Intravascular Large B-Cell Lymphoma Genomic Profile Is Characterized by Alterations in Genes Regulating NF-κB and Immune Checkpoints.

Intravascular large B-cell lymphoma (IVLBCL) is an uncommon lymphoma with an aggressive clinical course characterized by selective growth of tumor cells within the vessels. Its pathogenesis is still uncertain and there is little information on the underlying genomic alterations. In this study, we performed a clinicopathologic and next-generation sequencing analysis of 15 cases of IVLBCL using a custom panel for the detection of alterations in 68 recurrently mutated genes in B-cell lymphomagenesis. Six patients had evidence of hemophagocytic syndrome. Four patients presented concomitantly a solid malignancy. Tumor cells outside the vessels were observed in 7 cases, 2 with an overt diffuse large B-cell cell lymphoma. In 4 samples, tumor cells infiltrated lymphatic vessel in addition to blood capillaries. Programmed death-ligand 1 (PD-L1) was positive in tumor cells in 4 of 11 evaluable samples and in macrophages intermingled with tumor cells in 8. PD-L1 copy number gains were identified in a higher proportion of cases expressing PD-L1 than in negative tumors. The most frequently mutated gene was PIM1 (9/15, 60%), followed by MYD88L265P and CD79B (8/15, 53% each). In 6 cases, MYD88L265P and CD79B mutations were detected concomitantly. We also identified recurrent mutations in IRF4 , TMEM30A , BTG2 , and ETV6 loci (4/15, 27% each) and novel driver mutations in NOTCH2 , CCND3 , and GNA13 , and an IRF4 translocation in 1 case each. The mutational profile was similar in patients with and without evidence of hemophagocytic syndrome and in cases with or without dissemination of tumor cells outside the vessels. Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL

Effect of Oxidative Damage Due to Excessive Protein Ingestion on Pancreas Function in Mice

The present study was undertaken to evaluate the effect of oxidative damage due to excessive protein diet on pancreas function in mice. For this purpose, thirty male (C57BL/6J) mice were randomly divided into three groups and fed on different diets as follows: group 1 was fed on a normal diet, group 2 was fed on an excessive protein diet and group 3 was fed on an excessive protein diet supplemented with 0.06 g/kg cysteamine. Each group was fed for 2 weeks, and then pancreas samples were collected to examine oxidative and antioxidant parameters and pancreas function. The results showed that ingestion of an excessive protein diet markedly increased contents of malondialdehyde (MDA) and decreased T-AOC and activities of antioxidants SOD and GSH-Px, compared with a normal diet (P < 0.05). Pancreas weight and concentration of protein, DNA and RNA were significantly higher (P < 0.05), digestive enzyme activities were significantly lower and levels of somatostatin and insulin were higher in mice fed with an excessive protein diet than those fed with a normal protein diet. In the group fed with excessive protein diet supplemented with cysteamine, oxidative stress was mitigated and pancreas function was improved. These data demonstrate that excessive protein ingestion could increase oxidative damage of free radicals on pancreas function through destroying the balance of oxidants and antioxidants

Do Placebo Response Rates from Cessation Trials Inform on Strength of Addictions?

There is an implied assumption that addictions to different substances vary in strength from weak (easier to stop) to strong (harder to stop), though explicit definitions are lacking. Our hypothesis is that the strength of addictions can be measured by cessation rates found with placebo or no treatment controls, and that a weaker addiction would have a higher cessation rate than a stronger addiction. We report an overview of systematic reviews and meta-analyses of cessation trials, using randomised or quasi-randomised trials and reporting objectively-measured abstinence. The outcome for comparison was quit rates–typically the percentage of participants abstinent according to an objective test of abstinence at six months or longer. Twenty-eight cessation reviews (139,000 participants) were found. Most data came from reviews of smoking cessation in over 127,000 participants, and other reviews each covered a few thousand participants. Few reviews used data from studies shorter than three months, and almost all determined abstinence using objective measures. Cessation rates with placebo in randomised trials using objective measures of abstinence and typically over six months duration were 8% for nicotine, 18% for alcohol, 47% for cocaine, and 44% for opioids. Evidence from placebo cessation rates indicates that nicotine is more difficult to give up than alcohol, cocaine, and opioids. Tobacco is also a severe addiction, with a number of major deleterious health effects in a large number of people

Sinteza i cAMP-ovisna inhibicija fosfodiesteraze novih derivata tiazolokinazolina

The series of 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine) thiazolo(2,3-b)quinazolin-3(2H)-ones (4a-j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine)-3-(4-nitrophenylamino)thiazoloquinazolines (5a-j) were synthesized by the reported method and evaluated for their phosphodiesterase inhibitory activity. All test compounds exhibited good activity. The structure-activity relationships were also studied. In both series of compounds, electron-withdrawing substitutions showed higher activity. Among the tested compounds, 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-fluorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5e), 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-nitrobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-chlorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5f) were found to be more potent than theophylline (IC50 in mmol L–1 of 1.34 ± 0.09 for 5f, 1.44 ± 0.02 for 5e, 1.52 ± 0.05 for 5j vs. 1.72 ± 0.09 for theophylline).U radu je opisana sinteza serije 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)tiazolo(2,3-b)kinazolin-3(2H)-ona (4a-j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)-3-(4-nitrofenilamino)tiazolokinazolina (5a-j) prema objavljenoj metodi te ispitano njihovo inhibitorno djelovanje na fosfodiesterazu. Svi testirani spojevi pokazuju dobro djelovanje. Proučavan je i odnos strukture i djelovanja. U obje serije spojeva, elektron-odvlačeći supstituenti doprinose jačem djelovanju. Među ispitivanim spojevima pronađeno je da 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-fluorobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5e), 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-nitrobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-klorobenzilidin)-3-(4-nitrofenilamino)tiazolokinazolin (5f) imaju jače djelovanje od teofilina (IC50 u mmol L–1 1,34 ± 0,09 za 5f, 1,44 ± 0,02 za 5e, 1,52 ± 0,05 za 5j nasuprot 1,72 ± 0,09 za teofilin)

Computational Analysis of Constraints on Noncoding Regions, Coding Regions and Gene Expression in Relation to Plasmodium Phenotypic Diversity

Malaria-causing Plasmodium species exhibit marked differences including host choice and preference for invading particular cell types. The genetic bases of phenotypic differences between parasites can be understood, in part, by investigating constraints on gene expression and genic sequences, both coding and regulatory.We investigated the evolutionary constraints on sequence and expression of parasitic genes by applying comparative genomics approaches to 6 Plasmodium genomes and 2 genome-wide expression studies. We found that the coding regions of Plasmodium transcription factor and sexual development genes are relatively less constrained, as are those of genes encoding CCCH zinc fingers and invasion proteins, which all play important roles in these parasites. Transcription factors and genes with stage-restricted expression have conserved upstream regions and so do several gene classes critical to the parasite's lifestyle, namely, ion transport, invasion, chromatin assembly and CCCH zinc fingers. Additionally, a cross-species comparison of expression patterns revealed that Plasmodium-specific genes exhibit significant expression divergence.Overall, constraints on Plasmodium's protein coding regions confirm observations from other eukaryotes in that transcription factors are under relatively lower constraint. Proteins relevant to the parasite's unique lifestyle also have lower constraint on their coding regions. Greater conservation between Plasmodium species in terms of promoter motifs suggests tight regulatory control of lifestyle genes. However, an interspecies divergence in expression patterns of these genes suggests that either expression is controlled via genomic or epigenomic features not encoded in the proximal promoter sequence, or alternatively, the combinatorial interactions between motifs confer species-specific expression patterns

17β-Oestradiol treatment modulates nitric oxide synthase activity in MDA231 tumour with implications on growth and radiation response

The putative oestrogen receptor negative human breast cancer cell line MDA231, when grown as tumours in mice continually receiving 17β-oestradiol, showed substantially increased growth rate when compared to control animals. Further, we observed that 17β-oestradiol treatment could both increase the growth rate of established MDA231 tumours as well as decreasing the time taken for initiating tumour growth. We have also demonstrated that this increase in growth rate is accompanied by a four-fold increase in nitric oxide synthase activity, which was predominantly the inducible form. Inducible-nitric oxide synthase expression in these tumours was confirmed by immunohistochemical analysis and appeared localized primarily in areas between viable and necrotic regions of the tumour (an area that is presumably hypoxic). Prophylactic treatment with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester resulted in significant reduction in this apparent 17β-oestradiol-mediated growth promoting effect. Tumours derived from mice receiving 17β-oestradiol-treatment were characterized by a significantly lower fraction of perfused blood vessels and an indication of an increased hypoxic fraction. Consistent with these observations, 17β-oestradiol-treated tumours were less radio-responsive compared to control tumours when treated with a single radiation dose of 15 Gy. Our data suggests that long-term treatment with oestrogen could significantly alter the tumour oxygenation status during breast tumour progression, thus affecting response to radiotherapy

Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers

Contains fulltext : 73592.pdf (publisher's version ) (Open Access)RATIONALE: In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. OBJECTIVE: The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. MATERIALS AND METHODS: We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime. RESULTS: Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. CONCLUSIONS: Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function

Impact of Anti-Inflammatory Agents on the Gene Expression Profile of Stimulated Human Neutrophils: Unraveling Endogenous Resolution Pathways

Adenosine, prostaglandin E2, or increased intracellular cyclic AMP concentration each elicit potent anti-inflammatory events in human neutrophils by inhibiting functions such as phagocytosis, superoxide production, adhesion and cytokine release. However, the endogenous molecular pathways mediating these actions are poorly understood. In the present study, we examined their impact on the gene expression profile of stimulated neutrophils. Purified blood neutrophils from healthy donors were stimulated with a cocktail of inflammatory agonists in the presence of at least one of the following anti-inflammatory agents: adenosine A2A receptor agonist CGS 21680, prostaglandin E2, cyclic-AMP-elevating compounds forskolin and RO 20-1724. Total RNA was analyzed using gene chips and real-time PCR. Genes encoding transcription factors, enzymes and regulatory proteins, as well as secreted cytokines/chemokines showed differential expression. We identified 15 genes for which the anti-inflammatory agents altered mRNA levels. The agents affected the expression profile in remarkably similar fashion, suggesting a central mechanism limiting cell activation. We have identified a set of genes that may be part of important resolution pathways that interfere with cell activation. Identification of these pathways will improve understanding of the capacity of tissues to terminate inflammatory responses and contribute to the development of therapeutic strategies based on endogenous resolution