MicroRNA expression in lymphocyte development and malignancy

This article is available open access through the publisher’s website. Copyright @ 2008 Macmillan Publishers Limited.No abstract available.The Leukemia Research Fund, the Julian Starmer-Smith Memorial Fund, and the Medical Research Council

Genomic imbalances are confined to non-proliferating cells in paediatric patients with acute myeloid leukaemia and a normal or incomplete karyotype

Copyright @ 2011 Ballabio et al.Leukaemia is often associated with genetic alterations such as translocations, amplifications and deletions, and recurrent chromosome abnormalities are used as markers of diagnostic and prognostic relevance. However, a proportion of acute myeloid leukaemia (AML) cases have an apparently normal karyotype despite comprehensive cytogenetic analysis. Based on conventional cytogenetic analysis of banded chromosomes, we selected a series of 23 paediatric patients with acute myeloid leukaemia and performed whole genome array comparative genome hybridization (aCGH) using DNA samples derived from the same patients. Imbalances involving large chromosomal regions or entire chromosomes were detected by aCGH in seven of the patients studied. Results were validated by fluorescence in situ hybridization (FISH) to both interphase nuclei and metaphase chromosomes using appropriate bacterial artificial chromosome (BAC) probes. The majority of these copy number alterations (CNAs) were confirmed by FISH and found to localize to the interphase rather than metaphase nuclei. Furthermore, the proliferative states of the cells analyzed by FISH were tested by immunofluorescence using an antibody against the proliferation marker pKi67. Interestingly, these experiments showed that, in the vast majority of cases, the changes appeared to be confined to interphase nuclei in a non-proliferative status.This work was supported by a grant from Leukaemia Research UK (grant no. 0253). SJLK and RR were supported by the NIHR Biomedical Research Centre, Oxford, with funding from the Department of Health’s NIHR Biomedical Research Centres funding schemeThis article is available through the Brunel Open Access Publishing Fund

ULTRA-BRIGHT OPTICAL TRANSIENTS ARE LINKED WITH TYPE Ic SUPERNOVAE

Recent searches by unbiased, wide-field surveys have uncovered a group of extremely luminous optical transients. The initial discoveries of SN 2005ap by the Texas Supernova Search and SCP-06F6 in a deep Hubble pencil beam survey were followed by the Palomar Transient Factory confirmation of host redshifts for other similar transients. The transients share the common properties of high optical luminosities (peak magnitudes ~−21 to −23), blue colors, and a lack of H or He spectral features. The physical mechanism that produces the luminosity is uncertain, with suggestions ranging from jet-driven explosion to pulsational pair instability. Here, we report the most detailed photometric and spectral coverage of an ultra-bright transient (SN 2010gx) detected in the Pan-STARRS 1 sky survey. In common with other transients in this family, early-time spectra show a blue continuum and prominent broad absorption lines of O ii. However, about 25 days after discovery, the spectra developed type Ic supernova features, showing the characteristic broad Fe ii and Si ii absorption lines. Detailed, post-maximum follow-up may show that all SN 2005ap and SCP-06F6 type transients are linked to supernovae Ic. This poses problems in understanding the physics of the explosions: there is no indication from late-time photometry that the luminosity is powered by 56Ni, the broad light curves suggest very large ejected masses, and the slow spectral evolution is quite different from typical Ic timescales. The nature of the progenitor stars and the origin of the luminosity are intriguing and open questions

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Gene silencing by DNA methylation in haematological malignancies.

The past decade has seen an explosion of interest in the epigenetics of cancer, with an increasing understanding that this form of genomic modification plays a critical role in pathogenesis. The malignant phenotype results from a step-wise increase of both genetic abnormalities and epigenetic modifications, leading to dysregulation of critical genes controlling cell growth, differentiation and apoptosis. The methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer. This phenomenon (methylation of CpG islands) plays a critical role in the transcriptional silencing of tumour suppressor genes in cancer and has prompted the development and testing of several demethylating agents aimed at reversing this process. Clinical trials using epigenetically targeted therapies have yielded particularly promising results in the myelodysplastic syndromes (MDS), in which tumour suppressor gene silencing by promoter methylation is a frequent event. Several genes and gene pathways disrupted by aberrant CpG island methylation have now been identified in haematological malignancies, the most frequently studied being the cell cycle inhibitors p16 (now termed CDKN2A; mostly methylated in lymphoid malignancy) and p15 (now termed CDKN2B; commonly methylated in lymphoid and myeloid malignancies). This review will discuss the role that aberrant gene silencing by promoter hypermethylation plays in the molecular pathogenesis of haematological malignancies and assess the clinical potential of demethylating agents for the management of patients

Clonality in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDSs) comprise a heterogeneous group of stem cell disorders involving cytopenia and dysplastic changes in 3 hematopoietic lineages. Although it is accepted that MDS is a clonal disorder, the exact nature of the involvement of multipotent stem cells and progenitor cells has not been resolved. Most clonality studies of MDS support the proposal that the primary neoplastic event occurs, in most patients, at the level of a committed myeloid progenitor cell, capable of differentiation into multiple myeloid lineages. The extent of the involvement of T and B lymphocytes in MDS remains controversial. Much of the variation reported may result from disease heterogeneity and technical issues such as skewed methylation patterns occurring in studies analyzing X-chromosome inactivation patterns (XCIP) and possible impurities in lymphocyte preparation. A great deal of the evidence in support of T-lymphocyte involvement in MDS has been generated by XCIP studies, and some of these data need to be treated with caution, especially data from studies in which appropriate controls were omitted. In contrast, B-lymphocyte involvement in some patients with MDS is based on studies using more robust technology including combined immunophenotyping and fluorescence in situ hybridization. Clonality studies involving myeloid and lymphoid cells in MDS have yielded discrepant results with regard to the potential involvement of multipotent (lympho-myeloid) hematopoietic stem cells (HSCs). However, failure to detect a clonal marker in all cells of all lineages does not preclude multipotent-HSC involvement. Some recent studies have produced compelling evidence to show that, in some patients with MDS, the multipotent HSC is the target of the primary neoplastic event. It now seems probable that MDS arises in multipotent HSCs more commonly than previously recognized. Such data not only provide important new insights into the biology of MDS but also may have therapeutic implications. The determination of whether multipotent HSCs are involved in the MDS clone may be important for the use of autologous stem cell transplantation in these patients