Exploring the link between diabetes and pancreatic cancer

Introduction: Epidemiological studies indicate an association between type 2 diabetes and pancreatic cancer but the complex and multidirectional relationship between them remains unclear. Areas covered: We summarized epidemiological evidence on diabetes and pancreatic cancer exploring the time-risk relationship. We described mechanisms linking long-standing diabetes to pancreatic cancer. We discussed pancreatic cancer-associated diabetes and its implication in the early detection of pancreatic cancer. Expert opinion: The markedly increased risk of pancreatic cancer in patients with new-onset diabetes compared with long-standing diabetes indicates a complex and bidirectional connection, with long-standing diabetes being a predisposing factor for pancreatic cancer (increasing the risk of the malignancy 1.5- to 2-fold) and new-onset diabetes an early manifestation of the tumour. Identifying clinical features and biomarkers to distinguish pancreatic cancer-associated diabetes from type 2 diabetes is an important goal to improve management and survival of this cancer. Imaging (MRI) for middle age patients with new-onset diabetes may be considered

Epidemiological findings on interventional cardiology procedures during the COVID-19 pandemic: A multi-center study

Background: The rates of in-hospital mortality following percutaneous interventional procedures (PIP) during the COVID-19 pandemic period compared to the non-pandemic period has not been reported so far. Methods: We retrospectively enrolled all consecutive patients admitted for PIP across five centers from February 2020 to May 2020. Results: A total of 4092 PIP were performed during the reference periods. The total number of procedures dropped from 2380 to 1712 (28.0% reduction). Overall in-hospital mortality increased from 1.1% in 2019, to 2.6% in 2020 (63% relative increase). Conclusion: During the COVID-19 pandemic, in-hospital all-cause mortality significantly increased in patients admitted for cardiological PIP

Prospeccion biogeoquimica del oro en el yacimiento de Pau-a-Pique, Estado de Mato Grosso, Brasil

During the dry season (July-August 1997) eleven samples of soil-plant pairs were collected in the Pau-a-Pique gold deposit, southwestern of Amazonic Craton, about 440 km NW of Cuiabá city. The area contains rocks of Aguapeí Group, Rondonian Belt and recent cover. The area has a steep relief covered by thin soils. The vegetation is sparse and predominantly composed of xerophitic shrubs. Two kinds of plant species were sampled, one belonging to the Annonaceae family and the other one to the Piperaceae family. The ashes of these plants and the soils were analysed by INAA and ICP. The highest gold contents are found in the ashes of plants collected in the colluvium soil (white mica, clay minerals and Fe-oxyhydroxides) covering the hydrothermal halo of the deposit. In the soil, the highest gold values are those from eluvium related to the quartz veins. The higher gold values in plants respect to the soils suggest that the plants could be useful to establish hydrothermal targets.Se recogieron once muestras de pares suelo-planta durante la estación seca (julioagosto 1997) en el yacimiento de oro de Pau-a-Pique al suroeste del cratón Amazónico, unos 440 km al NO de la ciudad de Cuiabá. La geología de esta zona presenta rocas pertenecientes al Gmpo Aguapeí y al Cinturón Rondónico, así como sedimentos recientes de cobertera. La topografía presenta relieves abruptos y los suelos forman una delgada lámina. La vegetación es escasa y predominan los arbustos xerófitos. Se muestrearon dos especies de plantas, una de ellas perteneciente a la familia Annonaceae, y la otra a la familia Piperaceae. Las cenizas de estas plantas y de sus suelos fueron analizadas mediante las técnicas de INAA y ICP. Los más altos contenidos en oro se encontraron en las cenizas de las plantas recogidas en los coluviones (mica blanca, arcillas y oxihidróxidos de Fe) que recubren el halo hidrotermal de los depósitos. En el suelo, los valores más altos del oro corresponden a los productos relacionados con la meteorización de las vetas de cuarzo. El mayor contenido en oro en las plantas con respecto a los suelos sugiere que éstas pueden ser utilizadas para localizar posibles yacimientos hidrotermales

Assisted evolution enables HIV-1 to overcome a high trim5α-imposed genetic barrier to rhesus macaque tropism

Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5α protein (rhTRIM5α). Initially, we attempted to derive rhTRIM5α-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5α. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5α sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5α sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5α recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5α were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5α sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5α-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5α. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5α on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIVmac239 Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5α is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection

Nef Decreases HIV-1 Sensitivity to Neutralizing Antibodies that Target the Membrane-proximal External Region of TMgp41

Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of virion-associated Env, we searched for qualitative changes by examining whether Nef alters HIV-1 sensitivity to agents that target distinct features of Env. Nef conferred as much as 50-fold resistance to 2F5 and 4E10, two potent neutralizing monoclonal antibodies (nAbs) that target the membrane proximal external region (MPER) of TMgp41. In contrast, Nef had no effect on HIV-1 neutralization by MPER-specific nAb Z13e1, by the peptide inhibitor T20, nor by a panel of nAbs and other reagents targeting gp120. Resistance to neutralization by 2F5 and 4E10 was observed with Nef from a diverse range of HIV-1 and SIV isolates, as well as with HIV-1 virions bearing Env from CCR5- and CXCR4-tropic viruses, clade B and C viruses, or primary isolates. Functional analysis of a panel of Nef mutants revealed that this activity requires Nef myristoylation but that it is genetically separable from other Nef functions such as the ability to enhance virus infectivity and to downregulate CD4. Glycosylated-Gag from MoMLV substituted for Nef in conferring resistance to 2F5 and 4E10, indicating that this activity is conserved in a retrovirus that does not encode Nef. Given the reported membrane-dependence of MPER-recognition by 2F5 and 4E10, in contrast to the membrane-independence of Z13e1, the data here is consistent with a model in which Nef alters MPER recognition in the context of the virion membrane. Indeed, Nef and Glycosylated-Gag decreased the efficiency of virion capture by 2F5 and 4E10, but not by other nAbs. These studies demonstrate that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies. This newly discovered activity for Nef has important implications for anti-HIV-1 immunity and AIDS pathogenesis

Assembly of the Murine Leukemia Virus Is Directed towards Sites of Cell–Cell Contact

Applying 4D imaging, this study investigates the mechanism by which cell-cell contact enhances retrovirus spreading and demonstrates that viral budding is highly polarized towards sites of cell-cell contact

Galanin pathogenic mutations in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment