57 research outputs found
Multiple jejuno-jejunal fistulae of uncertain origin: a case report
A 43 year-old male patient presented with small bowel obstruction while being treated for cervical tuberculous lymphadenopathy. Laparotomy revealed multiple adhesions and multiple jejuno-jejunal fistulae. Absence of previous abdominal surgery or other abdominal insult favoured an 'idiopathic' origin of these unusual lesions, although treated tuberculosis may have been the underlying cause. To the best of our knowledge this intestinal condition has never previously been reported in the medical literature
Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene
In approximately 20% of cases of severe congenital neutropenia (SCN),
mutations are found in the gene encoding the granulocyte
colony-stimulating factor receptor (G-CSF-R). These mutations introduce
premature stop codons, which result in truncation of 82-98 COOH-terminal
amino acids of the receptor. SCN patients who develop secondary
myelodysplastic syndrome and acute myeloid leukemia almost invariably
acquired a GCSFR mutation, suggesting that this genetic alteration
represents a key step in leukemogenesis. Here we show that an equivalent
mutation targeted in mice (gcsfr-Delta715) results in the selective
expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the
bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with
G-CSF results in increased production of neutrophils leading to a
sustained neutrophilia. This hyperproliferative response to G-CSF is
accompanied by prolonged activation of signal transducer and activator of
transcription (STAT) complexes and extended cell surface expression of
mutant receptors due to defective internalization. In view of the
continuous G-CSF treatment of SCN patients, these data provide insight
into why progenitor cells expressing truncated receptors clonally expand
in vivo, and why these cells may be targets for additional genetic events
leading to leukemia
Genome-Wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia
Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer
Multiple jejuno-jejunal fistulae of uncertain origin: a case report
Abstract A 43 year-old male patient presented with small bowel obstruction while being treated for cervical tuberculous lymphadenopathy. Laparotomy revealed multiple adhesions and multiple jejuno-jejunal fistulae. Absence of previous abdominal surgery or other abdominal insult favoured an 'idiopathic' origin of these unusual lesions, although treated tuberculosis may have been the underlying cause. To the best of our knowledge this intestinal condition has never previously been reported in the medical literature.</p
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