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Abstract Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperoxidase (MPO) and reducing its levels and activity. Moreover, RNF128 regulates alveolar macrophage activation and neutrophil infiltration by interacting with TLR4, targeting it for degradation, and inhibiting NF-κB activation, hence decreasing pro-inflammatory cytokines. Our results demonstrate for the first time that RNF128 is a negative regulator of MPO and TLR4 in neutrophils and alveolar macrophages, respectively. However, AAV9-mediated RNF128 overexpression alleviated lung tissue damage and reduced inflammatory cell infiltration. Thus, RNF128 is a promising therapeutic candidate for pharmacological interventions in ALI.

IntroductionMicroRNAs may be implicated in the acquisition of drug resistance in chronic myeloid leukemia as they regulate the expression of not only BCR-ABL1 but also genes associated with the activation of drug transfer proteins or essential signaling pathways.MethodsTo understand the impact of specifically expressed miRNAs in chronic myeloid leukemia and their target genes, we collected peripheral blood mononuclear cells (PBMC) from patients diagnosed with chronic myeloid leukemia (CML) and healthy donors to determine whole miRNA expression by small RNA sequencing and screened out 31 differentially expressed microRNAs (DE-miRNAs) with high expression. With the utilization of miRNA set enrichment analysis tools, we present here a comprehensive analysis of the relevance of DE-miRNAs to disease and biological function. Furthermore, the literature-based miRNA-target gene database was used to analyze the overall target genes of the DE-miRNAs and to define their associated biological responses. We further integrated DE-miRNA target genes to identify CML miRNA targeted gene signature singscore (CMTGSS) and used gene-set enrichment analysis (GSEA) to analyze the correlation between CMTGSS and Hallmark gene-sets in PBMC samples from clinical CML patients. Finally, the association of CMTGSS stratification with multiple CML cell lineage gene sets was validated in PBMC samples from CML patients using GSEA.ResultsAlthough individual miRNAs have been reported to have varying degrees of impact on CML, overall, our results show that abnormally upregulated miRNAs are associated with apoptosis and aberrantly downregulated miRNAs are associated with cell cycle. The clinical database shows that our defined DE-miRNAs are associated with the prognosis of CML patients. CMTGSS-based stratification analysis presented a tendency for miRNAs to affect cell differentiation in the blood microenvironment.ConclusionCollectively, this study defined differentially expressed miRNAs by miRNA sequencing from clinical samples and comprehensively analyzed the biological functions of the differential miRNAs in association with the target genes. The analysis of the enrichment of specific myeloid differentiated cells and immune cells also suggests the magnitude and potential targets of differentially expressed miRNAs in the clinical setting. It helps us to make links between the different results obtained from the multi-faceted studies to provide more potential research directions.

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome, and the current standard of care is the use of tyrosine kinase inhibitors (TKI). However, some patients will not achieve a molecular response and may progress to blast crisis, and the underlying mechanisms remain to be clarified. In this study, next-generation sequencing was used to explore endogenous miRNAs in CML patients versus healthy volunteers, and miR-342-5p was identified as the primary target. We found that miR-342-5p was downregulated in CML patients and had a significant inhibitory effect on cell proliferation in CML. Through a luciferase reporter system, miR-342-5p was reported to target the 3’-UTR domain of CCND1 and downregulated its expression. Furthermore, overexpression of miR-342-5p enhanced imatinib-induced DNA double-strand breaks and apoptosis. Finally, by analyzing clinical databases, we further confirmed that miR-342-5p was associated with predicted molecular responses in CML patients. In conclusion, we found that both in vivo and in vitro experiments and database cohorts showed that miR-342-5p plays a key role in CML patients, indicating that miR-342-5p may be a potential target for future CML treatment or prognostic evaluation.

Abstract In obese adults, nonalcoholic fatty liver disease (NAFLD) is accompanied by multiple metabolic dysfunctions. Although upregulated hepatic fatty acid synthesis has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are yet to be elucidated. In this study, we reported upregulated expression of gene related to anergy in lymphocytes (GRAIL) in the livers of humans and mice with hepatic steatosis. Grail ablation markedly alleviated the high-fat diet-induced hepatic fat accumulation and expression of genes related to the lipid metabolism, in vitro and in vivo. Conversely, overexpression of GRAIL exacerbated lipid accumulation and enhanced the expression of lipid metabolic genes in mice and liver cells. Our results demonstrated that Grail regulated the lipid accumulation in hepatic steatosis via interaction with sirtuin 1. Thus, Grail poses as a significant molecular regulator in the development of NAFLD.

Cardiac complications caused by metastatic gastric cancer are rarely reported. Here, we report a 58-year old woman who presented with chronic cough and intermittent shortness of breath for weeks. Chest radiographs showed a cardiac silhouette sign and a small amount of pleural effusion. After serial examinations including biopsy of the pericardium, ovarian and stomach, metastatic strong HER2/neu expressive signet-ring cell carcinoma of the stomach was diagnosed. Despite aggressive management with best supportive care and intravenous administration of trastuzumab, the patient died of respiratory failure and refractory pleural effusion. Through this case, we demonstrate that HER2/neu positive metastatic gastric cancer can initially present with these unusual cardiac and systemic manifestations. Primary clinical physicians should be aware of this unusual manifestation of gastric cancer.

Appendiceal tumors, particularly those with patterns of advanced malignancy, are rare in clinical practice. This study describes a patient with a mucinous adenocarcinoma originating from the appendix, who also had disseminated peritoneal carcinomatosis and abundant mucinous ascites despite chemotherapy and targeted therapy. Salvage cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) resulted in nearly complete remission.

Pneumococcal disease leads to renal complications ranging from persistent proteinuria to end-stage renal disease. Studies on the association between pneumococcal pneumonia (PP) and acute kidney injury (AKI) are scant. This study assessed the relationship between PP and risk of AKI.This nationwide population-based cohort study examined data from the Taiwan National Health Insurance Research Database for the period 2000-2011. We identified inpatients with newly diagnosed PP according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. In addition, we selected a comparison cohort from inpatient claims without the diagnosis of PP that was randomly frequency-matched with the PP cohort according to age, sex, index year and comorbidities. We analyzed the risks of AKI by using Cox proportional hazards regression models, adjusted for sex, age, and comorbidities.A total of 10,069 patients with PP and 10,069 controls were enrolled in this study. After adjustments for age, sex, and comorbidities, patients with PP had a 1.11-fold risk of developing AKI compared with the comparison cohort.This study indicates that AKI risks are higher in patients with PP compared with the comparison cohort. Careful follow-up observation and aggressive treatment are necessary for patients with PP to reduce the risk of AKI.

BACKGROUND:The common differential diagnosis of microcytic anemia in young Asian men includes iron deficiency anemia (IDA), α-thalassemia (αT) and β-thalassemia (βT). In this study, we aimed to distinguish between these diseases in a distinct population of young men using a specific index. PATIENTS AND METHODS:We retrospectively reviewed the laboratory data of young men with microcytic anemia. The clinical, characteristic and laboratory data, including complete blood cell counts, serum ferritin and hemoglobin electrophoresis results, were collected; genomic DNA mutations were also evaluated. Based on these data, ten discrimination indices were used to differentiate thalassemia from IDA. The sensitivity, specificity, positive and negative predictive values, Youden's index and receiver operating characteristic (ROC) curves were also calculated. RESULTS:A total of 877 patients (92 patients with IDA, 332 with αT and 453 with βT) were enrolled; the Shine and Lal (S&L) formula was the best method with which to discriminate IDA from thalassemia (100% sensitivity, 91% specificity). The new cut-off values were evaluated, and the approaches used in our study cohort, particularly the Green & King (G&K) formula, significantly increased the accuracies of red cell distribution width-containing indices (cut-off value: 58.66; 89.62% sensitivity and 96.2% specificity; AUC: 0.9716). In addition, when applied properly, these indices could differentiate IDA patients from αT patients, especially Huber-Herklotz index (HH). CONCLUSIONS:The sensitivity and specificity differed among ethnic and age groups. We concluded that when using the original cut-off value, the S&L formula was the best discriminating index for differentiating between IDA and thalassemia in young Asian men. However, when using the G&K formula, the newly obtained cut-off value must be applied to increase accuracy based on the results from our cohort.

The aim of this study was to examine the specific chemoregimens selected for adjuvant therapy in the patients with stage III colon cancer. We investigated the trends in chemotherapeutic prescribing patterns and looked for adequate therapeutic setting for these patients.288 patients presenting with stage III colon cancer and undergoing adjuvant therapies after curative surgery for more than 3-month were enrolled between January 2006 and December 2011. Demographic characteristics and therapeutic factors were analyzed, including age, gender, histological grade, tumor sizes, tumor location, pathologic stage, performance status, serum carcinoembryonic antigen, regimens selection, interval from the operation to the start of adjuvant therapy and prolonged adjuvant therapy. Kaplan- Meier methods were utilized for drawing survival curves and Cox model was used to analyze survival, prognostic factors.The analysis showed that the patients aged under 70 received more intensive therapies than those aged over 70 (P

The merge control models proposed for work zones are classified into two types (Hard Control Merge (HCM) model and Soft Control Merge (SCM) model) according to their own control intensity and are compared with a new model, called Individual Subjective Initiative Merge (ISIM) model, which is based on the linear lane-changing probability strategy in the merging area. The attention of this paper is paid to the positive impact of the individual subjective initiative for the whole traffic system. Three models (ISIM, HCM, and SCM) are established and compared with each other by two order parameters, that is, system output and average vehicle travel time. Finally, numerical results show that both ISIM and SCM perform better than HCM. Compared with SCM, the output of ISIM is 20 vehicles per hour higher under the symmetric input condition and is more stable under the asymmetric input condition. Meanwhile, the average travel time of ISIM is 2000 time steps less under the oversaturated input condition.