Natural killer (NK) cells play an important role in the immune response to viral infection and tumors.The ability of NK cells depends on the integrated signals across the array of stimulatory and inhibitory receptors engaged upon interaction with target cell surface ligands. Some stimulators, including viruses, tumor cells and hot shock, could promote the expression of NKG2 receptors and their ligands via activating certain transcription factors which are capable of up-regulating NKG2 promoters' activity. Meanwhile, epigenetic mechanisms including DNA methylation and histone posttranslational modifications are also critical to expression of NKG2 receptors and their ligands and may control the clonally distribution of some NK cell receptors. Investigating the epigenetic mechanisms of NK cell receptors and their ligands might helpful to the rational design of therapy against infection, inflammation, cancer or autoimmune diseases.

Objective To describe and analyze the misdiagnosis and mistreatment status of pulmonary alveolar proteinosis (PAP), especially cases with combination of severe infection. Method The misdiagnosis and mistreatment of 84 PAP patients and 6 cases with combination of severe infection before admitting to PUMCH was analyzed retrospectively. Results 66.7%(56/84) had experienced misdiagnosis before admission. 32.1% (27/84) were misdiagnosed with idiopathic interstitial pneumonia (IIP) and 14.3% (12/84) with pulmonary tuberculosis. 88.1%(74/84) had received anti-infection treatment, 33.3%(28/84) received eortieosteroids, and 19.0%(16/84) received anti-tuberculosis treatment. The percentage of the pa-tients who had taken the bronchoscopic examination outside the PUMCH was 53.6%(45/84). The PAP pa-tients diagnosis was established through bronchoscopic examination (including BAL and TBLB) in 86.9% (73/84) patients. There were 6 patients who had severe infection when PAP established. All of these 6 cases had been misdiagnosed with IIP and received corticosteroids treatment, 2 of whom died. Conclusions The misdiagnosis and mistreatment happens commonly in PAP patients. The misuse of corticosteroids makes some PAP cases get the severe infection. The image feature and the examination of bronchoscopy, BAL and TBLB are the key point in avoiding misdiagnosis. The administration of corticosteroids in uncertain patients should be avoided.

OBJECTIVETo detect the in-vitro effects of arbidol hydrochloride against 2009 new influenza virus A (H1N1).

METHODSThe activity of arbidol hydrochloride against 2009 new influenza virus A (H1N1) was determined in MDCK cell cultures. Hemagglutination assay, observation of cytopathic effects, RT-PCR and quantitative RT-PCR tests were performed for determination of virus titers. Inhibition concentration 50% and cytotoxic concentration 50% were calculated with Chou's Menu of Dose-Effect Program.

RESULTSArbidol hydrochloride showed low cytotoxicity (cytotoxic concentration 50%>100 μmol/L)and significant anti-2009 new influenza virus A (H1N1) activity in cell cultures. Inhibition concentration 50% were (5.5 ± 0.9), (3.4 ± 0.8), and (1.5 ± 0.2) μmol/L in hemagglutination assay, cytopathic effect test, and quantitative RT-PCR assay, respectively.

CONCLUSIONArbidol has low cytotoxicity and high anti-virus activity and can effectively trigger the activities of interferon and immune response, and therefore can be a valuable anti-influenza virus drug.

Animals ; Antiviral Agents ; pharmacology ; Dogs ; Indoles ; pharmacology ; Influenza A Virus, H1N1 Subtype ; drug effects ; Madin Darby Canine Kidney Cells ; Virus Replication ; drug effects

Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the "cure HCV" goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others.

The pace of discovery of new antiretroviral (ARV) drugs has slowed, although the efficacy and safety of once-daily fixed dose combinations have been extensively investigated. Several traditional ARV drugs remain in phase III clinical trials. This review summarizes current information on ARV drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade.

We developed phase-switch microfluidic devices for molecular profiling of a large number of single cells. Whole genome microarrays and RNA-sequencing are commonly used to determine the expression levels of genes in cell lysates (a physical mix of millions of cells) for inferring gene functions. However, cellular heterogeneity becomes an inherent noise in the measurement of gene expression. The unique molecular characteristics of individual cells, as well as the temporal and quantitative information of gene expression in cells, are lost when averaged among all cells in cell lysates. Our single-cell technology overcomes this limitation and enables us to obtain a large number of single-cell transcriptomes from a population of cells. A collection of single-cell molecular profiles allows us to study carcinogenesis from an evolutionary perspective by treating cancer as a diverse population of cells with abnormal molecular characteristics. Because a cancer cell population contains cells at various stages of development toward drug resistance, clustering similar single-cell molecular profiles could reveal how drug-resistant sub-clones evolve during cancer treatment. Here, we discuss how single-cell transcriptome analysis technology could enable the study of carcinogenesis from an evolutionary perspective and the development of drug-resistance in leukemia. The single-cell transcriptome analysis reported here could have a direct and significant impact on current cancer treatments and future personalized cancer therapies.
Carcinogenesis ; genetics ; Drug Resistance, Neoplasm ; Gene Expression Profiling ; Hematopoietic Stem Cells ; metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; pathology ; Microfluidic Analytical Techniques ; Single-Cell Analysis ; methods ; Transcriptome

This study aimed to compare epithelial cells derived from human embryonic stem cells (hESCs) to human ameloblast-lineage cells (ALCs), as a way to determine their potential use as a cell source for ameloblast regeneration. Induced by various concentrations of bone morphogenetic protein 4 (BMP4), retinoic acid (RA) and lithium chloride (LiCl) for 7 days, hESCs adopted cobble-stone epithelial phenotype (hESC-derived epithelial cells (ES-ECs)) and expressed cytokeratin 14. Compared with ALCs and oral epithelial cells (OE), ES-ECs expressed amelogenesis-associated genes similar to ALCs. ES-ECs were compared with human fetal skin epithelium, human fetal oral buccal mucosal epithelial cells and human ALCs for their expression pattern of cytokeratins as well. ALCs had relatively high expression levels of cytokeratin 76, which was also found to be upregulated in ES-ECs. Based on the present study, with the similarity of gene expression with ALCs, ES-ECs are a promising potential cell source for regeneration, which are not available in erupted human teeth for regeneration of enamel.
Ameloblasts ; physiology ; Amelogenesis ; genetics ; Amelogenin ; analysis ; Bone Morphogenetic Protein 4 ; pharmacology ; Cell Culture Techniques ; Cell Differentiation ; drug effects ; Cell Line ; Cell Lineage ; Embryonic Stem Cells ; drug effects ; physiology ; Epithelial Cells ; drug effects ; physiology ; Fibroblast Growth Factor 8 ; analysis ; Hedgehog Proteins ; analysis ; Homeodomain Proteins ; analysis ; Humans ; Keratins ; analysis ; classification ; Lithium Chloride ; pharmacology ; MSX1 Transcription Factor ; analysis ; Mouth Mucosa ; cytology ; Phenotype ; Regeneration ; physiology ; Skin ; cytology ; Transcription Factors ; analysis ; Tretinoin ; pharmacology

In the two decades since AZT was first approved for clinical use in 1987, 24 additional antiretroviral agents have been approved. They include 7 nucleoside analogs, a nucleotide analog and 4 non-nucleoside reverse transcriptase inhibitors, 10 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. More than 20 investigational agents are currently being studied in clinical trials. Highly active antiretroviral therapy (HAART), which involves a combination of anti-HIV-1 drugs, is extremely effective in suppressing HIV-1 replication and increasing CD4+ number and results in substantial reductions in HIV-1-related morbidity and mortality. In last 20 years, much has been learned about resistance to antiretroviral drugs, drug interactions and metabolic complications of antiviral drug use. Drugs are now selected on the basis of resistance tests and on the risk of specific drug complications in individual patients. As a result, decisions about the therapy of HIV/AIDS have become personalized and are made on a patient-by-patient basis. With appropriate medical management, a person with HIV-1 now has the possibility of a nearly normal life expectancy.
Anti-HIV Agents ; adverse effects ; pharmacology ; therapeutic use ; Antiretroviral Therapy, Highly Active ; Cyclohexanes ; chemistry ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp41 ; chemistry ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Protease Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Reverse Transcriptase ; chemistry ; pharmacology ; therapeutic use ; HIV-1 ; drug effects ; physiology ; Humans ; Molecular Structure ; Peptide Fragments ; chemistry ; therapeutic use ; Pyrrolidinones ; chemistry ; pharmacology ; therapeutic use ; Raltegravir Potassium ; Saquinavir ; chemistry ; pharmacology ; therapeutic use ; Triazoles ; chemistry ; pharmacology ; therapeutic use ; Virus Replication ; drug effects ; Zidovudine ; chemistry ; pharmacology ; therapeutic use

Activation of interferon (IFN) signaling in the central nervous system (CNS) is usually associated with inflammation. However, a robust activation of type I IFN-stimulated genes (ISGs) at pre-symptomatic stages occurs in the spinal cord of SOD1(G93A) mice, an amyotrophic lateral sclerosis (ALS) animal model, without obvious signs of inflammation. To determine if the same signaling pathway is elevated in other types of neuronal injuries, we examined the protein expression levels of an IFN-stimulated gene, ISG15, in mouse models of acute and chronic neuronal injuries. We found that ISG15 protein was dramatically increased in the brains of mice subjected to global ischemia and traumatic brain injury, and in transgenic mice overexpressing HIV gp120 protein. These results suggest that activation of ISGs is a shared feature of neuronal injuries and that ISG15 may be a suitable biomarker for detecting neuronal injuries in the CNS.
Amyotrophic Lateral Sclerosis ; physiopathology ; Animals ; Brain Injuries ; physiopathology ; Brain Ischemia ; physiopathology ; Central Nervous System ; physiopathology ; Cytokines ; metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Ubiquitins ; metabolism