Serum amyloid A contributes to radiation-induced lung injury by activating macrophages through FPR2/Rac1/NF-κB pathway.

Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1ß, IL-6, TGF-ß1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.

[Comparison of efficacy and safety of immunosuppressive therapy and rituximab targeting therapy in idiopathic membranous nephropathy].

Objective To assess the efficacy and safety of three treatment modalities (rituximab targeted B-cell therapy, calcium-phosphate inhibitor in conjunction with low-dose corticosteroids, and full-dose corticosteroids combined with cyclophosphamide) for patients at intermediate or high risk of idiopathic membranous nephropathy (IMN) and to analyze the factors impacting the remission rates of IMN. Methods A retrospective cohort study was conducted to analyze patients diagnosed with IMN in our nephrology department via renal biopsy, identifying a total of 148 patients at intermediate or high risk. These patients were categorized into three treatment groups: a RTX group with 60 patients receiving rituximab, a CNI group with 42 patients receiving calcineurin inhibitors, and a CTX group with 46 patients received cyclophosphamide. Baseline measurements of 24-hour urine protein, serum albumin, blood creatinine, uric acid, estimated glomerular filtration rate (eGFR), and serum anti-phospholipase A2 receptor antibody levels were recorded at the onset of the follow-up. Subsequently, changes in 24-hour urine protein, eGFR, remission rates, and occurrence of adverse events among the three patient groups were compared at 6, 12, and 18 months post-treatment. Moreover, COX regression analysis was employed to ascertain factors influencing the remission rate of IMN. Results At the outset of the follow-up period, no significant difference existed in baseline characteristics such as gender, age, 24-hour urine protein quantification, serum albumin, serum creatinine, uric acid, eGFR, serum anti-PLA2R antibody levels, body mass index (BMI), and systolic blood pressure among the patients, indicating the comparability of three groups. After 6 months, there were no notable changes in 24-hour urine protein quantification and eGFR among the three groups; however, remission rates in the RTX and CTX groups were lower than those in the CNI group. By the 12-month mark, 24-hour urine protein quantification in the RTX group significantly decreased compared to the CTX group, with overall remission rates showing no significant differences among the three groups. By the 18-month milestone, 24-hour urine protein quantification in the RTX group remained notably lower than that in the CTX group, with significantly higher eGFR levels. Additionally, the CTX group exhibited lower 24-hour urine protein quantification compared to the CNI group, with both RTX and CTX groups displaying higher remission rates than the CNI group. Predominant adverse reactions in the RTX group included infusion reactions and infections, whereas the CNI group were associated with metabolic syndrome and elevated serum creatinine, and the CTX group primarily experienced hepatic dysfunction. Multifactorial COX regression analysis revealed an association between baseline anti-PLA2R antibodies and remission rates of IMN (HR=1.162, 95% CI 1.078-1.249). Conclusion RTX therapy for IMN exhibits a gradual onset of action, boasting a superior disease remission rate at 18 months in comparison to CNI. It demonstrates a similarity to CTX in this aspect and offers prolonged maintenance of remission. Conversely, CNI demonstrates a rapid onset of action but poses a risk of exacerbating renal impairment in patients. Notably, elevated levels of serum anti-PLA2R antibodies emerge as an independent risk factor influencing remission in IMN.

A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target.

Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

The anti-tumor effects of cosmosiin through regulating AhR/CYP1A1-PPARγ in breast cancer.

Breast cancer is one of the threatening malignant tumors with the highest mortality and incidence rate over the world. There are a lot of breast cancer patients dying every year due to the lack of effective and safe therapeutic drugs. Therefore, it is highly necessary to develop more effective drugs to overcome breast cancer. As a glycoside derivative of apigenin, cosmosiin is characterized by low toxicity, high water solubility, and wide distribution in nature. Additionally, cosmosiin has been shown to perform anti-tumor effects in cervical cancer, hepatocellular carcinoma and melanoma. However, its pharmacological effects on breast cancer and its mechanisms are still unknown. In our study, the anti-breast cancer effect and mechanism of cosmosiin were investigated by using breast cancer models in vivo and in vitro. The results showed that cosmosiin inhibited the proliferation, migration, and adhesion of breast cancer cells in vitro and suppressed the growth of tumor in vivo through binding with AhR and inhibiting it, thus regulating the downstream CYP1A1/AMPK/mTOR and PPARγ/Wnt/ß-catenin signaling pathways. Collectively, our findings have made contribution to the development of novel drugs against breast cancer by targeting AhR and provided a new direction for the research in the field of anti-breast cancer therapy.

Efficacy and safety analysis of PD-1 combined with regorafenib in the treatment of advanced hepatocellular carcinoma.

OBJECTIVE: To investigate the therapeutic efficacy and safety of programmed death-1 (PD-1) inhibitors combined with regorafenib in the treatment of advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was performed on 82 patients diagnosed with advanced HCC at Lanzhou Petrochemical General Hospital and the Second People's Hospital of Lanzhou City from October 2021 to October 2022. Patients were divided into two groups: the observation group (42 patients) received combined therapy with regorafenib and a PD-1 inhibitor, while the control group (40 patients) received only regorafenib monotherapy. Treatment efficacy, changes in serum tumor markers pre- and post-treatment, incidence of adverse reactions, progression-free survival (PFS), 1-year survival rate, and independent prognostic factors were evaluated for both groups. RESULTS: The treatment efficacy in the observation group was significantly better than that in the control group (P<0.05). Post-treatment levels of VEGF, sIL-2R, and CEA were significantly lower in the observation group compared to the control group (all P<0.05). The incidence of adverse reactions was similar between the two groups (P>0.05). However, the observation group demonstrated a significantly higher median PFS and 1-year survival rate than the control group (both P<0.05). Vascular invasion, degree of differentiation, and treatment regimen were identified as independent prognostic factors affecting outcomes (all P<0.05). CONCLUSION: For patients with advanced HCC, integrating PD-1 inhibitors with regorafenib treatment not only enhances clinical efficacy but also maintains safety. This combination therapy significantly improves progression-free survival and 1-year survival rates, supporting its further clinical application.

Clinical Features and Pathology of PLA2R and THSD7A-Associated Membranous Nephropathy: A Single-Center Study from China.

Objective: Serum-specific antibodies as a non-invasive means to effectively diagnose idiopathic membranous nephropathy and assess clinicopathology. Methods: Immunofluorescence of anti-PLA2R and THSD7A antibodies and kidney tissue PLA2R, THSD7A and IgG4 expression in IMN and non-IMN (2020-2021) was detected to assess the efficacy of diagnosing IMN. IMN patients were divided into two groups, anti-PLA2R antibody positive (161 cases) and negative (26 cases), and two groups, kidney tissue PLA2R (40 cases) and PLA2R+THSD7A (6 cases), to compare the clinical and pathological features, and to carry out a prognostic analysis of THSD7A-positive patients, with a focus on correlation with malignancy. Results: The positive rate of anti-PLA2R antibodies was significantly higher in IMN (P<0.05); anti-PLA2R antibodies, kidney tissue PLA2R and IgG4 and THSD7A had some diagnostic value. Anti-PLA2R antibodies correlated with proteinuria levels in IMN patients, and their levels were negatively correlated with blood albumin (r=-0.146, P=0.042); correlated with pathological stage and C3 and IgG4 immunodeposition; there was no significant difference in clinical pathology between kidney tissue THSD7A+PLA2R positive compared to kidney tissue PLA2R positive patients, but the probability of achieving complete remission was low and time longer, and no malignancy events were detected during follow-up. Conclusion: Anti-PLA2R antibodies, kidney tissue PLA2R, THSD7A and IgG4 have high diagnostic efficacy for IMN; anti-PLA2R antibodies can be used as diagnostic markers to assist in the assessment of clinical and pathological features; co-expression of kidney tissue PLA2R and THSD7A is not significantly different from kidney tissue PLA2R in assessing the clinical features, pathological manifestations and prognosis, but requires long-term. However, long-term follow-up is needed to monitor the potential risk, and a larger multicentre study with long-term follow-up is expected to be conducted to comprehensively assess IMN characteristics.

Transcriptome-wide m6A methylation profile reveals its potential role underlying drought response in wheat (Triticum aestivum L.).

MAIN CONCLUSION: This study revealed the transcriptome-wide m6A methylation profile under drought stress and found that TaETC9 might regulate drought tolerance through mediating RNA methylation in wheat. Drought is one of the most destructive environmental constraints limiting crop growth and development. N6-methyladenosine (m6A) is a prevalent and important post-transcriptional modification in various eukaryotic RNA molecules, playing the crucial role in regulating drought response in plants. However, the significance of m6A in wheat (Triticum aestivum L.), particularly its involvment in drought response, remains underexplored. In this study, we investigated the transcriptome-wide m6A profile under drought stress using parallel m6A immunoprecipitation sequencing (MeRIP-seq). Totally, 4221 m6A peaks in 3733 m6A-modified genes were obtained, of which 373 methylated peaks exhibited differential expression between the control (CK) and drought-stressed treatments. These m6A loci were significantly enriched in proximity to stop codons and within the 3'-untranslated region. Integration of MeRIP-seq and RNA-seq revealed a positive correlation between m6A methylation and mRNA abundance and the genes displaying both differential methylation and expression were obtained. Finally, qRT-PCR analyses were further performed and the results found that the m6A-binding protein (TaETC9) showed significant up-regulation, while the m6A demethylase (TaALKBH10B) was significantly down-regulated under drought stress, contributing to increased m6A levels. Furthermore, the loss-of-function mutant of TaECT9 displayed significantly higher drought sensitivity compared to the wild type, highlighting its role in regulating drought tolerance. This study reported the first wheat m6A profile associated with drought stress, laying the groundwork for unraveling the potential role of RNA methylation in drought responses and enhancing stress tolerance in wheat through epigenetic approaches.

Regulatory T cells inhibit FoxP3 to increase the population of tumor initiating cells in hepatocellular carcinoma.

PURPOSE: Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC 'stemness' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. METHODS: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC 'stemness'. Additionally, after forced expression or inhibition of FoxP3, ß-catenin expression and HCC 'stemness' were investigated. RESULTS: Tregs enhanced the 'stemness' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, ß-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC 'stemness' was inhibited after treatment with Wnt/ß-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3ß, decreased ß-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3ß, enhanced ß-catenin and TIC ratio of HCC. CONCLUSION: This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting ß-catenin expression.

Penthorum chinense Pursh extract ameliorates alcohol-related fatty liver disease in mice via the SIRT1/AMPK signaling axis.

Penthorum chinense Pursh (P. chinense), a functional food, has been applied to protect the liver against alcohol-related fatty liver disease (ALD) for a long history in China. This study was designed to evaluate the ameliorative activity of the polyphenolic fraction in P. chinense (PGF) depending on the relief of ALD. The ALD mouse model was established by exposing the mice to a Lieber-DeCarli alcohol liquid diet. We found that PGF administration significantly ameliorated alcohol-induced liver injury, steatosis, oxidative stress, and inflammation in mice. Furthermore, alcohol-increased levels of the critical hepatic lipid synthesis proteins sterol regulatory element binding transcription factor (SREBP-1) and diacylglycerol o-acyltransferase 2 (DGAT2) were attenuated by PGF. Similarly, PGF inhibited the expression of the lipid transport protein very low-density lipoprotein receptor (VLDLR). Interestingly, PGF restored alcohol-inhibited expression of carnitine palmitoyltransferase 1 (CPT1) and peroxisome proliferator-activated receptor alpha (PPARα), essential fatty acid ß-oxidation proteins. Mechanistic studies revealed that PGF protects against alcohol-induced hepatocyte injury and lipid deposition via the SIRT1/AMPK signaling pathway. In sum, this research clearly demonstrated the protective effects of PGF against ALD, which was mediated by activating SIRT1/AMPK pathways in hepatocytes. We provide a new theoretical basis for using P. chinense as a functional food in ALD.

Hunnivirus structural protein VP2 inhibits beta interferon production by targeting the IRF3 essential modulator.

Water buffalo Hunnivirus (BufHuV) belongs to the family Picornaviridae and is a newly discovered member of the Hunnivirus A genus. It causes intestinal diseases in cattle, mainly lead to subclinical infections, thereby seriously threatening the health of cattle herds. In addition, it can also bring about various clinical disease syndromes which results in severe economic losses to the cattle industry. To date, there have been no reports worldwide on the study of Hunnivirus virus infecting host cells and causing innate immune responses. In this study, we found that interferon treatment effectively blocked BufHuV replication and infection with the virus weakened the host antiviral responses. Inhibiting the transcription of IFN-ß and ISGs induced by either Sendai virus (SeV) or poly(I:C) in MDBK and HCT-8 cells, were dependent on the IRF3 or NF-κB signaling pathways, and this inhibited the activation of IFN-ß promoter by TBK1 and its upstream molecules, RIGI and MDA5. By constructing and screening five BufHuV proteins, we found that VP2, 2 C, 3 C and 3D inhibited the activation of IFN-ß promoter induced by SeV. Subsequently, we showed that VP2 inhibited the activation of IRF3 induced by SeV or poly (I:C), and it inhibited IRF3 activation by inhibiting its phosphorylation and nuclear translocation. In addition, we confirmed that VP2 inhibited the activation of IFNß induced by signaling molecules, MDA5 and TBKI. In summary, these findings provide new insights into the pathogenesis of Hunnivirus and its mechanisms involved in evading host immune responses.

miR-20a: a key regulator of orthodontic tooth movement via BMP2 signaling pathway modulation.

AIM: In this study, we aimed to establish a rat tooth movement model to assess miR-20's ability in enhancing the BMP2 signaling pathway and facilitate alveolar bone remodeling. METHOD: 60 male SD rats had nickel titanium spring devices placed between their left upper first molars and incisors, with the right side serving as the control. Forces were applied at varying durations (18h, 24h, 30h, 36h, 42h, 1d, 3d, 5d, 7d, 14d), and their bilateral maxillary molars and surrounding alveolar bones were retrieved for analysis. Fluorescent quantitative PCR was conducted to assess miR-20a, BMP2, Runx2, Bambi and Smad6 gene expression in alveolar bone, and western blot was performed to determine the protein levels of BMP2, Runx2, Bambi, and Smad6 after mechanical loading. RESULT: We successfully established an orthodontic tooth movement model in SD rats and revealed upregulated miR-20a expression and significantly increased BMP2 and Runx2 gene expression and protein synthesis in alveolar bone during molar tooth movement. Although Bambi and Smad6 gene expression did not significantly increase, their protein synthesis was found to decrease significantly. CONCLUSION: MiR-20a was found to be involved in rat tooth movement model alveolar bone remodeling, wherein it promoted remodeling by reducing Bambi and Smad6 protein synthesis through the BMP2 signaling pathway.

Fruquintinib-induced renal-limited thrombotic microangiopathy: a case report.

BACKGROUND: Fruquintinib is a highly selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Currently, there are no reported cases of fruquintinib causing kidney-restrictive thrombotic microangiopathy (TMA) in the available Chinese and foreign literature. CASE PRESENTATION: In this case report, we presented a 73-year-old patient receiving fruquintinib for metastatic colon cancer, manifesting abundant proteinuria, in which kidney-restrictive TMA was also diagnosed through renal biopsy. As far as we were concerned, this was the frst reported in terms of fruquintinib-induced kidney-restrictive TMA confrmed by renal biopsy. CONCLUSION: This case indicates that fruquintinib may result in kidney-restrictive TMA, which is a rare but life-threatening complication of cancer treatment drug. Therefore, regular monitoring of proteinuria and blood pressure is imperative for all patients undergoing anti-VEGF drug therapy. And renal biopsy should be promptly conducted to facilitate early detection of thrombotic microangiopathy.

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Development of FRET Biosensor to Characterize CSK Subcellular Regulation.

C-terminal Src kinase (CSK) is the major inhibitory kinase for Src family kinases (SFKs) through the phosphorylation of their C-tail tyrosine sites, and it regulates various types of cellular activity in association with SFK function. As a cytoplasmic protein, CSK needs be recruited to the plasma membrane to regulate SFKs' activity. The regulatory mechanism behind CSK activity and its subcellular localization remains largely unclear. In this work, we developed a genetically encoded biosensor based on fluorescence resonance energy transfer (FRET) to visualize the CSK activity in live cells. The biosensor, with an optimized substrate peptide, confirmed the crucial Arg107 site in the CSK SH2 domain and displayed sensitivity and specificity to CSK activity, while showing minor responses to co-transfected Src and Fyn. FRET measurements showed that CSK had a relatively mild level of kinase activity in comparison to Src and Fyn in rat airway smooth muscle cells. The biosensor tagged with different submembrane-targeting signals detected CSK activity at both non-lipid raft and lipid raft microregions, while it showed a higher FRET level at non-lipid ones. Co-transfected receptor-type protein tyrosine phosphatase alpha (PTPα) had an inhibitory effect on the CSK FRET response. The biosensor did not detect obvious changes in CSK activity between metastatic cancer cells and normal ones. In conclusion, a novel FRET biosensor was generated to monitor CSK activity and demonstrated CSK activity existing in both non-lipid and lipid raft membrane microregions, being more present at non-lipid ones.

Antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome.

Photodynamic therapy (PDT) is a promising cancer treatment. This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]-10,15,20-triphenyl-porphyrin (DTP) mediated PDT (DTP-PDT). Cell viability, reactive oxygen species (ROS), and apoptosis were measured with a Cell Counting Kit-8 assay, DCFH-DA fluorescent probe, and Hoechst staining, respectively. Cell apoptosis- and autophagy-related proteins were examined using western blotting. RNA sequencing was used to screen differentially expressed mRNAs (DERs), and bioinformatic analysis was performed to identify the major biological events after DTP-PDT. Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells. The ROS scavenger N-acetyl-L-cysteine (NAC) and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity. DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2, which could also be inhibited by NAC or SB203580. The level of LC3B-II, a marker of autophagy, was increased by DTP-PDT. A total of 3496 DERs were obtained after DTP-PDT. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes, the nuclear lumen, protein binding, cell cycle, protein targeting to the endoplasmic reticulum, and ribosomal DNA replication. Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints. Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes. Therefore, DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy, partly through ROS and the P38 MAPK signaling pathway. Genes associated with the cell cycle, ribosomes, DNA replication, and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

Afferent Renal Denervation Attenuates Sympathetic Overactivation From the Paraventricular Nucleus in Spontaneously Hypertensive Rats.

BACKGROUND: The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin-angiotensin system (RAS) pathway. METHODS: Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS: The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS: These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

Development and validation of serological dynamic risk score to predict outcome in gastric cancer with adjuvant chemotherapy: a multicentre, longitudinal, cohort study.

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

Development and Validation of Deep Learning Model for Intermediate-Stage Hepatocellular Carcinoma Survival with Transarterial Chemoembolization (MC-hccAI 002): a Retrospective, Multicenter, Cohort Study.

Background: There are few effective prediction models for intermediate-stage hepatocellular carcinoma (IM-HCC) patients treated with transarterial chemoembolization (TACE) to predict overall survival (OS) is available. The learning survival neural network (DeepSurv) was developed to showed a better performance than cox proportional hazards model in prediction of OS. This study aimed to develop a deep learning-based prediction model to predict individual OS. Methods: This multicenter, retrospective, cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007, to December 31, 2016. Patients were divided into a training set(n=1075) and a test set(n=269) at a ratio of 8:2 to develop a deep learning-based algorithm (deepHAP IV). The deepHAP IV model was externally validated on an independent cohort(n=414) from the other three centers. The concordance index, the area under the receiver operator characteristic curves, and the calibration curve were used to assess the performance of the models. Results: The deepHAP IV model had a c-index of 0.74, whereas AUROC for predicting survival outcomes of 1-, 3-, and 5-year reached 0.80, 0.76, and 0.74 in the training set. Calibration graphs showed good consistency between the actual and predicted OS in the training set and the validation cohort. Compared to the other five Cox proportional-hazards models, the model this study conducted had a better performance. Patients were finally classified into three groups by X-tile plots with predicted 3-year OS rate (low: ≤ 0.11; middle: > 0.11 and ≤ 0.35; high: >0.35). Conclusion: The deepHAP IV model can effectively predict the OS of patients with IM-HCC, showing a better performance than previous Cox proportional hazards models.

Effect of refined management in operating room nursing on surgical efficiency and nursing satisfaction during laparoscopic radical resection of colon cancer.

AIM: To assess the effect of refined management in the operating room nursing on surgical efficiency and nursing satisfaction during laparoscopic radical resection of colon cancer. METHODS: In this retrospective study, 100 patients with laparoscopic radical resection of colon cancer were enrolled into this study. There were 51 patients who received refined management (the observation group) and 49 patients who received routine nursing intervention (the control group). The effect of refined management in the operating room nursing was evaluated by comparing the surgical efficiency, quality of care ratings, pain scores, and the nursing satisfaction between the two groups. RESULTS: The preoperative preparation time, surgical time, intraoperative bleeding volume, and time to first postoperative defecation in the observation group were all less than those in the control group after nursing intervention (all P<0.05). The observation group had higher scores than the control group in five categories: operating room environment and safety, drug and instrument management, hygiene and sterilization, nursing records, and nursing professionalism (all P<0.05). The numerical rating scale (NRS) pain scores of the patients in the observation group were lower than those of the control group at 12, 24, and 48 hours postoperatively (all P<0.05). The rate of satisfaction in the observation group was 96.1%. This was higher than the 91.8% in the control group (P<0.05). The multivariate regression analysis demonstrated that refined management intervention is an independent factor for patients' prognosis. CONCLUSION: The implementation of a refined management model in the operating room is effective in improving the quality of surgical care and surgical efficiency, and increasing patient satisfaction with nursing staff.

The micro-743a-3p-GSTM1 pathway is an endogenous protective mechanism against alcohol-related liver disease in mice.

BACKGROUND AND AIMS: Epidemiological evidence suggests that the phenotype of glutathione S-transferase mu 1 (GSTM1), a hepatic high-expressed phase II detoxification enzyme, is closely associated with the incidence of alcohol-related liver disease (ALD). However, whether and how hepatic GSTM1 determines the development of ALD is largely unclear. This study was designed to elucidate the role and potential mechanism(s) of hepatic GSTM1 in the pathological process of ALD. METHODS: GSTM1 was detected in the liver of various ALD mice models and cultured hepatocytes. Liver-specific GSTM1 or/and micro (miR)-743a-3p deficiency mice were generated by adenoassociated virus-8 delivered shRNA, respectively. The potential signal pathways involving in alcohol-regulated GSTM1 and GSTM1-associated ALD were explored via both genetic manipulation and pharmacological approaches. RESULTS: GSTM1 was significantly upregulated in both chronic alcohol-induced mice liver and ethanol-exposed murine primary hepatocytes. Alcohol-reduced miR-743a-3p directly contributed to the upregulation of GSTM1, since liver specific silencing miR-743a-3p enhanced GSTM1 and miR-743a-3p loss protected alcohol-induced liver dysfunctions, which was significantly blocked by GSTM1 knockdown. GSTM1 loss robustly aggravated alcohol-induced hepatic steatosis, oxidative stress, inflammation, and early fibrotic-like changes, which was associated with the activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38. GSTM1 antagonized ASK1 phosphorylation and its downstream JNK/p38 signaling pathway upon chronic alcohol consumption via binding with ASK1. ASK1 blockage significantly rescued hepatic GSTM1 loss-enhanced disorders in alcohol-fed mice liver. CONCLUSIONS: Chronic alcohol consumption-induced upregulation of GSTM1 in the liver provides a feedback protection against hepatic steatosis and liver injury by counteracting ASK1 activation. Down-regulation of miR-743a-3p improves alcohol intake-induced hepatic steatosis and liver injury via direct targeting on GSTM1. The miR-743a-3p-GSTM1 axis functions as an innate protective pathway to defend the early stage of ALD.