Risk factors for antibiotic resistance development in healthcare settings in China: a systematic review.

Antibiotic resistance (ABR) threatens the effectiveness of infectious disease treatments and contributes to increasing global morbidity and mortality. In this study, we systematically reviewed the identified risk factors for ABR among people in the healthcare system of mainland China. Five databases were systematically searched to identify relevant articles published in either English and Chinese between 1 January 2003 and 30 June 2019. A total of 176 facility-based references were reviewed for this study, ranging across 31 provinces in mainland China and reporting information from over 50 000 patients. Four major ABR risk factor domains were identified: (1) sociodemographic factors (includes migrant status, low income and urban residence), (2) patient clinical information (includes disease status and certain laboratory results), (3) admission to healthcare settings (includes length of hospitalisation and performance of invasive procedures) and (4) drug exposure (includes current or prior antibiotic therapy). ABR constitutes an ongoing major public health challenge in China. The healthcare sector-associated risk factors was the most important aspect identified in this review and need to be addressed. Primary health care system and ABR surveillance networks need to be further strengthened to prevent and control the communicable diseases, over-prescription and overuse of antibiotics.

PLS3 predicts poor prognosis in pancreatic cancer and promotes cancer cell proliferation via PI3K/AKT signaling.

Plastin-3 plays a key role in cancer cell proliferation and invasion, but its prognostic value in pancreatic cancer (PACA) remains poorly defined. In this study, we show that PLS3 messenger RNA is overexpressed in PACA tissue compared with normal tissue. We accumulated 207 cases of PACA specimens to perform immunohistochemical analysis and demonstrated that PLS3 levels correlate with T-classification (p < .001) and pathology (p < .001). Furthermore, overall survival rates (p < .001) in tumors with high PLS3 expression were poor, as assessed through Kaplan-Meier survival analysis. PLS3 was found to be an independent prognostic factor for PACA through multivariate Cox regression analysis. Moreover, we found that PLS3 enhances the proliferation and invasion of tumor cells as assessed through Cell Counting Kit-8, wounding healing assays, and Transwell assays. The upregulation of PLS3 also led to enhanced phosphatidylinositol-3 kinase/protein kinase B signaling in PACA cells. These data suggest that PLS3 is a biomarker to estimate PACA progression and represents a molecular target for PACA therapy.

Construction of a prognostic model based on genome-wide methylation analysis of miRNAs for hepatocellular carcinoma.

Aim: Using the methylation level of miRNA genes to develop a prognostic model for patients with hepatocellular carcinoma (HCC). Materials & methods: least absolute shrinkage and selection operator and multivariate Cox regression analyses were performed to develop a prognostic model. One miRNA in the model was selected for verification. Results: A prognostic model was developed using eight miRNAs. The areas under the curve for predicting overall survival at 1, 3 and 5 years were 0.75, 0.81 and 0.81. miR-223 was found to be hypomethylated in 160 HCC tissues, and its methylation level was associated with Barcelona Clinic Liver Cancer stages and the prognosis of patients with HCC. Conclusion: The prognostic model based on miRNA methylation levels has the capability to partially forecast the prognosis of patients with HCC.

Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA.

Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Aberrant DNA Methylation Patterns of Deleted in Liver Cancer 1 Isoforms in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), a common primary liver cancer, is the third leading cause of death worldwide. DNA methylation changes are common in HCC and have been studied to be associated with hepatocarcinogenesis. In our study, we used the MassARRAY® EpiTYPER technology to investigate the methylation differences of deleted in liver cancer 1 (DLC1) (isoform 1 and 3) promoter between HCC tissues and corresponding adjacent noncancerous tissues and the association between methylation levels and clinicopathological features. In addition, the modified CRISPR-Cas9 system and the DNA methyltransferase inhibitor (DNMTi) were utilized to explore the functional correlation of epigenetic modifications and DLC1 gene regulation. The methylation levels of the DLC1 isoforms in HCC samples were found significantly lower than those in the adjacent noncancerous tissues (all p < 0.0001). Also, we found that the expression of DLC1 could be bidirectionally regulated by the modified CRISPR-Cas9 system and the DNMTi. Moreover, the hypomethylation of DLC1 in HCC samples was connected with the presence of satellite lesions (p = 0.0305) and incomplete tumor capsule (p = 0.0204). Receiver operator characteristic curve analysis demonstrated that the methylation levels of DLC1 could be applied to discriminate HCC patients (area under the curve = 0.728, p < 0.0001). The hypomethylation status was a key regulatory mechanism of DLC1 expression and might serve as a potential biomarker for HCC.

Identification and development of a novel risk model based on cuproptosis-associated RNA methylation regulators for predicting prognosis and characterizing immune status in hepatocellular carcinoma.

BACKGROUND: Cuproptosis, a novel cell death caused by excess copper, is quite obscure in hepatocellular carcinoma (HCC) and needs more investigation. METHODS: RNA-seq and clinical data of HCC patients TCGA database were analyzed to establish a predictive model through LASSO Cox regression analysis. External dataset ICGC was used for the verification. GSEA and CIBERSORT were applied to investigate the molecular mechanisms and immune microenvironment of HCC. Cuproptosis induced by elesclomol was confirmed via various in vitro experiments. The expression of prognostic genes was verified in HCC tissues using qRT-PCR analysis. RESULTS: Initially, 18 cuproptosis-associated RNA methylation regulators (CARMRs) were selected for prognostic analysis. A nine-gene signature was created by applying the LASSO Cox regression method. Survival and ROC assays were carried out to validate the model using TCGA and ICGC database. Moreover, there exhibited obvious differences in drug sensitivity in terms of common drugs. A higher tumor mutation burden was shown in the high-risk group. Additionally, significant discrepancies were found between the two groups in metabolic pathways and RNA processing via GSEA analysis. Meanwhile, CIBERSORT analysis indicated different infiltrating levels of various immune cells between the two groups. Elesclomol treatment caused a unique form of programmed cell death accompanied by loss of lipoylated mitochondrial proteins and Fe-S cluster protein. The results of qRT-PCR indicated that most prognostic genes were differentially expressed in the HCC tissues. CONCLUSION: Overall, our predictive signature displayed potential value in the prediction of overall survival of HCC patients and might provide valuable clues for personalized therapies.

A Machine-Learning-Based Bibliometric Analysis of Cell Membrane-Coated Nanoparticles in Biomedical Applications over the Past Eleven Years.

Cell membrane encapsulation is a growing concept in nanomedicine, for it achieves the purpose of camouflage nanoparticles, realizing the convenience for drug delivery, bio-imaging, and detoxification. Cell membranes are constructed by bilayer lipid phospholipid layers, which have unique properties in cellular uptake mechanism, targeting ability, immunomodulation, and regeneration. Current medical applications of cell membranes include cancers, inflammations, regenerations, and so on. In this article, a general bibliometric overview is conducted of cell membrane-coated nanoparticles covering 11 years of evolution in order to provide researchers in the field with a comprehensive view of the relevant achievements and trends. The authors analyze the data from Web of Science Core Collection database, and extract the annual publications and citations, most productive countries/regions, most influential scholars, the collaborations of journals and institutions. The authors also divided cell membranes into several subgroups to further understand the application of different cell membranes in medical scenarios. This study summarizes the current research overview in cell membrane-coated nanoparticles and intuitively provides a direction for future research.

TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression.

Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.

The paradoxical functions of long noncoding RNAs in hepatocellular carcinoma: Implications in therapeutic opportunities and precision medicine.

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being "transcriptional noise," they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.

Comprehensive analysis of cuproptosis-related lncRNAs for prognostic significance and immune microenvironment characterization in hepatocellular carcinoma.

Cuproptosis was characterized as a novel type of programmed cell death. Recently, however, the role of cuproptosis-related long noncoding RNAs (CRLs) in tumors has not yet been studied. Identifying a predictive CRL signature in hepatocellular carcinoma (HCC) and investigating its putative molecular function were the goals of this work. Initially, Pearson's test was used to assess the relationship between lncRNAs and cuproptosis-associated genes obtained from HCC data of The Cancer Genome Atlas (TCGA). By implementing differential expression and univariate Cox analysis, 61 prognostic CRLs were subsequent to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. A prognostic risk score model was then constructed to evaluate its ability to predict patients' survival when combined with clinicopathological parameters in HCC. The five-lncRNA prognostic signature categorized the HCC patients into high- and low-risk groups. The low-risk group exhibited more sensitivity to elesclomol than the high-risk one. Surprisingly, distinct mitochondrial metabolism pathways connected to cuproptosis and pivotal immune-related pathways were observed between the two groups via gene set enrichment analysis (GSEA). Meanwhile, there were substantial differences between the high-risk group and the low-risk group in terms of tumor-infiltrating immune cells (TIICs). Furthermore, a positive relationship was shown between the risk score and the expression of immune checkpoints. Additionally, differential expression of the five lncRNAs was confirmed in our own HCC samples and cell lines via RT-qPCR. Finally, in vitro assays confirmed that WARS2-AS1 and MKLN1-AS knockdown could sensitize HCC cells to elesclomol-induced cuproptosis. Overall, our predictive signature may predict the prognosis of HCC patients in an independent manner, give a better understanding of how CRLs work in HCC, and offer therapeutic reference for patients with HCC.

C8orf76 Modulates Ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. Chromosome 8 open reading frame 76 (C8orf76), a novel gene located in the nucleus, is highly expressed in many tumor types. However, the specific mechanisms and functions of C8orf76 in HCC remain unclear. Here, we reported for the first time that C8orf76 gene expression levels were frequently upregulated in liver cancer and significantly correlated with HCC development. C8orf76 downregulation induced G1-S arrest and inhibited cell proliferation. Intriguingly, C8orf76 deficiency could accelerate erastin or sorafenib-induced ferroptosis through increasing lipid reactive oxygen species (ROS) levels. Moreover, although C8orf76 overexpression did not affect tumorigenesis under normal conditions, it increased resistance to lipid disturbance and ferroptosis triggered by erastin or sorafenib, which further facilitated HCC cell growth and tumor progression. Mechanistically, C8orf76 bound to the promoter region of the solute carrier family 7 member 11 (SLC7A11) gene and upregulated SLC7A11 transcriptionally. SLC7A11-dependent cystine import led to sufficient GSH synthesis and lipid peroxidation inhibition, thus accelerating tumor growth. Our study indicated that C8orf76 could be a novel marker for HCC diagnosis. In addition, a better comprehensive understanding of the potential role of C8orf76 in HCC helped us develop novel therapeutic strategies for this intractable cancer.

Immunotherapy for Hepatocellular Carcinoma: Current Limits and Prospects.

Although many approaches have been used to treat hepatocellular carcinoma (HCC), the clinical benefits remain limited, particularly for late stage HCC. In recent years, studies have focused on immunotherapy for HCC. Immunotherapies have shown promising clinical outcomes in several types of cancers and potential therapeutic effects for advanced HCC. In this review, we summarize the immune tolerance and immunotherapeutic strategies for HCC as well as the main challenges of current therapeutic approaches. We also present alternative strategies for overcoming these limitations.

Cancer and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization and Bioinformatic Analysis.

The clinical management of patients with COVID-19 and cancer is a Gordian knot that has been discussed widely but has not reached a consensus. We introduced two-sample Mendelian randomization to investigate the causal association between a genetic predisposition to cancers and COVID-19 susceptibility and severity. Moreover, we also explored the mutation landscape, expression pattern, and prognostic implications of genes involved with COVID-19 in distinct cancers. Among all of the cancer types we analyzed, only the genetic predisposition to lung adenocarcinoma was causally associated with increased COVID-19 severity (OR = 2.93, ß = 1.074, se = 0.411, p = 0.009) with no obvious heterogeneity (Q = 17.29, p = 0.24) or symmetry of the funnel plot. In addition, the results of the pleiotropy test demonstrated that instrument SNPs were less likely to affect COVID-19 severity via approaches other than lung adenocarcinoma cancer susceptibility (p = 0.96). Leave-one-out analysis showed no outliers in instrument SNPs, whose elimination rendered alterations in statistical significance, which further supported the reliability of the MR results. Broad mutation and differential expression of these genes were also found in cancers, which may provide valuable information for developing new treatment modalities for patients with both cancer and COVID-19. For example, ERAP2, a risk factor for COVID-19-associated death, is upregulated in lung squamous cancer and negatively associated with patient prognosis. Hence, ERAP2-targeted treatment may simultaneously reduce COVID-19 disease severity and restrain cancer progression. Our results highlighted the importance of strengthening medical surveillance for COVID-19 deterioration in patients with lung adenocarcinoma by showing their causal genetic association. For these patients, a delay in anticancer treatment, such as chemotherapy and surgery, should be considered.

High Expression of COL17A1 Predicts Poor Prognosis and Promotes the Tumor Progression via NF-κB Pathway in Pancreatic Adenocarcinoma.

COL17A1 (collagen type XVII alpha 1 chain) is known to be upregulated and has a prognostic role in many malignancies, as well as contributing to cell proliferation, apoptosis, and invasion. However, little knowledge is available on the expression and prognostic value of COL17A1 in pancreatic adenocarcinoma (PDAC). In our study, we searched the public database and found that mRNA and protein levels of COL17A1 are commonly upregulated in PDAC tissues. The immunohistochemical analysis conducted by us revealed enhanced expression of COL17A1 protein in 169 PDAC samples compared with that in 67 adjacent normal tissues. We also observed a significantly positive correlation between COL17A1 expression and lymph node metastasis (p < 0.0001), TNM clinical stage (p < 0.0001), and pathology differentiation (p < 0.01). The KM-plot results indicated that PDAC patients with a high COL17A1 expression have a poorer overall survival (p < 0.001) than those with a low COL17A1 expression. The result of the Cox regression analysis of multivariate data suggested COL17A1 is an independent prognostic indicator of PDAC patients' overall survival. CCK-8, wound healing, and transwell assays suggested that COL17A1 knockdown markedly inhibited tumor proliferation and invasion in PDAC cells, and cells with COL17A1 overexpression had a prominently higher proliferative and invasive capacity. Knockdown of COL17A1 significantly upregulated the apoptosis rate. We deduce that upregulated COL17A1 activated the NF-κB pathway in PDAC cells. In summary, our studies showed the prognostic value of COL17A1 in PDAC and that COL17A1 may act as a molecular therapeutic target for PDAC treatment.

Pancreatic neuroendocrine tumours: Grade is superior to T, N, or M status in predicting outcome and selecting patients for chemotherapy:A retrospective cohort study in the SEER database.

BACKGROUND: Pancreatic neuroendocrine tumours (pNETs) are a rare and heterogeneous group of tumours with an increasing incidence. Current staging criteria for pNETs remain limited and controversial. Meanwhile, the impact of chemotherapy on overall survival has not been fully defined. OBJECTIVES: The current study aimed to explore epidemiologic trends of pancreatic neuroendocrine tumours (pNETs). To determine feasible improvements to staging criteria and investigate the relationship between chemotherapy and survival. METHODS: A retrospective cohort study design was used to analyse annual cancer incidence rates, patient demographics, tumour site and stage, and treatment of pNETs. Data were obtained from the National Cancer Institute's SEER registry for all patients diagnosed with pNETs between January 1973 and December 2015. RESULTS: Patients diagnosed after 2010 were more likely to present with age greater than 45 years, T0, T1 status, N0 status, M0 status, and well differentiation. Current AJCC staging criteria was applicable to patients with well differentiation, but not other differentiation. The revised system, defined by Grade, T, N, and M status, could robustly discriminate between survival curves. Chemotherapy was associated with significantly improved survival for patients with poorly differentiated and undifferentiated tumour grading. CONCLUSIONS: Grade is superior to 'T', 'N', or 'M' status in predicting outcomes and selecting patients for chemotherapy. It is necessary and feasible to combine grade into current staging criteria.

Identification of lncRNAs and Their Functional Network Associated with Chemoresistance in SW1990/GZ Pancreatic Cancer Cells by RNA Sequencing.

Drug resistance is a major problem in the treatment of pancreatic cancer (PC). Long noncoding (lnc)RNAs modulate a variety of cellular processes. This study was carried out to identify lncRNAs that are differentially expressed in drug-resistant PC by next-generation RNA sequencing. We identified 205 differentially expressed lncRNAs (DELs) and 847 differentially expressed mRNAs (DEMs) in a comparison of gemcitabine-resistant and -sensitive SW1990 human PC cells. The expression levels of 12 randomly selected lncRNAs were confirmed by quantitative real-time PCR. A total of 55 and 99 DEMs were predicted to be targeted by the DELs through cis and trans mechanisms, respectively. The DEMs were significantly enriched in the Gene Ontology terms cell part, binding, and cellular processes, and a Kyoto Encyclopedia of Genes and Genomes analysis showed that they were associated with metabolic pathway, pathways in cancer, insulin resistance, microRNAs in cancer, and phosphotidylinositol 3-kinase-Akt signaling pathway. A coexpression network revealed a hub comprising lncRNAs (MIR210HG, SNHG1, and LOC729970) and mRNAs (RAB3D, DDX17, and SPNS2) that presumably mediate drug resistance in PC. The identified lncRNAs can serve as diagnostic or prognostic biomarkers and therapeutic targets for PC.