Effect of the LSD1 inhibitor RN-1 on γ-globin and global gene expression during erythroid differentiation in baboons (Papio anubis).

Elevated levels of Fetal Hemoglobin interfere with polymerization of sickle hemoglobin thereby reducing anemia, lessening the severity of symptoms, and increasing life span of patients with sickle cell disease. An affordable, small molecule drug that stimulates HbF expression in vivo would be ideally suited to treat the large numbers of SCD patients that exist worldwide. Our previous work showed that administration of the LSD1 (KDM1A) inhibitor RN-1 to normal baboons increased Fetal Hemoglobin (HbF) and was tolerated over a prolonged treatment period.

Wnt pathway inhibitors are upregulated in XLH dental pulp cells in response to odontogenic differentiation.

X-linked hypophosphatemia (XLH) represents the most common form of familial hypophosphatemia. Although significant advances have been made in the treatment of bone pathology, patients undergoing therapy continue to experience significantly decreased oral health-related quality of life. The following study addresses this persistent oral disease by further investigating the effect of DMP1 expression on the differentiation of XLH dental pulp cells.

Dysregulated microRNA expression in IL-4 transgenic mice, an animal model of atopic dermatitis.

IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD). Previously we showed that the expression of genes in chemotaxis, angiogenesis, inflammation and barrier functions is dysregulated in IL-4 transgenic (Tg) mice, a well-characterized AD mouse model. In this study, we aim to study differential expression of microRNAs in IL-4 Tg mice.

Longitudinal Analysis of the T-cell Receptor Repertoire in Graft-infiltrating Lymphocytes Following Hand Transplantation.

Background: T lymphocyte-mediated acute rejection is a significant complication following solid organ transplantation. Standard methods of monitoring for acute rejection rely on assessing histological tissue damage but do not define the immunopathogenesis. Additionally, current therapies for rejection broadly blunt cellular immunity, creating a high risk for opportunistic infections.

HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers.

Complete Genome Sequence of a USA100 Methicillin-Resistant Staphylococcus aureus Strain.

We report the genome sequence of a methicillin-resistant (MRSA) strain, isolated from a surgical intensive care unit. This completely closed genome of a USA100 isolate contains a major chromosome and a plasmid and will serve as a reference genome for genetic analysis of MRSA strains.

Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia.

Background: Sphingosine- 1-Phosphate (S1P) is a bioactive lipid and an intracellular as well as an extracellular signaling molecule. S1P ligand specifically binds to five related cell surface G-protein-coupled receptors (S1P). S1P levels are tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases, lipid phosphate phosphatases and S1P lyase.

Investigation of Respiratory Syncytial Virus Outbreak on an Adult Stem Cell Transplant Unit by Use of Whole-Genome Sequencing.

A viral whole-genome sequencing (WGS) strategy, based on PCR amplification followed by next-generation sequencing, was used to investigate a nosocomial respiratory syncytial virus-B (RSV-B) outbreak in a hematology-oncology and stem cell transplant unit. RSV-B genomes from 16 patients and health care workers (HCWs) suspected to be involved in the outbreak were compared to RSV-B genomes that were acquired from outpatients during the same time period but epidemiologically unrelated to the outbreak. Phylogenetic analysis of the whole genome identified a cluster of 11 patients and HCWs who had an identical RSV-B strain which was clearly distinct from strains recovered from individuals unrelated to the outbreak.

Association of circulating transcriptomic profiles with mortality in sickle cell disease.

Sickle cell disease (SCD) complications are associated with increased morbidity and risk of mortality. We sought to identify a circulating transcriptomic profile predictive of these poor outcomes in SCD. Training and testing cohorts consisting of adult patients with SCD were recruited and prospectively followed.

Wnt proteins synergize to activate β-catenin signaling.

Wnt ligands are involved in diverse signaling pathways that are active during development, maintenance of tissue homeostasis and in various disease states. While signaling regulated by individual Wnts has been extensively studied, Wnts are rarely expressed alone, and the consequences of Wnt gene co-expression are not well understood. Here, we studied the effect of co-expression of Wnts on the β-catenin signaling pathway.

Differentially Expressed miRNAs in Hepatocellular Carcinoma Target Genes in the Genetic Information Processing and Metabolism Pathways.

To date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed.

Abundant copy-number loss of CYCLOPS and STOP genes in gastric adenocarcinoma.

Background: Gastric cancer, a leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar health burdens. Our goal is to assess genomic copy-number loss and the possible functional consequences and therapeutic implications thereof across a large series of gastric adenocarcinomas.

Methods: We used high-density single-nucleotide polymorphism microarrays to determine patterns of copy-number loss and allelic imbalance in 74 gastric adenocarcinomas.

Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes.

Purpose: Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment.

Experimental Design: Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics.

Results: We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes.

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression.

The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers.

Lipidomics identifies a requirement for peroxisomal function during influenza virus replication.

Influenza virus acquires a host-derived lipid envelope during budding, yet a convergent view on the role of host lipid metabolism during infection is lacking. Using a mass spectrometry-based lipidomics approach, we provide a systems-scale perspective on membrane lipid dynamics of infected human lung epithelial cells and purified influenza virions. We reveal enrichment of the minor peroxisome-derived ether-linked phosphatidylcholines relative to bulk ester-linked phosphatidylcholines in virions as a unique pathogenicity-dependent signature for influenza not found in other enveloped viruses.

ARTS: automated randomization of multiple traits for study design.

Unlabelled: Collecting data from large studies on high-throughput platforms, such as microarray or next-generation sequencing, typically requires processing samples in batches. There are often systematic but unpredictable biases from batch-to-batch, so proper randomization of biologically relevant traits across batches is crucial for distinguishing true biological differences from experimental artifacts. When a large number of traits are biologically relevant, as is common for clinical studies of patients with varying sex, age, genotype and medical background, proper randomization can be extremely difficult to prepare by hand, especially because traits may affect biological inferences, such as differential expression, in a combinatorial manner.

Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.

Background & Aims: Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents.

Methods: We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes.

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs).

A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.

Objective: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers.

Design: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples.

Assessing protein similarity with Gene Ontology and its use in subnuclear localization prediction.

Background: The accomplishment of the various genome sequencing projects resulted in accumulation of massive amount of gene sequence information. This calls for a large-scale computational method for predicting protein localization from sequence. The protein localization can provide valuable information about its molecular function, as well as the biological pathway in which it participates.

An SVM-based system for predicting protein subnuclear localizations.

Background: The large gap between the number of protein sequences in databases and the number of functionally characterized proteins calls for the development of a fast computational tool for the prediction of subnuclear and subcellular localizations generally applicable to protein sequences. The information on localization may reveal the molecular function of novel proteins, in addition to providing insight on the biological pathways in which they function. The bulk of past work has been focused on protein subcellular localizations.

Immobilized metal-ion chelating capillary microreactor for peptide mapping analysis of proteins by matrix assisted laser desorption/ ionization-time of flight-mass spectrometry.

Peptide mass mapping analysis, utilizing a regenerable enzyme microreactor with metal-ion chelated adsorption of enzyme, combined with matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) was developed. Different procedures from the conventional approaches were adopted to immobilize the chelator onto the silica supports, that is, the metal chelating agent of iminodiacetic acid (IDA) was reacted with glycidoxypropyltrimethoxysilane (GLYMO) before its immobilization onto the inner wall of the fused-silica capillary pretreated with NH(4)HF(2). The metal ion of copper and subsequently enzyme was specifically adsorbed onto the surface to form the immobilized enzyme capillary microreactor, which was combined with MALDI-TOF-MS to apply for the mass mapping analysis of nL amounts of protein samples.

Study of competitive binding of enantiomers to protein by affinity capillary electrochromatography.

Affinity capillary electrochromatography (CEC) with zonal elution method was used to probe the competitive interactions of enantiomers with protein. In this approach, a known concentration of a competing agent is continuously applied to a CEC column with bovine serum albumin (BSA) physically adsorbed on SAX packing while injections of a small amount of analyte are made. The binding sites of solutes on the BSA molecule were determined by the changes in the retention factors of the solutes resulted from the addition of competitive agent.