Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis

Background: Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment. Methods: SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR. Results: One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60 % of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate. Conclusion: Within the IFN treated SPMS population, 60 % of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment

The DNA damage response pathway regulates the expression of the immune checkpoint CD47

CD47 is a cell surface ligand expressed on all nucleated cells. It is a unique immune checkpoint protein acting as “don’t eat me” signal to prevent phagocytosis and is constitutively overexpressed in many tumors. However, the underlying mechanism(s) for CD47 overexpression is not clear. Here, we show that irradiation (IR) as well as various other genotoxic agents induce elevated expression of CD47. This upregulation correlates with the extent of residual double-strand breaks (DSBs) as determined by γH2AX staining. Interestingly, cells lacking mre-11, a component of the MRE11-RAD50-NBS1 (MRN) complex that plays a central role in DSB repair, or cells treated with the mre-11 inhibitor, mirin, fail to elevate the expression of CD47 upon DNA damage. On the other hand, both p53 and NF-κB pathways or cell-cycle arrest do not play a role in CD47 upregualtion upon DNA damage. We further show that CD47 expression is upregulated in livers harvested from mice treated with the DNA-damage inducing agent Diethylnitrosamine (DEN) and in cisplatin-treated mesothelioma tumors. Hence, our results indicate that CD47 is upregulated following DNA damage in a mre-11-dependent manner. Chronic DNA damage response in cancer cells might contribute to constitutive elevated expression of CD47 and promote immune evasion.</p

Development and preliminary effectiveness of an innovative treatment for binge eating in racially diverse adolescent girls

Binge and loss of control (LOC) eating are significant concerns among many adolescents and are associated with poor physical, social, and psychological functioning. Black girls appear to be particularly vulnerable to binge and LOC eating. Yet, empirically validated, culturally sensitive treatments for these disordered eating behaviors are not well established. This investigation examined satisfaction, feasibility, and preliminary outcomes of a binge eating intervention for ethnically diverse adolescent girls

LIBER8 design and methods: An integrative intervention for loss of control eating among African American and White adolescent girls

Loss of control (LOC) eating affects a significant number of adolescents of all racial and ethnic backgrounds and is associated with numerous psychosocial problems, including depression, anxiety, low self-esteem, body dissatisfaction, and weight concerns. However, empirically validated, culturally sensitive treatments for adolescents with these disordered eating behaviors are not available. This pilot project involved designing a developmentally and culturally appropriate treatment for LOC eating for adolescent girls. We intend to conduct multiple focus groups with adolescent girls who engage in LOC eating, and their primary caregivers. Data from these groups will inform the subsequent creation of a manualized treatment protocol. We will then evaluate the efficacy of this intervention (LIBER8—Linking Individuals Being Emotionally Real) to reduce LOC eating. This intervention will integrate components of dialectical behavior therapy, such as mindfulness and distress tolerance skills training, and cognitive-behavioral therapy. We will also integrate text-messaging, a key adolescent communication strategy, as a means of self-monitoring. Participants meeting study criteria will be offered participation in this 12-week randomized controlled trial comparing LIBER8 to a weight management control condition (2BFit). We hypothesize that this intervention will serve to reduce LOC eating, as well as improve psychosocial functioning as evidenced by decreased depression, anxiety, eating disorder cognitions, emotional eating, impulsivity, and improved quality of life. The feasibility and acceptability of this intervention will be extensively evaluated with the explicit intent of informing a subsequent larger randomized controlled trial

RepTar: a database of predicted cellular targets of host and viral miRNAs

Computational identification of putative microRNA (miRNA) targets is an important step towards elucidating miRNA functions. Several miRNA target-prediction algorithms have been developed followed by publicly available databases of these predictions. Here we present a new database offering miRNA target predictions of several binding types, identified by our recently developed modular algorithm RepTar. RepTar is based on identification of repetitive elements in 3′-UTRs and is independent of both evolutionary conservation and conventional binding patterns (i.e. Watson–Crick pairing of ‘seed’ regions). The modularity of RepTar enables the prediction of targets with conventional seed sites as well as rarer targets with non-conventional sites, such as sites with seed wobbles (G-U pairing in the seed region), 3′-compensatory sites and the newly discovered centered sites. Furthermore, RepTar’s independence of conservation enables the prediction of cellular targets of the less evolutionarily conserved viral miRNAs. Thus, the RepTar database contains genome-wide predictions of human and mouse miRNAs as well as predictions of cellular targets of human and mouse viral miRNAs. These predictions are presented in a user-friendly database, which allows browsing through the putative sites as well as conducting simple and advanced queries including data intersections of various types. The RepTar database is available at http://reptar.ekmd.huji.ac.il

Cytomegalovirus microRNAs Facilitate Persistent Virus Infection in Salivary Glands

Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Although some targets of viral miRNAs are known, their function in a physiologically relevant infection remains to be elucidated. As such, no in vivo phenotype of a viral miRNA knock-out mutant has been described so far. Here, we report on the first functional phenotype of a miRNA knock-out virus in vivo. During subacute infection of a mutant mouse cytomegalovirus lacking two viral miRNAs, virus production is selectively reduced in salivary glands, an organ essential for virus persistence and horizontal transmission. This phenotype depends on several parameters including viral load and mouse genetic background, and is abolished by combined but not single depletion of natural killer (NK) and CD4+ T cells. Together, our results point towards a miRNA-based immunoevasion mechanism important for long-term virus persistence

Association between translation efficiency and horizontal gene transfer within microbial communities

Horizontal gene transfer (HGT) is a major force in microbial evolution. Previous studies have suggested that a variety of factors, including restricted recombination and toxicity of foreign gene products, may act as barriers to the successful integration of horizontally transferred genes. This study identifies an additional central barrier to HGT—the lack of co-adaptation between the codon usage of the transferred gene and the tRNA pool of the recipient organism. Analyzing the genomic sequences of more than 190 microorganisms and the HGT events that have occurred between them, we show that the number of genes that were horizontally transferred between organisms is positively correlated with the similarity between their tRNA pools. Those genes that are better adapted to the tRNA pools of the target genomes tend to undergo more frequent HGT. At the community (or environment) level, organisms that share a common ecological niche tend to have similar tRNA pools. These results remain significant after controlling for diverse ecological and evolutionary parameters. Our analysis demonstrates that there are bi-directional associations between the similarity in the tRNA pools of organisms and the number of HGT events occurring between them. Similar tRNA pools between a donor and a host tend to increase the probability that a horizontally acquired gene will become fixed in its new genome. Our results also suggest that frequent HGT may be a homogenizing force that increases the similarity in the tRNA pools of organisms within the same community

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks.

PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P&nbsp;=&nbsp;.002), had worse VA at the time of PLEX (P &lt; .001), and longer delay to PLEX (P &lt; .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P&nbsp;=&nbsp;.04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society