p = 0.0098) and phenyllactate (195.45 fold; p<0.0023) in EOC. Ovarian cancer also displayed an enhanced oxidative stress response as indicated by increases in 2-aminobutyrate in EOC (1.46 fold, p = 0.0316) and in MOC (2.25 fold, p<0.001) and several isoforms of tocopherols. We have also identified novel metabolites in the ovary, specifically N-acetylasparate and N-acetyl-aspartyl-glutamate, whose role in ovarian physiology has yet to be determined. These data enhance our understanding of the diverse biochemistry of the human ovary and demonstrate metabolic alterations upon transformation. Furthermore, metabolites with significant changes between groups provide insight into biochemical consequences of transformation and are candidate biomarkers of ovarian oncogenesis. Validation studies are warranted to determine whether these compounds have clinical utility in the diagnosis or clinical management of ovarian cancer patients

Sequential therapy with bevacizumab and EGFR inhibitors for metastatic colorectal carcinoma: a national registry-based analysis

Tomas Buchler,1 Renata Chloupkova,2 Alexandr Poprach,3 Ondrej Fiala,4,5 Igor Kiss,3 Katerina Kopeckova,6 Ladislav Dusek,2 Veronika Veskrnova,1 Lubomir Slavicek,7 Milan Kohoutek,8 Jindrich Finek,4 Marek Svoboda,3 Lubos Petruzelka,9 Bohuslav Melichar10 1Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital, 140 59 Prague, Czech Republic; 2Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic; 3Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Brno 656 53, Czech Republic; 4Department of Oncology, University Hospital, 304 60 Pilsen, Czech Republic; 5Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic; 6Department of Oncology, Motol University Hospital and Second Faculty of Medicine, Charles University, 150 00 Prague, Czech Republic; 7Department of Oncology, Jihlava Hospital Comprehensive Cancer Centre, Jihlava, Czech Republic; 8Department of Oncology, T Bata Hospital and Comprehensive Cancer Centre, Zlin, Czech Republic; 9Department of Oncology, General University Hospital and Charles University First Faculty of Medicine, 128 08 Prague, Czech Republic; 10Department of Oncology, Palacky University Medical School and Teaching Hospital, 775 20 Olomouc, Czech Republic Purpose: Although inhibitors of vascular endothelial growth factor and inhibitors of epidermal growth factor receptor (EGFRi) are commonly used for the treatment of metastatic colorectal cancer (mCRC), the optimal sequencing of these agents is currently unclear. Methods: A national registry of targeted therapies was used to analyze baseline &shy;characteristics and outcomes of patients with mCRC and wild-type KRAS exon 2 status who received &shy;bevacizumab and EGFRi (cetuximab or panitumumab) as a part of first- and second-line &shy;treatment in either sequence. Results: The cohort included 490 patients (181 patients treated with first-line EGFRi and second-line bevacizumab and 309 patients treated with first-line bevacizumab and second-line EGFRi). Median overall survival (OS) from the initiation on first-line therapy was similar for patients treated with either sequence, reaching 31.8 (95% CI 27.5&ndash;36.1) vs 31.4 months (95% CI 27.8&ndash;35.0) for EGFRi &rarr; bevacizumab vs bevacizumab &rarr; EGFRi cohort, respectively. Time from first-line initiation to progression on the second-line therapy [progression-free survival (PFS)] was 21.1 (95% CI 19.3&ndash;23.0) vs 19.3 months (95% CI 17.3&ndash;21.3) for bevacizumab &rarr; EGFRi vs EGFRi &rarr; bevacizumab cohort, respectively (P=0.016). Conclusion: This retrospective analysis of real-world data of patients with wild-type KRAS exon 2 mCRC showed no differences in OS between cohorts treated with bevacizumab &rarr; EGFRi vs the reverse sequence while combined PFS favored the bevacizumab &rarr; EGFRi sequence. Keywords: colorectal carcinoma, bevacizumab, panitumumab, cetuximab, sequenc