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Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor‐associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement‐dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next‐generation GD2‐specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3‐16 IgG1m4 antibody from ch14.18 IgG1. H3‐16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2‐positive cell lines as revealed by ELISA, and its cross‐binding activity to other gangliosides was not altered. The CDC activity of H3‐16 IgG1m4 was decreased, and the antibody‐dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3‐16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague–Dawley (SD) rats. In summary, H3‐16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that pyroptosis, a form of programmed cell death, has been implicated in cancer progression. The involvement of specific proteins in pyroptosis is an area of growing interest. TOM20, an outer mitochondrial membrane protein, has recently garnered attention for its potential role in pyroptosis. Our previous study found that NBT could induce pyroptosis by ROS/JNK pathway in esophageal cancer cells. This study aims to investigate whether NBT induces pyroptosis and verify whether such effects are involved in up-regulation of TOM20 in esophageal cancer cells. The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) was used to analyze the clinical significance of GSDME in esophageal cancer. MTT assay, morphological observation and Western blot were performed to verify the roles of TOM20 and BAX in NBT-induced pyroptosis after CRISPR-Cas9-mediated knockout. Immunofluorescence was used to determine the subcellular locations of BAX and cytochrome c. MitoSOX Red was employed to assess the mitochondrial reactive oxygen species (ROS) level. KYSE450 and TOM20 knockout KYSE450-/- xenograft models were established to elucidate the mechanisms involved in NBT-induced cell death. In this study, NBT effectively upregulated the expression of TOM20 and facilitated the translocation of BAX to mitochondria, which promoted the release of cytochrome c from mitochondria to the cytoplasm, leading to the activation of caspase-9 and caspase-3, and finally induced pyroptosis. Knocking out TOM20 by CRISPR-Cas9 significantly inhibited the expression of BAX and the downstream BAX/caspase-3/GSDME pathway, which attenuated NBT-induced pyroptosis. The elevated mitochondrial ROS level was observed after NBT treatment. Remarkably, the inhibition of ROS by N-acetylcysteine (NAC) effectively suppressed the activation of TOM20/BAX pathway. Moreover, in vivo experiments demonstrated that NBT exhibited potent antitumor effects in both KYSE450 and TOM20 knockout KYSE450-/- xenograft models. Notably, the attenuated antitumor effects and reduced cleavage of GSDME were observed in the TOM20 knockout model. These findings reveal that NBT induces pyroptosis through ROS/TOM20/BAX/GSDME pathway, which highlight the therapeutic potential of targeting TOM20 and GSDME, providing promising prospects for the development of innovative and effective treatment approaches for esophageal cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

In this paper, a novel multiuser spatial modulation (SM) scheme is proposed and applied in downlink multiple input-multiple output (MIMO) visible light communication (VLC) system. In the transmitter side, each user's temporal symbol is first modulated onto user specific optical orthogonal code (OOC), then being emitted by the specific LED that is activated by its spatial symbol. At the front end of each user terminal (UT), array of photodetectors (PDs) convert optical into electrical signal, then chip-level detection scheme is employed to eliminate multiuser interference (MUI). Two computationally attractive detection algorithms are then proposed: Maximum likelihood (ML) algorithm premises on jointly estimating both temporal and spatial symbols. While the two-stages algorithm first identifies the index of the activated LED followed by a M -ary PAM demodulator to extract the desired user's spatial and temporal symbols sequentially. Extensive Monte Carlo simulations are undertaken to evaluate system performance in terms of the overall symbol error rate (SER). It is demonstrated that the chip-level detection scheme can effectively alleviate MUI and both ML and the two-stages detection algorithms work reliably in various scenarios. Hence, it is promising to apply the proposed scheme in multiuser MIMO-VLC system. [ABSTRACT FROM AUTHOR]

This study evaluated the potential effect of stock enhancement on a coastal ecosystem. Based on data collected from the 2020 bottom trawl survey and literature information, an Ecopath model was constructed containing 19 functional groups representing the coastal area of southern Zhejiang, China. Jellyfish (Rhopilema esculenta) and black seabream Acanthopagrus schlegelii were selected as target-enhancing species based on their extensive juvenile release records. The maximum carrying capacity of these two species was estimated by static Ecopath and the potential ecological effects of enhancement activity for these two species were evaluated by the Ecosim routine. The trophic level (TL) of the functional groups in the coastal area of southern Zhejiang ecosystem ranged from 1 (primary producers) to 4.56 (sharks). The mean transfer efficiency of the coastal area ecosystem of southern Zhejiang was 8.71%, in which the relatively low transfer efficiency from TL2 to 3 was considered the main bottleneck that limited the biomass of higher TL species in this ecosystem. System characteristics indicated that the coastal area ecosystem of southern Zhejiang was vulnerable to disturbances and had low recovery ability. Enhancement simulation results indicated that the enhancement of jellyfish and black seabream had a partial impact on the functional groups of the ecosystem. Both jellyfish and black seabream enhancements adversely affected most groups of fish, cephalopods, and crabs, while jellyfish release stimulated the biomass of crabs. Ultimately, the present study indicates that the enhancement of black seabream decreased the total fish biomass via complex trophic interactions in the food web. Additionally, this study shows that recapture rates might not be sufficient to evaluate the net effect of stock enhancement, and therefore highlight the importance of ecosystem-based assessments for stock enhancement. [Display omitted] • Ecosystem-level effects of different stock enhancement strategies were analyzed. • An ecosystem model represents the southern Zhejiang coastal area, China, was constructed. • The enhancement of Jellyfish and Black seabream had partial impacts on the functional groups of this ecosystem. • Recapture rates might not be sufficient to evaluate the effect of stock enhancement. [ABSTRACT FROM AUTHOR]

Vascular stiffening is associated with the prognosis of cardiovascular disease (CVD). Endothelial dysfunction, as shown by reduced vasodilation and increased vasoconstriction, not only affects vascular tone, but also accelerates the progression of CVD. However, the precise effect of vascular stiffening on endothelial function and its mechanism is unclear and a possible underlying has not been determined. In this study, we found that increasing substrate stiffness promoted endothelin-1 (ET-1) expression and inhibited endothelial nitric oxide synthase expression in human umbilical vein endothelial cells. Additionally, miR-6740-5p was identified as a stiffness-sensitive microRNA, which was downregulated by a stiff substrate, resulting in increased ET-1 expression. Furthermore, we found that substrate stiffening reduced the expression and activity of the calcium channel TRPV4, which subsequently enhanced ET-1 expression by inhibiting miR-6740-5p. Finally, analysis of clinical plasma samples showed that plasma miR-6740-5p levels in patients with carotid atherosclerosis were significantly lower than those in healthy people. Taken together, our findings show a novel mechanically regulated TRPV4/miR-6740/ET-1 signaling axis by which substrate stiffness affects endothelial function. Our findings indicate that vascular stiffening induces endothelial dysfunction, thereby accelerating progression of CVD. Furthermore, this study indicates that endothelial dysfunction induced by improper biophysical cues from cardiovascular implants may be an important reason for complications arising from the use of cardiovascular implants. Cardiovascular disease is the leading cause of morbidity and mortality worldwide. The incidence of cardiovascular disease is accompanied by increased vascular stiffness. Our work indicated that increased vascular stiffness accelerates the development of cardiovascular disease by inducing endothelial dysfunction, which is a key contributor to the pathogenesis of cardiovascular disease. In addition, we identified a novel underlying molecular pathophysiological mechanism by which increased stiffness induce endothelial dysfunction. Our work could help determine the pathogenesis of cardiovascular disease induced by biomechanical factors. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Background: Several kinds of crystalloid solutions have been used in the treatment of hemorrhagic shock (HS). Clinicians are faced with how to select the resuscitation fluids. The aim of the present study is to compare the effects of 3 crystalloid solutions, such as normal saline (NS), lactated Ringer's (LR), and Plasma-lyte A (PA), on acid-base status and intestine injury in rats subjected to HS.Methods: Thirty Wistar rats were divided into 4 groups. The sham group had no blood withdrawal. The other groups were subjected to severe HS and then injected with NS, LR, or PA. All treatments were followed with an infusion of red blood cell suspension. The mean arterial pressure was monitored throughout the experiment. The arterial blood gas, malonaldehyde, and myeloperoxidase levels in the small intestine were assayed 120 minutes after resuscitation.Results: Plasma-lyte A treatment could restore the pH, base excess (BE), HCO3-, Pao2, and Paco2. Comparing with sham group, NS failed to correct the decreased pH, BE, and HCO3- (P < .05), whereas LR treatment showed the decreased BE and HCO3- (P < .05) and increased Pao2 (P < .05). There were no significant differences in malonaldehyde among the 4 groups (P > .05). Both PA and LR were more effective than NS in decreasing the myeloperoxidase level in the small intestine (P < .01).Conclusions: Although the 3 crystalloid solutions play different roles, PA is better at correcting the acid-base balance and improving intestine injury during HS than NS and LR. [ABSTRACT FROM AUTHOR]

Background: Pyroptosis, an inflammatory form of programmed cell death (PCD), is reported to play important roles in the treatment of tumors. In our previous studies, we found that neobractatin (NBT), a caged prenylxanthone isolated from edible fruits of Garcinia bracteata C. Y. Wu ex Y. H. Li, showed anticancer effects against different cancer cells. However, the effect of NBT on pyroptosis is not well understood.Purpose: This study aims to investigate whether and how GSDME-mediated pyroptosis contributes to NBT-induced antitumor effects in esophageal cancer (EC) cells.Methods: Cell viability assay and colony formation assay were used to determine the anticancer effects of NBT in esophageal cancer cells. Lactate dehydrogenase (LDH) release assay and microscopy imaging were used to detect the main characteristic of pyroptosis. CRISPR-Cas9 knockout and siRNA knockdown were performed to verify the roles of GSDME and caspase-3 in NBT-induced pyroptosis. Flow cytometry was used to measure the reactive oxygen species (ROS) level and cell apoptosis. The changes of related protein level were detected by Western blot. Furthermore, animal experiments were used to verify the in vivo effect of NBT.Results: The results showed that NBT reduced the viability of EC cells mainly through GSDME-mediated pyroptosis. Morphologically, NBT induced cell swelling and formed large bubbles emerging from plasma membrane in wild type EC cells. Furthermore, NBT induced the cleavage of GSDME by activating caspase-3 in EC cells. On the other hand, caspase-3 activated by NBT also induced apoptosis especially at high dosage. Knocking down GSDME switched NBT-induced cell death from mainly pyroptosis to apoptosis in vivo and in vitro. Mechanistic studies indicated that NBT led to accumulation of ROS, which then regulated the phosphorylation of both JNK and MEK/ERK. In the absence of ROS or caspase-3, NBT-induced pyroptosis and apoptosis were completely reversed. Moreover, NBT showed a significant antitumor effect in both the KYSE150 and GSDME knockout KYSE150-/- xenograft models by inducing pyroptosis and apoptosis, respectively.Conclusion: Our results indicated that natural compound NBT could induce GSDME-mediated pyroptosis and apoptosis in esophageal cancer cells, making it a potential therapeutic drug in clinical treatment. [ABSTRACT FROM AUTHOR]

Abstract: Nitric oxide (NO), an endothelial-derived relaxing factor, plays important roles in a variety of pathophysiological conditions such as hemorrhagic shock (HS). So far, the impact of NO administration in HS treatment has been controversial. Through literature review, we summarize here the biphasic effects of NO in early and late phases of HS. Evidence suggests that NO administration is beneficial in the early stage while detrimental in the late stage of HS. We further propose inhalation of NO as a novel therapeutic strategy for the treatment of HS in the early stage. [Copyright &y& Elsevier]