Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) ...is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of
exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (
≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (
≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (
≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities.
Mesenchymal stem cells (MSCs) are known for being multi-potent. However, they also possess anticancer properties, which has prompted efforts to adapt MSCs for anticancer therapies. However, MSCs have ...also been widely implicated in pathways that contribute to tumor growth. Numerous studies have been conducted to adapt MSCs for further clinical use; however, the results have been inconclusive, possibly due to the heterogeneity of MSC populations. Moreover, the conflicting roles of MSCs in tumor inhibition and tumor growth impede their adaptation for anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in hematologic malignancies are not as well established as they are for solid malignancies, and data comparing them are still limited. Herein the effect of MSCs on hematologic malignancies, such as leukemia and lymphoma, their mechanisms, sources of MSCs, and their effects on different types of cancer, have been discussed. This review describes how MSCs preserve both antitumorigenic and protumorigenic effects, as they tend to not only inhibit tumor growth by suppressing tumor cell proliferation but also promote tumor growth by suppressing tumor cell apoptosis. Thus clinical studies trying to adapt MSCs for anticancer therapies should consider that MSCs could actually promote hematologic cancer progression. It is necessary to take extreme care while developing MSC-based cell therapies in order to boost anticancer properties while eliminating tumor-favoring effects. This review emphasizes that research on the therapeutic applications of MSCs must consider that they exert both antitumorigenic and protumorigenic effects on hematologic malignancies.
The formation of lithium sulfides as discharge products imparts high specific energy density to lithium sulfur batteries (LSBs), however, the involvement of soluble intermediates in the battery ...reaction makes it challenging to achieve it reversibly for extended cycles. The precise understanding of phase transitions from the soluble intermediates to solid discharge products would aid in fundamentally resolving practical issues involving the intermediates, and thus allow the realization of long-lived high-energy-density LSBs. Herein, we utilize liquid
in situ
transmission-electron-microscopy (TEM) to probe detailed liquid-solid reaction processes. It reveals that the surface nature of the host materials of the polysulfides critically influences the growth mechanism of lithium sulfides. It is elucidated that polar hosts induce instantaneous nucleation of lithium sulfides, followed by diffusion-controlled-to-reaction-limited growth kinetics and a crystalline-to-amorphous phase transition. Moreover, it is verified that polysulfides are better immobilized in polar hosts, whereas polysulfide diffusion through nonpolar hosts is evidently observed, leading to the eventual degradation of cells. Based on these findings, an optimal host structure for sulfur is proposed, where the dual walls of polar (inner)/nonpolar (outer) spheres confine the polysulfides. The new cathode exhibits remarkable electrochemical performance, retaining a capacity of 4.3 mA h cm
−2
over 400 cycles at a low electrolyte/sulfur ratio of 6.8 ml g
−1
, which rivals state-of-the-art LSBs. This work contributes the first liquid
in situ
TEM study of liquid-solid phase evolution for high energy electrode materials.
The nucleation and growth of lithium sulfides are directly observed by liquid
in situ
transmission electron microscopy.
Recently, as flexible and wearable electronic devices have become widely popular, research on light weight and large‐capacity batteries suitable for powering such devices has been actively conducted. ...In particular, graphene has attracted considerable attention from researchers in the battery field owing to its good mechanical properties and its applicability in various processes to fabricate electrodes for batteries. Graphene is classified into two types: flake‐type, fabricated from graphite, and film‐type, synthesized using chemical vapor deposition. The unique processes involved in these two types enable the fabrication of flexible and stretchable batteries with various shapes and functions. In this article, the recent progress in the development of flexible and stretchable batteries based on graphene, as well as its important technical issues are reviewed.
Recently, there has been a demand to develop large‐capacity batteries for flexible and stretchable electronic devices. For this purpose, graphene can be a key material owing to good mechanical properties and applicability in constructing various nanostructures. This article reviews the recent progress in the development of flexible and stretchable battery electrodes based on graphene and corresponding important technical issues.
The learning and inference efficiencies of an artificial neural network represented by a cross‐point synaptic memristor array can be achieved using a selector, with high selectivity (Ion/Ioff) and ...sufficient death region, stacked vertically on a synaptic memristor. This can prevent a sneak current in the memristor array. A selector with multiple jar‐shaped conductive Cu filaments in the resistive switching layer is precisely fabricated by designing the Cu ion concentration depth profile of the CuGeSe layer as a filament source, TiN diffusion barrier layer, and Ge3Se7 switching layer. The selector performs super‐linear‐threshold‐switching with a selectivity of > 107, death region of −0.70–0.65 V, holding time of 300 ns, switching speed of 25 ns, and endurance cycle of > 106. In addition, the mechanism of switching is proven by the formation of conductive Cu filaments between the CuGeSe and Ge3Se7 layers under a positive bias on the top Pt electrode and an automatic rupture of the filaments after the holding time. Particularly, a spiking deep neural network using the designed one‐selector‐one‐memory cross‐point array improves the Modified National Institute of Standards and Technology classification accuracy by ≈3.8% by eliminating the sneak current in the cross‐point array during the inference process.
An artificial neural network consisting of a hardware‐based cross‐point synaptic memristor array should employ selectors with two‐terminal electrodes to prevent an undesired sneak current and to improve learning and inference efficiencies. Here, a highly reliable super‐linear‐threshold‐switching selector with multiple jar‐shaped Cu‐filaments in the amorphous Ge3Se7 resistive switching layer by controlling the Cu ion concentration depth profile is developed.
Episodic ataxia (EA) is a rare neurological condition characterized by recurrent spells of truncal ataxia and incoordination. Five genes (KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4) have been linked to ...EA. Despite extensive efforts to genetically diagnose EA, many patients remain still undiagnosed. Whole-exome sequencing was carried out in 39 Korean patients with EA to identify pathogenic mutations of the five known EA genes. We also evaluated 40 candidate genes that cause EA as a secondary phenotype or cerebellar ataxia. Eighteen patients (46%) revealed genetic information useful for establishing a molecular diagnosis of EA. In 11 patients, 16 pathogenic mutations were detected in three EA genes. These included nine mutations in CACNA1A, three in SLC1A3, and four in UBR4. Three patients had mutations in two genes, either CACNA1A and SLC1A3 or CACNA1A and UBR4, suggesting that SLC1A3 and UBR4 may act as genetic modifiers with synergic effects on the abnormal presynaptic activity caused by CACNA1A mutations. In seven patients with negative results for screening of EA genes, potential pathogenic mutations were identified in the candidate genes ATP1A2, SCN1A, TTBK2, TGM6, FGF14, and KCND3. This study demonstrates the genetic heterogeneity of Korean EA, and indicates that whole-exome sequencing may be useful for molecular genetic diagnosis of EA.
Various low-volume bowel cleansing formulations that improve compliance have been approved and are being used in clinical practice. This study aimed to compare the effectiveness of 1 L polyethylene ...glycol (PEG) with ascorbic acid with that of sodium picosulfate (PICO) with magnesium citrate. This was a multicenter, randomized controlled, non-inferiority study. Patients were randomized into a 1 L PEG with ascorbic acid group and a PICO with magnesium citrate group according to the bowel cleansing agent used. Colonoscopy was performed as a single-blind study wherein the endoscopist had no information about any bowel preparation agent. The efficacy of bowel cleansing was assessed using the Harefield Cleansing Scale (HCS), and adverse events, preferences, and satisfaction were evaluated using a patient-reported questionnaire before colonoscopy. A total of 254 participants were randomly assigned to two groups: 115 in the 1 L PEG with ascorbic acid group and 113 in the PICO with magnesium citrate group. Overall bowel cleansing success was not statistically different between the two groups (97.4 vs. 97.3%), confirming that 1 L PEG with ascorbic acid was not inferior to PICO with magnesium citrate (lower confidence limit, -4.15%; p = 1.00). High-quality bowel cleansing was achieved in 87% of the 1 L PEG with ascorbic acid group and 77% of the PICO with magnesium citrate group (Lower confidence limit, 1.29%, p = 0.05). In terms of patient satisfaction, PICO with magnesium citrate was better, but compliance and side effects were similar in both groups. The 1 L PEG with ascorbic acid showed similar efficacy and adverse events as PICO with magnesium citrate. Although 1 L PEG with ascorbic acid is very effective in bowel preparation despite its small volume, it is necessary to increase satisfaction such as taste and feeling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•ML models were developed for Chla retrieval for inland and coastal waters using MSI.•Light gradient boosting machine (LGBM) outperformed other ML algorithms.•Post-hoc explanations to ...LGBM were provided using SHAP.•Rrs(704)/Rrs(665) was the most important input feature.•Percent forest within the 500-m buffer zone explained among-lake Chla variations.
The MultiSpectral Instrument (MSI) on-board Sentinel-2 provides satellite images at spatiotemporal resolutions suitable for chlorophyll a (Chla) retrieval from inland and coastal waters. Machine-learning (ML) algorithms including light gradient boosting machine (LGBM) were employed for Chl a retrieval from MSI. The study area encompasses 78 lakes and estuaries located across four major river watersheds in South Korea. Matchup data between MSI overpass and near-concurrent in situ Chl a measurements from December 2018 to April 2021 were included. The remote sensing reflectance (Rrs) values of six single spectral bands and four two-band ratios were used as the input features. Despite the difficulty in Chla estimation in optically complex waters, ML algorithms showed overall reasonable accuracy. Among the ML algorithms, LGBM exhibited the best performance (R2 = 0.75, bias = -0.15, slope = 0.73, RMSE = 15.15 mg·m-3, MAE = 9.49 mg·m-3) over a wide range of trophic states. Post-hoc interpretations of the best performing LGBM using Shapley additive explanations indicated that Rrs(704)/Rrs(665) was the most important feature, while Rrs(739)/Rrs(704) and Rrs(492)/Rrs(560) played auxiliary roles in Chl a retrieval through interaction with Rrs(704)/Rrs(665). Among-lake spatial variations of Chla were explained by percent forest and agricultural area within the buffer zone at multiple scales (buffer widths of 50 m and 500 m). The associations between the modeled Chla and buffer land cover types, that is, increase in Chla concentration with increase in percent forest and decrease in percent agricultural area, were consistent with the established ecological knowledge. Overall, the model interpretations and spatial variations in Chla within and among lakes confirmed the validity of LGBM for retrieving MSI-derived Chla from lakes and estuaries. Our study can serve as the reference for evaluating the validity of complex ML models for inland water remote sensing.
Background
Aspirin‐exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin‐tolerant asthma (ATA).
...Objectives
This study aimed to investigate the long‐term clinical outcomes between AERD and ATA.
Methods
AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real‐world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD.
Results
Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p < .05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p < .01) than those with ATA. In a 10‐year follow‐up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group.
Conclusion and Clinical Relevance
We demonstrated that AERD patients presented poorer long‐term clinical outcomes than ATA patients in real‐world data analyses.
Plug-in electric vehicles (PEVs) have immense potential for reducing greenhouse gas emissions and dependence on fossil fuels, and for smart grid applications. Although a great deal of research is ...focused on technological limitations that affect PEV battery performance targets, a major and arguably equal concern is the constraint imposed by the finite availability of elements or resources used in the manufacture of PEV batteries. Availability of resources, such as lithium, for batteries is critical to the future of PEVs and is, therefore, a topic that needs attention. This study addresses the issues related to lithium availability and sustainability, particularly supply and demand related to PEVs and the impact on future PEV growth. In this paper, a detailed review of the research on lithium availability for PEV batteries is presented, key challenges are pinpointed and future impacts on PEV technology are outlined.
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