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Chimeric antigen receptor (CAR) T-cell therapy plays a critical role in the treatment of B-cell hematologic malignancies. The combination of PD-1 inhibitors and CAR-T has shown encouraging results in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, there are still cases where treatment is ineffective. This study aimed to investigate the role of IL4I1 in the poor efficacy of CD19 CAR-T combined with PD-1 inhibitors in R/R DLBCL and to explore potential mechanisms. Transcriptomic and metabolomic correlation analyses were performed on tumor tissue from DLBCL patients. We employed an in vitro co-culture system consisting of Pfeiffer cells, CD19 CAR-T and macrophages to investigate the underlying mechanisms. It was found that IL4I1 levels were significantly increased in the tumor tissues of R/R DLBCL patients compared to responders. Correlation analysis revealed a positive association between IL4I1 and tryptophan (Trp)-kynurenic acid (Kyn) related metabolites. In the in vitro co-culture model, the presence of IL4I1 inhibited the cytotoxicity of CAR-T cells. Depletion of IL4I1 disrupted the IDO-AHR-Kyn signaling pathway, thereby enhancing the effectiveness of PD-1 inhibitors in combination with CD19 CAR-T for DLBCL treatment. CAR-T-mediated cytotoxicity was significantly inhibited when IL4I1 was present in the in vitro co-culture model. These findings suggest that IL4I1 may be a contributing factor to poor prognosis in R/R DLBCL patients. IL4I1 expression enhances immunosuppression via the IDO-AHR-Kyn pathway, inhibiting the effectiveness of PD-1 inhibitors combined with CD19 CAR-T. Therefore, suppression of IL4I1 may represent a potential target for combination therapy in DLBCL. [ABSTRACT FROM AUTHOR]

This article develops a predefined‐time sliding mode control approach for systems with external disturbances and uncertainties through a nonlinear disturbance observer (DO). For addressing predefined‐time stabilization problem of robotic manipulator system, a predefined‐time sliding mode surface is proposed, ensuring system states converge to origin within a predefined‐time once sliding mode surface is attained. Compared to conventional fixed‐time and finite‐time control strategies, a distinctive advantage of this scheme is that system settling time can be explicitly chosen in advance and independent of system states. To achieve predefined‐time performance, a disturbance observer is introduced to generate the disturbance estimate, which can be incorporated into controller to counteract disturbance. To address the systems uncertainty, an adaptive law is employed to estimate the unknown upper boundary of system uncertainties. Finally, the effectiveness and performance of the proposed scheme are illustrated by simulation and experiment. [ABSTRACT FROM AUTHOR]

Biologically inspired peptide‐based materials, as novel charge transport materials, have gained increasing interest in bioelectronics due to their remarkable electrical properties and inherent biocompatibility. Extensive studies have shown that peptides can self‐assemble into a variety of hierarchical nanostructures with unique physical properties through supramolecular interactions. Therefore, peptide‐based materials hold great promise for applications in emerging electronic fields such as sensing, energy harvesting, energy storage, and electronic transmission. Herein, this work proposes a review article to summarize the rational design and research progress of peptide‐based materials and devices in bioelectronics. This work first introduces the design strategies and assembly mechanism for constructing high‐performance peptide‐based electronic materials and devices. In the following part, the applications of peptide‐based electronic materials and devices are systematically classified and discussed, including sensors, piezoelectric nanogenerators, electrodes, and semiconductors. Finally, the remaining challenges and future perspectives of peptide‐based bioelectronic materials and devices are presented. This work believes that this review will provide inspiration and guidance for the design and development of innovative peptide‐based smart materials in the field of bioelectronics. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are a subpopulation of cancer cells that share similarities with somatic stem cells. CSCs are believed to play a key role in carcinogenesis, metastasis, cancer relapse, and drug resistance. Despite their significant impacts, the specific biological markers for the identification of CSCs and their differentiation/transformation mechanisms have not yet been fully characterized. Utilizing stem cell markers, the ability to differentiate in multiple directions, and resistance to radiotherapy and chemotherapy, CSCs were identified. To assess the variations in gene expression, gene alterations, protein expression, and cell proliferation between CSCs and U118MG glioma cells, second generation sequencing, Real-Time PCR, Western Blotting, and CCK-8 were employed. In this study, we identified a subset of CSCs in human U118MG glioma cells that expressed the stem cell biomarkers CD133+, OCT4+, and CD44+. These cells exhibited stem cell-like characteristics such as multilineage differentiation and resistance to chemical and radiation stresses. Notably, they can form neurons with electrical signals and sodium currents. Further study also revealed that the malignant growth of this CSC subset was controlled by long noncoding RNA (Lnc-DC) through the STAT3 pathway. As a potential therapeutic approach, inhibiting Lnc-DC may be beneficial in hindering carcinogenesis and drug resistance, as it selectively targets the growth of CSCs. [ABSTRACT FROM AUTHOR]

The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer. [ABSTRACT FROM AUTHOR]

Introduction: Due to the ability to mimic in vivo cellular microenvironments, the development of multicell culture systems has received increasing interest for use as research models and serving as platforms for drug evaluation. Methods: In this study, we developed a perfused microfluidic system to resemble the in vivo intercellular environment and applied it to study the differentiation from neural stem cells into neurons. Results: As determined by immunofluorescence chemistry and quantitative real-time PCR, the neural stem cells grown in this microfluidic system showed an elevated differentiation rate toward the formation of neurons as determined by the increased level of βIII-tubulin production, which is 4 times higher than that of culturing neural stem cells only. Conclusion: These results revealed that some factors secreted into the intercellular microenvironment by adult neuron cells can stimulate the differentiation of neural stem cells, pointing to the importance of developing multicellular culture systems such as the perfused microfluidic system we report here to better resemble the in vivo situation. [ABSTRACT FROM AUTHOR]

Introduction: Three-dimensional (3D) collagen scaffold models, due to their ability to mimic the tissue and organ structure in vivo, have received increasing interest in drug discovery and toxicity evaluation. Methods: In this study, we developed a perfused 3D model and studied cellular response to cytotoxic drugs in comparison with traditional 2D cell cultures as evaluated by cancer drug cisplatin. Results: Cancer cells grown in perfused 3D environments showed increased levels of reactive oxygen species (ROS) production compared to the 2D culture. As determined by growth analysis, cells in the 3D culture, after forming a spheroid, were more resistant to the cancer drug cisplatin compared to that of the 2D cell culture. In addition, 3D culturing cells showed elevated level of ROS, indicating a physiological change or the formation of a microenvironment that resembles tumor cells in vivo. Conclusions: These data revealed that cellular response to drugs for cells growing in 3D environments are dramatically different from that of 2D cultured cells. Thus, the perfused 3D collagen scaffold model we report here might be a potentially very useful tool for drug analysis. [ABSTRACT FROM AUTHOR]

Electrical property characterization of stem cells could be utilized as a potential label-free biophysical approach to evaluate the differentiation process. However, there has been a lack of technology or tools that can quantify the intrinsic cellular electrical markers (e.g., specific membrane capacitance (Cspecific membrane) and cytoplasm conductivity (σcytoplasm)) for a large amount of stem cells or differentiated cells. In this paper, a microfluidic platform enabling the high-throughput quantification of Cspecific membrane and σcytoplasm from hundreds of single neural stem cells undergoing differentiation was developed to explore the feasibility to characterize the neural stem cell differentiation process without biochemical staining. Experimental quantification using biochemical markers (e.g., Nestin, Tubulin and GFAP) of neural stem cells confirmed the initiation of the differentiation process featured with gradual loss in cellular stemness and increased cell markers for neurons and glial cells. The recorded electrical properties of neural stem cells undergoing differentiation showed distinctive and unique patterns: 1) in the suspension culture before inducing differentiation, a large distribution and difference in σcytoplasm among individual neural stem cells was noticed, which indicated heterogeneity that may result from the nature of suspension culture of neurospheres; and 2) during the differentiation in adhering monolayer culture, significant changes and a large difference in Cspecific membrane were located indicating different expressions of membrane proteins during the differentiation process, and a small distribution difference in σcytoplasm was less significant that indicated the relatively consistent properties of cytoplasm during the culture. In summary, significant differences in Cspecific membrane and σcytoplasm were observed during the neural stem cell differentiation process, which may potentially be used as label-free biophysical markers to monitor this process. [ABSTRACT FROM AUTHOR]

An in vitro three-dimensional (3D) cell culture system that can mimic organ and tissue structure and function in vivo will be of great benefit for drug discovery and toxicity testing. In this study, the neuroprotective properties of the three most prevalent flavonoid monomers extracted from EGb 761 (isorharmnetin, kaempferol, and quercetin) were investigated using the developed 3D stem cell-derived neural co-culture model. Rat neural stem cells were differentiated into co-culture of both neurons and astrocytes at an equal ratio in the developed 3D model and standard two-dimensional (2D) model using a two-step differentiation protocol for 14 days. The level of neuroprotective effect offered by each flavonoid was found to be aligned with its effect as an antioxidant and its ability to inhibit Caspase-3 activity in a dose-dependent manner. Cell exposure to quercetin (100 µM) following oxidative insult provided the highest levels of neuroprotection in both 2D and 3D models, comparable with exposure to 100 µM of Vitamin E, whilst exposure to isorhamnetin and kaempferol provided a reduced level of neuroprotection in both 2D and 3D models. At lower dosages (10 µM flavonoid concentration), the 3D model was more representative of results previously reported in vivo. The co-cultures of stem cell derived neurons and astrocytes in 3D hydrogel scaffolds as an in vitro neural model closely replicates in vivo results for routine neural drug toxicity and efficacy testing. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:735-744, 2016 [ABSTRACT FROM AUTHOR]