Targeted therapy of kidney disease with nanoparticle drug delivery materials.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.

Integrated analysis reveals crosstalk between pyroptosis and immune regulation in renal fibrosis.

Purpose: The pathogenesis of renal fibrosis (RF) involves intricate interactions between profibrotic processes and immune responses. This study aimed to explore the potential involvement of the pyroptosis signaling pathway in immune microenvironment regulation within the context of RF. Through comprehensive bioinformatics analysis and experimental validation, we investigated the influence of pyroptosis on the immune landscape in RF. Methods: We obtained RNA-seq datasets from Gene Expression Omnibus (GEO) databases and identified Pyroptosis-Associated Regulators (PARs) through literature reviews. Systematic evaluation of alterations in 27 PARs was performed in RF and normal kidney samples, followed by relevant functional analyses. Unsupervised cluster analysis revealed distinct pyroptosis modification patterns. Using single-sample gene set enrichment analysis (ssGSEA), we examined the correlation between pyroptosis and immune infiltration. Hub regulators were identified via weighted gene coexpression network analysis (WGCNA) and further validated in a single-cell RNA-seq dataset. We also established a unilateral ureteral obstruction-induced RF mouse model to verify the expression of key regulators at the mRNA and protein levels. Results: Our comprehensive analysis revealed altered expression of 19 PARs in RF samples compared to normal samples. Five hub regulators, namely PYCARD, CASP1, AIM2, NOD2, and CASP9, exhibited potential as biomarkers for RF. Based on these regulators, a classifier capable of distinguishing normal samples from RF samples was developed. Furthermore, we identified correlations between immune features and PARs expression, with PYCARD positively associated with regulatory T cells abundance in fibrotic tissues. Unsupervised clustering of RF samples yielded two distinct subtypes (Subtype A and Subtype B), with Subtype B characterized by active immune responses against RF. Subsequent WGCNA analysis identified PYCARD, CASP1, and NOD2 as hub PARs in the pyroptosis modification patterns. Single-cell level validation confirmed PYCARD expression in myofibroblasts, implicating its significance in the stress response of myofibroblasts to injury. In vivo experimental validation further demonstrated elevated PYCARD expression in RF, accompanied by infiltration of Foxp3+ regulatory T cells. Conclusions: Our findings suggest that pyroptosis plays a pivotal role in orchestrating the immune microenvironment of RF. This study provides valuable insights into the pathogenesis of RF and highlights potential targets for future therapeutic interventions.

Ordered sulfonated polystyrene particle chains organized through AC electroosmosis as reinforcing phases in Polyacrylamide hydrogels.

Polyacrylamide (PAM) hydrogels have garnered significant attention due to their unique swelling properties, biocompatibility, and stability, resulting in them being promising candidates for various applications, ranging from drug delivery to tissue engineering. However, traditional PAM hydrogels suffer from low strength and poor toughness, which limits their widespread use. In this study, based on the theory of filler-reinforced composites, we introduced ordered sulfonated polystyrene (SPS) particles into PAM hydrogels using electric field-assisted techniques. The effects of the geometric dimensions and filling concentration of SPS particles on thermal stability, swelling/deswelling behavior, and mechanical properties of composite hydrogels were investigated. When filled with ordered 100 nm SPS particles at a concentration of 2.0 g·L-1, the resulting SPS/PAM composite exhibited improved water retention capacity, as well as a fracture elongation of 316 % and a tensile strength of 23 kPa. These findings in the paper provide valuable insights into the understanding of PAM hydrogels and open up new avenues for the development of advanced hydrogel-based systems with enhanced performance and functionality.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

TGF-ß1 dominates stromal fibroblast-mediated EMT via the FAP/VCAN axis in bladder cancer cells.

BACKGROUND: Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor ß1 (TGF-ß1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-ß1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. METHODS: Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-ß1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. RESULTS: Among the TGF-ß family, TGF-ß1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-ß1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-ß1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-ß1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-ß1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-ß1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway. CONCLUSIONS: TGF-ß1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-ß1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.

Electric field-induced orientation of silicon carbide whiskers for directional and localized thermal management.

Incorporating high thermal conductivity fillers into the matrix material and optimizing their distribution offers a targeted approach to controlling heat flow conduction. However, the design of composite microstructure, particularly the precise orientation of fillers in the micro-nano domain, remains a formidable challenge to date. Here, we report a novel method for constructing directional/localized thermal conduction pathways based on silicon carbide whiskers (SiCWs) in the polyacrylamide (PAM) gel matrix using micro-structured electrodes. SiCWs are one-dimensional nanomaterials with ultra-high thermal conductivity, strength, and hardness. The outstanding properties of SiCWs can be maximized through ordered orientation. Under the conditions of 18 V voltage and 5 MHz frequency, SiCWs can achieve complete orientation in only about 3 s. In addition, the prepared SiCWs/PAM composite exhibits interesting properties, including enhanced thermal conductivity and localized conduction of heat flow. When the SiCWs concentration is 0.5 g·L-1, the thermal conductivity of SiCWs/PAM composite is about 0.7 W·m-1·K-1, which is 0.3 W·m-1·K-1 higher than that of PAM gel. This work achieved structural modulation of the thermal conductivity by constructing a specific spatial distribution of SiCWs units in the micro-nanoscale domain. The resulting SiCWs/PAM composite has unique localized heat conduction properties and is expected to become a new generation of composites with better characteristics and functions in thermal transmission and thermal management.

Soft Gripper with Electro-Thermally Driven Artificial Fingers Made of Tri-layer Polymers and a Dry Adhesive Surface.

Soft grippers have attracted great interest in the soft robotics research field. Due to their lack of deformability and control over compliance, it can be challenging for them to pick up objects that are too large or too small in size. In particular, compliant objects are vulnerable to the large grasping force. Therefore, it is crucial to be able to adjust the stiffness of the gripper materials. In this study, a soft gripper consisting of three artificial fingers is reported on. Each of the artificial fingers is made of a tri-layer polymer structure. An exterior layer, made of an ecoflex-graphene composite is embedded with electric wires as a heating source, by applying direct-current potential. The Joule heat not only allows for deformation of the exterior layer, but also transfers heat to the middle layer of the thermoplastic polyurethane (TPU) elastomer. As a result, the stiffness of the TPU layer can be adjusted using electro-thermal heating. Meanwhile, the third layer consists of a polydimethylsiloxane replica as a supporting layer with a gecko-inspired dry adhesive structure. By applying voltage through electric wires, the artificial fingers can bend and, thus, the soft gripper can hold the objects, with the help of the dry adhesive layer. Finally, objects like a shuttlecock, tennis ball and a glass beaker, can be picked up by the soft gripper. This research may provide an insight for the design and fabrication of soft robotic manipulators.

High-Performance Piezoelectric-Type MEMS Vibration Sensor Based on LiNbO3 Single-Crystal Cantilever Beams.

It is a great challenge to detect in-situ high-frequency vibration signals for extreme environment applications. A highly sensitive and robust vibration sensor is desired. Among the many piezoelectric materials, single-crystal lithium niobate (LiNbO3) could be a good candidate to meet the demand. In this work, a novel type of micro-electro-mechanical system (MEMS) vibration sensor based on a single crystalline LiNbO3 thin film is demonstrated. Firstly, the four-cantilever-beam MEMS vibration sensor was designed and optimized with the parametric method. The structural dependence on the intrinsic frequency and maximum stress was obtained. Then, the vibration sensor was fabricated using standard MEMS processes. The practical intrinsic frequency of the as-presented vibration sensor was 5.175 kHz, which was close to the calculated and simulated frequency. The dynamic performance of the vibration sensor was tested on a vibration platform after the packaging of the printed circuit board. The effect of acceleration was investigated, and it was observed that the output charge was proportional to the amplitude of the acceleration. As the loading acceleration amplitude is 10 g and the frequency is in the range of 20 to 2400 Hz, the output charge amplitude basically remains stable for the frequency range from 100 Hz to 1400 Hz, but there is a dramatic decrease around 1400 to 2200 Hz, and then it increases significantly. This should be attributed to the significant variation of the damping coefficient near 1800 Hz. Meanwhile, the effect of the temperature on the output was studied. The results show the nearly linear dependence of the output charge on the temperature. The presented MEMS vibration sensors were endowed with a high output performance, linear dependence and stable sensitivity, and could find potential applications for the detection of wide-band high-frequency vibration.

Piezo-Resistive Flexible Pressure Sensor by Blade-Coating Graphene-Silver Nanosheet-Polymer Nanocomposite.

The demand for flexible pressure sensors in wearable devices is dramatically increasing. However, challenges still exist in making flexible pressure sensors, including complex or costly fabrication processes and difficulty in mass production. In this paper, a new method is proposed for preparing the flexible pressure sensors that combines an imprinting technique with blade-coating of a graphene-silver nanosheet-polymer nanocomposite. The piezo-resistive type flexible pressure sensor consists of interdigital electrodes and nanocomposite as a sensing layer, as well as a micropillar array structure. The morphology of the sensitive layer of the sensor is characterized by scanning electron microscopy (SEM). The response performance, sensitivity, and stability of the sensor are investigated. The test results show that the initial resistance of the pressure sensor is only 1.6 Ω, the sensitivity is 0.04 kPa-1, and the response time is about 286 ms. In addition, a highly hydrophobic wetting property can be observed on the functional structure surface of the sensor. The contact angle is 137.2 degrees, revealing the self-cleaning property of the sensor. Finally, the prepared sensor is demonstrated as a wearable device, indicating promising potential in practical applications.

Predictive and Prognostic Potential of TP53 in Patients With Advanced Non-Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901).

BACKGROUND: Mutations in TP53 are commonly found in patients with epidermal growth factor receptor (EGFR) mutant advanced non-small-cell lung cancer (NSCLC). In this study, we determined the predictive and prognostic potential of different subtypes of TP53 using data from a phase III randomized trial (CTONG 0901). PATIENTS AND METHODS: The trial enrolled 195 patients who had undergone next-generation sequencing of 168 genes before treatment with EGFR tyrosine kinase inhibitors. Mutations in TP53 (exon 4 or 7, other mutations, and wild-type) were analyzed based on the therapeutic response and survival. A Cox proportional hazards model was used to determine the potential of the predictive and prognostic factors. RESULTS: All 195 patients harbored activating EGFR mutations: the most common concomitant mutations were TP53 (134/195, 68.7%), CTNNB1 (20/195, 10.3%), and RB1 (16/195, 8.2%). The genetic profiles between patient subgroups administered first-line (132, 67.7%) or later-line (63, 32.3%) treatments did not significantly differ. The median progression-free survival in patients with mutations in exon 4 or 7 of TP53, other TP53 mutations, and wild-type TP53 were 9.4, 11.0, and 14.5 months (P = .009), respectively. Overall survival times were 15.8, 20.0, and 26.1 months (P = .004), respectively. Mutations in exon 4 or 7 of TP53 served as independent prognostic factors for progression-free (P = .001) and overall survival (P = .004) in patients. CONCLUSION: Mutations in exon 4 and/or 7 in TP53 are promising predictive and prognostic indicators in EGFR-mutated NSCLC.

Microstructure Formation of Functional Polymers by Evaporative Self-Assembly under Flexible Geometric Confinement.

Polymer microstructures are widely used in optics, flexible electronics, and so forth. We demonstrate a cost-effective bottom-up manner for patterning polymer microstructures by evaporative self-assembly under a flexible geometric confinement at a high temperature. Two-parallel-plates confinement would become curve-to-flat shape geometric confinement as the polydimethylsiloxane (PDMS) cover plate deformed during solvent swelling. We found that a flexible cover plate would be favorable for the formation of gradient microstructures, with various periodicities and widths obtained at varied heights of clearance. After thermal annealing, the edge of the PMMA (Poly-methylmethacrylate) microstructures would become smooth, while the RR-P3HT (regioregular-poly(3-hexylthiophene)) might generate nanocrystals. The morphologies of RR-P3HT structures included thick films, straight lines, hierarchical stripes, incomplete stripes, and regular dots. Finally, a simple field-effect transistor (FET) device was demonstrated with the RR-P3HT micropattern as an active layer.

Periodic parallel array of nanopillars and nanoholes resulting from colloidal stripes patterned by geometrically confined evaporative self-assembly for unique anisotropic wetting.

In this paper we present an economical process to create anisotropic microtextures based on periodic parallel stripes of monolayer silica nanoparticles (NPs) patterned by geometrically confined evaporative self-assembly (GCESA). In the GCESA process, a straight meniscus of a colloidal dispersion is initially formed in an opened enclosure, which is composed of two parallel plates bounded by a U-shaped spacer sidewall on three sides with an evaporating outlet on the fourth side. Lateral evaporation of the colloidal dispersion leads to periodic "stick-slip" receding of the meniscus (evaporative front), as triggered by the "coffee-ring" effect, promoting the assembly of silica NPs into periodic parallel stripes. The morphology of stripes can be well controlled by tailoring process variables such as substrate wettability, NP concentration, temperature, and gap height, etc. Furthermore, arrayed patterns of nanopillars or nanoholes are generated on a silicon wafer using the as-prepared colloidal stripes as an etching mask or template. Such arrayed patterns can reveal unique anisotropic wetting properties, which have a large contact angle hysteresis viewing from both the parallel and perpendicular directions in addition to a large wetting anisotropy.