Application of the LymphGen classification tool to 928 clinically and genetically-characterised cases of diffuse large B cell lymphoma (DLBCL).

We recently published results of targeted sequencing applied to 928 unselected cases of DLBCL registered in the Haematological Malignancy Research Network (HMRN) registry (1). Clustering allowed us to resolve five genomic subtypes. These subtypes shared considerable overlap with those proposed in two independent genomic studies(2, 3), suggesting the potential to use genetics to stratify patients by both risk and biology. In the original studies, clustering techniques were applied to sample cohorts to reveal molecular substructure, but left open the challenge of how to classify an individual patient. This was addressed by the LymphGen classification tool (4). LymphGen assigns an individual case to one of six molecular subtypes. The tool accommodates data from exome or targeted sequencing, either with or without copy number variant (CNV) data. Separate gene expression data allows classification of a seventh, MYC-driven subtype defined by a double hit (DHL) or molecular high-grade (MHG) gene expression signature(5-7).HR was funded by a studentship from the Medical Research Council. DH was supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/M008584/1). The Hodson laboratory receives core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute and core funding from the CRUK Cambridge Cancer Centre. HMRN is supported by BCUK 15037 and CRUK 18362

A role for subchondral bone changes in the process of osteoarthritis; a micro-CT study of two canine models

BACKGROUND: This study evaluates changes in peri-articular bone in two canine models for osteoarthritis: the groove model and the anterior cruciate ligament transection (ACLT) model. METHODS: Evaluation was performed at 10 and 20 weeks post-surgery and in addition a 3-weeks time point was studied for the groove model. Cartilage was analysed, and architecture of the subchondral plate and trabecular bone of epiphyses was quantified using micro-CT. RESULTS: At 10 and 20 weeks cartilage histology and biochemistry demonstrated characteristic features of osteoarthritis in both models (very mild changes at 3 weeks). The groove model presented osteophytes only at 20 weeks, whereas the ACLT model showed osteophytes already at 10 weeks. Trabecular bone changes in the groove model were small and not consistent. This contrasts the ACLT model in which bone volume fraction was clearly reduced at 10 and 20 weeks (15-20%). However, changes in metaphyseal bone indicate unloading in the ACLT model, not in the groove model. For both models the subchondral plate thickness was strongly reduced (25-40%) and plate porosity was strongly increased (25-85%) at all time points studied. CONCLUSION: These findings show differential regulation of subchondral trabecular bone in the groove and ACLT model, with mild changes in the groove model and more severe changes in the ACLT model. In the ACLT model, part of these changes may be explained by unloading of the treated leg. In contrast, subchondral plate thinning and increased porosity were very consistent in both models, independent of loading conditions, indicating that this thinning is an early response in the osteoarthritis process

Quantum physics in inertial and gravitational fields

Covariant generalizations of well-known wave equations predict the existence of inertial-gravitational effects for a variety of quantum systems that range from Bose-Einstein condensates to particles in accelerators. Additional effects arise in models that incorporate Born reciprocity principle and the notion of a maximal acceleration. Some specific examples are discussed in detail.Comment: 25 pages,1 figure,to appear in "Relativity in Rotating Frame

Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls-A Voxel Based Morphometry Study.

Gender identity disorder (GID) refers to transsexual individuals who feel that their assigned biological gender is incongruent with their gender identity and this cannot be explained by any physical intersex condition. There is growing scientific interest in the last decades in studying the neuroanatomy and brain functions of transsexual individuals to better understand both the neuroanatomical features of transsexualism and the background of gender identity. So far, results are inconclusive but in general, transsexualism has been associated with a distinct neuroanatomical pattern. Studies mainly focused on male to female (MTF) transsexuals and there is scarcity of data acquired on female to male (FTM) transsexuals. Thus, our aim was to analyze structural MRI data with voxel based morphometry (VBM) obtained from both FTM and MTF transsexuals (n = 17) and compare them to the data of 18 age matched healthy control subjects (both males and females). We found differences in the regional grey matter (GM) structure of transsexual compared with control subjects, independent from their biological gender, in the cerebellum, the left angular gyrus and in the left inferior parietal lobule. Additionally, our findings showed that in several brain areas, regarding their GM volume, transsexual subjects did not differ significantly from controls sharing their gender identity but were different from those sharing their biological gender (areas in the left and right precentral gyri, the left postcentral gyrus, the left posterior cingulate, precuneus and calcarinus, the right cuneus, the right fusiform, lingual, middle and inferior occipital, and inferior temporal gyri). These results support the notion that structural brain differences exist between transsexual and healthy control subjects and that majority of these structural differences are dependent on the biological gender

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Green Fluorescent Protein Labeling of Listeria, Salmonella, and Escherichia coli O157:H7 for Safety-Related Studies

Many food safety-related studies require tracking of introduced foodborne pathogens to monitor their fate in complex environments. The green fluorescent protein (GFP) gene (gfp) provides an easily detectable phenotype so has been used to label many microorganisms for ecological studies. The objectives of this study were to label major foodborne pathogens and related bacteria, including Listeria monocytogenes, Listeria innocua, Salmonella, and Escherichia coli O157:H7 strains, with GFP and characterize the labeled strains for stability of the GFP plasmid and the plasmid's effect on bacterial growth. GFP plasmids were introduced into these strains by a CaCl2 procedure, conjugation or electroporation. Stability of the label was determined through sequential propagation of labeled strains in the absence of selective pressure, and rates of plasmid-loss were calculated. Stability of the GFP plasmid varied among the labeled species and strains, with the most stable GFP label observed in E. coli O157:H7. When grown in nonselective media for two consecutive subcultures (ca. 20 generations), the rates of plasmid loss among labeled E. coli O157:H7, Salmonella and Listeria strains ranged from 0%–30%, 15.8%–99.9% and 8.1%–93.4%, respectively. Complete loss (>99.99%) of the plasmid occurred in some labeled strains after five consecutive subcultures in the absence of selective pressure, whereas it remained stable in others. The GFP plasmid had an insignificant effect on growth of most labeled strains. E. coli O157:H7, Salmonella and Listeria strains can be effectively labeled with the GFP plasmid which can be stable in some isolates for many generations without adversely affecting growth rates

Quasi-Normal Modes of Stars and Black Holes

Perturbations of stars and black holes have been one of the main topics of relativistic astrophysics for the last few decades. They are of particular importance today, because of their relevance to gravitational wave astronomy. In this review we present the theory of quasi-normal modes of compact objects from both the mathematical and astrophysical points of view. The discussion includes perturbations of black holes (Schwarzschild, Reissner-Nordstr\"om, Kerr and Kerr-Newman) and relativistic stars (non-rotating and slowly-rotating). The properties of the various families of quasi-normal modes are described, and numerical techniques for calculating quasi-normal modes reviewed. The successes, as well as the limits, of perturbation theory are presented, and its role in the emerging era of numerical relativity and supercomputers is discussed.Comment: 74 pages, 7 figures, Review article for "Living Reviews in Relativity

Benign Orbital Tumors with Bone Destruction in Children

Purpose: To present rare benign orbital tumors with bone destruction in children who could not be diagnosed presurgically and may simulate malignant ones. Methods: A retrospective review of cases. Clinical, operative and pathological records in all children with a diagnosis of benign orbital tumors who showed remarkable bone destruction at a tertiary Ophthalmic Center in China between Jan 1, 2000 and Dec 31, 2009 were reviewed. All patients had definitive histopathologic diagnosis. Results: Eight patients with benign orbital tumors showed obvious bone destruction, including six cases of eosinophilic granuloma, one case of leiomyoma and one case of primary orbital intraosseous hemangioma. Among them, three patients were females and five patients were males. Tumors were unilateral in all cases, with both the right and left side affected equally. Age ranged from 3 to 7 years (mean 4.1 years). Symptom duration ranged from 1 to 5 weeks (mean 4.8 weeks). Eyelid swelling and palpable mass were the most common complaint. There was no evidence for multifocal involvement in cases with eosinophilic granuloma. Among six patients with eosinophilic granuloma, two were treated with low dose radiation (10 Gy), three received systemic corticosteroid and one was periodically observed only after incisional biopsy or subtotal curettage. There was no postoperative therapeutic intervention in the two patients with leiomyoma and intraosseous hemangioma. All eight patients regained normal vision without local recurrence after a mean follow-up time o

Distinct Origin of the Y and St Genome in Elymus Species: Evidence from the Analysis of a Large Sample of St Genome Species Using Two Nuclear Genes

Previous cytological and single copy nuclear genes data suggested the St and Y genome in the StY-genomic Elymus species originated from different donors: the St from a diploid species in Pseudoroegneria and the Y from an unknown diploid species, which are now extinct or undiscovered. However, ITS data suggested that the Y and St genome shared the same progenitor although rather few St genome species were studied. In a recent analysis of many samples of St genome species Pseudoroegneria spicata (Pursh) À. Löve suggested that one accession of P. spicata species was the most likely donor of the Y genome. The present study tested whether intraspecific variation during sampling could affect the outcome of analyses to determining the origin of Y genome in allotetraploid StY species. We also explored the evolutionary dynamics of these species.Two single copy nuclear genes, the second largest subunit of RNA polymerase II (RPB2) and the translation elongation factor G (EF-G) sequences from 58 accessions of Pseudoroegneria and Elymus species, together with those from Hordeum (H), Agropyron (P), Australopyrum (W), Lophopyrum (E(e)), Thinopyrum (E(a)), Thinopyrum (E(b)), and Dasypyrum (V) were analyzed using maximum parsimony, maximum likelihood and Bayesian methods. Sequence comparisons among all these genomes revealed that the St and Y genomes are relatively dissimilar. Extensive sequence variations have been detected not only between the sequences from St and Y genome, but also among the sequences from diploid St genome species. Phylogenetic analyses separated the Y sequences from the St sequences.Our results confirmed that St and Y genome in Elymus species have originated from different donors, and demonstrated that intraspecific variation does not affect the identification of genome origin in polyploids. Moreover, sequence data showed evidence to support the suggestion of the genome convergent evolution in allopolyploid StY genome species

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres