66 research outputs found
Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines
Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaig
The GAPS programme at TNG : XLIX. TOI-5398, the youngest compact multi-planet system composed of an inner sub-Neptune and an outer warm Saturn
Context. Short-period giant planets (P ≲ 10 days, Mp >0.1 MJ) are frequently found to be solitary compared to other classes of exo-planets. Small inner companions to giant planets with P ≲ 15 days are known only in five compact systems: WASP-47, Kepler-730, WASP-132, TOI-1130, and TOI-2000. Here, we report the confirmation of TOI-5398, the youngest known compact multi-planet system composed of a hot sub-Neptune (TOI-5398 c, Pc = 4.77271 days) orbiting interior to a short-period Saturn (TOI-5398 b, Pb = 10.590547 days) planet, both transiting around a 650 ± 150 Myr G-type star.
Aims. As part of the Global Architecture of Planetary Systems (GAPS) Young Object project, we confirmed and characterised this compact system, measuring the radius and mass of both planets, thus constraining their bulk composition.
Methods. Using multi-dimensional Gaussian processes, we simultaneously modelled stellar activity and planetary signals from the Transiting Exoplanet Survey Satellite (TESS) Sector 48 light curve and our High Accuracy Radial velocity Planet Searcher (HARPS-N) radial velocity (RV) time series. We confirmed the planetary nature of both planets, TOI-5398 b and TOI-5398 c, and obtained a precise estimation of their stellar parameters.
Results. Through the use of astrometric, photometric, and spectroscopic observations, our findings indicate that TOI-5398 is a young, active G dwarf star (650 ± 150 Myr) with a rotational period of Prot = 7.34 days. The transit photometry and RV measurements enabled us to measure both the radius and mass of planets b, Rb = 10.30 ± 0.40 R⊕, Mb = 58.7 ± 5.7 M⊕, and c, Rc = 3.52 ± 0.19 R⊕, Mc = 11.8 ± 4.8 M⊕. TESS observed TOI-5398 during sector 48 and no further observations are planned in the current Extended Mission, making our ground-based light curves crucial for improvement of the ephemeris. With a transmission spectroscopy metric (TSM) value of around 300, TOI-5398 b is the most amenable warm giant (10 < P < 100 days) for JWST atmospheric characterisation
Phenanthriplatin Acts As a Covalent Poison of Topoisomerase II Cleavage Complexes
Drugs
capable of trapping topoisomerase II (Top2), an essential
enzyme that cleaves DNA to remove naturally occurring knots and tangles,
can serve as potent anticancer agents. The monofunctional platinum
agent phenanthriplatin, <i>cis</i>-[PtÂ(NH<sub>3</sub>)<sub>2</sub>(phenanthridine)ÂCl]Â(NO<sub>3</sub>), is shown here to trap
Top2 in addition to its known modes of inhibition of DNA and RNA polymerases.
Its potency therefore combines diverse modes of action by which phenanthriplatin
kills cancer cells. The observation that phenanthriplatin can act
as a Top2 poison highlights opportunities to design nonclassical platinum
anticancer agents with this novel mechanism of action. Such complexes
have the potential to overcome current limitations with chemotherapy,
such as resistance, and to provide treatment options for cancers that
do not respond well to classical agents. Covalent DNA-platinum lesions
implicated in Top2 poisoning are distinctive from those generated
by known therapeutic topoisomerase poisons, which typically exert
their action by reversible binding at the interface of Top2-DNA cleavage
complexes
RNA-Seq Transcriptomic Responses of Full-Thickness Dermal Excision Wounds to <i>Pseudomonas aeruginosa</i> Acute and Biofilm Infection
<div><p><i>Pseudomonas aeruginosa</i> infections of wounds in clinical settings are major complications whose outcomes are influenced by host responses that are not completely understood. Herein we evaluated transcriptomic changes of wounds as they counter <i>P</i>. <i>aeruginosa</i> infection—first active infection, and then chronic biofilm infection. We used the dermal full-thickness, rabbit ear excisional wound model. We studied the wound response: towards acute infection at 2, 6, and 24 hrs after inoculating 10<sup>6</sup> bacteria into day-3 wounds; and, towards more chronic biofilm infection of wounds similarly infected for 24 hrs but then treated with topical antibiotic to coerce biofilm growth and evaluated at day 5 and 9 post-infection. The wounds were analyzed for bacterial counts, expression of <i>P</i>. <i>aeruginosa</i> virulence and biofilm-synthesis genes, biofilm morphology, infiltrating immune cells, re-epithelialization, and genome-wide gene expression (RNA-Seq transcriptome). This analysis revealed that 2 hrs after bacterial inoculation into day-3 wounds, the down-regulated genes (infected vs. non-infected) of the wound edge were nearly all non-coding RNAs (ncRNAs), comprised of snoRNA, miRNA, and RNU6 pseudogenes, and their down-regulation preceded a general down-regulation of skin-enriched coding gene expression. As the active infection intensified, ncRNAs remained overrepresented among down-regulated genes; however, at 6 and 24 hrs they changed to a different set, which overlapped between these times, and excluded RNU6 pseudogenes but included snRNA components of the major and minor spliceosomes. Additionally, the raw counts of multiple types of differentially-expressed ncRNAs increased on post-wounding day 3 in control wounds, but infection suppressed this increase. After 5 and 9 days, these ncRNA counts in control wounds decreased, whereas they increased in the infected, healing-impaired wounds. These data suggest a sequential and coordinated change in the levels of transcripts of multiple major classes of ncRNAs in wound cells transitioning from inflammation to the proliferation phase of healing.</p></div
Differentially-expressed immune-related and skin-enriched genes.
<p><b>(A)</b> The immune-related genes are from the Comprehensive List of Immune-Related Genes of The Immunology Database and Analysis Portal (ImmPort) ([<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165312#pone.0165312.ref020" target="_blank">20</a>]; <a href="http://www.immport.org/immport-open/public/home/studySearch?searchTerm=SDY144" target="_blank">http://www.immport.org/immport-open/public/home/studySearch?searchTerm=SDY144</a>). <b>(B)</b> The skin-enriched genes are comprised of 412 genes with elevated expression in skin compared to other tissue types (<a href="http://www.proteinatlas.org" target="_blank">www.proteinatlas.org</a>; [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165312#pone.0165312.ref021" target="_blank">21</a>]).</p
WRN protects against topo I but not topo II inhibitors by preventing DNA break formation
Non-coding RNA levels in infected vs. non-infected wounds.
<p><b>(A)</b> Percent of all significantly down-regulated transcripts (green line) and up-regulated transcripts (red line) that are ncRNA (p-value shown in parentheses for Fisher's exact test for overrepresentation of ncRNA). <b>(B)</b> Counts of significantly down-regulated (green) and up-regulated (red) ncRNAs in infected wounds (0.1 FDR). <b>(C)</b> Histogram of fold changes of 120 ncRNA whose levels changed significantly at least at one post-infection time point (no p-value cutoff). Dotted vertical lines indicate the mean log2FC. <b>(D)</b> Heat map of the 120 ncRNAs whose levels changed significantly at least at one post-infection time point. <b>(E)</b> Percent of the 120 ncRNAs with Log2 fold change greater than zero (no p-value cutoff). <b>(F)</b> Volcano plot of pooled samples from days 5 and 9 compared with the pooled samples from hours 6 and 24, which shows genes all up-regulated (red open circles) and down-regulated genes (green open circles) in the chronic biofilm-infected wounds vs. the acute active-infected wounds. The overlaid solid circles indicate genes of the innate immune response (blue [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165312#pone.0165312.ref023" target="_blank">23</a>]) or ncRNAs (brown, as annotated in the biotype category in Ensembl); FDR = 0.05.</p
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