ZNF8 Orchestrates with Smad3 to Promote Lung Metastasis by Recruiting SMYD3 in Breast Cancer.

Most deaths in breast cancer patients are attributed to metastasis, and lung metastasis is associated with a particularly poor prognosis; therefore it is imperative to identify potential target for intervention. The transforming growth factor-ß (TGF-ß) pathway plays a vital role in breast cancer metastasis, in which Smad3 is the key mediator and performs specific functions by binding with different cofactors. However, Smad3 cofactors involved in lung metastasis have not yet been identified. This study first establishes the interactome of Smad3 in breast cancer cells and identifies ZNF8 as a novel Smad3 cofactor. Furthermore, the results reveal that ZNF8 is closely associated with breast cancer lung metastasis prognosis, and specifically facilitates TGF-ß pathway-mediated breast cancer lung metastasis by participating in multiple processes. Mechanistically, ZNF8 binds with Smad3 to enhance the H3K4me3 modification and promote the expression of lung metastasis signature genes by recruiting SMYD3. SMYD3 inhibition by BCI121 effectively prevents ZNF8-mediated lung metastasis. Overall, the study identifies a novel cofactor of TGF-ß/Smad3 that promotes lung metastasis in breast cancer and introduces potential therapeutic strategies for the early management of breast cancer lung metastasis.

ZASP: A highly compatible and sensitive ZnCl2-precipitation assisted sample preparation method for proteomic analysis.

Universal sample preparation for proteomic analysis that enables unbiased protein manipulation, flexible reagent use, and low protein loss is required to ensure the highest sensitivity of downstream liquid chromatography-mass spectrometry (LC-MS) analysis. To address these needs, we developed a ZnCl2 precipitation-assisted sample preparation method (ZASP) that depletes harsh detergents and impurities in protein solutions prior to trypsin digestion via 10 min of ZnCl2 and methanol-induced protein precipitation at room temperature (RT). ZASP can remove trypsin digestion and LC-MS incompatible detergents such as SDS, Triton X-100, and urea at high concentrations in solution and unbiasedly recover proteins independent of the amount of protein input. We demonstrated the sensitivity and reproducibility of ZASP in an analysis of samples with 1 µg to 1000 µg of proteins. Compared to commonly used sample preparation methods such as SDC-based in-solution digestion, acetone precipitation, FASP, and SP3, ZASP has proven to be an efficient approach. Here, we present ZASP, a practical, robust, and cost-effective proteomic sample preparation method that can be applied to profile different types of samples.

Fabrication of 3D Biomimetic Smooth Muscle Using Magnetic Induction and Bioprinting for Tissue Regeneration.

Smooth muscles play a vital role in peristalsis, tissue constriction, and relaxation but lack adequate self-repair capability for addressing extensive muscle defects. Engineering scaffolds have been broadly proposed to repair the muscle tissue. However, efforts to date have shown that those engineered scaffolds focus on cell alignment in 2-dimension (2D) and fail to direct muscle cells to align in 3D area, which is irresolvable to remodel the muscle architecture and restore the muscle functions like contraction and relaxation. Herein, we introduced an iron oxide (Fe3O4) filament-embedded gelatin (Gel)-silk fibroin composite hydrogel in which the oriented Fe3O4 self-assembled and functioned as micro/nanoscale geometric cues to induce cell alignment growth. The hydrogel scaffold can be designed to fabricate aligned or anisotropic muscle by combining embedded 3D bioprinting with magnetic induction to accommodate special architectures of muscular tissues in the body. Particularly, the bioprinted muscle-like matrices effectively promote the self-organization of smooth muscle cells (SMCs) and the directional differentiation of bone marrow mesenchymal stem cells (BMSCs) into SMCs. This biomimetic muscle accelerated tissue regeneration, enhancing intercellular connectivity within the muscular tissue, and the deposition of fibronectin and collagen I. This work provides a novel approach for constructing engineered biomimetic muscles, holding significant promise for clinical treatment of muscle-related diseases in the future.

PoIL8-L, a teleost interleukin-8 like, enhances leukocyte cellular vitality and host defense against bacterial infections in Japanese flounder (Paralichthys olivaceus).

Interleukin-8 (IL-8), a CXC chemokine, exerts pivotal effect on cell migration, inflammatory response, and immune regulation. In this study, we examined the immunological characteristics of an IL-8 like homologue (PoIL8-L) in Japanese flounder (Paralichthys olivaceus). PoIL8-L contains a conserved chemokine CXC domain and 105 amino acid residues. PoIL8-L expression in tissues was constitutive, and significantly regulated by V. havieri or E. tarda infection. In vitro, rPoIL8-L could bind to eight tested bacteria, exhibited bacteriostatic and bactericidal effects against certain bacteria, and could bind to the targeted bacterial Ⅳ pilin protein rPilA of E. tarda. Furthermore, rPoIL8-L could attach to peripheral blood leukocytes, and enhance their immune genes expression, respiratory burst, chemotaxis, proliferation, acid phosphatase activity, and phagocytic activity. Additionally, rPoIL8-L induce neutrophils to extrude neutrophil extracellular traps. In vivo, rPoIL8-L could promote host resistance to E. tarda infection. In summary, these findings provide fresh perspectives on the immunological antibacterial properties of IL-8 in teleost.

The current status and future trends of BET research in oncology.

Background: BET family proteins are important epigenetic and transcriptional regulators involved in the control of tumorigenesis and development and have become important targets for cancer therapy. However, there is no systematic bibliometric analysis in this field. A visual analysis of the research hotspots and trends of BET is helpful to understand the future development direction. Method: We used CiteSpace, VOSviewer, and Excel to visualize and analyze the trends regarding authors, journals, countries or regions, highly cited papers, and keywords in the field. Result: The results included a total of 946 publications. There are many more papers on BET proteins published since 2013. The papers are mainly from 44 countries, led by the U.S. and China. A total of 7381 authors were identified, among which Bradner, J.E. had the greatest number of articles and the greatest influence. Cancer Discovery was the journal with the most citations per article. Our analysis identified the most influential papers in the field, including highly cited papers and citation burst references. The most frequent keywords included 'expression', 'c-Myc', 'cancer', 'BRD4', 'BET inhibition', 'resistance', 'differentiation', and 'JQ1', which represent the focus of current and developing research fields. Conclusion: Research on BET is thriving. Collaboration and exchanges between countries and institutions must be strengthened in the future, and the mechanisms of BET-related pathways, the relationship between BET and various diseases, and the development of new BET inhibitors have become the major focus of current research and the trend of future research.

Prebiotics improve frailty status in community-dwelling older individuals in a double-blind, randomized, controlled trial.

BACKGROUNDFrailty significantly affects morbidity and mortality rates in the older population (age >65 years). Age-related degenerative diseases are influenced by the intestinal microbiota. However, limited research exists on alterations in the intestinal microbiota in frail older individuals, and the effectiveness of prebiotic intervention for treating frailty remains uncertain.OBJECTIVEWe sought to examine the biological characteristics of the intestinal microbiome in frail older individuals and assess changes in both frailty status and gut microbiota following intervention with a prebiotic blend consisting of inulin and oligofructose.METHODSThe study consisted of 3 components: an observational analysis with a sample size of 1,693, a cross-sectional analysis (n = 300), and a multicenter double-blind, randomized, placebo-controlled trial (n = 200). Body composition, commonly used scales, biochemical markers, intestinal microbiota, and metabolites were examined in 3 groups of older individuals (nonfrail, prefrail, and frail). Subsequently, changes in these indicators were reevaluated after a 3-month intervention using the prebiotic mixture for the prefrail and frail groups.RESULTSThe intervention utilizing a combination of prebiotics significantly improved frailty and renal function among the older population, leading to notable increases in protein levels, body fat percentage, walking speed, and grip strength. Additionally, it stimulated an elevation in gut probiotic count and induced alterations in microbial metabolite expression levels as well as corresponding metabolic pathways.CONCLUSIONSThe findings suggest a potential link between changes in the gut microbiota and frailty in older adults. Prebiotics have the potential to modify the gut microbiota and metabolome, resulting in improved frailty status and prevention of its occurrence.TRIAL REGISTRATIONClinicalTrials.gov NCT03995342.

The role of HGH1 in breast cancer prognosis: a study on immune response and cell cycle.

BACKGROUND: Breast cancer (BRCA) remains to be among the main causes of cancer-associated mortality in women globally. HGH1 homolog (HGH1) has been reported to be associated with tumor immunity. However, the function of HGH1 in BRCA remains unclear. Therefore, the present study examined the potential role of HGH1 in BRCA. METHODS: The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) were used to obtain RNA-seq data for BRCA. A protein localization of HGH1 was determined by using the Human Protein Atlas (HPA), and immunohistochemistry (IHC) staining revealed an upregulation in the expression of HGH1 in clinical BRCA tissues. Xenograft mice were used to test tumor growth and HGH1 expression in breast cancer cells. The protein interaction information of HGH1 was analyzed using the GeneMANIA website. Based on univariate Cox regression and Kaplan-Meier methods, we evaluated the role of HGH1 in BRCA prognosis. HGH1-related differentially expressed genes were analyzed using GO, KEGG, and GSEA. We also examined the relationship between HGH1 expression, immune checkpoints, and immune infiltration. CCK-8, EdU, and colony formation assays were used to measure cell proliferation, and western blot analysis was used to evaluate HGH1's role in BRCA. RESULTS: IHC results showed that the expression of HGH1 was significantly upregulated in BRCA tissues compared to normal tissues. High levels of HGH1 expression was associated with worse clinical features and a worse prognosis. HGH1 expression was an independent predictor of BRCA outcomes in both univariate and multivariate analyses. Functionally, western blot analysis showed that HGH1 is implicated in cell cycle. As well, knocking down HGH1 significantly reduced BRCA cells' proliferative abilities. Crucially, HGH1 expression levels were positively correlated with Th2 cell infiltration and negatively correlated with Tcm cell infiltration. CONCLUSION: Biomarkers such as HGH1 can reliably predict prognosis in BRCA patients.

Ru Single Atom Dispersed Cu Nanoparticle with Dual Sites Enables Outstanding Photocatalytic CO2 Reduction.

Cu-based catalysts are promising candidates for CO2 reduction owing to the favorable energetics of Cu sites for CO2 adsorption and transformation. However, CO2 reduction involving insurmountable activation barriers and various byproducts remains a significant challenge to achieve high activity and selectivity. Herein, a photocatalyst constructed with single-Ru-site-on-Cu-nanoparticle on Bi4Ti3O12 exhibits exceptional activity and selectivity for CO2 conversion to CO. The experimental and theoretical results consistently reveal that the Ru-Cu dual sites allow the rapid transfer of photogenerated carriers for closely interacting with CO2 molecules. Importantly, the Ru-Cu dual sites exhibit extremely strong CO2 adsorption ability, and the Gibbs free energy of the rate-determining step (*CO2 to *COOH) has been significantly reduced, synergistically enhancing the entire CO2 conversion process. The optimal BTOCu2Ru0.5 photocatalyst manifests a high performance for selective reduction of CO2 to CO, yielding 10.84 µmol over 15 mg of photocatalyst in 4 h (180.67 µmol·g-1·h-1) under a 300 W Xe lamp without any photosensitizer and sacrificial reagent, outperforming all bismuth-based materials and being one of the best photocatalysts ever reported under similar reaction conditions. This work presents a strategy for the rational design of multiple metal sites toward efficient photocatalytic reduction of CO2.

[Species diversity of dark septate endophytes in tundra plants of Changbai Mountains, Northeast China]. / é•¿ç™½å±±è‹”åŽŸæ¤ç‰©æ·±è‰²æœ‰éš”å† ç”ŸçœŸèŒç‰©ç§å¤šæ ·æ€§.

We isolated the dark septate endophytic (DSE) fungi from roots of typical plant species in the tundra of Changbai Mountains Nature Reserve, including Rhododendron aureum, R. conferentiatum, Vaccinium uliginosum, and Dryas octopetala, and studied their colonization. We further investigated the DSE community composition and species diversity of the four tundra plant species by using morphological characteristics combined with rDNA ITS sequence analysis. The results showed that DSE formed a typical structure of "microsclerotia" in roots of the four plant species. A total of 69 strains of DSE fungi were isolated from the root samples, belonging to 10 genera, and 12 species. They were Phialocephala fortinii, Alternaria alternata, A. tenuissima, Epicocum nigrum, Canariomyces microsporus, Colletotrichum spaethianum, C. camelliae, Leptophoria sp., Cladosporium cladosporioides, Phoma sp., Cadophora sp., and Discosia italica, respectively. The DSE fungal species diversity was rich, and all these fungal species were firstly reported as DSE fungi in the alpine tundra belt of China. Among them, Phialocephala fortinii was the common and dominant species of all tundra plants. The Simpson, Pielou, and Shannon diversity indices of DSE fungi of the four plant species of tundra differed significantly. Our results showed that tundra plants have rich diversity of DSE fungi, and they can form a good symbiotic relationship, which enhance the adaptability of tundra plants to the harsh environment.

Breathomics for diagnosing tuberculosis in diabetes mellitus patients.

Introduction: Individuals with diabetes mellitus (DM) are at an increased risk of Mycobacterium tuberculosis (Mtb) infection and progressing from latent tuberculosis (TB) infection to active tuberculosis disease. TB in the DM population is more likely to go undiagnosed due to smear-negative results. Methods: Exhaled breath samples were collected and analyzed using high-pressure photon ionization time-of-flight mass spectrometry. An eXtreme Gradient Boosting (XGBoost) model was utilized for breathomics analysis and TB detection. Results: XGBoost model achieved a sensitivity of 88.5%, specificity of 100%, accuracy of 90.2%, and an area under the curve (AUC) of 98.8%. The most significant feature across the entire set was m106, which demonstrated a sensitivity of 93%, specificity of 100%, and an AUC of 99.7%. Discussion: The breathomics-based TB detection method utilizing m106 exhibited high sensitivity and specificity potentially beneficial for clinical TB screening and diagnosis in individuals with diabetes.

Ultrasonography findings of pediatric head and neck lymphatic malformations: A 10-year experience of 140 surgical cases.

OBJECTIVE: To discuss the usefulness of ultrasonography (US) in the diagnosis and management of pediatric head and neck lymphatic malformations (HNLMs). METHODS: We conducted a retrospective analysis of 140 children who were referred to our hospital for the treatment of HNLMs. RESULTS: The median age at presentation was 12 months (1 day-171 months; 66.4% under 2 years old; 35.7% neonatus). The majority clinical presentations were asymptomatic mass (65.7%, 92/140) and cosmetic deformity (25.7%, 36/140). HNLMs involved the neck accounting for 65.7% (92/140), especially posterior cervical trigone (22.1%, 31/140), and submandibular (20.0%, 28/140). The US diagnostic accuracy was 91.4% (128/140). Their boundary with the surrounding tissues was usually clear (87.9%, 123/140), whereas the shape was mostly irregular (97.1%, 136/140). Based on surgical findings, there were 67 pure HNLMs and 73 intracystic hemorrhage. Between the two groups, there were statistical differences in capsule contents (χ2 = 7.8299, p = 0.0051), flocculent echo floating (χ2 = 21.2964, p < 0.0001), overlying skin (χ2 = 9.0498, p = 0.0026), and palpation (χ2 = 13.4058, p = 0.0003). CONCLUSIONS: US typically reveals the lesion with clear boundary, irregular morphology, anechoic contents, no blood flow signal, and echoic intracapsular septum with blood flow signal. In contrast, bluish appearance, tensional palpation, and capsule contents with low/mixed echo or flocculent echo floating may indicate intracystic hemorrhage.

tsRNA-GlyGCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB.

BACKGROUND: tRNA-derived small RNAs (tsRNAs) are newly discovered non-coding RNA, which are generated from tRNAs and are reported to participate in several biological processes in diseases, especially cancer; however, the mechanism of tsRNA involvement in colorectal cancer (CRC) and 5-fluorouracil (5-FU) is still unclear. METHODS: RNA sequencing was performed to identify differential expression of tsRNAs in CRC tissues. CCK8, colony formation, transwell assays, and tumor sphere assays were used to investigate the role of tsRNA-GlyGCC in 5-FU resistance in CRC. TargetScan and miRanda were used to identify the target genes of tsRNA-GlyGCC. Biotin pull-down, RNA pull-down, luciferase assay, ChIP, and western blotting were used to explore the underlying molecular mechanisms of action of tsRNA-GlyGCC. The MeRIP assay was used to investigate the N(7)-methylguanosine RNA modification of tsRNA-GlyGCC. RESULTS: In this study, we uncovered the feature of tsRNAs in human CRC tissues and confirmed a specific 5' half tRNA, 5'tiRNA-Gly-GCC (tsRNA-GlyGCC), which is upregulated in CRC tissues and modulated by METTL1-mediated N(7)-methylguanosine tRNA modification. In vitro and in vivo experiments revealed the oncogenic role of tsRNA-GlyGCC in 5-FU drug resistance in CRC. Remarkably, our results showed that tsRNA-GlyGCC modulated the JAK1/STAT6 signaling pathway by targeting SPIB. Poly (ß-amino esters) were synthesized to assist the delivery of 5-FU and tsRNA-GlyGCC inhibitor, which effectively inhibited tumor growth and enhanced CRC sensitive to 5-FU without obvious adverse effects in subcutaneous tumor. CONCLUSIONS: Our study revealed a specific tsRNA-GlyGCC-engaged pathway in CRC progression. Targeting tsRNA-GlyGCC in combination with 5-FU may provide a promising nanotherapeutic strategy for the treatment of 5-FU-resistance CRC.

Cross-sectional survey to determine fatigue in patients with systemic lupus erythematosus.

Background: Fatigue is a prevalent symptom among individuals with active systemic lupus erythematosus (SLE). We aimed to investigate the status quo and influencing factors of fatigue in patients with SLE, to provide insights to the clinical SLE treatment and care. Methods: We conducted a longitudinal survey on the fatigue of active SLE patients from June 2022 to November 2023 in our hospital. Fatigue severity scale (FSS), Self-rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used for data collection. Pearson correlation and multiple stepwise regression analysis were conducted to analyze the relevant factors affecting the fatigue level of patients with SLE. Results: A total of 212 active SLE patients were included, the incidence of fatigue in active SLE patients was 55.66%. There were statistical differences in the fatigue score between SLE patients with different age and course of SLE (all p < 0.05). Fatigue was positively correlated with anxiety (r = 0.559) and depression (r = 0.591) in patients with SLE (all p < 0.05). Multiple stepwise regression analysis indicated that age, course of SLE, anxiety and depression were the influencing factors of fatigue in SLE patients (all p < 0.05). Conclusion: Patients with SLE exhibit a significant degree of fatigue, which varies with respect to age, disease duration, and the presence of comorbid anxiety and depression. It is imperative that healthcare providers closely monitor the fatigue levels in this patient population and implement targeted interventions to mitigate the impact of fatigue on the quality of life and overall well-being of individuals with SLE.

Application of 18F-FDG PET/CT imaging in a primary angiomatoid fibrous histiocytoma of pulmonary bronchus: case report and literature review.

Background: Angiomatoid fibrous histiocytoma (AFH) is a clinically rare, low-grade malignant soft tissue tumor that occasionally metastasizes. It accounts for 0.3% of all soft tissue tumors and most frequently occurs in the extremities, followed by the trunk, and the head and neck. Primary angiomatoid fibrous histiocytoma (PAFH) of the pulmonary bronchus is rare. In this paper, the clinical and imaging data of a case of PAFH of the pulmonary bronchus are reported, and the literature is reviewed. Case description: A 57-year-old female patient presented with a six-month history of cough without apparent cause, characterized by paroxysmal dry cough, chest tightness, and shortness of breath, which worsened with activity. She did not experience fever, chills, chest pain, hemoptysis, or night sweats. Laboratory tests revealed an elevated C-reactive protein and ferritin levels, while tumor markers such as AFP, CEA, CA199, CA125, CA50, and T-SPOT were negative. A chest CT scan showed bronchial obstruction, atelectasis, and a soft tissue density in the right middle lobe of the lung. The enhanced scan demonstrated uneven enhancement of endobronchial nodules. An 18F-FDG PET/CT scan revealed a nodular soft tissue density shadow in the right lung bronchus with uneven density, clear boundaries, and increased 18F-FDG uptake, with a maximum standard uptake value (SUVmax) of 11.2. Bronchoscopy revealed a nodular or polypoid mass that was yellow and tough. Based on imaging findings, the preoperative diagnosis favored lung cancer. However, the postoperative pathological diagnosis confirmed primary angiomatoid fibrous histiocytoma (PAFH) of the pulmonary bronchus. Conclusion: The incidence of primary angiomatoid fibrous histiocytoma (PAFH) is very low, and its clinical manifestations and imaging findings lack specificity, with the final diagnosis relying on pathology. PET/CT imaging has a certain value in the diagnosis of PAFH and holds significant application value in preoperative staging, postoperative efficacy evaluation, and follow-up monitoring. In conclusion, this case report further expands the spectrum of lung and bronchial tumors.

Suicidal ideation following ketamine prescription in patients with recurrent major depressive disorder: a nation-wide cohort study.

Ketamine has gained attention for its effective treatment for patients with major depressive disorder (MDD) and suicidal ideation; Despite numerous studies presenting the rapid efficacy, long-term benefit in real-world populations remains poorly characterized. This is a retrospective cohort study using TriNetX US Collaborative Network, a platform aggregating electronic health records (EHRs) data from 108 million patients from 62 health care organizations in the US, and the study population includes 514,988 patients with a diagnosis of recurrent MDD who were prescribed relevant treatment in their EHRs. The prescription of ketamine was associated with significantly decreased risk of suicidal ideation compared to the prescription of other common antidepressants: HR = 0.63 (95% CI: 0.53-0.76) at 1 day - 7 days, 0.67 (95% CI: 0.59-0.77) at 1 day - 30 days, 0.69 (95% CI: 0.62-0.77) at 1 day - 90 days, 0.74 (95% CI: 0.67-0.81) at 1 day - 180 days, and 0.78 (95% CI: 0.69-0.83) at 1 day - 270 days. This trend was especially robust among adults over 24 years of age, females, males, and White patients with recurrent MDD. This study provides real-world evidence that ketamine has long-term benefits in mitigating suicidal ideation in patients with recurrent MDD. Future work should focus on optimizing dosage regimens for ketamine, understanding the mechanism, and the difference in various demographic subpopulations.

Delayed diagnosis of TAFRO syndrome: A case report.

RATIONALE: TAFRO syndrome is a systemic inflammatory disorder, manifesting as thrombocytopenia (t), anasarca (a), fever (f), reticulin myelofibrosis/renal insufficiency (r), and organomegaly (o), and considered as a unique clinical subtype of idiopathic multicentric Castleman disease (iMCD). Such syndrome gave rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease. PATIENT CONCERNS: A Chinese young female initially presenting with arthralgia, Raynaud phenomenon, generalized edema, and a positive anti-small nuclear ribonucleoprotein particle antibody was diagnosed as mixed connective tissue disease. The kidney biopsy showed thrombotic microangiopathy. Bone marrow smear showed bone marrow hyperplasia and biopsy revealed suspected light chain restricted expression, megakaryocyte proliferation, and moderate to severe bone marrow fibrosis. A lymph node biopsy was conducted and the histopathological findings were consistent with the subtype of mixed Castleman disease. The clinical symptoms were relieved after regular chemotherapy. DIAGNOSES: After above examination results and clinical manifestations, the final diagnoses was TAFRO syndrome. INTERVENTION: The she was started on chemotherapy with bortezomib, cyclophosphamide, and dexamethasone. OUTCOME: After chemotherapy, symptoms such as thrombocytopenia, hematuria and proteinuria disappeared, lymphadenopathy and VEGF level decreased, and bone marrow fibrosis relieved. LESSONS: Our case illustrated the first cases of shared characteristics of mixed connective tissue disease and iMCD-TAFRO syndrome. Cytokines may play a role in the shared pathogenicity of the iMCD-TAFRO syndrome and systemic autoimmune diseases. Therapy directly against inflammatory factors such as corticosteroids or chemotherapy have an important therapeutic implication.

ITGB2 related to immune cell infiltration as a potential therapeutic target of inflammatory bowel disease using bioinformatics and functional research.

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition regarded as a major risk factor for colitis-associated cancer. However, the underlying mechanisms of IBD remain unclear. First, five GSE data sets available in GEO were used to perform 'batch correction' and Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs). Candidate molecules were identified using CytoHubba, and their diagnostic effectiveness was predicted. The CIBERSORT algorithm evaluated the immune cell infiltration in the intestinal epithelial tissues of patients with IBD and controls. Immune cell infiltration in the IBD and control groups was determined using the least absolute shrinkage selection operator algorithm and Cox regression analysis. Finally, a total of 51 DEGs were screened, and nine hub genes were identified using CytoHubba and Cytoscape. GSE87466 and GSE193677 were used as extra data set to validate the expression of the nine hub genes. CD4-naïve T cells, gamma-delta T cells, M1 macrophages and resting dendritic cells (DCs) are the main immune cell infiltrates in patients with IBD. Signal transducer and activator of transcription 1, CCR5 and integrin subunit beta 2 (ITGB2) were significantly upregulated in the IBD mouse model, and suppression of ITGB2 expression alleviated IBD inflammation in mice. Additionally, the expression of ITGB2 was upregulated in IBD-associated colorectal cancer (CRC). The silence of ITGB2 suppressed cell proliferation and tumour growth in vitro and in vivo. ITGB2 resting DCs may provide a therapeutic strategy for IBD, and ITGB2 may be a potential diagnostic marker for IBD-associated CRC.

Poly(ADP-Ribose) Polymerase-1 Regulates Pyroptosis Independent Function of NLRP3 Inflammasome in Neutrophil Extracellular Trap Formation.

Neutrophil extracellular traps (NETs) function to control infectious agents as well as to propagate inflammatory response in a variety of disease conditions. DNA damage associated with chromatin decondensation and NACHT domain-leucine-rich repeat-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation have emerged as crucial events in NET formation, but the link between the two processes is unknown. In this study, we demonstrate that poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair enzyme, regulates NET formation triggered by NLRP3 inflammasome activation in neutrophils. Activation of mouse neutrophils with canonical NLRP3 stimulants LPS and nigericin induced NET formation, which was significantly abrogated by pharmacological inhibition of PARP-1. We found that PARP-1 is required for NLRP3 inflammasome assembly by regulating post-transcriptional levels of NLRP3 and ASC dimerization. Importantly, this PARP-1-regulated NLRP3 activation for NET formation was independent of inflammasome-mediated pyroptosis, because caspase-1 and gasdermin D processing as well as IL-1ß transcription and secretion remained intact upon PARP-1 inhibition in neutrophils. Accordingly, pharmacological inhibition or genetic ablation of caspase-1 and gasdermin D had no effect on NLRP3-mediated NET formation. Mechanistically, PARP-1 inhibition increased p38 MAPK activity, which was required for downmodulation of NLRP3 and NETs, because concomitant inhibition of p38 MAPK with PARP-1 restored NLRP3 activation and NET formation. Finally, mice undergoing bacterial peritonitis exhibited increased survival upon treatment with PARP-1 inhibitor, which correlated with increased leukocyte influx and improved intracellular bacterial clearance. Our findings reveal a noncanonical pyroptosis-independent role of NLRP3 in NET formation regulated by PARP-1 via p38 MAPK, which can be targeted to control NETosis in inflammatory diseases.

Mechanisms of myocardial toxicity of antitumor drugs and potential therapeutic strategies: A review of the literature.

With the successive development of chemotherapy drugs, good results have been achieved in clinical application. However, myocardial toxicity is the biggest challenge. Anthracyclines, immune checkpoint inhibitors, and platinum drugs are widely used. Targeted drug delivery, nanomaterials and dynamic imaging evaluation are all emerging research directions. This article reviews the recent literature on the use of targeted nanodrug delivery and imaging techniques to evaluate the myocardial toxicity of antineoplastic drugs, and discusses the potential mechanisms.

Exploring the shared genetic basis of major depressive disorder and frailty.

BACKGROUND: Major depressive disorder (MDD) and frailty impose substantial health and economic burdens. MDD is recognized as a significant risk factor for frailty, but the genetic associations between these conditions remain unclear. This study investigates the genetic correlation, shared pleiotropic loci, causal relationships, and comorbid genes between MDD and frailty. METHODS: The genetic correlation between MDD and frailty was assessed using linkage disequilibrium score regression (LDSC) based on data from genome-wide association studies (GWAS). A detailed analysis was performed to identify shared pleiotropic loci and causal relationships through cross-phenotype association tests and Mendelian randomization. Additionally, tissue enrichment analysis was conducted using stratified LDSC, gene-based associations with both conditions were assessed using Multimarker Analysis of Genomic Annotation (MAGMA), and pathway analysis of comorbid genes was performed using the g: GOSt tool. RESULTS: Our findings revealed a significant positive genetic correlation between MDD and frailty (rg = 0.65, P = 1.49E-219). We identified 57 shared risk SNPs between the two conditions, including 6 novel SNPs. Mendelian randomization analyses indicated robust causal effects of MDD on frailty and vice versa. Furthermore, we observed tissue-specific heritability enrichment in 9 brain tissues. By combining MAGMA and CPASSOC analyses, we identified 10 comorbid genes associated with both MDD and frailty, primarily involved in synapse formation, modulation, plasticity, and desaturase activity. CONCLUSION: This study provides strong evidence for a shared genetic basis between MDD and frailty. The identification of comorbid genes offers new insights into the mechanisms underlying the relationship between these conditions.