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. Thu, 09 Feb 2012 16:56:41 +0100 http://www.medworm.com/index.php?rid=5673979&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100210 Discussion on these topics provided new insights into the biology of these pathogens and enriched the field with new ideas for understanding why colonization of the intracellular niche of eukaryotic cells is a preferred strategy used by important human pathogens. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5673979 Thu, 09 Feb 2012 05:00:00 +0100 5673979 http://www.medworm.com/index.php?rid=5673980&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100207 In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development. The finding that inhibition of NFAT enhances myeloid development provides a novel insight into understanding how the treatment with drugs targeting calcineurin/NFAT signalling influence the homeostasis of the innate immune system. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5673980 Tue, 07 Feb 2012 05:00:00 +0100 5673980 http://www.medworm.com/index.php?rid=5673978&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100208 AbstractThe large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells – tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL‐induced chronic myeloid (CML) and B‐cell acute lymphoid leukaemia (B‐ALL), resemble long‐term haematopoietic stem cells (LT‐HSCs). During disease‐maintenance, CML LT‐HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B‐ALL LT‐HSCs differentiate into CSCs that correspond to pro‐B cells. This transition step requires a tr... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5673978 Wed, 01 Feb 2012 05:00:00 +0100 5673978 http://www.medworm.com/index.php?rid=5656524&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201290001 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5656524 Wed, 01 Feb 2012 05:00:00 +0100 5656524 http://www.medworm.com/index.php?rid=5656523&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100201 In this report we show that genetic and pharmacologic inhibition of EGFR signalling reduces tumour growth in mouse models of HH/GLI driven basal cell carcinoma (BCC). We describe HH‐EGFR cooperation response genes including SOX2, SOX9, JUN, CXCR4 and FGF19 that are synergistically activated by HH‐EGFR signal integration and required for in vivo growth of BCC cells and tumour‐initiating pancreatic cancer cells. The data validate EGFR signalling as drug target in HH/GLI driven cancers and shed light on the molecular processes controlled by HH‐EGFR signal cooperation, providing new therapeutic strategies based on combined targeting of HH‐EGFR signalling and selected downstream target genes. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5656523 Wed, 01 Feb 2012 05:00:00 +0100 5656523 http://www.medworm.com/index.php?rid=5656522&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100200 AbstractEndometriosis is found in 5–15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let‐7 microRNA (miRNA) binding site in the 3'‐UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increase... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5656522 Wed, 01 Feb 2012 05:00:00 +0100 5656522 http://www.medworm.com/index.php?rid=5635469&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100196 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5635469 Wed, 25 Jan 2012 05:00:00 +0100 5635469 http://www.medworm.com/index.php?rid=5635468&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100197 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5635468 Wed, 25 Jan 2012 05:00:00 +0100 5635468 http://www.medworm.com/index.php?rid=5604042&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100193 AbstractCancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT‐dependent... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5604042 Wed, 18 Jan 2012 05:00:00 +0100 5604042 http://www.medworm.com/index.php?rid=5593118&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100190 AbstractWnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG−/LRP+ signature has a strong predictable value for recurrence�... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5593118 Fri, 13 Jan 2012 05:00:00 +0100 5593118 http://www.medworm.com/index.php?rid=5593117&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100205 AbstractSecreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro‐metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl‐Sema3E) binds to PlexinD1 like p61‐Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl‐Sema3E competes with endogenous p61‐Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl‐Sema3E also acts independently as a potent anti‐angiogenic factor. It activates a PlexinD1‐me... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5593117 Fri, 13 Jan 2012 05:00:00 +0100 5593117 http://www.medworm.com/index.php?rid=5593116&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100199 AbstractAnkyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock‐in mouse model for AEC syndrome (p63+/L514F) that recapitulates the human disorder. The AEC mutation exerts a selective dominant‐negative function on wild‐type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment. These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3, direct p63 target genes. In parallel, a defective stem cell comp... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5593116 Fri, 13 Jan 2012 05:00:00 +0100 5593116 http://www.medworm.com/index.php?rid=5576693&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100192 We reported that epithelial GM‐CSF–STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC)‐specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF‐κB activation and MLCK, and a reduction of zonula occludens expression in IECs. Deletion of MLCK restored intestinal barrier function in STAT5 knockout mice, and facilitated mucosal wound healing. Consistently, knockdown of stat5 in IEC monolayers led to increased NF‐κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which wer... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5576693 Mon, 09 Jan 2012 05:00:00 +0100 5576693 http://www.medworm.com/index.php?rid=5635467&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100198 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5635467 Sun, 01 Jan 2012 05:00:00 +0100 5635467 http://www.medworm.com/index.php?rid=5568949&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201290000 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5568949 Sun, 01 Jan 2012 05:00:00 +0100 5568949 http://www.medworm.com/index.php?rid=5520416&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100188 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5520416 Mon, 19 Dec 2011 05:00:00 +0100 5520416 http://www.medworm.com/index.php?rid=5520415&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100189 AbstractHistone deacetylases (HDACs) and microRNAs (miRs) have pro‐survival roles, but the mechanism behind this is unclear. Repression of ceramide synthase 1 (CerS1), altering C18‐ceramide generation, was linked to drug resistance and metastasis. Here we report that the CerS1 promoter was repressed by HDAC1‐dependent inhibition of Sp1 recruitment to two specific GC‐boxes spanning the −177 and −139 region. Moreover, an alternatively spliced variant CerS1 mRNA (CerS1‐2) was detected mainly in cancer cells or primary tumour tissues compared to controls, which was targeted by miR‐574‐5p for degradation. A specific 3′UTR‐targeting site, localized within the retained intron between exons 6 and 7, was identified, and its mutation, or miR‐574‐5p knockdown prevented the d... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5520415 Mon, 19 Dec 2011 05:00:00 +0100 5520415 http://www.medworm.com/index.php?rid=5520417&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100187 AbstractESR1 is one of the most important transcription factors and therapeutic targets in breast cancer. By applying systems‐level re‐analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to the promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)‐positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence‐free survival and a favourable response to tamoxifen treatment in women with ER‐positive breast cancer. Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 an... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5520417 Thu, 15 Dec 2011 05:00:00 +0100 5520417 http://www.medworm.com/index.php?rid=5501143&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100191 AbstractCardiovascular diseases are the most common causes of human morbidity and mortality despite significant therapeutic improvements by surgical, interventional and pharmacological approaches in the last decade. MicroRNAs (miRNAs) are important and powerful mediators in a wide range of diseases and thus emerged as interesting new drug targets. An array of animal and even human miRNA‐based therapeutic studies has been performed, which validate miRNAs as being successfully targetable to treat a wide range of diseases. Here, the current knowledge about miRNAs therapeutics in cardiovascular diseases on their way to clinical use are reviewed and discussed. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5501143 Tue, 13 Dec 2011 05:00:00 +0100 5501143 http://www.medworm.com/index.php?rid=5483151&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100185 AbstractMycolic acids are attractive diagnostic markers for tuberculosis (TB) infection because they are bacteria‐derived, contain information about bacterial species, modulate host–pathogen interactions and are chemically inert. Here, we present a novel approach based on mass spectrometry. Quantification of specific precursor → fragment transitions of approximately 2000 individual mycolic acids (MAs) resulted in high analytical sensitivity and specificity. We next used this tool in a retrospective case–control study of patients with pulmonary TB with varying disease burdens from South Korea, Vietnam, Uganda and South Africa. MAs were extracted from small volume sputum (200 µl) and analysed without the requirement for derivatization. Infected patients (70, 19 of whom were HI... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5483151 Wed, 07 Dec 2011 05:00:00 +0100 5483151 http://www.medworm.com/index.php?rid=5520414&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100194 AbstractCoordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress‐induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2+ release from the SR causing arrhythmogenic delayed afterdepolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC‐derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca2+ concentratio... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5520414 Thu, 01 Dec 2011 05:00:00 +0100 5520414 http://www.medworm.com/index.php?rid=5501142&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100195 AbstractA mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid‐β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β‐secretase rescues synaptic/memory deficits in a mouse model of FDD. β‐cleavage of APP yields amino‐terminal‐soluble APPβ (sAPPβ) and β‐carboxyl‐terminal fragments (β‐CTF). Processing of β‐CTF by γ‐secretase releases Aβ, which is assumed to cause AD. However, ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5501142 Thu, 01 Dec 2011 05:00:00 +0100 5501142 http://www.medworm.com/index.php?rid=5483150&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100186 AbstractMalignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt‐specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan‐Wnt protein secretion, affecting both canonical and non‐canonical signalling. We demonstrate that its depletion in glioma and glioma‐derived stem‐like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5483150 Thu, 01 Dec 2011 05:00:00 +0100 5483150 http://www.medworm.com/index.php?rid=5465223&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190005 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5465223 Thu, 01 Dec 2011 05:00:00 +0100 5465223 http://www.medworm.com/index.php?rid=5447668&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100182 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5447668 Tue, 01 Nov 2011 04:00:00 +0100 5447668 http://www.medworm.com/index.php?rid=5417672&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100184 AbstractA decline in ocular lens transparency known as cataract afflicts 90% of individuals by the age 70. Chronic deterioration of lens tissue occurs as a pathophysiological consequence of defective water and nutrient circulation through channel and transporter proteins. A key component is the aquaporin‐0 (AQP0) water channel whose permeability is tightly regulated in healthy lenses. Using a variety of cellular and biochemical approaches we have discovered that products of the A‐kinase anchoring protein 2 gene (AKAP2/AKAP‐KL) form a stable complex with AQP0 to sequester protein kinase A (PKA) with the channel. This permits PKA phosphorylation of serine 235 within a calmodulin (CaM)‐binding domain of AQP0. The additional negative charge introduced by phosphoserine 235 perturbs elec... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5417672 Tue, 01 Nov 2011 04:00:00 +0100 5417672 http://www.medworm.com/index.php?rid=5375480&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190004 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5375480 Tue, 01 Nov 2011 04:00:00 +0100 5375480 http://www.medworm.com/index.php?rid=5375479&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100183 AbstractIn their role as small chemotactic cytokines, chemokines are crucial mediators and regulators of leukocyte trafficking during immune surveillance and inflammation. Their involvement in the development and progression of inflammatory diseases has been subject of intense investigation. Concordantly, the chemokine system has been explored in search for therapeutic targets to prevent or treat inflammatory disorders, such as atherosclerosis. Targeting the chemokine system offers various entry points for a causative treatment of this widespread and chronic illness. Although this approach has encountered some setbacks, several innovative compounds are currently in an advanced stage of development. In this review, the current standing of this dynamic field is highlighted and the potential ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5375479 Fri, 28 Oct 2011 04:00:00 +0100 5375479 http://www.medworm.com/index.php?rid=5321537&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100180 AbstractPantothenate kinase‐associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl‐Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well‐known determining factor for the acetylation status of proteins. However, the influence of Coenzyme A levels on protein acetylation is unknown. Here we investigate whether decreased levels of the central metabolite Coenzyme A induce alterations in protein acetylation and whether this correl... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5321537 Fri, 14 Oct 2011 04:00:00 +0100 5321537 http://www.medworm.com/index.php?rid=5301845&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100177 This study provides an example of a simple and direct use of adult stem cells from one organ to another, without introducing additional inductive genes.See accompanying article http://dx.doi.org/10.1002/emmm.201100178 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5301845 Mon, 10 Oct 2011 04:00:00 +0100 5301845 http://www.medworm.com/index.php?rid=5292960&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100178 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5292960 Fri, 07 Oct 2011 04:00:00 +0100 5292960 http://www.medworm.com/index.php?rid=5301847&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190003 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5301847 Sat, 01 Oct 2011 04:00:00 +0100 5301847 http://www.medworm.com/index.php?rid=5301846&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100171 AbstractMicroRNAs (miRNAs) have been implicated in B cell lineage commitment, regulation of T cell differentiation, TCR signalling, regulation of IFN signalling, and numerous other immunological processes. However, their function in autoimmunity, and specifically in systemic lupus erythematosus (SLE), remains poorly understood. B6.Sle123 is a spontaneous genetic mouse model of SLE characterized by autoantibody production, lymphosplenomegaly, and glomerulonephritis. We identified several differentially regulated miRNAs in B and T lymphocytes of B6.Sle123 mice. We found that miR‐21 expression in lupus B and T cells is up‐regulated and that in vivo silencing of miR‐21 using a tiny seed‐targeting LNA reversed splenomegaly, one of the cardinal manifestations of autoimmunity in B6.Sle123... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5301846 Sat, 01 Oct 2011 04:00:00 +0100 5301846 http://www.medworm.com/index.php?rid=5257308&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100169 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5257308 Fri, 23 Sep 2011 04:00:00 +0100 5257308 http://www.medworm.com/index.php?rid=5257307&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100175 AbstractThe death of cardiac myocytes diminishes the heart's pump function and is a major cause of heart failure, one of the dominant causes of death worldwide. Other than transplantation, there are no therapies that directly address the loss of cardiac myocytes, which explains the current excitement in cardiac regeneration. The field is evolving in two important directions. First, although endogenous mammalian cardiac regeneration clearly seems to decline rapidly after birth, it may still persist in adulthood. The careful elucidation of the cellular and molecular mechanisms of endogenous heart regeneration may therefore provide an opportunity for developing therapeutic interventions that amplify this process. Second, recent breakthroughs have enabled reprogramming of cells that were appar... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5257307 Fri, 23 Sep 2011 04:00:00 +0100 5257307 http://www.medworm.com/index.php?rid=5257306&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100176 AbstractA decade has elapsed since the concept of oncogene addiction was first proposed. It postulates that – despite the diverse array of genetic lesions typical of cancer – some tumours rely on one single dominant oncogene for growth and survival, so that inhibition of this specific oncogene is sufficient to halt the neoplastic phenotype. A large amount of evidence has proven the pervasive power of this notion, both in basic research and in therapeutic applications. However, in the face of such a considerable body of knowledge, the intimate molecular mechanisms mediating this phenomenon remain elusive. At the clinical level, successful translation of the oncogene addiction model into the rational and effective design of targeted therapeutics against individual oncoproteins still face... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5257306 Fri, 23 Sep 2011 04:00:00 +0100 5257306 http://www.medworm.com/index.php?rid=5204221&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100167 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5204221 Fri, 09 Sep 2011 04:00:00 +0100 5204221 http://www.medworm.com/index.php?rid=5217713&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100801 AbstractBreast cancer is a molecularly, biologically and clinically heterogeneous group of disorders. Understanding this diversity is essential to improving diagnosis and optimising treatment. Both genetic and acquired epigenetic abnormalities participate in cancer, but the involvement of the epigenome in breast cancer and its contribution to the complexity of the disease are still poorly understood. By means of DNA methylation profiling of 248 breast tissues, we have highlighted the existence of previously unrecognized breast cancer groups that go beyond the currently known “expression subtypes”. Interestingly, we showed that DNA methylation profiling can reflect the cell type composition of the tumour microenvironment, and in particular a T lymphocyte infiltration of the tumours. Fur... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5217713 Thu, 01 Sep 2011 04:00:00 +0100 5217713 http://www.medworm.com/index.php?rid=5204220&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100179 AbstractThe migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase‐3 (GSK‐3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibers and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulfate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544‐treated mice. A variety of in vitro and in vivo ex... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5204220 Thu, 01 Sep 2011 04:00:00 +0100 5204220 http://www.medworm.com/index.php?rid=5191230&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190002 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5191230 Wed, 31 Aug 2011 23:00:00 +0100 5191230 http://www.medworm.com/index.php?rid=5191229&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100171 AbstractMicroRNAs (miRNAs) have been implicated in B cell lineage commitment, regulation of T cell differentiation, TCR signalling, regulation of IFN signalling, and numerous other immunological processes. However, their function in autoimmunity, and specifically in systemic lupus erythematosus (SLE), remains poorly understood. B6.Sle123 is a spontaneous genetic mouse model of SLE characterized by autoantibody production, lymphosplenomegaly, and glomerulonephritis. We identified several differentially regulated miRNAs in B and T lymphocytes of B6.Sle123 mice. We found that miR‐21 expression in lupus B and T cells is up‐regulated and that in vivo silencing of miR‐21 using a tiny seed‐targeting LNA reversed splenomegaly, one of the cardinal manifestations of autoimmunity in B6.Sle123... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5191229 Wed, 31 Aug 2011 23:00:00 +0100 5191229 http://www.medworm.com/index.php?rid=5191228&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100173 AbstractStaphylococcus aureus is an important human pathogen that can cause long‐lasting persistent infections. The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response. So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host. Here, we used an experimental mouse model to investigate the host response to persistent S. aureus infection. Our results demonstrated that T cells, which are critical for controlling S. aureus infection, gradually lost their ability to respond to antigenic stimulation and entered a state of anergy with the progression of infection towards persistence. The T cell hyporesponsiveness was reverted by co‐stimulation with the ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5191228 Wed, 31 Aug 2011 23:00:00 +0100 5191228 http://www.medworm.com/index.php?rid=5173939&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100170 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5173939 Sun, 28 Aug 2011 23:00:00 +0100 5173939 http://www.medworm.com/index.php?rid=5155702&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100161 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5155702 Thu, 18 Aug 2011 23:00:00 +0100 5155702 http://www.medworm.com/index.php?rid=5155701&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100166 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5155701 Thu, 18 Aug 2011 23:00:00 +0100 5155701 http://www.medworm.com/index.php?rid=5117135&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100162 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5117135 Mon, 08 Aug 2011 23:00:00 +0100 5117135 http://www.medworm.com/index.php?rid=5117134&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100160 AbstractThe innate immune system recognizes microbial components through pattern‐recognition receptors (PRRs), including membrane‐bound Toll‐like receptors and cytosolic receptors such as RIG‐I‐like receptors and deoxyribonucleic acid (DNA) sensors. These PRRs trigger distinct signal transduction pathways that culminate in induction of an array of cytokines and other mediators required for host defense. The tripartite motif (TRIM) family is a diverse family of RING finger domain‐containing proteins, which are involved in a variety of cellular functions. Importantly, recent studies have shown that they are also involved in the regulation of innate immune responses through the modulation of PRR signalling pathways. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5117134 Mon, 08 Aug 2011 23:00:00 +0100 5117134 http://www.medworm.com/index.php?rid=5094344&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100164 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5094344 Tue, 02 Aug 2011 23:00:00 +0100 5094344 http://www.medworm.com/index.php?rid=5173938&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100174 AbstractLafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin‐positive (PV+) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some proc... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5173938 Sun, 31 Jul 2011 23:00:00 +0100 5173938 http://www.medworm.com/index.php?rid=5155700&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100172 AbstractObesity is a well‐known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid‐related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorγ‐deficient mice is enhanced and obese Rorγ−/− mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ−/− mice are protected from hyperglycemia and insulin resistance in the state... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5155700 Sun, 31 Jul 2011 23:00:00 +0100 5155700 http://www.medworm.com/index.php?rid=5117133&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100163 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5117133 Sun, 31 Jul 2011 23:00:00 +0100 5117133 http://www.medworm.com/index.php?rid=5094345&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190001 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5094345 Sun, 31 Jul 2011 23:00:00 +0100 5094345 http://www.medworm.com/index.php?rid=5085276&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190001 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5085276 Sun, 31 Jul 2011 23:00:00 +0100 5085276 http://www.medworm.com/index.php?rid=5085275&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100157 AbstractAutism spectrum disorders (ASD) are important neuropsychiatric disorders, currently estimated to affect approximately 1% of children, with considerable emotional and financial costs. Significant collaborative effort has been made over the last 15 years in an attempt to unravel the genetic mechanisms underlying these conditions. This has led to important discoveries, both of the roles of specific genes, as well as larger scale chromosomal copy number changes. Here, we summarize some of the latest genetic findings in the field of ASD and attempt to link them with the results of pathophysiological studies to provide an overall picture of at least one of the mechanisms by which ASD may develop. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5085275 Sun, 31 Jul 2011 23:00:00 +0100 5085275 http://www.medworm.com/index.php?rid=5106130&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100168 AbstractThe Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium (Ep) and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumour suppressor (TS). In stark contrast, using various measures, we found that Runx3 expression is undetectable in GIT Ep. Employing a variety of biochemical and genetic techniques, including analysis of Runx3‐GFP and R26LacZ/Runx3Cre or R26tdTomato/Runx3Cre reporter strains, we readily detected Runx3 in GIT‐embedded leukocytes, dorsal root ganglia, skeletal elements and hair follicles. However, none ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5106130 Thu, 21 Jul 2011 23:00:00 +0100 5106130 http://www.medworm.com/index.php?rid=5048333&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100158 AbstractAcute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N‐terminus of the polypeptide. Among those, the N‐terminus of monocyte chemoattractant protein 1 (CCL2 and MCP‐1) is modified to a pyroglutamate (pE‐) residue protecting against degradation in vivo. Here, we show that the N‐terminal pE‐formation depends on glutaminyl cyclase activity. The pE‐residue increases stability against N‐terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso‐enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE1‐CCL2 formation and monocyte infi... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5048333 Tue, 19 Jul 2011 23:00:00 +0100 5048333 http://www.medworm.com/index.php?rid=5017863&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100154 AbstractLung cancer is the first cause of cancer mortality worldwide, and its early detection is currently the main available strategy to improve disease prognosis. While early diagnosis can be successfully achieved through tomography‐based population screenings in high‐risk individuals, simple methodologies are needed for effective cancer prevention programs. We developed a test, based on the detection of 34 microRNAs (miRNAs) from serum, that could identify patients with early stage non‐small cell lung carcinomas (NSCLCs) in a population of asymptomatic high‐risk individuals with 80% accuracy. The signature could assign disease probability accurately either in asymptomatic or symptomatic patients, is able to distinguish between benign and malignant lesions, and to capture the ons... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5017863 Sun, 10 Jul 2011 23:00:00 +0100 5017863 http://www.medworm.com/index.php?rid=5017862&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100153 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5017862 Sun, 10 Jul 2011 23:00:00 +0100 5017862 http://www.medworm.com/index.php?rid=5017865&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100155 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5017865 Thu, 07 Jul 2011 23:00:00 +0100 5017865 http://www.medworm.com/index.php?rid=5017864&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100152 AbstractEpithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive. Here, we investigated the expression and functional role of neural cell adhesion molecule (NCAM), a cell surface glycoprotein involved in brain development and plasticity, in EOC. NCAM is absent from normal ovarian epithelium but becomes highly expressed in a subset of human EOC, in which NCAM expression is associated with high tumour grade, suggesting a causal role in cancer aggressiveness. We demonstrate that NCAM stimulates EOC cell migration and invasion in vitro and promotes metastatic dissemination in mice. This pro‐malignant function of NCAM is mediated by its interaction with fibroblast g... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5017864 Thu, 07 Jul 2011 23:00:00 +0100 5017864 http://www.medworm.com/index.php?rid=5006363&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100156 AbstractBasal‐like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR−, PR−, Her2neu−). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal‐like breast tumours and identified Lysyl‐oxidase‐like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal‐like human breast carcinomas. Breast carcinoma cell lines with basal‐like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal‐like breast carcinomas. LOXL2 silenci... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5006363 Tue, 05 Jul 2011 23:00:00 +0100 5006363 http://www.medworm.com/index.php?rid=5057260&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100168 AbstractThe Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumor suppressor. In stark contrast, using various measures, we found that Runx3 expression is undetectable in GIT epithelium. Employing a variety of biochemical and genetic techniques, including analysis of Runx3‐GFP and R26LacZ/Runx3Cre or R26tdTomato/Runx3Cre reporter strains, we readily detected Runx3 in GIT‐embedded leukocytes, dorsal root ganglia, skeletal elements, and hair follicles. However, none of... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5057260 Thu, 30 Jun 2011 23:00:00 +0100 5057260 http://www.medworm.com/index.php?rid=5017861&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100165 AbstractT cell receptor (TCR) down‐modulation after antigen presentation is a fundamental process that regulates TCR signal transduction. Current understanding of this process is that intrinsic TCR/CD28 signal transduction leads to TCR down‐modulation. Here, we show that the interaction between Programmed cell death 1 ligand 1 (PD‐L1) on dendritic cells (DCs) and Programmed death 1 (PD‐1) on CD8 T cells contributes to ligand‐induced TCR down‐modulation. We provide evidence that this occurs via Casitas B‐lymphoma (Cbl)‐b E3 ubiquitin ligase up‐regulation in CD8 T cells. Interference with PD‐L1/PD‐1 signalling markedly inhibits TCR down‐modulation leading to hyper‐activated, proliferative CD8 T cells as assessed in vitro and in vivo in an arthritis model. PD‐L1 si... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=5017861 Thu, 30 Jun 2011 23:00:00 +0100 5017861 http://www.medworm.com/index.php?rid=4932321&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100148 AbstractThe recent EMBO Molecular Medicine Workshop on Cell Death and Disease was held this past March in the picturesque Alpen ski‐town of Obergurgl, Austria. Scientists working on diverse mechanisms and pathways of cell death convened to present and discuss their current research. Topics included not only cell death signalling pathways, their etiology in human disease, and potential avenues for therapeutic intervention, but also new approaches and perspectives for understanding the subtle mechanisms regulating cell fate. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4932321 Mon, 13 Jun 2011 23:00:00 +0100 4932321 http://www.medworm.com/index.php?rid=4910410&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100144 AbstractMorphine, heroin and other commonly abused opioids induce little mu opioid receptor (MOR) trafficking compared to endogenous opioids. We utilized knock‐in mice expressing a mutant recycling MOR (RMOR) that desensitizes and is internalized in response to morphine to show that facilitating MOR trafficking not only enhances morphine reward but, despite this, reduces the development of addiction‐like behaviours. To demonstrate this, we developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards. These behaviours emerged spontaneously in wild‐type but not RMOR mice, and their intensity predicted ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4910410 Tue, 07 Jun 2011 23:00:00 +0100 4910410 http://www.medworm.com/index.php?rid=4997158&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100159 AbstractA fat‐enriched diet modifies intestinal microbiota and initiates a low‐grade inflammation, insulin resistance, and type‐2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high‐fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This “metabolic bacteremia” is characterized by an increased co‐localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non‐pathogenic Escherichia coli. The bacterial translocati... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4997158 Tue, 31 May 2011 23:00:00 +0100 4997158 http://www.medworm.com/index.php?rid=4932320&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100151 AbstractMutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin (‘mini‐agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini‐agrin and anti‐apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini‐agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini‐agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdo... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4932320 Tue, 31 May 2011 23:00:00 +0100 4932320 http://www.medworm.com/index.php?rid=4910409&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100150 AbstractSecretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole‐genome data‐mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal‐type 1 (SPINK1) to be associated with poor survival in estrogen receptor‐positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER− cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down‐regulation of SPINK1 resulted i... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4910409 Tue, 31 May 2011 23:00:00 +0100 4910409 http://www.medworm.com/index.php?rid=4891622&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100143 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4891622 Tue, 31 May 2011 23:00:00 +0100 4891622 http://www.medworm.com/index.php?rid=4839747&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100145 AbstractSepsis is a deadly disease characterized by the inability to regulate the inflammatory–coagulation response in which the endothelium plays a key role. The cause of this perturbation remains poorly understood and has hampered the development of effective therapeutics. Matrix metalloproteases (MMPs) are involved in the host response to pathogens, but can also cause uncontrolled tissue damage and contribute to mortality. We found that human sepsis patients had markedly elevated plasma proMMP‐1 and active MMP‐1 levels, which correlated with death at 7 and 28 days after diagnosis. Likewise, septic mice had increased plasma levels of the MMP‐1 ortholog, MMP‐1a. We identified mouse MMP‐1a as an agonist of protease‐activated receptor‐1 (PAR1) on endothelial cells. MMP‐1a ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4839747 Tue, 17 May 2011 23:00:00 +0100 4839747 http://www.medworm.com/index.php?rid=4839746&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100147 AbstractThe differentiation of stem cells is a fundamental process in cell biology and understanding its mechanism might open a new avenue for therapeutic strategies. Using an ex vivo co‐culture system consisting of human primary haematopoietic stem and progenitor cells growing on multipotent mesenchymal stromal cells as a feeder cell layer, we describe here the exosome‐mediated release of small membrane vesicles containing the stem and cancer stem cell marker prominin‐1 (CD133) during haematopoietic cell differentiation. Surprisingly, this contrasts with the budding mechanism underlying the release of this cholesterol‐binding protein from plasma membrane protrusions of neural progenitors. Nevertheless, in both progenitor cell types, protein–lipid assemblies might be the essentia... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4839746 Tue, 17 May 2011 23:00:00 +0100 4839746 http://www.medworm.com/index.php?rid=4839745&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100146 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4839745 Tue, 17 May 2011 23:00:00 +0100 4839745 http://www.medworm.com/index.php?rid=4779727&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100137 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4779727 Mon, 02 May 2011 23:00:00 +0100 4779727 http://www.medworm.com/index.php?rid=4794238&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100149 AbstractTherapy of mitochondrial respiratory chain diseases is complicated by limited understanding of cellular mechanisms, which cause the widely variable clinical findings. Here, we show that focal segmental glomerulopathy‐like kidney disease in Pdss2 mutant animals with primary coenzyme Q deficiency is significantly ameliorated by oral treatment with probucol (1% wt/wt). Preventative effects in missense mutant mice are similar whether fed probucol from weaning or for three weeks prior to typical nephritis onset. Furthermore, treating symptomatic animals for two weeks with probucol significantly reduces albuminuria. Probucol has a more pronounced health benefit than high‐dose CoQ10 supplementation and uniquely restores CoQ9 content in mutant kidney. Probucol substantially mitigates t... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4794238 Sat, 30 Apr 2011 23:00:00 +0100 4794238 http://www.medworm.com/index.php?rid=4758170&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100139 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4758170 Tue, 26 Apr 2011 23:00:00 +0100 4758170 http://www.medworm.com/index.php?rid=4682902&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100136 We report here the involvement of miR‐146a and miR‐146b‐5p that bind to the same site in the 3′UTR of BRCA1 and down‐regulate its expression as demonstrated using reporter assays. This was further confirmed with the endogenous BRCA1 gene by transfecting microRNA (miRNA) precursors or inhibitors in mammary cell lines. This down‐regulation was accompanied by an increased proliferation and a reduced homologous recombination rate, two processes controlled by BRCA1. Furthermore, we showed that the highest levels of miR‐146a and/or miR‐146b‐5p are found in basal‐like mammary tumour epithelial cell lines and in triple negative breast tumours, which are the closest to tumours arising in carriers of BRCA1 mutations. This work provides further evidence for the involvement of miRN... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4682902 Mon, 04 Apr 2011 23:00:00 +0100 4682902 http://www.medworm.com/index.php?rid=4779728&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100142 AbstractIL‐28 (IFN‐λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL‐28 cytokine family members were found to be profoundly down‐regulated in allergic asthma. We now reveal a novel role of IL‐28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild‐type mice with recombinant or adenovirally expressed IL‐28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN‐γ. Moreover, abrogation of endogenous IL‐28 cytokine function in IL‐28Rα−/− mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL‐28A immunoregulatory activity was its capacity to m... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4779728 Sun, 03 Apr 2011 23:00:00 +0100 4779728 http://www.medworm.com/index.php?rid=4779729&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100141 AbstractImproved colonoscopy is revealing precancerous lesions that were frequently missed in the past, and ∼30% of those detected today have nonpolypoid morphologies ranging from slightly raised to depressed. To characterize these lesions molecularly, we assessed transcription of 23,768 genes in 42 precancerous lesions (25 slightly elevated nonpolypoid and 17 pedunculated polypoid), each with corresponding samples of normal mucosa. Nonpolypoid versus polypoid morphology explained most gene expression variance among samples; histology, size, and degree of dysplasia were also linked to specific patterns. Expression changes in polypoid lesions frequently affected cell‐cycling pathways, whereas cell‐survival dysregulation predominated in nonpolypoid lesions. The latter also displayed fe... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4779729 Thu, 31 Mar 2011 23:00:00 +0100 4779729 http://www.medworm.com/index.php?rid=4779726&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100140 We report that skin‐specific retroviral‐like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing p... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4779726 Thu, 31 Mar 2011 23:00:00 +0100 4779726 http://www.medworm.com/index.php?rid=4676031&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100142 AbstractIL‐28 (IFN‐λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL‐28 cytokine family members were found to be profoundly down‐regulated in allergic asthma. We now reveal a novel role of IL‐28 cytokines in inducing type 1 immunity and protecting from allergic airway disease. Treatment of wild‐type mice with recombinant or adenovirally‐expressed IL‐28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN‐γ. Moreover, abrogation of endogenous IL‐28 cytokine function in IL‐28Rα−/− mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL‐28A immunoregulatory activity was its capacity to... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4676031 Thu, 31 Mar 2011 23:00:00 +0100 4676031 http://www.medworm.com/index.php?rid=4630853&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100134 AbstractCold hypersensitivity is the hallmark of oxaliplatin‐induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over‐excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro‐excitatory channels such as the hyperpolarization‐activated channels (HCNs). These findings are corroborated by the analysis of TREK1‐TRAAK nul... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4630853 Thu, 24 Mar 2011 00:00:00 +0100 4630853 http://www.medworm.com/index.php?rid=4630852&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100135 AbstractKCNN3, encoding the small conductance calcium‐activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino‐terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for Schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype‐based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats re... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4630852 Thu, 24 Mar 2011 00:00:00 +0100 4630852 http://www.medworm.com/index.php?rid=4599916&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100131 We present evidence that such non‐canonical functions of the TSC‐Rheb signalling network exist, propose a standard of evidence for these non‐canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM). (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4599916 Wed, 16 Mar 2011 00:00:00 +0100 4599916 http://www.medworm.com/index.php?rid=4718967&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100138 We describe here the identification of a novel APP mutation E682K located at this β′‐site in an early onset Alzheimer's disease (AD) case. Functional analysis revealed that this E682K mutation blocked the β′‐site and shifted cleavage of APP to the β‐site, causing increased Aβ production. This work demonstrates the functional importance of APP processing at the β′‐site and shows how disruption of the balance between β‐ and β′‐site cleavage may enhance the amyloidogenic processing and consequentially risk for AD. Increasing exon‐ and exome‐based sequencing efforts will identify many more putative pathogenic mutations without conclusive segregation‐based evidence in a single family. Our study shows how functional analysis of such mutations allows to determine ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4718967 Thu, 10 Mar 2011 00:00:00 +0100 4718967 http://www.medworm.com/index.php?rid=4570054&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100128 AbstractSince the luminal B tumours are associated with poor recurrence‐free and disease‐specific survivals in all adjuvant systemic treatment categories including hormone therapy, the identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. Sircoulomb et al. and Holland et al. have independently identified the ZNF703 gene, located in chromosomal region 8p12, as preferentially amplified in luminal B tumours. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4570054 Thu, 10 Mar 2011 00:00:00 +0100 4570054 http://www.medworm.com/index.php?rid=4570053&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100132 AbstractSequence‐specific knockdown of gene expression is a goal that has been long sought by both basic and clinical investigators. In this regard, the discovery of RNA interference (RNAi) in Caenorhabditis elegans was immediately recognized as a potential breakthrough for studying gene function (Fire et al, 1998). These findings demonstrated that double‐stranded (ds)RNAs are triggers for sequence‐specific, post‐transcriptional gene silencing via targeted degradation of messenger RNAs harbouring a complementary sequence to one of the two strands. Initially, it was thought that such post‐transcriptional regulation of gene expression could not be achieved in mammalian systems due to the strong induction of interferon by dsRNAs. This potential restriction was short lived with the d... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4570053 Thu, 10 Mar 2011 00:00:00 +0100 4570053 http://www.medworm.com/index.php?rid=4549334&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100127 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4549334 Fri, 04 Mar 2011 00:00:00 +0100 4549334 http://www.medworm.com/index.php?rid=4663252&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100141 AbstractImproved colonoscopy is revealing precancerous lesions that were frequently missed in the past, and ∼30% of those detected today have nonpolypoid morphologies ranging from slightly raised to depressed. To characterize these lesions molecularly, we assessed transcription of 23,768 genes in 42 precancerous lesions (25 slightly‐elevated nonpolypoid, 17 pedunculated polypoid), each with corresponding samples of normal mucosa. Nonpolypoid versus polypoid morphology explained most gene expression variance among samples; histology, size, and degree of dysplasia were also linked to specific patterns. Expression changes in polypoid lesions frequently affected cell‐cycling pathways, whereas cell‐survival dysregulation predominated in nonpolypoid lesions. The latter also displayed few... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4663252 Tue, 01 Mar 2011 00:00:00 +0100 4663252 http://www.medworm.com/index.php?rid=4570052&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100138 We describe here the identification of a novel APP mutation E682K located at this β'‐site in an early‐onset Alzheimer's disease (AD) case. Functional analysis revealed that this E682K mutation blocked the β'‐site and shifted cleavage of APP to the β‐site, causing increased Aβ production. This work demonstrates the functional importance of APP processing at the β'‐site and shows how disruption of the balance between β‐ and β'‐ site cleavage may enhance the amyloidogenic processing and consequentially risk for AD. Increasing exon‐ and exome‐based sequencing efforts will identify many more putative pathogenic mutations without conclusive segregation‐based evidence in a single family. Our study shows how functional analysis of such mutations allows determining the po... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4570052 Tue, 01 Mar 2011 00:00:00 +0100 4570052 http://www.medworm.com/index.php?rid=4535498&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201190000 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4535498 Tue, 01 Mar 2011 00:00:00 +0100 4535498 http://www.medworm.com/index.php?rid=4521525&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100123 AbstractStaphylococcus aureus small colony variants (SCVs), which are characterized by slow growth and a range of morphological and metabolic changes including altered antibiotic resistance profiles, have been studied for several decades. This Closeup highlights findings described in this issue of EMBO Molecular Medicine by Tuchscherr et al (2011), who present strong evidence that SCVs can arise in chronic infection models when S. aureus is internalized in non‐professional phagocytes and survives intracellularly. As the intracellular residency time increases, the proportion of SCVs grows and the host cell inflammatory response diminishes. The study suggests that this mode of phenotype switching is an essential feature of the S. aureus infection process and can explain an underlying cause... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4521525 Fri, 25 Feb 2011 00:00:00 +0100 4521525 http://www.medworm.com/index.php?rid=4559362&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100130 AbstractThe promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes mTOR‐HIF1α‐VEGF signalling in hypoxia. To determine the relevance of PML‐mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre‐tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TO... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4559362 Thu, 17 Feb 2011 00:00:00 +0100 4559362 http://www.medworm.com/index.php?rid=4549335&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100129 AbstractAutologous haematopoietic stem cell transplantation is highly efficient for the treatment of systemic autoimmune diseases, but its consequences for the immune system remain poorly understood. Here, we describe an optimized RNA‐based technology for unbiased amplification of T cell receptor beta‐chain libraries and use it to perform the first detailed, quantitative tracking of T cell clones during 10 months after transplantation. We show that multiple clones survive the procedure, contribute to the immune response to activated infections, and form a new skewed and stable T cell receptor repertoire. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4549335 Wed, 16 Feb 2011 00:00:00 +0100 4549335 http://www.medworm.com/index.php?rid=4488801&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100129 AbstractAutologous hematopoietic stem cell transplantation is highly efficient for the treatment of systemic autoimmune diseases, but its consequences for the immune system remain poorly understood. Here, we describe an optimized RNA‐based technology for unbiased amplification of T cell receptor beta‐chain libraries and use it to perform the first detailed, quantitative tracking of T cell clones during 10 months after transplantation. We show that multiple clones survive the procedure, contribute to the immune response to activated infections, and form a new skewed and stable T cell receptor repertoire. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4488801 Wed, 16 Feb 2011 00:00:00 +0100 4488801 http://www.medworm.com/index.php?rid=4488803&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100121 AbstractLuminal B breast cancers represent a fraction of oestrogen receptor (ER)‐positive tumours associated with poor recurrence‐free and disease‐specific survival in all adjuvant systemic treatment categories including hormone therapy alone. Identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. We have studied 100 luminal breast tumours by combined analysis of genome copy number aberrations and gene expression. We show that amplification of the ZNF703 gene, located in chromosomal region 8p12, preferentially occurs in luminal B tumours. We explored the functional role of ZNF703 in luminal B tumours by overexpressing ZNF703 in the MCF7 luminal cell line. Using mass spectrometry, we identified ZNF703 as a co‐factor of a nuclear c... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4488803 Tue, 15 Feb 2011 00:00:00 +0100 4488803 http://www.medworm.com/index.php?rid=4488802&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100124 AbstractHyaline Fibromatosis Syndrome (HFS) is a human genetic disease caused by mutations in the anthrax toxin receptor 2 (or cmg2) gene, which encodes a membrane protein thought to be involved in the homeostasis of the extracellular matrix. Little is known about the structure and function of the protein or the genotype–phenotype relationship of the disease. Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level. Altogether, we show that missense mutations that map to the extracellular von Willebrand domain or the here characterized Ig‐like domain of CMG2 lead to folding defects and thereby to retention of the mutated protein in the endoplasmic reticulum (ER). Mutations in the Ig‐like domain prevent proper disulphide ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4488802 Tue, 15 Feb 2011 00:00:00 +0100 4488802 http://www.medworm.com/index.php?rid=4549336&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100126 We report on the use of barrier modulation in tandem with systemic drug therapy to prevent retinal degeneration and to suppress laser‐induced choroidal neovascularization (CNV), the latter being the hallmark pathology associated with the exudative, or wet, form of age‐related macular degeneration (AMD). These observations constitute the basis of a minimally invasive systemic therapeutic modality for retinal diseases, including retinitis pigmentosa and AMD, where, in early stage disease, the iBRB is intact and impervious to systemically administered drugs.→See accompanying Closeup by Rossi DOI 10.1002/emmm.201100132 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4549336 Fri, 11 Feb 2011 00:00:00 +0100 4549336 http://www.medworm.com/index.php?rid=4531485&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100133 We describe that, as consequence of fiber damage, specific muscle‐miRNAs are released in the bloodstream of DMD patients and that their levels correlate with the severity of the disease. The same miRNAs are abundant also in the blood of mdx mice and recover to wild type levels in animals “cured” through the exon skipping. Even though Creatine Kinase (CK) blood levels have been utilized as diagnostic markers of several neuromuscular diseases, including DMD, we demonstrate that they correlate less well with the severity of the disease. Even though the analysis on a larger number of patients should allow to obtain more refined correlations with the different stages of disease progression, we propose that miR‐1, miR‐133 and miR‐206, are new and valuable biomarkers for the diagnosis... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4531485 Tue, 01 Feb 2011 00:00:00 +0100 4531485 http://www.medworm.com/index.php?rid=4488800&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100130 AbstractThe promyelocytic leukemia gene PML is a pleiotropic tumor suppressor. We have recently demonstrated that PML opposes mTOR‐HIF1α‐VEGF signaling in hypoxia. To determine the relevance of PML‐mTOR antagonism in tumorigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre‐tumoral kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumor progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 ac... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4488800 Tue, 01 Feb 2011 00:00:00 +0100 4488800 http://www.medworm.com/index.php?rid=4464064&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100126 We report on the use of barrier modulation in tandem with systemic drug therapy to prevent retinal degeneration and to suppress laser‐induced‐choroidal‐neovascularisation (CNV), the latter being the hallmark pathology associated with the exudative, or wet form of age‐related macular degeneration (AMD). These observations constitute the basis of a minimally invasive systemic therapeutic modality for retinal diseases, including retinitis pigmentosa and AMD, where, in early stage disease, the iBRB is intact and impervious to systemically administered drugs. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4464064 Tue, 01 Feb 2011 00:00:00 +0100 4464064 http://www.medworm.com/index.php?rid=4398888&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000116 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398888 Wed, 26 Jan 2011 00:00:00 +0100 4398888 http://www.medworm.com/index.php?rid=4398887&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000118 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398887 Wed, 26 Jan 2011 00:00:00 +0100 4398887 http://www.medworm.com/index.php?rid=4398886&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000115 AbstractStaphylococcus aureus is a frequent cause for serious, chronic and therapy‐refractive infections in spite of susceptibility to antibiotics in vitro. In chronic infections, altered bacterial phenotypes, such as small colony variants (SCVs), have been found. Yet, it is largely unclear whether the ability to interconvert from the wild‐type to the SCV phenotype is only a rare clinical and/or just laboratory phenomenon or is essential to sustain an infection. Here, we performed different long‐term in vitro and in vivo infection models with S. aureus and we show that viable bacteria can persist within host cells and/or tissues for several weeks. Persistence induced bacterial phenotypic diversity, including SCV phenotypes, accompanied by changes in virulence factor expression and au... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398886 Wed, 26 Jan 2011 00:00:00 +0100 4398886 http://www.medworm.com/index.php?rid=4398885&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000120 This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398885 Wed, 26 Jan 2011 00:00:00 +0100 4398885 http://www.medworm.com/index.php?rid=4398884&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000117 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398884 Wed, 26 Jan 2011 00:00:00 +0100 4398884 http://www.medworm.com/index.php?rid=4398883&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000121 AbstractLuminal B breast cancers represent a fraction of ER‐positive tumors associated with poor recurrence‐free and disease‐specific survivals in all adjuvant systemic treatment categories including hormone therapy alone. Identification of specific signaling pathways driving luminal B biology is paramount to improve treatment. We have studied 100 luminal breast tumors by combined analysis of genome copy number aberrations and gene expression. We show that amplification of the ZNF703 gene, located in chromosomal region 8p12, preferentially occurs in luminal B tumors. We explored the functional role of ZNF703 in luminal B tumors by overexpressing ZNF703 in the MCF7 luminal cell line. Using mass spectrometry, we identified ZNF703 as a cofactor of a nuclear complex comprising DCAF7, PHB... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398883 Wed, 26 Jan 2011 00:00:00 +0100 4398883 http://www.medworm.com/index.php?rid=4382014&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000110 AbstractRetroviral pre‐integration complexes (PICs) provide a most efficient mechanism to integrate foreign DNA into cellular chromatin. This has made retrovirus‐based vectors a preferred tool for gene delivery in therapeutic settings where the chromosomal integration of a recombinant expression cassette that encodes a protein of interest can lead to a long‐lasting correction of monogenetic diseases (so‐called gene addition strategy). However, the efficiency of retroviral gene addition comes at the expense of a lack of precision in the choice of the integration site. Insertional mutagenesis with potential activation of proto‐oncogenes as a first hit in a multistep scenario of cancer development thus represents one of the major hurdles to a more widespread exploration of gene‐ba... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4382014 Fri, 21 Jan 2011 00:00:00 +0100 4382014 http://www.medworm.com/index.php?rid=4370430&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000114 AbstractDefects in the repair of deoxyribonucleic acid (DNA) damage underpin several hereditary neurological diseases in humans. Of the different activities that repair chromosomal DNA breaks, defects in resolving damaged DNA termini are among the most common causes of neuronal cell death. Here, the molecular mechanisms of some of the DNA end processing activities are reviewed and the association with human neurodegenerative disease is discussed. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4370430 Wed, 19 Jan 2011 00:00:00 +0100 4370430 http://www.medworm.com/index.php?rid=4398889&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000119 AbstractDespite the recent success of gene‐based complementation approaches for genetic recessive traits, the development of therapeutic strategies for gain‐of‐function mutations poses great challenges. General therapeutic principles to correct these genetic defects mostly rely on post‐transcriptional gene regulation (RNA silencing). Engineered zinc‐finger (ZF) protein‐based repression of transcription may represent a novel approach for treating gain‐of‐function mutations, although proof‐of‐concept of this use is still lacking. Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors. The strategy was designed to suppress both the mutated and the wild‐type hRHO allele in a... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398889 Fri, 07 Jan 2011 00:00:00 +0100 4398889 http://www.medworm.com/index.php?rid=4418525&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201100122 AbstractThe telomeric amplicon at 8p12 is common in estrogen receptor positive (ER+) breast cancers. Array‐CGH and expression analyses of 1172 primary breast tumors revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF‐7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human bre... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4418525 Sat, 01 Jan 2011 00:00:00 +0100 4418525 http://www.medworm.com/index.php?rid=4398882&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000125 AbstractMycobacterium bovis Bacille Calmette‐Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α‐1,2‐oligomannoside. Both systemic and intratracheal challenge of mice with M. tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer‐term survival. Persis... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4398882 Sat, 01 Jan 2011 00:00:00 +0100 4398882 http://www.medworm.com/index.php?rid=4322088&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000119 AbstractDespite the recent success of gene‐based complementation approaches for genetic recessive traits, the development of therapeutic strategies for gain‐of‐function mutations poses great challenges. General therapeutic principles to correct these genetic defects mostly rely on post‐transcriptional gene regulation (RNA silencing). Engineered zinc‐finger‐protein‐based repression of transcription may represent a novel approach for treating gain‐of‐function mutations, although proof‐of‐concept of this use is still lacking. Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors. The strategy was designed to suppress both the mutated and the wild‐type hRHO allele in a mu... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4322088 Sat, 01 Jan 2011 00:00:00 +0100 4322088 http://www.medworm.com/index.php?rid=4308996&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000109 AbstractOculopharyngeal muscular dystrophy (OPMD) is an adult‐onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6‐aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We s... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4308996 Sat, 01 Jan 2011 00:00:00 +0100 4308996 http://www.medworm.com/index.php?rid=4284668&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000111 AbstractCopy number variations (CNV) within the genome are extremely abundant. In this closeup, Canales and Walz discuss how CNV are associated with normal variation, genomic disorders, genome evolution, adaptive traits and how the use of a novel screen described by Ermakova et al in this issue that is designed to identify human disease‐relevant phenotypes associated with CNV in the mouse can help elucidating susceptibility or predisposition to diseases loci.See related article in EMBO Molecular Medicine by Olga Ermakova et al: http://dx.doi.org/10.1002/emmm.201000112 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4284668 Thu, 23 Dec 2010 00:00:00 +0100 4284668 http://www.medworm.com/index.php?rid=4376994&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000113 We report here that this is in part mediated by the release of the anti‐inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2‐26 significantly reduced IL‐6 signalling and the release of TNF‐α from endotoxin‐challenged monocytes. Ac2‐26 activated STAT3 in a JAK‐dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2‐26‐mediated inhibition of IL‐6 signalling. This identifies annexin A1 as part of the anti‐inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti‐inflammator... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4376994 Fri, 17 Dec 2010 00:00:00 +0100 4376994 http://www.medworm.com/index.php?rid=4257997&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000105 This study was designed to assess whether heat shock protein Hsp72 is an early and sensitive biomarker of acute kidney injury (AKI) as well as to monitor a renoprotective strategy. Seventy‐two Wistar rats were divided into six groups: sham‐operated and rats subjected to 10, 20, 30, 45 and 60 min of bilateral ischemia (I) and 24 h of reperfusion (R). Different times of reperfusion (3, 6, 9, 12, 18, 24, 48, 72, 96 and 120 h) were also evaluated in 30 other rats subjected to 30 min of ischemia. Hsp72 messenger RNA (mRNA) and protein levels were determined in both kidney and urine. Hsp72‐specificity as a biomarker to assess the success of a renoprotective intervention was evaluated in rats treated with different doses of spironolactone before I/R. Renal Hsp72 mRNA and protein, as... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4257997 Tue, 14 Dec 2010 00:00:00 +0100 4257997 http://www.medworm.com/index.php?rid=4264338&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000113 We report here that this is in part mediated by the release of the anti‐inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2‐26 significantly reduced IL‐6 signaling and the release of TNF‐α from endotoxin‐challenged monocytes. Ac2‐26 activated STAT3 in a JAK‐dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2‐26‐mediated inhibition of IL‐6 signaling. This identifies annexin A1 as part of the anti‐inflammatory pattern of apoptotic cells and links the activation of formyl peptide receptors to established signaling pathways triggering anti‐... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4264338 Wed, 01 Dec 2010 00:00:00 +0100 4264338 http://www.medworm.com/index.php?rid=4248530&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090007 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4248530 Wed, 01 Dec 2010 00:00:00 +0100 4248530 http://www.medworm.com/index.php?rid=4248529&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090006 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4248529 Wed, 01 Dec 2010 00:00:00 +0100 4248529 http://www.medworm.com/index.php?rid=4248528&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000106 AbstractFocal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a fundamental role in integrin and growth factor mediated signalling and is an important player in cell migration and proliferation, processes vital for angiogenesis. However, the role of FAK in adult pathological angiogenesis is unknown. We have generated endothelial‐specific tamoxifen‐inducible FAK knockout mice by crossing FAK‐floxed (FAKfl/fl) mice with the platelet derived growth factor b (Pdgfb)‐iCreER mice. Tamoxifen‐treatment of Pdgfb‐iCreER;FAKfl/fl mice results in FAK deletion in adult endothelial cells (ECs) without any adverse effects. Importantly however, endothelial FAK‐deletion in adult mice inhibited tumour growth and reduced tumour angiogenesis. Furthermore, in in vivo angiogenic ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4248528 Wed, 01 Dec 2010 00:00:00 +0100 4248528 http://www.medworm.com/index.php?rid=4248527&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000112 AbstractThe identification of susceptibility genes for human disease is a major goal of current biomedical research. Both sequence and structural variation have emerged as major genetic sources of phenotypic variability and growing evidence points to copy number variation as a particularly important source of susceptibility for disease. Here we propose and validate a strategy to identify genes in which changes in dosage alter susceptibility to disease‐relevant phenotypes in the mouse. Our approach relies on sensitized phenotypic screening of megabase‐sized chromosomal deletion and deficiency lines carrying altered copy numbers of ∼30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the fe... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4248527 Wed, 01 Dec 2010 00:00:00 +0100 4248527 http://www.medworm.com/index.php?rid=4212889&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000104 AbstractPolyglutamine expansions in huntingtin (Htt) are known to cause the profound neurodegenerative disorder, Huntington's disease (HD). Mitochondrial dysfunction has long been implicated in the pathophysiology of HD, but the underlying mechanism remains obscure. An article by Costa et al in this months edition describes a smooth mechanistic cascade from the well‐accepted upstream event that mutant Htt is associated with Ca2+ handling abnormalities, through to apoptotic neuronal death. The proposed cascade implicates calcineurin, activated by abnormal Ca2+ levels, in the dephosphorylation of dynamin‐1‐like protein (Drp1), increasing its association with mitochondria and promoting fission, cristae disruption, cytochrome c release and apoptosis (Fig 1). Together with the recent repo... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4212889 Mon, 29 Nov 2010 00:00:00 +0100 4212889 http://www.medworm.com/index.php?rid=4264339&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000107 AbstractThe forkhead box M1b (FoxM1b) transcription factor is over‐expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over‐expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf‐null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial–mesenchymal transition, cell motility, invasion and a pre‐metastatic niche formation. FoxM1b activates the Akt‐Snail1 pathway and stimulates expr... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4264339 Mon, 22 Nov 2010 00:00:00 +0100 4264339 http://www.medworm.com/index.php?rid=4212888&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000108 AbstractThe analysis of genomic distribution of retroviral vectors is a powerful tool to monitor “vector‐on‐host” effects in gene therapy (GT) trials but also provides crucial information about “host‐on‐vector” influences based on target cell genetic and epigenetic state. We had the unique occasion to compare the insertional profile of the same therapeutic MLV‐vector in the context of the ADA‐SCID genetic background in two GT trials based on infusions of transduced mature lymphocytes (PBL) or a single infusion of hematopoietic stem/progenitor cells (HSC). We found that vector insertions are cell‐specific according to differential expression profile of target cells, favouring, in PBL‐GT, genes involved in immune system and T cell functions\pathways as well as T‐cel... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4212888 Mon, 01 Nov 2010 00:00:00 +0100 4212888 http://www.medworm.com/index.php?rid=4189334&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000107 AbstractThe forkhead box M1b (FoxM1b) transcription factor is over‐expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over‐expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf‐null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial‐mesenchymal transition, cell motility, invasion and a pre‐metastatic niche formation. FoxM1b activates the Akt‐Snail1 pathway and stimulates expr... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4189334 Mon, 01 Nov 2010 00:00:00 +0100 4189334 http://www.medworm.com/index.php?rid=4149837&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000102 In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.See accompanying Closeup by Oliveira and Lightowlers DOI 10.1002/emmm.201000104. (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4149837 Mon, 01 Nov 2010 00:00:00 +0100 4149837 http://www.medworm.com/index.php?rid=4117090&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000101 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4117090 Mon, 25 Oct 2010 23:00:00 +0100 4117090 http://www.medworm.com/index.php?rid=4096029&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000100 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4096029 Thu, 21 Oct 2010 23:00:00 +0100 4096029 http://www.medworm.com/index.php?rid=4149838&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000103 AbstractApoptosis signal‐regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen‐activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll‐like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1‐p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE‐induced autoimmune inflammation in both spinal cords and optic nerves. These results sugg... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4149838 Fri, 15 Oct 2010 00:00:00 +0100 4149838 http://www.medworm.com/index.php?rid=4064610&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000099 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4064610 Tue, 12 Oct 2010 23:00:00 +0100 4064610 http://www.medworm.com/index.php?rid=4073001&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000103 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4073001 Thu, 30 Sep 2010 23:00:00 +0100 4073001 http://www.medworm.com/index.php?rid=4064609&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000098 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4064609 Thu, 30 Sep 2010 23:00:00 +0100 4064609 http://www.medworm.com/index.php?rid=4011569&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000097 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4011569 Mon, 27 Sep 2010 23:00:00 +0100 4011569 http://www.medworm.com/index.php?rid=4011568&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000096 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=4011568 Tue, 31 Aug 2010 23:00:00 +0100 4011568 http://www.medworm.com/index.php?rid=3891485&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000094 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3891485 Sun, 22 Aug 2010 23:00:00 +0100 3891485 http://www.medworm.com/index.php?rid=3888685&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000092 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3888685 Thu, 19 Aug 2010 23:00:00 +0100 3888685 http://www.medworm.com/index.php?rid=3888684&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000091 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3888684 Thu, 19 Aug 2010 23:00:00 +0100 3888684 http://www.medworm.com/index.php?rid=3880288&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000093 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3880288 Tue, 17 Aug 2010 23:00:00 +0100 3880288 http://www.medworm.com/index.php?rid=3880287&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000090 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3880287 Tue, 17 Aug 2010 23:00:00 +0100 3880287 http://www.medworm.com/index.php?rid=3880286&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000089 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3880286 Tue, 17 Aug 2010 23:00:00 +0100 3880286 http://www.medworm.com/index.php?rid=3871932&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000095 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3871932 Sat, 31 Jul 2010 23:00:00 +0100 3871932 http://www.medworm.com/index.php?rid=3861428&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090004 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3861428 Sat, 31 Jul 2010 23:00:00 +0100 3861428 http://www.medworm.com/index.php?rid=3853951&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000088 Abstract (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3853951 Sat, 31 Jul 2010 23:00:00 +0100 3853951 http://www.medworm.com/index.php?rid=3853950&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201090005 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3853950 Sat, 31 Jul 2010 23:00:00 +0100 3853950 http://www.medworm.com/index.php?rid=3805433&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000086 Gene therapy is one potential novel therapeutic avenue for the treatment of inherited monogenic disorders. Diseases of the blood are frequent targets for gene therapy because it is relatively easy to harvest haematopoiesis stem cells (HSCs) from the bone marrow, genetically modify the cells ex vivo, and then re-administer the corrected cells back into the patient via intra-venous injection. In this Closeup, Milsom and Williams discuss the work of Roselli et al, who describe the pre-clinical evaluation of the treatment for [beta]-thalassemia in erythroid cells via the genetic correction of patient HSCs using a lentiviral vector.See related article in EMBO Mol Med (Roselli et al. (2010) EMBO Mol Med 2: 315-328) (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3805433 Fri, 30 Jul 2010 23:00:00 +0100 3805433 http://www.medworm.com/index.php?rid=3853947&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000086 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3853947 Thu, 29 Jul 2010 23:00:00 +0100 3853947 http://www.medworm.com/index.php?rid=3805434&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000087 The first EMBO workshop on Emerging Themes in Infection Biology was held last June in the South of France. It gathered scientists working on various pathogens from viruses and bacteria to larger eukaryotic fungi and parasites. Topics included not only the crosstalk between pathogens and their hosts but also the tools researchers are using to study and image such cellular and molecular conversations.So it is said that if you know your enemies and know yourself, you can win a hundred battles without a single lossThe Art of War, Sun Tzu (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3805434 Thu, 29 Jul 2010 23:00:00 +0100 3805434 http://www.medworm.com/index.php?rid=3779951&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000085 The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. Of particular interest are cytokines and growth factors, which control different phases of liver regeneration. Historically, their potential functions in this process were addressed by analyzing their expression in the regenerating liver of rodents. Some of the predicted roles were confirmed using functional studies, including systemic delivery of recombinant growth factors, neutralizing antibodies or siRNAs prior to liver injury or during liver ... EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3779951 Thu, 22 Jul 2010 23:00:00 +0100 3779951 http://www.medworm.com/index.php?rid=3775800&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000082 We report that ablation or overexpression of PrPC had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrPC as a mediator of A[beta] toxicity.See accompanying article: . (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3775800 Wed, 21 Jul 2010 23:00:00 +0100 3775800 http://www.medworm.com/index.php?rid=3853949&cid=s_38725_67_f&fid=38725&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Femmm.201000082 (Source: EMBO Molecular Medicine) EMBO Molecular Medicine journals http://www.medworm.com/rss/comments.php?id=3853949 Tue, 20 Jul 2010 23:00:00 +0100 3853949