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1.  Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis 
Infection and Immunity  2013;81(12):4421-4430.
Previous studies have shown that cells and cytokines associated with interleukin-17 (IL-17)-driven inflammation are involved in the arthritic response to Borrelia burgdorferi infection. Here, we report that IL-17 is a contributing factor in the development of Lyme arthritis and show that its production and histopathological effects are regulated by interleukin-10 (IL-10). Spleen cells obtained from B. burgdorferi-infected, “arthritis-resistant” wild-type C57BL/6 mice produced low levels of IL-17 following stimulation with the spirochete. In contrast, spleen cells obtained from infected, IL-10-deficient C57BL/6 mice produced a significant amount of IL-17 following stimulation with B. burgdorferi. These mice developed significant arthritis, including erosion of the bones in the ankle joints. We further show that treatment with antibody to IL-17 partially inhibited the significant hind paw swelling and histopathological changes observed in B. burgdorferi-infected, IL-10-deficient mice. Taken together, these findings provide additional evidence of a role for IL-17 in Lyme arthritis and reveal an additional regulatory target of IL-10 following borrelial infection.
doi:10.1128/IAI.01129-13
PMCID: PMC3837975  PMID: 24042116
2.  Thalidomide in Total Therapy 2 Overcomes Inferior Prognosis of Myeloma with Low Expression of the Glucocorticoid Receptor Gene NR3C1 
Purpose
Because dexamethasone remains a key component of myeloma therapy, we wished to examine the impact of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 on survival outcomes in the context of treatment with or without thalidomide.
Experimental Design
We investigated the clinical impact of gene expression profiling (GEP)–derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to Total Therapy 2 (TT2).
Results
Low NR3C1 expression levels had a negative impact on progression-free survival (PFS, HR=1.47; p=0.030) and overall survival (OS, HR=1.90; p=0.002) in the no-thalidomide arm. Conversely, there was a significant clinical benefit of thalidomide for patients with low receptor levels (OS, HR=0.54, p=0.015; PFS, HR=0.54, p=0.004), mediated most likely by thalidomide’s up-regulation of NR3C1. In the context of both baseline and relapse parameters, post-relapse survival (PRS) was adversely affected by low NR3C1 levels at relapse in a multivariate analysis (HR=2.61, p=0.012).
Conclusion
These findings justify the inclusion of NR3C1 expression data in the work-up of patients with myeloma as it can significantly influence the choice of therapy and, ultimately, OS. The identification of an interaction term between thalidomide and NR3C1 underscores the importance of pharmacogenomic studies in the systematic study of new drugs.
doi:10.1158/1078-0432.CCR-12-0019
PMCID: PMC3677537  PMID: 22855579
Myeloma; Glucocorticoids; Glucocorticoid Receptor; Total Therapy 2; Thalidomide
3.  Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling, and clinical outcome with Total Therapy protocols 
To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene expression profiling (GEP), we reviewed records of 1474 patients with myeloma who were enrolled in Total Therapy protocols or treated identically off protocol. 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin, and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (1.8 years), progression-free survival (0.8 years), and complete response duration (1.3 years) than the remainder whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to overall survival, progression-free survival, and complete response duration. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation, and LPS/IL-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.
doi:10.1038/leu.2012.107
PMCID: PMC3426639  PMID: 22508408
plasma cell leukemia; myeloma; total therapy; prognosis; gene expression profiling
4.  Interleukin-6 Receptor Polymorphism Is Prevalent in HIV-negative Castleman Disease and Is Associated with Increased Soluble Interleukin-6 Receptor Levels 
PLoS ONE  2013;8(1):e54610.
Multicentric Castleman Disease is largely driven by increased signaling in the pathway for the plasma cell growth factor interleukin-6. We hypothesized that interleukin-6/interleukin-6 receptor/gp130 polymorphisms contribute to increased interleukin-6 and/or other components of the interleukin-6 signaling pathway in HIV-negative Castleman Disease patients. The study group was composed of 58 patients and 50 healthy donors of a similar racial/ethnic profile. Of seven polymorphisms chosen for analysis, we observed an increased frequency between patients and controls of the minor allele of interleukin-6 receptor polymorphism rs4537545, which is in linkage disequilibrium with interleukin-6 receptor polymorphism rs2228145. Further, individuals possessing at least one copy of the minor allele of either polymorphism expressed higher levels of soluble interleukin-6 receptor. These elevated interleukin-6 receptor levels may contribute to increased interleukin-6 activity through the trans-signaling pathway. These data suggest that interleukin-6 receptor polymorphism may be a contributing factor in Castleman Disease, and further research is warranted.
doi:10.1371/journal.pone.0054610
PMCID: PMC3553080  PMID: 23372742
5.  Factors associated with initiation and exclusive breastfeeding at hospital discharge: late preterm compared to 37 week gestation mother and infant cohort 
Background
To investigate and examine the factors associated with initiation of, and exclusive breastfeeding at hospital discharge of, late preterm (34 0/7 - 36 6/7 weeks) compared to 37 week gestation (37 0/7 - 37 6/7 week) mother and baby pairs.
Methods
A retrospective population-based cohort study using a Perinatal National Minimum Data Set and clinical medical records review, at the Royal Hobart Hospital, Tasmania, Australia in 2006.
Results
Late preterm and 37 week gestation infants had low rates of initiation of breastfeeding within one hour of birth, 31 (21.1%) and 61 (41.5%) respectively. After multiple regression analysis, late preterm infants were less likely to initiate breastfeeding within one hour of birth (OR 0.3 95% CI 0.1, 0.7 p = 0.009) and were less likely to be discharged exclusively breastfeeding from hospital (OR 0.4 95% CI 0.1, 1.0 p = 0.04) compared to 37 week gestation infants.
Conclusion
A late preterm birth is predictive of breastfeeding failure, with late preterm infants at greater risk of not initiating breastfeeding and/or exclusively breastfeeding at hospital discharge, compared with those infants born at 37 weeks gestation. Stratifying breastfeeding outcomes by gestational age groups may help to identify those sub-populations at greatest risk of premature cessation of breastfeeding.
doi:10.1186/1746-4358-7-16
PMCID: PMC3546019  PMID: 23181740
Exclusive breastfeeding; Initiation; Late preterm; Infant
6.  A Comparison of Two Classes of Methods for Estimating False Discovery Rates in Microarray Studies 
Scientifica  2012;2012:519394.
The goal of many microarray studies is to identify genes that are differentially expressed between two classes or populations. Many data analysts choose to estimate the false discovery rate (FDR) associated with the list of genes declared differentially expressed. Estimating an FDR largely reduces to estimating π1, the proportion of differentially expressed genes among all analyzed genes. Estimating π1 is usually done through P-values, but computing P-values can be viewed as a nuisance and potentially problematic step. We evaluated methods for estimating π1 directly from test statistics, circumventing the need to compute P-values. We adapted existing methodology for estimating π1 from t- and z-statistics so that π1 could be estimated from other statistics. We compared the quality of these estimates to estimates generated by two established methods for estimating π1 from P-values. Overall, methods varied widely in bias and variability. The least biased and least variable estimates of π1, the proportion of differentially expressed genes, were produced by applying the “convest” mixture model method to P-values computed from a pooled permutation null distribution. Estimates computed directly from test statistics rather than P-values did not reliably perform well.
doi:10.6064/2012/519394
PMCID: PMC3820438  PMID: 24278709
7.  Preliminary crystallographic analysis of GpgS, a key glucosyltransferase involved in methylglucose lipopolysaccharide biosynthesis in Mycobacterium tuberculosis  
Glucosyl-3-phosphoglycerate synthase (GpgS) is a key enzyme that catalyses the first glucosylation step in methylglucose lipopolysaccharide biosynthesis in Mycobacterium spp. Here, the crystallization and preliminary crystallographic analysis of GpgS from M. tuberculosis and of its complex with UDP are reported.
Glucosyl-3-phosphoglycerate synthase (GpgS) is a key enzyme that catalyses the first glucosylation step in methylglucose lipopolysaccharide biosynthesis in mycobacteria. These important molecules are believed to be involved in the regulation of fatty-acid and mycolic acid synthesis. The enzyme belongs to the recently defined GT81 family of retaining glycosyltransferases (CAZy, Carbohydrate-Active Enzymes Database; see http://www.cazy.org). Here, the purification, crystallization and preliminary crystallographic analysis are reported of GpgS from Mycobacterium tuberculosis and of its complex with UDP. GpgS crystals belonged to space group I4, with unit-cell parameters a = 98.85, b = 98.85, c = 127.64 Å, and diffracted to 2.6 Å resolution. GpgS–UDP complex crystals belonged to space group I4, with unit-cell parameters a = 98.32, b = 98.32, c = 127.96 Å, and diffracted to 3.0 Å resolution.
doi:10.1107/S1744309108032892
PMCID: PMC2593697  PMID: 19052364
glycosyltransferases; methylglucose lipopolysaccharides; Mycobacterium tuberculosis
8.  Preliminary crystallographic analysis of GpgS, a key glucosyltransferase involved in methylglucose lipopolysaccharides biosynthesis in Mycobacterium tuberculosis 
Synopsis Glucosyl-3-phosphoglycerate synthase (GpgS) is a key enzyme that catalyses the first glucosylation step in methylglucose lipopolysaccharides (MGLP) biosynthesis in Mycobacterium spp. Here we report the crystallization and preliminary crystallographic analysis of GpgS from Mycobacterium tuberculosis and its complex with UDP at 2.6 Å and 3.0 Å resolution, respectively.
Glucosyl-3-phosphoglycerate synthase (GpgS) is a key enzyme that catalyses the first glucosylation step in methylglucose lipopolysaccharides (MGLP) biosynthesis in mycobacteria. These important molecules are believed to be involved in the regulation of fatty acid and mycolic acid synthesis. The enzyme belongs to the recently defined GT81 family of retaining glycosyltransferases (CAZy, Carbohydrate-Active enZymes data base; see www.cazy.org). Here we report the purification, crystallization and preliminary crystallographic analysis of GpgS from Mycobacterium tuberculosis and its complex with UDP. GpgS crystals belong to space group I4, with unit-cell parameters a = 98.85, b = 98.85, c= 127.64 Å, and diffract to 2.6 Å resolution. GpgS-UDP complex crystals belong to space group I4 with unit-cell parameters a= 98.32, b= 98.32, c= 127.96 Å, and diffract to 3.0 Å resolution.
doi:10.1107/S1744309108032892
PMCID: PMC2593697  PMID: 19052364
glycosyltransferase; methylglucose lipopolysaccharides; Mycobacterium; X ray structure

Results 1-8 (8)