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author:("onnisi, A")
1.  HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas 
Background
A close association between HIV infection and the development of cancer exists. Although the advent of highly active antiretroviral therapy has changed the epidemiology of AIDS-associated malignancies, a better understanding on how HIV can induce malignant transformation will help the development of novel therapeutic agents.
Methods
HIV has been reported to induce the expression of DNMT1 in vitro, but still no information is available about the mechanisms regulating DNMT expression in HIV-related B-cell lymphomas.
In this paper, we investigated the expression of DNMT family members (DNMT1, DNMT3a/b) in primary cases of aggressive B-cell lymphomas of HIV-positive subjects.
Results
Our results confirmed the activation of DNMT1 by HIV in vivo, and reported for the first time a marked up-regulation of DNMT3a and DNMT3b in HIV-positive aggressive B-cell lymphomas. DNMT up-regulation in HIV-positive tumors correlated with down-regulation of specific microRNAs, as the miR29 family, the miR148-152 cluster, known to regulate their expression. Literature reports the activation of DNMTs by the human polyomavirus BKV large T-antigen and adenovirus E1a, through the pRb/E2F pathway. We have previously demonstrated that the HIV Tat protein is able to bind to the pocket proteins and to inactivate their oncosuppressive properties, resulting in uncontrolled cell proliferation. Therefore, we focused on the role of Tat, due to its capability to be released from infected cells and to dysregulate uninfected ones, using an in vitro model in which Tat was ectopically expressed in B-cells.
Conclusions
Our findings demonstrated that the ectopic expression of Tat was per se sufficient to determine DNMT up-regulation, based on microRNA down-regulation, and that this results in aberrant hypermethylation of target genes and microRNAs.
These results point at a direct role for Tat in participating in uninfected B-cell lymphomagenesis, through dysregulation of the epigenetical control of gene expression.
doi:10.1186/1750-9378-9-41
PMCID: PMC4334912
HIV; Aggressive B-cell lymphomas; microRNAs; DNMTs; Tat
2.  The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma 
Background
Burkitt lymphoma is an aggressive B-cell lymphoma presenting in three clinical forms: endemic, sporadic and immunodeficiency-associated. More than 90% of endemic Burkitt lymphoma carry latent Epstein-Barr virus, whereas only 20% of sporadic Burkitt lymphoma are associated with Epstein-Barr infection. Although the Epstein-Barr virus is highly related with the endemic form, how and whether the virus participates in its pathogenesis remains to be fully elucidated. In particular, the virus may impair cellular gene expression by its own encoded microRNAs.
Methods
Using microRNA profiling we compared Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for both cellular and viral microRNAs. The array results were validated by qRT-PCR, and potential targets of viral microRNAs were then searched by bioinformatic predictions, and classified in functional categories, according to the Gene Ontology. Our findings were validated by in vitro functional studies and by immunohistochemistry on a larger series of cases.
Results
We showed that a few cellular microRNAs are differentially expressed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases, and identified a subset of viral microRNAs expressed in Epstein-Barr-positive Burkitt lymphomas. Of these, we characterized the effects of viral BART6-3p on regulation of cellular genes. In particular, we analyzed the IL-6 receptor genes (IL-6Rα and IL-6ST), PTEN and WT1 expression for their possible relevance to Burkitt lymphoma. By means of immunohistochemistry, we observed a down-regulation of the IL-6 receptor and PTEN specifically in Epstein-Barr-positive Burkitt lymphoma cases, which may result in the impairment of key cellular pathways and may contribute to malignant transformation. On the contrary, no differences were observed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for WT1 expression.
Conclusions
Our preliminary results point at an active role for the Epstein-Barr virus in Burkitt lymphomagenesis and suggest new possible mechanisms used by the virus in determining dysregulation of the host cell physiology.
doi:10.1186/1750-9378-9-12
PMCID: PMC4005456  PMID: 24731550
EBV; Burkitt lymphoma; MicroRNAs
3.  Language experience changes subsequent learning 
Cognition  2012;126(2):268-284.
What are the effects of experience on subsequent learning? We explored the effects of language-specific word order knowledge on the acquisition of sequential conditional information. Korean and English adults were engaged in a sequence learning task involving three different sets of stimuli: auditory linguistic (nonsense syllables), visual non-linguistic (nonsense shapes), and auditory non-linguistic (pure tones). The forward and backward probabilities between adjacent elements generated two equally probable and orthogonal perceptual parses of the elements, such that any significant preference at test must be due to either general cognitive biases, or prior language-induced biases. We found that language modulated parsing preferences with the linguistic stimuli only. Intriguingly, these preferences are congruent with the dominant word order patterns of each language, as corroborated by corpus analyses, and are driven by probabilistic preferences. Furthermore, although the Korean individuals had received extensive formal explicit training in English and lived in an English-speaking environment, they exhibited statistical learning biases congruent with their native language. Our findings suggest that mechanisms of statistical sequential learning are implicated in language across the lifespan, and experience with language may affect cognitive processes and later learning.
doi:10.1016/j.cognition.2012.10.008
PMCID: PMC3800190  PMID: 23200510
Corpus analyses; Experience-dependent learning; Implicit learning; Linguistic typology; Prediction; Retrodiction; Second language acquisition; Sequential learning; Statistical learning; Transitional probabilities; Word order
4.  Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide 
A dual-action cyclooxygenase (COX) - fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4′-isobutylphenyl)propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 μM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 μM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of ~6, ~10 and ~19 μM, respectively. 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.
doi:10.3109/14756366.2011.643304
PMCID: PMC3606911  PMID: 22225576
fatty acid amide hydrolase; cyclooxygenase; ibuprofen; analgesia; cannabinoid
5.  Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context 
Toxicology  2012;297(1-3):26-33.
The Aryl hydrocarbon receptor (AhR) mediates the induction of a variety of xenobiotic metabolism genes. Activation of the AhR occurs through binding to a group of structurally diverse compounds, most notably dioxins, which are exogenous ligands. Isoflavones are part of a family which include some well characterised endogenous AhR ligands. This paper analysed a novel family of these compounds, based on the structure of 2-amino-isoflavone. Initially two luciferase-based cell models, mouse H1L6.1c2 and human HG2L6.1c3, were used to identify whether the compounds had AhR agonistic and/or antagonistic properties. This analysis showed that some of the compounds were weak agonists in mouse and antagonists in human. Further analysis of two of the compounds, Chr-13 and Chr-19, was conducted using quantitative real-time PCR in rat H4IIE and human MCF-7 cells. The results indicated that Chr-13 was an agonist in rat but an antagonist in human cells. Chr-19 was shown to be an agonist in rat but more interestingly, a partial agonist in human. Luciferase induction results not only revealed that subtle differences in the structure of the compound could produce species-specific differences in response but also dictated the ability of the compound to be an AhR agonist or antagonist. Substituted 2-amino-isoflavones represent a novel group of AhR ligands that must differentially interact with the AhR ligand binding domain to produce their species-specific agonist or antagonist activity and future ligand binding analysis and docking studies with these compounds may provide insights into the differential mechanisms of action of structurally similar compounds.
doi:10.1016/j.tox.2012.03.011
PMCID: PMC3515069  PMID: 22507882
Aryl hydrocarbon receptor; AhR; dioxin; isoflavone; species-specific
6.  Similar Neural Correlates for Language and Sequential Learning: Evidence from Event-Related Brain Potentials 
Language and cognitive processes  2011;27(2):231-256.
We used event-related potentials (ERPs) to investigate the time course and distribution of brain activity while adults performed (a) a sequential learning task involving complex structured sequences, and (b) a language processing task. The same positive ERP deflection, the P600 effect, typically linked to difficult or ungrammatical syntactic processing, was found for structural incongruencies in both sequential learning as well as natural language, and with similar topographical distributions. Additionally, a left anterior negativity (LAN) was observed for language but not for sequential learning. These results are interpreted as an indication that the P600 provides an index of violations and the cost of integration of expectations for upcoming material when processing complex sequential structure. We conclude that the same neural mechanisms may be recruited for both syntactic processing of linguistic stimuli and sequential learning of structured sequence patterns more generally.
doi:10.1080/01690965.2011.606666
PMCID: PMC3652480  PMID: 23678205
Event-Related Potentials (ERP); Sequential Learning; Implicit Learning; Language Processing; Prediction; P600; LAN
7.  Prokineticin Receptor 1 Antagonist PC-10 as a Biomarker for Imaging Inflammatory Pain 
Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumor-supporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo.
Methods
A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine, which contains a free guanidine group, was labeled with 18F by reacting the guanidine function with N-succinimidyl-4-18F-fluorobenzoate to give the guanidinyl amide N-(4-18F-fluoro-benzoyl)-N′-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine (18F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with 18F-PC-10, 18F-FDG, and 64Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) (64Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device.
Results
18F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). 18F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with 18F-PC-10, 18F-FDG and 64Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. 18F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract.
Conclusion
18F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of 18F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility.
doi:10.2967/jnumed.110.084772
PMCID: PMC3629974  PMID: 21421710
prokineticin receptor; inflammation; positron emission tomography (PET); 18F
8.  Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells 
The Journal of Clinical Investigation  2013;123(4):1615-1629.
IL-11 and its receptor, IL-11Ra, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11Ra subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen- and VHL-regulated gene and provide evidence of a pathway “hijacked” by hypoxic cancer cells that may contribute to tumor progression.
doi:10.1172/JCI59623
PMCID: PMC3613900  PMID: 23549086
9.  Epstein-Barr nuclear antigen 1 induces expression of the cellular microRNA hsa-miR-127 and impairing B-cell differentiation in EBV-infected memory B cells. New insights into the pathogenesis of Burkitt lymphoma 
Blood Cancer Journal  2012;2(8):e84-.
Epstein-Barr Virus (EBV) is a γ-herpesvirus that infects >90% of the human population. Although EBV persists in its latent form in healthy carriers, the virus is also associated with several human cancers. EBV is strongly associated with Burkitt lymphoma (BL), even though there is still no satisfactory explanation of how EBV participates in BL pathogenesis. However, new insights into the interplay between viruses and microRNAs (miRNAs) have recently been proposed. In particular, it has been shown that B-cell differentiation in EBV-positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines. A good understanding of these mechanisms will help to clarify the complex regulatory networks between host and pathogen, and favor the design of more specific treatments for EBV-associated malignancies.
doi:10.1038/bcj.2012.29
PMCID: PMC3432484  PMID: 22941339
Epstein-Barr virus; microRNAs; Burkitt lymphoma
10.  Learn Locally, Act Globally: Learning Language from Variation Set Cues 
Cognition  2008;109(3):423-430.
Variation set structure — partial overlap of successive utterances in child-directed speech — has been shown to correlate with progress in children’s acquisition of syntax. We demonstrate the benefits of variation set structure directly: in miniature artificial languages, arranging a certain proportion of utterances in a training corpus in variation sets facilitated word and phrase constituent learning in adults. Our findings have implications for understanding the mechanisms of L1 acquisition by children, and for the development of more efficient algorithms for automatic language acquisition, as well as better methods for L2 instruction.
doi:10.1016/j.cognition.2008.10.004
PMCID: PMC3164301  PMID: 19019350
11.  Alteration of MicroRNAs Regulated by c-Myc in Burkitt Lymphoma 
PLoS ONE  2010;5(9):e12960.
Background
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma, with a characteristic clinical presentation, morphology and immunophenotype. Over the past years, the typical translocation t(8;14) and its variants have been considered the molecular hallmark of this tumor. However, BL cases with no detectable MYC rearrangement have been identified. Intriguingly, these cases express MYC at levels comparable with cases carrying the translocation. In normal cells c-Myc expression is tightly regulated through a complex feedback loop mechanism. In cancer, MYC is often dysregulated, commonly due to genomic abnormalities. It has recently emerged that this phenomenon may rely on an alteration of post-transcriptional regulation mediated by microRNAs (miRNAs), whose functional alterations are associated with neoplastic transformation. It is also emerging that c-Myc modulates miRNA expression, revealing an intriguing crosstalk between c-Myc and miRNAs.
Principal Findings
Here, we investigated the expression of miRNAs possibly regulated by c-Myc in BL cases positive or negative for the translocation. A common trend of miRNA expression, with the exception of hsa-miR-9*, was observed in all of the cases. Intriguingly, down-regulation of this miRNA seems to specifically identify a particular subset of BL cases, lacking MYC translocation. Here, we provided evidence that hsa-miR-9-1 gene is heavily methylated in those cases. Finally, we showed that hsa-miR-9* is able to modulate E2F1 and c-Myc expression.
Conclusions
Particularly, this study identifies hsa-miR-9* as potentially relevant for malignant transformation in BL cases with no detectable MYC translocation. Deregulation of hsa-miR-9* may therefore be useful as a diagnostic tool, suggesting it as a promising novel candidate for tumor cell marker.
doi:10.1371/journal.pone.0012960
PMCID: PMC2945769  PMID: 20930934
13.  The Secret Is in the Sound 
Developmental science  2009;12(3):388-395.
When learning language young children are faced with many seemingly formidable challenges, including discovering words embedded in a continuous stream of sounds and determining what role these words play in syntactic constructions. We suggest that knowledge of phoneme distributions may play a crucial part in helping children segment words and determine their lexical category, and propose an integrated model of how children might go from unsegmented speech to lexical categories. We corroborated this theoretical model using a two-stage computational analysis of a large corpus of English child-directed speech. First, we used transition probabilities between phonemes to find words in unsegmented speech. Second, we used distributional information about word edges—the beginning and ending phonemes of words—to predict whether the segmented words from the first stage were nouns, verbs, or something else. The results indicate that discovering lexical units and their associated syntactic category in child-directed speech is possible by attending to the statistics of single phoneme transitions and word-initial and final phonemes. Thus, we suggest that a core computational principle in language acquisition is that the same source of information is used to learn about different aspects of linguistic structure.
doi:10.1111/j.1467-7687.2009.00824.x
PMCID: PMC2743257  PMID: 19371361
14.  Development of HIF-1 Inhibitors for Cancer Therapy 
Intratumor hypoxia has long been considered a driving force of tumor progression and a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for the discovery and development of targeted therapies exploiting the hypoxic tumor microenvironment. In spite of an ever increasing number of putative small molecule inhibitors of HIF, only few are progressing through preclinical and early clinical development. In this review, we will focus primarily on: 1) HIF inhibitors that have been more recently described and 2) small molecules targeting HIF that are being tested in early clinical trials or that are already approved for use in patients. A rigorous “validation” of HIF targeted therapies in relevant preclinical models and eventually in pharmacodynamic-based early clinical trials is essential for “credentialing” HIF-1 as a legitimate target that can be pharmacologically modulated in cancer patients.
doi:10.1111/j.1582-4934.2009.00876.x
PMCID: PMC2832082  PMID: 19674190
HIF-1; hypoxia; cancer therapy
15.  Effect of Lysine at C-Terminus of the Dmt-Tic Opioid Pharmacophore 
Journal of medicinal chemistry  2006;49(18):5610-5617.
Substitution of Gly with side-chain protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH2-Ph, μ agonist / δ antagonist; H-Dmt-Tic-Gly-NH-Ph, μ agonist / δ agonist and H-Dmt-Tic-NH-CH2-Bid, δ agonist (Bid = 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high δ- (Kiδ = 0.068-0.64 nM) and μ-opioid affinities (Kiδ = 0.13-5.50 nM) with a bioactivity that ranged from μ-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI = 39.7 nM)} to a selective μ-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2μ = 7.96)] and a selective δ-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2δ = 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and / or antagonist properties.
doi:10.1021/jm060741w
PMCID: PMC2533050  PMID: 16942034
16.  Further Studies on the Effect of Lysine at the C-Terminus of the Dmt-Tic Opioid Pharmacophore 
Bioorganic & medicinal chemistry  2007;15(9):3143-3151.
A wide range of bioactivities are induced by Lys when introduced at the C-terminus of the δ-opioid Dmt-Tic pharmacophore through the α-amine group, such as improved δ-antagonism, and presence of μ-agonism and μ-antagonism. We report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH2)4-CH(R)-R’ (R = -NH2, -NH-Ac, -NH-Z; R’ = CO-NH-Ph, -CO-NH-CH2-Ph, -Bid) in which Lys is linked to Dmt-Tic through its amine group side chain. The compounds (1-9) displayed a potent and selective δ-antagonism (pA2 = 7.81-8.27) independent of the functionalized α-amine and carboxylic groups of the C-terminal Lys. This suggests direct application as a prototype intermediate, such as Boc-Dmt-Tic-ε-Lys(Z)-OMe, which could be applied in the synthesis (after Z or methyl ester removal) of unique “designed multiple ligands” containing the pharmacophore of the quintessential δ-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.
doi:10.1016/j.bmc.2007.02.039
PMCID: PMC2377021  PMID: 17339114

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