Codon Bias of the DDR1 Gene and Transcription Factor EHF in Multiple Species.

Milk production is an essential economic trait in cattle, and understanding the genetic regulation of this trait can enhance breeding strategies. The discoidin domain receptor 1 (DDR1) gene has been identified as a key candidate gene that influences milk production, and ETS homologous factor (EHF) is recognized as a critical transcription factor that regulates DDR1 expression. Codon usage bias, which affects gene expression and protein function, has not been fully explored in cattle. This study aims to examine the codon usage bias of DDR1 and EHF transcription factors to understand their roles in dairy production traits. Data from 24 species revealed that both DDR1 and EHF predominantly used G/C-ending codons, with the GC3 content averaging 75.49% for DDR1 and 61.72% for EHF. Synonymous codon usage analysis identified high-frequency codons for both DDR1 and EHF, with 17 codons common to both genes. Correlation analysis indicated a negative relationship between the effective number of codons and codon adaptation index for both DDR1 and EHF. Phylogenetic and clustering analyses revealed similar codon usage patterns among closely related species. These findings suggest that EHF plays a crucial role in regulating DDR1 expression, offering new insights into genetically regulating milk production in cattle.

A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

Core-Shell Engineered Fillers Overcome the Electrical-Thermal Conductance Trade-Off.

The rapid development of modern electronic devices increasingly requires thermal management materials with controllable electrical properties, ranging from conductive and dielectric to insulating, to meet the needs of diverse applications. However, highly thermally conductive materials usually have a high electrical conductivity. Intrinsically highly thermally conductive, but electrically insulating materials are still limited to a few kinds of materials. To overcome the electrical-thermal conductance trade-off, here, we report a facile Pechini-based method to prepare multiple core (metal)/shell (metal oxide) engineered fillers, such as aluminum-oxide-coated and beryllium-oxide-coated Ag microspheres. In contrast to the previous in situ growth method which mainly focused on small-sized spheres with specific coating materials, our method combined with ultrafast joule heating treatment is more versatile and robust for varied-sized, especially large-sized core-shell fillers. Through size compounding, the as-synthesized core-shell-filled epoxy composites exhibit high isotropic thermal conductivity (∼3.8 W m-1 K-1) while maintaining high electrical resistivity (∼1012 Ω cm) and good flowability, showing better heat dissipation properties than commercial thermally conductive packaging materials. The successful preparation of these core-shell fillers endows thermally conductive composites with controlled electrical properties for emerging electronic package applications, as demonstrated in circuit board and battery thermal management.

Evolution and biological characteristics of H11 avian influenza viruses isolated from migratory birds and pigeons.

The emergence of novel avian influenza reassortants in wild birds in recent years is a public health concern. However, the viruses that circulate in migratory birds are not fully understood. In this study, we summarized and categorized global H11 avian influenza viruses and reported that waterfowl and shorebirds are the major reservoirs of the identified H11 viruses. The surveillance data of the 35,749 faecal samples collected from wild bird habitats in eastern China over the past seven years revealed a low prevalence of H11 viruses in birds, with a positive rate of 0.067% (24 isolates). The phylogenetic analysis of the twenty viruses indicated that H11 viruses have undergone complex reassortment with viruses circulating in waterfowl and shorebirds. These tested viruses do not acquire mammalian adaptive mutations in their genomes and preferentially bind to avian-type receptors. Experimental infection studies demonstrated that the two tested H11N9 viruses of wild bird origin replicated and transmitted more efficiently in ducks than in chickens, whereas the pigeon H11N2 virus isolated from a live poultry market was more adapted to replicate in chickens than in ducks. In addition, some H11 isolates replicated efficiently in mice and caused body weight loss but were not lethal. Our study revealed the role of waterfowl and shorebirds in the ecology and evolution of H11 viruses and the potential risk of introducing circulating H11 viruses into ducks or chickens, further emphasizing the importance of avian influenza surveillance at the interface of migratory birds and poultry.

Metal-Phenolic Nanomaterial with Organelle-Level Precision Primes Antitumor Immunity via mtDNA-dependent cGAS-STING Activation.

New generation of nanomaterials with organelle-level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria-targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damage by the synergistic action of oxidative stress and furan-mediated DNA cross-linking. Moreover, the phenolic units on PF enable further self-assembly with Mn2+ via metal-phenolic coordination to form metal-phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS-STING pathway by Mn2+ and tumor-derived mtDNA in tumor-associated macrophages (TAMs), and subsequently repolarizing M2-like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS-STING-dependent immunity at the organelle level for potent antitumor efficacy.

Dried tangerine peel polysaccharide accelerates wound healing by recruiting anti-inflammatory macrophages.

Macrophage polarization is a key process involved in wound healing. The continuous release of proinflammatory cytokines by macrophages inhibits the healing process of chronic wounds, such as diabetic wounds. To promote wound healing, it is important to change the phenotype of resident macrophages to prevent inflammation. We previously reported that dried tangerine peel polysaccharide (DTPP) binds to and inhibits the TLR4/MD-2 complex, which is crucial for the inflammatory activation of macrophages, suggesting the potential of DTPP in wound healing applications. Both zebrafish and mouse models were used to evaluate the therapeutic efficacy of DTPP. Moreover, we found that DTPP recruited macrophages to the wound area and promoted their M2 repolarization. Using hyperglycaemic zebrafish and db/db mouse models, we discovered that DTPP accelerated wound healing in vivo in metabolic disorders. Our results suggest that DTPP promotes the recruitment of macrophages, shifts macrophages towards the anti-inflammatory M2 phenotype, and ultimately accelerates the wound healing process.

Cortical response characteristics of passive, active, and resistance movements: a multi-channel fNRIS study.

Objective: This study aimed to explore the impact of exercise training modes on sensory and motor-related cortex excitability using functional near-infrared spectroscopy technology (fNIRS) and reveal specific cortical effects. Materials and methods: Twenty participants with no known health conditions took part in a study involving passive, active, and resistance tasks facilitated by an upper-limb robot, using a block design. The participants wore functional near-infrared spectroscopy (fNIRS) devices throughout the experiment to monitor changes in cortical blood oxygen levels during the tasks. The fNIRS optode coverage primarily targeted key areas of the brain cortex, including the primary motor cortex (M1), primary somatosensory cortex (S1), supplementary motor area (SMA), and premotor cortex (PMC) on both hemispheres. The study evaluated cortical activation areas, intensity, and lateralization values. Results: Passive movement primarily activates M1 and part of S1, while active movement mainly activates contralateral M1 and S1. Resistance training activates brain regions in both hemispheres, including contralateral M1, S1, SMA, and PMC, as well as ipsilateral M1, S1, SMA, and PMC. Resistance movement also activates the ipsilateral sensorimotor cortex (S1, SMA, PMC) more than active or passive movement. Active movement has higher contralateral activation in M1 compared to passive movement. Resistance and active movements increase brain activity more than passive movement. Different movements activate various cortical areas equally on both sides, but lateralization differs. The correlation between lateralization of brain regions is significant in the right cortex but not in the left cortex during three movement patterns. Conclusion: All types of exercise boost motor cortex excitability, but resistance exercise activates both sides of the motor cortex more extensively. The PMC is crucial for intense workouts. The right cortex shows better coordination during motor tasks than the left. fNIRS findings can help determine the length of treatment sessions.

Oxysulfonylation of Alkynes with Sodium Sulfinates to Access ß-Keto Sulfones Catalyzed by BF3·OEt2.

An efficient and operationally simple method for the synthesis of ß-keto sulfones through the BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed. With its facile and selective access to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and good yields. Notably, the reaction does not require metal catalysts or chemical reagents with pungent odors.

The relationship between rehabilitation motivation and upper limb motor function in stroke patients.

Objective: Insufficient motivation among post-stroke survivors may be an important factor affecting their motor function recovery. This study seeks to investigate the relationship between motivation and functional recovery in stroke patients undergoing rehabilitation training. Materials and methods: 103 stroke patients with upper limb impairments were studied during their hospital stays. Assessments were done before and after rehabilitation training to measure motivation, emotional state, motor function, and independence in daily activities. Data analysis was conducted to examine the distribution of these factors among the participants. Pearson and Spearman correlation analyses were used to study the relationships between motivation, emotional state, and motor function. Patients were divided into high and low motivation groups based on the Rehabilitation Motivation Scale (RMS), and chi-square and rank-sum tests were used to compare functional differences before and after treatment among patients with varying levels of motivation. Results: 66 participants were found to have low motivation in the initial assessment of the RMS (64.08%). Consistency in motivation levels was observed among patients with high motivation (r = 0.648, P<0.001). Apathy was identified as the main factor affecting motivation in patients with low motivation (p = 0.027), while depression and anxiety were not significantly correlated. Motivation was strongly linked to improvements in upper limb motor function, daily living activities, and self-exercise duration (p < 0.001) for stroke patients undergoing rehabilitation. Post-training, there was a notable increase in motivation, motor function, and independence in daily activities (p < 0.001). Increased rehabilitation motivation was linked to better upper limb motor function and daily independence in patients, particularly those with low motivation. This correlation was significant for both the FMA-UE and FIM scores. Discussion: Old patients with poor upper limb motor function often have low motivation, which hinders their recovery. Using strategies to boost motivation in stroke patients with impaired upper limb function could greatly improve their rehabilitation and motor skills. It is crucial to prioritize these intervention strategies. Conclusion: Enhancing rehabilitation motivation in stroke patients with low motivation and upper limb motor impairments can foster the restoration of their functional capabilities.

Genomic and functional diversity of the human-derived isolates of Faecalibacterium.

Introduction: Faecalibacterium is one of the most abundant bacteria in the gut microbiota of healthy adults, highly regarded as a next-generation probiotic. However, the functions of Faecalibacterium genomes from cultured strains and the distribution of different species in populations may differ among different sources. Methods: We here performed an extensive analysis of pan-genomes, functions, and safety evaluation of 136 Faecalibacterium genomes collected from 10 countries. Results: The genomes are clustered into 11 clusters, with only five of them were characterized and validly nomenclated. Over 80% of the accessory genes and unique genes of Faecalibacterium are found with unknown function, which reflects the importance of expanding the collection of Faecalibacterium strains. All the genomes have the potential to produce acetic acid and butyric acid. Nine clusters of Faecalibacterium are found significantly enriched in the healthy individuals compared with patients with type II diabetes.. Discussion: This study provides a comprehensive view of genomic characteristic and functions and of culturable Faecalibacterium bacterium from human gut, and enables clinical advances in the future.

Isolation of potentially novel species expands the genomic and functional diversity of Lachnospiraceae.

The Lachnospiraceae family holds promise as a source of next-generation probiotics, yet a comprehensive delineation of its diversity is lacking, hampering the identification of suitable strains for future applications. To address this knowledge gap, we conducted an in-depth genomic and functional analysis of 1868 high-quality genomes, combining data from public databases with our new isolates. This data set represented 387 colonization-selective species-level clusters, of which eight genera represented multilineage clusters. Pan-genome analysis, single-nucleotide polymorphism (SNP) identification, and probiotic functional predictions revealed that species taxonomy, habitats, and geography together shape the functional diversity of Lachnospiraceae. Moreover, analyses of associations with atherosclerotic cardiovascular disease (ACVD) and inflammatory bowel disease (IBD) indicated that several strains of potentially novel Lachnospiraceae species possess the capacity to reduce the abundance of opportunistic pathogens, thereby imparting potential health benefits. Our findings shed light on the untapped potential of novel species enabling knowledge-based selection of strains for the development of next-generation probiotics holding promise for improving human health and disease management.

Improving rehabilitation motivation and motor learning ability of stroke patients using different reward strategies: study protocol for a single-center, randomized controlled trial.

Background: Stroke survivors often face challenges in motor learning and motivation during rehabilitation, which can impede their recovery progress. Traditional rehabilitation methods vary in effectiveness, prompting the exploration of novel approaches such as reward strategies. Previous research indicates that rewards can enhance rehabilitation motivation and facilitate motor learning. However, most reward paradigms have utilized fixed reward amounts, which also have limitations. Exploring alternative, more effective reward strategies, such as probabilistic rewards, is warranted to optimize stroke patient rehabilitation. Methods: A total of 81 stroke patients will be recruited and randomly assigned to control, fixed reward, or probabilistic reward groups at a ratio of 1:1:1 using a randomized number table method. Participants will undergo 10 days of daily hand motor function rehabilitation training, with sessions lasting 20 min each. The training will involve pegboard tests and box and block tests. Control group participants will receive standard training, while fixed reward group members will receive monetary incentives for completing tests, and probabilistic reward group members will have the chance to win monetary rewards through a lottery box. Rehabilitation motivation and motor performance and functional near-infrared spectroscopy brain imaging will be conducted at designated time points. The primary outcome measure is the stroke rehabilitation motivation scale, and the second outcome measures include motor performance, simple test for evaluating hand function, motivation and pleasure scale self-report, and Pittsburgh rehabilitation participation scale. Discussion: Reward-based training enhance rehabilitation participation and adherence, it also improve motor learning speed and memory retention of stroke patients. The fixed reward applied in the past studies could diminish the sensitivity of stroke patients to rewards, while probabilistic reward may provide unpredictable or variable incentives or reinforcements for motor rehabilitation. This study will compare the efficacy of different reward strategies in enhancing motor learning ability and rehabilitation motivation among stroke patients. By conducting a randomized controlled trial, the study seeks to provide valuable insights into optimizing stroke rehabilitation protocols and improving patient outcomes.Clinical Trial Registration:https://www.chictr.org.cn/, ChiCTR2400082419.

Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Sparsely-Supervised Object Tracking.

Recent years have witnessed the incredible performance boost of data-driven deep visual object trackers. Despite the success, these trackers require millions of sequential manual labels on videos for supervised training, implying the heavy burden of human annotating. This raises a crucial question: how to train a powerful tracker from abundant videos using limited manual annotations? In this paper, we challenge the conventional belief that frame-by-frame labeling is indispensable, and show that providing a small number of annotated bounding boxes in each video is sufficient for training a strong tracker. To facilitate that, we design a novel SParsely-supervised Object Tracking (SPOT) framework. It regards the sparsely annotated boxes as anchors and progressively explores in the temporal span to discover unlabeled target snapshots. Under the teacher-student paradigm, SPOT leverages the unique transitive consistency inherent in the tracking task as supervision, extracting knowledge from both anchor snapshots and unlabeled target snapshots. We also utilize several effective training strategies, i.e., IoU filtering, asymmetric augmentation, and temporal calibration to further improve the training robustness of SPOT. The experimental results demonstrate that, given less than 5 labels for each video, trackers trained via SPOT perform on par with their fully-supervised counterparts. Moreover, our SPOT exhibits two desirable properties: 1) SPOT enables us to fully exploit large-scale video datasets by efficiently allocating sparse labels to more videos even under a limited labeling budget; 2) when equipped with a target discovery module, SPOT can even learn from purely unlabeled videos for performance gain. We hope this work could inspire the community to rethink the current annotation principles and make a step towards practical label-efficient deep tracking.

Nicotine inhalant via E-cigarette facilitates sensorimotor function recovery by upregulating neuronal BDNF-TrkB signalling in traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes. EXPERIMENTAL APPROACH: Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation. KEY RESULTS: Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation. CONCLUSIONS AND IMPLICATIONS: Post-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

Correction: Antimicrobial peptide-modified silver nanoparticles for enhancing the antibacterial efficacy.

[This corrects the article DOI: 10.1039/D0RA05640E.].

Dried tangerine peel polysaccharide (DTPP) alleviates hepatic steatosis by suppressing TLR4/MD-2-mediated inflammation and endoplasmic reticulum stress.

Non-alcoholic fatty liver disease (NAFLD) is a complex pathogenic metabolic syndrome characterized by increased inflammation and endoplasmic reticulum stress. In recent years, natural polysaccharides derived from traditional Chinese medicine have shown significant anti-inflammatory effects, making them an attractive therapeutic option. However, little research has been conducted on the therapeutic potential of dried tangerine peel polysaccharide (DTPP) - one of the most important medicinal resources in China. The results of the present study showed that DTPP substantially reduced macrophage infiltration in vivo and suppressed the expression of pro-inflammatory factors and endoplasmic reticulum stress-related genes. Additionally, surface plasmon resonance analysis revealed that DTPP had a specific affinity to myeloid differentiation factor 2, which consequently suppressed lipopolysaccharide-induced inflammation via interaction with the toll-like receptor 4 signaling pathway. This study provides a potential molecular mechanism underlying the anti-inflammatory effects of DTPP on NAFLD and suggests DTPP as a promising therapeutic strategy for NAFLD treatment.

Genomic and functional diversity of cultivated Bifidobacterium from human gut microbiota.

The genus Bifidobacterium widely exists in human gut and has been increasingly used as the adjuvant probiotics for the prevention and treatment of diseases. However, the functional differences of Bifidobacterium genomes from different regions of the world remain unclear. We here describe an extensive study on the genomic characteristics and function annotations of 1512 genomes (clustered to 849 non-redundant genomes) of Bifidobacterium cultured from human gut. The distribution of some carbohydrate-active enzymes varied among different Bifidobacterium species and continents. More than 36% of the genomes of B. pseudocatenulatum harbored biosynthetic gene clusters of lanthipeptide-class-iv. 99.76% of the cultivated genomes of Bifidobacterium harbored genes of bile salt hydrolase. Most genomes of B. adolescentis, and all genomes of B. dentium harbored genes involved in gamma-aminobutyric acid synthesis. B. longum subsp. infantis were characterized harboring most genes related to human milk oligosaccharide utilization. Significant differences between the distribution of antibiotic resistance genes among different species and continents revealed the importance to use antibiotics precisely in the clinical treatment. Phages infecting Bifidobacterium and horizontal gene transfers occurring in genomes of Bifidobacterium were dependent on species and region sources, and might help Bifidobacterium adapt to the environment. In addition, the distribution of Bifidobacterium in human gut was found varied from different regions of the world. This study represents a comprehensive view of characteristics and functions of genomes of cultivated Bifidobacterium from human gut, and enables clinical advances in the future.

Cuproptotic nanoinducer-driven proteotoxic stress potentiates cancer immunotherapy by activating the mtDNA-cGAS-STING signaling.

Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA-cGAS-STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu+. Cu+ thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS-STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

Dual-Epigenetically Relieving the MYC-Correlated Immunosuppression via an Advanced Nano-Radiosensitizer Potentiates Cancer Immuno-Radiotherapy.

Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.