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Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 ( IRF4 ) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ null xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin ( IG ) and cross-lineage T-cell receptor ( TCR ) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1 . Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage. Leukemia (2015) 29, 839-846; doi: 10.1038/leu.2014.322

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.

Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.

Philadelphia chromosome-positive (Ph+) hemopoietic cells predominate in patients with chronic myeloid leukemia (CML) in chronic phase, but some Ph presumably normal stem cells persist in most patients. Ph cells are relatively frequent, compared to mature cell populations, in primitive hemopoietic cell populations from CML patients. We have purified CD34+ cells from chronic phase CML blood and separated them into two fractions on the basis of adherence or non-adherence to tissue culture plastic. We also separated CD34+ CML cell populations into HLA-DR(hi) and HLA-DR(lo) fractions and CD38(hi) and CD38(lo) fractions by flow cytometry. The CD34+ cells that adhered to plastic were predominantly CD33-, CD38- and HLA(-)-DR; cells with these phenotypic properties were significantly rarer in the CD34+ non-adherent cell population (P = 0.008-0.02). Expression of p210 BCR/ABL mRNA by adherent, non-adherent, HLA-DR(hi) and HLA-DR(lo)CD34+ cell subpopulations was demonstrated by RT-PCR. Using fluorescence in situ hybridization (FISH) in conjunction with BCR and ABL probes we detected Ph+ and Ph- cells in both adherent and non-adherent CD34+ cell fractions of 15/15 patients studied and in the HLA-DR(lo) or CD38(lo) sorted CD34+ cell fractions. The concentration of Ph- cells in the adherent CD34+ cell fraction was three-fold higher than in the non-adherent fraction (P = 0.001). Ph- adherent cells were detected in untreated CML patients and as late as 6 years after diagnosis of CML in patients treated with hydroxyurea (HU) or interferon-alpha (IFN-alpha). We conclude that whilst appreciable numbers of Ph- primitive hemopoietic progenitors are present in the circulation in untreated patients and also in treated patients in late chronic phase, the majority of cells expressing CD34 but not CD33, CD38 or HLA-DR antigens, are part of the CML clone.

Philadelphia chromosome-positive (Ph super(+)) hemopoietic cells predominate in patients with chronic myeloid leukemia (CML) in chronic phase, but some Ph super(-) presumably normal stem cells persist in most patients. Ph super(-) cells are relatively frequent, compared to mature cell populations, in primitive hemopoietic cell populations from CML patients. We have purified CD34 super(+) cells from chronic phase CML blood and separated them into two fractions on the basis of adherence or non-adherence to tissue culture plastic. We also separated CD34 super(+) CML cell populations into HLA-DR super(hi) and HLA-DR super(lo) fractions and CD38 super(hi) and CD38 super(lo) fractions by flow cytometry. The CD34 super(+) cells that adhered to plastic were predominantly CD33 super(-), CD38 super(-) and HLA super(-)-DR; cells with these phenotypic properties were significantly rarer in the CD34 super(+) non-adherent cell population (P = 0.008-0.02). Expression of p210 BCR/ABL mRNA by adherent, non-adherent, HLA-DR super(hi) and HLA-DR super(lo)CD34 super(+) cell subpopulations was demonstrated by RT-PCR. Using fluorescence in situ hybridization (FISH) in conjunction with BCR and ABL probes we detected Ph super(+) and Ph super(-) cells in both adherent and non-adherent CD34 super(+) cell fractions of 15/15 patients studied and in the HLA-DR super(lo) or CD38 super(lo) sorted CD34 super(+) cell fractions. The concentration of Ph super(-) cells in the adherent CD34 super(+) cell fraction was three-fold higher than in the non-adherent fraction (P = 0.001). Ph- adherent cells were detected in untreated CML patients and as late as 6 years after diagnosis of CML in patients treated with hydroxyurea (HU) or interferon- alpha (IFN- alpha ). We conclude that whilst appreciable numbers of Ph super(-) primitive hemopoietic progenitors are present in the circulation in untreated patients and also in treated patients in late chronic phase, the majority of cells expressing CD34 but not CD33, CD38 or HLA-DR antigens, are part of the CML clone.

Over the last 25 years, research on biodiversity has expanded dramatically, fuelled by increasing threats to the natural world. However, the number of published studies is heavily weighted towards certain taxa, perhaps influencing conservation awareness of and funding for less-popular groups. Few studies have systematically quantified these biases, although information on this topic is important for informing future research and conservation priorities. We investigated: i) which animal taxa are being studied; ii) if any taxonomic biases are the same in temperate and tropical regions; iii) whether the taxon studied is named in the title of papers on biodiversity, perhaps reflecting a perception of what biodiversity is; iv) the geographical distribution of biodiversity research, compared with the distribution of biodiversity and threatened species; and v) the geographical distribution of authors' countries of origin. To do this, we used the search engine Web of Science to systematically sample a subset of the published literature with 'biodiversity' in the title. In total 526 research papers were screened-5% of all papers in Web of Science with biodiversity in the title. For each paper, details on taxonomic group, title phrasing, number of citations, study location, and author locations were recorded. Compared to the proportions of described species, we identified a considerable taxonomic weighting towards vertebrates and an under-representation of invertebrates (particularly arachnids and insects) in the published literature. This discrepancy is more pronounced in highly cited papers, and in tropical regions, with only 43% of biodiversity research in the tropics including invertebrates. Furthermore, while papers on vertebrate taxa typically did not specify the taxonomic group in the title, the converse was true for invertebrate papers. Biodiversity research is also biased geographically: studies are more frequently carried out in developed countries with larger economies, and for a given level of species or threatened species, tropical countries were understudied relative to temperate countries. Finally, biodiversity research is disproportionately authored by researchers from wealthier countries, with studies less likely to be carried out by scientists in lower-GDP nations. Our results highlight the need for a more systematic and directed evaluation of biodiversity studies, perhaps informing more targeted research towards those areas and taxa most depauperate in research. Only by doing so can we ensure that biodiversity research yields results that are relevant and applicable to all regions and that the information necessary for the conservation of threatened species is available to conservation practitioners.

Dark Age recounts the turbulent political career of recently deceased Jean-Bedel Bokassa, the flamboyant president-for-life and later emperor of the Central African Republic/Empire. Brian Titley examines the myths and legends surrounding the man, probes their origins and veracity, and attempts to provide a more balanced perspective on this controversial and misunderstood figure. Following a lengthy career in the French army, Bokassa seized power in the Central African Republic in 1966. His flamboyance and excesses soon became legendary: he was accused of cannibalism, feeding enemies to lions and crocodiles, and beating schoolchildren to death. Bokassa's tendency for self-aggrandizement culminated in 1977 when he named himself emperor and orchestrated a coronation in the style of Napoleon's. He was overthrown by French paratroopers in 1979 and went into exile, but returned to his homeland in 1985 to face a sensational trial. Titley interprets Bokassa's authoritarian and self-aggrandizing style as an attempt to legitimize his regime in a context devoid of indigenous political structures and explores the troubled relations between France and its former colonies. Combining techniques of historical inquiry and investigative journalism, he has produced a fascinating account of a pivotal chapter in contemporary African history.