This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer.
In this phase III, ...double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/μl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.
Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 95% confidence interval (CI), 10.9-not evaluable versus 5.4 (95% CI, 3.7-5.7) months hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001, and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%).
Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.
•Chinese patients with platinum-sensitive recurrent ovarian cancer received maintenance niraparib (n = 177) or placebo (n = 88).•Median PFS was longer for niraparib versus placebo: 18.3 versus 5.4 months (HR = 0.32; 95% CI, 0.23-0.45; P < 0.0001).•Niraparib had a similar PFS benefit for 249 patients receiving individualized dosing based on bodyweight and platelet count.•Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively.•In the niraparib group, Grade ≥3 platelet count decreased/thrombocytopenia occurred in 11.3% of patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A novel Ralstonia Bcul-1 strain was isolated from soil samples that was closest to Ralstonia pickettii. Broad-spectrum resistance was identified to a group of heavy metal ions and tolerance to ...concentrations of Cd2+ up to 400 mg L-1. Low concentrations of heavy metal ions did not have distinctive impact on heavy metal resistance genes and appeared to induce greater expression. Under exposure to Cd2+, cell wall components were significantly enhanced, and some proteins were also simultaneously expressed allowing the bacteria to adapt to the high Cd2+ living environment. The maximum removal rate of Cd2+ by the Ralstonia Bcul-1 strain was 78.97% in the culture medium supplemented with 100 mg L-1 Cd2+. Ralstonia Bcul-1 was able to survive and grow in a low nutrient and cadmium contaminated (0.42 mg kg-1) vegetable soil, and the cadmium removal rate was up to 65.76% in 9th growth. Ralstonia Bcul-1 mixed with biochar could maintain sustainable growth of this strain in the soil up to 75 d and the adsorption efficiency of cadmium increased by 16.23–40.80% as compared to biochar application alone. Results from this work suggests that Ralstonia Bcul-1 is an ideal candidate for bioremediation of nutrient deficient heavy metal contaminated soil.
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•A novel Ralstonia was identified by genes and phenotypic characteristics.•Few studies on Ralstonia bioremediation to the soil contaminated by heavy metals.•Ralstonia Bcul-1 has broad-spectrum resistance to heavy metal ions, which is regulated by heavy metal-resistant genes.•Cell wall components change and protein expression to adapt to the living environment under the action of Cd2+.•The mixture of Ralstonia Bcul-1 and biochar show excellent practice application prospect to adsorb cadmium in low nutrition soil.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer
, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by ...integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
The flare-associated stellar coronal mass ejections (CMEs) of solar-like and late-type stars profoundly impact the habitability of any expolanets in the systems. In this paper, we report the ...detection of flare-associated CMEs for two M-dwarfs, thanks to a high-cadence survey carried out by the Ground Wide-angle Camera system and fast photometric and spectroscopic follow-ups. The flare energies in the
R
band are determined to be 1.6 × 10
35
erg and 8.1 × 10
33
erg based on modeling of their light curves. The time-resolved spectroscopic observations start at about 20 and 40 minutes after the trigger in both cases. The large projected maximum velocity of ∼500–700 km s
−1
suggests that the high-velocity wings of their H
α
emission lines most likely result from CME events in both stars, after excluding the possibility of chromospheric evaporation and coronal rain. The masses of the CMEs are estimated to be 1.5–4.5 × 10
19
g and 7.1 × 10
18
g.
Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The ...goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. ...The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2/seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. In addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomal-lysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in ...animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of (14)Cdapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.
An AAV5 vector containing the factor IX Padua allele was administered to 54 men with hemophilia B. Factor IX expression increased to approximately 39% of normal, and the annualized bleeding rate was ...decreased to 1.5.
Cobalt hydroxide (Co(OH)2) has received extensive attention for its exceptional splendid electrical properties as a promising supercapacitor electrode material. Co(OH)2 study so far prefers to ...crystal instead of amorphous, in spite of amorphous impressive electrochemical properties including the ability to improve the electrochemical efficiency based on the disorder structure. The amorphous Co(OH)2 nanostructures with excellent electrochemical behaviors were successfully synthesized by a simple and green electrochemistry. Our as-prepared Co(OH)2 electrode exhibited ultrahigh capacitance of 1094 F g–1 and super long cycle life of 95% retention over 8000 cycle numbers at a nominal 100 mV s–1 scan rate. The united pseudo-capacitive performances of the amorphous Co(OH)2 nanostructures in electrochemical capacitors are totally comparable to those of the crystalline Co(OH)2 nanomaterials. These findings actually open a door to applications of amorphous nanomaterials in the field of energy storage as superior electrochemical pseudocapacitors materials.
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IJS, KILJ, NUK, PNG, UL, UM
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