Unusual Fluorescent Granulomas and Myonecrosis in Danio Rerio Infected by the Microsporidian Pathogen Pseudoloma Neurophilia

Zebrafish are a powerful model organism to study disease. Like other animal models, Danio rerio colonies are at risk of pathogenic infection. Microsporidia, a group of intracellular fungus-like parasites, are one potential threat. Microsporidian spores germinate and spread causing pathological changes in the central nervous system, skeletal muscle, and other anatomic sites. Infection can impair breeding, cause other morbidities, and ultimately be lethal. Previously, detecting microsporidia in zebrafish has required sacrificing animals for histopathologic analysis or microscopic examination of fresh tissues. Here, we show that fish with microsporidial infection often have autofluorescent nodules, and we demonstrate infectious spread from nodule-bearing fish to healthy D. rerio. Histologic analyses revealed that fluorescent nodules are granulomatous lesions composed of spores, degenerating muscle, and inflammatory cells. Additional histologic staining verified that microsporidia were present, specifically, Pseudoloma neurophilia. Polymerase chain reaction (PCR)-based testing confirmed the presence of P. neurophilia. Further PCR testing excluded infection by another common zebrafish microsporidial parasite, Pleistophora hyphessobryconis. Collectively, these studies show that P. neurophilia can induce skeletal muscle granulomas in D. rerio, a previously unknown finding. Moreover, since granulomas autofluoresce, microscopic screening for P. neurophilia infection is feasible in live fish, avoiding the need to sacrifice fish for surveillance for this pathogen

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Background Immunoactivation is less evident in secondary progressive MS (SPMS) compared to relapsing-remitting disease. MicroRNA (miRNA) expression is integral to the regulation of gene expression; determining their impact on immune-related cell functions, especially CD4+ T cells, during disease progression will advance our understanding of MS pathophysiology. This study aimed to compare miRNA profiles of CD4+ T cells from SPMS patients to healthy controls (HC) using whole miRNA transcriptome next-generation sequencing (NGS). Total RNA was extracted from CD4+ T cells and miRNA expression patterns analyzed using Illumina-based small-RNA NGS in 12 SPMS and 12 HC samples. Results were validated in a further cohort of 12 SPMS and 10 HC by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results The ten most dysregulated miRNAs identified by NGS were selected for qPCR confirmation; five (miR-21-5p, miR-26b-5p, miR-29b-3p, miR-142-3p, and miR-155-5p) were confirmed to be down-regulated in SPMS (p < 0.05). SOCS6 is targeted by eight of these ten miRNAs. Consistent with this, SOCS6 expression is up-regulated in SPMS CD4+ T cells (p < 0.05). This is of particular interest as SOCS6 has previously been shown to act as a negative regulator of T cell activation. Conclusions Ninety-seven percent of miRNA candidates identified by NGS were down-regulated in SPMS. The down-regulation of miRNAs and increased expression of SOCS6 in SPMS CD4+ T cells may contribute to reduced immune system activity in progressive MS

Multi-phenotype genome-wide association studies of the Norfolk Island isolate implicate pleiotropic loci involved in chronic kidney disease

Chronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple correlated phenotypes. GWAS of a PC derived from glomerular filtration rate, serum creatinine, and serum urea identified a suggestive peak (pmin = 1.67 × 10-7) that mapped to KCNIP4. Inclusion of other secondary CKD measurements with these three kidney function traits identified the KCNIP4 locus with GWAS significance (pmin = 1.59 × 10-9). Finally, we identified a group of two SNPs with increased minor allele frequencies as potential functional variants. With the use of genetic isolate and the PCA-based multi-phenotype GWAS approach, we have revealed a potential pleotropic effect locus for CKD. Further studies are required to assess functional relevance of this locus

Genomic characterization of pediatric B‐lymphoblastic lymphoma and B‐lymphoblastic leukemia using formalin‐fixed tissues

BackgroundRecurrent genomic changes in B‐lymphoblastic leukemia (B‐ALL) identified by genome‐wide single‐nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B‐lymphoblastic lymphoma (B‐LBL), is limited by the low incidence and lack of fresh tissue for genomic testing.ProcedureWe used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin‐fixed paraffin‐embedded pediatric B‐LBL (n = 23) and B‐ALL (n = 55).ResultsSimilar to B‐ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B‐LBL cases. Eleven of 23 (48%) B‐LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B‐ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B‐LBL, respectively, which was similar to the reported frequency in B‐ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B‐LBL cases, compared with only 1% in B‐ALL samples. None of the B‐LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B‐ALL.ConclusionsOur study demonstrates that the copy number profile of B‐LBL is distinct from B‐ALL, suggesting possible differences in pathogenesis between these closely related diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/1/pbc26363.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/2/pbc26363_am.pd

Construction of the Literature Graph in Semantic Scholar

We describe a deployed scalable system for organizing published scientific literature into a heterogeneous graph to facilitate algorithmic manipulation and discovery. The resulting literature graph consists of more than 280M nodes, representing papers, authors, entities and various interactions between them (e.g., authorships, citations, entity mentions). We reduce literature graph construction into familiar NLP tasks (e.g., entity extraction and linking), point out research challenges due to differences from standard formulations of these tasks, and report empirical results for each task. The methods described in this paper are used to enable semantic features in www.semanticscholar.orgComment: To appear in NAACL 2018 industry trac

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children’s Oncology Group trial AALL15P1

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children’s Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin’s Lymphoma in Children

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.)