IntroductionFollicular lymphoma (FL) constitutes the second most common B-cell malignancy among B-cell non-Hodgkin lymphomas (BNHLs). 1 It is considered an indolent lymphoma with a median overall survival of 8 to 10 years, but with an upward trend toward even further increased survival times because of more recent, improved treatment regimens. 2,3 FL is currently viewed as a germinal center (GC) B-cell derived lymphoma. Its origin in the GC influences the molecular characteristics but is also reflected at the morphologic level, as FL usually forms atypical follicles that in many aspects mimic their physiologic counterparts and typically express GC-associated B-cell markers, such as CD10, BCL6, and IRF-8. 1 Approximately 90% of FLs carry the translocation t(14;18)(q32;q21), leading to deregulated and aberrant expression of the antiapoptotic protein BCL2. Even with advanced, high-resolution techniques, however, a molecular rearrangement of the BCL2 gene cannot be detected in 10% of FLs, 4,5 raising the question of whether these cases belong to the biologic spectrum of "conventional" FLs. It is unclear whether they differ in their clinical behavior and whether these lymphomas display pathogenetic features equivalent to BCL2 deregulation in t(14;18)-positive FLs. Such molecular events in t(14;18)-negative FLs, however, have not been identified as of yet.We and others 4,6,7 have previously investigated the morphologic and molecular features of t(14;18)-negative FLs. Current evidence suggests that these lymphomas share many morphologic, genetic, and molecular characteristics with their t(14;18)-positive counterparts that would not justify a diagnosis other than FL (eg, marginal zone lymphoma) according to currently established WHO guidelines. In this study, we performed microRNA (miR) profiling of t(14;18)-negative FLs to further characterize this FL subgroup on the molecular level and to substantiate findings previously derived from gene expression profiling experiments. miR are transcriptional and translational inhibitors with important functions in physiologic cellular processes, but there is increasing evidence that they also play a pivotal role in the oncogenic evolution in many types of cancer. 8 In FLs, data on miR profiles are scarce, 9,10 and t(14;18)-negative FLs have not been characterized yet. We here show that t(14;18)-negative FLs have distinct miR expression profiles that are in support of a late GC B-cell phenotype and that may be associated with particular biologic properties of this Submitted June 28, 2011; accepted September 18, 2011. Prepublished online as Blood First Edition paper, September 29, 2011; DOI 10.1182 DOI 10. /blood-2011 *G.O., L.H., and A.R. contributed equally to this study as co-senior authors.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 5550BLOOD, 17 N...

The role of TP53 mutation in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL) was examined in a panel of 91 lymph node biopsies derived from 29 patients pre-and post-transformation. The entire TP53 coding sequence was screened and immunocytochemistry performed to determine expression of p53 and its key regulator MDM2. A total of 10 mutations were detected in eight patients (28%), although none were present at FL diagnosis. Mutations were not detected solely at the time of transformation; in three patients, mutated TP53 arose in at least one antecedent FL sample (6 months, 2.5 years and 4 years prior to transformation). Loss of heterozygosity at the TP53 locus occurred in 2/20 informative patients (only in t-FL samples). p53 staining was positive in 82% (9/11) of available biopsies with a missense mutation, and negative in 71% (45/63) with wtTP53. MDM2 expression was significantly higher in t-FL samples (mean 72% positive; 95% confidence interval (95% CI) 68-76%) than FL (mean 58% positive; 95% CI 54-62%) (Po0.001) but did not correlate with TP53 status. TP53 mutation has only a limited role in the transformation of FL, exerting a heterogeneous influence upon phenotypic change. In contrast, dysregulation of MDM2 is frequent and may provide a more rational therapeutic target.

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Nicotine, scopolamine, oxotremorine, diisopropyl-fluorophosphate (DFP) and tetrahydroaminoacridine (THA) were administered chronically to different groups of rats in doses reported to alter central muscarinic and/or nicotinic receptor numbers. Beginning 24 h after final drug injection, the groups were compared to a vehicle control group on acquisition of a hidden platform position in the Morris water maze over 20 trials with a 30-min inter-trial interval. Chronic treatment with either nicotine or scopolamine significantly improved the rate of learning, but oxotremorine and DFP retarded learning and THA had no effect on learning. The chronic drug effects on behaviour were consistent with known effects of the injected drugs on muscarinic and nicotinic binding in the forebrain and on the sensitivity of frontal cortex neurones to iontophoretically applied cholinoceptor agonists. However, alternative explanations for the observed changes cannot be ruled out, since the drugs used are known to have a wide range of effects on other neurotransmitters.

The effects of chronic nicotine treatment and of unilateral AMPA lesion of the nucleus basalis magnocellularis (nbm) on the sensitivity of frontal cortical neurones to iontophoretically applied nicotine were studied. Chronic nicotine treatment increased the number of [3H]nicotine binding sites from 2.9 to 3.9 pmol g-1 wet weight, and increased the proportion of cortical neurones responding to nicotine from 32.3% to 60.0%. After unilateral nbm lesions, the densities of AChE-positive fibers and [3H]nicotine binding sites were reduced by approximately 97% and 55%, respectively, and the proportion of neurones responding to nicotine increased from 32.3% to 53.8%. The two treatments, chronic nicotine administration and nbm lesion, also increased the size of individual neuronal responses, prolonged their duration, and shortened the response latency. Responses to glutamate were unaffected by either procedures. The results show that the increase in [3H]nicotine binding produced by chronic nicotine administration is associated with an increased response to iontophoretically applied nicotine, suggesting that the receptor upregulation induced by the chronic treatment were functional. Less easily explained is the association between increased sensitivity of frontal cortical neurons to nicotine after nbm lesion with a decreased receptor density. It is suggested that a substantial proportion of nicotinic receptors are located presynaptically, and that their loss after lesion concealed an upregulation at postsynaptic sites.