Background and Aims
Cancer‐associated fibroblasts (CAFs) are key players in multicellular, stromal‐dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and ...other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor‐associated neutrophils (TANs) during different stages of HCC pathogenesis.
Approach and Results
In the HCC‐TME, CAF‐derived cardiotrophin‐like cytokine factor 1 (CLCF1) increased chemokine (C‐X‐C motif) ligand 6 (CXCL6) and TGF‐β secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF‐β secreted by HCC cells activated extracellular signal‐regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1‐mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up‐regulation of the CLCF1−CXCL6/TGF‐β axis exhibited a marked correlation with increased cancer stem cells, “N2”‐polarized TANs, tumor stage, and poor prognosis.
Conclusions
This study reveals a cytokine‐mediated cellular crosstalk and clinical network involving the CLCF1−CXCL6/TGF‐β axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.
This paper presents an adaptive fuzzy control approach for a category of uncertain nonstrict-feedback systems with input saturation and output constraint. A variable separation approach is introduced ...to overcome the difficulty arising from the nonstrict-feedback structure. The problem of input saturation is solved by introducing an auxiliary design system, and output constraint is handled by utilizing a barrier Lyapunov function. Combing fuzzy logic system with the adaptive backstepping technique, the semi-global boundedness of all variables in the closed-loop systems is guaranteed, and the tracking error is driven to the origin with a small neighborhood. The stability of the closed-loop systems is proved, and the simulation results reveal the effectiveness of the proposed approach.
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•Antimicrobial peptide antibiotics are key therapeutic options for the treatment of multidrug-resistant infections.•Pharmacokinetics/Pharmacodynamics is essential to the rational use ...of antimicrobials.•Structural modifications of the antimicrobial peptide antibiotics can substantially alter their pharmacokinetics and pharmacodynamics.•Therapeutic drug monitoring is recommended for antimicrobial peptide antibiotics due to their relatively narrow therapeutic windows.
Antimicrobial resistance is a major global health challenge. As few new efficacious antibiotics will become available in the near future, peptide antibiotics continue to be major therapeutic options for treating infections caused by multidrug-resistant pathogens. Rational use of antibiotics requires optimisation of the pharmacokinetics and pharmacodynamics for the treatment of different types of infections. Toxicodynamics must also be considered to improve the safety of antibiotic use and, where appropriate, to guide therapeutic drug monitoring. This review focuses on the pharmacokinetics/pharmacodynamics/toxicodynamics of peptide antibiotics against multidrug-resistant Gram-negative and Gram-positive pathogens. Optimising antibiotic exposure at the infection site is essential for improving their efficacy and minimising emergence of resistance.
Dry powder inhalers have become increasingly attractive for pulmonary delivery of locally and systemically effective medications. In comparison to the liquid counterparts, such as nebulisation and ...pressurised metered dose inhalers, the powder form generally offers better chemical stability, improved portability and potentially superior patient adherence. Currently, the aerosol performance between dry powder inhalers varies to a large extent due to differences in the design of inhaler device and formulation. The particulate properties have a significant influence on the inter-particle interactions, which impacts on the aerosolisation of the inhaled powder. In this review, critical particulate properties that affect aerosol performance are discussed. Recent advances in powder production and particle engineering techniques are also assessed, aiming to develop new inhaled powder formulations or improve the aerosolisation efficiency of existing products.
The pig is an important livestock for food supply and an ideal model for various human diseases. Efficient and precise genetic engineering in pigs holds great promise in agriculture and biomedicine . ...Using currently available approach, generating specific gene modifications in pigs requires two steps. First, site-specific nucleases such as zinc finger nucleases （ZFNs） and transcription activator-like effector nucleases （TALENs） are used to generate targeted mutations in pig somatic cells.
Dentro del campo de investigación pragmático-discursivo, los marcadores del discurso despiertan cada vez más el interés de los lingüistas. A medida que se incrementa el número de especialistas que se ...dedican al estudio lingüístico del español y el chino mandarín, han surgido varios trabajos de carácter contrastivo sobre los marcadores del discurso; la mayoría se centra en comparar determinados grupos de marcadores en ambas lenguas y examinar su aplicación didáctica en el aula. Dado que dicha línea de investigación sigue floreciendo —y aún quedan bastantes aspectos por analizar—, muchos marcadores discursivos, por su índole polifuncional, merecen un análisis individual y profundo. El presente trabajo tiene como objetivo acercarse a los marcadores del discurso bueno y好 (hǎo) —de gran utilidad en las dos lenguas—, los cuales manifiestan ciertas similitudes semántico-pragmáticas. Para llevar a cabo este objetivo, el análisis se enfoca en las formas y funciones de ambos marcadores con base en investigaciones intralingüísticas.
ABSTRACT
Purpose
This study aims to investigate the influence of different storage humidity conditions on crystallization and aerosol performance of inhalable spray dried amorphous powder ...formulations (Ciprofloxacin hydrochloride as the model drug).
Methods
The spray dried samples were stored at 20%, 55% and 75% relative humidity (RH). Crystallinity was monitored by Powder X-ray diffraction (PXRD), and particle morphology was measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI).
Results
PXRD diffractograms showed the spray dried Ciprofloxacin stored at 20% RH for three weeks were amorphous; whereas those stored at 55% RH and 75% RH started crystallizing after one hour. Fine particle fraction (FPF) of the particles was improved from 28% to 42% after storage at 55% RH for three days. Such improvement was attributed to the crystallization of amorphous powders, which led to increased particle roughness and reduced particulate contact area, as visualized by SEM and quantified by AFM. A linear relationship was observed between degree of crystallinity/crystallite size and FPF (R
2
= 0.94 and R
2
= 0.96, respectively). However, deterioration in aerosol performance was observed after storage at 75% RH due to formation of inter-particulate liquid/solid bridges, as confirmed by SEM.
Conclusions
This study provides a fundamental understanding in moisture-induced physical and aerosol instability of the spray dried powder formulations.
Comprehensive Summary
Hydrofluoride is an industry‐preferred fluoride source, and finds extensively application to manufacture diverse fluoro chemicals. The Et3N‐3HF complex is a liquid HF with ...improve safety. In this work, we report electrochemical synthesis of a series of sulfonyl fluoride with Et3N‐3HF as fluoride source. The sulfinic salt is a smell‐less, non‐volatile, and air‐stable sulfur source in this reaction. With the combination of Et3N‐3HF and aryl/alkyl sulfinic salt, the sulfonyl fluorides are achieved without the use of external oxidant. In addition, we demonstrate further advantage in a tandem reaction involving Pd‐catalyzed C—S cross‐coupling and formation of S—F bond. A variety of functional groups including amino acids, heterocycles, halides are well tolerated.
Herein, we report the first method for electrochemical synthesis of sulfonyl fluorides with triethylamine hydrofluoride as a fluorine source. These electricity‐driven reactions of odorless sulfinic salts were carried out under oxidant‐free conditions. Aryl, aliphatic, and alkenyl sulfonyl fluorides could be accessed by means of this method. In addition, we report a one‐pot protocol for Pd‐catalyzed C—S cross‐coupling and oxidative fluorination under electrochemical conditions. A reaction pathway involving the supporting electrolyte is proposed.
A macroscopic ribbon of oriented cellulose nanofibrils bearing polyethylene glycol is fabricated by stretching the cellulose nanofibrils network structure in the hydrogel state. The covalently ...grafted polyethylene glycol on the nanofibril surface facilitates the alignment and compartmentalization of individual nanofibrils in the ribbon. The ribbon has ultrahigh tensile strength (576 ± 54 MPa), modulus (32.3 ± 5.7 GPa), high transparency, and haze.
Anhedonia is the inability to experience pleasure from rewarding or enjoyable activities and is a core symptom of depression in humans. Here, we describe a protocol for the measurement of anhedonia ...in mice, in which anhedonia is measured by a sucrose preference test (SPT) based on a two-bottle choice paradigm. A reduction in the sucrose preference ratio in experimental relative to control mice is indicative of anhedonia. To date, inconsistent and variable results have been reported following the use of the SPT by different groups, probably due to the use of different protocols and equipment. In this protocol, we describe how to set up a clearly defined apparatus for SPT and provide a detailed protocol to ensure greater consistency when carrying out SPT. This optimized protocol is highly sensitive, reliable, and adaptable for evaluation of chronic stress-related anhedonia, as well as morphine-induced dependence. The whole SPT, including adaptation, baseline measurement, and testing, takes 8 d.
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