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Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal tomoderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68⁺ macrophages and VISTA⁺ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.

The 26S proteasome holoenzyme comprises 20S catalytic and 19S regulatory complexes. Accumulating evidence suggests that the majority of proteasomes in the extracellular space exist as free 20S proteasomes; however, their origin and pathophysiological function remain to be determined. Here, we report that cellular proteasomes are effectively packaged into the lumen of extracellular vesicles (EVs) and secreted in a structurally intact and enzymatically active 20S form. We further demonstrate that EV‐encapsulated 20S proteasomes are delivered to recipient cells and facilitate the degradation of overexpressed tau proteins without disrupting global proteolytic pathways. These findings highlight a novel cell‐to‐cell communication system that transports the proteasomes to target cells for the clearance of proteotoxic substrates. Further characterisation of this homeostatic mechanism will improve our understanding of organismal stress response mechanisms and may provide a therapeutic approach to treat various proteinopathies, including Alzheimer's disease. This study demonstrates that the 20S proteasomes are packaged into extracellular vesicles (EVs), secreted as an active proteolytic enzyme and transferred to recipient cells. These EV‐encapsulated proteasomes selectively degrade excess proteins, highlighting a novel mechanism of a cell‐to‐cell communication system that supports proteostasis and proteome remodelling.

The use of mesenchymal stem cells (MSCs) for clinical purposes has skyrocketed in the past decade. Their multilineage differentiation potentials and immunomodulatory properties have facilitated the discovery of therapies for various illnesses. MSCs can be isolated from infant and adult tissue sources, which means they are easily available. However, this raises concerns because of the heterogeneity among the various MSC sources, which limits their effective use. Variabilities arise from donor- and tissue-specific differences, such as age, sex, and tissue source. Moreover, adult-sourced MSCs have limited proliferation potentials, which hinders their long-term therapeutic efficacy. These limitations of adult MSCs have prompted researchers to develop a new method for generating MSCs. Pluripotent stem cells (PSCs), such as embryonic stem cells and induced PSCs (iPSCs), can differentiate into various types of cells. Herein, a thorough review of the characteristics, functions, and clinical importance of MSCs is presented. The existing sources of MSCs, including adult- and infant-based sources, are compared. The most recent techniques for deriving MSCs from iPSCs, with a focus on biomaterial-assisted methods in both two- and three-dimensional culture systems, are listed and elaborated. Finally, several opportunities to develop improved methods for efficiently producing MSCs with the aim of advancing their various clinical applications are described.

Degenerative disc disease (DDD) is the leading cause of excruciating lower back pain and disability in adults worldwide. Among the current treatments for DDD, cell-based therapies such as the injection of both disc- and non-disc-derived chondrocytes have shown significant improvements in the patients’ condition. However, further advancement of these therapies is required to not only ensure a supply of healthy chondrocytes but also to promote regeneration of the defective cells in the injury site. Here, we report that the incorporation of gelatin microparticles coloaded with transforming growth factor beta 3 and matrilin 3 promoted chondrogenic differentiation of adipose-derived mesenchymal stem cell spheroids while preventing hypertrophy and terminal differentiation of cells. Moreover, these composite spheroids induced the release of chondrogenic cytokines that, in turn, promoted regeneration of degenerative chondrocytes in vitro. Finally, injections of these composite spheroids in a rat model of intervertebral disc disease promoted restoration of the chondrogenic properties of the cells, thereby allowing regeneration of the chondrogenic tissue in vivo.

This study is to present acceptable measurement values through decision tree analysis for the seepage, which is an important measuring item of the fill dam. The seepage of the dam under study increases rapidly when rainfall occurs, when the direct inflow of rainfall from the downstream slope and both sides occur. Therefore, the allowable seepage of fill dam considering rainfall and water level is required. Decision tree analysis was conducted for one domestic fill dam by setting the seepage as a response variable and setting rainfall and water level as explanatory variables. At this time, in order to analyze the effects of rainfall on the seepage more closely, the data subject was classified into two groups consisting of a rainfall-free group and a rainfall-occurring group. Group A, which is a rainfall-free group, had 97.7% of the seepage data distributed under the conditions of 98.50 mm/day of the antecedent 5-day rainfall selected as the first explanatory variable. The average seepage of the group was between 12.01 L/min and 26.35 L/min. Group B, which is a rainfall-occurring group, had 85.7% of the water leakage data distributed under conditions of 38.50 mm/day of daily rainfall selected as the first explanatory variable, with an average of 23.70 L/min.

This study deals with the utilization of the pore pressure meter for evaluating the stability of a dam through the correlation between the porewater pressure installed in the fill dam and the water level of the dam. To this end, principal components analysis was performed on a total of 18 porewater pressure meters, and the main components were classified into three groups: internal (Group A), external (Group B), and upper (Group C), on the basis of the seepage line formed within the dam body. The coefficient of correlation between the porewater pressure and water level was found to be 0.86 to 1.00, indicating a strong positive linear relationship. This means that the maintenance of the dam is possible through the pore pressure meter present in Group A. Furthermore, the regression analysis for porewater pressures and water levels resulted in a linear regression model with the coefficient of determination (R2) of Group A being between 0.74 and 0.99. In particular, R2 between the power water pressure installed at the base of the dam and the water level was more than 0.99. Therefore, it was shown that the prediction of the porewater pressure is possible by using the relationships with the water level, making it possible to determine the safety of the dam by comparing it with the currently measured values.

Background: The ultimate goal of regenerative medicine is to restore damaged tissues to a healthy state in the body. Direct reprogramming, also referred to as transdifferentiation, holds significant therapeutic potential by converting abundant somatic cells, such as fibroblasts, into functionally distinct cell types for tissue regeneration. Despite its potential applications in regenerative medicine, direct reprogramming faces major challenges, including low efficiency and poor In vivo applicability. In this study, we propose a novel therapeutic strategy for osteoporosis based on In vivo direct reprogramming using a stepwise delivery approach that first enhances cellular stemness and subsequently induces osteogenic transdifferentiation. Enhancing stemness in lineage-committed cells facilitates their conversion into other functional cell types. Method: To investigate the efficiency of direct reprogramming via stepwise delivery, we utilized valproic acid (VPA) and tauroursodeoxycholic acid (TUDCA) as reprogramming and bone-stimulating factors, respectively. VPA increased the expression of stemness genes, including Oct4, Nanog, and Sox2, and subsequent treatment of TUDCA enhanced the expression of osteogenic genes in the mouse fibroblast. Targeted delivery of these factors to fibroblasts surrounding bone tissue, enabling subsequent direct reprogramming into osteoblasts, was achieved using bisphosphonate (BP)-conjugated lipid nanoparticles as carriers. Results: Our findings demonstrate that sequential induction of cell reprogramming and tissue regeneration through stepwise administration of VPA and TUDCA significantly enhances therapeutic efficacy in a mouse model of osteoporosis compared to their simultaneous administration. Conclusion: This stepwise bone-targeted drug delivery system presents a promising strategy for osteoporosis treatment via In vivo direct reprogramming. Graphical abstract Stepwise administration of VPA-LNPs and TUDCA-LNPs enhances In vivo direct reprogramming for osteoporosis therapy.

Human induced pluripotent stem cells (iPSCs) hold great promise for personalized medicine, as they can be differentiated into specific cell types, especially mesenchymal stem cells (MSCs). Therefore, our study sought to assess the feasibility of deriving MSCs from teratomas generated from human iPSCs. Teratomas serve as a model to mimic multilineage human development, thus enriching specific somatic progenitors and stem cells. Here, we discovered a small, condensed mass of MSCs within iPSC‐generated teratomas. Afterward, we successfully isolated MSCs from this condensed mass, which was a byproduct of teratoma development. To evaluate the characteristics and cell behaviors of iPSC‐derived MSCs (iPSC‐MSCs), we conducted comprehensive assessments using qPCR, immunophenotype analysis, and cell proliferation‐related assays. Remarkably, iPSC‐MSCs exhibited an immunophenotype resembling that of conventional MSCs, and they displayed robust proliferative capabilities, similar to those of higher pluripotent stem cell‐derived MSCs. Furthermore, iPSC‐MSCs demonstrated the ability to differentiate into multiple lineages in vitro. Finally, we evaluated the therapeutic potential of iPSC‐MSCs using an osteochondral defect model. Our findings demonstrated that teratomas are a promising source for the isolation of condensed MSCs. More importantly, our results suggest that iPSC‐MSCs derived from teratomas possess the capacity for tissue regeneration, highlighting their promise for future therapeutic applications.

The purpose of this study is to grasp the behavior characteristics of a single batter pile under vertical load by performing a model test. The changes in the resistance of the pile, the bending moment, etc. by the slope of the pile and the relative density of the ground were analyzed. According to the results of the test, when the relative density of the ground was medium and high, the bearing capacity kept increasing when the angle of the pile moved from a vertical position to 20°, and then decreased gradually after 20°. The bending moment of the pile increased as the relative density of the ground and the batter angle of the pile increased. The position of the maximum bending moment came closer to the ground surface as the batter angle of the pile further increased, and it occurred at a point of 5.2~6.7 times the diameter of the pile from the ground surface.

In this study, to use carbon nanotubes (CNTs) as a conductive material instead of carbon black in cathode electrodes, their dispersions were prepared in 1-Methyl-2-pyrrolidinone (NMP) solvent by using an ultrasonic horn, and their dispersion stability was analyzed using CNTs on the formation of the network between cathode electrode constituent materials comprised of cathode material, CNTs, and current collectors, and their correlation with electrochemical performance results were investigated using various analytical techniques. Particularly, in the analysis, terahertz time domain spectroscopy (THz-TDS), a new non-destructive analysis method, was used to analyze and compare the various optical properties of the cathode’s slurries that co-existed with CNTs and cathode material, suggesting the suitability of its analytical use in the field of materials dispersion and the slurry manufacturing process for lithium-ion batteries (LIBs). In the investigated results, the sample with the highest dispersion stability of CNTs uniformly formed the networks of CNTs and cathode material in the electrode, which results in the highest electrical conductivity among all samples, and as a result, the best performance in electrochemical evaluations.