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.
Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.
...In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.
Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval CI, 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.
Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck Darmstadt, Germany; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).
•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.
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.
JCO
Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) ...significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 95% CI, 0.63 to 0.91; 2-sided
= .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.
•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 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.
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.
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