Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to ...affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.
Metal–organic framework nanoparticles (nanoMOFs) have been widely studied in biomedical applications. Although substantial efforts have been devoted to the development of biocompatible approaches, ...the requirement of tedious synthetic steps, toxic reagents, and limitations on the shelf life of nanoparticles in solution are still significant barriers to their translation to clinical use. In this work, we propose a new postsynthetic modification of nanoMOFs with phosphate-functionalized methoxy polyethylene glycol (mPEG–PO3) groups which, when combined with lyophilization, leads to the formation of redispersible solid materials. This approach can serve as a facile and general formulation method for the storage of bare or drug-loaded nanoMOFs. The obtained PEGylated nanoMOFs show stable hydrodynamic diameters, improved colloidal stability, and delayed drug-release kinetics compared to their parent nanoMOFs. Ex situ characterization and computational studies reveal that PEGylation of PCN-222 proceeds in a two-step fashion. Most importantly, the lyophilized, PEGylated nanoMOFs can be completely redispersed in water, avoiding common aggregation issues that have limited the use of MOFs in the biomedical field to the wet forma critical limitation for their translation to clinical use as these materials can now be stored as dried samples. The in vitro performance of the addition of mPEG–PO3 was confirmed by the improved intracellular stability and delayed drug-release capability, including lower cytotoxicity compared with that of the bare nanoMOFs. Furthermore, z-stack confocal microscopy images reveal the colocalization of bare and PEGylated nanoMOFs. This research highlights a facile PEGylation method with mPEG–PO3, providing new insights into the design of promising nanocarriers for drug delivery.
The development of nanoparticle (NP)-based drug carriers has presented an exciting opportunity to address challenges in oncology. Among the 100,000 available possibilities, zirconium-based ...metal–organic frameworks (MOFs) have emerged as promising candidates in biomedical applications. Zr-MOFs can be easily synthesized as small-size NPs compatible with intravenous injection, whereas the ease of decorating their external surfaces with functional groups allows for targeted treatment. Despite these benefits, Zr-MOFs suffer degradation and aggregation in real, in vivo conditions, whereas the loaded drugs will suffer the burst effecti.e., the fast release of drugs in less than 48 h. To tackle these issues, we developed a simple but effective bilayer coating strategy in a generic, two-step process. In this work, bilayer-coated MOF NU-901 remained well dispersed in biologically relevant fluids such as buffers and cell growth media. Additionally, the coating enhances the long-term stability of drug-loaded MOFs in water by simultaneously preventing sustained leakage of the drug and aggregation of the MOF particles. We evaluated our materials for the encapsulation and transport of pemetrexed, the standard-of-care chemotherapy in mesothelioma. The bilayer coating allowed for a slowed release of pemetrexed over 7 days, superior to the typical 48 h release found in bare MOFs. This slow release and the related performance were studied in vitro using both A549 lung cancer and 3T mesothelioma cells. Using high-resolution microscopy, we found the successful uptake of bilayer-coated MOFs by the cells with an accumulation in the lysosomes. The pemetrex-loaded NU-901 was indeed cytotoxic to 3T and A549 cancer cells. Finally, we demonstrated the general approach by extending the coating strategy using two additional lipids and four surfactants. This research highlights how a simple yet effective bilayer coating provides new insights into the design of promising MOF-based drug delivery systems.
Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug ...loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.
Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, ...and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple “mix-and-go” addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway. Recent studies ...have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5. To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage-CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms. Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule. Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element. Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A. STAT5A-STAT5A homodimers and STAT5A-STAT5B heterodimers formed in response to GM-CSF. Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR. Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF.
Perovskite nanocrystals are exceptional candidates for light-emitting diodes (LEDs). However, they are unstable in the solid film and tend to degrade back to the bulk phase, which undermines their ...potential for LEDs. Here we demonstrate that perovskite nanocrystals stabilized in metal–organic framework (MOF) thin films make bright and stable LEDs. The perovskite nanocrystals in MOF thin films can maintain the photoluminescence and electroluminescence against continuous ultraviolet irradiation, heat and electrical stress. As revealed by optical and X-ray spectroscopy, the strong emission originates from localized carrier recombination. Bright LEDs made from perovskite-MOF nanocrystals are demonstrated with a maximum external quantum efficiency of over 15% and a high brightness of over 105 cd m−2 after the device reaches stabilization. During LED operation, the nanocrystals can be well preserved, free of ion migration or crystal merging through protection by the MOF matrix, leading to a stable performance over 50 hours.The use of metal–organic frameworks helps protect perovskite nanocrystals, resulting in bright, stable light-emitting diodes.
This paper presents a recent rainfall-induced reactivated compound soil slide in Yanyuan County, China, on July 19, 2018. In this paper, according to the elaborate investigation of the soil slide ...area at field and prefailure slope stability analysis, the corresponding failure mechanisms are comprehensively studied. Unmanned aerial vehicle (UAV) based on remote sensing, three-dimensional modelling, in situ and laboratory experimental testing, borehole exploration, and numerical simulation were carried out in this work. According to the results, two different sliding processes were identified involving the main sliding and lateral collapse. The main sliding occurred as multiple stages along with two different types of slip zones, which involve a preexisting basal zone of the ancient landslide and an interlaminar shear zone within the ancient landslide deposits. The predominance of reactivated surface geomorphology provides a clue to elucidate the dominant compound movement of the event. Unconsolidated sliding mass and the basal sliding surface are ideal for the development of the reactivation motion. Saltatory microrelief of the original slope determined the retrogressive failure type of the soil slide. The well-developed groundwater in the landslide area significantly increased the soil mass saturation, with an average saturation value of 98%, formed dominant seepage in the sliding mass, and promoted landslide reactivation. Furthermore, rainwater infiltration due to 14 days’ antecedent cumulative rainfall of 350.6 mm directly contributed to the occurrence of the landslide by increasing the pore water pressure in the slope. The maximum shear plastic strain and displacement obtained by numerical simulation show that the lateral slope was unstable with the removal of the main sliding. Because the soil slide is located in the west area of the Emeishan Large Igneous Province (ELIP), it is a partial resurrection of the ancient basalt landslide. Therefore, this study has a certain significance for revealing the reactivated mechanism of basalt ancient landslide.
A high-position destructive rockfall, significantly influenced by post-seismic effect of Wenchuan earthquake in 2008 and associated aftershocks, was reported in Miansi Town of Wenchuan County, ...Sichuan Province, China. About 3,000 m
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of rock at high position detached from a dipping rocky slope, which manifested as a translational motion. Detailed field investigation, geological mapping, kinematic analysis, and numerical modelling are presented to comprehensively analyze the complex failure mode of the post-seismic rockfall. The results demonstrated that the sliding surfaces are mainly controlled by the internal shear discontinuity sets. The backscarps are progressively evolved from the tensile cracks at rear slopes caused by the Wenchuan earthquake. Because of the combination effect of heavily shocks of previous earthquake and local geomorphology of the rockfall with beneficial for facilitating the magnification effect on peak ground acceleration (PGA), the rock mass of slopes is dramatically damaged and fractured. The original intact slopes finally developed to the shattered slopes as an optimum birthplace for the post-seismic rockfalls. It should be noticed that intensive precipitation plays a triggering factor that generates the hydrostatic water pressure in the rear cracks and the uplift pressure at the bottom sliding surface within a short time. The evolution processes are divided into three stages: slope relaxation stage, rock shattering and disaggregation stage, and high-speed falling stage. Velocities, energy, and bounce heights of falling rock blocks are computed by the RocPro3D software for understanding the corresponding kinematics. The paper can provide an insight into post-seismic rockfalls in the tectonic areas associated with the combination of seismic activities and intense rainfall.
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