PCDH1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds. RESULTS: The RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD. CONCLUSION: PCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.

Comparison of bloodstream and non-bloodstream infections caused by carbapenem-resistant Klebsiella pneumoniae in the intensive care unit: a 9-year respective study.

Background: Bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) have received much attention. However, few studies have identified risk factors for CRKP BSIs in comparison to CRKP non-bloodstream infections (non-BSIs). This study aimed to compare the epidemiology, risk factors, and outcomes of CRKP BSIs and CRKP non-BSIs. Methods: We conducted a retrospective study of patients infected with CRKP in the ICU from January 2012 to December 2020. Clinical characteristics and outcomes were compared between CRKP BSIs and CRKP non-BSIs. Predictors associated with 28-day all-cause mortality in CRKP-infected patients were also evaluated. Results: 326 patients infected with CRKP were enrolled, including 96 patients with CRKP BSIs and 230 with CRKP non-BSIs. The rates of CRKP BSIs in CRKP infections were generally raised from 2012 (12.50%) to 2020 (45.76%). Multivariate logistic analysis indicated that the use of carbapenems within the prior 90 days was an independent risk factor for CRKP BSIs (p = 0.019). Compared to CRKP non-BSIs, CRKP isolates in the CRKP BSI group were found to be non-susceptible to more tested carbapenems (p = 0.001). Moreover, the CRKP BSI group exhibited a higher mortality rate (p = 0.036). The non-susceptibility of CRKP isolates to more tested carbapenems (p = 0.025), a high SOFA score (p = 0.000), and the use of antifungal drugs within the prior 90 days (p = 0.018) were significant factors for 28-day all-cause mortality in CRKP-infected patients. Conclusion: The proportion of CRKP BSI increased progressively in CRKP-infected patients over 9 years. The use of carbapenems within the prior 90 days was an independent risk factor for the development of CRKP BSIs. The non-susceptibility of CRKP isolates to more tested carbapenems and a higher mortality rate were found in the CRKP BSI group.

Clinical characteristics of carbapenem-resistant Klebsiella pneumoniae infection/colonisation in the intensive care unit: a 9-year retrospective study.

OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection/colonisation has been reported in hospitals. The clinical characteristics of CRKP infection/colonisation in the intensive care unit (ICU) have received little attention. This study aims to investigate the epidemiology and extent of K. pneumoniae (KP) resistance to carbapenems, the sources of CRKP patients and CRKP isolates, and the risk factors for CRKP infection/colonisation. DESIGN: Retrospective single-centre study. DATA SOURCE: Clinical data were obtained from electronic medical records. PARTICIPANTS: Patients isolated with KP in the ICU from January 2012 to December 2020. MAIN OUTCOME MEASURES: The prevalence and changing trend of CRKP were determined. The extent of KP isolates resistance to carbapenems, the specimen types of KP isolates, and the sources of CRKP patients and CRKP isolates were all examined. The risk factors for CRKP infection/colonisation were also assessed. RESULTS: The rate of CRKP in KP isolates raised from 11.11% in 2012 to 48.92% in 2020. CRKP isolates were detected in one site in 266 patients (70.56%). The percentage of CRKP isolates not susceptible to imipenem increased from 42.86% in 2012 to 98.53% in 2020. The percentage of CRKP patients from general wards in our hospital and other hospitals gradually converged in 2020 (47.06% vs 52.94%). CRKP isolates were mainly acquired in our ICU (59.68%). Younger age (p=0.018), previous admission (p=0.018), previous ICU stay (p=0.008), prior use of surgical drainage (p=0.012) and gastric tube (p=0.001), and use of carbapenems (p=0.000), tigecycline (p=0.005), ß-lactams/ß-lactamase inhibitors (p=0.000), fluoroquinolones (p=0.033), and antifungal drugs (p=0.011) within the prior 3 months were independent risk factors for CRKP infection/colonisation. CONCLUSIONS: Overall, the rate of KP isolates resistance to carbapenems increased, and the severity of this resistance significantly increased. Intensive and local infection/colonisation control measures are necessary for ICU patients, especially those with risk factors for CRKP infection/colonisation.

Nonsteroidal anti-inflammatory drug diclofenac accelerates the emergence of antibiotic resistance via mutagenesis.

Overuse of antimicrobial agents are generally considered to be a key factor in the occurrence of antibiotic resistance bacteria (ARB). Nevertheless, it is unclear whether ARB can be induced by non-antibiotic chemicals such as nonsteroidal anti-inflammatory drug (NSAID). Thus, the objective of this study is to investigate whether NSAID diclofenac (DCF) promote the emergence of antibiotic resistance in Escherichia coli K12 MG1655. Our results suggested that DCF induced the occurrence of ARB which showed hereditary stability of resistance. Meanwhile, gene variation was identified on chromosome of the ARB, and DCF can cause bacterial oxidative stress and SOS response. Subsequently, transcriptional levels of antioxidant (soxS, sodA, sodC, gor, katG, ahpF) and SOS (recA, lexA, uvrA, uvrB, ruvA, ruvB, dinB, umuC, polB) system-related genes were enhanced. However, the expression of related genes cannot be increased in high-dosage treatment compared with low-dosage samples because of cytotoxicity and cellular damage. Simultaneously, high-dosage DCF decreased the mutation frequency but enhanced the resistance of mutants. Our findings expand our knowledge of the promoting effect on the emergence of ARB caused by DCF. More attention and regulations should be given to these potential ecological and health risks for widespread DCF.

Anti-influenza virus activity of the REV-ERBα agonist SR9009 and related analogues.

REV-ERBα is a member of the nuclear receptor superfamily of transcription factors that aids in the regulation of many diseases. However, the prospect of using REV-ERBα for anti-influenza virus treatment remains poorly described, and there is an urgent need to develop effective anti-influenza agents due to the emergence of drug-resistant influenza viruses. In this study, eight SR9009 analogues were designed, synthesized, and evaluated for their biological activities against multiple influenza virus strains (H1N1, H3N2, adamantane- and oseltamivir-resistant H1N1 and influenza B virus), using ribavirin as the positive control. SR9009 and its analogues showed low micromolar or submicromolar EC50 values and exhibited modestly improved antiviral potency compared to that of ribavirin. In particular, compound 5a possessed the most potent inhibitory activity (EC50 = 0.471, 0.644, 1.644, 0.712 and 0.661 µM for A/PR/8/34, A/WSN/33, A/Wisconsin/67/2005, B/Yamagata/16/88 and Hebei/SWL1/2006, respectively). Cotransfection assays showed that all synthesized derivatives efficaciously suppressed transcription driven by the Bmal1 promoter. Mechanistic study results indicated that 5a efficiently inhibited IAV replication and interfered with the ealry stage of influenza virus life cycle. In addition, we found that 5a upregulated the key antiviral interferon-stimulated genes MxA, OAS2 and CH25H. Further in-depth transcriptome analysis revealed a series of upregulated genes that may contribute to the antiviral activities of 5a. These findings may provide an important direction for the development of new host-targeted broad-spectrum antiviral agents.

[Influence of match-pair of huanglian-rougui on rat intestinal absorption of total huanglian alkali].

OBJECTIVE: To research the principle of match-pair of huanglian-rougui. METHOD: A rat intestinal model in vitro had been applied to investigate the absorption and transport characteristics of total huanglian alkali across intestinal mucosa, as well as the influence of match-pair of huanglian-rougui on its intestinal absorption. The identification of alkalis in primitive solution, serosal solution and intestinal homogenate were analyzed by TLC. RESULT: The transport and uptake characteristic of total alkali in huanglian solution was similar to berberine. The uptake and transport of total alkali across intestinal mucosa was concentration-and time-dependent. Transport directions had strong effects on the transport of total alkali. The amount of total alkali transport from serosal side to mucosal side was much more than that from mucosal side to serosal side. After matching with rougui as some ration, the intestinal absorption of total alkali increased significantly comparing with huanglian alone, and there was an optimal ration among match-pair of huanglian-rougui. CONCLUSION: Chemical reaction in vitro and intestinal absorption were the key factors of match-pair of huanglian-rougui.