Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes ...to chemo-immunotherapy combinations is still unknown.
In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions.
Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 95% confidence interval (CI): 0.91-2.22; P = 0.1207} and PFS HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552, compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS HR = 1.29 (95% CI: 0.91-1.84); P = 0.149 and PFS HR = 1.20 (95% CI: 0.89-1.63); P = 0.222 when evaluated as time-varying covariate in multivariable analysis.
In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.
Metronidazole (MZ), a common antibacterial drug used in treatment of
H. pylori, was prepared in chitosan-treated alginate beads by the ionotropic gelation method. A (3
×
2
×
2) factorially designed ...experiment was used in which 3 viscosity-imparting polymers namely, methyl cellulose, carbopol 934P and κ-carrageenan, 2 concentrations (0.2 and 0.4% w/v) of chitosan as encapsulating polymer and 2 concentrations (2.5 and 5% w/w) of the low density magnesium stearate as a floating aid were tested. The drug entrapment efficiency (%), the percent of floating beads and the time for 80% of the drug to be released (
T
80%) were the responses evaluated. The bead formula containing 0.5% κ-carrageenan, 0.4% chitosan and 5% magnesium stearate showed immediate buoyancy, optimum drug entrapment efficiency and extended drug release. The histopathological examination of mice stomachs and
in vivo H. pylori clearance tests were carried out by orally administering MZ floating alginate beads or MZ suspension, to
H. pylori infected mice under fed conditions as a single daily dose for 3 successive days in different doses 5, 10, 15 and 20 mg/kg. The histopathological examination showed that groups receiving MZ in the form of floating alginate beads at doses 10, 15 and 20 mg/kg were better than the corresponding suspension form, regarding eradication of
H. pylori infection. The
in vivo H. pylori clearance tests showed that MZ floating beads with a dose of 15 mg/kg provided 100% clearance rate whereas the MZ suspension with a dose of 20 mg/kg gave only 33.33%.
ABSTRACT
The Tunka Advanced Instrument for Gamma- and cosmic-ray Astronomy (TAIGA) is a multicomponent experiment for the measurement of TeV to PeV gamma- and cosmic rays. Our goal is to establish a ...novel hybrid direct air shower technique, sufficient to access the energy domain of the long-sought Pevatrons. The hybrid air Cherenkov light detection technique combines the strengths of the HiSCORE shower front sampling array, and two ∼4 m class, ∼9.6° field of view Imaging Air Cherenkov Telescopes (IACTs). The HiSCORE array provides good angular and shower core position resolution, while the IACTs provide the image shape and orientation for gamma-hadron separation. In future, an additional muon detector will be used for hadron tagging at ≥100 TeV energies. Here, only data from the first IACT of the TAIGA experiment are used. A randomforest algorithm was trained using Monte Carlo (MC) simulations and real data, and applied to $85\, \mathrm{h}$ of selected observational data tracking the Crab Nebula at a mean zenith angle of 33.5°, resulting in a threshold energy of 6 TeV for this data set. The analysis was performed using the gammapy package. A total of 163.5 excess events were detected, with a statistical significance of 8.5 σ. The observed spectrum of the Crab Nebula is best fit with a power law above 6 TeV with a flux normalization of (3.20 ± 0.42) · 10−10 TeV−1 cm−2 s−1at a reference energy of $13\, \mathrm{TeV}$ and a spectral index of −2.74 ± 0.16.
The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin ...(DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway.
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•Hepatotoxicity is the major side effect of methotrexate chemotherapy that hinders its clinical application.•Dihydromyricetin is a natural flavonoid with antioxidant and anti-inflammatory effects.•Administration of dihydromyricetin with methotrexate attenuates induced liver toxicity via down-regulation of hepatic TLR4/NF-κB and NLRP3/caspase 1 signaling pathways.
The current investigation reports the optoelectronics studies for (Ge
2
S
8
)
100−x
(As
2
Te
3
)
x
(GSAT) (0 ≤
x
≤ 100) non-crystalline films. The GSAT glasses have been synthesised by using the ...conventional melt quench method. At 300 K and a vacuum of 10
−5
Torr, the GAST films have been thermally evaporated on cleaned glass substrates. The XRD (X-ray diffraction) curves insist the non-crystalline state of the GAST samples. The transmittance and reflectance spectra have been used to evaluate the absorption parameters, optical band gap (
E
g
), and tailing constraints of the Ge-S-As-Te glasses. Both the values of
E
g
and the absorption edge energy are lessening; nevertheless, the energy of band tail width rises with the enhancement of As
2
Te
3
ratio at the expense of Ge
2
S
8
contents. Some of the physically criteria viz. glass densities (
ρ
), compactness (
δ
), and main atomic volume (
V
m
) were estimated for GAST glasses. Both the conductance and valance band positions have also been evaluated. The index of refraction (
n
) has been correlated with
E
g
values. The obtained results suggest that
GSAT
films are suitable for many optic devices.
Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study ...addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk.
Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days.
Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1.
This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.
ABSTRACT
We introduce a study of the massive star forming region IRAS 18144–1723 using observations of the 6.7 GHz methanol maser line. Such regions are opaque at short wavelengths but can be ...observed through radio emission lines. In this study, we traced the kinematics of the source on milliarcsecond scales using the Multi-Element-Radio-Interferometer-Network (MERLIN). We found 52 maser spots in the LSR velocity range 45–52 km s−1, near the centre of the previously detected CO range of 21.3–71.3 km s−1, lying within ∼ 0${_{.}^{\prime\prime}}$5 of IRAS 18144–1723 ‘B’, thought to be a young Class I protostar. Their distribution can be approximated as an ellipse, which, if it were rotating, would have its axis oriented south-east to north-west. The most probable morphology of the emitting regions is interaction between a disc and an outflow, possibly with a very large opening angle. The arcmin-scale CO outflow centred on source ‘B’ is oriented East–West, and the methanol masers do show the highest dispersion of velocity gradients in approximately this direction, so the kinematics are complex and suggest that more than one source may be responsible. We also tested kinematic models for a Keplerian disc or a simple bipolar outflow, but neither are compatible with the kinematics of the maser clumps and the characteristics of their internal velocities.
This study intends to examine different dynamics of the chaotic incommensurate fractional-order Hopfield neural network model. The stability of the proposed incommensurate-order model is analyzed ...numerically by continuously varying the values of the fractional-order derivative and the values of the system parameters. It turned out that the formulated system using the Caputo differential operator exhibits many rich complex dynamics, including symmetry, bistability, and coexisting chaotic attractors. On the other hand, it has been detected that by adapting the corresponding controlled constants, such systems possess the so-called offset boosting of three variables. Besides, the resultant periodic and chaotic attractors can be scattered in several forms, including 1D line, 2D lattice, and 3D grid, and even in an arbitrary location of the phase space. Several numerical simulations are implemented, and the obtained findings are illustrated through constructing bifurcation diagrams, computing Lyapunov exponents, calculating Lyapunov dimensions, and sketching the phase portraits in 2D and 3D projections.
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