Comprehensive molecular analyses and experimental validation of CDCAs with potential implications in kidney renal papillary cell carcinoma prognosis.

Previous reports have revealed that the abnormal expression of the cell division cycle-associated gene family (CDCAs) is closely associated with some human cancers. However, the precise functional roles and mechanisms of CDCAs in kidney renal papillary cell carcinoma (KIRP) remain unclear. In this study, RNA sequencing data from the Cancer Genome Atlas database and Genotype-Tissue Expression databases were utilized to perform the expression, correlation, survival, mutation, functional enrichment analysis, and immunoinfiltration analyses of CDCAs in KIRP. We found that the expression levels of CDCA genes were significantly increased in KIRP across multiple databases, as confirmed by immunohistochemistry and quantitative reverse transcription PCR (RT-qPCR). Moreover, increased expression of CDCA genes is significantly associated with poor prognosis. Univariate and multivariate Cox regression analyses demonstrated that pathologic T and N staging, NUF2, CDCA2, CDCA3, CDCA5, CBX2, CDCA7, and CDCA8 were independent prognostic factors for patients with KIRP. Utilizing these nine variables, we developed a nomogram prognostic model. Furthermore, the results of GO and KEGG functional enrichment analyses suggested that CDCA genes were associated with nuclear division, mitotic nuclear division, and chromosome segregation and were involved in the cell cycle, p53 signaling pathway, and cellular senescence. We found that the expression of NUF2, CDCA2, CDCA5, and CBX2 was closely associated with the expression of lymphocytes, immunostimulatory molecules, immunoinhibitory molecules, and chemokines. In summary, NUF2, CDCA2, CDCA3, CDCA5, CBX2, CDCA7, and CDCA8 are potential biomarkers for KIRP diagnosis and prognosis.

Percutaneous coronary intervention leads to microplastics entering the blood: Interventional devices are a major source.

Microplastics (MPs) is an emerging pollutant potentially harmful to health. Medical practices using plastic devices, such as percutaneous coronary interventions (PCI), may result in MPs entering into the blood. The purpose of this study was to quantify the effect of PCI on microplastic levels in patients' blood. Laser direct infrared (LDIR) was used to detect MPs in the blood of 23 patients before and after PCI. MPs in the water in which devices used in PCI were washed were also examined. The concentration of MPs in the blood was significantly elevated (93.57 ± 35.95 vs. 4.96 ± 3.40 particles/10 mL of blood, P < 0.001) after PCI compared to before, and the increased MPs were polyamide (PA), polyethylene (PE), polyurethane (PU), and polyethylene terephthalate (PET), which was consistent with the types of MPs detected in the device washing water. The maximum diameter of MPs in blood before PCI was 50 µm, whereas after PCI it was 213 µm, and even 336 µm in device washing water. These findings indicated that PCI will cause MPs to enter the blood, and devices used during PCI were a major source, a range of medical practices that use plastic devices may be a new route for MPs to enter the human body.

miR-181d-5p ameliorates hypercholesterolemia by targeting PCSK9.

Hypercholesterolemia is an independent risk factor for cardiovascular disease and lowering circulating levels of low-density lipoprotein cholesterol (LDL-C) can prevent and reduce cardiovascular events. microRNA-181d (miR-181d) can reduce the levels of triglycerides and cholesterol esters in cells. However, it is not known whether miR-181d-5p can lower levels of circulating LDL-C. Here, we generated two animal models of hypercholesterolemia to analyze the potential relationship between miR-181d-5p and LDL-C. In hypercholesterolemia model mice, adeno-associated virus (AAV)-mediated liver-directed overexpression of miR-181d-5p decreased the serum levels of cholesterol and LDL-C and the levels of cholesterol and triglyceride in the liver compared with control mice. Target Scan 8.0 indicated Proprotein convertase subtilisin/kexin type 9 (PCSK9) to be a possible target gene of miR-181d-5p, which was confirmed by in vitro experiments. miR-181d-5p could directly interact with both the PCSK9 3'-UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, Dil-LDL uptake assays in PCSK9 knockdown Huh7 cells demonstrated that miR-181d-5p promotion of LDL-C absorption was dependent on PCSK9. Collectively, our findings show that miR-181d-5p targets the PCSK9 3'-UTR to inhibit PCSK9 expression and to reduce serum LDL-C. miR-181d-5p is therefore a new therapeutic target for the development of anti-hypercholesterolemia drugs.

Development and validation of a predicting nomogram for in-hospital mortality of COVID-19 Omicron variant: A cohort study of 1324 cases in Beijing Anzhen Hospital.

Coronavirus disease 2019 (COVID-19) is continuously posing high global public health concerns due to its high morbidity and mortality. This study aimed to construct a convenient risk model for predicting in-hospital mortality of COVID-19 Omicron variant. A total of 1324 hospitalized patients with Omicron variant were enrolled from Beijing Anzhen Hospital. During hospitalization, the Omicron variant mortality rate was found to be 24.4%. Using the datasets of clinical demographics and laboratory tests, three machine learning algorithms, including best subset selection, stepwise selection, and least absolute shrinkage and selection operator regression analyses were employed to identify the potential predictors of in-hospital mortality. The results found that a panel of twenty-four clinical variables (including age, hyperlipemia, stroke, tumor, and several cardiovascular markers) identified by stepwise selection model exhibited significant performances in predicting the in-hospital mortality of COVID-19. The resultant nomogram showed good discrimination, highlighted by the areas under the curve values of 0.88 for 10 days, 0.81 for 20 days, and 0.82 for 30 days, respectively. Furthermore, decision curve analysis showed a significant reliability and precision for the established stepwise selection model. Collectively, this study developed an accurate and convenience risk model for predicting the in-hospital mortality of COVID-19 Omicron.

Microplastics in three types of human arteries detected by pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS).

Microplastics are ubiquitous in the environment. Human body can be exposed to microplastics through inhalation and ingestion and some microplastics can enter the blood and accumulate in various tissues and organs throughout the body. Animal experiments have suggested that microplastics may promote atherosclerosis. However, data on microplastics in human arteries and clinical evidence supporting a link between microplastics and atherosclerosis are currently lacking. Pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) was used in this study to detect microplastics in three types of human arteries: coronary and carotid arteries with atherosclerotic plaques, as well as the aorta without plaques. Microplastics were detected in all 17 arterial samples, with an average concentration of 118.66 ± 53.87 µg/g tissue. Four types of microplastics were identified: polyethylene terephthalate (PET, 73.70%), polyamide-66 (PA-66, 15.54%), polyvinyl chloride (PVC, 9.69%), and polyethylene (PE, 1.07%). Most importantly, the concentration of microplastics in arteries containing atherosclerotic plaques, both coronary arteries (156.50 ± 42.14 vs. 76.26 ± 14.86 µg/g tissue, P = 0.039), and carotid arteries (133.37 ± 60.52 vs. 76.26 ± 14.86 µg/g tissue, P = 0.015), was significantly higher than that in aortas which did not contain atherosclerotic plaques, suggesting that microplastics might be associated with atherosclerosis in humans. This study provides valuable data for further hazard assessments of microplastics on human cardiovascular health.

Impact of Metabolic Syndrome on Post-Operative Infection in Patients Undergoing Flexible Ureteroscopy Lithotripsy.

Background: To investigate retrospectively whether metabolic syndrome (MetS) of flexible ureteroscopy (fURS) lithotripsy can be used to predict post-operative infection. Patients and Methods: After screening, 1,110 patients who received fURS lithotripsy for upper urinary tract stones in our center between January 2015 and December 2022 were analyzed retrospectively. Patients were divided into MetS-positive group and MetS-negative group. Post-operative infection was divided into fever, urosepsis, and septic shock. Relevant data during the peri-operative period were collected. Univariable and multivariable logistic regression analyses were adopted to estimate the impact of metabolic syndrome on post-operative infection in patients undergoing fURS lithotripsy. Results: Among the 1,110 patients, 427 tested positive for MetS, whereas 683 tested negative. Eighty-eight patients suffered from fever (67 patients in the MetS-positive group and 21 in the MetS-negative group). Forty-nine patients had urosepsis (29 patients in the MetS-positive group and 20 in the MetS-negative group), of whom seven patients developed septic shock. No patient developed multiple organ failure or died because of infection. The prevalence of post-operative infections in the MetS-positive group was higher than that in the MetS-negative group (p < 0.001). Multivariable logistic regression analyses showed that diabetes mellitus, MetS-positive, positive urine culture, and longer operation time were positively correlated with post-operative fever. Positive MetS, positive urine culture, and longer operation time were strongly correlated with post-operative urosepsis. Conclusions: Metabolic syndrome was found to be associated with post-operative infection in patients undergoing fURS lithotripsy, suggesting it can serve as a predictive factor.

Chiral Nanomaterials for Cancer Vaccines.

Chirality is a fundamental characteristic of living organisms and is commonly observed at the biomolecule, cellular, and tissue levels. Chiral nanomaterials play an irreplaceable role in nanomedicine and nanobiology because of their unique enantioselectivity with biological components. Here, research progress relating to chiral nanomaterials in the field of vaccines is reviewed, including antigen presenting systems, immune adjuvants, and cancer vaccines. First, the common synthesis methods are outlined for different types of chiral nanomaterials, as well as their chiral sources, optical properties, and potential biological applications. Then, the application of chiral nanomaterials are discussed in the field of vaccines with reference to the promotion of antigen presentation and activation of the immune system for tumor immunotherapy. Finally, the current obstacles and future research directions of chiral nanomaterials are revealed with regard to regulating the immune system.

The impact of negative pressure wound therapy on surgical wound infection, hospital stay and postoperative complications after spinal surgery: A meta-analysis.

To systematically assess the effect of negative pressure wound therapy (NPWT) on postoperative surgical wound infection, length of hospital stay and postoperative complications after spinal surgery. Relevant studies on the application of NPWT in spinal surgery were conducted via a computerised database search, including PubMed, EMBASE, Web of Science, MEDLINE, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang, from inception to June 2023. The identified literature was rigorously screened and data extraction was performed by two investigators independently. The quality of the relevant studies was evaluated using the Newcastle-Ottawa scale (NOS). The effect size for count data was determined by the odds ratio (OR), while the impact size for measurement data was expressed as the standardised mean difference (SMD). The 95% confidence interval (CI) was calculated for each effect magnitude. Stata 17.0 software was used for the meta-analysis. Ten papers, totalling 1448 patients, were finally included. This study demonstrated that NPWT led to a statistically significant reduction in the occurrence of postoperative surgical wound infections (OR: 0.377, 95% CI: 0.238-0.598, p < 0.001), fewer postoperative complications (OR: 0.526, 95% CI: 0.360-0.770, p = 0.001) and a shortened hospital stay (SMD: -0.678, 95%CI: -1.324 to -0.031, p = 0.040) after spinal surgery compared with the control group. When compared with other treatment approaches, NPWT also demonstrated a substantial reduction in surgical wound infections and postoperative complications, as well as a shorter duration of hospitalisation after spinal surgery.

Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies. METHODS: Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients. RESULTS: Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients. CONCLUSIONS: Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.

Detection of Various Microplastics in Patients Undergoing Cardiac Surgery.

Microplastics have been detected in human stool, lungs, and placentas, which have direct exposure to the external environment through various body cavities, including the oral/anal cavity and uterine/vaginal cavity. Crucial data on microplastic exposure in completely enclosed human organs are still lacking. Herein, we used a laser direct infrared chemical imaging system and scanning electron microscopy to investigate whether microplastics exist in the human heart and its surrounding tissues. Microplastic specimens were collected from 15 cardiac surgery patients, including 6 pericardia, 6 epicardial adipose tissues, 11 pericardial adipose tissues, 3 myocardia, 5 left atrial appendages, and 7 pairs of pre- and postoperative venous blood samples. Microplastics were not universally present in all tissue samples, but nine types were found across five types of tissue with the largest measuring 469 µm in diameter. Nine types of microplastics were also detected in pre- and postoperative blood samples with a maximum diameter of 184 µm, and the type and diameter distribution of microplastics in the blood showed alterations following the surgical procedure. Moreover, the presence of poly(methyl methacrylate) in the left atrial appendage, epicardial adipose tissue, and pericardial adipose tissue cannot be attributed to accidental exposure during surgery, providing direct evidence of microplastics in patients undergoing cardiac surgery. Further research is needed to examine the impact of surgery on microplastic introduction and the potential effects of microplastics in internal organs on human health.

Comparison of computed tomography and magnetic resonance imaging findings and histopathological features of macrotrabecular-massive hepatocellular carcinoma.

Background: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel subtype of HCC, one of eight distinct subtypes, that accounts for 5% of all cases of HCC and is associated with a worse prognosis. Preoperative diagnosis of MTM-HCCs using imaging findings can facilitate patient treatment decision-making. The purpose of this study was to describe computed tomography (CT) and magnetic resonance imaging (MRI) findings of MTM-HCCs and compare these findings with histopathological features. Methods: This retrospective case-control study was performed at Shenzhen People's Hospital. The cohort included 17 patients with surgically confirmed MTM-HCCs and 232 patients with surgically confirmed non-MTM-HCCs who were enrolled by searching the pathological database from January 2018 to June 2022. CT and MRI findings were retrospectively analyzed and compared with pathological features. Student's t-test or Mann-Whitney U test for continuous variables and χ2 test or Fisher's exact test for categorical variables were implemented to compare imaging manifestations between MTM-HCCs and non-MTM-HCCs, as appropriate. Results: Seventeen tumors with a mean diameter of 8.58±2.83 cm were identified in the 17 patients. In addition to the typical findings of hepatocellular carcinomas (HCCs), such as arterial phase hyperenhancement (APHE), wash out, restricted diffusion, capsule and non-uptake at the hepatobiliary phase (HBP), the most common findings in MTM-HCCs were necrosis in 11 patients (64.7%, 11/17), followed by intratumoral arteries in 6 patients (35.3%, 6/17), peritumoral arterial transitive enhancement in 3 patients (17.6%, 3/17) and peritumoral hypointensive areas at the HBP in 3 of 8 patients (37.5%, 3/8) who received gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhancement. The tumor size of non-MTM-HCCs was 5.26±1.94 cm, which was smaller than the 8.58±2.83 cm of MTM-HCCs (P<0.001). The frequency of necrosis and intratumoral arteries was significantly higher in MTM-HCCs than in non-MTM-HCCs (necrosis: 64.7% vs. 34.6%, P=0.012; intratumoral arteries: 47.1% vs. 19.7%, P=0.008). Conclusions: MTM-HCCs tend to be large in size with intratumoral artery and intratumoral necrosis, which are characteristics that may distinguish them from non-MTM-HCCs.

ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice.

Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on AAA in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly up-regulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.

Metabolomics and network analysis uncovered profound inflammation-associated alterations in hepatitis B virus-related cirrhosis patients with early hepatocellular carcinoma.

Patients with hepatitis B virus (HBV)-related liver cirrhosis (LC) are at high risk for hepatocellular carcinoma (HCC). Limitations in the early detection of HCC give rise to poor survival in this high-risk population. Here, we performed comprehensive metabolomics on health individuals and HBV-related LC patients with and without early HCC. Compared to non-HCC patients (N = 108) and health controls (N = 80), we found that patients with early HCC (N = 224) exhibited a specific plasma metabolome map dominated by lipid alterations, including lysophosphatidylcholines, lysophosphatidic acids and bile acids. Pathway and function network analyses indicated that these metabolite alterations were closely associated with inflammation responses. Using multivariate regression and machine learning approaches, we identified a five-metabolite combination that showed significant performances in differentiating early-HCC from non-HCC than α-fetoprotein (area under the curve values, 0.981 versus 0.613). At metabolomic levels, this work provides additional insights of metabolic dysfunction related to HCC progressions and demonstrates the plasma metabolites might be measured to identify early HCC in patients with HBV-related LC.

Metabolic signatures in pericardial fluid and serum are associated with new-onset atrial fibrillation after isolated coronary artery bypass grafting.

Postoperative atrial fibrillation (POAF) is a common complication of coronary artery bypass grafting (CABG) procedures. However, the molecular mechanism of POAF remains poorly understood, hence the absence of effective prevention strategies. Here we used targeted metabolomics on pericardial fluid and serum samples from CABG patients to investigate POAF-associated metabolic alterations and related risk prediction of new-onset AF. Nine differential metabolites in various metabolic pathways were found in both pericardial fluid and serum samples from patients with POAF and without POAF. By using machine learning algorithms and regression models, a 4-metabolite (aceglutamide, ornithine, methionine, and arginine) risk prediction model was constructed and showed accurate performance in predicting POAF in both discovery and validation sets. This work extends the metabolic insights of the cardiac microenvironment and blood in patients with POAF and paves the way for the use of targeted metabolomics for predicting POAF in patients with CABG surgery.

Cognitive function and delirium following sevoflurane or propofol anesthesia for valve replacement surgery: A multicenter randomized controlled trial.

Cognitive dysfunction is a common postoperative neurological complication in patients undergoing valve replacement surgery. This study aimed to compare the effects of sevoflurane versus propofol-based total intravenous anesthesia on the incidence of cognitive dysfunction following valve replacement surgery. This multicenter, randomized, controlled double-blinded study was conducted in three teaching hospitals in China. Patients receiving on-pump valve replacement surgery were enrolled. Stratified block randomization was used to randomly assign patients 1:1 to receive sevoflurane (1.0-1.5 MAC) or propofol (2.0-3.0 mg/kg/h) for anesthesia maintenance. The primary outcome was the incidence of cognitive dysfunction assessed by four cognitive tests before, as well as 7-14 days after surgery. Patients were randomly assigned to receive sevoflurane anesthesia (n = 144) or propofol-based total intravenous anesthesia (n = 145). The incidence of postoperative cognitive dysfunction in the sevoflurane anesthesia group (31.9%) was significantly lower than that in the total intravenous anesthesia group (43.4%; relative risk 0.61, 95% confidence interval [CI]: 0.38-0.97, p = 0.044). There was no difference in the incidence of delirium between patients receiving sevoflurane and total intravenous anesthesia (27.8% [35/144] vs. 25.9% [35/145], 1.10, 95% CI: 0.64 to 1.90, p = 0.736). There was a significant difference in the Katz Index on day 3 after surgery (3 [0.9) vs. 3 (1.0], 0.095, 95% CI: 0.05 to 0.43, p = 0.012). No difference was observed in other outcomes between the two groups. For patients undergoing on-pump valve replacement surgery, sevoflurane anesthesia had a smaller effect on cognitive function and independence in daily life activities compared with propofol anesthesia.

Increasing circulating ESM-1 and adhesion molecules are associated with earlystage atherosclerosis in OSA patients:A cross-sectional study.

BACKGROUND: There are increasing evidences for a direct relationship between the vascular system and obstructive sleep apnea (OSA). The aim of this study was to investigate the relationship between circulating endothelial cell specific molecule-1 (ESM-1), adhesion molecules and subclinical atherosclerosis in patients with OSA. METHODS: This was a cross-sectional study in which 161 patients with OSA and 56 controls were recruited. Demographic data, biochemical and polysomnography parameters were collected. We used a powerful high-throughput Multiplex Immunobead Assay technique to simultaneously test plasm levels of ESM-1, P-selectin, E-selectin, L-selectin, inter-cellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Carotid intima-media thickness (CIMT) were measured as parameters of vascular endothelial dysfunction and early atherosclerosis. RESULTS: Increasing circulating levels of ESM-1, P-selectin, E-selectin, L-selectin, ICAM-1 and VCAM-1 were found increased in patients with OSA (all P < 0.001). Furthermore, OSA patients exhibited increased CIMT than controls (P < 0.05). Multivariate linear analysis indicated that elevated ESM-1, P-Selectin, E-selectin, and L-selectin levels were associated with AHI (all P < 0.05). Moreover, multivariate analysis showed that increasing ESM-1, VCAM-1, P-Selectin, and L-selectin were significantly associated with thick CIMT in OSA patients (all P < 0.05). CONCLUSIONS: Increased circulating ESM-1 and adhesion molecules associated with thick CIMT in OSA, which is a marker of subclinical atherosclerosis. Strict attention to monitor circulating ESM-1 and adhesion molecules is necessary for early detection of subclinical atherosclerosis in OSA patients.

Comprehensive Analysis of the Butyrate-Metabolism-Related Gene Signature in Tumor Microenvironment-Infiltrating Immune Cells in Clear Cell Renal Cell Carcinoma.

A wealth of experimental evidence has validated that butyrate is capable of inhibiting tumorigenesis, while the potential role of butyrate metabolism in the tumor immune microenvironment (TIME) has been rarely explored. This study aims to explore the potential of butyrate-metabolism-related genes as prognostic biomarkers and their correlations with immune infiltrates in clear cell renal cell carcinoma (ccRCC) patients. Based on The Cancer Genome Atlas dataset (TCGA; n = 539), a total of 22 differentially expressed genes (DEGs) related with butyrate metabolism in ccRCC and normal samples were identified. Among them, a prognostic signature involving six butyrate-metabolism-related genes was created (Bu-Meta-GPS) in the training set (n = 271) and validation set (n = 268), and risk scores were calculated based on them. ccRCC patients with high-risk scores exhibited an unfavorable prognosis, high immunoscore, upregulated immuno-oncological targets (PD1, PD-L1, CTLA4, and CD19), and distinct immune-cell infiltration than those with low-risk scores. High-risk ccRCC patients without radiotherapy had a better survival rate than radiotherapy-treated patients. The negative regulation of cytokine production and cytokine-mediated signaling pathways was remarkably enriched in ccRCC patients with high-risk scores. A nomogram was then formulated to assess the overall survival (OS) of ccRCC patients. In summary, we illuminated the key role of butyrate metabolism in ccRCC TIME. The developed Bu-Meta-GPS was a sensitive predictive biomarker for the prognosis of ccRCC, which also provided new perspectives in improving immunotherapeutic efficacy.

Proanthocyanidins Promote Endothelial Cell Viability and Angiogenesis.

ABSTRACT: Botanic drugs are reportedly effective in treating ischemic conditions by improving vascular circulation. However, it has been very rare for biomaterial researchers to look into the possibility of using such products in the context of tissue regeneration. This work studied 4 botanic drugs to explore their effects on vascular endothelial cell growth. Human umbilical endothelial cells were cultured in the presence of different doses of astragalus powder extract, astragalus injection, puerarin injection, and proanthocyanidin (PAC). Among the 4 drugs, PAC showed a potent effect on cell viability and stimulated cell growth in a dose-dependent manner. In particular, the PAC under test was able to maintain a high level of cell viability/proliferation comparable with the cells supplemented with the endothelial cell growth medium, at both low and normal serum conditions. Blocking either endothelial cell growth factor receptors or epithelial cell growth factor receptors was ineffective in reducing the stimulatory effect. The PAC released from polyvinyl alcohol cryogels stimulated HUVECs proliferation. The chick embryo chorioallantoic membrane model was further used to test the angiogenicity of PAC, showing that this botanic drug was potent in stimulating vasculature development. This work therefore demonstrates for the first time that PAC is capable of upregulating endothelial cell activity and growth in vitro in the absence of growth factors and that PAC can be loaded and released from drug carriers and can stimulate angiogenesis. These findings suggest the application of PAC in angiogenesis and tissue regeneration.

Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL.

BACKGROUND: Hepatic fibrosis is attributed to an imbalance of extracellular matrix production and lysis. Human hepatic stellate cells (HSCs) have been uncovered to converge through complex interactions with hepatocytes and immune cells, causing scarring in liver damage. AIMS: We aimed to investigate the expression status of ubiquitin specific peptidase 1 (USP1) and its potential mechanisms on HSCs and hepatic fibrosis. METHODS: Hepatic fibrosis animal and cell models were generated using mice with carbon tetrachloride (CCl4) treatment and HSCs LX-2 with TGF-ß1 treatment. Relationships among USP1, SNAIL, and CXCL1 were identified via dual-luciferase reporter gene assay, co-immunoprecipitation, and chromatin immunoprecipitation. With gain- and loss-of-experiments, CCK-8 and flow cytometry assays were employed for cell proliferation and apoptosis. RESULTS: USP1 upregulated SNAIL expression through deubiquitination to increase CXCL1 expression. USP1 downregulation decreased expressions of fibrosis-related genes, suppressed proliferation, and promoted apoptosis in TGF-ß1-induced LX-2 cells, which were reversed by SNAIL overexpression. The pro-fibrosis role caused by SNAIL upregulation was abolished by CXCL1 reduction. Promotive function of USP1/SNAIL/CXCL1 axis in hepatic fibrosis was further confirmed in vivo. CONCLUSION: These data supported siRNA-mediated silencing of USP1 improved hepatic fibrosis through inhibition of SNAIL and CXCL1, which yields a new therapeutic target for hepatic fibrosis treatment.