571 research outputs found
Expression profiles of adult T-cell leukemia-lymphoma and associations with clinical responses to zidovudine and interferon alpha
Adult T-cell leukemia-lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon alpha (IFNalpha). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT-IFNalpha therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT-IFNalpha differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT-IFNalpha therapy may provide novel insights into the mechanisms of action in ATLL
Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus
callosum (TCC) is a common and clinically distinct form of familial spastic
paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected
families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval
and identified ten mutations in a previously unidentified gene expressed
ubiquitously in the nervous system but most prominently in the cerebellum,
cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense
or insertions and deletions leading to a frameshift, suggesting a
loss-of-function mechanism. The identification of the function of the gene will
provide insight into the mechanisms leading to the degeneration of the
corticospinal tract and other brain structures in this frequent form of ARHSP
Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome
This work was funded by grants number 18237 and 20089 from Arthritis Research UK (http://www.arthritisresearchuk.org) to MB and the William Harvey Research Foundation. EC was recipient of short-term travel fellowships from EMBO (ASTF 318-2010) and EFIS-IL
Investigating Safety And Preliminary Efficacy Of Afm13 Plus Pembrolizumab In Patients With Relapsed/Refractory Hodgkin Lymphoma After Brentuximab Vedotin Failure
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149522/1/hon134_2629.pd
The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain
BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor
EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias
Background and purpose: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders.Methods: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members.Results and conclusion: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided
Concomitant sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease) and diffuse large B-cell lymphoma: a case report
IntroductionSinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman Disease, is a rare and benign source of lymphadenopathy first described in 1969, which mimics neoplastic processes. This disease commonly presents in children and young adults with supra-diaphragmatic lymphadenopathy or extranodal lesions consisting of tissue infiltrates composed of a polyclonal population of histiocytes. Since its description greater than 400 cases have been described, sometimes in patients with a variety of treated and untreated neoplastic diseases. However, the literature contains reports of only 19 cases of Rosai-Dorfman Disease in association with lymphomas, Hodgkin's or non-Hodgkin's. The majority of these cases have the two diagnoses, malignant lymphoma and Rosai-Dorfman Disease, separated in time. Interestingly, infradiaphragmatic lymphadenopathy was a feature in the majority of previously reported cases of Rosai-Dorfman Disease and non-Hodgkin's lymphoma.Case presentationThis report provides details of a case with co-existing sinus histiocytosis with massive lymphadenopathy and diffuse large B cell non-Hodgkin's lymphoma. This case is the fifth described case of simultaneous Rosai-Dorfman Disease and concurrent non-Hodgkin's lymphoma. Unfortunately, the diagnosis of a clinically aggressive diffuse large B cell lymphoma was made at autopsy. The aggressive biological behavior of the diffuse large B cell lymphoma in this patient may have been related to the underlying immune dysregulation believed to be part of the pathophysiology of Rosai-Dorfman Disease.ConclusionTaken together this report and the preceding reports of Rosai-Dorfman Disease and non-Hodgkin's lymphoma suggests that in cases with a diagnosis of Rosai-Dorfman Disease in the setting of prominent infradiaphragmatic lymphadenopathy, clinicians should maintain a high index of suspicion for the presence of occult non-Hodgkin's lymphoma especially if the clinical course is atypical for classic Rosai-Dorfman Disease
Hierarchical information clustering by means of topologically embedded graphs
We introduce a graph-theoretic approach to extract clusters and hierarchies
in complex data-sets in an unsupervised and deterministic manner, without the
use of any prior information. This is achieved by building topologically
embedded networks containing the subset of most significant links and analyzing
the network structure. For a planar embedding, this method provides both the
intra-cluster hierarchy, which describes the way clusters are composed, and the
inter-cluster hierarchy which describes how clusters gather together. We
discuss performance, robustness and reliability of this method by first
investigating several artificial data-sets, finding that it can outperform
significantly other established approaches. Then we show that our method can
successfully differentiate meaningful clusters and hierarchies in a variety of
real data-sets. In particular, we find that the application to gene expression
patterns of lymphoma samples uncovers biologically significant groups of genes
which play key-roles in diagnosis, prognosis and treatment of some of the most
relevant human lymphoid malignancies.Comment: 33 Pages, 18 Figures, 5 Table
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