Graphene materials have entered a phase of maturity in their development that is characterized by their explorative utilization in various types of applications and fields from electronics to ...biomedicine. Herein, we describe the recent advances made with graphene‐related materials in the biomedical field and the challenges facing these exciting new tools both in terms of biological activity and toxicological profiling in vitro and in vivo. Graphene materials today have mainly been explored as components of biosensors and for construction of matrices in tissue engineering. Their antimicrobial activity and their capacity to act as drug delivery platforms have also been reported, however, not as coherently. This report will attempt to offer some perspective as to which areas of biomedical applications can expect graphene‐related materials to constitute a tool offering improved functionality and previously unavailable options.
Graphene offers one of the most exciting tools for biomedicine due to its spectacular physicochemical characteristics. This Progress Report attempts to provide a snapshot of the current‐state‐of‐the‐art of graphene‐related materials in biomedical applications and a perspective on the challenges around the development of biologically active and safe graphene‐based technologies that could serve medical needs.
The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive ...microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.
Ordered mesoporous TiO2 films with increased pore connectivity are introduced in this work. Crack generation was accomplished by thermal shock using rapid thermal annealing to obtain a connected pore ...structure. Due to the increased pore connectivity caused by crack generation, the specific surface area of mesoporous TiO2 films increased by 2.6 times. As specific surface area increased, gas sensing properties of the ordered mesoporous TiO2 film were enhanced, thus, ordered mesoporous TiO2 films with increased pore connectivity are ideal candidates for gas sensor applications.
Adenosine signaling via the A2a receptor (A2aR) is emerging as an important checkpoint of immune responses. The presence of adenosine in the inflammatory milieu or generated by the CD39/CD73 axis on ...tissues or T regulatory cells serves to regulate immune responses. By nature of the specialized metabolism of cancer cells, adenosine levels are increased in the tumor microenvironment and contribute to tumor immune evasion. To this end, small molecule inhibitors of the A2aR are being pursued clinically to enhance immunotherapy. Herein, we demonstrate the ability of the novel A2aR antagonist, CPI-444, to dramatically enhance immunologic responses in models of checkpoint therapy and ACT in cancer. Furthermore, we demonstrate that A2aR blockade with CPI-444 decreases expression of multiple checkpoint pathways, including PD-1 and LAG-3, on both CD8+ effector T cells (Teff) and FoxP3+ CD4+ regulatory T cells (Tregs). Interestingly, our studies demonstrate that A2aR blockade likely has its most profound effects during Teff cell activation, significantly decreasing PD-1 and LAG-3 expression at the draining lymph nodes of tumor bearing mice. In contrast to previous reports using A2aR knockout models, pharmacologic blockade with CPI-444 did not impede CD8 T cell persistence or memory recall. Overall these findings not only redefine our understanding of the mechanisms by which adenosine inhibits immunity but also have important implications for the design of novel immunotherapy regimens.
The mechanistic/mammalian target of rapamycin (mTOR) has emerged as a critical integrator of signals from the immune microenvironment capable of regulating T cell activation, differentiation, and ...function. The precise role of mTOR in the control of regulatory T cell (Treg) differentiation and function is complex. Pharmacologic inhibition and genetic deletion of mTOR promotes the generation of Tregs even under conditions that would normally promote generation of effector T cells. Alternatively, mTOR activity has been observed to be increased in Tregs, and the genetic deletion of the mTOR complex 1 (mTORC1)-scaffold protein Raptor inhibits Treg function. In this study, by employing both pharmacologic inhibitors and genetically altered T cells, we seek to clarify the role of mTOR in Tregs. Our studies demonstrate that inhibition of mTOR during T cell activation promotes the generation of long-lived central Tregs with a memory-like phenotype in mice. Metabolically, these central memory Tregs possess enhanced spare respiratory capacity, similar to CD8
memory cells. Alternatively, the generation of effector Tregs (eTregs) requires mTOR function. Indeed, genetic deletion of
leads to the decreased expression of ICOS and PD-1 on the eTregs. Overall, our studies define a subset of mTORC1
eTregs and mTORC1
central Tregs.
Colonic perfusion status can be assessed easily by indocyanine green (ICG) angiography to predict ischemia related anastomotic complications during laparoscopic colorectal surgery. Recently, various ...parameter-based perfusion analysis have been studied for quantitative evaluation, but the analysis results differ depending on the use of quantitative parameters due to differences in vascular anatomical structure. Therefore, it can help improve the accuracy and consistency by artificial intelligence (AI) based real-time analysis microperfusion (AIRAM).
To evaluate the feasibility of AIRAM to predict the risk of anastomotic complication in the patient with laparoscopic colorectal cancer surgery.
The ICG curve was extracted from the region of interest (ROI) set in the ICG fluorescence video of the laparoscopic colorectal surgery. Pre-processing was performed to reduce AI performance degradation caused by external environment such as background, light source reflection, and camera shaking using MATLAB 2019 on an I7-8700k Intel central processing unit (CPU) PC. AI learning and evaluation were performed by dividing into a training patient group (
= 50) and a test patient group (
= 15). Training ICG curve data sets were classified and machine learned into 25 ICG curve patterns using a self-organizing map (SOM) network. The predictive reliability of anastomotic complications in a trained SOM network is verified using test set.
AI-based risk and the conventional quantitative parameters including
, time ratio (TR), and rising slope (RS) were consistent when colonic perfusion was favorable as steep increasing ICG curve pattern. When the ICG graph pattern showed stepped rise, the accuracy of conventional quantitative parameters decreased, but the AI-based classification maintained accuracy consistently. The receiver operating characteristic curves for conventional parameters and AI-based classification were comparable for predicting the anastomotic complication risks. Statistical performance verifications were improved in the AI-based analysis. AI analysis was evaluated as the most accurate parameter to predict the risk of anastomotic complications. The F1 score of the AI-based method increased by 31% for
, 8% for TR, and 8% for RS. The processing time of AIRAM was measured as 48.03 s, which was suitable for real-time processing.
In conclusion, AI-based real-time microcirculation analysis had more accurate and consistent performance than the conventional parameter-based method.
Fabricating thermoelectric generators (TEGs) using the screen‐printing process has advantages, including mass production, device scalability, and system applicability. However, the thick film formed ...through the process typically has low film density, and reduced performance, because of the presence of pores in the film created by the vaporization of the resin during high‐temperature annealing. During the soldering process used for thermoelectric module fabrication, the printed solder infiltrates into the screen‐printed electrodes through the micropores in the electrodes, causing cracks of the electrode film and an increase in resistivity. In this paper, an ultraviolet radiation (UV)‐curable process for screen‐printed electrodes is reported. The paste for the electrodes is synthesized by mixing Ag flakes that can be cured at low temperature with a UV resin. Scanning electron microscope images show that the UV‐curing process significantly reduces pores and thereby results in a smooth‐surfaced electrode layer. The film density after crystallization is also enhanced. TEGs composed of 72 couples with UV‐curable Ag electrodes generate a high power density of ≈6.69 mW cm−2 at a temperature difference of 25 °C; the device resistance is ≈0.75 Ω, and the figure of merit of the device is recorded to be 0.57, which is the highest among the printed TEGs.
A new forming technique for printing‐based electrodes is proposed to improve the properties of thermoelectric devices. The ultraviolet‐curing system and the flake‐type metal powder are introduced to exclude the conventional high‐temperature crystallization, and problems due to low density are improved. This improvement increases the stability of the device fabrication and improves the output of the fabricated device.
Abstract
Metabolic programming is integrally linked to immune cell function. Nowhere is this clearer than in the differentiation of macrophages. Proinflammatory M1 macrophages primarily use ...glycolysis as a rapid energy source but also to generate antimicrobial compounds, whereas alternatively activated M2 macrophages primarily rely on oxidative phosphorylation for the longevity required for proper wound healing. mTOR signaling has been demonstrated to be a key regulator of immune cell metabolism and function. mTORC2 signaling is required for the generation of M2 macrophages, whereas the role of mTORC1 signaling, a key regulator of glycolysis, has been controversial. By using genetic deletion of mTORC1 signaling in C57BL/6 mouse macrophages, we observed enhanced M1 macrophage function in vitro and in vivo. Surprisingly, this enhancement occurred despite a significant defect in M1 macrophage glycolytic metabolism. Mechanistically, enhanced M1 function occurred because of inhibition of the class III histone deacetylases the sirtuins, resulting in enhanced histone acetylation. Our findings provide a counterpoint to the paradigm that enhanced immune cell function must occur in the presence of increased cellular metabolism and identifies a potential, pharmacologic target for the regulation of inflammatory responses.
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only ...were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.
Matrix-assisted laser desorption/ionization mass spectrometry has been considered an important tool for various biochemical analyses and proteomics research. Although addition of conventional matrix ...efficiently supports laser desorption/ionization of analytes with minimal fragmentation, it often results in high background interference and misinterpretation of the spatial distribution of biomolecules especially in low-mass regions. Here, we show design, systematic characterization, and application of graphene oxide/multiwalled carbon nanotube-based films fabricated on solid substrates as a new matrix-free laser desorption/ionization platform. We demonstrate that the graphene oxide/multiwalled carbon nanotube double layer provides many advantages as a laser desorption/ionization substrate, such as efficient desorption/ionization of analytes with minimum fragmentation, high salt tolerance, no sweet-spots for mass signal, excellent durability against mechanical and photoagitation and prolonged exposure to ambient conditions, and applicability to tissue imaging mass spectrometry. This platform will be widely used as an important tool for mass spectrometry-based biochemical analyses because of its outstanding performance, long-term stability, and cost effectiveness.
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