Single-cell analysis reveals insights into epithelial abnormalities in ovarian endometriosis.

Ovarian endometriosis is characterized by the growth of endometrial tissue within the ovary, causing infertility and chronic pain. However, its pathophysiology remains unclear. Utilizing high-precision single-cell RNA sequencing, we profile the normal, eutopic, and ectopic endometrium from 34 individuals across proliferative and secretory phases. We observe an increased proportion of ciliated cells in both eutopic and ectopic endometrium, characterized by a diminished expression of estrogen sulfotransferase, which likely confers apoptosis resistance. After translocating to ectopic lesions, endometrial epithelium upregulates nicotinamide N-methyltransferase expression that inhibits apoptosis by promoting deacetylation and subsequent nuclear exclusion of transcription factor forkhead box protein O1, thereby leading to the downregulation of the apoptotic gene BIM. Moreover, epithelial cells in ectopic lesions elevate HLA class II complex expression, which stimulates CD4+ T cells and consequently contributes to chronic inflammation. Altogether, our study provides a comprehensive atlas of ovarian endometriosis and highlights potential therapeutic targets for modulating apoptosis and inflammation.

Efficacy of personalized 3D-printed osteotomy guide in maximizing fibular utilization and minimizing graft length for reconstruction of large mandibular defect.

OBJECTIVE: The study addresses the long-standing challenge of insufficient length in vascularized fibular flaps when reconstructing large mandibular defects that require dual-barrel grafts. Employing personalized 3D-printed osteotomy guides, the study aims to optimize fibular utilization and minimize the required graft length. MATERIAL AND METHODS: Two reconstruction methods for distal bone defects were compared: a fold-down (FD) group that employed a specialized osteotomy guide for folding down a triangular bone segment, and a traditional double-barrel (DB) group. Metrics for comparison included defect and graft lengths, as well as the graft-to-defect length ratio. Postoperative quality of life was assessed using the University of Washington Quality of Life questionnaire (UW-QoL). RESULT: Both FD and DB groups achieved successful mandibular reconstruction. Despite larger defects in the FD group (117 ± 31.35 mm vs 84 ± 35.34 mm, p = 0.028), the used fibula length was not statistically longer in the FD group. The median ratio of graft-to-defect length was also lower in the FD group (1.327 vs 1.629, p = 0.024), suggesting that FD required only 82.47% of the graft length needed in the DB approach. Quality of life scores post-surgery were comparable between the groups. CONCLUSION: Personalized 3D-printed osteotomy guides enhance fibula graft efficacy for reconstructing larger mandibular defects, necessitating shorter graft lengths while preserving postoperative quality of life. CLINICAL RELEVANCE: This study confirms the utility of 3D printing technology as an effective and precise tool in orthopedic surgery, particularly for complex reconstructions like large mandibular defects. It suggests a viable alternative that could potentially revolutionize current practices in bone grafting.

Custom-designed polyphenol lignin for the enhancement of poly(vinyl alcohol)-based wood adhesive.

Adhesives are used extensively in the wood industry. As resource and environmental issues become increasingly severe, the development of green and sustainable biomass-based adhesives has attracted increasing attention. In this work, a green wood adhesive is developed from poly(vinyl alcohol) and lignin with molecular designs of lignin extending beyond those in nature. The lignin undergoes extraction from corncob residue, aldehydration, and phenolisation (phenol, resorcinol, and catechol) to significantly increase the phenolic hydroxyl groups (over 7.92 mmol/g), which has the effect of enhancing the hydrogen bonding force between the adhesive and the wood, thereby greatly improving adhesive performance. Compared with pure PVA, polyphenol lignin-containing PVA showed improved adhesion strength and hydrophobicity. PVA/resorcinol-lignin has the significantly improved wood lap shear strength (6.27 MPa, 77.6 % improvement) and hydrophobicity (almost 100 % increase in wet shear strength). This research not only provides a green and high-performance alternative raw material for wood adhesives but also broadens the path for large-scale application of biomass.

Ubiquitination, SUMOylation, and NEDDylation related genes serve as prognostic and therapeutic biomarkers for oral squamous cell carcinoma.

BACKGROUND: Ubiquitination, small ubiquitin-related modifiers, and NEDDylation are now found to function in cancer biology; however, its role in the oral cancer patients remains unclear. METHODS: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ubiquitin and ubiquitin-like (UB/UBL) genes. A UB/UBL-related risk score was developed via correlation analyses, univariate Cox regression, and multivariate Cox regression. Nomogram analysis evaluates the model's prediction performance. The drug sensitivity analysis, immune profiles of UB/UBL-classified oral squamous cell carcinoma (OSCC) patients, and their related function pathway were investigated, and the role of UB/UBL-related genes in drug therapy was analyzed. RESULTS: A total of six prognostic UB/UBL-related genes were obtained. PSMD3, PCGF2, and H2BC10 were significantly downregulated in OSCC tissue and associated with longer survival time. OSCC patients in the high-risk group showed a significantly lower overall survival and enriched in cancer-related pathways. The prognostic potential of genes associated with UB/UBL was discovered, and patients with high-risk scores showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve of the annual survival rate was 0.616, 0.671, and 0.673, respectively. Besides, patients in the high-risk group are more sensitive to docetaxel, doxorubicin, and methotrexate therapy. CONCLUSIONS: We construct a prognosis model for OSCC patients with UB/UBL-related genes and try to find a new approach to treating oral cancer patients. The UB/UBL-related signature is helpful in developing new tumor markers, prognostic prediction, and in guiding treatment for OSCC patients.

ABO-incompatible living donor kidney transplantation failure due to acute blood group antibody-dependent rejection triggered by human parvovirus B19 infection: a case report and literature review.

Background: With the improvement of immunosuppressive regimens, the success rate and availability of ABO-incompatible (ABO-i) kidney transplantation (KT) have gradually increased. However, the management of immunosuppression protocols and complications associated with ABO-i KT is complex. Here, we report a clinical case of ABO-i living donor KT with allograft dysfunction caused by acute blood group antibody-dependent rejection triggered by human parvovirus B19 (B19V). Case report: The ABO blood group of the recipient was O, and that of the donor was B. The recipient had high baseline anti-B antibody titers (IgM, 1:1024; IgG, 1:64). Before transplantation, he completed a desensitization protocol comprising plasma exchange, double-filtration plasmapheresis, and rituximab, which maintained a low blood group antibody level and resulted in successful transplantation. Two weeks after surgery, the recipient developed a B19V infection combined with acute T-cell-mediated rejection. After the anti-rejection regimen, acute rejection (AR) was successfully reversed, but B19V persisted. One week after AR stabilization, the patient experienced acute antibody-mediated rejection that was more severe and refractory, resulting in the loss of the transplanted kidney. Conclusion: Desensitization combined with immunosuppressants can lead to overimmunosuppression and cause various infections. Infections could break the accommodation state of the patient, thereby inducing AR and resulting in the loss of the transplanted kidney.

Based on metabolomics, the optimum wind speed process parameters of flue-cured tobacco in heat pump bulk curing barn were explored.

To explore the influence of wind speed on the quality of tobacco in this study, we employed a heat pump-powered intensive curing barn and a three-stage curing process. By evaluating the influence of fan parameters on the quality of tobacco leaves at different curing stages, the optimal wind speed was determined. After adopting the optimized wind speed process, the degradation of macromolecular substances was faster, the accumulation of aroma substances was delayed to 55 °C, and the accumulation was more complete. Among them, the contents of reducing sugar and total sugar in flue-cured tobacco leaves were 22.25% and 29.2%, respectively, which were lower than those in the control group. The sugar was converted into more aroma substances, and the total amount of neutral aroma substances was 48.82% higher than that of the control group. The content of related aroma substances increased significantly. The content of petroleum ether extract related to aroma substances increased by 0.93% compared with the control group. The macromolecular substances were degraded more fully than the control group, such as the starch content decreased to 1.56%. The results of metabolomics showed that the contents of aldehydes, heterocyclic compounds, alcohols, ketones and esters increased significantly in different degrees after this process. These results show that the optimization of wind speed parameters can significantly improve the baking quality of tobacco leaves. This study provides a reference for the optimization of the flue-cured tobacco baking process.

Sirolimus in combination with low-dose extended-release tacrolimus in kidney transplant recipients.

Introduction: Many challenges remain for long-term survival of renal allografts. Once-daily sirolimus (SRL) combined with low-dose extended-release tacrolimus (LER-TAC) may improve medication adherence and reduce the potential nephrotoxicity of calcineurin inhibitors (CNI) compared with standard immunosuppression regimens, thus potentially improving long-term graft survival. Methods: This retrospective, observational, single-center, propensity score matching (PSM) study compared conversion to SRL combined with low-dose ER-TAC and mycophenolic acid (MPA) combined with standard-dose TAC in kidney transplant recipients. After PSM, there were 56 patients in each group. Efficacy, safety, and medication adherence were evaluated over 12 months. Results: There was no significant difference between the two groups in terms of graft and recipient survival and incidence of biopsy-proven acute rejection (p = 1.000), and none of the recipients developed dnDSA after conversion. The mean eGFR improved in SRL + LER-TAC group after conversion compared to before conversion (51.12 ± 20.1 ml/min/1.73 m2 vs. 56.97 ± 19.23 ml/min/1.73 m2, p < 0.05). The medication adherence at 12 months after conversion was superior to before conversion (p = 0.002). Discussion: Our findings suggest that an immunosuppressive regimen of SRL combined with low-dose ER-TAC is no less effective and safe than standard immunosuppressive regimens for renal transplant recipients and may improve graft renal function and medication adherence.

A novel hypoxia-associated gene signature for prognosis prediction in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of head and neck, which seriously threatens human life and health. However, the mechanism of hypoxia-associated genes (HAGs) in HNSCC remains unelucidated. This study aims to establish a hypoxia-associated gene signature and the nomogram for predicting the prognosis of patients with HNSCC. METHODS: Previous literature reports provided a list of HAGs. The TCGA database provided genetic and clinical information on HNSCC patients. First, a hypoxia-associated gene risk model was constructed for predicting overall survival (OS) in HNSCC patients and externally validated in four GEO datasets (GSE27020, GSE41613, GSE42743, and GSE117973). Then, immune status and metabolic pathways were analyzed. A nomogram was constructed and assessed the predictive value. Finally, experimental validation of the core genes was performed by qRT-PCR. RESULTS: A HNSCC prognostic model was constructed based on 8 HAGs. This risk model was validated in four external datasets and exhibited high predictive value in various clinical subgroups. Significant differences in immune cell infiltration levels and metabolic pathways were found between high and low risk subgroups. The nomogram was highly accurate for predicting OS in HNSCC patients. CONCLUSIONS: The 8 hypoxia-associated gene signature can serve as novel independent prognostic indicators in HNSCC patients. The nomogram combining the risk score and clinical stage enhanced predictive performance in predicting OS compared to the risk model and clinical characteristics alone.

Integrative analysis of lysine acetylation-related genes and identification of a novel prognostic model for oral squamous cell carcinoma.

Introduction: Oral squamous cell carcinoma (OSCC), which accounts for a high proportion of oral cancers, is characterized by high aggressiveness and rising incidence. Lysine acetylation is associated with cancer pathogenesis. Lysine acetylation-related genes (LARGs) are therapeutic targets and potential prognostic indicators in various tumors, including oral squamous cell carcinoma. However, systematic bioinformatics analysis of the Lysine acetylation-related genes in Oral squamous cell carcinoma is still unexplored. Methods: We analyzed the expression of 33 Lysine acetylation-related genes in oral squamous cell carcinoma and the effects of their somatic mutations on oral squamous cell carcinoma prognosis. Consistent clustering analysis identified two lysine acetylation patterns and the differences between the two patterns were further evaluated. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to develop a lysine acetylation-related prognostic model using TCGA oral squamous cell carcinoma datasets, which was then validated using gene expression omnibus (GEO) dataset GSE41613. Results: Patients with lower risk scores had better prognoses, in both the overall cohort and within the subgroups These patients also had "hot" immune microenvironments and were more sensitive to immunotherapy. Disscussion: Our findings offer a new model for classifying oral squamous cell carcinoma and determining its prognosis and offer novel insights into oral squamous cell carcinoma diagnosis and treatment.

Heteroatom-engineered multicolor lignin carbon dots enabling bimodal fluorescent off-on detection of metal-ions and glutathione.

Carbon dots (CDs) have emerged as a promising subclass of optical nanomaterials with versatile functions in multimodal biosensing. Howbeit the rapid, reliable and reproducible fabrication of multicolor CDs from renewable lignin with unique groups (e.g., -OCH3, -OH and -COOH) and alterable moieties (e.g., ß-O-4, phenylpropanoid structure) remains challenging due to difficult-to-control molecular behavior. Herein we proposed a scalable acid-reagent strategy to engineer a family of heteroatom-doped multicolor lignin carbon dots (LCDs) that are functioned as the bimodal fluorescent off-on sensing of metal-ions and glutathione (GSH). Benefiting from the modifiable photophysical structure via heteroatom-doping (N, S, W, P and B), the multicolor LCDs (blue, green and yellow) with a controllable size distribution of 2.06-2.22 nm deliver the sensing competences to fluorometric probing the distinctive metal-ion systems (Fe3+, Al3+ and Cu2+) under a broad response interval (0-500 µM) with excellent sensitivity and limit of detection (LOD, 0.45-3.90 µM). Meanwhile, we found that the addition of GSH can efficiently restore the fluorescence of LCDs by forming a stable Fe3+-GSH complex with a LOD of 0.97 µM. This work not only sheds light on evolving lignin macromolecular interactions with tunable luminescent properties, but also provides a facile approach to synthesize multicolor CDs with advanced functionalities.

Identification and initial validation of maximal tumor area as a novel prognostic factor for overall and disease-free survival in patients with resectable colon cancer: a retrospective study.

BACKGROUND: The tumor area may be a potential prognostic indicator. The present study aimed to determine and validate the prognostic value of tumor area in curable colon cancer. METHODS: This retrospective study included a training and validation cohorts of patients who underwent radical surgery for colon cancer. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using Cox proportional hazards regression models. The prognostic discrimination was evaluated using the integrated area under the receiver operating characteristic curves (iAUCs) for prognostic factors and models. The prognostic discrimination between tumor area and other individual factors was compared, along with the prognostic discrimination between the tumor-node-metastasis (TNM) staging system and other prognostic models. Two-sample Wilcoxon tests were carried out to identify significant differences between the two iAUCs. A two-sided P <0.05 was considered statistically significant. RESULTS: A total of 3051 colon cancer patients were included in the training cohort and 872 patients in the validation cohort. Tumor area, age, differentiation, T stage, and N stage were independent prognostic factors for both OS and DFS in the training cohort. Tumor area had a better OS and DFS prognostic discrimination characteristics than T stage, maximal tumor diameter, differentiation, tumor location, and number of retrieved lymph nodes. The novel prognostic model of T stage + N stage + tumor area (iAUC for OS, 0.714, P <0.001; iAUC for DFS, 0.694, P <0.001) showed a better prognostic discrimination than the TNM staging system (T stage + N stage; iAUC for OS, 0.664; iAUC for DFS, 0.658). Similar results were observed in an independent validation cohort. CONCLUSIONS: Tumor area was identified as an independent prognostic factor for both OS and DFS in curable colon cancer patients, and in cases with an adequate number of retrieved lymph nodes. The novel prognostic model of combining T stage, N stage, and tumor area may be an alternative to the current TNM staging system.

Circ-SNX27 sponging miR-375/RPN1 axis contributes to hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor with high fatality. It has yet to be reported whether circ-SNX27 can affect the progression of HCC. This study attempted to analyze circ-SNX27's precise role and underlying mechanisms in HCC. HCC cell lines and tumor specimens from HCC patients were analyzed using quantitative real-time PCR and Western blotting to quantify the expressions of circ-SNX27, miR-375, and ribophorin I (RPN1). Cell invasion and cell counting kit 8 experiments were conducted for the evaluation of HCC cell invasion and proliferation. Caspase-3 Activity Assay Kit was utilized to gauge the caspase-3 activity. Luciferase reporter and RNA immunoprecipitation assays were executed to ascertain the relationships among miR-375, circ-SNX27, and RPN1. To determine how circ-SNX27 knockdown affects the growth of HCC xenografts in vivo, tumor-bearing mouse models were constructed. Elevated expressions of circ-SNX27 and RPN1 as well as a reduced miR-375 expression were observed among HCC cells and HCC patient tumor specimens. Knocking-down circ-SNX27 in HCC cells abated their proliferative and invasive abilities but raised their caspase-3 activity. Moreover, the poor levels of circ-SNX27 inhibited HCC tumor growth among the mice. Circ-SNX27 enhanced RPN1 by competitively binding with miR-375. Silencing miR-375 in HCC cells promoted their malignant phenotypes. Nonetheless, the promotive effect of miR-375 silencing was reversible via the knockdown of circ-SNX27 or RPN1. This research demonstrated that circ-SNX27 accelerated the progression of HCC by modulating the miR-375/RPN1 axis. This is indicative of circ-SNX27's potential as a target for the treatment of HCC.

The catalytic hydrodeoxygenation of bio-oil for upgradation from lignocellulosic biomass.

The increasing depletion of oil resources and the environmental problems caused by using much fossil energy in the rapid development of society. The bio-oil becomes a promising alternative energy source to fossil. However, bio-oil cannot be directly utilized, owing to its high proportion of oxygenated compounds with low calorific value and poor thermal stability. Catalytic hydrodeoxygenation (HDO) is one of the most effective methods for refining oxygenated compounds from bio-oil. HDO catalysts play a crucial role in the HDO reaction. This review emphasizes the description of the main processing of HDO and various catalytic systems for bio-oil, including noble/non-noble metal catalysts, porous organic polymer catalysts, and polar solvents. A discussion based on recent studies and evaluations of different catalytic materials and mechanisms is considered. Finally, the challenges and future opportunities for the development of catalytic hydrodeoxygenation for bio-oil upgradation are looked forward.

Combined model with acoustic radiation force impulse to rule out high-risk varices in HBV-related cirrhosis with viral suppression.

AIMS: To prospectively evaluate the performance of spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) via acoustic radiation force impulse (ARFI) imaging combined with platelet counts (PLT) in ruling out HRV in HBV-related cirrhotic patients with viral suppression. METHODS: Patients with cirrhosis enrolled between June 2020-March 2022 were divided into a derivation cohort and validation cohort. LSM and SSM ARFI-based, and esophagogastroduodenoscopy (EGD) were performed at enrollment. RESULTS: In the derivation cohort, overall, 236 HBV-related cirrhotic patients with maintained viral suppression were enrolled, and the prevalence of HRV was 19.5% (46/236). With the aim of identifying HRV, the most accurate LSM and SSM cut-offs were chosen of 1.46 m/s and 2.28 m/s, respectively. The combined model (LSM<1.46 m/s and PLT>150 × 109/L strategy combined with SSM ≤ 2.28 m/s) can spare 38.6% of EGDs and 4.3% of HRV cases were misclassified. In the validation cohort, we analysed 323 HBV-related cirrhotic patients with maintained viral suppression and validated the combined model can spare 33.4% (108/323) of EGD, and the HRV missed rate was 3.4%. CONCLUSIONS: A non-invasive prediction model combining LSM<1.46 m/s and PLT>150 × 109/L strategy with SSM ≤ 2.28 m/s exhibited excellent performance in ruling out HRV and avoided a significantly large number (38.6% vs 33.4%) of unnecessary EGDs in HBV-related cirrhotic patients with viral suppression.

Genome-wide methylation analysis of circulating tumor DNA: A new biomarker for recurrent glioblastom.

Background: Glioblastoma (GBM) is a malignant tumor with a short survival and poor prognosis and a lack of clinically validated biomarkers for diagnosis and prognosis. Methods: We collected cerebrospinal fluid (CSF) samples and normal CSF sample from recurrent GBM patients and paired tissue samples. Methylation profiles of CSF circulating tumor DNA (ctDNA) and transcriptional profiles of tumor tissues were analyzed. The China Glioma Genome Atlas (CGGA) database and Gene Expression Omnibus (GEO) was used for data analysis. Results: Lasso analysis and multiplex Cox analysis were performed using intersecting genes of differentially methylated regions and differentially expressed genes. 8 hub genes were screened to construct diagnostic and prognostic models. Based on these 8 hub genes, the diagnostic (AUC = 0.944) and prognostic (3-years, AUC = 0.876) models were accurate. Conclusions: In this study, 8 hub genes were identified for the diagnosis and prognosis of recurrent GBM, providing new biomarkers for the clinical study of recurrent GBM.

Genome-wide analysis of circulating tumor DNA methylation profiles in cerebrospinal fluid: a clinical trial of oncolytic virus for glioblastoma.

Glioblastoma (GBM) is a common malignant tumor of the central nervous system with a poor prognosis and a short survival period. A novel tumor oncolytic virus, Ad-TD-nsIL-12, has manifested anti-tumor properties in preclinical studies. However, the genetic changes caused by Ad-TD-nsIL-12 after GBM treatment are unclear. Therefore, we collected cerebrospinal fluid and tumor tissues from patients injected with Ad-TD-nsIL-12 at different time points and analyzed the methylation and expression profiles of cerebrospinal fluid-derived circulating tumor DNA (ctDNA). The differential genes were screened using the least absolute selection and shrinkage operator (LASSO) and Cox regression analyses. The CIBERSORT algorithm was used to assess the abundance of glioma immune cell infiltration in The Cancer Genome Atlas (TCGA) dataset. The role of hub genes in the diagnosis, prognosis, and immune cell correlation was analyzed using R software, SPSS software, and GraphPad Prism. The results showed that after Ad-TD-nsIL-12 injection, 3631 differential methylation regions (DMRs) were up-regulated and 497 DMRs were down-regulated. The methylation levels of these DMRs recovered within 70 to 82 days. Combined with the TCGA dataset, 8 key genes were selected for the construction of diagnostic and prognostic models. There was a significant correlation between core genes and immune cells. The results revealed that the hub genes in CSF could be used as a biomarker for the diagnosis and prognosis of GBM and led us to speculate the effect of the hub gene on the immune mechanism underlying Ad-TD-nsIL-12.

Whole-genome sequencing of extrachromosomal circular DNA of cerebrospinal fluid of medulloblastoma.

Background: Medulloblastoma (MB) is a malignant tumor associated with a poor prognosis in part due to a lack of effective detection methods. Extrachromosomal circular DNA (eccDNA) has been associated with multiple tumors. Nonetheless, little is currently known on eccDNA in MB. Methods: Genomic features of eccDNAs were identified in MB tissues and matched cerebrospinal fluid (CSF) and compared with corresponding normal samples using Circle map. The nucleotides on both sides of the eccDNAs' breakpoint were analyzed to understand the mechanisms of eccDNA formation. Bioinformatics analysis combined with the Gene Expression Omnibus (GEO) database identified features of eccDNA-related genes in MB. Lasso Cox regression model, univariate and multivariate Cox regression analysis, time-dependent ROC, and Kaplan-Meier curve were used to assess the potential diagnostic and prognostic value of the hub genes. Results: EccDNA was profiled in matched tumor and CSF samples from MB patients, and control, eccDNA-related genes enriched in MB were identified. The distribution of eccDNAs in the genome was closely related to gene density and the mechanism of eccDNA formation was evaluated. EccDNAs in CSF exhibited similar distribution with matched MB tissues but were differentially expressed between tumor and normal. Ten hub genes prominent in both the eccDNA dataset and the GEO database were selected to classify MB patients to either high- or low-risk groups, and a prognostic nomogram was thus established. Conclusions: This study provides preliminary evidence of the characteristics and formation mechanism of eccDNAs in MB and CSF. Importantly, eccDNA-associated hub genes in CSF could be used as diagnostic and prognostic biomarkers for MB.

Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc.

Dysregulated cholesterol metabolism is a hallmark of colorectal cancer (CRC). However, the usage of cholesterol-lowering agents seemed to have no benefit in CRC patients. In this study, we focused on the cholesterol-nuclear receptors (NRs) axis as a strategy. Cholesterol and its derivatives work as ligands for different nuclear receptors, thus promoting cancer progression. The key NR downstream of cholesterol in CRC is unknown. Here, we treated CRC cells with a cholesterol-lowering agent and lipoprotein-depleted conditioned medium, and then detected the change of the putative NRs. The results revealed that RORα/γ (Retinoic acid receptor-related Orphan Receptor α/γ) levels exhibited the most obvious increases in CRC cells subjected them to cholesterol deprivation. RORα/γ agonists significantly inhibited CRC cells proliferation and migration in vitro and in vivo. Also, RORα/γ overexpression repressed CRC cells proliferation and migration in vitro and in vivo and RORα/γ knockdown promoted it. Mechanistically, RORα/γ agonists promoted c-myc degradation by activating the transcription of the ubiquitinase NEDD4. Intriguingly, the combination of RORα/γ agonists and atorvastatin had a synergistic effect on inhibiting CRC cells. These findings demonstrate that the cholesterol- RORα/γ axis is important for maintaining c-myc protein levels. Combination therapy with atorvastatin and RORα/γ agonist is a promising therapeutic strategy for CRC.

Identification of small-molecule inhibitors of the DNA repair proteins RuvAB from Pseudomonas aeruginosa.

The Holliday junction (HJ) branch migrator RuvAB complex plays a fundamental role during homologous recombination and DNA damage repair, and therefore, is an attractive target for the treatment of bacterial pathogens. Pseudomonas aeruginosa (P. aeruginosa, Pa) is one of the most common clinical opportunistic bacterial pathogens, which can cause a series of life-threatening acute or chronic infections. Here, we performed a high throughput small-molecule screening targeting PaRuvAB using the FRET-based HJ branch migration assay. We identified that corilagin, bardoxolone methyl (BM) and 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SKQ1) could efficiently inhibit the branch migration activity of PaRuvAB, with IC50 values of 0.40 ± 0.04 µM, 0.38 ± 0.05 µM and 4.64 ± 0.27 µM, respectively. Further biochemical and molecular docking analyses demonstrated that corilagin directly bound to PaRuvB at the ATPase domain, and thus prevented ATP hydrolysis. In contrast, BM and SKQ1 acted through blocking the interactions between PaRuvA and HJ DNA. Finally, these compounds were shown to increase the susceptibility of P. aeruginosa to UV-C irradiation. Our work, for the first time, reports the small-molecule inhibitors of RuvA and RuvB from any species, providing valuable chemical tools to dissect the functional role of each individual protein in vivo.

Differential detection of metastatic and inflammatory lymph nodes using inflow-based vascular-space-occupancy (iVASO) MR imaging.

PURPOSE: To investigate the potential value of inflow-based vascular-space-occupancy (iVASO) MR imaging in differentiating metastatic from inflammatory lymph nodes (LNs). METHODS: Ten female New Zealand rabbits with 2.5-3.0 kg body weight were studied. VX2 cells and egg yolk emulsion were inoculated into left and right thighs, respectively, to induce ten metastatic and ten inflammatory popliteal LNs. Conventional MRI and iVASO were performed 2 h prior to, and 10, 20 days after inoculation (D0, D10, D20). The short-axis diameter (S), short- to long-axis diameter ratio (SLR), and arteriolar blood volume (BVa) at each time point and their longitudinal changes of each model were recorded and compared. At D20, all rabbits were sacrificed to perform histological evaluation after the MR scan. RESULTS: The mean values of S, SLR and BVa showed no significant difference between the two groups at D0 (P = 0.987, P = 0.778, P = 0.975). The BVa of the metastatic group was greater than that of the inflammatory at both D10 and D20 (P < 0.05; P < 0.001), whereas the S and SLR of the metastatic group were greater only at D20 (P < 0.001; P = 0.001). Longitudinal analyses showed that the BVa of the metastatic group increased at both D10 and D20 (P = 0.004; P = 0.001), while that of the inflammatory group only increased at D10 (P = 0.024). CONCLUSION: The BVa measured with iVASO has the potential to detect early metastatic LNs.