Cancer immunotherapy has emerged as a novel cancer treatment, although recent immunotherapy trials have produced suboptimal outcomes, with durable responses seen only in a small number of patients. ...The tumor microenvironment (TME) has been shown to be responsible for tumor immune escape and therapy failure. The vital component of the TME is tumor-associated macrophages (TAMs), which are usually associated with poor prognosis and drug resistance, including immunotherapies, and have emerged as promising targets for cancer immunotherapy. Recently, nanoparticles, because of their unique physicochemical characteristics, have emerged as crucial translational moieties in tackling tumor-promoting TAMs that amplify immune responses and sensitize tumors to immunotherapies in a safe and effective manner. In this review, we mainly described the current potential nanomaterial-based therapeutic strategies that target TAMs, including restricting TAMs survival, inhibiting TAMs recruitment to tumors and functionally repolarizing tumor-supportive TAMs to antitumor type. The current understanding of the origin and polarization of TAMs, their crucial role in cancer progression and prognostic significance was also discussed in this review. We also highlighted the recent evolution of chimeric antigen receptor (CAR)-macrophage cell therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Computed tomography (CT) is one of the most widely used clinical imaging modalities. In order to increase the sensitivity of CT, small iodinated compounds are used as injectable contrast agents. ...However, the iodinated contrast agents are excreted through the kidney and have short circulation times. This rapid renal clearance not only restricts in vivo applications that require long circulation times but also sometimes induces serious adverse effects related to the excretion pathway. In addition, the X‐ray attenuation of iodine is not efficient for clinical CT that uses high‐energy X‐ray. Due to these limitations, nano‐sized iodinated CT contrast agents have been developed that can increase the circulation time and decrease the adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides, and tantalum are used as more efficient CT contrast agents. In this review, we summarize the recent progresses made in nano‐sized CT contrast agents.
Various nano‐sized materials are developed as novel CT contrast agents to overcome the limitations of current iodinated agents. These novel agents using heavy atoms such as gold, tantalum, lanthanides, and bismuth provide more efficient X‐ray contrast effects, and their long‐circulation time and facile surface modification allow a variety of applications including targeted imaging, angiography, multimodal imaging, and simultaneous diagnosis and therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Indocyanine green (ICG) has been used in clinical practice for more than 40 years and its safety and preferential accumulation in tumors has been reported for various tumor types, including colon ...cancer. However, reports on clinical assessments of ICG-based molecular endoscopy imaging for precancerous lesions are scarce. We determined visualization ability of ICG fluorescence endoscopy in colitis-associated colon cancer using 30 lesions from an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and 16 colon cancer patient tissue-samples. With a total of 60 images (optical, fluorescence) obtained during endoscopy observation of mouse colon cancer, we used deep learning network to predict four classes (Normal, Dysplasia, Adenoma, and Carcinoma) of colorectal cancer development. ICG could detect 100% of carcinoma, 90% of adenoma, and 57% of dysplasia, with little background signal at 30 min after injection via real-time fluorescence endoscopy. Correlation analysis with immunohistochemistry revealed a positive correlation of ICG with inducible nitric oxide synthase (iNOS; r > 0.5). Increased expression of iNOS resulted in increased levels of cellular nitric oxide in cancer cells compared to that in normal cells, which was related to the inhibition of drug efflux via the ABCB1 transporter down-regulation resulting in delayed retention of intracellular ICG. With artificial intelligence training, the accuracy of image classification into four classes using data sets, such as fluorescence, optical, and fluorescence/optical images was assessed. Fluorescence images obtained the highest accuracy (AUC of 0.8125) than optical and fluorescence/optical images (AUC of 0.75 and 0.6667, respectively). These findings highlight the clinical feasibility of ICG as a detector of precancerous lesions in real-time fluorescence endoscopy with artificial intelligence training and suggest that the mechanism of ICG retention in cancer cells is related to intracellular nitric oxide concentration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concentration. Herein, we design biocompatible manganese ferrite ...nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amount of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addition, MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy.
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IJS, KILJ, NUK, PNG, UL, UM
Implantable electronic devices for recording electrophysiological signals and for stimulating muscles and nerves have been widely used throughout clinical medicine. Mechanical mismatch between ...conventional rigid biomedical devices and soft curvilinear tissues, however, has frequently resulted in a low signal to noise ratio and/or mechanical fatigue and scarring. Multifunctionality ranging from various sensing modalities to therapeutic functions is another important goal for implantable biomedical devices. Here, a stretchable and transparent medical device using a cell‐sheet–graphene hybrid is reported, which can be implanted to form a high quality biotic/abiotic interface. The hybrid is composed of a sheet of C2C12 myoblasts on buckled, mesh‐patterned graphene electrodes. The graphene electrodes monitor and actuate the C2C12 myoblasts in vitro, serving as a smart cell culture substrate that controls their aligned proliferation and differentiation. This stretchable and transparent cell‐sheet–graphene hybrid can be transplanted onto the target muscle tissue, to record electromyographical signals, and stimulate implanted sites electrically and/or optically in vivo. Additional cellular therapeutic effect of the cell‐sheet–graphene hybrid is obtained by integrated myobalst cell sheets. Any immune responses within implanted muscle tissues are not observed. This multifunctional device provides many new opportunities in the emerging field of soft bioelectronics.
Stretchable and transparent cell‐sheet–graphene hybrid composed of cultured C2C12 myoblast sheets on mesh‐patterned, and buckled graphene electrodes brings high quality biotic/abiotic interface with multifunctional properties ranging from various sensing and actuating modalities to therapeutic functions in vitro and in vivo. Reduced acute immune responses due to the cell sheet support the advantage of the cell‐sheet–graphene hybrid.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To construct a highly efficient photoelectrochemical tandem device with silicon photocathode operating in alkaline conditions, it is desirable to develop stable and active catalysts which enable the ...photocathode to reliably perform under an alkaline environment. With nanostructured passivation layer and edge‐exposed transition metal disulfides, silicon photocathode provides new opportunities for achieving unbiased alkaline solar water splitting. Here, the TiO2 nanorod arrays decorated by edge‐rich MoS2 nanoplates are elaborately synthesized and deposited on p‐Si. The vertically aligned TiO2 nanorods fully stabilize the Si surface and improve anti‐reflectance. Moreover, MoS2 nanoplates with exposed edge sites provide catalytically active regions resulting in the kinetically favored hydrogen evolution under an alkaline environment. Interfacial energy band bending between p‐Si and catalyst layers facilitates the transport of photogenerated electrons under steady‐state illumination. Consequently, the MoS2 nanoplates/TiO2 nanorods/p‐Si photocathode exhibits significantly improved photoelectrochemical‐hydrogen evolution reaction (PEC‐HER) performance in alkaline media with a high photocurrent density of 10 mA cm−2 at 0 V versus RHE and high stability. By integrating rationally designed photocathode with earth‐abundant Fe60(NiCo)30Cr10 anode and perovskite/Si tandem photovoltaic cell, an unassisted alkaline solar water splitting is accomplished with a current density of 5.4 mA cm−2 corresponding to 6.6% solar‐to‐hydrogen efficiency, which is the highest among p‐Si photocathodes.
TiO2 nanorods decorated by edge‐exposed MoS2 nanoplates are successfully deposited on silicon photocathode using hydrothermal method. The device shows remarkable photoelectrochemical performance under alkaline environment due to enhanced anti‐reflectance, edge‐rich active sites, and energetically favorable photogenerated electron transfer. Based on as‐fabricated photocathode, photoelectrochemical‐photovoltaic tandem device is constructed for unbiased alkaline solar water splitting, exhibiting 6.6% solar‐to‐hydrogen efficiency.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a recently recognized rare neuronal tumor, and its pathogenesis is unclear. We analyzed 7 cases of histologically typical MVNT: 6 ...were adults (mean age, 43.0 years range, 23-56 years) and 1 was a child (age, 10 years). The most common symptoms were seizures (n = 4) and headache (n = 2). The tumors were supratentorial (temporal, 5; frontal lobes, 2) in origin as reported. Vacuolated tumor cells were robustly positive for α-INA and Olig2 and at least partly positive for synaptophysin and MAP2, but negative for Neu-N, nestin and CD34. GFAP and vimentin were expressed in reactive astrocytes but not in tumor cells. Negative results were obtained for p53, IDH-1, BRAFV600E, H3 K27M, EGFR, Lin28A, and L1CAM. ATRX, BRG1, INI-1, and TMHH were retained. The Ki-67 labeling index was very low (<1%), and pHH3 revealed no mitotic figure. Ultrastructural features of tumor cells were comparable with those of immature neuronal cells, with several intracytoplasmic myelin-like autophagosomes and pericellular vacuolization. No IDH1/IDH2 and BRAFV600E mutations were found upon direct sequencing. Whole-exome sequencing revealed FGFR2-ZMYND11 gene fusion in 1 case. After gross total resection, all patients were alive without seizures. There was no tumor recurrence during an average period of 68 months (range, 23-101 months). The analysis of 7 typical cases of MVNT suggested that these lesions may be clonal tumors because FGFR2-ZMYND11 fusion was found (1 case).
•“MVNT” of the cerebrum is a recently recognized rare epileptogenic neuronal tumor.•Whole-exome sequencing revealed FGFR2-ZMYND11 gene fusion in one of our MVNT cases.•The tumor cell is robustly positive for α-INA and Olig2, but negative for Neu-N.•Ultrastructurally, tumor cells have autophagolysosomes with pericellular vacuolization.•There was no tumor recurrence during an average period of 68 months.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A simple, low‐cost, large area, and continuous scalable coating method is proposed for the fabrication of hybrid organic–inorganic perovskite solar cells. A megasonic spray‐coating method utilizing a ...1.7 MHz megasonic nebulizer that could fabricate reproducible large‐area planar efficient perovskite films is developed. The coating method fabricates uniform large‐area perovskite film with large‐sized grain since smaller and narrower sized mist droplets than those generated by existing ultrasonic spray methods could be generated by megasonic spraying. The volume flow rate of the CH3NH3PbI3 precursor solution and the reaction temperature are controlled, to obtain a high quality perovskite active layer. The devices reach a maximum efficiency of 16.9%, with an average efficiency of 16.4% from 21 samples. The applicability of megasonic spray coating to the fabrication of large‐area solar cells (1 cm2), with a power conversion efficiency of 14.2%, is also demonstrated. This is a record high efficiency for large‐area perovskite solar cells fabricated by continuous spray coating.
A megasonic spray‐coating system is developed for continuous fabrication of highly uniform, and large‐grain MAPbI3 films. The large‐area MAPbI3 layer (56.25 cm2) is coated via a megasonic spray‐coating system and the fabricated solar cells achieve a maximum efficiency of 16.9% with an average efficiency of 16.4% for small active area cells and 14.2% for large active area (1 cm2) cells, respectively.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hepatic resection is the most curative treatment option for early‐stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. ...Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early‐stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high‐copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer‐specific and recurrence‐free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). Conclusion: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti‐FGF19 treatment in these patients. (Hepatology 2014;60:1971–1981)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGECs) and disease parameters in an animal model of Sjögren's syndrome (SS).
Common ...differentially expressed genes (DEGs) were analyzed among peripheral blood mononuclear cells from patients with primary SS and other data sets, using blood and SG tissue. Validation of expression in SGs was analyzed by focus score. Inhibition of messenger RNA expression of DEGs and BAFF by filgotinib was analyzed using reverse transcription-polymerase chain reaction in primary SGECs. SG organoid cultures were used to determine the association between DEGs and BAFF via knockdown using small interfering RNAs or to determine regulation of BAFF by JAK inhibitor. Filgotinib (1.5 mg/kg) was intraperitoneally injected into 8-week-old NOD/ShiLtJ mice 3 times per week to analyze manifestations of disease. Finally, STAT signaling was assessed in human and mouse SGECs.
Expression of the DEGs IFNG and BAFF increased in SGs from patients with primary SS, as assessed by focus score. There was a significant correlation between IFIT2 and BAFF expression. JAK inhibitor suppressed interferon (IFN)-induced transcription of DEGs and BAFF in human primary SGECs. Knockdown of DEGs or inhibition of JAK caused reduced secretion of BAFF in human SG organoid cultures. In addition, filgotinib-treated mice exhibited increased salivary flow rates and marked reductions in lymphocytic infiltration of SGs. JAK inhibitor regulated IFNα- and IFNγ-induced pSTAT-1
, pSTAT-3
, and protein inhibitor of activated STAT-3 (PIAS-3) in human SGECs as well as IFNγ-induced pSTAT-1
, pSTAT-3
, and PIAS-1 in mouse SGECs.
JAK inhibition controls aberrant activation of SGECs and may be a novel therapeutic approach for primary SS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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