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The pattern-recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non-Hodgkin lymphoma (NHL). We evaluated NHL risk associated with genetic variation in pattern-recognition genes using data from a case–control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern-recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency-matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and common NHL subtypes in relation to individual SNPs and haplotypes. A gene-based analysis that adjusted for the number of tagSNPs genotyped in each gene showed a significant association with overall NHL for the MBP gene (P = 0.028), with the diffuse large B-cell lymphoma (DLBCL) subtype for the MASP2 gene (P = 0.011), and with the follicular lymphoma (FL) subtype for DEFB126 (P = 0.041). A SNP-based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR = 0.72, P-trend = 0.0018), DLBCL (allele risk OR = 0.72, P-trend = 0.036), and FL (allele risk OR = 0.67, P-trend = 0.021), while MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR = 0.57, P-trend = 0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR = 1.39, P-trend = 0.033). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NHL or specific NHL subtypes, but these preliminary findings require replication in larger studies. Mol. Mutagen. 2013. © 2012 Wiley Periodicals, Inc.

SummaryMammalian neural progenitor cells divide asymmetrically to self-renew and produce a neuron by segregating cytosolic Numb proteins primarily to one daughter cell. Numb signaling specifies progenitor over neuronal fates but, paradoxically, also promotes neuronal differentiation. Here we report that ACBD3 is a Numb partner in cell-fate specification. ACBD3 and Numb proteins interact through an essential Numb domain, and the respective loss- and gain-of-function mutant mice share phenotypic similarities. Interestingly, ACBD3 associates with the Golgi apparatus in neurons and interphase progenitor cells but becomes cytosolic after Golgi fragmentation during mitosis, when Numb activity is needed to distinguish the two daughter cells. Accordingly, cytosolic ACBD3 can act synergistically with Numb to specify cell fates, and its continuing presence during the progenitor cell cycle inhibits neuron production. We propose that Golgi fragmentation and reconstitution during cell cycle differentially regulate Numb signaling through changes in ACBD3 subcellular distribution and represent a mechanism for coupling cell-fate specification and cell-cycle progression.

Studies have demonstrated that common polymorphisms in Th1 and Th2 cytokine genes can alter gene expression, modulate the balance between Th1/Th2 responsiveness, and influence susceptibility for autoimmune disorders, infectious diseases, and cancer. We analyzed one or more single nucleotide polymorphisms (SNPs) in 20 candidate Th1/Th2 genes in a population-based case-control study of non-Hodgkin lymphoma (NHL; n = 518 cases, 597 controls) among women in Connecticut. SNPs in critical genes, IL4, IL5, IL6, and IL10, were associated with risk for NHL and in some instances with a specific histologic subtype. Analysis of 4 SNPs in the IL10 promoter (–3575T>A, –1082A>G, –819C>T, and –592C>A) revealed that both the AGCC haplotype (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.21-1.96, P < .001) and the TATA haplotype (OR = 1.37, 95% CI = 1.05-1.79, P = .02) were associated with increased risk for B-cell lymphomas. In contrast, the IL4-1098G allele was associated with increased risk of T-cell lymphomas (OR = 3.84; 95% CI = 1.79-8.22; P < .001). Further, the IL10 and IL4 SNP associations remained significant after adjusting for multiple comparisons. These results suggest that SNPs in Th2 cytokine genes may be associated with risk of NHL.

Asymmetric cell division is an attractive means to diversify cell fates during development and for stem cells to balance self-renewal and differentiation. In Drosophila, two signaling pathways, one mediated by Numb and the other by Notch, play essential but antagonistic roles in enabling the two daughters to adopt different fates after a wide variety of asymmetric cell divisions. However, recent studies show that mutating mammalian Numb homologues, m-Numb and Numblike (Numbl or Nbl), and eliminating Notch signaling in the developing nervous system both lead to premature depletion of neural stem/progenitor cells in mice. These findings raise an interesting question as to whether and how the antagonistic roles of Numb and Notch signaling are conserved in vertebrates. Here we provide evidence that loss of m-Numb and Numbl outside the embryonic nervous system also causes phenotypes similar to those exhibited by mice with defective Notch signaling. We further show that very little Numb protein is necessary for embryogenesis and that the presence of different m-Numb isoforms is unlikely to provide a molecular basis for differential regulation of Notch signaling in mammals, as these isoforms are functionally indistinguishable in cell fate specification. We discuss possible mechanisms by which the antagonistic roles of Numb and Notch are evolutionarily conserved to meet the needs of stem cell maintenance during mammalian neurogenesis.

Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities.

Recent studies have shown that the B-cell lymphoma 6 gene (BCL6) is an oncogene that contributes to lymphomagenesis. Exon 6 of BCL6 contains a common single nucleotide polymorphism (SNP) (-195 C>T; dbSNP ID: rs1056932) that alters a potential binding site for an exonic splicing enhancer. We used unconditional logistic regression models to examine the association between this SNP and the risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study of women residing in Connecticut (461 case patients and 535 control subjects). The risk of NHL among women with the CC genotype was more than double that of women with the TT genotype (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.5 to 3.3). Higher risks were observed for two NHL subtypes, namely B-cell chronic lymphatic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma (OR = 3.5, 95% CI = 1.6 to 7.8) and T-cell lymphoma (OR = 5.2, 95% CI = 2.0 to 13.3). Our results support the hypothesis that a genetic variant that could alter mRNA transcripts of BCL6 may contribute to the etiology of NHL and suggest that this variant warrants further investigation.

The complement system plays an important role in inflammatory and immune responses, and recent evidence has suggested that it may also play a role in lymphomagenesis. We evaluated the association between genetic variation in complement system genes and risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study conducted among women in Connecticut. Tag SNPs in 30 complement genes were genotyped in 432 Caucasian incident cases and 494 frequency-matched controls. A gene-based analysis that adjusted for the number of tag SNPs genotyped in each gene showed a significant association with NHL overall (P = 0.04) as well as with diffuse large B-cell lymphoma (DLBCL) (P = 0.01) for the C1RL gene. A SNP-based analysis showed that a C>T base substitution for C1RL rs3813729 (odds ratio (OR)(CT) = 0.60, 95% confidence interval (CI) = 0.42-0.87, P(trend) = 0.0062) was associated with a decreased risk of overall NHL, as well as for DLBCL (OR(CT) = 0.39, 95% CI = 0.20-0.73; P(trend) = 0.0034). Additionally, SNPs (C2 rs497309, A>C and C3 rs344550, G>C) in two complement genes were positively associated with marginal zone lymphoma (MZL) and C1QG was associated with CLL/SLL, but these results were based on a limited number of cases. Our results suggest a potential role of the complement system in susceptibility to NHL; however, our results should be viewed as exploratory and further replication is needed to clarify these preliminary findings.

Several hereditary syndromes characterized by defective DNA repair are associated with high risk of non-Hodgkin lymphoma (NHL). To explore whether common polymorphisms in DNA repair genes affect risk of NHL in the general population, we evaluated the association between single nucleotide polymorphisms (SNPs) in DNA repair genes and risk of NHL in a population-based case–control study among women in Connecticut. A total of 518 NHL cases and 597 controls recruited into the study provided a biologic sample. Thirty-two SNPs in 18 genes involved in several DNA repair pathways were genotyped. Genotype data were analyzed by unconditional logistic regression adjusting for age and race. SNPs in four genes (ERCC5, ERCC2, WRN, and BRCA1) were associated with altered risk of NHL and diffuse large B-cell lymphoma (DLBCL), the major B cell subtype. In particular, ERCC5 Asp1104His was associated with increased risk of NHL overall (OR: 1.46; 95% CI: 1.13–1.88; P = 0.004), DLBCL (OR: 1.44; 95% CI: 0.99–2.09; P = 0.058), and also T cell lymphoma. WRN Cys1367Arg was associated with decreased risk of NHL overall (OR: 0.71; 95% CI: 0.56–0.91; P = 0.007) and DLBCL (OR: 0.66; 95% CI: 0.45–0.95; P = 0.024), as well as follicular and marginal zone lymphomas. Genetic polymorphisms in DNA repair genes, particularly ERCC5 and WRN, may play a role in the pathogenesis of NHL, especially for DLBCL. Further work is needed to extend these findings by carrying out extended haplotype analyses of these and related genes and to replicate the observations in other studies.

金沢大学大学院医学系研究科病態検査学, Neurotoxigenic Clostridium butyricum was isolated from the food implicated in an outbreak of clinically diagnosed type E botulism in China. PCR assay showed that the isolate (LCL 155) contained the type E botulinum toxin gene. This appears to be the first report of neurotoxigenic C. butyricum causing food-borne botulism.

Neural progenitor cells in the developing neocortex change over time to produce different neurons, a phenomenon that is also observed in other regions of the nervous system. Mouse Numb (also known as m-numb) and Numbl (also known as numblike or Nbl) are redundant but essential in maintaining virtually all progenitor cells during early neurogenesis. They do this by allowing cells to choose progenitor over neuronal fates. To determine whether their roles change as neurogenesis progresses, we conditionally ablated both genes in the embryonic dorsal forebrain after initial waves of neurogenesis. Here we report that these proteins continue to be required for progenitor-cell maintenance, contrary to recently reported findings. As occurs during early neurogenesis, the loss of Numb and Numbl causes premature progenitor-cell depletion and, consequently, a highly specific malformation of the neocortex and hippocampus. Because progenitor cells can proliferate without Numb and Numbl before neurogenesis, we propose that Numb-mediated asymmetric cell divisions, which diversify many cell fates in Drosophila melanogaster, represent a general mechanism in mammals for stem cells to balance self-renewal and differentiation.