853 research outputs found

    Lapatinib and Poziotinib Overcome ABCB1-Mediated Paclitaxel Resistance in Ovarian Cancer

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    Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q \u3c 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer

    Low-Resolution Imaging Spectrometer for the Keck Telescope

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    The Low Resolution Imaging Spectrometer is designed for use at the Cassegrain focus of the Keck 10-m telescope. It provides the capability of acquiring low resolution (R equals 1000 to 5000) digital spectra, as well as 6 X 8 arc-minute moderately high spatial resolution (4.65 pixels/arc-second) direct images. Spectroscopy can be carried out with single slits which are 3 arc-minutes long. In addition punched multi-slits can also be employed which allow for the acquisition of at least forty spectra simultaneously. Since the instrument is designed to be as efficient as possible, it is a double spectrograph, with a dichroic splitting the blue and red light into separate optical paths after the collimator. Only the red side has been constructed thus far. With a 2048 by 2048 thinned Tektronix CCD as the detector the total efficiency of the red side at the peak of the grating blaze is predicted to be nearly 40%. Results of the commissioning observing runs will be described

    Characterization of the Moraxella catarrhalis uspA1 and uspA2 Genes and Their Encoded Products

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    The uspA1 and uspA2 genes of M. catarrhalis O35E encode two different surface-exposed proteins which were previously shown to share a 140-amino-acid region with 93% identity (C. Aebi, I. Maciver, J. L. Latimer, L. D. Cope, M. K. Stevens, S. E. Thomas, G. H. McCracken, Jr., and E. J. Hansen, Infect. Immun. 65:4367–4377, 1997). The N-terminal amino acid sequences of the mature forms of both UspA1 and UspA2 from strain O35E were determined after enzymatic treatment to remove the N-terminal pyroglutamyl residue that had blocked Edman degradation. Mass spectrometric analysis indicated that the molecular mass of UspA1 from M. catarrhalis O35E was 83,500 ± 116 Da. Nucleotide sequence analysis of the uspA1 and uspA2 genes from three other M. catarrhalis strains (TTA24, ATCC 25238, and V1171) revealed that the encoded protein products were very similar to those from strain O35E. Western blot analysis was used to confirm that each of these three strains of M. catarrhalis expressed both UspA1 and UspA2 proteins. Several different and repetitive amino acid motifs were present in both UspA1 and UspA2 from these four strains, and some of these were predicted to form coiled coils. Linear DNA templates were used in an in vitro transcription-translation system to determine the sizes of the monomeric forms of the UspA1 and UspA2 proteins from strains O35E and TTA24

    Phylogenomics of \u3ci\u3eTetraopes\u3c/i\u3e longhorn beetles unravels their evolutionary history and biogeographic origins

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    Tetraopes longhorn beetles are known for their resistance to milkweed plant toxins and their coevolutionary dynamics with milkweed plants (Asclepias). This association is considered a textbook example of coevolution, in which each species of Tetraopes is specialized to feed on one or a few species of Asclepias. A major challenge to investigating coevolutionary hypotheses and conducting molecular ecology studies lies in the limited understanding of the evolutionary history and biogeographical patterns of Tetraopes. By integrating genomic, morphological, paleontological, and geographical data, we present a robust phylogeny of Tetraopes and their relatives, using three inference methods with varying subsets of data, encompassing 2–12 thousand UCE loci. We elucidate the diversification patterns of Tetraopes species across major biogeographical regions and their colonization of the American continent. Our findings suggest that the genus originated in Central America approximately 21 million years ago during the Miocene and diversified from the Mid-Miocene to the Pleistocene. These events coincided with intense geological activity in Central America. Additionally, independent colonization events in North America occurred from the Late Miocene to the early Pleistocene, potentially contributing to the early diversification of the group. Our data suggest that a common ancestor of Tetraopini migrated into North America, likely facilitated by North Atlantic land bridges, while closely related tribes diverged in Asia and Europe during the Paleocene. Establishing a robust and densely sampled phylogeny of Tetraopes beetles provides a foundation for investigating micro- and macroevolutionary phenomena, including clinal variation, coevolution, and detoxification mechanisms in this ecologically important group

    The First Definitive Binary Orbit Determined with the Hubble Space Telescope Fine Guidance Sensors: Wolf 1062 (Gliese 748)

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    The M dwarf binary, Wolf 1062 (Gliese 748), has been observed with the Hubble Space Telescope (HST) Fine Guidance Sensor 3 in the transfer function scan mode to determine the apparent orbit. This is the first orbit defined fully and exclusively with HST, and is the most accurate definitive orbit for any resolved, noneclipsing system. The orbital period is 2.4490 ± 0.0119 yr and the semimajor axis is 01470 ± 00007—both quantities are now known to better than 1%. Using the weighted mean of seven parallax measurements and these HST data, we find the system mass to be 0.543 ± 0.031 M⊙, where the error of 6% is due almost entirely to the parallax error. An estimated fractional mass from the infrared brightness ratio and infrared mass-luminosity relation yields a mass for the primary of 0.37 M⊙, and the secondary falls in the regime of very low mass stars, with a mass of only 0.17 M⊙
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