Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor.

The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

Prevalence and genetic characterization of Campylobacter from clinical poultry cases in China.

IMPORTANCE: Campylobacter is a major cause of campylobacteriosis worldwide, and poultry is the main reservoir for its transmission. Campylobacter was generally considered to be a harmless commensal organism in poultry without pathogenic properties. However, it was proposed that a Campylobacter-like organism may be the cause of vibrionic hepatitis, which poses a significant public health risk. The occurrence and epidemiology of Campylobacter in healthy poultry have been studied systematically, but little is known about the epidemiology of Campylobacter isolates from diseased poultry in China. Therefore, this study determined the prevalence and molecular characterization of Campylobacter from diseased chickens, ducks, and geese in Yangzhou Veterinary Hospital between December 2016 and September 2017, which was critical for improving the diagnosis and prevention of Campylobacter infections.

On the Optimal Error Exponent of Type-Based Distributed Hypothesis Testing.

Distributed hypothesis testing (DHT) has emerged as a significant research area, but the information-theoretic optimality of coding strategies is often typically hard to address. This paper studies the DHT problems under the type-based setting, which is requested from the popular federated learning methods. Specifically, two communication models are considered: (i) DHT problem over noiseless channels, where each node observes i.i.d. samples and sends a one-dimensional statistic of observed samples to the decision center for decision making; and (ii) DHT problem over AWGN channels, where the distributed nodes are restricted to transmit functions of the empirical distributions of the observed data sequences due to practical computational constraints. For both of these problems, we present the optimal error exponent by providing both the achievability and converse results. In addition, we offer corresponding coding strategies and decision rules. Our results not only offer coding guidance for distributed systems, but also have the potential to be applied to more complex problems, enhancing the understanding and application of DHT in various domains.

Probiotics formulation and cancer nanovaccines show synergistic effect in immunotherapy and prevention of colon cancer.

Probiotics play essential roles in immune modulation. Combining probiotics with cancer vaccines potentially can achieve a synergistic effect. To maximize the efficacy of probiotics, proper probiotics formulation is necessary. Herein, Lactobacillus rhamnosus and Bifidobacterium longum are coated with lipid membrane to achieve the goal of losing less activity and bettering colonization in colon. In the subcutaneous transplanted colon cancer mouse model, probiotics formulation showed potent preventive and therapeutic efficacy, and the efficacy could be further improved by combining with cancer nanovaccines. Probiotics formulation can perform as immune adjuvants to enhance the innate immune response or as in-situ cancer vaccines. In the study of preventing chemical-induced orthotopic colon cancer model, probiotics formulation alone efficiently reduced tumor number in colon and the efficacy is improved by combining with cancer nanovaccines. All in all, the studies demonstrated that probiotics formulation can assist to maximize the efficacy of cancer nanovaccines.

Application of metabolomics in intrahepatic cholestasis of pregnancy: a systematic review.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a severe idiopathic disorder of bile metabolism; however, the etiology and pathogenesis of ICP remain unclear. AIMS: This study comprehensively reviewed metabolomics studies related to ICP, to help in identifying the pathophysiological changes of ICP and evaluating the potential application of metabolomics in its diagnosis. METHODS: Relevant articles were searched through 2 online databases (PubMed and Web of Science) from January 2000 to March 2022. The metabolites involved were systematically examined and compared. Pathway analysis was conducted through the online software MetaboAnalyst 5.0. RESULTS: A total of 14 papers reporting 212 metabolites were included in this study. There were several highly reported metabolites: bile acids, such as glycocholic acid, taurochenodeoxycholic acid, taurocholic acid, tauroursodeoxycholic acid, and glycochenodeoxycholic acid. Dysregulation of metabolic pathways involved bile acid metabolism and lipid metabolism. Metabolites related to lipid metabolism include phosphatidylcholine, phosphorylcholine, phosphatidylserine, sphingomyelin, and ceramide. CONCLUSIONS: This study provides a systematic review of metabolomics of ICP and deepens our understanding of the etiology of ICP.

Mechanism of vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug resistance in lung cancer.

To overcome the resistance of tumour cells to cis-diaminedichloroplatinum(II) (cisplatin, DDP), we designed and synthesised platinum(II) complexes with copper coordination active sites using vitamin B6 and benzohydrazide derivatives as raw materials.The 3D structures of the complexes were confirmed by X-ray single-crystal diffraction. The results of the biological activity assay showed that the Pt(II) complexes (VB6-Pt1 and VB6-Pt2) have higher anti-tumour activity on detected typical lung cancer cells than DDP. Among them, VB6-Pt1 (IC50 = 0.78 µM) efficiently reversed DDP resistance in A549/DDP cell line and increased selectivity index (26) against mortal MRC-5 fibroblasts. The study showed that VB6-Pt1 overcomes tumor drug resistance by significantly increasing the level of reactive oxyge species and inducing lysosomal membrane permeability, which leads to mitochondrial dysfunction and cell apoptosis. Furthermore, the inhibitory effect of VB6-Pt1 on A549 xenograft tumours was 81.5%, which was much higher than that of cisplatin (50.0%), without significantly increasing p-glycoprotein (P-gp) protein expression. The copper-coordinated active site in Pt(II) complexes may be a key factor in their ability to overcome DDP-resistant cancer cells.

An Information Theoretic Interpretation to Deep Neural Networks.

With the unprecedented performance achieved by deep learning, it is commonly believed that deep neural networks (DNNs) attempt to extract informative features for learning tasks. To formalize this intuition, we apply the local information geometric analysis and establish an information-theoretic framework for feature selection, which demonstrates the information-theoretic optimality of DNN features. Moreover, we conduct a quantitative analysis to characterize the impact of network structure on the feature extraction process of DNNs. Our investigation naturally leads to a performance metric for evaluating the effectiveness of extracted features, called the H-score, which illustrates the connection between the practical training process of DNNs and the information-theoretic framework. Finally, we validate our theoretical results by experimental designs on synthesized data and the ImageNet dataset.

Assessment of Acute Pancreatitis Severity and Prognosis with CT-Measured Body Composition.

OBJECTIVE: The aim of this study was to investigate the possible association of muscle and adipose parameters with the severity and prognosis of patients hospitalized with acute pancreatitis (AP). METHODS: A total of 392 hospitalized patients and 309 controls were enrolled in the study analysis from April 1, 2016, to February 1, 2021. The computed tomography scans of each population were evaluated for muscle and adipose parameters. The effects of parameters on developing moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) were evaluated using univariate and multivariate logistic regression analyses. Associations with disease recurrence and death were analyzed through Cox regression analysis. RESULTS: The AP patients had higher levels of visceral adipose tissue (144.25 vs 97.81 cm2, p < 0.001) and subcutaneous adipose tissue (135 vs 120 cm2, p < 0.001) but lower levels of adipose tissue attenuation (visceral and subcutaneous) and skeletal muscle attenuation (SMA) than the controls (p < 0.05, respectively). Visceral adipose tissue (VAT) and SMA differed significantly with p-values of 0.014 and 0.003 in the different severity groups of AP. In multivariate analysis, VAT and SMA were associated with MSAP or SAP, with odds ratios of 1.003 and 0.973, respectively (95% CI 1.000-1.006, p = 0.041; 95% CI 0.953-0.993, p = 0.010). Cox regression analysis showed that low SMA was strongly associated with an increased mortality in MSAP and SAP patients (HR 10.500, 95% CI 1.344-82.025, p = 0.025). Regression analysis also showed an association of VAT loss of more than 17% with reduced 1-year recurrence of acute pancreatitis (HR 0.427, 95% CI 0.189-0.967, p = 0.041). CONCLUSION: VAT and SMA were influential factors for the severity and prognosis of patients with AP. Patients should proper diet and exercise after discharge to reduce VAT and strengthen muscle function to improve prognosis.

Human umbilical cord-derived mesenchymal stem cells improve chronic pancreatitis in rats via the AKT-mTOR-S6K1 signaling pathway.

Chronic pancreatitis (CP) is a progressive inflammatory disease. In clinical treatment, many patients cannot get a timely diagnosis and effective treatment due to the lack of early diagnosis indicators. Mesenchymal stem cells have immunomodulatory and anti-inflammatory effects, and have broad application prospects in treating auto-immune diseases and inflammatory diseases. This study aimed to clarify the mechanisms of human umbilical cord mesenchymal stem cells (HUCMSCs) in the treatment of CP. The rats were randomly divided into four groups, with six rats in each group: control group, CP group, CP + HUCMSCs-treated group I, and CP + HUCMSCs-treated group II. We evaluated the levels of inflammatory factors, fibrosis and apoptosis markers, detected the protein expression levels of AKT-mTOR-S6K1 and assessed histological changes of the pancreas. The results showed that HUCMSCs not only inhibited the secretion of inflammatory cytokines and activation of pancreatic stellate cells but also suppressed the apoptosis of acinar cells. Further investigation revealed that HUCMSCs noticeably suppressed the AKT-mTOR-S6K1 pathway in the pancreatic tissue of DBTC-induced CP. In addition, the therapeutic effect of HUCMSCs injected into the inferior vena cava and left gastric artery in the CP model was also observed, thus providing the basis for the clinical application of intervention measures.

STRAP as a New Therapeutic Target for Poor Prognosis of Pancreatic Ductal Adenocarcinoma Patients Mainly Caused by TP53 Mutation.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. KRAS, TP53, CDKN2A, and SMAD4 are driver genes of PDAC and 30-75% patients have mutations in at least two of these four genes. Herein, we analyzed the relationship between these genes and prognosis of 762 patients in the absence of coexisting mutations, using data from three independent public datasets. Interestingly, we found that compared with mutations in other driver genes, TP53 mutation plays a significant role in leading to poor prognosis of PDAC. Additionally, we found that snoRNA-mediated rRNA maturation was responsible for the progression of cancer in PDAC patients with TP53 mutations. Inhibition of STRAP, which regulates the localization of SMN complexes and further affects the assembly of snoRNP, can effectively reduce maturation of rRNA and significantly suppress progression of TP53-mutant or low p53 expression pancreatic cancer cells in vitro and in vivo. Our study highlighted the actual contribution rate of driver genes to patient prognosis, enriching traditional understanding of the relationship between these genes and PDAC. We also provided a possible mechanism and a new target to combat progression of TP53-mutant PDAC patients.

Correction to: Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma.

[This corrects the article DOI: 10.1186/s12935-020-01243-6.].

Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma.

BACKGROUND: Emerging evidence suggests that competing endogenous RNAs plays a crucial role in the development and progress of pancreatic adenocarcinoma (PAAD). The objective was to identify a new lncRNA-miRNA-mRNA network as prognostic markers, and develop and validate a multi-mRNAs-based classifier for predicting overall survival (OS) in PAAD. METHODS: Data on pancreatic RNA expression and clinical information of 445 PAAD patients and 328 normal subjects were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype-Tissue Expression (GTEx). The weighted correlation network analysis (WGCNA) was used to analyze long non-coding RNA (lncRNA) and mRNA, clustering genes with similar expression patterns. MiRcode was used to predict the sponge microRNAs (miRNAs) corresponding to lncRNAs. The downstream targeted mRNAs of miRNAs were identified by starBase, miRDB, miRTarBase and Targetscan. A multi-mRNAs-based classifier was develop using least absolute shrinkage and selection operator method (LASSO) COX regression model, which was tested in an independent validation cohort. RESULTS: A lncRNA-miRNA-mRNA co-expression network which consisted of 60 lncRNAs, 3 miRNAs and 3 mRNAs associated with the prognosis of patients with PAAD was established. In addition, we constructed a 14-mRNAs-based classifier based on a training cohort composed of 178 PAAD patients, of which the area under receiver operating characteristic (AUC) in predicting 1-year, 3-year, and 5-year OS was 0.719, 0.806 and 0.794, respectively. The classifier also shown good prediction function in independent verification cohorts, with the AUC of 0.604, 0.639 and 0.607, respectively. CONCLUSIONS: A novel competitive endogenous RNA (ceRNA) network associated with progression of PAAD could be used as a reference for future molecular biology research.

Development and validation of a risk score for predicting mortality after resection of primary hepatocellular carcinoma.

BACKGROUND: Primary hepatocellular carcinoma (PHCC) has a poor prognosis and high short-term mortality rate, even after resection. Thus, early diagnosis in PHCC cases can help improve quality of life via personalized management strategies. RESULTS: The risk score system (RSS) were classified as low risk (<5 points), medium risk (5-10 points), or high risk (>10 points). The areas under the receiver operating characteristic curves were 0.80 in the training cohort and 0.69 in the validation cohort, which indicated satisfactory prognostic performance. The Hosmer-Lemeshow goodness of fit test (P>0.05) revealed consistent performance in both groups. The concordance index (C-index: 0.663, 95% CI: 0.618-0.708) revealed excellent discrimination and good calibration in the validation cohort. CONCLUSIONS: This simple RSS, which is based on clinical and laboratory data from patients undergoing resection of PHCC, might allow clinicians and medical staff to better manage PHCC. MATERIALS AND METHODS: A total of 672 PHCC cases were retrospectively obtained from the First Affiliated Hospital of Wenzhou Medical University between January 2007 and February 2015. Cox proportional hazard models were used to identify independent predictors of mortality. Kaplan-Meier curves and the log-rank test were used to examine the relationships between the prognostic factors and overall mortality.

Adipose­derived mesenchymal stem cells ameliorate dibutyltin dichloride­induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway.

Adipose­derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC­induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase­3, BAX and Bcl­2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC­induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC­induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future.

DPP4 Inhibitor Attenuates Severe Acute Pancreatitis-Associated Intestinal Inflammation via Nrf2 Signaling.

Severe acute pancreatitis (SAP) is a challenging disease with high morbidity and mortality, often complicated by multiple organ dysfunction syndrome (MODS). The intestine, a major organ involved in MODS, correlates strongly with the evolution of the disease. In this study, we demonstrated that the DPP4 inhibitor, sitagliptin, protects SAP-associated intestinal injury both in vitro and in vivo. These beneficial effects were achieved by suppressing oxidative stress and inflammatory responses. Moreover, in sitagliptin-treated SAP mice, expression of Nrf2 was induced and that of NF-κB was reduced, compared to the control SAP mice. In addition, we used Nrf2-/- mice to test the protective effect of Nrf2 during sitagliptin treatment of SAP; our results indicated that Nrf2-/- mice had greater pancreatic and intestinal injury than wild-type mice. Taken together, high levels of ROS induced by SAP may be inhibited by sitagliptin, possibly by inactivating the Nrf2-NF-κB pathway.

High Glucose-Induced ROS Production Stimulates Proliferation of Pancreatic Cancer via Inactivating the JNK Pathway.

Aberrant glucose metabolism of diabetes mellitus or hyperglycemia stimulates pancreatic tumorigenesis and progression. Hyperglycemic environment can increase the ROS level of tumors, but the role of upregulation of ROS levels in pancreatic cancer (PC) still remains controversial. Here, the same as other reports, we demonstrate that high glucose promoted pancreatic cancer cell growth and resulted in an increase in the level of ROS. However, it is interesting that the phosphorylation of JNK was reduced. When treating PC cells with N-acetyl-L-cysteine (NAC), the intracellular ROS generation is repressed, but the expression of phosphorylation of JNK and c-Jun increased. Moreover, the JNK inhibitor SP600125 significantly promoted cell proliferation and suppressed cell apoptosis of pancreatic cancer cells under high glucose conditions. Collectively, high levels of ROS induced by high glucose conditions stimulated the proliferation of pancreatic cancer cells, and it may be achieved by inactivating the JNK pathway.

Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the 'reversed' amide scaffold.

The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure-activity-relationship of the novel porcupine inhibitors based on a 'reversed' amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.

Involvement of human chorionic gonadotropin in regulating vasculogenic mimicry and hypoxia-inducible factor-1α expression in ovarian cancer cells.

BACKGROUND: Human chorionic gonadotropin (hCG) can play a crucial role in angiogenesis. In the present study, we focused on hCG to gain insight into its potential effects on vasculogenic mimicry (VM) in ovarian cancer cells. METHODS: Ovarian cancer OVCAR-3 cells were incubated with different concentrations of recombinant hCG in 3-dimensional cultures. VM was identified by morphological observations and vascular endothelial cell marker detection in OVCAR-3 cells. Expression of hCG, hypoxia-inducible factor-1α (HIF-1α), and the endothelial cell markers CD31, VEGF, and factor VIII were detected by reverse transcription polymerase chain reaction and western blotting. The effect of hCG on endothelial cell-marker expression in ovarian cancer cells was further explored using small interfering RNA (siRNA) and plasmid-based approaches. RESULTS: Incubation of OVCAR-3 cells with recombinant hCG induced vessel-like network formation, which was accompanied by significant elevation of vascular marker expression. Attenuation of hCG expression by siRNA in OVCAR-3 cells suppressed the expression of endothelial cell markers and HIF-1α by tumour cells. Overexpression of hCG in OVCAR-3 cells resulted in increased expression of endothelial cell markers and HIF-1α. CONCLUSIONS: HCG was crucial for changing the phenotype of OVCAR-3 cells to endothelial-like cells. The effect of hCG induction on VM in ovarian cancer cells is potentially associated with HIF-1α.

Role of hCG in vasculogenic mimicry in OVCAR-3 ovarian cancer cell line.

OBJECTIVES: Vasculogenic mimicry (VM) is induced by hypoxia in 3-dimensional culture of ovarian cancer cells. By using this 3D model system, we explored the expression of human chorionic gonadotropin (hCG) and its effects on VM formation in ovarian cancer cell line OVCAR-3 both under normoxic and hypoxic conditions. METHODS: Vasculogenic mimicry was identified by morphological observation and detection of vascular cell marker expressed by OVCAR-3. Potential formation of tumor channels was observed by light microscopy and scanning electron microscopy. Expression of vascular cell marker CD31, vascular endothelial growth factor, and Factor VIII were detected by flow cytometry, immunochemistry, and Western blot. Expression of hCG was investigated by enzyme-linked immunosorbent assay, chemiluminescence immunoassay, real-time polymerase chain reaction (PCR), and Western blot. Expression of hypoxia-inducible factor-1α (HIF-1α) was detected by real-time PCR, Western blot, and blocked by small interference RNA. Incubation of OVCAR-3 with recombinant hCG was used to evaluate its effect on VM formation. The specificity of the effect of hCG was assessed by inhibition with the neutralizing anti-hCG antibody. RESULTS: OVCAR-3 cells formed vessel-like network structures and expressed vascular marker significantly under hypoxia in 3D. The expression level of hCG under hypoxia was significantly higher than that under normoxia. Attenuating hypoxia-inducible factor (HIF)-1α expression via small interference RNA resulted in a significantly decreased hCG expression in OVCAR-3, which indicated that the effect of hypoxia on hCG expression was mediated through HIF-1α. Treatment of OVCAR-3 with 5000 mU/mL hCG resulted in the presence of tumor cell-lined vasculature and significant elevation in vascular marker expression, even under normoxia. Expression level of vascular marker and HIF-1α in OVCAR-3 increased in response to hCG treatment in a dose-dependent manner. The effect of hCG was inhibited by the neutralizing anti-hCG antibody. CONCLUSIONS: Human chorionic gonadotropin has the potential to induce VM in OVCAR-3. Human chorionic gonadotropin might have synergistic hypoxia-induced effect on vascular marker and HIF-1α expression.