An unusual T-cell childhood acute lymphoblastic leukemia harboring a yet unreported near-tetraploid karyotype

<p>Abstract</p> <p>Background</p> <p>Near-tetraploid (model #81-103) and near-triploid (model #67-81) karyotypes are found in around 1% of childhood acute lymphoblastic leukemia. Due to its rarity, these two cytogenetic subgroups are generally included in the hyperdiploid group (model # > 51). Therefore separate informations about these two subgroups are limited to a few reports. Some studies found that near-tetraploidy is relatively more frequent in higher median ages and it is associated to Frech-American-British Classification subtype L2. Although the mechanisms by which leukemic blast cells divide is still unclear, studies have suggested that hyperdiploidy, near-triploidy and near-tetraploidy do not seem to share the same mechanism.</p> <p>Findings</p> <p>Herewith, we present a new childhood T-acute lymphoblastic leukemia case of near-tetraploid karyotype with loss of two p53-gene copies, characterized in detail by cytogenetic and molecular studies.</p> <p>Conclusion</p> <p>We suggest that p53 is a good target gene to be screened, once p53 is one of the main effectors of cell cycle checkpoints.</p

P2X7 Receptor-Dependent microRNA Expression Profile in the Brain Following Status Epilepticus in Mice

The ionotropic ATP-gated P2X7 receptor is an important contributor to inflammatory signaling cascadesviathe release of Interleukin-1 beta, as well as having roles in cell death, neuronal plasticity and the release of neurotransmitters. Accordingly, there is interest in targeting the P2X7 receptor for the treatment of epilepsy. However, the signaling pathways downstream of P2X7 receptor activation remain incompletely understood. Notably, recent studies showed that P2X7 receptor expression is controlled, in part, by microRNAs (miRNAs). Here, we explored P2X7 receptor-dependent microRNA expression by comparing microRNA expression profiles of wild-type (wt) and P2X7 receptor knockout mice before and after status epilepticus. Genome-wide microRNA profiling was performed using hippocampi from wt and P2X7 receptor knockout mice following status epilepticus induced by intra-amygdala kainic acid. This revealed that the genetic deletion of the P2X7 receptor results in distinct patterns of microRNA expression. Specifically, we found that in vehicle-injected control mice, the lack of the P2X7 receptor resulted in the up-regulation of 50 microRNAs and down-regulation of 35 microRNAs. Post-status epilepticus, P2X7 receptor deficiency led to the up-regulation of 44 microRNAs while 13 microRNAs were down-regulated. Moreover, there was only limited overlap among identified P2X7 receptor-dependent microRNAs between control conditions and post-status epilepticus, suggesting that the P2X7 receptor regulates the expression of different microRNAs during normal physiology and pathology. Bioinformatic analysis revealed that genes targeted by P2X7 receptor-dependent microRNAs were particularly overrepresented in pathways involved in intracellular signaling, inflammation, and cell death;processes that have been repeatedly associated with P2X7 receptor activation. Moreover, whereas genes involved in signaling pathways and inflammation were common among up- and down-regulated P2X7 receptor-dependent microRNAs during physiological and pathological conditions, genes associated with cell death seemed to be restricted to up-regulated microRNAs during both physiological conditions and post-status epilepticus. Taken together, our results demonstrate that the P2X7 receptor impacts on the expression profile of microRNAs in the brain, thereby possibly contributing to both the maintenance of normal cellular homeostasis and pathological processes

FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma

Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.Fil: Cooke, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. University of Pennsylvania; Estados UnidosFil: Kreider Letterman, Gabriel. University Of Toledo (utoledo); Estados UnidosFil: Baker, Martin James. University of Pennsylvania; Estados UnidosFil: Zhang, Suli. University of Pennsylvania; Estados UnidosFil: Sullivan, Neil T.. University of Pennsylvania; Estados UnidosFil: Eruslanov, Evgeniy. University of Pennsylvania; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Goicoechea, Silvia M.. University Of Toledo (utoledo); Estados UnidosFil: Garcia Mata, Rafael. University Of Toledo (utoledo); Estados UnidosFil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unido

Detecting Personal Microbiota Signatures at Artificial Crime Scenes

When mapped to the environments we interact with on a daily basis, the 36 million microbial cells per hour that humans emit leave a trail of evidence that can be leveraged for forensic analysis. We employed 16S rRNA amplicon sequencing to map unique microbial sequence variants between human skin and building surfaces in three experimental conditions: over time during controlled and uncontrolled incidental interactions with a door handle, and during multiple mock burglaries in ten real residences. We demonstrate that humans (n = 30) leave behind microbial signatures that can be used to track interaction with various surfaces within a building, but the likelihood of accurately detecting the specific burglar for a given home was between 20-25%. Also, the human microbiome contains rare microbial taxa that can be combined to create a unique microbial profile, which when compared to 600 other individuals can improve our ability to link an individual ‘burglar’ to a residence. In total, 5,512 discriminating, non-singleton unique exact sequence variants (uESVs) were identified as unique to an individual, with a minimum of 1 and a maximum of 568, suggesting some people maintain a greater degree of unique taxa compared to our population of 600. Approximate 60-77% of the unique exact sequence variants originated from the hands of participants, and these microbial discriminators spanned 36 phyla but were dominated by the Proteobacteria (34%). A fitted regression generated to determine whether an intruder’s uESVs found on door handles in an office decayed over time in the presence or absence of office workers, found no significant shift in proportion of uESVs over time irrespective of the presence of office workers. While it was possible to detect the correct burglars’ microbiota as having contributed to the invaded space, the predictions were very weak in comparison to accepted forensic standards. This suggests that at this time 16S rRNA amplicon sequencing of the built environment microbiota cannot be used as a reliable trace evidence standard for criminal investigations

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base

Cyclodextrin/cellulose hydrogel with gallic acid to prevent wound infection

Cyclodextrin-based hydrogels have been described as suitable for the controlled-release of bioactive molecules to be used as wound dressing. These materials have major advantages, since they gather the hydrogel properties (high degree of swelling and easy manipulation) and the encapsulation ability of cyclodextrins. β-cyclodextrin (β) or hydroxypropyl-β-cyclodextrin (HPβ) was cross-linked (1,4-butanediol diglycidyl ether) with hydroxypropyl methylcellulose under mild conditions. The hydrogels were chemically characterized by swelling degree, FTIR, DSC and contact angle. The gallic acid loading and release was also analysed, as well the antibacterial activity and cytotoxicity of the polymeric networks. The hydrogels obtained were firm and transparent, with good swelling ability. The gel-HPβ had a surface more hydrophilic when compared with the gel-β. Nevertheless, both hydrogels were capable to incorporate gallic acid and sustain the release for 48 h. The antibacterial activity of gallic acid was maintained after its adsorption within the polymeric matrix, as well as, gallic acid effect on fibroblast proliferation. Therefore, gel-β and gel-HPβ conjugated with gallic acid were shown to be a viable option for antibacterial wound dressing.The authors thank the FCT Strategic Projects PEst-OE/EQB/LA0023/2013, PEst-C/CTM/UI0264/2011, the Project "BioHealth-Biotechnology and Bioengineering approaches to improve health quality'', Ref. NORTE-07-0124-FEDER-000027, co-funded by the Programa Operacional Regional doNorte (ON.2-ONovoNorte), QREN, FEDER, and E. Pinho grant (SFRH/BD/62665/2009)

Tracking antioxidant properties and color changes in low-sugar bilberry jam as effect of processing, storage and pectin concentration

<p>Abstract</p> <p>Background</p> <p>Recently, an increased interest in the identification of valuable possibilities for preserving the antioxidant properties of products obtained by thermal processing of fruits rich in bioactive compounds can be noticed. In this regard, an extensive analysis is necessary in terms of thermal processed products behavior in relation to various factors. The purpose of the present study was to assess the effect which processing and storage at 20°C has on the antioxidant properties and color quality of low-sugar bilberry jam with different low-methoxyl pectin (LMP) concentrations.</p> <p>Results</p> <p>For all measured parameters, it should be noted that thermal processing induced significant alterations reported to the values registered for fresh fruit. Most important losses due to thermal processing were recorded for total monomeric anthocyanins (TMA) (81-84%), followed by L-ascorbic acid (L-AsAc) content (53-58%), total phenolics (TP) content (42-51%) and FRAP (ferric reducing antioxidant power) values (36-47%). Moreover, depreciation of the investigated compounds occurred during storage at 20°C. Jam storage for 7 months resulted in severe losses in TMA content in the range 58-72% from the value recorded one day after processing. This coincided with marked increases in polymeric color percent of these products after 7 months of storage. Also, bilberry jam storage for 7 months resulted in a decrease in L-AsAc content of 40-53% from the value recorded one day after processing, 41-57% in TP content and 33-46% from the value recorded one day after processing for FRAP values. By decreasing of LMP concentration in the jam recipe from 1 to 0.3% there has been an increase in losses of investigated compounds.</p> <p>Conclusion</p> <p>Overall, the results indicated that bilberry jams can also represent a good source of antioxidant compounds, although compared to the fruit, important losses seem to occur. Practical application of this work is that this kind of information will be very useful in optimizing the jam processing technology and storage conditions, in order to improve the quality of these products.</p

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis