A Pt(II) complex bearing N-heterocycle ring induced ferroptotic cell death in ovarian cancer.

Cisplatin is a widely used chemotherapeutic agent which interacts with DNA to form Pt-DNA adducts, leading to DNA double-strand breaks and apoptosis. Resistance is the major obstacle in the clinical application of cisplatin. A quinoline derivative based Pt(II) complex PtQ was synthesized and characterized. As an analogue of cisplatin, PtQ demonstrated a novel anticancer mechanism in ovarian cancer. PtQ caused excessive production of reactive oxygen species (ROS), which triggered ferroptotic cell death in ovarian cancer. Cystine/glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4) which alleviate lipid peroxidation were both downregulated in PtQ-treated SKOV3 cells. Furthermore, PtQ induced DNA single-strand breaks and suppressed the expression of single-strand breaks repair protein PARP1. Mechanism studies demonstrated that PtQ can hopefully bypass the signaling pathways mediated cisplatin resistance in ovarian cancer.

A monofunctional Pt(II) complex combats triple negative breast cancer by triggering lysosome-dependent cell death.

Monofunctional Pt(II) complexes with potent efficacy to overcome the drawbacks of current platinum drugs represent a promising therapeutic approach for triple negative breast cancer (TNBC). A heterocyclic-ligated monofunctional Pt(II) complex PtL with a unique action of mode was designed and investigated. PtL induced DNA single-strand breaks and caused genomic instability in TNBC cells. Mechanism studies demonstrated that PtL disrupted lysosomal acidity and function, which in turn triggered lysosome-dependent cell death. Furthermore, PtL showed convincing suppression in the tube forming and cell migratory abilities against the metastatic potential of TNBC cells. The synthesis and investigation of PtL revealed its potential value as an anti-TNBC drug and extended the family of monofunctional Pt(II) complexes.

[Effect of electroacupuncture on the multifidus muscle in patients with lumbar disc herniation].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on lumbar dysfunction and multifidus muscle characteristics in patients with lumbar disc herniation (LDH). METHODS: Sixty patients with LDH were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the control group were treated with symptomatic treatment. On the basis of the treatment of the control group, the patients in the observation group were treated with acupuncture at L3-S1 Jiaji (Ex-B 2) and Dachangshu (BL 25), and the ipsilateral L3 and L5 Jiaji point were connected with EA (continuous wave, frequency of 20 Hz, and the intensity was appropriate to the patient's tolerance). The needles were retained for 20 min, once every other day, and 10 times were taken as a course of treatment. A total of 2 courses of treatment was given. The modified Oswestry disability index (ODI) as well as the physical component summary (PCS) and mental component summary (MCS) of the 36-item short form health survey (SF-36) were compared between the two groups before and after treatment. Lumbar MRI was performed before and after treatment to measure the cross-sectional area (CSA), fatty infiltration (FI) and T2 values of multifidus muscle at the lower edge of L4 and L5 vertebral bodies. RESULTS: After treatment, the ODI, PCS and MCS socres in the two groups were improved compared with those before treatment (P<0.05), and the ODI and PCS socres in the observation group were better than those in the control group (P<0.05). After treatment, the FI and value of T2 in the observation group were lower than those before treatment (P<0.05), and lower than those in the control group (P<0.05). CONCLUSION: EA could improve lumbar dysfunction, relieve edema and fatty infiltration of multifidus muscle in patients with LDH.

Revisiting artificial intelligence diagnosis of hepatocellular carcinoma with DIKWH framework.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high morbidity and fatality rate. Traditional diagnostic methods for HCC are primarily based on clinical presentation, imaging features, and histopathology. With the rapid development of artificial intelligence (AI), which is increasingly used in the diagnosis, treatment, and prognosis prediction of HCC, an automated approach to HCC status classification is promising. AI integrates labeled clinical data, trains on new data of the same type, and performs interpretation tasks. Several studies have shown that AI techniques can help clinicians and radiologists be more efficient and reduce the misdiagnosis rate. However, the coverage of AI technologies leads to difficulty in which the type of AI technology is preferred to choose for a given problem and situation. Solving this concern, it can significantly reduce the time required to determine the required healthcare approach and provide more precise and personalized solutions for different problems. In our review of research work, we summarize existing research works, compare and classify the main results of these according to the specified data, information, knowledge, wisdom (DIKW) framework.

Biological evaluation of a novel bilirubin adsorbent and its therapeutic effect on animal models of hyperbilirubinemia.

Hyperbilirubinemia caused severe hepatobiliary diseases with various causes, especially hepatic fibrosis and cirrhosis caused by end-stage hepatitis B and C. Plasma adsorption perfusion (PP) has a tremendous advantage in treating patients with hyperbilirubinemia and liver failure, wherein, a safe and effective adsorbent is the key to filter out bilirubin successfully in PP. In this work, a simple engineering strategy, a new porous polymer adsorption resin ERM-0100 based on the homopolymer predispersion system, is proposed to produce high-performance bilirubin adsorbents. Preliminary experimental results show that ERM-0100 exhibits a large surface area and uniformly porous structure. Experimental results verify that ERM-0100 has high biocompatibility and bilirubin adsorption efficiency (TBIL:35%, direct bilirubin [DBIL]:30%, IBIL:87%) that is significantly higher than most of the reported adsorbents. Animal experiments prove that ERM-0100 has high bilirubin adsorption efficiency and can improve the liver function of animals. The combination of high biocompatibility and high adsorption capacity positions the ERM-0100 as a promising candidate for bilirubin removal.

Impact of Muscle Mass on Survival in Patients with Sepsis: A Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of this study is to investigate the association between loss of muscle mass and prognosis of sepsis. METHODS: Six databases, including PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Ovid, were searched by the deadline of August 18, 2020. A meta-analysis was conducted on the collected data by means of a random-effects model. The quality of each included article was assessed according to the Newcastle-Ottawa Scale. RESULTS: Out of 1,819 references, 6 articles and 1 conference abstract were included. Sepsis patients with a loss of muscle mass or sarcopenia had higher mortality (risk ratio [RR]: 1.94, 95% confidence intervals [CI]: 1.59-2.37; I-squared = 18.7%, p < 0.001). The RR of mortality within 30 days (RR: 2.31, 95% CI: 1.78-2.99, p < 0.001) was higher than that of mortality over 30 days. Loss of psoas muscle mass, as evaluated by CT, showed the highest RR of sepsis mortality. In addition, based on data on overall survival retrieved from 4 trials, the pooled hazard ratio (HR) for patients with a loss of muscle mass or sarcopenia was 3.04. Subgroup analysis showed that survival time was the main source of heterogeneity for the overall HR. Furthermore, the scanning areas of muscle mass in survival patients were 0.33 cm2/m2 higher than those measured in deceased patients. CONCLUSION: A loss of muscle mass, as evaluated by CT scan, was associated with a poor outcome in sepsis.

Development and validation of LRP1B mutation-associated prognostic model for hepatocellular carcinoma.

PURPOSE: To develop a lipoprotein receptor-related protein 1B (LRP1B) gene mutation-based prognostic model for hepatocellular carcinoma (HCC) patients risk prediction. METHODS: The LRP1B gene mutation rate was calculated from HCC patient samples. Meanwhile, differentially expressed genes according to LRP1B mutant were screened out for prognostic model establishment. Based on this innovative model, HCC patients were categorized into high- and low-risk groups. The immune status including immune cell infiltration ratio and checkpoints have been explored in two groups. The functions of LRP1B and risk factors in the model were verified using both in vivo and in vitro experiments. RESULTS: It could be demonstrated that LRP1B was a potential negative predictor for HCC patients prognosis with high mutation frequency. The functions of LRP1B were verified with ELISA and Quantitative Real-time PCR method based on clinic-recruited HCC participants. Eleven genes displayed significant differences according to LRP1B status, which could better predict HCC patient prognosis. The functions of these genes were examined using HCC cell line HCCLM3, suggesting they played a pivotal role in determining HCC cell proliferation and apoptosis. From the immune cell infiltration ratio analysis, there was a significant difference in the infiltration degree of seven types of immune cells and two immune checkpoints between high- and low-risk HCC patients. CONCLUSION: The present study hypothesized a potential prognostic biomarker and developed a novel LRP1B mutation-associated prognostic model for HCC, which provided a systematic reference for future understanding of clinical research.

Accuracy of circulating microRNAs in diagnosis of sepsis: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to systematically assess the accuracy of circulating microRNAs (miRNAs) as a promising biomarker for sepsis via a meta-analysis. METHODS: PubMed, Cochrane Library, Embase, Web of Science, Scopus, and Ovid databases were searched up to April 3, 2020. The Quality in Prognostic Studies (QUADAS-2) tool was used to assess methodological quality. The pooled sensitivity (Sen), specificity (Spe), positive or negative likelihood ratios (PLR or NLR), diagnostic odds ratio (DOR), curve, and area under the curve (AUC) were calculated with 95% confidence interval (95% CI). The overall accuracy (OA) of miRNAs, procalcitonin (PCT), and C-reactive protein (CRP) was analyzed by the chi-square test. RESULTS: A total of 22 records were eligible for systematic review, including 2210 sepsis, 426 systemic inflammatory response syndrome (SIRS), and 1076 healthy controls (HC). The pooled Sen, Spe, and DOR of miRNAs were 0.80 (95% CI 0.75-0.83), 0.85 (95% CI 0.80-0.89), and 22 (15-32), respectively. The DOR of PCT and CRP were 17 (95% CI 4-68) and 7 (95% CI 1-48), respectively. The OA value of miRNAs (79.02%) and PCT (76.95%) were higher than CRP (61.22%) (P < 0.000). The subgroup analysis indicated that miRNAs in adults, serum type, downregulation of miRNA expression, criteria of Sepsis-3, internal reference of non-U6, and dysregulation expression of miR-223 had superior diagnostic accuracy. In addition, there was no significant publication bias among the included studies. Fagan's nomogram showed valuable clinical utility. CONCLUSIONS: Our meta-analysis indicated that the level of circulating miRNAs, particularly the miR-223, could be used as an indicator for sepsis.

The Clinical and Radiological Manifestations in Coronavirus Disease 2019 With Negative Nucleic Acid Results.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was a new emerging disease with high infectiousness. Its diagnosis primarily depended on real-time polymerase chain reaction (RT-PCR) results. This study investigated epidemiological, clinical, and radiological characteristics of COVID-19 with negative RT-PCR results before confirmation. METHODS: Patients with COVID-19 were enrolled and divided into 2 groups: a negative group with negative RT-PCR results before confirmation and a positive group with positive results at the first detection. Epidemiological and clinical features were compared. Dynamic chest computerized tomography (CT) images of the negative group were evaluated. RESULTS: Ninety-nine laboratory-confirmed patients with COVID-19 including 8 patients (8%) with negative RT-PCR results were included. Patients from the negative group had similar epidemiological features: the average age (50.25 ±â€…13.27 years in the negative group and 53.70 ±â€…16.64 years in the positive group) and gender distribution (males made up 50% of the negative group and 62.6% of the positive group) were comparable. No significant differences were observed in clinical symptoms between the 2 groups. We found that fever was the most common symptom for both groups, followed by cough, expectoration, chest distress, fatigue, and gastroenterological symptoms. Moreover, ground-glass opacities and consolidations were the main manifestation in chest CT of patients with COVID-19 with or without confirmed RT-PCR results. CONCLUSIONS: Regardless of initial RT-PCR results, patients with COVID-19 had similar epidemiological, clinical, and chest CT features. Our study suggests value from early chest CT scans in COVID-19 screening and dynamic significance of radiology in disease monitoring should guide clinical decisions.

Potential biomarkers of HCC based on gene expression and DNA methylation profiles.

The aim of the present study was to identify potential biomarkers of hepatocellular carcinoma (HCC). Three gene expression profiles of GSE95698, GSE49515 and GSE76427 and a DNA methylation profile of GSE73003 were downloaded from the Gene Expression Omnibus (GEO) database, each comprising data regarding HCC and control tissue samples. The differentially expressed genes (DEGs) between the HCC group and the control group were identified using the limma software package. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the overlapping DEGs. The PPI network of the overlapping DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. A total of 41 DEGs were identified in HCC the group compared with control group. The overlapping DEGs were enriched in 11 GO terms and 3 KEGG pathways. A total of 6,349 DMSs were identified, and 6 of the differentially expressed genes were also differentially methylated [Denticleless protein homolog (DTL), Dual specificity phosphatase 1 (DUSP1), Eomesodermin, Endothelial cell specific molecule 1, Nuclear factor κ-light-chain gene enhancer of activated B cells inhibitor, α (NFKBIA) and suppressor of cytokine signaling 2 (SOCS2)]. The present study suggested that DTL, DUSP1, NFKBIA and SOCS2 may be potential biomarkers of HCC, and the tumor protein 'p53 signaling', 'forkhead box O1' signaling and 'metabolic' pathways may serve roles in the pathogenesis of HCC.

Antioxidant Role of PcGSTd1 in Fenpropathrin Resistant Population of the Citrus Red Mite, Panonychus citri (McGregor).

The citrus red mite, Panonychus citri, a major citrus pest distributed worldwide, has evolved severe resistance to various classes of chemical acaricides/insecticides including pyrethroids. It is well known that the resistance to pyrethroids is mainly caused by point mutations of voltage-gated sodium channel gene in a wide range of pests. However, increasing number of evidences support that pyrethroids resistance might also be resulted from the integrated mechanisms including metabolic mechanisms. In this study, firstly, comparative analysis of RNA-seq data showed that multiple detoxification genes, including a GSTs gene PcGSTd1, were up-regulated in a fenpropathrin-resistant population compared with the susceptible strain (SS). Quantitative real time-PCR results showed that the exposure of fenpropathrin had an induction effect on the transcription of PcGSTd1 in a time-dependent manner. In vitro inhibition and metabolic assay of recombinant PcGSTd1 found that fenpropathrin might not be metabolized directly by this protein. However, its antioxidant role in alleviating the oxidative stress caused by fenpropathrin was demonstrated via the reversely genetic experiment. Our results provide a list of candidate genes which may contribute to a multiple metabolic mechanisms implicated in the evolution of fenpropathrin resistance in the field population of P. citri. Furthermore, during the detoxification process, PcGSTd1 plays an antioxidant role by detoxifying lipid peroxidation products induced by fenpropathrin.

Prediction of Lymph Node Metastases in Gastric Cancer by Serum APE1 Expression.

Aims: To investigate the functional role of serum Human apurinic/apyrimidinic endonuclease 1 (APE1) in prediction of lymph node metastasis in gastric cancer patients. Materials and methods: Serum samples were pre-operational collected from 86 patients with gastric cancer from Tianjin Medical University Cancer Institute and Hospital from March 2016 to August 2016. The serum of APE1 was measured by ELISA development kit and other CA242, CA724, CA199 and CEA levels by electrochemiluminescence assay. Results: The total of 86 patients with gastric cancer was classified into two groups (lymph node positive and negative groups). Using ELISA assay, we found out that the concentration of serum APE1 was higher in lymph node positive group than that of lymph node negative group. The receiver operating characteristic (ROC) curve was performed to analyze, indicating that area under the ROC curve of serum APE1 were better than those of each regular markers (CEA+CA199+CA242+CA724) or combination of these markers. Additionally, the APE1 overexpression was uncovered in tissue of gastric cancer patients with lymph nodes metastases, which is correlation with results of serum APE1. Conclusion: Serum APE1 was identified as a valuable marker for prediction of lymph node metastases in patients with gastric cancer.

Clinical features and treatment of patients with Vibrio vulnificus infection.

OBJECTIVES: Infections with Vibrio vulnificus are commonly fatal, and the speed and accuracy of diagnosis and treatment is directly linked to mortality. The main aims of this study were to investigate the clinical characteristics of six patients with V. vulnificus infections retrospectively and to determine the effect of treatment with tigecycline (TGC) alone compared with doxycycline plus ceftazidime (DOX/CAZ). METHODS: The medical records of patients were reviewed. The species-specific and pathogenic gene markers were detected by PCR, and multilocus sequence typing (MLST) was performed. Furthermore, the effects of TGC and of DOX/CAZ were determined using time-kill assays. RESULTS: MLST revealed six different sequence types and five of them were novel. The complete clinical pattern (vcg type C, CPS operon allele 1, 16S-rRNA type B) was found in one strain and the others had a mixed pattern. The lesion was mainly located at the distal end of the extremities and the most common clinical symptoms were fever, pain, erythema, and local swelling. The in vitro time-kill assay indicated that TGC monotherapy at a concentration of 0.1mg/l had a rapid bactericidal effect against the six tested V. vulnificus strains at 24h. CONCLUSIONS: TGC alone might be a better potential therapeutic option than the traditional combination of DOX/CAZ against V. vulnificus.

Identification of responsive proteins in Panonychus citri exposed to abamectin by a proteomic approach.

Abamectin is a microbial-derived pesticide widely used for control of agricultural pests. However, sustained use of abamectin has led to the development of resistance in some target species. Previous studies on arthropod resistance to abamectin have mainly used traditional biochemical and molecular approaches. To understand the responses of citrus red mite, Panonychus citri, exposed to abamectin, comparative proteomic analysis was conducted using two-dimensional electrophoresis (2-DE). A total of 26 distinct protein spots were present in response to abamectin exposure. Tandem mass spectrometry (MS/MS) identified 16 proteins that were mainly involved in energy metabolism and detoxification. Some remaining proteins were not identifiable, suggesting that they may be novel. The expression levels of transcripts associated with proteins were analyzed by quantitative reverse transcription PCR (qRT-PCR). Furthermore, to validate the proteomic data obtained in the present study, Western-blot experiment was performed and the expression of sHsp and PcE1 proteins were confirmed, respectively. BIOLOGICAL SIGNIFICANCE: The citrus red mite has developed resistance to many acaricides, including abamectin. In the current study, we used the proteomic approaches involving 2-DE, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), and MS/MS to document changes in adult P. citri during 24h of abamectin exposure. Abamectin stress induced a total of 16 differentially regulated proteins. The proteomic results were validated in mRNA expression patterns using qRT-PCR. This is the first analysis of differentially expressed proteins in P. citri exposed to abamectin. The results help clarify the physiological mechanisms of P. citri responses to abamectin exposure.

Involvement of Three Esterase Genes from Panonychus citri (McGregor) in Fenpropathrin Resistance.

The citrus red mite, Panonychus citri (McGregor), is a major citrus pest with a worldwide distribution and an extensive record of pesticide resistance. However, the underlying molecular mechanism associated with fenpropathrin resistance in this species have not yet been reported. In this study, synergist triphenyl phosphate (TPP) dramatically increased the toxicity of fenpropathrin, suggesting involvement of carboxylesterases (CarEs) in the metabolic detoxification of this insecticide. The subsequent spatiotemporal expression pattern analysis of PcE1, PcE7 and PcE9 showed that three CarEs genes were all over-expressed after insecticide exposure and higher transcripts levels were observed in different field resistant strains of P. citri. Heterologous expression combined with 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) cytotoxicity assay in Spodoptera frugiperda (Sf9) cells revealed that PcE1-, PcE7- or PcE9-expressing cells showed significantly higher cytoprotective capability than parental Sf9 cells against fenpropathrin, demonstrating that PcEs probably detoxify fenpropathrin. Moreover, gene silencing through the method of leaf-mediated dsRNA feeding followed by insecticide bioassay increased the mortalities of fenpropathrin-treated mites by 31% (PcE1), 27% (PcE7) and 22% (PcE9), respectively, after individual PcE gene dsRNA treatment. In conclusion, this study provides evidence that PcE1, PcE7 and PcE9 are functional genes mediated in fenpropathrin resistance in P. citri and enrich molecular understanding of CarEs during the resistance development of the mite.

Over-expression of ASIC1a promotes proliferation via activation of the ß-catenin/LEF-TCF axis and is associated with disease outcome in liver cancer.

Acid-sensing ion channels 1a (ASIC1a) has been reported to promote migration and invasion in liver cancer. However, the clinical significance and molecular mechanism of ASIC1a in liver cancer remain unknown. In the study, we found that ASIC1a is frequently up-regulated in liver cancer tissues. The over-expression of ASIC1a is associated with advanced clinical stage and poor prognosis. The pro-proliferative of ASIC1a is pH dependent. Knockout of ASIC1a by CRISPR/CAS9 inhibited liver cancer cell proliferation and tumorigenicity in vitro and in vivo through ß-catenin degradation and LEF-TCF inactivation. Our results indicated a potential diagnostic marker and chemotherapeutic target for liver cancer.

Functional analysis of a chitinase gene during the larval-nymph transition in Panonychus citri by RNA interference.

Chitinases are hydrolytic enzymes that are required for chitin degradation and reconstruction in arthropods. In this study, we report a cDNA sequence encoding a putative chitinase (PcCht1) from the citrus red mite, Panonychus citri. The PcCht1 (564 aa) possessed a signal peptide, a conserver domain, and a chitin-binding domain. Structural and phylogenetic analyses found that PcCht1 had high sequence similarity to chitinases in Tetranychus urticae. Real-time quantitative PCR analyses showed that the transcript levels of PcCht1 peaked periodically in larval and nymph stages. Moreover, significant increase of PcCht1 transcript level in the larvae was observed upon the exposure of diflubenzuron. In contrast, exposures of the larvae to diflubenzuron resulted in the decreased chitin content. Furthermore, through a feeding-based RNA interference approach, we were able to reduce the PcCht1 transcript level by 59.7 % in the larvae, and consequently the treated larvae showed a very low molting rate compared with the control. Our results expanded the understanding of the important role of PcCht1 in the growth and development of P. citri.

Preparation and Adsorption Properties of Novel Porous Microspheres with Different Concentrations of Bilirubin.

BACKGROUND: Plasma perfusion was widely used to clear toxic substances of plasma. Particle size and uniformity of adsorbent microspheres also affect the absorption rate. METHODS: Conventional suspension polymerization was improved using a pre-dispersion homogenizer to obtain novel adsorbent microspheres, named ERM-0100. Microsphere-related characteristics and attributes were analysed. RESULT: The ERM-0100 microspheres efficiently adsorbed different bilirubin concentrations, with a maximum rate of 59.72 ± 1.08%. At high bilirubin concentrations, ERM-0100 exhibited similar adsorption rate with BRS350 and BS330 (p = 0.303, p = 1.000, relatively), and higher than HB-H-6 (p = 0.000). At different concentration, ERM-0100 showed good adsorption performance. The ERM-0100 had no significant adsorption for electrolyte; for TP and ALB, the loss rates of ERM-0100 were 15.65 ± 0.36 and 23.23 ± 1.11%, respectively. In addition, ERM-0100 showed good blood compatibility. CONCLUSION: The ERM-0100 is a potential biomedical material for plasma perfusion for good effect, less costs and more safety. The microspheres may be coated to reduce its protein adsorption.