Pregnane X Receptor (PXR), a master regulator of drug metabolism and inflammation, is abundantly expressed in the gastrointestinal tract. Baicalein and its O-glucuronide baicalin are potent ...anti-inflammatory and anti-cancer herbal flavonoids that undergo a complex cycle of interconversion in the liver and gut. We sought to investigate the role these flavonoids play in inhibiting gut inflammation by an axis involving PXR and other potential factors. The consequences of PXR regulation and activation by the herbal flavonoids, baicalein and baicalin were evaluated in vitro in human colon carcinoma cells and in vivo using wild-type, Pxr-null, and humanized (hPXR) PXR mice. Baicalein, but not its glucuronidated metabolite baicalin, activates PXR in a Cdx2-dependent manner in vitro, in human colon carcinoma LS174T cells, and in the murine colon in vivo. While both flavonoids abrogate dextran sodium sulfate (DSS)-mediated colon inflammation in vivo, oral delivery of a potent bacterial β-glucuronidase inhibitor eliminates baicalin's effect on gastrointestinal inflammation by preventing the microbial conversion of baicalin to baicalien. Finally, reduction of gastrointestinal inflammation requires the binding of Cdx2 to a specific proximal site on the PXR promoter. Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions.
•Zeolite 4A loaded Pebax-1657 mixed matrix membranes were synthesized.•Performance of membranes was studied with pure CO2, CH4, O2 and N2 gases.•Pebax/4A membranes showed better gas permeation ...properties to those of Pebax-1657.•Increasing the zeolite loading enhanced the selectivity CO2/CH4, CO2/N2 and O2/N2.
Mixed matrix membranes (MMMs) made from selective inorganic fillers and polymers have received extensive attention in the field of gas separation. In this work, poly(ether-block-amide), (Pebax)/zeolite 4A MMMs were prepared using ethanol/water as solvent mixture. The concentration of zeolite 4A in membrane was varied from 5 to 30wt.% of the polymer. The membranes were characterized by SEM, FTIR and XRD to study the morphologies, the effect of zeolite 4A incorporation on intermolecular interactions and degree of crystallinity, respectively. The pure gas permeabilities were recorded at the ambient temperature, using an indigenously built high-pressure gas separation manifold. The permeabilities of Pebax-1657/zeolite 4A membranes were enhanced from 71.4 to 155.7 Barrers for CO2, 2.2–19.6 Barrers for CH4, 5.8–17.9 Barrers O2 and 1.4–12.0 Barrers for N2. The ideal selectivity of 10wt.% zeolite 4A MMM enhanced from 54.1 to 94.2 for the CO2/N2 gas pair with increase in feed pressure from 5 to 25kg/cm2, whereas the corresponding values for CO2/CH4 and O2/N2 were found to rise from 26.4 to 41.3 and 4.3 to 4.9, respectively. The Pebax/zeolite 4A membranes thus provide a potentially promising means for separation of CO2/N2, CO2/CH4, and enrichment of O2 and N2 from air.
In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with ...a deleterious
alteration. Data are needed to confirm and expand on the findings of the phase 2 study.
In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a
,
, or
alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI abiraterone acetate or enzalutamide). The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a
alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval CI, 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea.
The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a
alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).
Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared ...with traditional chemotherapy is crucial for clinical practice.
A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1) with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism. Paule–Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects.
Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm OR = 0.26, 95% confidence interval (CI) 0.19–0.35, I2 = 92%. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28–0.44; I2 = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39–0.78, I2 = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46–0.98, I2 = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy.
Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs.
•22 trials involving 12,727 patients with advanced solid organ malignancies were included in this meta-analysis.•Patients receiving immunotherapy were less likely to develop severe adverse events than those receiving chemotherapy.•Fewer terminations due to adverse events or deaths due to adverse events occurred in the immunotherapy group.•Fatigue and diarrhea were more likely to occur in patients treated with chemotherapy.
Abstract
The nuclear star cluster surrounding the massive black hole at the Galactic Centre consists of young and old stars, with most of the stellar mass in an extended, cuspy distribution of old ...stars. The compact cluster of young stars was probably born in situ in a massive accretion disc around the black hole. We investigate the effect of the growing gravity of the disc on the orbits of the old stars, using an integrable model of the deformation of a spherical star cluster with anisotropic velocity dispersions. A formula for the perturbed phase-space distribution function is derived using linear theory, and new density and surface density profiles are computed. The cusp undergoes a spheroidal deformation with the flattening increasing strongly at smaller distances from the black hole; the intrinsic axis ratio ∼0.8 at ∼0.15 pc. Stellar orbits are deformed such that they spend more time near the disc plane and sample the dense inner parts of the disc; this could result in enhanced stripping of the envelopes of red giant stars. Linear theory accounts only for orbits whose apsides circulate. The non-linear theory of adiabatic capture into resonance is needed to understand orbits whose apsides librate. The mechanism is a generic dynamical process, and it may be common in galactic nuclei.
In this paper, an online fault detection and classification method is proposed for thermocouples used in nuclear power plants. In the proposed method, the fault data are detected by the ...classification method, which classifies the fault data from the normal data. Deep belief network (DBN), a technique for deep learning, is applied to classify the fault data. The DBN has a multilayer feature extraction scheme, which is highly sensitive to a small variation of data. Since the classification method is unable to detect the faulty sensor; therefore, a technique is proposed to identify the faulty sensor from the fault data. Finally, the composite statistical hypothesis test, namely generalized likelihood ratio test, is applied to compute the fault pattern of the faulty sensor signal based on the magnitude of the fault. The performance of the proposed method is validated by field data obtained from thermocouple sensors of the fast breeder test reactor.
One of the most promising materials for fabricating cold cathodes for next generation high-performance flat panel devices is carbon nanotubes (CNTs). For this purpose, CNTs grown on metallic ...substrates are used to minimize contact resistance. In this report, we compare properties and field emission performance of CNTs grown via water assisted chemical vapor deposition using Inconel vs silicon (Si) substrates. Carbon nanotube forests grown on Inconel substrates are superior to the ones grown on silicon; low turn-on fields (∼1.5 V/μm), high current operation (∼100 mA/cm2) and very high local field amplification factors (up to ∼7300) were demonstrated, and these parameters are most beneficial for use in vacuum microelectronic applications.
•Synthesis of novel solvent resistant sodium alginate/polyaniline polyion complex membrane.•Effect of ultraporous polyacrylonitrile (PAN) and polyethersulfone (PES) supports on pervaporation ...performance.•Dehydration of polar aprotic acetic acid solvent by pervaporation.•Hydrodynamic simulation using computational fluid dynamics.
Sodium alginate/polyaniline (SA/PAni) composite membranes were synthesized on ultraporous polyacrylonitrile (PAN) and polyethersulfone (PES) supports and subjected to pervaporation (PV) dehydration of acetic acid, which is a widely used chemical in several industries. Membranes were characterized by SEM, XRD and FTIR to study the morphologies of surface and cross-section of the films, degree of crystallinity and formation of new functional groups and intermolecular interactions. Sorption studies were carried out with pure acetic acid, water and binary mixtures of varying compositions to establish membrane–liquid interactions. Operating parameters such as feed composition, permeate pressure and membrane thickness were varied to study membrane performance. For a feed mixture containing 2wt% of water, selectivity of 441 and 359.33 were observed with reasonable water fluxes of 0.07 and 0.04kg/m2h for PAN and PES supported SA/PAni composite membranes, respectively. With increasing permeate pressure, water flux was found to decrease owing to lower driving force. A model using computational fluid dynamics (CFD) was developed to predict the concentration profile within the membrane. SA/PAni blend membrane deposited on PAN substrate appear to have considerable commercial potential for dehydration of acetic acid to purity level of more than 99% owing to its permselective nature, mechanical strength and chemical stability.
In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival ...relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.
PDF
