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Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma-interferon-inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099-0.361) and breast cancer-specific survival (BCSS; HR = 0.187, 95% CI: 0.080-0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235-0.873 for DFS, HR = 0.488, 95% CI: 0.245-0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression-mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

This study aimed to evaluate predictors for adverse cardiovascular outcomes in patients with atrial fibrillation (AF) undergoing coronary stenting.We retrospectively recruited consecutive patients with previously documented non-valvular AF who underwent coronary stenting between January 2010 and June 2015 in 12 hospitals of Beijing, China. Major adverse cardiac/cerebrovascular events (MACCE) were a composite of all-cause death, non-fatal myocardial infarction, repeat revascularization, and ischaemic stroke/systemic thromboembolism (IS/STE). Major bleeding referred to grade 2 or higher of Bleeding Academic Research Consortium criteria.A total of 2394 patients (men: 72.3%Chinese patients with AF and coronary stenting had high mortality and incidence of MACCE. We compiled separate predictive models for all-cause death, IS/STE, MACCE, and major bleeding.

Background Talaromyces marneffei (T. marneffei) is a thermally dimorphic fungus causing systemic mycosis. Due to the atypical symptoms and diverse imaging findings, T. marneffei-infected patients may be misdiagnosed thus preventing timely antifungal therapy. Moreover, HIV-negative patients with T. marneffei infection may be congenitally immunocompromised because of the mutation of immune-related genes. Case presentation We describe a case of an HIV-negative child who developed disseminated T. marneffei infection in a nonendemic area. Chest CT showed similar imaging changes of miliary pulmonary tuberculosis, while there was no other evidence of tuberculosis infection, and empirical antituberculosis treatment was not effective. Lymphocyte subset analysis showed reduced natural killer cells, and the immunoglobulin profile showed low levels of IgM, C3 and C4. A bone marrow smear revealed T. marneffei infection, and ascites culture also proved T. marneffei infection. Despite antifungal treatment, the child died of multiple organ failure. Two gene mutations in caspase recruitment domain-containing protein 9 (CARD9) were detected, which had not been reported previously in T. marneffei-infected patients. Conclusions HIV-negative patients with CARD9 mutations may be potential hosts of T. marneffei. Abnormalities in the immunoglobin profile and lymphocyte subset may provide clues for immunocompromised patients, and further genetic testing is advised to identify gene mutations in HIV-negative patients with T. marneffei infection.

Visceral myopathy is a rare genetic disorder that commonly affects the digestive and renal systems. Manifestations include a clinical spectrum covering chronic intestinal pseudo-obstruction (CIPO) and megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). The smooth muscle actin γ-2 gene (ACTG2) is one of the most common disease-causing genes. Here, we present a case of pediatric intestinal pseudo-obstruction associated with a novel missense ACTG2 mutation, c.588G>C/p.E196D. His parents had no this mutation, which suggested the possibility of spontaneous mutation. Amino acid conservation analysis of γ-2 actin showed replacement of glutamate at position 196 by aspartate. The patient suffered from recurrent episodes of abdominal bloating, undergone repeated gastrointestinal surgery, had feeding difficulties, and required long-term parenteral nutrition support. The patient had no other specific symptoms or underlying diseases. X-ray of the abdomen showed dilation of the intestine as well as an air-fluid pattern. The manifestations of biopsy were various. All biochemical tests were normal, and the possibility of secondary intestinal pseudo-obstruction was excluded. The mutation site of ACTG2 in the present study has not been previously described in patients with visceral myopathy, and thus, our study reveals a novel mutation of ACTG2-associated visceral myopathy in a patient with CIPO. This report can serve as a reference for future research and further expands the map of genetic variation for visceral myopathy.

PurposeSocial influence plays a crucial role in determining the size of information diffusion. Drawing on threshold models, we reformulate the nonlinear threshold hypothesis of social influence.Design/methodology/approachWe test the threshold hypothesis of social influence with a large dataset of information diffusion on social media.FindingsThere exists a bell-shaped relationship between social influence and diffusion size. However, the large network threshold, limited diffusion depth and intense bursts become the bottlenecks that constrain the diffusion size.Practical implicationsThe practice of viral marketing needs innovative strategies to increase information novelty and reduce the excessive network threshold.Originality/valueIn all, this research extends threshold models of social influence and underlines the nonlinear nature of social influence in information diffusion.

Oxidative stress has a key role in brain injury and melatonin possesses antioxidant effects. We aimed to ascertain the potential relationship between serum melatonin concentrations and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH).This prospective and observational study was conducted of 169 aSAH patients. Baseline serum melatonin concentrations were determined. A worse 6-month functional outcome was defined as a Glasgow Outcome Scale score of 1-3.Patients with a worse outcome (56 cases) compared to those with a good outcome (113 cases) exhibited significantly higher concentrations of serum melatonin (P 0.001). An area under the receiver operating curve of 0.819 was revealed for the prediction of 6-month worse outcome by serum melatonin concentrations. Multiple logistic regression analysis showed an independent association of serum melatonin concentrations with 6-month worse outcome (odds ratio = 1.204). An intimate correlation existed between serum melatonin concentrations and World Federation of Neurological Surgeons subarachnoid hemorrhage scale scores as well as between serum melatonin concentrations and modified Fisher scores (P 0.001).Patients with higher serum melatonin concentrations are more likely to have a poor prognosis. Serum melatonin can be considered as an independent predictor of functional outcome after aSAH.

BACKGROUND Intracranial infection is a common clinical disease. Computed tomography (CT) and magnetic resonance imaging (MRI) have certain sensitivity and have good diagnostic efficacy. AIM To study the application value of MRI and CT in the diagnosis of intracranial infection after craniocerebral surgery. METHODS We selected 82 patients who underwent craniocerebral surgery (including 40 patients with intracranial infection and 42 patients without infection) during the period from April 2016 to June 2019 in our hospital. All 82 patients received CT and MRI examinations, and their clinical data were reviewed. A retrospective analysis was performed, and the coincidence rate of positive diagnosis and the overall diagnosis coincidence rate of different pathogenic infection types were measured with the two examination methods. The diagnostic sensitivity and specificity as well as the positive and negative predictive values of the two examination methods were compared. RESULTS For all types of pathogenic infections (Staphylococcus aureus, Staphylococcus hemolyticus, Staphylococcus epidermidis, and others), MRI scans had higher positive diagnostic coincidence rates than CT scans; the overall diagnostic coincidence rate, sensitivity, specificity, positive predictive value, and negative predictive values were significantly higher with MRI examinations than with CT examinations, and the differences were statistically significant (P < 0.05). CONCLUSION MRI examination can accurately diagnose intracranial infection after clinical craniocerebral surgery. Compared with CT, MRI had higher diagnostic efficiency. The diagnostic sensitivity and specificity, the diagnostic coincidence rate, and the positive and negative predictive values were significantly higher with MRI than with conventional CT, which can be actively promoted.

Adult-onset Still's disease (AOSD) is a rare but clinically well-known, polygenic, and systemic autoinflammatory disease, which is characterized by spiking fever, evanescent skin rash, arthralgia, and sore throat. The application of non-steroidal anti-inflammatory drugs and glucocorticoids, which are first-line therapies of AOSD, is limited due to their side effects such as liver injury or disorder of blood glucose. Therefore, patients who suffer from systemic diseases in China prefer to seek help from Chinese herbal medicine (CHM), which is an important part of complementary and alternative medicine. In this case, we report a 28-year-old male badminton coach presenting with a 15-day history of fever and skin rash, accompanied by sore throat, fatigue, myalgia and chills. Additionally, hepatosplenomegaly, multiple lymphadenopathies, aminotransferase abnormality, and elevated inflammatory factor levels were observed during hospitalization. Infectious diseases, solid tumors, hematological diseases, and common autoimmune diseases were excluded. Not benefitting from antibiotic therapy, the patient was finally diagnosed with AOSD, after a careful examination, then showed rapid remission after a six-week treatment with CHM granules based on Xiaochaihu Decoction and Yinqiao Powder. After stopping the treatment, there was no relapse within a 15-month follow-up period. To the best of our knowledge, this is the first well-documented case of this successful treatment. The present case report suggests that CHM is a reliable choice for complementary and alternative therapy for AOSD, but confirming the utility of CHM for AOSD requires further support from prospective studies.

Interferons are a family of class II α-helical cytokines playing vital roles in antiviral immune response, and little information is available to date regarding the interferon system of tilapia. In this study, a type I IFN gene, named On-IFNc, was identified in Nile tilapia, Oreochromis niloticus. The predicted protein of On-IFNc contains several structural features known in type I IFNs, and On-IFNc was clustered together with the known IFNc in fish into a separated clade in the phylogenetic tree. On-IFNc gene was constitutively expressed in all tissues examined, with the highest expression level observed in liver, and was rapidly induced in all organs/tissues tested following the stimulation of poly(I:C). In addition, recombinant On-IFNc has been proven to markedly induce the expression of the antiviral effectors, Mx and viperin, the signalling components, STAT1, STAT2, and IRF9, and the transcription factors, IRF3 and IRF7, as well as the tyrosine phosphorylation of STAT1 and STAT2 in fish cells. Furthermore, recombinant On-IFNc has been proven to possess antiviral activity against ISKNV. The present study thus contributes to a better understanding of the functional properties of the type I IFN system in tilapia.

Streptococcus agalactiae is a Gram-positive facultative intracellular bacterium that leads to severe economic loss of tilapia worldwide. Previous studies demonstrated that CD40 contributes to host protection against intracellular injection. In this study, CD40 was characterized from Nile tilapia (Oreochromis niloticus), named OnCD40. Sequence analysis showed that open reading frame of OnCD40 was 933 bp, containing a single peptide, a transmembrane domain and four cysteine-rich domains. The qRT-PCR revealed that OnCD40 was expressed in all examined tissues with the most abundant ones in spleen and thymus. After S. agalactiae stimulation, the expression of OnCD40 was significantly induced in most of the detected organs. Moreover, OnCD40-overexpressing fish elicited significant protection against subsequent S. agalactiae challenge; approximately 10000-fold fewer bacteria were detected in spleen of OnCD40-overexpressing fish in comparison with control fish. Thus, CD40 had protecting function in Nile tilapia against intracellular pathogens.

BACKGROUND AND PURPOSE To assess a 3D high-resolution IR-prepped fast SPGR high-resolution MRI sequence for evaluating hypoglossal nerve lesions. METHODS The clinical data of 8 patients with hypoglossal nerve lesions admitted from December 2011 to February 2016 were retrospectively analyzed. MRI included contrast-enhanced conventional sequences and a 3D IR-prepped fast SPGR high-resolution T1-weighted (BRAVO) MRI sequence at 3T. RESULTS Eight patients had hypoglossal lesions detected by MRI. Conventional enhanced scanning could not clearly display the hypoglossal nerve and canal, while the enhanced 3D high-resolution sequence could. In addition, multiple planar reconstruction clearly displayed the hypoglossal nerve, hypoglossal canal, and lesions in multiple planes. CONCLUSIONS Compared with conventional MRI, we show superior results from an advanced sequence to improve image quality in characterizing hypoglossal nerve lesions.

This study was to screen out potential driver long non-coding RNAs (lncRNAs) in lung cancer in Xuanwei (LCXW) differently expressed mRNAs and lncRNAs were detected by gene expression microarrays in 23 paired lung adenocarcinoma and adjacent tissues. Combined bioinformatics analysis was performed to identify potential driver lncRNAs and their potential regulatory relationships. Transcriptome and clinical data in TCGA-LUAD were used as comparison and validation dataset. The comparison of LCXW and TCGA-LUAD revealed significant differences in expression of some genes, signaling pathways affected by differentially expressed genes, and the 5-year survival rate of patients. We identified 14 consistently deregulated mRNAs and 5 lncRNAs as candidate genes, which affected multiple cancer-related pathways and influenced patients' overall survival. By combined bioinformatics analysis, we further identified a potential driver lncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) and proposed its possible regulation mechanism. The low expression of FENDRR was positively correlated with Kruppel-like factor4 (KLF4), KLF4 down-regulation may loss the activation function of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1C (CDKN1C) and the inhibition function of CyclinB1 (CCNB1), eventually cause excessive cell cycle activation and lead to lung cancer. This study revealed a potential FENDRR-KLF4-cell cycle regulation axis. These results lay an important foundation for further research on the pathogenesis of LCXW and identification of potential novel biomarkers or therapeutic targets.

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)−/− mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP−/− mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein. NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP−/− mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.

Objectives To observe the clinical effect on opioid-induced constipation of liver stagnation and spleen deficiency treated with the ultrasonic penetration of the No.1 constipation herbal formula at Tiānshū (天枢 ST25). Methods A total of 126 patients that were in compliance with the inclusion criteria were randomized into an acupoint group (41 cases), a Chinese medication group (42 cases) and a western medication group (43 cases). In the acupoint group, the ultrasonic penetration of the No.1 constipation herbal formula at bilateral Tiānshū (天枢 ST25) were given. In the Chinese herbal medication group, the No.1 constipation herbal formula was prescribed for oral administration. In the western medication group, polyethylene glycol electrolyte powder was prescribed for oral administration. The treatment was given once a day, for 14 days totally. Before and after treatment, the constipation symptom score, the score of the patient assessment of constipation quality of life (PAC-QOL), the situation of nitric oxide synthetase (NOS) in serum were observed in each group. The safety indicators in the observation included diarrhea, allergic reaction, liver dysfunction, skin lesions, etc. Results A total of 122 cases accomplished the trial. The total effective rate was 82.5% in the acupoint group, 80.48% in the Chinese medication group and 78.04% in the western medication group. The constipation symptoms were all relieved in the three groups, indicating the statistical significance as compared with those before treatment (P Conclusion The ultrasonic penetration of the No.1 constipation herbal formula at Tiānshū (天枢 ST25) is effective on opioid-induced constipation of liver stagnation and spleen deficiency. This therapy achieves the significant therapeutic effect and presents the good compliance in treatment. Hence, it deserves to be further promoted in clinical application.

Purpose: The aim was to explore the clinical-pathological shrinkage modes which oriented by breast conserving surgery (BCS) purpose after neoadjuvant therapy (NAT) using three-dimensional (3D) MRI and pathology reconstruction, in order to guide the individualized selection of BCS candidates and scope of resection after NAT. Methods: From April 2014 to 2018, 104 breast cancer patients underwent operation after NAT were included in this prospective study. All patients underwent MRI examinations before and after NAT. Breast residual tumors were prepared with sub-serial section. The 3D MRI and pathology models were reconstructed with 3D-DOCTOR software. The association and correlation between 3D MRI and pathology models were assessed. The traditional shrinkage modes included the surgical pathology complete response, solitary lesions without surrounding lesions, multinodular lesions, solitary lesions with adjacent spotty lesions and diffuse lesions. Combined with the MD Anderson Cancer Center BCS indications after NAT and traditional shrinkage modes, we derived clinical-pathological shrinkage modes which oriented by BCS purpose: clinical pathological-concentric shrinkage modes (CP-CSM) and clinical pathological-non concentric shrinkage modes (CP-NCSM). The CP-CSM means the longest diameter of residual tumor was less than 50% and ≤2cm in comparison with the primary tumor before NAT. Other shrinkage modes were classified as CP-NCSM. Univariate and multivariate logistic regression analysis was conducted to identify the independent predictive factors of clinical-pathological shrinkage modes. A nomogram was developed based on variables in the final model with pResults: Based on the gold standard of 3D pathology reconstruction model-measured shrinkage modes, the accuracy, sensitivity and specificity of 3D MRI reconstruction for predicting the traditional shrinkage modes were 84.6%, 61.9% and 90.4%, respectively (Kappa value=0.497). The accuracy, sensitivity and specificity of 3D MRI reconstruction in predicting clinical-pathological shrinkage modes were 93.3%, 97.0% and 86.5%, respectively (Kappa value=0.850). Multivariate analysis showed that primary tumor stage (OR=2.059, 95%CI: 1.187-3.574), mammographic malignant calcification (OR=3.424, 95%CI: 1.437-8.161), molecular subtypes (OR=0.530, 95%CI: 0.364-0.772) and nodal down-staging after NAT (OR=0.183, 95%CI: 0.067-0.497) were independent predictors of clinical-pathological shrinkage modes (all pp=0.002). Patients with CP-CSM had a better overall survival and disease-free survival (all pConclusion: The 3D MRI reconstruction after NAT could accurately predict the extent of residual tumor. Combining clinical, imaging, molecular subtypes and NAT efficacy, the nomogram of clinical-pathological shrinkage modes showed sufficient predicting accuracy. And it could help to guide the individualized selection of BCS candidates and scope of resection after NAT, thereby achieve the minimum and effective treatment. However, the applicability of the nomogram still needs to be externally validated. Patients with CP-NCSM after NAT had a worse prognosis.

IntroductionEstrogen receptors (ESRs) and progesterone receptors (PGRs) are associated with the development and progression of various tumors. The feasibility of ESRs and PGRs as prognostic markers and therapeutic targets for multiple cancers was evaluated via pan-cancer analysis.MethodsThe pan-cancer mRNA expression levels, genetic variations, and prognostic values of ESR1, ESR2, and PGR were analyzed using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and cBioPortal. The expression levels of ERa, ERb, and PGR proteins were detected by immunohistochemical staining using paraffin-embedded tissue specimens of ovarian serous cystadenocarcinoma (OV) and uterine endometrioid adenocarcinoma (UTEA). Correlation between immunomodulators and immune cells was determined based on the Tumor and Immune System Interaction Database (TISIDB).ResultsESR1, ESR2, and PGR mRNAs were found to be differentially expressed in different cancer types, and were associated with tumor progression and clinical prognosis. ERa, ERb, and PGR proteins were further determined to be significantly differentially expressed in OV and UTEA via immunohistochemical staining. The expression of ERa protein was positively correlated with a high tumor stage, whereas the expression of PGR protein was conversely associated with a high tumor stage in patients with OV. In patients with UTEA, the expression levels of both ERa and PGR proteins were conversely associated with tumor grade and stage. In addition, the expression levels of ESR1, ESR2, and PGR mRNAs were significantly associated with the expression of immunomodulators and immune cells.ConclusionESR1, ESR2, and PGR are potential prognostic markers and therapeutic targets, as well as important factors for the prediction, evaluation, and individualized treatment in several cancer types.

Yuan Xu,1– 4 Huan Yang,2,5 Jing Wang,6 Xiaoying Li,2,5 Chengjun Xue,6 Changchun Niu,2 Pu Liao1,2 1Chongqing Medical University, Chongqing, 400014, People’s Republic of China; 2Department of Clinical Laboratory, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 400014, People’s Republic of China; 3Chongqing College, University of Chinese Academy of Sciences, Chongqing, 400014, People’s Republic of China; 4Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China; 5Southwest Medical University, Luzhou, 646000, People’s Republic of China; 6Department of Clinical Laboratory, Chongqing Public Health Medical Center, Chongqing, 400036, People’s Republic of ChinaCorrespondence: Pu Liao Email liaopu@ucas.ac.cnBackground: COVID-19 infections are still at pandemic levels globally and there are currently no specific drugs to treat these infections. Previous studies have demonstrated that serum albumin levels were abnormally low in COVID-19 patients and might be used as a prognosis biomarker. Supplemental albumin has been used as an experimental therapeutic method. However, dynamic evaluation of albumin in patients with COVID-19 was limited and whether serum albumin could predict the prognosis of these patients is unknown.Methods: We enrolled 79 COVID-19 patients in the present study and reviewed electronic medical laboratory records. Data was processed using SPSS software (Version 20.0) and correlation analysis was performed between serum albumin and other clinical and laboratory findings.Results: Serum albumin levels were gradually decreased both in severe and non-severe COVID-19 patients. Moreover, 17.7% of the patients presented with hypoalbuminemia at least one time during 3 consecutive weekly time points. The hypoalbuminemia group displayed more severe disease and comorbidity that included fever, fatigue, headache, and dizziness on admission. Moreover, serum albumin levels were positively correlated with lymphocyte and RBC numbers, Hb and prealbumin levels as well as with total T cell numbers and the presence of CD4+ and CD8+ T cells. In contrast, there was a negative correlation with C-reactive protein levels and this was an indicator of patient recovery.Conclusion: Our results demonstrated that hypoalbuminemia was common in COVID-19 patients and its levels were linked to disease severity. Patients with fever, fatigue and headache or dizziness on admission were more likely to experience hypoalbuminemia. Dynamic monitoring of serum albumin is therefore necessary and should be performed during COVID-19 patient treatments as a tool for evaluating the prognosis of COVID-19 infections.Keywords: COVID-19, SARS-CoV-2, albumin, liver function, prognosis

Chronic pulmonary hypertension (PH) is a fatal disease characterized by the persistent activation of pulmonary vascular cells that exhibit aberrant expression of genes including miRNAs. We and others reported that decreased levels of mature microRNA-124 (miR-124) plays an important role in modulating the activated phenotype of pulmonary vascular cells and HDAC inhibitors (HDACi) can restore the levels of mature miR-124 and reverse the persistently activated phenotype of PH vascular cells. In this study, we sought to determine the mechanisms contributing to reduced levels of miRNAs, as well as how HDACi restores the levels of reduced miRNA in PH vascular cells. We found that pulmonary artery fibroblasts isolated from IPAH patients (PH-Fibs) exhibit reduced levels of mature miR-124 and several other miRNAs including let-7i, miR-224, and miR-210, and that these reduced levels can be restored by HDACi. Using miR-124 expression in human PH-Fibs as a model, we determined that reduced miR-124 gene transcription, not decreased expression of miRNA processing genes, is responsible for reduced levels of mature miR-124 in human PH-Fibs. Using both DNase I Sensitivity and chromatin immunoprecipitation assays, we found that the miR-124-1 gene exhibits a more condensed chromatin structure in human PH-Fibs, compared to corresponding controls. HDACi relaxed miR-124-1 chromatin structure, evidenced by increased levels of the open chromatin mark H3K27Ac, but decreased levels of closed chromatin mark H3K27Me3. Most importantly, the delivery of histone acetyltransferase (HAT) via CRISPR-dCas9-HAT and guiding RNAs to the promoter of the miR-124-1 gene increased miR-124-1 gene transcription. Thus, our data indicate epigenetic events play important role in controlling miR-124 and likely other miRNA levels and epigenetic regulators such as HDACs appear to be promising therapeutic targets for chronic PH.

Primary hepatocellular carcinoma (HCC) is the fifth most frequently reported malignancy, and it is also the second most common cause of cancer-related deaths worldwide. Although most HCC cases have been reported to develop from cirrhosis, accumulating data suggest that HCC is also closely related to non-cirrhotic chronic liver disease. Traditionally, HCC was thought to develop mostly from cirrhosis; however, an increasing number of reports have found that HCC can develop directly from inflammation without cirrhosis. The incidence of HCC in non-cirrhotic liver (HCC-NCL) is high, especially in developed countries. Studies have found that the most common cause of HCC-NCL is neglected fatty liver disease. This type of HCC has unique clinical characteristics and is closely related to metabolic disorders. Unfortunately, the prevention of HCC-NCL has not received enough attention worldwide, and there is also a lack of specific screening methods and clinical guidelines. This article mainly reviews the etiology, incidence, clinical characteristics, and screening markers of HCC-NCL to improve the understanding and prevention of this disease.

Purpose Results of some epidemiological studies suggest that moderate alcohol consumption may be associated with a decreased risk to develop NAFLD. Here, the effect of the consumption of moderate beer and diluted ethanol, respectively, on the development of NAFLD were assessed. Methods Female C57BL/6J mice were fed a control diet (C-D) or a diet rich in fructose, fat and cholesterol (FFC) enriched isocalorically and isoalcoholically with beer (FFC + B) or plain ethanol (FFC + E) (2.5 g ethanol/kg body weight/day) for 7 weeks. Liver damage was assessed by histology using NAFLD activity score. Markers of inflammation, insulin resistance and adiponectin signaling were measured at mRNA and protein levels. Using J774A.1 cells as a model of Kupffer cells, the effect of alcoholic beverages on adiponectin receptor 1 (Adipor1) was assessed. Results Hepatic triglyceride concentration, neutrophil granulocytes, iNOS protein concentrations and early signs of insulin resistance found in FFC-fed mice were significantly attenuated in FFC+ B-fed mice (P

OBJECTIVE To investigate the association between curcumin and the differentially expressed genes (DEG) in synovial tissues of osteoarthritis. METHODS Microarray analysis was used to screen for the DEG in osteoarthritis synovial cells. Curcumin-related genes were identified through the drug-gene interaction network STITCH (http://stitch.embl.de/cgi/input.pl). Expression levels of fibronectin 1 (FN1) and collagen III protein were measured by western blot. MTT assay was used to examine the effects of different concentrations of curcumin on cell viability. Western blot and quantitative real-time polymerase chain reaction were used to validate the different expression levels of matrix metalloproteinase-3 (MMP3). Clone formation assay, flow cytometry, and the TUNEL method were conducted for detecting the cell proliferation and apoptosis rate. RESULTS In the two chips of GSE1919 and GSE55235, the average expression of MMP3 in the osteoarthritis group was 63.7% and 12.9% higher than that of the healthy control, respectively. The results of western blot also showed that the average expression of MMP3 in 30 osteoarthritis patients was 132% higher than that of the healthy group, which confirmed that MMP3 was highly expressed in osteoarthritis group. The results of MTT showed that at 72 h, the cell viability of 40 μmol/L curcumin was the lowest and 79.6% lower than for the 0 μmol/L group, so the final curcumin concentration of 40 μmol/L was selected for subsequent experiments. Western blot results further showed that the expression of MMP3 was 44% lower in the untreated groups compared with the curcumin group, and the expressions of FN1 and collagen III were increased by 112% and 84%, respectively, which indicated that curcumin inhibited MMP3 expression and decreased osteoarthritis synovial cell activity. Cloning formation experiments showed that cell numbers increased by 75% and 20.5% in untreated and curcumin groups, and compared with the untreated group, the cells in the curcumin group decreased by 30.8%. Flow cytometry showed that the apoptotic rate in the curcumin group increased by 85.1% compared with the untreated group, but for a single group, MMP3 decreased the apoptotic rate by 53.9% and 46.7%, respectively. CONCLUSIONS MMP3 was highly expressed in osteoarthritis synovial cells. Curcumin could reduce cell viability, inhibit cell proliferation, increase cell apoptosis, and eventually alleviate inflammation of osteoarthritis by inhibiting the expression of MMP3.

Subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy has become a viable alternative to conventional transvenous ICD implantation. Patients with congenitally corrected transposition of the great arteries (ccTGA) have a high risk of sudden cardiac death due to malignant arrhythmia. The interaction between the S-ICD system and the transvenous pacemaker system is not fully understood. We report a case of S-ICD implantation in a patient with ccTGA and a DDD pacemaker. The patient was a 30-year-old man with a previously placed pacemaker with diagnoses of congenital heart disease, ccTGA (SLL), left atrioventricular valve insufficiency, and third-degree atrioventricular block. He presented with an out-of-hospital cardiac arrest, and an S-ICD was implanted to prevent sudden cardiac death. Defibrillation checks were performed successfully. We tested the compatibility of the DDD pacemaker with the S-ICD and found that there was no interference between them. In conclusion, an S-ICD system is a reasonable and safe option in patients with ccTGA.

The structural-functional organization of ammonia and glutamine metabolism in the liver acinus involves highly specialized hepatocyte subpopulations like glutamine synthetase (GS) expressing perivenous hepatocytes (scavenger cells). However, this cell population has not yet been characterized extensively regarding expression of other genes and potential subpopulations. This was investigated in the present study by proteome profiling of periportal GS-negative and perivenous GS-expressing hepatocytes from mouse and rat. Apart from established markers of GS+ hepatocytes such as glutamate/aspartate transporter II (GLT1) or ammonium transporter Rh type B (RhBG), we identified novel scavenger cell-specific proteins like basal transcription factor 3 (BTF3) and heat-shock protein 25 (HSP25). Interestingly, BTF3 and HSP25 were heterogeneously distributed among GS+ hepatocytes in mouse liver slices. Feeding experiments showed that RhBG expression was increased in livers from mice fed with high protein diet compared to standard chow. While spatial distributions of GS and carbamoylphosphate synthetase 1 (CPS1) were unaffected, periportal areas constituted by glutaminase 2 (GLS2)-positive hepatocytes were enlarged or reduced in response to high or low protein diet, respectively. The data suggest that the population of perivenous GS+ scavenger cells is heterogeneous and not uniform as previously suggested which may reflect a functional heterogeneity, possibly relevant for liver regeneration.