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The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours 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 clinical 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 MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.

Familial hypertrophic cardiomyopathy (HCM) is largely caused by dominant mutations in genes encoding cardiac sarcomeric proteins, and it is etiologically distinct from secondary cardiomyopathies resulting from pressure/volume overload and neurohormonal or inflammatory stimuli. Here, we demonstrate that decreased left ventricular contractile function in male, but not female, HCM mice is associated with reduced fatty acid translocase (CD36) and AMP-activated protein kinase (AMPK) activity. As a result, the levels of myocardial ATP and triglyceride (TG) content are reduced, while the levels of oleic acid and TG in circulating very low density lipoproteins (VLDLs) and liver are increased. With time, these metabolic changes culminate in enhanced glucose production in male HCM mice. Remarkably, restoration of ventricular TG and ATP deficits via AMPK agonism as well as inhibition of gluconeogenesis improves ventricular architecture and function. These data underscore the importance of the systemic effects of a primary genetic heart disease to other organs and provide insight into potentially novel therapeutic interventions for HCM.

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression.

Mutations in the XRCC4 gene have been recently identified through whole-exome sequencing (WES). While the overall clinical presentation of the patients (severe short stature, microcephaly, gonadal failure) generally conforms with what is expected for the defect of a critical non-homologous end-joining (NHEJ) DNA repair factor, the absence of consequence on the proper development of the immune system is rather surprising, given the role of NHEJ in V(D)J recombination. Several hypotheses can be envisioned to explain this discrepancy. Overall, these findings highlight the power of WES in identifying new molecular causes for human diseases while providing with new exciting scientific question to address.

The gastrointestinal tract is a principal route of entry and site of persistence of human immunodeficiency virus type 1 (HIV-1). The intestinal mucosa, being rich of cells that are the main target of the virus, represents a primary site of viral replication and CD4(+) T-cell depletion. Here, we show both in vitro and ex vivo that HIV-1 of R5 but not X4 phenotype is capable of selectively triggering dendritic cells (DCs) to migrate within 30 min between intestinal epithelial cells to sample virions and transfer infection to target cells. The engagement of the chemokine receptor 5 on DCs and the viral envelope, regardless of the genetic subtype, drive DC migration. Viruses penetrating through transient opening of the tight junctions likely create a paracellular gradient to attract DCs. The formation of junctions with epithelial cells may initiate a haptotactic process of DCs and at the same time favour cell-to-cell viral transmission. Our findings indicate that HIV-1 translocation across the intestinal mucosa occurs through the selective engagement of DCs by R5 viruses, and may guide the design of new prevention strategies.

Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-‘high-risk’ sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34high and CD34low blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia. See accompanying article http://dx.doi.org/10.1002/emmm.201202207

Secreted 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-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading. ispartof: EMBO Molecular Medicine vol:4 issue:3 pages:234-50 ispartof: location:England status: published

The 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 similar to 30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the feasibility of such a screen, we performed sensitized phenotyping in five therapeutic areas (metabolic syndrome, immune dysfunction, atherosclerosis, cancer and behaviour) of a 0.8 Mb reciprocal chromosomal duplication and deficiency on chromosome 11 containing 27 genes. Gene dosage in the region significantly affected risk for high-fat diet-induced metabolic syndrome, antigen-induced immune hypersensitivity, ApoE-induced atherosclerosis, and home cage activity. Follow up studies on individual gene knockouts for two candidates in the region showed that copy number variation in Stat5 was responsible for the phenotypic variation in antigen-induced immune hypersensitivity and metabolic syndrome. These data demonstrate the power of sensitized phenotypic screening of segmental aneuploidy lines to identify disease susceptibility genes.

5'AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.

Inositol-requiring 1 (IRE1)/X-box-binding protein 1 (XBP1)-mediated signalling represents the most conserved branch of the unfolded protein response. A series of recent studies reveal novel and potentially ancient roles for this pathway in the coordination of metabolic and immune responses.

Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na(+):Cl(-) cotransporter (NCC) and Na(+):K(+):2Cl(-) cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WNKs. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in messenger RNA (mRNA) levels. On a normal Na(+)-diet, the SPAK knock-in mice were normokalaemic, but developed mild hypokalaemia when the renin-angiotensin system was activated by a low Na(+)-diet. These observations establish that SPAK plays an important role in controlling blood pressure in mammals. Our results imply that SPAK inhibitors would be effective at reducing blood pressure by lowering phosphorylation as well as expression of NCC and NKCC2. See accompanying Closeup by Maria Castañeda-Bueno and Gerald Gamba (DOI 10.1002/emmm.200900059).

Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (Abeta42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Abeta-like peptides (APL1beta) that are generated by beta- and gamma-cleavages at a concentration of approximately 4.5 nM. These novel peptides, APL1beta25, APL1beta27 and APL1beta28, were not deposited in AD brains. Interestingly, most gamma-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Abeta42 cause a parallel increase in the production of APL1beta28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1beta28 levels are higher than in non-AD controls, while the relative Abeta42 levels are unchanged or lower. Most strikingly, the relative APL1beta28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1beta28 in the CSF as a candidate surrogate marker for the relative level of Abeta42 production in the brain.

It is generally accepted that a distinguishing property of stem cells (SCs), as compared to their more differentiated progenitors, is that of infrequent division, often referred to as ‘quiescence’. As regards hematopoietic stem cells (HSC), their resistance to antiproliferative drugs supports this notion. Maintenance of quiescence is thought to be critical for the preservation of HSCs' function.

The neurodevelopmental disorder Williams-Beuren syndrome is caused by spontaneous approximately 1.5 Mb deletions comprising 25 genes on human chromosome 7q11.23. To functionally dissect the deletion and identify dosage-sensitive genes, we created two half-deletions of the conserved syntenic region on mouse chromosome 5G2. Proximal deletion (PD) mice lack Gtf2i to Limk1, distal deletion (DD) mice lack Limk1 to Fkbp6, and the double heterozygotes (D/P) model the complete human deletion. Gene transcript levels in brain are generally consistent with gene dosage. Increased sociability and acoustic startle response are associated with PD, and cognitive defects with DD. Both PD and D/P males are growth-retarded, while skulls are shortened and brains are smaller in DD and D/P. Lateral ventricle (LV) volumes are reduced, and neuronal cell density in the somatosensory cortex is increased, in PD and D/P. Motor skills are most impaired in D/P. Together, these partial deletion mice replicate crucial aspects of the human disorder and serve to identify genes and gene networks contributing to the neural substrates of complex behaviours and behavioural disorders.

Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.

Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.

Iron-sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.

International audience; There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy.

Antibiotic therapy in patients currently treated with corticosteroids is common in chronic respiratory diseases when exacerbation symptoms attributable to infection appear. Among them, obstructive diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health issues affecting hundreds of million people worldwide that are frequently treated with inhaled corticosteroids. Systemic corticosteroids are also used for idiopathic pulmonary fibrosis, a less prevalent chronic respiratory disease. In this issue of EMBO Molecular Medicine, Earl et al (2015) report a potentially baleful relationship between steroid and antibiotic treatment in chronic respiratory diseases, affecting colonization persistence and antibiotic tolerance for Haemophilus influenzae, one of the leading potentially pathogenic microorganisms (PPMs) of the respiratory system.

As tuberculosis (TB) toll is revised upward according to the WHO's last estimates, the lack of vaccine strategy and the lengthy antibiotic treatments that unfortunately promote the emergence of drug resistance are a major set back in the fight against this pathogen. In this issue of EMBO Molecular Medicine, Schiebler et al (Mtb) propose a novel and compelling new approach to target Mycobacterium tuberculosis (Mtb) by pharmacologically stimulating intracellular mycobacteria clearance through autophagy.

Ca2+ signalling plays a critical role in almost every cell type of the immune system—T cells, B cells, NK cells, macrophages and mast cells. Intracellular Ca2+ signals in immunology have importance in both the short term and long term function of these cells. Short term functions like release of cytotoxic granules with inflammatory mediators, immune synapse formations and long term functions like cell differentiation, expression and proliferation are all regulated to various degrees by intracellular Ca2+ signals. Store operated calcium entry (SOCE) is one of the critical modulators of the Ca2+ signals that control these processes. The importance of SOCE in normal immune physiology has already been demonstrated in families with mutations in STIM1, STIM2 and Orai1 who demonstrate a severe immunodeficiency that causes bacterial, viral and fungal infections (Picard et al, 2009). Alterations in the immune system due to changes in Ca2+ homeostasis has spiked interest in studying the role of SOCE in another critical function of the immune system—anticancer immunity. Relatively little is known about SOCE and its role in oncology and the evidence gathered so far seems to suggest that it is both important in tumour detection as well as tumour growth (Prevarskaya et al, 2011). Mouse models have shown that STIM1 and Orai1 expression is critical for breast cell tumour migration and metastasis (Yang et al, 2009). Other work in human prostate cancer cells has shown that normal expression of Orai1 and SOCE are critical in maintaining the rate of apoptosis and thus, resistance to prostate cancer (Flourakis et al, 2010). Given the conflicting nature of the research in the role of SOCE in cancer immunity, it is necessary to appreciate that Ca2+ regulates a variety of complex immune functions, not all of which are cancer protective. More importantly, delineating …

Despite the encouraging results with enzyme replacement therapy for several lysosomal storage diseases (LSDs), successful delivery of enzyme to brain to correct central nervous system (CNS) storage has been an elusive target (Grubb et al, 2010). In that regard, the paper by Sorrentino et al (2013) in this issue is a major breakthrough. It is likely to generate widespread interest and have a large impact on research in the field. Why is this work so important? Most of the LSDs have some element of CNS involvement. In many of them, like Sanfilippo disease type IIIA, CNS involvement is the dominant feature (Rozaklis et al, 2011). Correction of this aspect of LSDs that profoundly affects brain and leads to progressive neurological deterioration has posed the greatest challenge. Successfully meeting that challenge is a big deal! > Why is this work so important? Most of the LSDs have some element of CNS involvement. In many of them, like Sanfilippo disease type IIIA, CNS involvement is the dominant feature. Correction of this aspect of LSDs that profoundly affects brain and leads to progressive neurological deterioration has posed the greatest challenge. Successfully meeting that challenge is a big deal! Access of corrective enzyme to lysosomes in cells of most tissues relies on receptor‐mediated endocytosis, by the ubiquitously expressed mannose‐6‐phosphate (Man‐6‐P) receptor and mannose receptors on cells of the macrophage lineage. Cells in the CNS have limited access to enzymes targeting these receptors. Indeed, the blood–brain barrier (BBB) effectively blocks access of such proteins except in the perinatal period. In the mouse, access to Man‐6‐P receptors on the brain capillaries is limited to the …

Acute exacerbations are the major cause of morbidity, mortality and healthcare costs for individuals with asthma. They are the main cause of hospitalizations and are poorly controlled by current medication. It is therefore disappointing that we still know so little about the mechanistic details of asthma exacerbations. In this issue of EMBO Molecular Medicine , Bartlett et al. suggest that the transcription factor NF‐κB, and specifically its subunit p65, is a key determinant of acute exacerbations of asthma, and propose a molecular dichotomy in the regulation of pro‐inflammatory versus antiviral responses in asthmatic individuals that is mediated by p65 NF‐κB and the type I interferon (IFN) system (Bartlett et al, 2012). Asthma exacerbations are mostly triggered by respiratory infections of which rhinoviruses (RV), ssRNA viruses of the Picornaviridae family that cause common cold, are the most frequent (Busse et al, 2010). Other respiratory tract infections that can also trigger exacerbations include influenza, parainfluenza and respiratory syncytial virus in children. Asthmatic patients have increased susceptibility to respiratory infections, especially of the lower respiratory tract, and respiratory infections cause in turn more severe episodes of dyspnoea and wheezing in these patients. Presence of allergic sensitization further increases the risk for infections, the severity of exacerbations and the chances for hospital admission compared to non‐sensitized asthmatic individuals. It is therefore essential to understand the complex interplay between sensitivity to infections, viral clearance and exacerbation of asthmatic inflammation in order to pave the way for the development of novel therapeutics.. . .it is possible to dissociate antiviral from pro‐inflammatory responses simply by inhibiting the p65 subunit of NF‐κB. . . To explain virus‐induced exacerbations, several hypotheses have been advanced that attribute asthma attacks to immune‐mediated exacerbations, direct viral injury, or both (Jackson et al, 2011). Virus infections can fuel innate and adaptive …

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201201689 ‘The Great White Plague, which only 10 years ago was thought to be immune to drug therapy, is gradually being eliminated. . . Streptomycin pointed a way. Later supplemented with PAS (para‐amino salicylic acid) and more recently with isoniazid, it has brought the control of this disease within sight’. Selman A. Waksman, Noble Prize Banquet Speech 1952. Despite the breakthroughs in management of tuberculosis noted by Waksman 8 years after his discovery of the first effective antitubercular drug, streptomycin (Schatz et al, 1944), the disease continues to infect, incapacitate and kill in the 21st century. Over 8.8 million are infected and 1.4 million die every year (www.who.int/mediacentre/factsheets/fs104/en/index.html). The organism that causes tuberculosis, Mycobacterium tuberculosis , has proven to be a formidable match for our ability to control disease. At the core of this challenge is the remarkable physiology and biochemistry of M. tuberculosis and its ability to reside in a dormant state within human macrophages. These unique characteristics necessitate multidrug therapy, typically ≥4 antibiotics, and extended periods of dosing (6–12 months). The rise of strains resistant to multiple drugs MDR (multi‐drug‐resistant) resistant to rifampin and isoniazid, XDR (extensive‐drug‐resistant) resistant to even more antibiotics, and now some strains totally impervious to all available drugs, TDR (totally drug‐resistant) raises the specter of the emergence of a global health care disaster and a return to a pre‐Waksman era of tuberculosis treatment (Zumla et al, 2012). The result is a great need for new therapies and a renewed effort to find new anti‐TB antibiotics. The result is a great need for new therapies …

Diabetes mellitus is a disorder resulting from lack of either production or action of insulin signalling. It affects more than 200 million people worldwide. There is no cure for diabetes and the patients rely on exogenous supply of insulin and/or oral use of hypoglycemic substances. Type I diabetes results from the destruction of pancreatic insulin‐producing beta cells in the islets of Langerhans, usually through an autoimmune reaction, while type II diabetes is associated with dysfunctional beta cells. Thus, diabetes presents an ideal model for cell therapy, since it is the lack of a single defined cell type that is largely responsible for the disease pathology. Transplantation of isolated islets or entire pancreases from cadavers to replenish the lost beta cell pool has yielded some promising results. However, limited availability of the islets, side effects of continuous immunosuppressant administration and the logistics of finding suitable donors have proven major setbacks. In the absence of an ex vivo culture system to expand pancreatic progenitors, alternative sources of beta cells have attracted great attention (Mishra et al, 2010). The discovery of stem cells which have virtually unlimited self‐renewal and multi‐differentiation potential raised great expectations for their use in regenerative medicine. Isolation and cultivation of pancreas stem cells as renewable sources of beta cells would be a major breakthrough Isolation and cultivation of pancreas stem cells as renewable sources of beta cells would be a major breakthrough. . .although their presence in the adult human pancreas remains controversial. Recent studies have highlighted the possible use of embryonic stem (ES) cells and induced pluripotent stem (iPS) cells as the source. ES cells are derived from the early developing embryo and can generate all differentiated cell types of the adult organism, including beta cells. Major ethical and logistical concerns regarding their use in the …

Typical haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy, leading to severe renal disease as well as life‐threatening extrarenal complications. HUS is primarily caused by infections with enterohaemorrhagic Escherichia coli (EHEC) and 5–20% of EHEC infections result in HUS. EHEC bacteria produce several virulence factors, of which Shiga toxins are believed to play a central role. About 10% of all HUS cases are not caused by E. coli and are thus termed atypical HUS. These are observed as familial or sporadic forms and are most commonly caused by a dysregulation of the alternative pathway of the complement system due to inherited mutations of, or acquired auto‐antibodies against, complement regulator proteins. The, thereby, impaired control of complement, which plays a prominent role in the humoral immune system and in immune homeostasis, leads to a hyperactive state, including activation of endothelial cells and platelets, inflammation of small vessel and eventually to the destruction of the kidney and other organs (summarized in Orth et al, 2009). Lapeyraque et al have published the successful use of the licensed terminal complement C5 inhibitor eculizumab for the treatment of severe Shiga toxin‐associated HUS in three 3‐year‐old children with devastating prognoses (Lapeyraque et al, 2011). The three patients continued to show progression of the HUS despite having received multiple plasma exchanges. Treatment with eculizumab markedly improved their clinical status, in particular their neurological and renal functions, after two to four administrations of this complement inhibitor. Dialysis was reported to be discontinued after 3–16 days in all three patients. Recovery was attributed to eculizumab and absence of mutations of complement proteins …

See related article in The New England Journal of Medicine http://dx.doi.org/10.1056/NEJMoa1101324

Results of the RV144 study of a prime‐boost regimen combining a canarypox vector‐based candidate ALVAC‐HIV (vCP1521) and AIDSVAX B/E gp120 human immunodeficiency virus (HIV) envelope showed a modest but statistically significant 31% reduction in the rate of HIV infection in healthy volunteers (Rerks‐Ngarm et al, 2009). These promising results need to be confirmed in further clinical trials and researchers are hoping to gain more information about the correlates of protection against HIV and the mechanisms of action of these vaccines. In addition, from a clinical standpoint, the RV144 study provides two interesting pieces of information. First, at the end of the first year of the study the rate of protection was up to 60% in vaccinees compared to placebo recipients. Second, no differences in terms of peak of viral load were seen between vaccinated and placebo recipients who became infected. This suggests that the protective efficacy wanes overtime and that vaccines were unable to control viral replication once a systemic infection is established. The immune system controls pathogens through the generation of memory T cells, which can be divided in, at least, two populations of central and effector memory T cells (Tcm and Tem) ensuring protection for years after the first encounter of the pathogen. Following antigen exposure, Tcm undergone expansion, differentiation towards effector cells, which patrol mucosal tissues, the site of entry of HIV and kill infected cells. Clearly, the initial hours following exposure of HIV to mucosal tissues represents a window of opportunity for the immune system to control and/or to eliminate smaller and localized foci of HIV‐infected cells. Therefore, an effective vaccine must confer to the host the capability to win the race between the differentiation capacity of Tcm and the extraordinary burst of HIV replication, which occurs within hours before the establishment of an irreversible disseminated …

The identification of the genetic factors that influence susceptibility to neuropsychiatric illness has proven challenging. Currently, several approaches are being utilized to enhance the potential of these studies. Most commonly, a ‘discovery’ genome wide association study (GWAS) with a focus on a single clinical diagnostic group such as schizophrenia, with subsequent replication in independent cohorts is the standard for the field. A major challenge for this approach is the necessity for increasingly large sample sizes, presumably due to modest effect sizes and genetic heterogeneity, with commensurate increased heterogeneity of study samples. A complementary approach is to seek support for genetic loci by collecting additional phenotypic data, often termed endophenotypes, which suggest that specific genetic variants have significant effects on key biological or clinical parameters that are more closely linked to gene function. For example, studies demonstrating that a putative schizophrenia risk variant in ZNF804A influences phenotypes assessing brain structure or function as measured by neuroimaging or neurocognitive studies (Esslinger et al, 2009; Lencz et al, 2010). In this issue of EMBO Molecular Medicine, Grube et al (2011) report on a variant of this approach, the so‐called phenotype‐based genetic association study (PGAS). These authors tested the relationship of genetic variation in the KCNN3 gene; a gene that codes for the calcium‐activated potassium channel SK3, previously implicated in cognitive function (Blank et al, 2003), but only inconsistently linked with schizophrenia, to a number of …

Staphylococcus 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 auxotrophism. However, the recovered SCV phenotypes were highly dynamic and rapidly reverted to the fully virulent wild-type form when leaving the intracellular location and infecting new cells. Our findings demonstrate that bacterial phenotype switching is an integral part of the infection process that enables the bacteria to hide inside host cells, which can be a reservoir for chronic and therapy-refractive infections.

Retroviral 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-based treatments (Kustikova et al, 2010). To date, four clinical trials were reported to be associated with severe adverse reactions induced by insertional mutagenesis in haematopoietic stem and progenitor cells (HSC/P); two targeting the X-linked form of severe combined immunodeficiency (SCID-X1), one targeting chronic granulomatous disease, and most recently another trial exploring gene therapy for the Wiskott–Aldrich-Syndrome. In contrast, in the SCID caused by mutations in the gene encoding the metabolic enzyme adenosine deaminase (ADA), retroviral gene addition so far has been free of such complications. Furthermore, numerous trials using similar gene vectors to transfer genes into mature T cells have not been complicated by clonal outgrowth. This explains the great interest in a deeper understanding of retroviral vector–host interactions in the therapeutic setting of SCID-ADA.

The survival of higher organisms requires constant vigilance against encroachment by potentially pathogenic microorganisms. Every portal of entry, and every potential niche, must be defended simultaneously against a wide spectrum of invaders. Each of these invaders – whether symbiotic or potentially pathogenic – has adopted their own cunning strategy to avoid detection and elimination, and to hijack the host's nutritional resources and metabolic apparatus to multiply and spread. In response to these threats humans have evolved a bewildering array of innate and adaptive defenses of which our knowledge is still only in its infancy. Among the innate defenses are mechanisms designed to withhold nutritional resources from the invaders and, of all the nutrients, iron is by far the most critical. It lies at the epicenter of most host‐pathogen battles for resource control; it is the equivalent of crude oil in global geopolitics. But 32% of the earth's crust is composed of iron (and 88% of its core) making it the most abundant element on the planet, so why should it be the subject of such blatant avarice? And what is the evidence that it is the focus of a fierce arms race between host and pathogen? The avarice is generally explained by the very low solubility of iron compounds in their usual oxidized ferric state and by the usefulness of iron's redox potentials, which make it a suitable co‐factor for numerous enzymes and pathways. The evidence for its centrality in host‐pathogen competition comes, inter alia , from the following sources: (i) most bacteria have made a disproportionate genetic investment in processes for iron acquisition; (ii) many of these genes are concentrated in islands of high pathogenicity, are important in defining niche specificity, and …

Sequence-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 demonstration that endonuclease processed dsRNAs of 21–25 nucleotides in length, designated small interfering RNAs (siRNAs), were able to elicit sequence-specific degradation of mRNAs in mammalian cells without triggering interferon responses (Elbashir et al, 2001). These findings provided a huge impetus to develop RNAi as a therapeutic modality. The dream to selectively block the expression of deleterious proteins and treat formerly non-drugable diseases led to the rapid establishment of new biotech companies and branches of major pharmaceutical companies devoted to RNAi therapeutics.

2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic-like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl-CpG-binding domain protein 5 (MBD5), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene-trap mouse model. Our study indicates that the Mbd5+/GT mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5+/GT mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion-associated behavioral and cognitive symptoms. Subject Categories Genetics, Gene Therapy & Genetic Disease; Neuroscience

Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.

Mutations in mitochondrial DNA are an important cause of human disease and from a therapeutic standpoint, these disorders are currently untreatable. New studies now show that a non-cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt-tRNA mutation and that the isolated carboxy-terminal domain of human mt-leucyl tRNA synthetase can ameliorate the pathologic phenotype. See also: HT Hornig-Do et al (February 2014) and E Perli et al (February 2014)

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.

High mobility group box 1 (HMGB1) is a molecular alarm signal that triggers an immune response when released. It was assumed that the receptor for advanced glycation end-products (RAGE) would mediate the signal to the immune system. Recently pattern recognition receptors that are triggered by molecules of bacterial origin (the Toll-like receptor (TLR) family) were shown to also respond to HMGB1. Now two papers establish the TLR4-HMGB1 axis as proinflammatory, eventually leading to disparate conditions like seizures or skin cancer. These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1.

Targeted cancer therapy requires the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. We sought to develop a high-throughput genotyping platform that would allow prospective patient selection to the best available therapies, and that could readily and inexpensively be adopted by most clinical laboratories. We developed a highly sensitive multiplexed clinical assay that performs very well with nucleic acid derived from formalin fixation and paraffin embedding (FFPE) tissue, and tests for 120 previously described mutations in 13 cancer genes. Genetic profiling of 250 primary tumours was consistent with the documented oncogene mutational spectrum and identified rare events in some cancer types. The assay is currently being used for clinical testing of tumour samples and contributing to cancer patient management. This work therefore establishes a platform for real-time targeted genotyping that can be widely adopted. We expect that efforts like this one will play an increasingly important role in cancer management.

Incorporation of locally produced signaling molecules into cellderived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro ,A 2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil–endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.

Shah et al have recently reported the first successful sequencing of the entire genome of a solid tumour (Shah et al, 2009). Philippe Bedard and Christos Sotiriou analyse their findings as well as the challenges of applying the study of cancer genomes to clinical cancer care., Journal Article, SCOPUS: sh.j, info:eu-repo/semantics/published

Loud sound exposure is a significant cause of hearing loss worldwide. We asked whether a lack of vezatin, an ubiquitous adherens junction protein, could result in noise-induced hearing loss. Conditional mutant mice bearing non-functional vezatin alleles only in the sensory cells of the inner ear (hair cells) indeed exhibited irreversible hearing loss after only one minute exposure to a 105 dB broadband sound. In addition, mutant mice spontaneously underwent late onset progressive hearing loss and vestibular dysfunction related to substantial hair cell death. We establish that vezatin is an integral membrane protein with two adjacent transmembrane domains, and cytoplasmic N- and C-terminal regions. Late recruitment of vezatin at junctions between MDCKII cells indicates that the protein does not play a role in the formation of junctions, but rather participates in their stability. Moreover, we show that vezatin directly interacts with radixin in its actin-binding conformation. Accordingly, we provide evidence that vezatin associates with actin filaments at cell-cell junctions. Our results emphasize the overlooked role of the junctions between hair cells and their supporting cells in the auditory epithelium resilience to sound trauma.

Cardiosphere-derived cells (CDCs) have been shown to regenerate infarcted myocardium in patients after myocardial infarction (MI). However, whether the cells of the newly formed myocardium originate from the proliferation of adult cardiomyocytes or from the differentiation of endogenous stem cells remains unknown. Using genetic fate mapping to mark resident myocytes in combination with long-term BrdU pulsing, we investigated the origins of postnatal cardiomyogenesis in the normal, infarcted and cell-treated adult mammalian heart. In the normal mouse heart, cardiomyocyte turnover occurs predominantly through proliferation of resident cardiomyocytes at a rate of ∼1.3–4%/year. After MI, new cardiomyocytes arise from both progenitors as well as pre-existing cardiomyocytes. Transplantation of CDCs upregulates host cardiomyocyte cycling and recruitment of endogenous progenitors, while boosting heart function and increasing viable myocardium. The observed phenomena cannot be explained by cardiomyocyte polyploidization, bi/multinucleation, cell fusion or DNA repair. Thus, CDCs induce myocardial regeneration by differentially upregulating two mechanisms of endogenous cell proliferation.

Atherosclerosis, the leading cause of death in Westernized countries, derives from a non‐resolving inflammation of the large arteries. A critical step in the initiation of an atherosclerotic plaque is the expansion of intimal space (the area between the endothelial cell (EC) lining and the medial smooth muscle cell layer) in susceptible regions of arteries (Tabas et al, 2007). The disease‐prone locations are largely determined by arterial blood flow characteristics, with branch points and the lesser curvatures of arteries, where the flow is turbulent, being particularly disposed to plaque formation. At these sites, the normally thin intimal space expands with the deposition of extracellular matrix (ECM), which then serves as a sticky surface to trap LDL particles that are constantly crossing the endothelial layer to enter the artery. One reason for this retention is that the apoB100 molecule on the LDL particle has a specific domain that binds tightly to the ECM, and genetic causation studies in a mouse model of atherosclerosis have shown that when this domain is deleted, plaque burden is significantly reduced despite equivalent hyperlipidemia (Skalen et al, 2002). As implied by the ‘Response to Retention’ hypothesis (Tabas et al, 2007), the retained lipoprotein particles set in motion the invasion of the arterial wall by monocytes that quickly become macrophages that engorge themselves on cholesterol and the other lipids to form foam cells. Foam cells not only physically expand the plaque, but by secreting a variety of chemokines and cytokines, they also create and amplify an inflammatory state (Fig 1). Figure 1. Plasma derived FN promotes atherogenesis in mouse models of atherosclerosis. pFN, synthesized in the liver, is deposited in susceptible regions of the arteries and contributes to early atherosclerotic lesion formation and the recruitment of smooth muscle cells that shape the fibrous cap of advanced lesions (upper panel). …

There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms9 tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated – NCAM1 expressing – “blastema” phenotype, including a capacity to expand and differentiate into the mature renal‐like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR‐200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. →See accompanying article http://dx.doi.org/10.1002/emmm.201202173

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100199 In a rich and comprehensive piece of work, Ferone et al report in this issue of EMBO Molecular Medicine the first mouse model of the AEC (Ankyloblepharon‐Ectodermal defects‐Cleft lip/palate, OMIM 106260) syndrome (Ferone et al, 2012). The mechanistic insights are of likely general relevance for a number of conditions resulting from deranged keratinocyte growth control, including cancer. AEC is part of a group of genetic syndromes with compromised skin development that go under the general name of ectodermal dysplasias (EDs). These are caused by mutations of genes with disparate functions, including transcription factors like p63. This close cousin of p53 plays a key role in ectodermal development as first demonstrated by the lack of stratified epithelia and their adnexa in mice with homozygous deletion of the gene. Importantly, no such alterations occur in mice with heterozygous p63 deletion, which are phenotypically normal. In the human population, at least five ED malformation syndromes have been linked to p63 gene mutations (Rinne et al, 2006). These are heterozygous missense mutations likely to cause the disorders by interfering with the function of wild type p63, which controls transcription by binding to DNA in a tetrameric form (Crum & McKeon, 2010). p63 can be produced in multiple isoforms as the result of transcription from two different promoters and differential splicing. The predominant p63 isoform expressed in stratified epithelia is ΔNp63α, which contains, in its C‐terminus region, asterile‐alpha‐motif (SAM) domain thought to be mediating interactions with other proteins and, possibly, lipid or RNA molecules (Crum & McKeon, 2010). The different ED syndromes result from p63 mutations that tend to cluster at different locations (Rinne et al, 2006). The AEC syndrome is mostly caused by mutations in the p63 …

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C‐reactive protein, >10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01–0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour‐induced cachexia in rats or intra‐peritoneal injection of lipopolysaccharide in mice. P‐selectin was found to be significantly upregulated in muscle in both models. Identification of P‐selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia. Open Access article. Published by Wiley Open Access 2012.