Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Artificial intelligence: opportunities and challenges in the clinical applications of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all invasive breast cancer subtypes. Owing to its clinical characteristics, such as the lack of effective therapeutic targets, high invasiveness, and high recurrence rate, TNBC is difficult to treat and has a poor prognosis. Currently, with the accumulation of large amounts of medical data and the development of computing technology, artificial intelligence (AI), particularly machine learning, has been applied to various aspects of TNBC research, including early screening, diagnosis, identification of molecular subtypes, personalised treatment, and prediction of prognosis and treatment response. In this review, we discussed the general principles of artificial intelligence, summarised its main applications in the diagnosis and treatment of TNBC, and provided new ideas and theoretical basis for the clinical diagnosis and treatment of TNBC.

Strain effects on lithium ion diffusion in various crystal structures.

Electrodes of lithium-ion batteries (LIBs) work in a complex force environment with volume changes during charging and discharging, which greatly affect the electrochemical performance of LIBs. To investigate the effect of volumetric strain on Li diffusion under mechano-electro-chemical coupling, the activation energies of Li diffusion for four types of face-centered cubic structures, Li3M, Li2MN, Li2MNY6 and Li3MY6, and four conventional types of structures, olivine, spinel, LISICON and layered structures, were analyzed with the effect of strain under different conditions. The results show that tensile strain favors lithium diffusion, that is the effect of in-plane strain on lithium diffusion is greater than that of uniaxial strain. Furthermore, the transition metal valence change induced by strain also has a significant effect on lithium diffusion.

Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy.

PURPOSE OF REVIEW: In this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S -adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionine-MAT2A-SAM axis will be discussed. RECENT FINDINGS: SAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer. SUMMARY: The methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.

GelMA-MXene hydrogel nerve conduits with microgrooves for spinal cord injury repair.

Repair of spinal cord injury (SCI) depends on microenvironment improvement and the reconnection between injured axons and regenerated neurons. Here, we fabricate a GelMA-MXene hydrogel nerve conduit with electrical conductivity and internal-facing longitudinal grooves and explore its function in SCI repair. It is found that the resultant grooved GelMA-MXene hydrogel could effectively promote the neural stem cells (NSCs) adhesion, directed proliferation and differentiation in vitro. Additionally, when the GelMA-MXene conduit loaded with NSCs (GMN) is implanted into the injured spinal cord site, effective repair capability for the complete transection of SCI was demonstrated. The GMN group shows remarkable nerve recovery and significantly higher BBB scores in comparison to the other groups. Therefore, GMN with the microgroove structure and loaded with NSCs is a promising strategy in treating SCI.

α-Ketoglutarate Promotes Pancreatic Progenitor-Like Cell Proliferation.

A major source of ß cell generation is pancreatic progenitor-like cell differentiation. Multiple studies have confirmed that stem cell metabolism plays important roles in self-renewal and proliferation. In the absence of glucose, glutamine provides the energy for cell division and growth. Furthermore, α-ketoglutarate (αKG), a precursor for glutamine synthesis, is sufficient for enabling glutamine-independent cell proliferation. We have demonstrated that αKG contributes to the large-scale proliferation of pancreatic progenitor-like cells that can provide an ample amount of clinically relevant ß cells. We compared the mRNA expression of a subset of genes, the abundance of ATP, reactive oxide species, mitochondrial number, and the colony-forming frequency between mouse pancreatic CD133⁺ and CD133- cells. We employed Real-Time PCR, immunostaining and passage assays to investigate self-renewal and proliferation of pancreatic progenitor-like cells in a 3D culture system in the presence and absence of αKG. The energy metabolism of CD133⁺ cells was more prone to oxidative phosphorylation. However, in the 3D culture system, when αKG was supplemented to the culture medium, the proliferation of the pancreatic progenitor-like cells was significantly elevated. We confirmed that the presence of αKG correlated with the up-regulation of Ten-Eleven Translocation (Tet). αKG can promote the proliferation of pancreatic progenitor-like cells via the up-regulation of Tet.

Pretreatment Sarcopenia and MRI-Based Radiomics to Predict the Response of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

The association between sarcopenia and the effectiveness of neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) remains uncertain. This study aims to examine the potential of sarcopenia as a predictive factor for the response to NAC in TNBC, and to assess whether its combination with MRI radiomic signatures can improve the predictive accuracy. We collected clinical and pathological information, as well as pretreatment breast MRI and abdominal CT images, of 121 patients with TNBC who underwent NAC at our hospital between January 2012 and September 2021. The presence of pretreatment sarcopenia was assessed using the L3 skeletal muscle index. Clinical models were constructed based on independent risk factors identified by univariate regression analysis. Radiomics data were extracted on breast MRI images and the radiomics prediction models were constructed. We integrated independent risk factors and radiomic features to build the combined models. The results of this study demonstrated that sarcopenia is an independent predictive factor for NAC efficacy in TNBC. The combination of sarcopenia and MRI radiomic signatures can further improve predictive performance.

Glial fibrillary acidic protein astrocytopathy presented as meningitis: A case report.

Introduction: Glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune neurological disorder and is diagnosed by GFAP-IgG in cerebrospinal fluid (CSF) measurement. Case report: Herein, we described a 10-year-old boy with abnormal neurological symptoms and signs. GFAP-IgG was detected in CSF using cell-based assay (CBA), and his CSF showed an increase in lymphocytes, a slight decrease in glucose and an increase in protein level in the early stage. The cranial MRI showed multiple strips of T2-FLAIR hyperintense signal changes on the surface of medulla oblongata, pons, and gyrus in bilateral cerebral hemispheres. He was treated with immunoglobulin (IVIG) and high-dose methylprednisolone pulse treatment, and his clinical presentations gradually improved. Conclusion: We highlight that patients with normal inflammatory markers in peripheral blood have obvious meningitis-like symptoms, and clinicians need to consider GFAP astrocytopathy. The early diagnosis and treatment of GFAP astrocytopathy are important for improving the prognosis.

ACE Gene Mutations (rs577350502) in Early-Onset and Recurrent Myocardial Infarction: A Case Report and Review.

Background: Acute myocardial infarction (AMI) is a severe acute coronary syndrome, demonstrating a trend toward affecting younger individuals in recent years. The association between early-onset myocardial infarction and single nucleotide polymorphism necessitates further exploration and evaluation. Case description: We present a case of a patient experiencing early-onset and recurrent myocardial infarction. The patient underwent stent implantation for myocardial infarction at the age of 53 and subsequently encountered two more myocardial infarctions within a span of 16 years. Following interventional therapy, genetic testing was conducted to assess the efficacy of subsequent anti-heart failure medications, with the aim to preemptively address heart failure risks. Genetic testing revealed a mutation in the angiotensin-converting enzyme (ACE) gene (rs577350502, g.63488533C>A), characterized by an intron-deletion single nucleotide variant. Conclusion: While this variant has not been previously reported to be associated with any specific disease, we hypothesize that it may contribute to the susceptibility and risk of myocardial infarction and coronary heart disease in the patient under consideration. This observation underscores the significance of investigating the insertion/deletion polymorphisms of the ACE gene in the context of AMI and emphasizes the necessity for further validation of this variant and other genetic markers associated with AMI in related diseases.

Wound microenvironment self-adaptive all-in-one hydrogel for rapid healing of the diabetic wound.

The natural healing of diabetic wounds is collectively impeded by multiple factors, including hyperglycemia, angiogenesis disorders, acute oxidative stress, and prolonged inflammation. Although considerable effort has been devoted to solving these problems, the treatment of diabetic wounds remains a major clinical obstacle. In light of this, we developed an innovative wound microenvironment self-adaptive hydrogel to promote the healing of diabetic wounds. The hydrogel was constructed by the crosslinking of 3-aminobenzeneboronic acid (PBA)-modified gelatin (Gel) and polyvinyl alcohol (PVA) by borate ester bonds, which showed high responsiveness to glucose. Meanwhile, the liposomes that encapsulated metformin, L-arginine, and L(+)-ascorbic acid were incorporated into the hydrogel framework. The hydrogel@lipo composite demonstrated shape adaptability, glucose responsiveness, and all-in-one capability, thereby effectively improving the intricate microenvironment of diabetic wounds. In vitro and in vivo experiments demonstrated the ability of hydrogel@lipo to mitigate oxidative stress, enhance angiogenesis, and attenuate inflammatory responses. Consequently, the hydrogel@lipo could accelerate diabetic wound healing (within two weeks). The cumulative findings strongly suggest the potential of hydrogel@lipo as a highly promising therapeutic dressing for advancing diabetic wound recovery.

The single-cell transcriptomic landscape of the topological differences in mammalian auditory receptors.

Mammalian hair cells (HCs) are arranged spirally along the cochlear axis and correspond to different frequency ranges. Serving as primary sound detectors, HCs spatially segregate component frequencies into a topographical map. HCs display significant diversity in anatomical and physiological characteristics, yet little is known about the organization of the cochleotopic map of HCs or the molecules involved in this process. Using single-cell RNA sequencing, we determined the distinct molecular profiles of inner hair cells and outer hair cells, and we identified numerous position-dependent genes that were expressed as gradients. Newly identified genes such as Ptn, Rxra, and Nfe2l2 were found to be associated with tonotopy. We employed the SCENIC algorithm to predict the transcription factors that potentially shape these tonotopic gradients. Furthermore, we confirmed that Nfe2l2, a tonotopy-related transcription factor, is critical in mice for sensing low-to-medium sound frequencies in vivo. the analysis of cell-cell communication revealed potential receptor-ligand networks linking inner hair cells to spiral ganglion neurons, including pathways such as BDNF-Ntrk and PTN-Scd4, which likely play essential roles in tonotopic maintenance. Overall, these findings suggest that molecular gradients serve as the organizing principle for maintaining the selection of sound frequencies by HCs.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

Exosome is a Fancy Mobile Sower of Ferroptosis.

Exosomes, nano-sized small extracellular vesicles, have been shown to serve as mediators between intercellular communications by transferring bioactive molecules, such as non-coding RNA, proteins, and lipids from secretory to recipient cells, modulating a variety of physiological and pathophysiological processes. Recent studies have gradually demonstrated that altered exosome charges may represent a key mechanism driving the pathological process of ferroptosis. This review summarizes the potential mechanisms and signal pathways relevant to ferroptosis and then discusses the roles of exosome in ferroptosis. As well as transporting iron, exosomes may also indirectly convey factors related to ferroptosis. Furthermore, ferroptosis may be transmitted to adjacent cells through exosomes, resulting in cascading effects. It is expected that further research on exosomes will be conducted to explore their potential in ferroptosis and will lead to the creation of new therapeutic avenues for clinical diseases.

Multidimensional poverty of persons with disabilities in China: An analysis of poverty reduction effect of employment services.

Introduction: Disability is a global public health problem, and poverty due to illness and disability has always been a major problem and challenge for global poverty governance. In order to eradicate poverty, China has carried out a series of welfare reforms and employment interventions for people with disabilities. The purpose of this study is to examine the levels of multidimensional poverty of persons with disabilities aged 16-59 in China and the poverty reduction effect of employment services. Methods: The Alkire-Foster (AF) method is applied to measure and decompose the multidimensional poverty index (MPI) of people with disabilities in this study. In order to make the results more robust, ordinary least squares (OLS) regression and the combination of propensity score matching and difference-in-differences (PSM-DID) are used to study the effect of employment services on multidimensional poverty of the disabled. Results: The results show that among persons with disabilities aged 16-59, about 90% are deprived in at least one dimension, and about 30% are in a state of severe multidimensional poverty until 2019. The contributions of deprivation in the dimensions of education and social participation are remarkably higher than dimensions of economy, health and insurance. In addition, employment services have a significant improvement effect on multidimensional poverty, which is reflected not only in the economic dimension, but also in the dimensions of education, insurance and social participation. Conclusion: People with disabilities are generally in multidimensional poverty in China, and their abilities in learning and social integration are seriously inadequate. Employment services have played a great role in improving poverty, but the improvement has been different in different dimensions and different disability categories. These findings provide important evidence for recognizing multidimensional poverty of persons with disabilities and the poverty reduction effect of employment services, which will help to formulate more reasonable public policies to eradicate poverty.

Progress in the treatment of urethral adenocarcinoma.

BACKGROUND: Urothelial adenocarcinoma (UA) is a rare subtype of primary urothelial carcinoma, which is more common in women and has a poor prognosis. Because of their low incidence, most of the existing literature is based on case reports and there is a lack of comprehensive literature on this type of tumor. PURPOSE: This article provides a comprehensive and systematic review of the epidemiology, pathological types, treatment, and prognosis of UA. Especially in the treatment section, we reviewed the various treatment methods including surgery, radiotherapy, chemotherapy, immunotherapy and molecular targeted therapy. This review aims to provide a theoretical basis for the clinical diagnosis and management of UA. METHODS: We reviewed the relevant literature of UA from Pubmed. CONCLUSION: There is no standard treatment for UA. Multidisciplinary therapy, including surgery, radiotherapy and chemotherapy, is the current trend. Immunotherapy and molecular targeted therapy will also become viable options for the treatment of UA in future.

The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy.

The advent of immunotherapy has significantly reshaped the landscape of cancer treatment, greatly enhancing therapeutic outcomes for multiple types of cancer. However, only a small subset of individuals respond to it, underscoring the urgent need for new methods to improve its response rate. Ferroptosis, a recently discovered form of programmed cell death, has emerged as a promising approach for anti-tumor therapy, with targeting ferroptosis to kill tumors seen as a potentially effective strategy. Numerous studies suggest that inducing ferroptosis can synergistically enhance the effects of immunotherapy, paving the way for a promising combined treatment method in the future. Nevertheless, recent research has raised concerns about the potential negative impacts on anti-tumor immunity as a consequence of inducing ferroptosis, leading to conflicting views within the scientific community about the interplay between ferroptosis and anti-tumor immunity, thereby underscoring the necessity of a comprehensive review of the existing literature on this relationship. Previous reviews on ferroptosis have touched on related content, many focusing primarily on the promoting role of ferroptosis on anti-tumor immunity while overlooking recent evidence on the inhibitory effects of ferroptosis on immunity. Others have concentrated solely on discussing related content either from the perspective of cancer cells and ferroptosis or from immune cells and ferroptosis. Given that both cancer cells and immune cells exist in the tumor microenvironment, a one-sided discussion cannot comprehensively summarize this topic. Therefore, from the perspectives of both tumor cells and tumor-infiltrating immune cells, we systematically summarize the current conflicting views on the interplay between ferroptosis and anti-tumor immunity, intending to provide potential explanations and identify the work needed to establish a translational basis for combined ferroptosis-targeted therapy and immunotherapy in treating tumors.

Relief effects of Laoshan cherry extracts as a dietary supplement against the symptoms of acute gouty arthritis in rats induced by urate crystals.

We evaluated the effects of Laoshan cherry as a food or dietary supplement on relieving the symptoms of acute gouty arthritis in rats induced by urate crystals. Rats in groups of 10 were given Laoshan cherry functional extracts at doses of 5, 10, and 20 mg/kg by oral gavage for 21 days and then injected with a sodium nitrate suspension in the rear ankle area as an induced acute gouty arthritis model. The ankle swelling and inflammations in the model (no treatment) group increased significantly compared with blank group; the ankle inflammations reduced in experimental groups receiving three different doses of the cherry extract and the joint swelling reduced in the high-dose group by 43% compared with the model group. Serum uric acid and xanthine oxidase activities were also elevated in the model group and these parameters were reduced by a maximum of 8% and 33%, respectively, in the rats receiving the cherry extracts. The serum levels of the inflammatory cytokine IL-1ß in the high-dose group decreased by 12% compared with the model group. These results demonstrated that the cherries possess a functional substance that has a significant alleviating effect on the symptoms of gouty arthritis in rats induced by sodium urate injection.

A Day/Night Leader-Following Method Based on Adaptive Federated Filter for Quadruped Robots.

The quadruped robots have superior adaptability to complex terrains, compared with tracked and wheeled robots. Therefore, leader-following can help quadruped robots accomplish long-distance transportation tasks. However, long-term following has to face the change of day and night as well as the presence of interference. To solve this problem, we present a day/night leader-following method for quadruped robots toward robustness and fault-tolerant person following in complex environments. In this approach, we construct an Adaptive Federated Filter algorithm framework, which fuses the visual leader-following method and the LiDAR detection algorithm based on reflective intensity. Moreover, the framework uses the Kalman filter and adaptively adjusts the information sharing factor according to the light condition. In particular, the framework uses fault detection and multisensors information to stably achieve day/night leader-following. The approach is experimentally verified on the quadruped robot SDU-150 (Shandong University, Shandong, China). Extensive experiments reveal that robots can identify leaders stably and effectively indoors and outdoors with illumination variations and unknown interference day and night.

Advance and Application of Single-cell Transcriptomics in Auditory Research.

Hearing loss and deafness, as a worldwide disability disease, have been troubling human beings. However, the auditory organ of the inner ear is highly heterogeneous and has a very limited number of cells, which are largely uncharacterized in depth. Recently, with the development and utilization of single-cell RNA sequencing (scRNA-seq), researchers have been able to unveil the complex and sophisticated biological mechanisms of various types of cells in the auditory organ at the single-cell level and address the challenges of cellular heterogeneity that are not resolved through by conventional bulk RNA sequencing (bulk RNA-seq). Herein, we reviewed the application of scRNA-seq technology in auditory research, with the aim of providing a reference for the development of auditory organs, the pathogenesis of hearing loss, and regenerative therapy. Prospects about spatial transcriptomic scRNA-seq, single-cell based genome, and Live-seq technology will also be discussed.

Prognostic biomarker SYK and its correlation with immune infiltrates in glioma.

The tumor microenvironment (TME) provides excellent conditions for the development of glioma. The present study sought to identify the prognostic factors of glioma that could be used to improve the prognosis of patients with this disease. In the present study, Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data calculations were employed to estimate the ratio of tumor-infiltrating immune cells and the quantity of immune and stromal components in 698 glioma cases from the Cancer Genome Atlas database. In addition, certain differentially expressed genes were studied by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and single genes associated with prognosis were identified by protein-protein interaction (PPI) network and Cox combined analysis. The immune and stromal scores of the TME were significantly associated with glioma patient survival. By using the PPI network and Cox regression analyses, spleen tyrosine kinase (SYK) was eventually identified as the best prognostic factor for patients with glioma. In addition, Gene Set Enrichment Analysis and CIBERSORT analyses were employed. The former indicated that the high-expression SYK group genes were mainly enriched in immune-related activities. The latter revealed that SYK expression was positively associated with T cell cluster of differentiation 4 memory resting and monocytes. The aforementioned experimental analyses provided the theoretical basis for the biological prediction of SYK. The data indicated that SYK contributed to immune predictors in patients with glioma by facilitating the shift of the TME from immune dominance to metabolic activity. Finally, reverse transcription-quantitative PCR and western blotting were used to verify the single gene expression in glioma cells. This may provide prognostic value for the treatment of glioma.