Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer.

As a highly invasive malignancy, esophageal cancer (EC) is a global health issue, and was the eighth most prevalent cancer and the sixth leading cause of cancer-related death worldwide in 2020. Due to its highly immunogenic nature, emer-ging immunotherapy approaches, such as immune checkpoint blockade, have demonstrated promising efficacy in treating EC; however, certain limitations and challenges still exist. In addition, tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment (TIME); thus, understanding the TIME is urgent and crucial, especially given the im-portance of an immunosuppressive microenvironment in tumor progression. The aim of this review was to better elucidate the mechanisms of the suppressive TIME, including cell infiltration, immune cell subsets, cytokines and signaling pathways in the tumor microenvironment of EC patients, as well as the downregulated expression of major histocompatibility complex molecules in tumor cells, to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies. Therefore, personalized treatments could be developed to maximize the advantages of immunotherapy.

Differentiating Plasmon-Enhanced Chemical Reactions on AgPd Hollow Nanoplates through Surface-Enhanced Raman Spectroscopy.

Plasmonic photocatalysis demonstrates great potential for efficiently harnessing light energy. However, the underlying mechanisms remain enigmatic due to the transient nature of the reaction processes. Typically, plasmonic photocatalysis relies on the excitation of surface plasmon resonance (SPR) in plasmonic materials, such as metal nanoparticles, leading to the generation of high-energy or "hot electrons", albeit accompanied by photothermal heating or Joule effect. The ability of hot electrons to participate in chemical reactions is one of the key mechanisms, underlying the enhanced photocatalytic activity observed in plasmonic photocatalysis. Interestingly, surface-enhanced Raman scattering (SERS) spectroscopy allows the analysis of chemical reactions driven by hot electrons, as both SERS and hot electrons stem from the decay of SPR and occur at the hot spots. Herein, we propose a highly efficient SERS substrate based on cellulose paper loaded with either Ag nanoplates (Ag NPs) or AgPd hollow nanoplates (AgPd HNPs) for the in situ monitoring of C-C homocoupling reactions. The data analysis allowed us to disentangle the impact of hot electrons and the Joule effect on plasmon-enhanced photocatalysis. Computational simulations revealed an increase in the rate of excitation of hot carriers from single/isolated AgPd HNPs to an in-plane with a vertical stacking assembly, suggesting its promise as a photocatalyst under broadband light. In addition, the results suggest that the incorporation of Pd into an alloy with plasmonic properties may enhance its catalytic performance under light irradiation due to the collection of plasmon-excitation-induced hot electrons. This work has demonstrated the performance-oriented synthesis of hybrid nanostructures, providing a unique route to uncover the mechanism of plasmon-enhanced photocatalysis.

Selective adsorption of anionic dyes by a macropore magnetic lignin-chitosan adsorbent.

Dyes pollution is well known for their hazardous impacts on human health and the environment. The removal of dyes from wastewater has become an important issue. In this study, magnetic micrometer-sized particles AL-CTS@MNPs were synthesized from alkaline lignin (AL) and chitosan (CTS) by "one-pot method". The adsorbent presented higher selectivity adsorption effect on anionic dyes than amphoteric and cationic dyes, and even no adsorption effect on cationic methylene blue (MB), which showed that the anionic dyes could be better separated from the other two types of dyes. The adsorption isotherms of the dyes were highly consistent with the Langmuir model, and the maximum adsorption capacity was 329.50 mg/g for methyl orange (MO) and 20.00 mg/g for rhodamine B (RhB). AL-CTS@MNPs showed good adsorption of anionic dyes (MO) in the pH range of 3-9. Meanwhile, the adsorbent AL-CTS@MNPs were also characterized, showing rough surface with specific surface areas of 37.38 m2/g, pore diameter of 95.8 nm and porosity of 17.62 %. The particle sizes were ranged from 800 µm to 1300 µm. The electrostatic attraction and π-π* electron donor-acceptor interactions were the main forces between the adsorbent and anionic dyes. While the electrostatic repulsive force between the adsorbent and the cationic dyes resulted in the non-absorption of MB by AL-CTS@MNPs. Subsequently, the adsorbent maintained a removal rate of >95 % after five adsorption-desorption cycles, demonstrating its excellent stability and recoverability. Ultimately, the prepared AL-CTS@MNPs illuminated good prospect on complex components dyes wastewater treatment.

ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

Guiding Transient Peptide Assemblies with Structural Elements Embedded in Abiotic Phosphate Fuels.

Despite great progress on the construction of non-equilibrium systems, most approaches do not consider the structure of the fuel as a critical element to control the processes. Herein, we show that the amino acid side chains (A, F, Nal) in the structure of abiotic phosphates can direct assembly and reactivity during transient structure formation. The fuels bind covalently to substrates and subsequently influence the structures in the assembly process. We focus on the ways in which the phosphate esters guide structure formation and how structures and reactivity cross regulate when constructing assemblies. Through the chemical functionalization of energy-rich aminoacyl phosphate esters, we are able to control the yield to esters and thioesters upon adding dipeptides containing tyrosine or cysteine residues. The structural elements around the phosphate esters guide the lifetime of the structures formed and their supramolecular assemblies. These properties can further be influenced by the peptide sequence of substrates, incorporating anionic, aliphatic and aromatic residues. Furthermore, we illustrate that oligomerization of esters can be initiated from a single aminoacyl phosphate ester incorporating a tyrosine residue (Y). These findings suggest that activated amino acids with varying reactivity and energy contents can pave the way for designing and fabricating structured fuels.

Polyethylene fibers containing directional microchannels for passive radiative cooling.

Passive radiative cooling (PRC) that realizes thermal management without consuming any energy has attracted increasing attention. Unfortunately, polymer fibers with radiative cooling function fabricated via a facile, continuous, large-scale and eco-friendly method have been scarcely reported. Herein, polyethylene fibers containing directional microchannels (PFCDM) are facilely fabricated via melt extrusion and water leaching. Interestingly, fabric based on such hydrophobic PFCDM shows high sunlight reflectivity (93.6%), and mid-infrared emissivity (93.9%), endowing it with remarkable PRC performance. Compared with other reported examples, the as-prepared PFDCM fabric has the highest cooling power (i.e., 104.285 W m-2) and temperature drop (i.e., 27.71 °C). Furthermore, decent self-cleaning performance can keep the PFCDM fabric away from contamination and enable it to retain an excellent radiative cooling effect. The method proposed to fabricate PFCDM in this paper will widen the potential application of thermoplastic polyolefins in the field of radiative cooling.

Inhibiting RIPK1-driven neuroinflammation and neuronal apoptosis mitigates brain injury following experimental subarachnoid hemorrhage.

RIPK1, a receptor-interacting serine/threonine protein kinase, plays a crucial role in maintaining cellular and tissue homeostasis by integrating inflammatory responses and cell death signaling pathways including apoptosis and necroptosis, which have been implicated in diverse physiological and pathological processes. Suppression of RIPK1 activation is a promising strategy for restraining the pathological progression of many human diseases. Neuroinflammation and neuronal apoptosis are two pivotal factors in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH). In this study, we established in vivo and in vitro models of SAH to investigate the activation of RIPK1 kinase in both microglia and neurons. We observed the correlation between RIPK1 kinase activity and microglia-mediated inflammation as well as neuronal apoptosis. We then investigated whether inhibition of RIPK1 could alleviate neuroinflammation and neuronal apoptosis following SAH, thereby reducing brain edema and ameliorating neurobehavioral deficits. Additionally, the underlying mechanisms were also explored. Our research findings revealed the activation of RIPK1 kinase in both microglia and neurons following SAH, as marked by the phosphorylation of RIPK1 at serine 166. The upregulation of p-RIPK1(S166) resulted in a significant augmentation of inflammatory cytokines and chemokines, including TNF-α, IL-6, IL-1α, CCL2, and CCL5, as well as neuronal apoptosis. The activation of RIPK1 in microglia and neurons following SAH could be effectively suppressed by administration of Nec-1 s, a specific inhibitor of RIPK1. Consequently, inhibition of RIPK1 resulted in a downregulation of inflammatory cytokines and chemokines and attenuation of neuronal apoptosis after SAH in vitro. Furthermore, the administration of Nec-1 s effectively mitigated neuroinflammation, neuronal apoptosis, brain edema, and neurobehavioral deficits in mice following SAH. Our findings suggest that inhibiting RIPK1 kinase represents a promising therapeutic strategy for mitigating brain injury after SAH by attenuating RIPK1-driven neuroinflammation and neuronal apoptosis.

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

Unveiling the Occurrence and Non-Negligible Role of Amino Sugars in Waste Activated Sludge Fermentation by an Enriched Chitin-Degradation Consortium.

Polysaccharides in extracellular polymeric substances (EPS) can form a hybrid matrix network with proteins, impeding waste-activated sludge (WAS) fermentation. Amino sugars, such as N-acetyl-d-glucosamine (GlcNAc) polymers and sialic acid, are the non-negligible components in the EPS of aerobic granules or biofilm. However, the occurrence of amino sugars in WAS and their degradation remains unclear. Thus, amino sugars (∼6.0%) in WAS were revealed, and the genera of Lactococcus and Zoogloea were identified for the first time. Chitin was used as the substrate to enrich a chitin-degrading consortium (CDC). The COD balances for methane production ranged from 83.3 and 95.1%. Chitin was gradually converted to oligosaccharides and GlcNAc after dosing with the extracellular enzyme. After doing enriched CDC in WAS, the final methane production markedly increased to 60.4 ± 0.6 mL, reflecting an increase of ∼62%. Four model substrates of amino sugars (GlcNAc and sialic acid) and polysaccharides (cellulose and dextran) could be used by CDC. Treponema (34.3%) was identified as the core bacterium via excreting chitinases (EC 3.2.1.14) and N-acetyl-glucosaminidases (EC 3.2.1.52), especially the genetic abundance of chitinases in CDC was 2.5 times higher than that of WAS. Thus, this study provides an elegant method for the utilization of amino sugar-enriched organics.

ViT-MVT: A Unified Vision Transformer Network for Multiple Vision Tasks.

In this work, we seek to learn multiple mainstream vision tasks concurrently using a unified network, which is storage-efficient as numerous networks with task-shared parameters can be implanted into a single consolidated network. Our framework, vision transformer (ViT)-MVT, built on a plain and nonhierarchical ViT, incorporates numerous visual tasks into a modest supernet and optimizes them jointly across various dataset domains. For the design of ViT-MVT, we augment the ViT with a multihead self-attention (MHSE) to offer complementary cues in the channel and spatial dimension, as well as a local perception unit (LPU) and locality feed-forward network (locality FFN) for information exchange in the local region, thus endowing ViT-MVT with the ability to effectively optimize multiple tasks. Besides, we construct a search space comprising potential architectures with a broad spectrum of model sizes to offer various optimum candidates for diverse tasks. After that, we design a layer-adaptive sharing technique that automatically determines whether each layer of the transformer block is shared or not for all tasks, enabling ViT-MVT to obtain task-shared parameters for a reduction of storage and task-specific parameters to learn task-related features such that boosting performance. Finally, we introduce a joint-task evolutionary search algorithm to discover an optimal backbone for all tasks under total model size constraint, which challenges the conventional wisdom that visual tasks are typically supplied with backbone networks developed for image classification. Extensive experiments reveal that ViT-MVT delivers exceptional performances for multiple visual tasks over state-of-the-art methods while necessitating considerably fewer total storage costs. We further demonstrate that once ViT-MVT has been trained, ViT-MVT is capable of incremental learning when generalized to new tasks while retaining identical performances for trained tasks. The code is available at https://github.com/XT-1997/vitmvt.

Point-NAS: A Novel Neural Architecture Search Framework for Point Cloud Analysis.

Recently, point-based networks have exhibited extraordinary potential for 3D point cloud processing. However, owing to the meticulous design of both parameters and hyperparameters inside the network, constructing a promising network for each point cloud task can be an expensive endeavor. In this work, we develop a novel one-shot search framework called Point-NAS to automatically determine optimum architectures for various point cloud tasks. Specifically, we design an elastic feature extraction (EFE) module that serves as a basic unit for architecture search, which expands seamlessly alongside both the width and depth of the network for efficient feature extraction. Based on the EFE module, we devise a searching space, which is encoded into a supernet to provide a wide number of latent network structures for a particular point cloud task. To fully optimize the weights of the supernet, we propose a weight coupling sandwich rule that samples the largest, smallest, and multiple medium models at each iteration and fuses their gradients to update the supernet. Furthermore, we present a united gradient adjustment algorithm that mitigates gradient conflict induced by distinct gradient directions of sampled models and supernet, thus expediting the convergence of the supernet and assuring that it can be comprehensively trained. Pursuant to the provided techniques, the trained supernet enables a multitude of subnets to be incredibly well-optimized. Finally, we conduct an evolutionary search for the supernet under resource constraints to find promising architectures for different tasks. Experimentally, the searched Point-NAS with weights inherited from the supernet realizes outstanding results across a variety of benchmarks. i.e., 94.2% and 88.9% overall accuracy under ModelNet40 and ScanObjectNN, 68.6% mIoU under S3DIS, 63.6% and 69.3% mAP@0.25 under SUN RGB-D and ScanNet V2 datasets.

Spontaneous and Selective Peptide Elongation in Water Driven by Aminoacyl Phosphate Esters and Phase Changes.

Nature chose phosphates to activate amino acids, where reactive intermediates and complex machinery drive the construction of polyamides. Outside of biology, the pathways and mechanisms that allow spontaneous and selective peptide elongation in aqueous abiotic systems remain unclear. Herein we work to uncover those pathways by following the systems chemistry of aminoacyl phosphate esters, synthetic counterparts of aminoacyl adenylates. The phosphate esters act as solubility tags, making hydrophobic amino acids and their oligomers soluble in water and enabling selective elongation and different pathways to emerge. Thus, oligomers up to dodecamers were synthesized in one flask and on the minute time scale, where consecutive additions activated autonomous phase changes. Depending on the pathway, the resulting phases initially carry nonpolar peptides and amphiphilic oligomers containing phosphate esters. During elongation and phosphate release, shorter oligomers dominate in solution, while the aggregated phase favors the presence of longer oligomers due to their self-assembly propensity. Furthermore we demonstrated that the solution phases can be isolated and act as a new environment for continuous elongation, by adding various phosphate esters. These findings suggest that the systems chemistry of aminoacyl phosphate esters can activate a selection mechanism for peptide bond formation by merging aqueous synthesis and self-assembly.

Rapidly determining the 3D structure of proteins by surface-enhanced Raman spectroscopy.

Despite great advances in protein structure analysis, label-free and ultrasensitive methods to obtain the natural and dynamic three-dimensional (3D) structures are still urgently needed. Surface-enhanced Raman spectroscopy (SERS) can be a good candidate, whereas the complexity originated from the interactions between the protein and the gradient surface electric field makes it extremely challenging to determine the protein structure. Here, we propose a deciphering strategy for accurate determination of 3D protein structure from experimental SERS spectra in seconds by simply summing SERS spectra of isolated amino acids in electric fields of different strength with their orientations in protein. The 3D protein structure can be reconstructed by comparing the experimental spectra obtained in a well-defined gap-mode SERS configuration with the simulated spectra. The gradient electric field endows SERS with a unique advantage to section biomolecules with atomic precision, which makes SERS a competent tool for monitoring biomolecular events under physiological conditions.

Mushroom-mimetic 3D hierarchical architecture-based e-skin with high sensitivity and a wide sensing range for intelligent perception.

Electronic skin (e-skin) is one of the most important components of future wearable electronic devices, whose sensing performances can be improved by constructing micropatterns on its sensitive layer. However, in traditional e-skins it is difficult to balance sensitivity and the pressure sensing range, and most micropatterns are generally prepared by some complex technologies. Herein, mushroom-mimetic micropatterns with 3D hierarchical architecture and an interdigital electrode are facilely prepared. The micropatterned sensitive layer is further developed through spraying carbon nanotube (CNT) dispersion on the thermoplastic polyurethane (TPU) film with mushroom-mimetic micropatterns (denoted as MMTC). Thanks to the "interlocking effect" between mushroom-mimetic micropatterns and the interdigital electrode in the as-prepared MMTC/interdigital electrode e-skin, the e-skin exhibits a high sensitivity (up to 600 kPa-1), a wide pressure sensing range (up to 150 kPa), a short response time (<20 ms) and excellent durability (15 000 cycles). The MMTC/interdigital electrode e-skin is capable of precisely monitoring health conditions via the as-acquired physiological parameters in real time. Moreover, such e-skins can be used to monitor gestures wirelessly, sense the trajectory of pressure stimuli and recognize Morse code under water. This study provides a cost-efficient, facile strategy to design e-skin for future-oriented wearable intelligent systems.

Nightmare or delight: Taxonomic circumscription meets reticulate evolution in the phylogenomic era.

Phylogenetic studies in the phylogenomics era have demonstrated that reticulate evolution greatly impedes the accuracy of phylogenetic inference, and consequently can obscure taxonomic treatments. However, the systematics community lacks a broadly applicable strategy for taxonomic delimitation in groups characterized by pervasive reticulate evolution. The red-fruit genus, Stranvaesia, provides an ideal model to examine the influence of reticulation on generic circumscription, particularly where hybridization and allopolyploidy dominate the evolutionary history. In this study, we conducted phylogenomic analyses integrating data from hundreds of single-copy nuclear (SCN) genes and plastomes, and interrogated nuclear paralogs to clarify the inter/intra-generic relationship of Stranvaesia and its allies in the framework of Maleae. Analyses of phylogenomic discord and phylogenetic networks showed that allopolyploidization and introgression promoted the origin and diversification of the Stranvaesia clade, a conclusion further bolstered by cytonuclear and gene tree discordance. With a well-inferred phylogenetic backbone, we propose an updated generic delimitation of Stranvaesia and introduce a new genus, Weniomeles. This new genus is distinguished by its purple-black fruits, thorns trunk and/or branches, and a distinctive fruit core anatomy characterized by multilocular separated by a layer of sclereids and a cluster of sclereids at the top of the locules. Through this study, we highlight a broadly-applicable workflow that underscores the significance of reticulate evolution analyses in shaping taxonomic revisions from phylogenomic data.

Graphene-like structure of bio-carbon with CoFe Prussian blue derivative composites for enhanced microwave absorption.

Traditional carbon materials such as graphene are often applied in the field of electromagnetic wave (EMW) absorption but they have unbalanced impedance matching and high conductivity. Bio-carbon with graphene-like structure derived from apples has many advantages over graphene: it can be prepared in large quantities and the abundant heteroatoms present in the lattice can provide many polarization phenomena. Herein, Prussian blue analogue (PBA) as a source of magnetic component was combined with bio-carbon or reduced graphene oxide (rGO) to study the EMW absorption properties. The fabricated BC/CFC-12-7 displayed performance with a minimum reflection loss (RLmin) of -72.57 dB and a wide effective absorption bandwidth (EAB) of 5.25 GHz with an ultra-thin and nearly equal matching thickness at 1.61 mm. The results show that the good EMW absorption property of bio-carbon composites comes from good conduction loss, large relaxation polarization loss especially from pyridinic-N, and better impedance matching. The optimized radar cross section is found to be -33.55 dB m2 in the far-field condition using CST. This work explored the advantages of bio-carbon as a novel EMW absorbing material compared with graphene and provided ideas for realizing high-performance EMW absorbing materials in the future.

APE1 regulates mitochondrial DNA damage repair after experimental subarachnoid haemorrhage in vivo and in vitro.

BACKGROUND: Subarachnoid haemorrhage (SAH) can result in a highly unfavourable prognosis. In recent years, the study of SAH has focused on early brain injury (EBI), which is a crucial progress that contributes to adverse prognosis. SAH can lead to various complications, including mitochondrial dysfunction and DNA damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein with multifaceted functionality integral to DNA repair and redox signalling. However, the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear. METHODS: Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention. Then, the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot, immunofluorescence, quantitative real-time PCR, mitochondrial bioenergetics measurement and neurobehavioural experiments. RESULTS: We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH. Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH. In vitro, after primary neurons exposed to oxyhaemoglobin, APE1 expression significantly decreased along with increased mitochondrial DNA damage, a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction. Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis. CONCLUSION: In conclusion, APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain. APE1 may potentially play a vital role in the EBI stage after SAH, making it a critical target for treatment.

Real-Time Tracking of Laryngeal Motion via the Surface Depth-Sensing Technique for Radiotherapy in Laryngeal Cancer Patients.

Radiotherapy (RT) is an important modality for laryngeal cancer treatment to preserve laryngeal function. During beam delivery, laryngeal motion remains uncontrollable and may compromise tumor-targeting efficacy. We aimed to examine real-time laryngeal motion by developing a surface depth-sensing technique with preliminary testing during RT-based treatment of patients with laryngeal cancer. A surface depth-sensing (SDS) camera was set up and integrated into RT simulation procedures. By recording the natural swallowing of patients, SDS calculation was performed using the Pose Estimation Model and deep neural network technique. Seven male patients with laryngeal cancer were enrolled in this prospective study. The calculated motion distances of the laryngeal prominence (mean ± standard deviation) were 1.6 ± 0.8 mm, 21.4 ± 5.1 mm, 6.4 ± 3.3 mm, and 22.7 ± 4.9 mm in the left-right, cranio-caudal, and anterior-posterior directions and for the spatial displacement, respectively. The calculated differences in the 3D margins for generating the planning tumor volume by senior physicians with and without SDS data were -0.7 ± 1.0 mm (-18%), 11.3 ± 6.8 mm (235%), and 1.8 ± 2.6 mm (45%) in the left-right, cranio-caudal, and anterior-posterior directions, respectively. The SDS technique developed for detecting laryngeal motion during swallowing may be a practical guide for individualized RT design in the treatment of laryngeal cancer.

Edge Length-Programmed Single-Stranded RNA Origami for Predictive Innate Immune Activation and Therapy.

Ligands targeting nucleic acid-sensing receptors activate the innate immune system and play a critical role in antiviral and antitumoral therapy. However, ligand design for in situ stability, targeted delivery, and predictive immunogenicity is largely hampered by the sophisticated mechanism of the nucleic acid-sensing process. Here, we utilize single-stranded RNA (ssRNA) origami with precise structural designability as nucleic acid sensor-based ligands to achieve improved biostability, organelle-level targeting, and predictive immunogenicity. The natural ssRNAs self-fold into compact nanoparticles with defined shapes and morphologies and exhibit resistance against RNase digestion in vitro and prolonged retention in macrophage endolysosomes. We find that programming the edge length of ssRNA origami can precisely regulate the degree of macrophage activation via a toll-like receptor-dependent pathway. Further, we demonstrate that the ssRNA origami-based ligand elicits an anti-tumoral immune response of macrophages and neutrophils in the tumor microenvironment and retards tumor growth in the mouse pancreatic tumor model. Our ssRNA origami strategy utilizes structured RNA ligands to achieve predictive immune activation, providing a new solution for nucleic acid sensor-based ligand design and biomedical applications.