PD-1 Blockade Reinvigorates Bone Marrow CD8 T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors.

Purpose: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.

Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients.

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.

During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers.

Transcriptional profiling of human intestinal plasma cells reveals effector functions beyond antibody production.

Background: Plasma cells (PCs) are terminally differentiated B-lymphocytes producing antibodies. In coeliac disease (CeD) there is increased density of PCs in the small-intestinal lesion. Many of these PCs produce disease-specific autoantibodies targeting transglutaminase 2 (TG2).

Targeting of HA to chemokine receptors induces strong and cross-reactive T cell responses after DNA vaccination in pigs.

Efficient influenza vaccination of pigs can reduce disease burdens for the swine industry, but also represents an important measure for reducing the risk from novel viral reassortments that pose pandemic threats to the human population. Here, we have vaccinated pigs with a DNA vaccine encoding influenza virus hemagglutinin (HA) linked to the chemokine MIP1α that bind chemokine receptors 1, 3, and 5 expressed on antigen presenting cells (APC). Such MIP1α targeting of HA to APC enhanced induction of HA reactive antibodies, particularly IgG2.

Discovery and annotation of novel microRNAs in the porcine genome by using a semi-supervised transductive learning approach.

Despite the broad variety of available microRNA (miRNA) prediction tools, their application to the discovery and annotation of novel miRNA genes in domestic species is still limited. In this study we designed a comprehensive pipeline (eMIRNA) for miRNA identification in the yet poorly annotated porcine genome and demonstrated the usefulness of implementing a motif search positional refinement strategy for the accurate determination of precursor miRNA boundaries. The small RNA fraction from gluteus medius skeletal muscle of 48 Duroc gilts was sequenced and used for the prediction of novel miRNA loci.

Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with C-Metoclopramide PET.

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain.

A new method for pharmaceutical compounding and storage of anti-VEGF biologics for intravitreal use in silicone oil-free prefilled plastic syringes.

Intravitreal injections of antibody-based biologics targeting vascular endothelial growth factor (VEGF) are highly effective and have markedly decreased the risk of visual impairment associated with prevalent retinal diseases, such as neovascular age-related macular degeneration and diabetes macular oedema. The diseases are chronic in their nature, and most patients need long-term therapy to suppress disease activity. We previously reported a compounding method for repackaging and storage of aflibercept (Eylea), a commonly used anti-VEGF biologic, in silicone oil-coated plastic syringes without compromising drug stability or activity.

Single-cell TCR sequencing of gut intraepithelial γδ T cells reveals a vast and diverse repertoire in celiac disease.

A hallmark of celiac disease (CeD), a chronic condition driven by cereal gluten exposure, is increase of gut intraepithelial γδ T cells. This may indicate pathogenic involvement of γδ T cells and existence of disease-specific γδ T-cell receptors (TCRs) recognizing defined antigen(s). We performed high-throughput and paired γδ TCR sequencing of single intraepithelial γδ T cells of untreated CeD patients (n = 8; 1821 cells), CeD patients treated with a gluten-free diet (n = 5; 436 cells) and controls (n = 7; 1068 cells).

FRET-based cyclic GMP biosensors measure low cGMP concentrations in cardiomyocytes and neurons.

Several FRET (fluorescence resonance energy transfer)-based biosensors for intracellular detection of cyclic nucleotides have been designed in the past decade. However, few such biosensors are available for cGMP, and even fewer that detect low nanomolar cGMP concentrations. Our aim was to develop a FRET-based cGMP biosensor with high affinity for cGMP as a tool for intracellular signaling studies.

Jasmine: a Java pipeline for isomiR characterization in miRNA-Seq Data.

Motivation: The existence of complex subpopulations of miRNA isoforms, or isomiRs, is well established. While many tools exist for investigating isomiR populations, they differ in how they characterize an isomiR, making it difficult to compare results across different tools. Thus, there is a need for a more comprehensive and systematic standard for defining isomiRs.

Gastric bypass versus sleeve gastrectomy in patients with type 2 diabetes (Oseberg): a single-centre, triple-blind, randomised controlled trial.

Background: For patients with obesity and type 2 diabetes, weight loss improves insulin sensitivity and β-cell function, and can induce remission of diabetes. The comparative efficacy of various bariatric procedures for the remission of type 2 diabetes has not been fully elucidated. We aimed to compare the effects of the two most common bariatric procedures, gastric bypass and sleeve gastrectomy, on remission of diabetes and β-cell function.

GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far.

Common Nodes of Virus-Host Interaction Revealed Through an Integrated Network Analysis.

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases.

The association of birthweight with age at natural menopause: a population study of women in Norway.

Background: Previous studies suggest that birthweight may influence age at natural menopause, but the evidence remains inconclusive. Thus, we aimed to estimate the association of birthweight with age at natural menopause.

Methods: A retrospective population study of 164 608 women in Norway, aged 48-71 years.

On the immune response to barley in celiac disease: Biased and public T-cell receptor usage to a barley unique and immunodominant gluten epitope.

Celiac disease (CeD) is driven by CD4  T-cell responses to dietary gluten proteins of wheat, barley, and rye when deamidated gluten epitopes are presented by certain disease-associated HLA-DQ allotypes. About 90% of the CeD patients express HLA-DQ2.5.

Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial.

Objective: To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes).

Design: Double blind, parallel group, placebo controlled, multicentre trial.

Setting: Hospital outpatient clinics at six hospitals in Norway.

HLA and sleep parameter associations in post-H1N1 narcolepsy type 1 patients and first-degree relatives.

Study Objectives: To explore HLA (human leukocyte antigen) in post-H1N1 narcolepsy type 1 patients (NT1), first-degree relatives and healthy controls, and assess HLA associations with clinical and sleep parameters in patients and first-degree relatives.

Methods: Ninety post-H1N1 NT1 patients and 202 of their first-degree relatives were HLA-genotyped (next generation sequencing) and phenotyped (semistructured interviews, Stanford Sleep Questionnaire, polysomnography, and multiple sleep latency test). HLA allele distributions were compared between DQB1*06:02-heterozygous individuals (77 patients, 59 parents, 1230 controls).

A TRAV26-1-encoded recognition motif focuses the biased T cell response in celiac disease.

The semi-public T-cell response towards the gluten epitope DQ2.5-glia-α2 uses a prototypic TCR encoded by the germline segments TRAV26-1 and TRBV7-2. Through mutagenesis experiments, we show that a TRAV26-1encoded recognition motif contacts the MHC β-chain and the TCR CDR3β loop underpinning this conserved T-cell response restricted to the prototypic TCRs.

Targeting the MHC Ligandome by Use of TCR-Like Antibodies.

Monoclonal antibodies (mAbs) are valuable as research reagents, in diagnosis and in therapy. Their high specificity, the ease in production, favorable biophysical properties and the opportunity to engineer different properties make mAbs a versatile class of biologics. mAbs targeting peptide-major histocompatibility molecule (pMHC) complexes are often referred to as "TCR-like" mAbs, as pMHC complexes are generally recognized by T-cell receptors (TCRs).

Cognitive functioning in patients with first-episode psychosis stratified by level of negative symptoms: A 1-year follow-up study.

We investigate negative symptoms over a 1-year follow-up period with the objective to see how groups defined according to level of symptom severity are related to cognition. Eighty-seven participants with first-episode psychosis (FEP) and matched healthy controls were assessed at baseline and follow-up. FEP participants were sub-grouped based on negative symptom items from the Positive and Negative Syndrome Scale (PANSS-R) with either no, mild, transitory or sustained symptoms over one year.

The emerging pattern of shared polygenic architecture of psychiatric disorders, conceptual and methodological challenges.

Genome-wide association studies have transformed psychiatric genetics and provided novel insights into the genetic etiology of psychiatric disorders. Two major discoveries have emerged; the disorders are polygenic, with a large number of common variants each with a small effect and many genetic variants influence more than one phenotype, suggesting shared genetic etiology. These concepts have the potential to revolutionize the current classification system with diagnostic categories and facilitate development of better treatments.

Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease.

Celiac disease (CeD), caused by immune reactions to cereal gluten, is treated with gluten -elimination diets. Within hours of gluten exposure, either perorally or extraorally by intradermal injection, treated patients experience gastrointestinal symptoms. To test whether gluten exposure leads to systemic cytokine production time -related to symptoms, series of multiplex cytokine measurements were obtained in CeD patients after gluten challenge.

The Effects of Adipocytes on the Regulation of Breast Cancer in the Tumor Microenvironment: An Update.

Obesity is a global pandemic and it is well evident that obesity is associated with the development of many disorders including many cancer types. Breast cancer is one of that associated with a high mortality rate. Adipocytes, a major cellular component in adipose tissue, are dysfunctional during obesity and also known to promote breast cancer development both in vitro and in vivo.