Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 µm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Advances in precision therapy of low-grade serous ovarian cancer: A review.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer that accounts for approximately 6% to 10% of serous ovarian cancers. The clinical treatment of LGSOC is similar to that of high-grade serous ovarian carcinoma, however, its clinical and molecular characteristics are different from those of high-grade serous ovarian carcinoma. This article reviews the research on gene diagnosis, surgical treatment, chemotherapy, and biological therapy of LGSOC, providing reference for clinical diagnosis and treatment of LGSOC. Surgery is the cornerstone of LGSOC treatment and maximum effort must be made to achieve R0 removal. Although LGSOC is not sensitive to chemotherapy, postoperative platinum-based combination chemotherapy remains the first-line treatment option for LGSOC. Additional clinical trials are needed to confirm the clinical benefits of chemotherapy and explore new chemotherapy protocols. Hormone and targeted therapies may also play important roles. Some patients, particularly those with residual lesions after treatment, may benefit from hormone maintenance therapy after chemotherapy. Targeted therapies, such as MEKi, show good application prospects and are expected to change the treatment pattern of LGSOC. Continuing to further study the genomics of LGSOC, identify its specific gene changes, and combine traditional treatment methods with precision targeted therapy based on second-generation sequencing may be the direction for LGSOC to overcome the treatment bottleneck. In future clinical work, comprehensive genetic testing should be carried out for LGSOC patients to accumulate data for future scientific research, in order to find more effective methods and drugs for the treatment of LGSOC.

Association of tet methylcytosine dioxygenase 2 and 5-hydroxymethylcytosine in endometrioid adenocarcinoma and its clinical significance.

BACKGROUND: Aberrant DNA methylation is a vital molecular alteration commonly detected in type I endometrial cancers (EC), and tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine (5hmC) play significant roles in DNA demethylation. However, little is known about the function and correlation of TET2 and 5hmC co-expressed in EC. This study intended to investigate the clinical significance of TET2 and 5hmC in EC. METHODS: The levels of TET2 and 5hmC were detected in 326 endometrial tissues by immumohistochemistry, and the correlation of their level was detected by Pearson analysis. The association between the levels of TET2 and 5hmC and clinicopathologic characteristics was analyzed. Prognostic value of TET2 and 5hmC was explored by Kaplan-Meier analysis. The Cox proportional hazard regression model was used for univariate and multivariate analyses. RESULTS: Based on the analysis results, TET2 protein level was positively correlated with 5hmC level in EC tissues (r = 0.801, P < 0.001). TET2+5hmC+ (high TET2 and high 5hmC) association was significantly associated with well differentiation, myometrial invasion, negative lymph node metastasis, and tumor stage in EC. Association of TET2 and 5hmC was confirmed as a prognostic factor (HR = 2.843, 95%CI = 1.226-3.605, P = 0.007) for EC patients, and EC patients with TET2-5hmC- level had poor overall survival. CONCLUSIONS: In summary, the association of TET2 and 5hmC was downregulated in EC tissues, and may be a potential poor prognostic indicator for EC patients. Combined detection of TET2 and 5hmC may be valuable for the diagnosis and prognosis of EC.

Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-ß/SMAD axis.

This study was aimed to investigate the preventive effects of N-acetyl-L-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-ß/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&E staining, immunohistochemical and Pizzolato method. The expression of TGF-ß/SMAD pathway related proteins (TGF-ß1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-ß1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-ß/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-ß/SMAD axis.

Modulation of the RAC1/MAPK/ERK signalling pathway by farnesyl diphosphate synthase regulates granulosa cells proliferation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex gynaecological endocrine disease that occurs in women of childbearing age. The pathogenesis of PCOS is still unclear and further exploration is needed. Here, proteomic analysis indicated that the expression of farnesyl diphosphate synthase (FDPS) protein in ovarian tissue of PCOS mice was significantly decreased. The purpose of this study is to investigate the relationship between potential biomarkers of PCOS and granulosa cells (GCs) function. The mechanisms by which FDPS affected the proliferation of granulosa cells were also explored both in vitro and in vivo. We found that knockdown of FDPS inhibited the proliferation of KGN (human ovarian granulosa cell line), while overexpression of FDPS had the opposite effect. FDPS activated Rac1 (Rac Family Small GTPase 1) activity and regulated MAPK/ERK signalling pathway, which affecting the proliferation of KGN cells significantly. In addition, treatment with the adeno-associated virus (AAV)-FDPS reverses the dehydroepiandrosterone (DHEA)-induced PCOS-phenotype in mice. Our data indicated that FDPS could regulate the proliferation of ovarian GCs by modulating MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases) pathway via activating Rac1 activity. These findings suggest that FDPS could be of great value for the regulation of ovarian granulosa cell function and the treatment of PCOS.

Transceptor NRT1.1 and receptor-kinase QSK1 complex controls PM H+-ATPase activity under low nitrate.

NRT1.1, a nitrate transceptor, plays an important role in nitrate binding, sensing, and nitrate-dependent lateral root (LR) morphology. However, little is known about NRT1.1-mediated nitrate signaling transduction through plasma membrane (PM)-localized proteins. Through in-depth phosphoproteome profiling using membranes of Arabidopsis roots, we identified receptor kinase QSK1 and plasma membrane H+-ATPase AHA2 as potential downstream components of NRT1.1 signaling in a mild low-nitrate (LN)-dependent manner. QSK1, as a functional kinase and molecular link, physically interacts with NRT1.1 and AHA2 at LN and specifically phosphorylates AHA2 at S899. Importantly, we found that LN, not high nitrate (HN), induces formation of the NRT1.1-QSK1-AHA2 complex in order to repress the proton efflux into the apoplast by increased phosphorylation of AHA2 at S899. Loss of either NRT1.1 or QSK1 thus results in a higher T947/S899 phosphorylation ratio on AHA2, leading to enhanced pump activity and longer LRs under LN. Our results uncover a regulatory mechanism in which NRT1.1, under LN conditions, promotes coreceptor QSK1 phosphorylation and enhances the NRT1.1-QSK1 complex formation to transduce LN sensing to the PM H+-ATPase AHA2, controlling the phosphorylation ratio of activating and inhibitory phosphorylation sites on AHA2. This then results in altered proton pump activity, apoplast acidification, and regulation of NRT1.1-mediated LR growth.

Immune-related cardiovascular toxicities of PD-1/PD-L1 inhibitors in solid tumors: an updated systematic review and meta-analysis.

Purpose: The objective of this study was to investigate the risk of cardiovascular toxicities related to PD-1/PD-L1 inhibitors in solid tumors. Methods: A literature search was performed following the participants, interventions, comparisons, outcomes, and study design (PICOS) principles, and the study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analysis was conducted using Review Manager version 5.4. Results: This meta-analysis included 69 randomized controlled trials (RCTs) divided into five groups based on the treatment regimens: PD-1/PD-L1 + chemotherapy versus chemotherapy, PD-1/PD-L1 versus chemotherapy, PD-1/PD-L1 versus placebo, PD-1/PD-L1 + CTLA-4 versus PD-1/PD-L1 and PD-1/PD-L1 + CTLA-4 versus chemotherapy. Compared to chemotherapy treatment alone, PD-1/PD-L1 +chemotherapy significantly increased the risk of hypertension [all-grade (OR = 1.27, 95% CI [1.05, 1.53], p = 0.01); grade 3-5 (OR = 1.36, 95% CI [1.04, 1.79], p = 0.03)], hypotension [all-grade (OR = 2.03, 95% CI [1.19, 3.45], p = 0.009); grade 3-5 (OR = 3.60, 95% CI [1.22, 10.60], p = 0.02)], arrhythmia [all-grade (OR = 1.53, 95% CI [1.02, 2.30], p = 0.04); grade 3-5 (OR = 2.91, 95% CI [1.33, 6.39], p = 0.008)] and myocarditis [all-grade (OR = 2.42, 95% CI [1.06, 5.54], p = 0.04)]. The risk of all-grade hypotension (OR = 2.87, 95% CI [1.26, 6.55], p = 0.01) and all-grade arrhythmia (OR = 2.03, 95% CI [1.13, 3.64], p = 0.02) significantly increased when treated with PD-1/PD-L1 inhibitors compared to the placebo. The risks of cardiovascular toxicities are significantly higher with PD-1+CTLA-4 compared to PD-1 alone (OR = 2.02, 95% CI [1.12, 3.66], p = 0.02). Conclusion: PD-1/PD-L1 inhibitor leads to an increased risk of cardiovascular toxicities, especially hypertension, hypotension, arrhythmia, and myocarditis.

Empagliflozin attenuates inflammation levels in autoimmune myocarditis through the STAT3 pathway and macrophage phenotype transformation.

OBJECTIVE: To investigate the anti-inflammatory actions and molecular mechanisms of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin on autoimmune myocarditis. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was constructed using peptides, and the therapeutic effects of empagliflozin on cardiac inflammation and fibrosis were observed using hematoxylin and eosin (HE), Sirius red staining, and Masson's trichome staining. Western blotting was used to identify the actions of empagliflozin on the surface marker expression levels of M2 macrophages and inflammatory factors. In vitro, experiments were completed using lentiviral overexpression of SGLT-2 in macrophages. Macrophage inflammation and anti-inflammatory models were constructed using lipopolysaccharide and interleukin-4, respectively. Enzyme-linked immunosorbent assay, immunofluorescence staining, and reverse-transcription polymerase chain reaction were applied to detect the effects of empagliflozin on the levels of inflammatory factors and macrophage surface markers. Western blotting was used to identify variability in SGLT-2 expression and the role of empagliflozin on the signal transducer and activator of the transcription 3 (STAT3) pathway. The Genomic Spatial Event 142564 dataset was studied in an EAM mouse model. We selected single-cell sequencing results from day 0 and day 21 of modeling to visualize differentially expressed genes. Immune cell infiltration correlation analysis was implemented to explore the expression of inflammatory factors and phenotypic markers. RESULTS: Empagliflozin increased the expression of the M2 macrophage surface marker CD206 and reduced the level of inflammatory factors in the EAM mouse model while reducing the levels of inflammation and fibrosis. In vitro experiments revealed that the phosphorylation of STAT3 pathway was enhanced after macrophages were polarized to M1 phenotype by LPS, the phosphorylation of STAT3 pathway was inhibited after empagliflozin intervention, and the levels of inflammatory factors were decreased. CONCLUSION: Empagliflozin can reduce the level of inflammation in autoimmune myocarditis through the STAT3 pathway and macrophage phenotype transformation. These results indicate the expression of SGLT-2 can be a target for autoimmune myocarditis therapy.

Photoresponsive metal-organic framework with combined photodynamic therapy and hypoxia-activated chemotherapy for the targeted treatment of rheumatoid arthritis.

Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA.

Exploring the induction of endometrial epithelial cell apoptosis in clinical-type endometritis in yaks through the cyt-c/caspase-3 signaling axis.

Endometritis is a significant contributor to reduced productivity in yaks in Tibet, China. The Cyt-c/Caspase-3 signaling axis plays a crucial role in the mitochondrial pathway that triggers cell apoptosis due to endogenous factors. In this study, we examined the endometrial epithelial tissue of yaks with endometritis using pathological examination, immunohistochemical analysis, TUNEL staining, qRT-PCR, and Western blot. The results indicated significant changes in the apoptotic factors of the Cyt-c/Caspase-3 signaling axis. The expression levels of Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 were significantly increased (P < 0.05), while the expression level of Bcl-2 was significantly decreased. Immunohistochemistry results revealed significant increase in Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 expression in the cytoplasm compared to the healthy group, except for Bcl-2, which showed a significant decrease. Pathological section analysis demonstrated that clinical endometritis in yaks led to structural damage, bleeding, congestion, and inflammatory cell infiltration in the endometrial epithelium. Our study findings indicated that clinical endometritis in yaks can modulate apoptosis of endometrial epithelial cells via the Cyt-c/Caspase-3 signaling pathway, resulting in different levels of damage. This research is pioneering in exploring cell apoptosis induced by clinical endometritis in yaks, offering novel insights and potential strategies for the future prevention and treatment of endometritis in yaks.

Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts.

BACKGROUND: Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. METHODS: We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. RESULTS: In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. CONCLUSIONS: We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.

Machine Learning Model of ResNet50-Ensemble Voting for Malignant-Benign Small Pulmonary Nodule Classification on Computed Tomography Images.

BACKGROUND: The early detection of benign and malignant lung tumors enabled patients to diagnose lesions and implement appropriate health measures earlier, dramatically improving lung cancer patients' quality of living. Machine learning methods performed admirably when recognizing small benign and malignant lung nodules. However, exploration and investigation are required to fully leverage the potential of machine learning in distinguishing between benign and malignant small lung nodules. OBJECTIVE: The aim of this study was to develop and evaluate the ResNet50-Ensemble Voting model for detecting the benign and malignant nature of small pulmonary nodules (<20 mm) based on CT images. METHODS: In this study, 834 CT imaging data from 396 patients with small pulmonary nodules were gathered and randomly assigned to the training and validation sets in an 8:2 ratio. ResNet50 and VGG16 algorithms were utilized to extract CT image features, followed by XGBoost, SVM, and Ensemble Voting techniques for classification, for a total of ten different classes of machine learning combinatorial classifiers. Indicators such as accuracy, sensitivity, and specificity were used to assess the models. The collected features are also shown to investigate the contrasts between them. RESULTS: The algorithm we presented, ResNet50-Ensemble Voting, performed best in the test set, with an accuracy of 0.943 (0.938, 0.948) and sensitivity and specificity of 0.964 and 0.911, respectively. VGG16-Ensemble Voting had an accuracy of 0.887 (0.880, 0.894), with a sensitivity and specificity of 0.952 and 0.784, respectively. CONCLUSION: Machine learning models that were implemented and integrated ResNet50-Ensemble Voting performed exceptionally well in identifying benign and malignant small pulmonary nodules (<20 mm) from various sites, which might help doctors in accurately diagnosing the nature of early-stage lung nodules in clinical practice.

MiR-525-5p inhibits diffuse large B cell lymphoma progression via the Myd88/NF-κB signaling pathway.

Diffuse large B-cell lymphoma (DLBCL) is a B-cell lymphoma with a high degree of aggressiveness. Recently, evidence has shown that miR-525-5p is decreased in DLBCL, suggesting its possible involvement in tumor progression. In this study, miR-525-5p suppressed proliferation, invasion and clonogenicity, and increased apoptosis of U2932 cells, whereas miR-525-5p silencing enhanced tumor cell growth. Next, miR-525-5p targets the 3'-UTR of Myd88, and Myd88 protein was increased in lymphoma tissues. Similar to the miR-525-5p mimic, Myd88 siRNA suppressed proliferation, invasion, and clonogenicity, and enhanced apoptosis of U2932 cells. We observed that Myd88 reversed the inhibitory effect of miR-525-5p on tumor cell growth by transfecting cells with miR-525-5p mimics alone or together with Myd88 overexpression vector. In addition, in vivo studies have shown that compared to the control group, U2932 cells with upregulated miR-525-5p expression have a reduced ability to induce tumor formation. In conclusion, our results demonstrate that miR-525-5p inhibits the progression of DLBCL through the Myd88/NF-κB pathway, which largely fills the gap of previous studies, and our results may provide a new reference for the targeted treatment of DLBCL.

Applications and Research Advances in the Delivery of CRISPR/Cas9 Systems for the Treatment of Inherited Diseases.

The rapid advancements in gene therapy have opened up new possibilities for treating genetic disorders, including Duchenne muscular dystrophy, thalassemia, cystic fibrosis, hemophilia, and familial hypercholesterolemia. The utilization of the clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) system has revolutionized the field of gene therapy by enabling precise targeting of genes. In recent years, CRISPR/Cas9 has demonstrated remarkable efficacy in treating cancer and genetic diseases. However, the susceptibility of nucleic acid drugs to degradation by nucleic acid endonucleases necessitates the development of functional vectors capable of protecting the nucleic acids from enzymatic degradation while ensuring safety and effectiveness. This review explores the biomedical potential of non-viral vector-based CRISPR/Cas9 systems for treating genetic diseases. Furthermore, it provides a comprehensive overview of recent advances in viral and non-viral vector-based gene therapy for genetic disorders, including preclinical and clinical study insights. Additionally, the review analyzes the current limitations of these delivery systems and proposes avenues for developing novel nano-delivery platforms.

Oncolytic virus oHSV2 combined with PD-1/PD-L1 inhibitors exert antitumor activity by mediating CD4 + T and CD8 + T cell infiltration in the lymphoma tumor microenvironment.

A novel therapeutic regimen showed that the oncolytic type II herpes simplex virus (oHSV2) was able to prevent colorectal cancer growth, recurrence, and metastasis. However, no study has yet explored whether oHSV2 has an impact on the development of diffuse large B-cell lymphoma (DLBCL). We chose the clinical chemotherapeutic drug doxorubicin (DOX) as a positive control to evaluate the effect of oHSV2 infection on the apoptotic, invasive, and proliferative capacity of DLBCL cells. We next further explored the therapeutic efficacy of oncolytic virus oHSV2 or DOX in DLBCL tumor bearing BALB/c mice, and evaluated the infiltration of CD8 + T cells and CD4 + T cells in tumor tissues. A pathological approach was used to explore the effects of oHSV2 on various organs of tumor bearing mice, including the heart, liver, and kidney. Next, SU-DHL-4 cells were co-cultured with cytotoxic T lymphocytes (CTLs) to mimic the tumor immune microenvironment (TME), to explore the impact of oHSV2 on the immune environment at the cellular level, and then analyzed the relationship between oHSV2 and the PD-1/PD-L1 immune-checkpoint. Subsequently, we further validated the efficacy of combined oHSV2 and PD-L1 treatment on transplanted tumor growth in mice at the in vivo level. DLBCL cells were sensitive to the action of the oncolytic virus oHSV2, and the decline in their proliferative activity showed a time-and dose-dependent manner. oHSV2 and DOX intervention preeminently increased the cell apoptosis, restrained cell proliferation and invasion, with the greatest changes occurring in response to oHSV2 infection. oHSV2 application effectively improved the immune status of the tumor microenvironment, favoring the invasion of CD8 + T and CD4 + T cells, thereby enhancing their antitumor effects. Besides, oHSV2 treatment has a safety profile in the organs of tumor bearing mice and indeed inhibits the PD-1/PD-L1 immune checkpoint in DLBCL. Interestingly, the combination of oHSV2 and PD-L1 antibodies results in more profound killing of DLBCL cells than oHSV2 infection alone, with a significant increase in the proportion of CD4 + T cells and CD8 + T cells. The antitumor effect was the best after combining oHSV2 and PD-L1 antibodies, suggesting that the combination therapy of oHSV2 and PD-L1 would have a better prospect for clinical application.

N-methyl-d-aspartate receptor 1 activation mediates cadmium-induced epithelial-mesenchymal transition in proximal tubular cells.

Cadmium (Cd) is a commonly found environmental pollutant and is known to damage multiple organs with kidneys being the most common one. N-methyl-d-aspartate receptor 1 (NMDAR1) is a ligand-gated ion channel that is highly permeable to calcium ion (Ca2+). Because Cd2+ and Ca2+ have structural and physicochemical similarities, whether and how Cd could interfere NMDAR1 function to cause renal epithelial cells dysfunction remains unknown. In this study, we investigated the role of NMDAR1 in Cd-induced renal damage and found that Cd treatment upregulated NMDAR1 expression and promoted epithelial-mesenchymal transition (EMT) in mouse kidneys in vivo and human proximal tubular epithelial HK-2 cells in vitro, which were accompanied with activation of the inositol-requiring enzyme 1 (IRE-1α) / spliced X box binding protein-1 (XBP-1s) pathway, an indicative of endoplasmic reticulum (ER) stress. Mechanistically, NMDAR1 upregulation by Cd promoted Ca2+ channel opening and Ca2+ influx, resulting in ER stress and subsequently EMT in HK-2 cells. Inhibition of NMDAR1 by pharmacological antagonist MK-801 significantly attenuated Cd-induced Ca2+ influx, ER stress, and EMT. Pretreatment with the IRE-1α/XBP-1s pathway inhibitor STF-083010 also restored the epithelial phenotype of Cd-treated HK-2 cells. Therefore, our findings suggest that NMDAR1 activation mediates Cd-induced EMT in proximal epithelial cells likely through the IRE-1α/XBP-1s pathway, supporting the idea that NMDAR1 could be a potential therapeutic target for Cd-induced renal damage.

Multifunctional nanoadjuvant-driven microenvironment modulation for enhanced photothermal immunotherapy in breast cancer.

Intracellular redox imbalance, achieved by exploiting the tumor microenvironment (TME), has emerged as a promising strategy for cancer therapy. In this study, we developed a multifunctional nanoadjuvant, termed GITFe/Z-HA, by modified a metal-organic backbone Fe/ZIF-8 with hyaluronic acid (HA) targeting. The nanocarriers were loaded with glucose oxidase (Gox), neoindocyanine green (IR820) and tilazamine (TPZ). This design aimed to achieve a cascade reaction within tumor cells, mediated by Gox, Fe3+, and IR820, which consumes intrinsic glucose and oxygen, leading to an elevated production of reactive oxygen species (ROS). This cascade reaction creates a hypoxic environment conducive for TPZ to exert its therapeutic action. Consequently, the combination of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy demonstrates a good synergistic effect. Moreover, the imbalanced ROS/glutathione (GSH) induced by this treatment approach, along with PTT, promote immunogenic cell death (ICD). This ICD triggers the release of damage-related molecular patterns and CD8+ lymphocyte infiltration sensitizes the immune checkpoint blockade (αPD-L1) response, thereby eliciting a systemic anti-tumor immune response. Collectively, this comprehensive treatment regimen, driven by environmentally stimulated multiple pathways, overcomes the limitations of single therapeutic modalities, thereby improving tumor outcomes. Additionally, these findings provide valuable insights for strategies aimed at modulating the tumor immune microenvironment.

The development and validation of a non-invasive prediction model of hyperuricemia based on modifiable risk factors: baseline findings of a health examination population cohort.

This study aims to establish a simple and non-invasive risk prediction model for hyperuricemia in Chinese adults based on modifiable risk factors. In 2020-2021, the baseline survey of the Beijing Health Management Cohort (BHMC) was conducted in Beijing city among the health examination population. Diverse life-style risk factors including dietary patterns and habits, cigarette smoking, alcohol intake, sleep duration and cell-phone use were collected. We developed hyperuricemia prediction models using three machine-learning techniques, namely logistic regression (LR), random forest (RF), and XGBoost. Performances in discrimination, calibration, and clinical applicability of the three methods were compared. Decision curve analysis (DCA) was used to assess the model's clinical usefulness. A total of 74 050 people were included in the study, of whom 55 537 (75%) were randomly selected into the training set and the other 18 513 (25%) were in the validation set. The prevalence of HUA was 38.43% in men and 13.29% in women. The XGBoost model has better performance than the LR and RF models. The area under the curve (AUC) (95% CI) in the training set for the LR, RF and XGBoost models were 0.754 (0.750-0.757), 0.844 (0.841-0.846) and 0.854 (0.851-0.856), respectively. The XGBoost model had a higher classification accuracy of 0.774 than the logistic (0.592) and RF (0.767) models. The AUC (95% CI) values in the validation set for the LR, RF and XGBoost models were 0.758 (0.749-0.765), 0.809 (0.802-0.816) and 0.820 (0.813-0.827), respectively. As demonstrated by the DCA curves, all the three models could bring net benefits within the appropriate threshold probability. XGBoost had better discrimination and accuracy. Various modifiable risk factors included in the model were helpful in facilitating the easy identification and life-style interventions of the HUA high-risk population.

A Label-Free and Antibody-Free Molecularly Imprinted Polymer-Based Impedimetric Sensor for NSCLC-Cells-Derived Exosomes Detection.

In this study, a label-free and antibody-free impedimetric biosensor based on molecularly imprinting technology for exosomes derived from non-small-cell lung cancer (NSCLC) cells was established. Involved preparation parameters were systematically investigated. In this design, with template exosomes anchored on a glassy carbon electrode (GCE) by decorated cholesterol molecules, the subsequent electro-polymerization of APBA and elution procedure afforded a selective adsorption membrane for template A549 exosomes. The adsorption of exosomes caused a rise in the impedance of the sensor, so the concentration of template exosomes can be quantified by monitoring the impedance of GCEs. Each procedure in the establishment of the sensor was monitored with a corresponding method. Methodological verification showed great sensitivity and selectivity of this method with an LOD = 2.03 × 103 and an LOQ = 4.10 × 104 particles/mL. By introducing normal cells and other cancer cells derived exosomes as interference, high selectivity was proved. Accuracy and precision were measured, with an obtained average recovery ratio of 100.76% and a resulting RSD of 1.86%. Additionally, the sensors' performance was retained at 4 °C for a week or after undergoing elution and re-adsorption cycles seven times. In summary, the sensor is competitive for clinical translational application and improving the prognosis and survival for NSCLC patients.