Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.

The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

Position of meristems and the angles of the cell division plane regulate the uniqueness of lateral organ shape.

Leaf meristem is a cell proliferative zone present in the lateral organ primordia. In this study, we examined how cell proliferative zones in primordia of planar floral organs and polar auxin transport inhibitor (PATI)-treated leaf organs differ from those of non-treated foliage leaves of Arabidopsis thaliana, with a focus on the accumulation pattern of ANGUSTIFOLIA3 (AN3) protein, a key element for leaf meristem positioning. We found that PATI-induced leaf shape changes were correlated with cell division angle but not with meristem positioning/size or AN3 localisation. In contrast, different shapes between sepals and petals compared with foliage leaves were associated with both altered meristem position, due to altered AN3 expression patterns, and different distributions of cell division angles. A numerical simulation showed that meristem position majorly affected the final shape but biased cell division angles had a minor effect. Taken together, these results suggest that the unique shapes of different lateral organs depend on the position of the meristem in the case of floral organs and cell division angles in the case of leaf organs with different auxin flow.

Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing.

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, which lead to various findings in transcriptomic research. This study addresses these challenges by integrating 34 datasets, including 26 control groups, 6 prognostic datasets and 2 single-cell RNA sequencing (scRNA-seq) datasets to identify 10,000 AML-related genes (ARGs). We focused on genes with low variability and high consistency and successfully discovered 191 AML signatures (ASs). Leveraging machine learning techniques, specifically the XGBoost model and our custom framework, we classified AML subtypes with both scRNA-seq and bulk RNA-seq data, complementing the ELN2022 classification approach. Our research also identified promising treatments for AML through drug repurposing, with solasonine showing potential efficacy for high-risk AML patients, supported by molecular docking and transcriptomic analyses. To enhance reproducibility and customizability, we developed CSAMLdb, a user-friendly database platform. It facilitates the reuse and personalized analysis of nearly all results obtained in this research, including single-gene prognostics, multi-gene scoring, enrichment analysis, machine learning risk assessment, drug repositioning analysis and literature abstract named entity recognition. CSAMLdb is available at http://www.csamldb.com.

High-Fidelity Sensitive Tracing Circulating Tumor Cell Telomerase Activity.

Dynamic tracing of intracellular telomerase activity plays a crucial role in cancer cell recognition and correspondingly in earlier cancer diagnosis and personalized precision therapy. However, due to the complexity of the required reaction system and insufficient loading of reaction components into cells, achieving a high-fidelity determination of telomerase activity is still a challenge. Herein, an Aptamer-Liposome mediated Telomerase activated poly-Molecular beacon Arborescent Nanoassembly(ALTMAN) approach was described for direct high-fidelity visualization of telomerase activity. Briefly, intracellular telomerase activates molecular beacons, causing their hairpin structures to unfold and produce fluorescent signals. Furthermore, multiple molecular beacons can self-assemble, forming arborescent nanostructures and leading to exponential amplification of fluorescent signals. Integrating the enzyme-free isothermal signal amplification successfully increased the sensitivity and reduced interference by leveraging the skillful design of the molecular beacon and the extension of the telomerase-activated TTAGGG repeat sequence. The proposed approach enabled ultrasensitive visualization of activated telomerase exclusively with a prominent detection limit of 2 cells·µL-1 and realized real-time imaging of telomerase activity in living cancer cells including blood samples from breast cancer patients and urine samples from bladder cancer patients. This approach opens an avenue for establishing a telomerase activity determination and in situ monitoring technique that can facilitate both telomerase fundamental biological studies and cancer diagnostics.

Development of α-Tocopherol Loaded PLGA Nanoparticles and Its Evaluation as a Novel Immune Adjuvant.

With the continuous development of preventive and therapeutic vaccines, traditional adjuvants cannot provide sufficient immune efficacy and it is of high necessity to develop safe and effective novel nanoparticle-based vaccine adjuvants. α-Tocopherol (TOC) is commonly used in oil-emulsion adjuvant systems as an immune enhancer, yet its bioavailability is limited by poor water solubility. This study aims to develop TOC-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TOC-PLGA NPs) to explore the potential of TOC-PLGA NPs as a novel nanoparticle-immune adjuvant. TOC-PLGA NPs are prepared by a nanoprecipitation method and their physicochemical properties are characterized. It is shown that TOC-PLGA NPs are 110.8 nm, polydispersity index value of 0.042, and Zeta potential of -13.26 mV. The encapsulation efficiency and drug loading of NPs are 82.57% and 11.80%, respectively, and the cumulative release after 35 days of in vitro testing reaches 47%. Furthermore, TOC-PLGA NPs demonstrate a superior promotion effect on RAW 264.7 cell proliferation compared to PLGA NPs, being well phagocytosed and also promoting antigen uptake by macrophages. TOC-PLGA NPs can strongly upregulate the expression of co-stimulatory surface molecules and the secretion of cytokines. In conclusion, TOC-PLGA NPs can be a novel vaccine adjuvant with excellent biocompatibility and significant immune-enhancing activity.

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling.

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

Bone Marrow Stimulation Does Not Lead to Lower Retear Rates, Better Functional Outcomes, or Higher Complication Rates at Short-Term Follow-Up for Arthroscopic Rotator Cuff Repair: A Meta-analysis of Randomized Controlled Trials.

PURPOSE: To determine the effect of bone marrow stimulation (BMS) on retear rates, functional outcomes, and complication rates in patients who underwent arthroscopic rotator cuff repair (RCR) through a meta-analysis of randomized controlled trials. METHODS: PubMed, EMBASE, Web of Science, and The Cochrane Library were searched on March 25, 2023. Two evaluators independently screened the literature, extracted data, and assessed the methodologic quality of the enrolled studies. Meta-analysis was conducted using RevMan software, version 5.4. RESULTS: A total of 7 randomized controlled trials with 638 patients were included. The evaluation of rotator cuff tendon integrity was conducted using distinct imaging modalities. Specifically, 259 patients underwent magnetic resonance imaging whereas 208 patients underwent ultrasound. Additionally, a subset of 95 patients underwent either of these modalities; however, the precise distribution between these 2 modalities was not explicitly delineated. Compared with RCR alone, RCR combined with BMS provided similar retear rates (P = .51, I2 = 46%), Constant-Murley scores (P = .14, I2 = 0%), American Shoulder and Elbow Surgeons (standardized shoulder assessment form) scores (P = .56, I2 = 0%), Western Ontario Rotator Cuff Index scores (P = .20, I2 = 0%), visual analog scale scores (P = .19, I2 = 0%), forward flexion (P = .18, I2 = 0%), external rotation (P = .62, I2 = 0%), severe complication rates (P = .56, I2 = 0%), and mild complication rates (P = .10, I2 = 0%). CONCLUSIONS: Compared with the outcomes observed after isolated arthroscopic RCR, arthroscopic RCR with BMS showed comparable results in terms of retear rate, functional outcomes, and incidence of complications. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies.

5-Fluorouracil for the Treatment of Pustulosis Caused by Vascular Occlusion After Receiving Filler Injection.

With the increase of cosmetic injections in recent years, complications, like filler embolism, had also increased. The pustulosis, as a result of vascular occlusion and hypoxia, requires a long treatment cycle and often develops pigmentation and scarring, leaved patients with bad memories and affected esthetics. In this study, we report three cases of pustulosis after hyaluronic acid injection. We used 5-fluorouracil preparations to heal the pustulosis and the pustules resolved in an average of 24 hours.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Comprehensive Multi-drug Strategy for the Management of Foreign Body Granuloma Following Mesotherapy.

BACKGROUND: Mesotherapy is a medical technique that administers cosmetic nutrients directly to the dermis through microdrop injections for aesthetic purposes. Its application has become increasingly widespread. However, there have also been a growing number of reported cases of multiple foreign body granulomas following mesotherapy. It is crucial to find an effective and safe treatment. METHODS: In this study, 31 patients with facial foreign body granuloma after mesotherapy were included. A mixture of 5-fluorouracil, lidocaine injection , and normal saline was prepared in a ratio of 1:1:4 and injected subcutaneously. Triamcinolone acetonide, 5-fluorouracil, lidocaine injection, and normal saline were prepared in a ratio of 2:5:3:10. Subcutaneous injections were administered to each papule using a 34G needle. The treatments were scheduled at intervals of 10-14 days. Color Doppler ultrasound was used to evaluate the condition before the initial treatment and after the final treatment. RESULTS: The preoperative ultrasonography revealed diffuse hypoechoic areas in the dermis of the facial skin. After an average of 2-4 treatment sessions, a significant improvement was observed in all patients' appearance, with reduced redness and swelling, softened nodules, absence of pain and itching symptoms, and no evident abnormal echo on ultrasound examination. During a follow-up period ranging from 1 to 8 months, no recurrence or adverse reactions were reported. CONCLUSION: This technique demonstrates clear efficacy. And this formulation effectively reduces the dosage of triamcinolone acetonide and minimizes the risk of adverse reactions such as skin atrophy. Therefore, it can be considered an effective treatment for multiple foreign body granulomas following mesotherapy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.