Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

Adar3 is involved in learning and memory in mice

© 2018 Mladenova, Barry, Konen, Pineda, Guennewig, Avesson, Zinn, Schonrock, Bitar, Jonkhout, Crumlish, Kaczorowski, Gong, Pinese, Franco, Walkley, Vissel and Mattick. The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

PINA v2.0: Mining interactome modules

Peer reviewe

Mitochondrial mutations and metabolic adaptation in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. METHODS: We deployed an integrated approach combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Genome analysis was performed via targeted sequencing of the mitochondrial genome (mtDNA) and nuclear genes encoding mitochondrial components and metabolic genes. Phenotypic characterization of PDCLs included measurement of cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a Seahorse XF extracellular flux analyser, targeted metabolomics and pathway profiling, and radiolabelled glutamine tracing. RESULTS: We identified 24 somatic mutations in the mtDNA of 12 patient-derived pancreatic cancer cell lines (PDCLs). A further 18 mutations were identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Comparison with reference datasets indicated a strong selection bias for non-synonymous mutants with predicted functional effects. Phenotypic analysis showed metabolic changes consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis. Metabolomics and radiolabeled substrate tracing indicated the initiation of reductive glutamine metabolism and lipid synthesis in tumours. CONCLUSIONS: The heterogeneous genomic landscape of pancreatic tumours may converge on a common metabolic phenotype, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. Targeting resulting metabolic phenotypes may be a productive therapeutic strategy

Messina: A Novel Analysis Tool to Identify Biologically Relevant Molecules in Disease

BACKGROUND: Morphologically similar cancers display heterogeneous patterns of molecular aberrations and follow substantially different clinical courses. This diversity has become the basis for the definition of molecular phenotypes, with significant implications for therapy. Microarray or proteomic expression profiling is conventionally employed to identify disease-associated genes, however, traditional approaches for the analysis of profiling experiments may miss molecular aberrations which define biologically relevant subtypes. METHODOLOGY/PRINCIPAL FINDINGS: Here we present Messina, a method that can identify those genes that only sometimes show aberrant expression in cancer. We demonstrate with simulated data that Messina is highly sensitive and specific when used to identify genes which are aberrantly expressed in only a proportion of cancers, and compare Messina to contemporary analysis techniques. We illustrate Messina by using it to detect the aberrant expression of a gene that may play an important role in pancreatic cancer. CONCLUSIONS/SIGNIFICANCE: Messina allows the detection of genes with profiles typical of markers of molecular subtype, and complements existing methods to assist the identification of such markers. Messina is applicable to any global expression profiling data, and to allow its easy application has been packaged into a freely-available stand-alone software package

Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways

Introduction Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets. Methods We applied an immunoaffinity/mass spectrometry workflow to three mouse models: murine stem cell virus-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus-polyoma virus middle T antigen (PyMT); and the p53?/? transplant model (p53). Pathways and protein¿protein interaction networks were identified by bioinformatics analysis. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterised by Western blot analysis and array comparative genomic hybridisation. The functional role of mesenchymal¿epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering RNA (siRNA)¿mediated knockdown and cell proliferation assays. Results The three models could be distinguished on the basis of tyrosine phosphorylation signatures and signalling networks. HER2 tumours exhibited a protein¿protein interaction network centred on avian erythroblastic leukaemia viral oncogene homologue 2 (Erbb2), epidermal growth factor receptor and platelet-derived growth factor receptor ?, and they displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1. In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol 3-kinase signalling pathway, whereas p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton and shared signalling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, as well as Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were recapitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2. Conclusion This study provides network-level insights into signalling in the breast cancer models utilised and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signalling pathways. The Met-amplified, p53-null tumours provide a new preclinical model for a subset of triple-negative breast cancers