Time-space evolution and volcanological features of the Late Miocene-Quaternary Calimani-Gurghiu-Harghita Volcanic Range, East Carpathians, Romania. A Review.

The Carpathian-Pannonian Region (CPR) hosts one of the major Cainozoic volcanic provinces of Europe extending in space over 6 eastern European countries.The lithospheric evolution of this large area governed by large-scale asthenospheric processes is recorded by products of volcanic activity occurred during a time interval of more than 21 million years. According to their surface occurrence areas, ages and composition the Neogene volcanics of CPR were systematized in three main groups: 1) mostly explosive products of felsic magmas generated at the beginning of volcanism in the whole CPR and in their particular occurrence areas (21-12 Ma) developed in the actual intra-Carpathian Pannonian Basin, 2) mostly intermediate calc-alkaline rocks emplaced in both the intra-Carpathian areas and along the arcuate Carpathian fold-and-thrust belt, and 3) Na- and K- alkaline and ultra-alkaline products clustered in a number of monogenetic volcanic fields across the whole intra-Carpathian realm developed in the final stages of volcanic activity of the CPR as a whole and of their particular occurrence areas. The ca. 160 km long Călimani-Gurghiu-Harghita volcanic range (CGH) developed as part of the intermediate calc-alkaline volcanism closely related in space with the fold-and-thrust belt of the Carpathians, representing the south-eastern segment of the CPR. Although its map view and general petrochemical and volcanological characteristics are quite similar with those of other segments of the orogene belt- tied calc-alkaline volcanic segments, at a closer look CGH displays a number of unique features. The time-space evolution of CGH is particular not only in that it is the youngest (10.5 to < 0.05 Ma) dominantly calc-alkaline segment in CPR but also it shows a transient character. Unlike other segments along which volcanism occurred simultaneously forming true subduction-related 400 to 800 km long volcanic fronts which were stable in time for millions of year, in CGH volcanic activity migrated continuously along the range from NW to SE. So, during any given 1 Ma time interval active volcanism was restricted to very limited areas and to just a few active volcanic centers. The along-range shift of volcanic foci was concurrent with progressively lower volumes of magma erupted and decreasing magma output rates. As a result, gradually lower-volume and less complex volcanic edifices were built up. Moreover, at the range-ending and youngest South Harghita sub-segment, magma compositions gradually changed from normal calc-alkaline to high-K calc-alkaline and shoshonitic, and adakitic features emerged at the end of volcanic activity, after a time gap of 0.5 Ma. This marks a major geodynamic event in the development of the East Carpathians themselves. During the transient volcanism of CGH, edifices of varying volume and complexity were built up forming a row of tightly- packed adjoining stratovolcanoes/composite volcanoes whose peripheral volcaniclastic aprons complexly juxtaposed, overlapped and merged with each other. The largest ones (Călimani caldera, and Fâncel-Lăpuşna) developed until caldera stage. Some of them (Rusca-Tihu in the Călimani Mts., Vârghiş in the North Harghita Mts.) became unstable during their growth and collapsed, generating widespread large-volume debris avalanche deposits. Edifice instability was solved by volcano-basement interaction processes, such as volcano spreading, at some large-volume volcanoes (in particular those in the Gurghiu Mts.). Volcano typology changed at the smaller-volume constructs toward the southeastern terminus of the range in the South Harghita Mts. from typical large stratovolcanoes to smaller composite volcanoes, dome clusters and isolated domes and simpler internal structures. As a whole, CGH displays an extremely particular evolutionary pattern strongly suggesting a transient character and decreasing to extinguishing volcanic activity along its length from NW to SE

ABCC1 and Glutathione Metabolism Limit the Efficacy of Bcl-2 Inhibitors in Acute Myeloid Leukemia

The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies

Noble gas and carbon isotope systematics at the seemingly inactive Ciomadul volcano (Eastern‐Central Europe, Romania): evidence for volcanic degassing

Ciomadul is the youngest volcano in the Carpathian-Pannonian Region, Eastern-Central Europe, which last erupted 30 ka. This volcano is considered to be inactive, however, combined evidence from petrologic and magnetotelluric data, as well as seismic tomography studies suggest the existence of a subvolcanic crystal mush with variable melt content. The volcanic area is characterized by high CO2 gas output rate, with a minimum of 8.7 × 103 t yr-1. We investigated 31 gas emissions at Ciomadul to constrain the origin of the volatiles. The δ13C-CO2 and 3He/4He compositions suggest the outgassing of a significant component of mantle-derived fluids. The He isotope signature in the outgassing fluids (up to 3.10 Ra) is lower than the values in the peridotite xenoliths of the nearby alkaline basalt volcanic field (R/Ra 5.95Ra±0.01) which are representative of a continental lithospheric mantle and significantly lower than MORB values. Considering the chemical characteristics of the Ciomadul dacite, including trace element and Sr- Nd and O isotope compositions, an upper crustal contamination is less probable, whereas the primary magmas could have been derived from an enriched mantle source. The low He isotopic ratios could indicate a strongly metasomatized mantle lithosphere. This could be due to infiltration of subduction-related fluids and postmetasomatic ingrowth of radiogenic He. The metasomatic fluids are inferred to have contained subducted carbonate material resulting in a heavier carbon isotope composition (13C is in the range of -1.4 to -4.6 ‰) and an increase of CO2/3He ratio. Our study shows the magmatic contribution to the emitted gases

Experimental Evolution of Resistance to Artemisinin Combination Therapy Results in Amplification of the mdr1 Gene in a Rodent Malaria Parasite

Background: Lacking suitable alternatives, the control of malaria increasingly depends upon Artemisinin Combination Treatments (ACT): resistance to these drugs would therefore be disastrous. For ACTs, the biology of resistance to the individual components has been investigated, but experimentally induced resistance to component drugs in combination has not been generated. Methodology/Principal Findings: We have used the rodent malaria parasite Plasmodium chabaudi to select in vivo resistance to the artesunate (ATN) + mefloquine (MF) version of ACT, through prolonged exposure of parasites to both drugs over many generations. The selection procedure was carried out over twenty-seven consecutive sub-inoculations under increasing ATN + MF doses, after which a genetically stable resistant parasite, AS-ATNMF1, was cloned. AS-ATNMF1 showed increased resistance to ATN + MF treatment and to artesunate or mefloquine administered separately. Investigation of candidate genes revealed an mdr1 duplication in the resistant parasites and increased levels of mdr1 transcripts and protein. There were no point mutations in the atpase6 or ubp1genes. Conclusion: Resistance to ACTs may evolve even when the two drugs within the combination are taken simultaneously and amplification of the mdr1 gene may contribute to this phenotype. However, we propose that other gene(s), as ye

Drug-induced trafficking of p-glycoprotein in human brain capillary endothelial cells as demonstrated by exposure to mitomycin C.

P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid rafts to gain its full functionality

Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is the most common tumor in the adult liver, with high relapse and mortality rates despite diverse treatment modalities. In this study, nicotinamide N-methyltransferase (NNMT), a key enzyme in drug metabolism, was investigated as a potential prognostic factor.</p> <p>Methods</p> <p>Frozen tumors and non-cancerous surrounding tissues from 120 patients with primary HCC were studied. Expressions of NNMT and internal control genes were measured by real-time reverse-transcription PCR (RT-PCR). The relationship of NNMT mRNA level with clinicopathologic parameters and clinical outcome was evaluated.</p> <p>Results</p> <p>NNMT mRNA level is markedly reduced in HCCs compared to non-cancerous surrounding tissues (P < 0.0001), and NNMT expression in tumors was significantly correlated with tumor stage (P = 0.010). Moreover, stratification of patients based on tumor NNMT mRNA levels revealed that the patients who expressed higher NNMT mRNA levels tended to have a shorter overall survival (OS) time (P = 0.053) and a significantly shorter disease-free survival (DFS) time (P = 0.016). Both NNMT expression (P = 0.0096) and tumor stage (P = 0.0017) were found to be significant prognostic factors for DFS in a multivariate analysis.</p> <p>Conclusion</p> <p>The results of this study indicated that NNMT gene expression is associated with tumor stage and DFS time in HCC cases. Because of the broad substrate specificity of NNMT, which could alter the efficacy and adverse effects of chemotherapy, NNMT merits further investigation regarding its role as a prognostic factor with a larger cohort of HCC patients.</p