Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarci-noma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy

Effects of Embryonic Exposure to Salinity Stress or Hypoxia on Post-metamorphic Growth and Survival of the Polychaete Capitella teleta

Although a good number of studies have investigated the impact of larval experience on aspects of post-metamorphic performance, only a few have considered the potential impact of stresses experienced by brooded embryos. In this study we separately investigated the impact of salinity stress (as low as 10) and hypoxia (1 ml O2 1 sub-1) experienced by brooded embryos of the deposit-feeding polychaete Capitella teleta on hatching success, metamorphosis, post-metamorphic survival, and post-metamorphic growth. Salinity reduction from 30 to 10 or 15 reduced relative hatching success, presumably by reducing embryonic survival, but generally had no negative latent effects on juvenile survival or growth. Prolonged exposure to hypoxic conditions had no negative effects, as seen on measurements recorded, other than abandonment of brood tubes by some females. There were no negative effects on days to emergence from brood tubes, numbers of larvae emerging from brood tubes, juvenile survival, or juvenile growth. Future studies should consider the potential role of maternal behavior in protecting embryos from at least short-term exposures to hypoxia, and the capacity for anaerobic metabolism in both embryos and adults of this species

Expression of UDP-glucuronosyltransferase 1A6 isoform in Caco-2 cells stimulated with lipopolysaccharide

Glucuronidation is an important metabolic process of detoxification in all vertebrates. The reaction is catalyzed by a multigene family of UDP-glucuronosyltransferases (UGTs) able to convert many xenobiotics and endobiotics (hydrophobic substances) to inactive, water-soluble glucuronides. The UGTs play a protective role, facilitating the elimination of potentially toxic metabolites via urine, bile and feces; therefore, impairment of UGTs may have important toxicological consequences. The regulation of UGTs during bacterial infection or inflammation is not well described. In this study, we investigated the in vitro effect of lipopolysaccharide (LPS) on the expression of the UGT1A6 isoform in human colon carcinoma Caco-2 cells. Results demonstrated a significant down-regulation of UGT1A6 expression, both in terms of mRNA and protein levels, and a reduced UGT activity after LPS exposure of cell cultures, suggesting a role for endotoxins on UGT regulation mechanisms

MKRN3 and KISS1R mutations in precocious and early puberty

Background Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socio-economic factors, although the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing. Methods We analyzed the DNA sequence of these genes in 13 girls affected by central precocious puberty (CPP) who showed onset of puberty before 8 years of age, and in 6 girls affected by early puberty (EP) between 8 and 10 years of age. Results Direct sequencing of the KISS1R (GPR54) gene revealed two SNPs. One SNP is a missense variant (rs 350,132) that has been previously reported in connection to CPP in Korean girls. The other variant that we found in the GPR54 gene (rs764046557) was a missense SNP located in exon 5 at position 209 of the aminoacid. We identified this variant in only one CPP patient. Automatic sequencing of MKRN3 in all patients revealed three variants in eight subjects. In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient. Conclusion In conclusion, we identified sequence variations of the KISS1R and MKRN3 genes, two of the most frequent genetic causes of ICPP. Our results suggest that these variants might be inducible factors in the pathogenesis of CPP

Late-Proterozoic to Paleozoic history of the peri-Gondwana Calabria–Peloritani Terrane inferred from a review of zircon chronology

U–Pb analyses of zircon from ten samples of augen gneisses, eight mafic and intermediate metaigneous rocks and six metasediments from some tectonic domains along the Calabria–Peloritani Terrane (Southern Italy) contribute to knowledge of peri-Gondwanan evolution from Late-Proterozoic to Paleozoic times. All samples were equilibrated under amphibolite to granulite facies metamorphism during the Variscan orogeny. The zircon grains of all considered samples preserve a Proterozoic memory suggestive of detrital, metamorphic and igneous origin. The available data fit a frame involving: (1) Neoproterozoic detrital input from cratonic areas of Gondwana; (2) Pan-African/Cadomian assemblage of blocks derived from East and West African Craton; (3) metamorphism and bimodal magmatism between 535 and 579 Ma, within an active margin setting; (4) rifting and opening of Ordovician basins fed by detrital input from the assembled Cadomian blocks. The Paleozoic basins evolved through sedimentation, metamorphism and magmatism during the Variscan orogeny involving Palaeozoic and pre-Paleozoic blocks. The Proterozoic zircon records decidedly decrease in the high grade metamorphic rocks affected by Variscan pervasive partial melting. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40064-016-1839-8) contains supplementary material, which is available to authorized users

Intraoperative assessment of fluid responsiveness in normotensive dogs under isoflurane anaesthesia

The aim of this study was to evaluate the incidence of fluid responsiveness (FR) to a fluid challenge (FC) in normotensive dogs under anaesthesia. The accuracy of pulse pressure variation (PPV), systolic pressure variation (SPV), stroke volume variation (SVV), and plethysmographic variability index (PVI) for predicting FR was also evaluated. Dogs were anaesthetised with methadone, propofol, and inhaled isoflurane in oxygen, under volume-controlled mechanical ventilation. FC was performed by the administration of 5 mL/kg of Ringer’s lactate within 5 min. Cardiac index (CI; L/min/m2), PPV, (%), SVV (%), SPV (%), and PVI (%) were registered before and after FC. Data were analysed with ANOVA and ROC tests (p < 0.05). Fluid responsiveness was defined as 15% increase in CI. Eighty dogs completed the study. Fifty (62.5%) were responders and 30 (37.5%) were nonresponders. The PPV, PVI, SPV, and SVV cut-off values (AUC, p) for discriminating responders from nonresponders were PPV >13.8% (0.979, <0.001), PVI >14% (0.956, <0.001), SPV >4.1% (0.793, <0.001), and SVV >14.7% (0.729, <0.001), respectively. Up to 62.5% of normotensive dogs under inhalant anaesthesia may be fluid responders. PPV and PVI have better diagnostic accuracy to predict FR, compared to SPV and SVV

Electron neutrino tagging through tertiary lepton detection

We discuss an experimental technique aimed at tagging electron neutrinos in multi-GeV artificial sources on an event-by-event basis. It exploits in a novel manner calorimetric and tracking technologies developed in the framework of the LHC experiments and of rare kaon decay searches. The setup is suited for slow-extraction, moderate power beams and it is based on an instrumented decay tunnel equipped with tagging units that intercept secondary and tertiary leptons from the bulk of undecayed \pi^+ and protons. We show that the taggers are able to reduce the \nue contamination originating from K_e3 decays by about one order of magnitude. Only a limited suppression (~60%) is achieved for \nue produced by the decay-in-flight of muons; for low beam powers, similar performance as for K_e3 can be reached supplementing the tagging system with an instrumented beam dump.Comment: 19 pages, 7 figures; minor changes, version to appear in EPJ

Electronics design of the RPC system for the OPERA muon spectrometer

The present document describes the front-end electronics of the RPC system that instruments the magnet muon spectrometer of the OPERA experiment. The main task of the OPERA spectrometer is to provide particle tracking information for muon identification and simplify the matching between the Precision Trackers. As no trigger has been foreseen for the experiment, the spectrometer electronics must be self-triggered with single-plane readout capability. Moreover, precision time information must be added within each event frame for off-line reconstruction. The read-out electronics is made of three different stages: the Front-End Boards (FEBs) system, the Controller Boards (CBs) system and the Trigger Boards(TBs) system. The FEB system provides discrimination of the strip incoming signals; a FAST-OR output of the input signals is also available for trigger plane signal generation. FEB signals are acquired by the CB system that provides the zero suppression and manages the communication to the DAQ and Slow Control. A Trigger Board allows to operate in both self-trigger mode (the FEB’s FAST-OR signal starts the plane acquisition) or in external-trigger mode (different conditions can be set on the FAST-OR signals generated from different planes)

Underground Neutrino Detectors for Particle and Astroparticle Science: the Giant Liquid Argon Charge Imaging ExpeRiment (GLACIER)

The current focus of the CERN program is the Large Hadron Collider (LHC), however, CERN is engaged in long baseline neutrino physics with the CNGS project and supports T2K as recognized CERN RE13, and for good reasons: a number of observed phenomena in high-energy physics and cosmology lack their resolution within the Standard Model of particle physics; these puzzles include the origin of neutrino masses, CP-violation in the leptonic sector, and baryon asymmetry of the Universe. They will only partially be addressed at LHC. A positive measurement of $\sin^22\theta_{13}>0.01$ would certainly give a tremendous boost to neutrino physics by opening the possibility to study CP violation in the lepton sector and the determination of the neutrino mass hierarchy with upgraded conventional super-beams. These experiments (so called ``Phase II'') require, in addition to an upgraded beam power, next generation very massive neutrino detectors with excellent energy resolution and high detection efficiency in a wide neutrino energy range, to cover 1st and 2nd oscillation maxima, and excellent particle identification and $\pi^0$ background suppression. Two generations of large water Cherenkov detectors at Kamioka (Kamiokande and Super-Kamiokande) have been extremely successful. And there are good reasons to consider a third generation water Cherenkov detector with an order of magnitude larger mass than Super-Kamiokande for both non-accelerator (proton decay, supernovae, ...) and accelerator-based physics. On the other hand, a very massive underground liquid Argon detector of about 100 kton could represent a credible alternative for the precision measurements of ``Phase II'' and aim at significantly new results in neutrino astroparticle and non-accelerator-based particle physics (e.g. proton decay).Comment: 31 pages, 14 figure

Mesenchymal Stromal Cell on Liver Decellularised Extracellular Matrix for Tissue Engineering

Background: In end-stage chronic liver disease, transplantation represents the only curative option. However, the shortage of donors results in the death of many patients. To overcome this gap, it is mandatory to develop new therapeutic options. In the present study, we decellularised pig livers and reseeded them with allogeneic porcine mesenchymal stromal cells (pMSCs) to understand whether extracellular matrix (ECM) can influence and/or promote differentiation into hepatocyte-like cells (HLCs). Methods: After decellularisation with SDS, the integrity of ECM-scaffolds was examined by histological staining, immunofluorescence and scanning electron microscope. DNA quantification was used to assess decellularisation. pMSCs were plated on scaffolds by static seeding and maintained in in vitro culture for 21 days. At 3, 7, 14 and 21 days, seeded ECM scaffolds were evaluated for cellular adhesion and growth. Moreover, the expression of specific hepatic genes was performed by RT-PCR. Results: The applied decellularisation/recellularisation protocol was effective. The number of seeded pMSCs increased over the culture time points. Gene expression analysis of seeded pMSCs displayed a weak induction due to ECM towards HLCs. Conclusions: These results suggest that ECM may address pMSCs to differentiate in hepatocyte-like cells. However, only contact with liver-ECM is not enough to induce complete differentiation