MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'EMBO Molecular Medicine' source. Fri, 19 Mar 2010 17:24:09 +0100 http://www.medworm.com/index.php?rid=3326375&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000062 Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G0/G1 cell cycle... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3326375 Wed, 03 Mar 2010 00:00:00 +0100 3326375 http://www.medworm.com/index.php?rid=3326374&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000063 Atherosclerosis, a chronic inflammatory disease of the vascular system, presents significant challenges to developing effective molecular diagnostics and novel therapies. A systems biology approach integrating data from large-scale measurements (e.g. transcriptomics, proteomics and genomics) is successfully contributing to deciphering regulatory networks underlying the response of many different cellular systems to perturbations. Such a network analysis strategy using pathway information and data from multiple measurement platforms, tissues and species is a promising approach to elucidate the mechanistic underpinnings of complex diseases. Here, we present our views on the contributions that a systems approach can bring to the study of atherosclerosis, propose ways to tackle the complexity ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3326374 Wed, 03 Mar 2010 00:00:00 +0100 3326374 http://www.medworm.com/index.php?rid=3279472&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000061 X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X-ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; [ge]C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal [beta]-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl-CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is no... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3279472 Wed, 17 Feb 2010 00:00:00 +0100 3279472 http://www.medworm.com/index.php?rid=3279471&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000060 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3279471 Wed, 17 Feb 2010 00:00:00 +0100 3279471 http://www.medworm.com/index.php?rid=3243194&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090001 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3243194 Thu, 04 Feb 2010 00:00:00 +0100 3243194 http://www.medworm.com/index.php?rid=3243193&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090000 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3243193 Mon, 01 Feb 2010 00:00:00 +0100 3243193 http://www.medworm.com/index.php?rid=3219914&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900059 Arterial hypertension is one of the most important health problems in industrialized cities. Blood pressure levels are influenced by renal salt handling and salt reabsorption in the kidney. In this Closeup, Castañeda-Bueno and Gamba discuss the work from Alessi and coworkers on the in vivo roles of the SPAK kinase in defining blood pressure levels. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3219914 Fri, 29 Jan 2010 00:00:00 +0100 3219914 http://www.medworm.com/index.php?rid=3193161&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900057 In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and 'damaged' myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term. (Source: EMBO Molecular Medi... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3193161 Thu, 21 Jan 2010 00:00:00 +0100 3193161 http://www.medworm.com/index.php?rid=3193162&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900058 Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na+:Cl- cotransporter (NCC) and Na+:K+:2Cl- cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WNKs. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was a... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3193162 Wed, 20 Jan 2010 00:00:00 +0100 3193162 http://www.medworm.com/index.php?rid=3171310&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900055 Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17[beta]-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10-/- mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. Impairment of this function in neural cells causes apoptotic cell de... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3171310 Thu, 14 Jan 2010 00:00:00 +0100 3171310 http://www.medworm.com/index.php?rid=3133227&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990014 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3133227 Thu, 31 Dec 2009 15:52:44 +0100 3133227 http://www.medworm.com/index.php?rid=3133230&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990015 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3133230 Wed, 30 Dec 2009 00:00:00 +0100 3133230 http://www.medworm.com/index.php?rid=3133229&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900054 Shah et al have recently reported the first successful sequencing of the entire genome of a solid tumour (Shah et al, ). Philippe Bedard and Christos Sotiriou analyse their findings as well as the challenges of applying the study of cancer genomes to clinical cancer care. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3133229 Wed, 30 Dec 2009 00:00:00 +0100 3133229 http://www.medworm.com/index.php?rid=3133228&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900056 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3133228 Wed, 30 Dec 2009 00:00:00 +0100 3133228 http://www.medworm.com/index.php?rid=3074882&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900053 Epigenetic regulation is important for stable maintenance of cell identity. For continued function of organs and tissues, illegitimate changes in cell identity must be avoided. Failure to do so can trigger tumour development and disease. How epigenetic patterns are established during cell differentiation has been explored by studying model systems such as X inactivation. Mammals balance the X-linked gene dosage between the sexes by silencing of one of the two X chromosomes in females. This is initiated by expression of the non-coding X-inactive specific transcript (Xist) RNA and depends on specific cellular contexts, in which essential silencing factors are expressed. Normally X inactivation is initiated in early embryogenesis, but recent reports identified instances where Xist is expresse... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3074882 Thu, 10 Dec 2009 00:00:00 +0100 3074882 http://www.medworm.com/index.php?rid=3029311&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900050 This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3029311 Thu, 26 Nov 2009 00:00:00 +0100 3029311 http://www.medworm.com/index.php?rid=3029312&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900047 Myc is activated in many tumours, yet, paradoxically, stimulates differentiation in mammalian epidermis. To test whether the epidermis responds differently to different levels of Myc, we treated K14MycER transgenic mice with a range of concentrations of the inducing agent, 4-hydroxy-tamoxifen (4OHT). Proliferation was stimulated at all levels of Myc activity; sebocyte differentiation was stimulated at low and intermediate levels; and interfollicular epidermal differentiation at intermediate and high levels. Mutational inactivation of the Myc p21 activated kinase 2 (PAK2) phosphorylation sites increased Myc activity and further enhanced epidermal differentiation. We conclude that Myc induced differentiation acts as a fail-safe device to prevent uncontrolled proliferation and neoplastic conv... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3029312 Wed, 25 Nov 2009 00:00:00 +0100 3029312 http://www.medworm.com/index.php?rid=3007542&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900048 Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-[beta]42 (A[beta]42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF A[beta]42 but not for plasma A[bet... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3007542 Thu, 19 Nov 2009 00:00:00 +0100 3007542 http://www.medworm.com/index.php?rid=2845873&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900045 We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-[beta])/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intri... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2845873 Tue, 29 Sep 2009 23:00:00 +0100 2845873 http://www.medworm.com/index.php?rid=2838642&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990009 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2838642 Sun, 27 Sep 2009 23:00:00 +0100 2838642 http://www.medworm.com/index.php?rid=2838641&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900043 Recent advances in our understanding of the molecular pathways that govern the association of inflammation with organ fibrosis and cancer point to the epithelial to mesenchymal transition (EMT) as the common link in the progression of these devastating diseases. The EMT is a crucial process in the development of different tissues in the embryo and its reactivation in the adult may be regarded as a physiological attempt to control inflammatory responses and to 'heal' damaged tissue. However, in pathological contexts such as in tumours or during the development of organ fibrosis, this healing response adopts a sinister nature, steering these diseases towards metastasis and organ failure. Importantly, the chronic inflammatory microenvironment common to fibrotic and cancer cells emerges as a d... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2838641 Sun, 27 Sep 2009 23:00:00 +0100 2838641 http://www.medworm.com/index.php?rid=2838640&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900044 While the use of synthetic lethality has been around for decades in model organism studies, it has only recently been applied to cancer therapy and judging by recent results, with great success. Following on a recent paper that demonstrates the clinical application of this strategy (Fong et al, ), Chris Lord and Alan Ashworth further explore the approach and show that poly(ADP-ribose) polymerase (PARP) inhibitors such as Olaparib can selectively target cancer cells defective in phosphatase and tensin homologue (PTEN, Mendes-Pereira et al, ) and that methotrexate is selectively lethal to MutS-homologue-2 (MSH2)-deficient tumour cells (Martin et al, ). (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2838640 Sun, 27 Sep 2009 23:00:00 +0100 2838640 http://www.medworm.com/index.php?rid=2838639&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990011 No Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2838639 Sun, 27 Sep 2009 23:00:00 +0100 2838639 http://www.medworm.com/index.php?rid=2803485&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900041 The tumour suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most commonly mutated genes in human cancers. Recent evidence suggests that PTEN is important for the maintenance of genome stability. Here, we show that PTEN deficiency causes a homologous recombination (HR) defect in human tumour cells. The HR deficiency caused by PTEN deficiency, sensitizes tumour cells to potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), both in vitro and in vivo. PARP inhibitors are now showing considerable promise in the clinic, specifically in patients with mutations in either of the breast cancer susceptibility genes BRCA1 or BRCA2. The data we present here now suggests that the clinical assessment of PARP inhibitors should be extended beyond those with BRC... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2803485 Tue, 15 Sep 2009 23:00:00 +0100 2803485 http://www.medworm.com/index.php?rid=2751230&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900042 The participation of the HH pathway in colon cancer has remained controversial. In this issue, Varnat et al (2009) demonstrate that HH signalling is essential for human colon cancer growth, recurrence, metastases and stem cell expansion. This closeup by Gulino et al discusses the paper and its implications. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2751230 Mon, 31 Aug 2009 23:00:00 +0100 2751230 http://www.medworm.com/index.php?rid=2740870&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900040 Mutations in the MSH2 gene predispose to a number of tumourigenic conditions, including hereditary non-polyposis colon cancer (HNPCC). MSH2 encodes a protein in the mismatch repair (MMR) pathway which is involved in the removal of mispairs originating during replication or from damaged DNA. To identify new therapeutic strategies for the treatment of cancer arising from MMR deficiency, we screened a small molecule library encompassing previously utilized drugs and drug-like molecules to identify agents selectively lethal to cells lacking functional MSH2. This approach identified the drug methotrexate as being highly selective for cells with MSH2 deficiency. Methotrexate treatment caused the accumulation of potentially lethal 8-hydroxy-2'-deoxyguanosine (8-OHdG) oxidative DNA lesions in both... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2740870 Thu, 27 Aug 2009 23:00:00 +0100 2740870 http://www.medworm.com/index.php?rid=2740871&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900039 Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced [beta]CATENIN ([beta]CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2740871 Wed, 26 Aug 2009 23:00:00 +0100 2740871 http://www.medworm.com/index.php?rid=2670428&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900037 Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency a... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670428 Tue, 04 Aug 2009 23:00:00 +0100 2670428 http://www.medworm.com/index.php?rid=2670427&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900036 Lysosomal storage diseases (LSDs) are a group of genetic disorders due to defects in any aspect of lysosomal biology. During the past two decades, different approaches have been introduced for the treatment of these conditions. Among them, enzyme replacement therapy (ERT) represented a major advance and is used successfully in the treatment of some of these disorders. However, ERT has limitations such as insufficient biodistribution of recombinant enzymes and high costs. An emerging strategy for the treatment of LSDs is pharmacological chaperone therapy (PCT), based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. After proof-of-concept studies, PCT is now being translated into clinical applications for Fabr... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670427 Tue, 04 Aug 2009 23:00:00 +0100 2670427 http://www.medworm.com/index.php?rid=2670426&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900033 Mammalian epidermis is maintained by self-renewal of stem cells and terminal differentiation of their progeny. New data reveal a diversity amongst stem cells that was previously unrecognized. Different stem cell populations have different locations and differ in whether they are quiescent or actively cycling. During normal epidermal homeostasis, each stem cell population feeds a restricted number of differentiated lineages. However, in response to injury or genetic manipulation the different pools of stem cells demonstrate multi-lineage differentiation ability. While it is well established that Wnt signalling promotes hair follicle (HF) differentiation, new observations suggest a role for EGF receptor signalling in promoting differentiation of interfollicular epidermis. NFATc1 maintains qu... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670426 Tue, 04 Aug 2009 23:00:00 +0100 2670426 http://www.medworm.com/index.php?rid=2670425&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900034 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670425 Tue, 04 Aug 2009 23:00:00 +0100 2670425 http://www.medworm.com/index.php?rid=2670424&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900035 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670424 Tue, 04 Aug 2009 23:00:00 +0100 2670424 http://www.medworm.com/index.php?rid=2670423&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990008 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670423 Tue, 04 Aug 2009 23:00:00 +0100 2670423 http://www.medworm.com/index.php?rid=2838638&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990010 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2838638 Fri, 31 Jul 2009 23:00:00 +0100 2838638 http://www.medworm.com/index.php?rid=2590952&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900089 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590952 Thu, 09 Jul 2009 23:00:00 +0100 2590952 http://www.medworm.com/index.php?rid=2590951&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900027 Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590951 Thu, 09 Jul 2009 23:00:00 +0100 2590951 http://www.medworm.com/index.php?rid=2590949&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900032 The global rise of anti-microbial resistance, combined with the rapid rate of microbial evolution, and the slower development of novel antibiotics, underscores the urgent need for innovative therapeutics. We are facing a post-antibiotic era with a decreased armamentarium to combat infectious diseases. Development of novel drugs will rely on basic research aimed to increase our understanding of bacterial pathogenesis and the inter-cellular chemical signalling among bacterial cells. Such basic science, when combined with contemporary drug discovery technologies, may be translated into therapeutic applications to combat bacterial infections. In this review, we discuss many strategies aimed to interfere with bacterial cell-to-cell signalling via the quorum-sensing (QS) pathway to inhibit bacte... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590949 Thu, 09 Jul 2009 23:00:00 +0100 2590949 http://www.medworm.com/index.php?rid=2590948&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900029 In the war on cancer, a great deal of attention is being paid to knowing the 'enemy'. It is widely believed that by understanding the driving forces underlying cancer, researchers can develop better ways to target the disease. Currently, large-scale efforts have been under taken to completely characterize molecular changes in common human cancers () (Collins & Barker, ). However, as more is learned about cancer, the debate increases on what exactly the enemy is: cells making up the bulk of the tumour, rare tumour stem cells that can regrow the tumour, tumour microenvironment, the subset of cancer cells with metastatic potential, etc. Studies of the cancers associated with Neurofibromatosis type 1 (NF1) are helping to define the relationship between many of these different cell types. It is... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590948 Thu, 09 Jul 2009 23:00:00 +0100 2590948 http://www.medworm.com/index.php?rid=2590947&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900030 Alzheimer's disease (AD) is the most common cause of dementia. There are currently no effective treatments that may delay the onset, slow the progression or prevent the disease. Unless such treatments are developed, the number of AD cases is expected to double in the next 30 years. There is overwhelming genetic and biochemical evidence that the aggregation and buildup of the amyloid-[beta] (A[beta]) peptide plays a critical role in AD pathogenesis. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590947 Thu, 09 Jul 2009 23:00:00 +0100 2590947 http://www.medworm.com/index.php?rid=2590946&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900031 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590946 Thu, 09 Jul 2009 23:00:00 +0100 2590946 http://www.medworm.com/index.php?rid=2590945&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990006 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590945 Thu, 09 Jul 2009 23:00:00 +0100 2590945 http://www.medworm.com/index.php?rid=2670422&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990007 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670422 Tue, 30 Jun 2009 23:00:00 +0100 2670422 http://www.medworm.com/index.php?rid=2590944&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990005 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590944 Tue, 30 Jun 2009 23:00:00 +0100 2590944 http://www.medworm.com/index.php?rid=2504170&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900026 Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-[beta] (A[beta]42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived A[beta]-like peptides (APL1[beta]) that are generated by [beta]- and [gamma]-cleavages at a concentration of [sim]4.5 nM. These novel peptides, APL1[beta]25, APL1[beta]27 and APL1[beta]28, were not deposited in AD brains. Interestingly, most [gamma]-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of A[beta]42 cause a parallel increase in the production of APL1[beta]28 in cultured cells. Moreover, in CSF from patients with pa... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2504170 Wed, 24 Jun 2009 23:00:00 +0100 2504170 http://www.medworm.com/index.php?rid=2587748&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990002 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587748 Thu, 11 Jun 2009 23:00:00 +0100 2587748 http://www.medworm.com/index.php?rid=2587745&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900018 We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell KATP currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po(0)), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po(0) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importanc... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587745 Thu, 11 Jun 2009 23:00:00 +0100 2587745 http://www.medworm.com/index.php?rid=2587744&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900024 The role of mitochondria in sporadic (PD) has been debated for a little over 20 years since the description of deficiency in the substantia nigra pars compacta () of PD patients. However, the identification of recessive pathogenic mutations in the pink1 gene in familial PD cases firmly re-ignited interest in the pathophysiology of mitochondria in PD. PINK1 is a putative mitochondrial serine/threonine kinase, which protects cells against oxidative stress induced apoptosis. The mechanism by which this is achieved and the effect of the pathogenic mutations has been an area of intensive research over the past five years. Significant progress has been made and, in this review, we summarize the physiological roles that have been assigned to PINK1 and the potential mechanisms behind pathogenesis.... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587744 Thu, 11 Jun 2009 23:00:00 +0100 2587744 http://www.medworm.com/index.php?rid=2587743&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900023 (RNAi) is a collection of small RNA directed mechanisms that result in sequence specific inhibition of gene expression. The notion that RNAi could lead to a new class of therapeutics caught the attention of many investigators soon after its discovery. The field of applied RNAi therapeutics has moved very quickly from lab to bedside. The RNAi approach has been widely used for drug development and several phase I and II clinical trials are under way. However, there are still some concerns and challenges to overcome for therapeutic applications. These include the potential for , triggering innate immune responses and most importantly obtaining specific delivery into the cytoplasm of target cells. This review focuses on the current status of RNAi-based therapeutics, the challenges it faces and... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587743 Thu, 11 Jun 2009 23:00:00 +0100 2587743 http://www.medworm.com/index.php?rid=2587742&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900021 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587742 Thu, 11 Jun 2009 23:00:00 +0100 2587742 http://www.medworm.com/index.php?rid=2587741&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990004 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587741 Thu, 11 Jun 2009 23:00:00 +0100 2587741 http://www.medworm.com/index.php?rid=2670429&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900028 Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor [alpha] (TNF[alpha]). Anti-TNF[alpha] regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction i... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2670429 Tue, 09 Jun 2009 23:00:00 +0100 2670429 http://www.medworm.com/index.php?rid=2587740&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200990003 No Abstract. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587740 Sun, 31 May 2009 23:00:00 +0100 2587740 http://www.medworm.com/index.php?rid=2590950&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900025 This study describes a novel role of pneumolysin in the evasion of human DC surveillance that could have a profound clinical impact upon inflammatory disease progression and highlights the need to study human responses to human-specific pathogens. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2590950 Tue, 26 May 2009 23:00:00 +0100 2590950 http://www.medworm.com/index.php?rid=2587746&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.200900022 Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1[alpha], [beta] and [gamma], which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1[alpha] shows a proliferation-dependent regulation, which neither HP1[beta] nor [gamma] display. During transient cell cycle exit, the HP1[alpha] mRNA and protein levels diminish. Transient depletion of HP1[alpha], but not HP1[beta] or [gamma], in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=2587746 Thu, 07 May 2009 23:00:00 +0100 2587746