Gut mechanoimmunology: Shaping immune response through physical cues.

The gut immune system embodies a complex interplay between the gut mucosal barrier, the host's immune cells, and gut microbiota. These components exist within a dynamic environment characterized by a variety of physical cues, e.g., compression, tension, shear stress, stiffness, and viscoelasticity. The physical cues can be modified under specific pathological conditions. Given their dynamic nature, comprehending the specific effects of these physical cues on the gut immune system is critical for pathological and therapeutic studies of intestinal immune-related diseases. This review aims to discuss how physical cues influence gut immunology by affecting the gut mucosal barrier, host immune cells, and gut microbiota, defining this concept as gut mechanoimmunology. This review seeks to highlight that an enhanced understanding of gut mechanoimmunology carries therapeutic implications, not only for intestinal diseases but also for extraintestinal diseases.

Synergistic Effects of Matrix Biophysical Properties on Gastric Cancer Cell Behavior via Integrin-Mediated Cell-ECM Interactions.

The biophysical properties of the extracellular matrix (ECM) play a pivotal role in modulating cancer progression via cell-ECM interactions. However, the biophysical properties specific to gastric cancer (GC) remain largely unexplored. Pertinently, GC ECM shows significantly heterogeneous metamorphoses, such as matrix stiffening and intricate restructuring. By combining collagen I and alginate, this study designs an in vitro biomimetic hydrogel platform to independently modulate matrix stiffness and structure across a physiological stiffness spectrum while preserving consistent collagen concentration and fiber topography. With this platform, this study assesses the impacts of matrix biophysical properties on cell proliferation, migration, invasion, and other pivotal dynamics of AGS. The findings spotlight a compelling interplay between matrix stiffness and structure, influencing both cellular responses and ECM remodeling. Furthermore, this investigation into the integrin/actin-collagen interplay reinforces the central role of integrins in mediating cell-ECM interactions, reciprocally sculpting cell conduct, and ECM adaptation. Collectively, this study reveals a previously unidentified role of ECM biophysical properties in GC malignant potential and provides insight into the bidirectional mechanical cell-ECM interactions, which may facilitate the development of novel therapeutic horizons.

A novel nomogram based on inflammation biomarkers for predicting radiation cystitis in patients with local advanced cervical cancer.

BACKGROUNDS: Platelet-to-albumin ratio (PAR) is a new systemic inflammatory prognostic indicator associated with many inflammatory diseases. However, its role in radiation cystitis (RC) is obscure. This study aimed to explore whether PAR could be used as an effective parameter for predicting the RC risk in local advanced cervical cancer (CC) treated with radiotherapy. METHODS: A total of 319 local advanced CC patients who received radical radiotherapy at Fujian Cancer Hospital were enrolled between December 2018 and January 2021. Demographics and clinical parameters were retrospectively analyzed. Univariate and multivariate analyses were used to identify the risk factors for RC. Backward and stepwise regression was applied to construct two monograms-one with primary significant factors and the other with extra inflammatory biomarkers. A DeLong test was applied to compare the prediction abilities of two nomograms. Calibration curves and decision curve analysis (DCA) evaluated its prediction consistency, discrimination ability, and clinical net benefit. RESULTS: Univariate analysis showed that age, tumor size, stage, total radiation dose, pelvic radiation dose, Systemic Immune-Inflammation Index (SII), platelet-to-lymphocyte ratio (PLR), and PAR were significantly associated with RC occurrence (all p < 0.05). Multivariate analyses indicated that age, tumor size, stage, total radiation dose, and PAR were independent factors (all p < 0.05). Then, the area under curve (AUC) value of the nomogramSII+PAR was higher (AUC = 0.774) compared to that of the baseline nomogram (AUC = 0.726) (pDelong = 0.02). Also, the five-cross validation confirmed the stability of the nomogramSII+PAR. Moreover, the calibration curve and DCA exhibited the nomograms' good prediction consistency and clinical practicability. CONCLUSIONS: PAR and SII could be valued for CC patients who are treated with radiation therapy. The nomogram based on PAR and SII could stratify patients who need extra intervention and nursing care to prevent bladder radiation damage and improve patients' quality of life.

Humans vs. Fungi: An Overview of Fungal Pathogens against Humans.

Human fungal diseases are infections caused by any fungus that invades human tissues, causing superficial, subcutaneous, or systemic diseases. Fungal infections that enter various human tissues and organs pose a significant threat to millions of individuals with weakened immune systems globally. Over recent decades, the reported cases of invasive fungal infections have increased substantially and research progress in this field has also been rapidly boosted. This review provides a comprehensive list of human fungal pathogens extracted from over 850 recent case reports, and a summary of the relevant disease conditions and their origins. Details of 281 human fungal pathogens belonging to 12 classes and 104 genera in the divisions ascomycota, basidiomycota, entomophthoromycota, and mucoromycota are listed. Among these, Aspergillus stands out as the genus with the greatest potential of infecting humans, comprising 16 species known to infect humans. Additionally, three other genera, Curvularia, Exophiala, and Trichophyton, are recognized as significant genera, each comprising 10 or more known human pathogenic species. A phylogenetic analysis based on partial sequences of the 28S nrRNA gene (LSU) of human fungal pathogens was performed to show their phylogenetic relationships and clarify their taxonomies. In addition, this review summarizes the recent advancements in fungal disease diagnosis and therapeutics.

A comprehensive Mendelian randomization study highlights the relationship between psychiatric disorders and non-tumor gastrointestinal diseases.

Objective: Previous observational studies revealed the potential correlation between psychiatric disorders (PDs) and non-tumor gastrointestinal diseases (NTGDs). However, their causation remains unclear. Methods: We explored the causal relationship between PDs and NTGDs through bidirectional two-sample Mendelian randomization (MR) study. Large-scale genome-wide association study (GWAS) summary statistics and bidirectional two-sample MR study were used to assess the causality between PDs and NTGDs. Multiple sensitivity analyses were used to identify the robustness of our results. Results: We found that major depression was causally associated with increased risk of gastric ulcer (OR: 1.812, 95% CI: 1.320-2.487, p < 0.001) and irritable bowel syndrome (OR: 1.645, 95% CI: 1.291-2.097, p < 0.001). Meanwhile, genetically predicted gastroesophageal reflux disease contributed to the increased risk of anxiety disorders (OR: 1.425, 95% CI: 1.295-1.568, p < 0.001), and ulcerative colitis was related to increased risk of attention deficit/hyperactivity disorder (OR: 1.042, 95% CI: 1.008-1.078, p = 0.0157). Conclusion: Our study provided MR evidence to support the close causality and identify the specific direction between eight PDs and eight common NTGDs. Experimental studies to further examine the causality, underlying mechanism, and therapeutic potential of PDs and NTGDs are required.

Role of durotomy on function outcome, tissue sparing, inflammation, and tissue stiffness after spinal cord injury in rats.

Currently, there is a lack of effective treatments for spinal cord injury (SCI), a debilitating medical condition associated with enduring paralysis and irreversible neuronal damage. Extradural decompression of osseous as well as soft tissue components has historically been the principal objective of surgical procedures. Nevertheless, this particular surgical procedure fails to tackle the intradural compressive alterations that contribute to secondary SCI. Here, we propose an early intrathecal decompression strategy and evaluate its role on function outcome, tissue sparing, inflammation, and tissue stiffness after SCI. Durotomy surgery significantly promoted recovery of hindlimb locomotor function in an open-field test. Radiological analysis suggested that lesion size and tissue edema were significantly reduced in animals that received durotomy. Relative to the group with laminectomy alone, the animals treated with a durotomy had decreased cavitation, scar formation, and inflammatory responses at 4 weeks after SCI. An examination of the mechanical properties revealed that durotomy facilitated an expeditious restoration of the injured tissue's elastic rigidity. In general, early decompressive durotomy could serve as a significant strategy to mitigate the impairments caused by secondary injury and establish a more conducive microenvironment for prospective cellular or biomaterial transplantation.

Exploring ascomycete diversity in Yunnan II: Introducing three novel species in the suborder Massarineae (Dothideomycetes, Pleosporales) from fern and grasses.

This article presents the results of an ongoing inventory of Ascomycota in Yunnan, China, carried out as part of the research project series "Exploring ascomycete diversity in Yunnan". From over 100 samples collected from diverse host substrates, microfungi have been isolated, identified and are currently being documented. The primary objective of this research is to promote the discovery of novel taxa and explore the ascomycete diversity in the region, utilising a morphology-phylogeny approach. This article represents the second series of species descriptions for the project and introduces three undocumented species found in the families Bambusicolaceae, Dictyosporiaceae and Periconiaceae, belonging to the suborder Massarineae (Pleosporales, Dothideomycetes). These novel taxa exhibit typical morphological characteristics of Bambusicola, Periconia and Trichobotrys, leading to their designation as Bambusicolahongheensis, Periconiakunmingensis and Trichobotryssinensis. Comprehensive multigene phylogenetic analyses were conducted to validate the novelty of these species. The results revealed well-defined clades that are clearly distinct from other related species, providing robust support for their placement within their respective families. Notably, this study unveils the phylogenetic affinity of Trichobotrys within Dictyosporiaceae for the first time. Additionally, the synanamorphism for the genus Trichobotrys is also reported for the first time. Detailed descriptions, illustrations and updated phylogenies of the novel species are provided, and thus presenting a valuable resource for researchers and mycologists interested in the diversity of ascomycetes in Yunnan. By enhancing our understanding of the Ascomycota diversity in this region, this research contributes to the broader field of fungal taxonomy and their phylogenetic understanding.

Enhanced adsorption of Pb2+ by the oxygen-containing functional groups enriched activated carbon.

Lead is one of the primary pollutants found in water and poses significant toxicity risks to humans; thus, it is necessary to investigate techniques for removing it economically and efficiently. In order to enhance the removal capacity of Pb2+, coconut shell-based activated carbon (AC) was modified with introducing oxygen-containing functional groups (OFGs) via nitric acid (HNO3) or hydrogen peroxide (H2O2) modification in this study. The characterization results show that after oxidation treatment, the content of OFGs increased, and the textural properties of the samples do not change significantly. This indicates that the modification conditions used in this study effectively introduced OFGs while avoiding the adverse effects on physical adsorption ability of AC caused by oxidation treatment. The Pb2+ adsorption capacities of the AC modified with 10 M HNO3 and 30 wt.% H2O2 were 4.26 and 3.64 times that of the pristine AC, respectively. The experimental data can be well fitted using the Langmuir isotherm model and the Elovich kinetic model, suggesting that the adsorption of Pb2+ on AC belongs to single-layer adsorption, and chemical adsorption dominates the adsorption process. In summary, the hydrothermal-assisted HNO3/H2O2-modified coconut shell-based AC shows great potential in efficiently removing Pb2+ from solutions, offering a solution for utilizing coconut shell waste.

PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

[Corrigendum] Induction of microRNA­let­7a inhibits lung adeno-carcinoma cell growth by regulating cyclin D1.

After the publication of the article, an interested reader drew to the authors' attention that, in the western blots shown in Fig. 5C and D, a pair of data panels were inadvertently duplicated comparing between panels (C) and (D); in addition, the cell migration data shown in Fig. 7F on p. 1852 were selected incorrectly. The authors have examined their original data, and realize that these errors arose inadvertently as a consequence of their mishandling of their data. The revised versions of Figs. 5 and 7, featuring the corrected data for the caspase-8 experiment in Fig. 5C and alternative data for the cell migration assay experiments in Fig. 7F, are shown on the next two pages. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this. Furthermore, the authors apologize to the readership for any inconvenience caused. [Oncology Reports 40: 1843-1854, 2018; DOI: 10.3892/or.2018.6593].

On the electrokinetic remediation of Pb-contaminated soil: A coupled electro-transport-reaction modelling study based on chemical reaction kinetics.

The accumulation of lead (Pb) in soil resulted from industrialization and urbanization poses a threat to human health and the ecosystem. This study proposes a mathematical model for Pb migration and transformation in soil porous media, aiming to guide the design of electrokinetic remediation schemes for Pb-contaminated soils. To improve the validity of the model, the chemical reactions considered in the model are all based on chemical reaction kinetics, which were usually overlooked for model simplification. The model quantitatively describes various physical and chemical processes of Pb at the soil-pore fluid interface and in the pore fluid, including diffusion, electromigration, electroosmosis, electrolytic water reaction, precipitation, adsorption/desorption, protonation/deprotonation reaction, and water self-ionization reaction. The numerical results show that the pH value is a key factor affecting the distribution of Pb in the soil and determining the removal efficiency of Pb. The effects of different enhancement methods on Pb concentration distribution and removal efficiency were evaluated with this model. It was found that placing a cation exchange membrane at the cathode boundary while using 0.01 M nitric acid as anode electrolyte can effectively improve Pb removal efficiency from 3.9% to 93.6%. The developed model can be used to guide the design of the enhanced electrokinetic remediation schemes.

Eye-Hand Typing: Eye Gaze Assisted Finger Typing via Bayesian Processes in AR.

Nowadays, AR HMDs are widely used in scenarios such as intelligent manufacturing and digital factories. In a factory environment, fast and accurate text input is crucial for operators' efficiency and task completion quality. However, the traditional AR keyboard may not meet this requirement, and the noisy environment is unsuitable for voice input. In this article, we introduce Eye-Hand Typing, an intelligent AR keyboard. We leverage the speed advantage of eye gaze and use a Bayesian process based on the information of gaze points to infer users' text input intentions. We improve the underlying keyboard algorithm without changing user input habits, thereby improving factory users' text input speed and accuracy. In real-time applications, when the user's gaze point is on the keyboard, the Bayesian process can predict the most likely characters, vocabulary, or commands that the user will input based on the position and duration of the gaze point and input history. The system can enlarge and highlight recommended text input options based on the predicted results, thereby improving user input efficiency. A user study showed that compared with the current HoloLens 2 system keyboard, Eye-Hand Typing could reduce input error rates by 28.31 % and improve text input speed by 14.5%. It also outperformed a gaze-only technique, being 43.05% more accurate and 39.55% faster. And it was no significant compromise in eye fatigue. Users also showed positive preferences.

Semantics Disentangling for Cross-Modal Retrieval.

Cross-modal retrieval (e.g., query a given image to obtain a semantically similar sentence, and vice versa) is an important but challenging task, as the heterogeneous gap and inconsistent distributions exist between different modalities. The dominant approaches struggle to bridge the heterogeneity by capturing the common representations among heterogeneous data in a constructed subspace which can reflect the semantic closeness. However, insufficient consideration is taken into the fact that learned latent representations are actually heavily entangled with those semantic-unrelated features, which obviously further compounds the challenges of cross-modal retrieval. To alleviate the difficulty, this work makes an assumption that the data are jointly characterized by two independent features: semantic-shared and semantic-unrelated representations. The former presents characteristics of consistent semantics shared by different modalities, while the latter reflects the characteristics with respect to the modality yet unrelated to semantics, such as background, illumination, and other low-level information. Therefore, this paper aims to disentangle the shared semantics from the entangled features, andthus the purer semantic representation can promote the closeness of paired data. Specifically, this paper designs a novel Semantics Disentangling approach for Cross-Modal Retrieval (termed as SDCMR) to explicitly decouple the two different features based on variational auto-encoder. Next, the reconstruction is performed by exchanging shared semantics to ensure the learning of semantic consistency. Moreover, a dual adversarial mechanism is designed to disentangle the two independent features via a pushing-and-pulling strategy. Comprehensive experiments on four widely used datasets demonstrate the effectiveness and superiority of the proposed SDCMR method by achieving a new bar on performance when compared against 15 state-of-the-art methods.

In vivo PSC differentiation as a platform to identify factors for improving the engraftability of cultured muscle stem cells.

Producing an adequate number of muscle stem cells (MuSCs) with robust regenerative potential is essential for the successful cell therapy of muscle-wasting disorders. We have recently developed a method to produce skeletal myogenic cells with exceptional engraftability and expandability through an in vivo pluripotent stem cell (PSC) differentiation approach. We have subsequently mapped engraftment and gene expression and found that leukemia inhibitory factor receptor (Lifr) expression is positively correlated with engraftability. We therefore investigated the effect of LIF, the endogenous ligand of LIFR, on cultured MuSCs and examined their engraftment potential. We found that LIF-treated MuSCs exhibited elevated expression of PAX7, formed larger colonies from single cells, and favored the retention of PAX7+ "reserve cells" upon myogenic differentiation. This suggested that LIF promoted the maintenance of cultured MuSCs at a stem cell stage. Moreover, LIF enhanced the engraftment capability of MuSCs that had been expanded in vitro for 12 days by 5-fold and increased the number of MuSCs that repopulated the stem cell pool post-transplantation. These results thereby demonstrated the effectiveness of our in vivo PSC differentiation platform to identify positive regulators of the engraftability of cultured MuSCs.

The management of uterine tumor resembling an ovarian sex cord tumor (UTROSCT): case series and literature review.

AIMS: To present a case series of 11 rare uterine tumors resembling ovarian sex cord tumors (UTROSCTs), and review the literature on this topic to offer up-to-date treatment management for UTROSCTs. METHOD: Eight cases from Fujian Cancer Hospital between January 2017 and May 2023 and three patients from Fujian Union Hospital between October 2012 and October 2020 were retrospectively reviewed. All cases were pathologically confirmed as UTROSCTs by two senior and experienced pathologists. Clinical behaviors, medical data, histopathological features, therapy approaches, and survival outcomes were discussed. RESULTS: The median age at initial diagnosis was 53 years (29-70 years). 3 (27.3%) patients were under 40. Seven cases presented with abnormal vaginal bleeding, one with menstrual disorder, one with abnormal vaginal secretion, and two patients were accidentally found by physical examination without any symptoms. Three patients were initially misdiagnosed with endometrial cancer by MRI. Curettage was performed in all cases. Nine of them were well diagnosed by routine curettage, except for two samples, which were identified after surgery. Immunohistochemical biomarkers, such as CD99, Desmin, WT-1, CK, Vimentin, SMA, α-Inhibin, Ki67, CD56, ER, PR, and CR, tend to be positive in UTRO SCs patients. Six patients underwent hysterectomy with bilateral salpingo-oophorectomy. Two cases received a radical hysterectomy with bilateral salpingo-oophorectomy, retroperitoneal lymph node dissection, and omentum dissection. Three UTROSCTs were under observation after mass resection. The median PFS was 24 months (range 1-125 months). CONCLUSION: UTROSCT is a rare mesenchymal tumor with low malignant potential. Treatment modalities should be carefully considered to balance the therapy outcomes and patient needs. Surgery conservative management might be suitable for young women with fertility desires.

m6A-methylated KCTD21-AS1 regulates macrophage phagocytosis through CD47 and cell autophagy through TIPR.

Blocking immune checkpoint CD47/SIRPα is a useful strategy to engineer macrophages for cancer immunotherapy. However, the roles of CD47-related noncoding RNA in regulating macrophage phagocytosis for lung cancer therapy remain unclear. This study aims to investigate the effects of long noncoding RNA (lncRNA) on the phagocytosis of macrophage via CD47 and the proliferation of non-small cell lung cancer (NSCLC) via TIPRL. Our results demonstrate that lncRNA KCTD21-AS1 increases in NSCLC tissues and is associated with poor survival of patients. KCTD21-AS1 and its m6A modification by Mettl14 promote NSCLC cell proliferation. miR-519d-5p gain suppresses the proliferation and metastasis of NSCLC cells by regulating CD47 and TIPRL. Through ceRNA with miR-519d-5p, KCTD21-AS1 regulates the expression of CD47 and TIPRL, which further regulates macrophage phagocytosis and cancer cell autophagy. Low miR-519d-5p in patients with NSCLC corresponds with poor survival. High TIPRL or CD47 levels in patients with NSCLC corresponds with poor survival. In conclusion, we demonstrate that KCTD21-AS1 and its m6A modification promote NSCLC cell proliferation, whereas miR-519d-5p inhibits this process by regulating CD47 and TIPRL expression, which further affects macrophage phagocytosis and cell autophagy. This study provides a strategy through miR-519-5p gain or KCTD21-AS1 depletion for NSCLC therapy by regulating CD47 and TIPRL.

Development of a novel prognostic signature based on single-cell combined bulk RNA analysis in breast cancer.

BACKGROUND: Breast cancer (BC), a malignant tumor, is a significant cause of death and disability among women globally. Recent research indicates that copy number variation plays a crucial role in tumor development. In this study, we employed the Single-Cell Variational Aneuploidy Analysis (SCEVAN) algorithm to differentiate between malignant and non-malignant cells, aiming to identify genetic signatures with prognostic relevance for predicting patient survival. METHODS: We analyzed gene expression profiles and associated clinical data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Using the SCEVAN algorithm, we distinguished malignant from non-malignant cells and investigated cellular interactions within the tumor microenvironment (TME). We categorized TCGA samples based on differentially expressed genes (DEGs) between these cell types. Subsequent Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted. Additionally, we developed polygenic models for the DEGs using least absolute shrinkage and selection operator-penalized Cox regression analysis. To assess the prognostic accuracy of these characteristics, we generated Kaplan-Meier and receiver operating characteristic curves from training and validation datasets. We also monitored the expression variations of prognostic genes across the pseudotime of malignant cells. Patients were divided into high-risk and low-risk groups based on median risk scores to compare their TME and identify potential therapeutic agents. Lastly, polymerase chain reaction was used to validate seven pivotal genes. RESULTS: The SCEVAN algorithm identified distinct malignant and non-malignant cells in GSE180286. Cellchat analysis revealed significantly increased cellular communication, particularly between fibroblasts, endothelial cells and malignant cells. The DEGs were predominantly involved in immune-related pathways. TCGA samples were classified into clusters A and B based on these genes. Cluster A, enriched in immune pathways, was associated with poorer prognosis, whereas cluster B, predominantly involved in circadian rhythm pathways, showed better outcomes. We constructed a 14-gene prognostic signature, validated in a 1:1 internal TCGA cohort and external GEO datasets (GSE42568 and GSE146558). Kaplan-Meier analysis confirmed the prognostic signature's accuracy (p < 0.001). Receiver operating characteristic curve analysis demonstrated the predictive reliability of these prognostic features. Single-cell pseudotime analysis with monocle2 highlighted the distinct expression trends of these genes in malignant cells, underscoring the intratumoral heterogeneity. Furthermore, we explored the differences in TME between high- and low-risk groups and identified 16 significantly correlated drugs. CONCLUSION: Our findings suggest that the 14-gene prognostic signature could serve as a novel biomarker for forecasting the prognosis of BC patients. Additionally, the immune cells and pathways in different risk groups indicate that immunotherapy may be a crucial component of treatment strategies for BC patients.

An Integrated Network Pharmacology and RNA-seq Approach for Exploring the Protective Effect of Andrographolide in Doxorubicin-Induced Cardiotoxicity.

PURPOSE: Doxorubicin (Dox) is clinically limited due to its dose-dependent cardiotoxicity. Andrographolide (Andro) has been confirmed to exert cardiovascular protective activities. This study aimed to investigate protective effects of Andro in Dox-induced cardiotoxicity (DIC). METHODS: The cardiotoxicity models were induced by Dox in vitro and in vivo. The viability and apoptosis of H9c2 cells and the myocardial function of c57BL/6 mice were accessed with and without Andro pretreatment. Network pharmacology and RNA-seq were employed to explore the mechanism of Andro in DIC. The protein levels of Bax, Bcl2, NLRP3, Caspase-1 p20, and IL-1ß were qualified as well. RESULTS: In vitro, Dox facilitated the downregulation of cell viability and upregulation of cell apoptosis, after Andro pretreatment, the above symptoms were remarkably reversed. In vivo, Andro could alleviate Dox-induced cardiac dysfunction and apoptosis, manifesting elevation of LVPWs, LVPWd, EF% and FS%, suppression of CK, CK-MB, c-Tnl and LDH, and inhibition of TUNEL-positive cells. Using network pharmacology, we collected and visualized 108 co-targets of Andro and DIC, which were associated with apoptosis, PI3K-AKT signaling pathway, and others. RNA-seq identified 276 differentially expressed genes, which were enriched in response to oxidative stress, protein phosphorylation, and others. Both network pharmacology and RNA-seq analysis identified Tap1 and Timp1 as key targets of Andro in DIC. RT-QPCR validation confirmed that the mRNA levels of Tap1 and Timp1 were consistent with the sequenced results. Moreover, the high expression of NLRP3, Caspase-1 p20, and IL-1ß in the Dox group was reduced by Andro. CONCLUSIONS: Andro could attenuate DIC through suppression of Tap1 and Timp1 and inhibition of NLRP3 inflammasome activation, serving as a promising cardioprotective drug.

Subtype recognition and identification of a prognosis model characterized by antibody-dependent cell phagocytosis-related genes in breast cancer.

BACKGROUND: Breast cancer (BC) is a heterogeneous tumor with a variety of etiology and clinical features. Antibody-dependent cell phagocytosis (ADCP) is the last step of immune checkpoint inhibition (ICI), and macrophages detect and recognize tumor cells, then destroy and engulf tumor cells. Despite the large number, negative regulators that inhibit phagocytic activity are still a key obstacle to the full efficacy of ICI. PATIENTS AND METHODS: An ADCP-related risk score prognostic model for risk stratification as well as prognosis prediction was established in the Cancer Genome Atlas (TCGA) cohort. The predictive value of ADCP risk score in prognosis and immunotherapy was also further validated in the TCGA along with International Cancer Genome Consortium cohorts. To promote the clinical application of the risk score, a nomogram was established, with its effectiveness verified by different methods. RESULTS: In this study, the genes collected from previous studies were defined as ADCP-related genes. In BC patients, two ADCP-related subtypes were identified. The immune characteristics and prognostic stratification were significant different between them. CONCLUSIONS: We identified two subtypes associated with ADCP gene expression in breast cancer. They have significant differences in immune cells, molecular functions, HLA family genes, immune scores, stromal scores, and inflammatory gene expression, which have important guiding significance for the selection of clinical treatment methods. At the same time, we constructed a risk model based on ADCP, and the risk score can be used as a good indicator of prognosis, providing potential therapeutic advantages for chemotherapy and immunotherapy, thus helping the clinical decision-making of BC patients.