Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions.

Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies.

Distinct isoforms of the Drosophila Brd4 homologue are present at enhancers, promoters and insulator sites.

Brd4 is a double bromodomain protein that has been shown to interact with acetylated histones to regulate transcription by recruiting Positive Transcription Elongation Factor b to the promoter region. Brd4 is also involved in gene bookmarking during mitosis and is a therapeutic target for the treatment of acute myeloid leukemia. The Drosophila melanogaster Brd4 homologue is called Fs(1)h and, like its vertebrate counterpart, encodes different isoforms.

Genome-wide phosphoacetylation of histone H3 at Drosophila enhancers and promoters.

Transcription regulation is mediated by enhancers that bind sequence-specific transcription factors, which in turn interact with the promoters of the genes they control. Here, we show that the JIL-1 kinase is present at both enhancers and promoters of ecdysone-induced Drosophila genes, where it phosphorylates the Ser10 and Ser28 residues of histone H3. JIL-1 is also required for CREB binding protein (CBP)-mediated acetylation of Lys27, a well-characterized mark of active enhancers.

[Magnetic resonance imaging in rheumatology].

Imaging plays a major role in the diagnosis and meanwhile also in the therapy control of rheumatic diseases. Besides the commonly used X-ray technique and musculoskeletal ultrasound, magnetic resonance imaging (MRI) is able to provide a three-dimensional view of musculature, ligaments, tendons, capsules, synovial membranes, bones and cartilage with high resolution quality. Therefore, MRI is being employed more and more in the early diagnosis of inflammatory joint and spinal diseases.

14-3-3 mediates histone cross-talk during transcription elongation in Drosophila.

Post-translational modifications of histone proteins modulate the binding of transcription regulators to chromatin. Studies in Drosophila have shown that the phosphorylation of histone H3 at Ser10 (H3S10ph) by JIL-1 is required specifically during early transcription elongation. 14-3-3 proteins bind H3 only when phosphorylated, providing mechanistic insights into the role of H3S10ph in transcription.

Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis.

Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach for modifying the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation, which lead to system failures. The DeltaF508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) results in the absence of the cell surface chloride channel and a loss of airway hydration, leading to the premature lung failure and reduced lifespan responsible for cystic fibrosis.

Identification of interleukin-7 as a candidate disease mediator in spondylarthritis.

Objective: Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA.

Chemical and biological folding contribute to temperature-sensitive DeltaF508 CFTR trafficking.

Proteostasis (Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science 2008;319:916-919) refers to the biology that maintains the proteome in health and disease.

Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.

The pathways that distinguish transport of folded and misfolded cargo through the exocytic (secretory) pathway of eukaryotic cells remain unknown. Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding in the endoplasmic reticulum (ER). Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1.

Uprobe: a genome-wide universal probe resource for comparative physical mapping in vertebrates.

Interspecies comparisons are important for deciphering the functional content and evolution of genomes. The expansive array of >70 public vertebrate genomic bacterial artificial chromosome (BAC) libraries can provide a means of comparative mapping, sequencing, and functional analysis of targeted chromosomal segments that is independent and complementary to whole-genome sequencing. However, at the present time, no complementary resource exists for the efficient targeted physical mapping of the majority of these BAC libraries.

Interventional radiology and the musculoskeletal system.

Imaging-guided interventional procedures are becoming increasingly important in clinical rheumatology, since arthrocentesis of peripheral joints and the spine, as well as soft tissue injections, have a high rate of para-articular localisation when performed as blind techniques. Ultrasound-guided needle placement is the method of choice for interventional procedures on peripheral joints and for soft tissue injections. Fluoroscopy and computed tomography (CT) are not recommended for these indications due to the application of ionising radiation and the high procedural effort.

Endovascular repair of inflammatory abdominal aortic aneurysms: a valuable alternative?--Case report and review of literature.

While endovascular repair (ER) has become a routine procedure in the treatment of arteriosclerotic abdominal aortic aneurysms with a suitable configuration, only rare reports of interventional treatment of inflammatory aortic abdominal aneurysms (IAAA) exist. We present a case study of a male patient with IAAA, who presented with inflammatory thickening involving the entire circumference of the aortic vessel wall. The MRI performed 8 months after successful ER demonstrated complete regression of vessel wall induration.

Ankle and hindfoot arthropathy in hereditary hemochromatosis.

Arthropathy is a leading clinical manifestation of hereditary hemochromatosis (HH), but involvement of the ankle and hindfoot joints is rare. We describe 3 male patients who presented with symmetrical pain and swelling of the ankles. Radiographs and magnetic resonance imaging showed severe osteoarthritic degenerative changes with a radiological triad of joint space narrowing, subchondral sclerosis, and cyst formation.

Staging of recurrent and advanced lung cancer with 18F-FDG PET in a coincidence technique (hybrid PET).

The aim of this study was to evaluate [18F]fluorodeoxyglucose ( F-FDG) imaging of recurrent or inoperable lung cancer using a hybrid positron emission tomography (PET) device of the third generation. Examinations were compared with the results of conventional staging. Thirty-six patients suffering from recurrent or primarily inoperable lung cancer (29 men, seven women; age 64.

Adult moyamoya disease with peripheral artery involvement.

We report the case of a young white woman in whom cerebrovascular moyamoya disease, which was associated with nonarteriosclerotic peripheral artery disease of the subclavian, iliac, and femoropopliteal arteries, was diagnosed by means of angiography. During 8 years of follow-up, the peripheral artery disease progressed, without any signs characteristic of systemic inflammation or vasculitis, leading to severe calf and arm claudication. Despite the absence of histologic confirmation, this observation strongly suggests that peripheral artery involvement may be a feature of moyamoya disease.

[Roentgen, magnetic resonance with contrast medium, scintigraphy. Staged diagnosis of sacroiliitis].

Radiographic imaging techniques including conventional tomography and computed tomography play a major role in the diagnosis of sacroiliitis (SI). In acute or early stages, however, it may take years before the first morphologic changes become apparent, and the diagnosis of early stages of sacroiliitis still challenges the diagnostician. While scintiscanning is capable of depicting early changes to the joints, it has only low specificity, and interpretation is often difficult, especially in young patients or in cases with bilateral SI arthritis.

[1: Clinical aspects, laboratory diagnosis and therapy. Low backache--when is sacroiliitis the cause?].

Despite the availability of modern imaging modalities, early diagnosis of sacroiliitis remains a challenge. The patient's history and the results of the clinical examination form the basis for establishing a working diagnosis, which then needs to be confirmed by laboratory tests and diagnostic imaging. Common causes of sacroiliitis are inflammatory diseases of the spine, in particular seronegative spondyloarthropathies; infectious sacroiliitis is much less common.

[Angina abdominalis: duplex ultrasound diagnosis and percutaneous revascularization].

Intestinal ischemia is still a challenge for clinicians and requires a close interdisciplinary cooperation between internist, surgeon and radiologist. In the last years the diagnosis and therapy, classically invasive and surgical, was supplemented by duplex ultrasound and percutaneous techniques like angioplasty and stenting. A 56 year-old man from Greece presented with epigastric pain, which was intensified by food ingestion.

Endoluminal repair of peripheral arterial aneurysms: 4-year experience with the cragg endopro system I.

Purpose: To assess the efficiency and long-term patency of the Cragg EndoPro System I in patients with peripheral arterial aneurysms.

Materials And Methods: In 10 patients, 13 stent-grafts were used to treat 15 arterial aneurysms. Aneurysms were located in the common iliac (n = 4), superficial femoral (n = 4), popliteal (n = 3), and subclavian arteries (n = 2), and in a femoropopliteal bypass-graft (n = 2).

[Simultaneous vascular and endovascular surgery of complex vascular diseases].

Complex vascular disease requires combined, intraoperative endovascular and reconstructive therapy. Hereby, transprosthetic, transluminal angioplasty is particularly well suited for this purpose. The 5-year patency rate after combined inguinal patch plasty and femoral balloon dilation (n = 58) was 70%.

MR imaging of soft-tissue changes after percutaneous transluminal angioplasty and stent placement.

Purpose: To evaluate the different tissue reactions at magnetic resonance (MR) imaging after balloon dilation and placement of covered and uncovered stents.

Materials And Methods: Contrast material-enhanced MR imaging was performed in 14 patients with polyester-covered nitinol stents, 10 patients with conventional metallic stents, and 12 patients who underwent peripheral percutaneous transluminal angioplasty. Lesions were located in the subclavian, iliac, femoral, and popliteal arteries.

Contrast-enhanced MRI of the breast after limited surgery and radiation therapy.

Objective: Posttherapeutic changes in the breast after tumorectomy (TE) and radiation therapy (RT) may mimic or obscure recurrent or new malignancies and thus interfere with conventional diagnostic studies. We investigated the enhancement of tissue during variable time intervals after therapy with contrast-enhanced MRI in 62 patients.

Materials And Methods: We report the results of 77 studies in 62 patients undergoing TE and RT.