British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

Experimental Evaluation of Polyphenylsulfone (PPSF) Powders as Fire-Retardant Materials for Processing by Selective Laser Sintering.

Additive manufacturing has progressed rapidly, and the unique attributes of the layer-wise material consolidation are attracting ever increasing application potentials in critical sectors such as medical and aerospace industries. A lack of materials options has been the main bottleneck for the much wider uptake of these promising new technologies. Inventing new material alternatives has been central to most of the research attention in additive manufacturing in recent times. The current research is focused on evaluating the polyphenylsulfone polymer powders for the first time as fire-resistant candidate materials for processing by selective laser sintering, the most promising additive processing method for polymeric material systems. Experimental evaluations were undertaken based on a selective laser sintering test bed. Single layer and multi-layer samples were produced for microstructural and mechanical characterisations. The microstructural evaluations and the mechanical property results indicate sufficient intra- and inter-layer consolidation together with reasonable tensile property responses. The lower viscosity and thermal conductivity characteristics rendered lower tensile strengths, which will require some further attention in the future, for better consolidation and mechanical properties.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.

BACKGROUND: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. This study explored DPYD*9A genotype and clinical phenotype correlation in patients with gastrointestinal (GI) malignancies treated with fluoropyrimidines. METHODS: Between 2011 and 2017, 67 patients with GI malignancies were genotyped for DPYD variants. Fluoropyrimidines-associated toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Fisher's exact test was used for statistical analysis. RESULTS: DPYD variants were identified in 17 out of 67 (25%) patients. One patient was homozygous for DPYD*9A variant and one patient was double heterozygous for DPYD*9A and DPYD*9B variants. In patients with identified DPYD variants, 13/17 (76%) patients had DPYD*9A variant, 3/17 (18%) patients had DPYD*2A variant and 2/17 (12%) patient had DPYD*9B variant. Only patients genotyped prior to 2015 were genotyped for DPYD*9A variant (N=28). Of those, 13/28 patients (46%) had DPYD*9A variant. Grade 3-4 diarrhea was associated with DPYD*9A variant in patients treated with full dose fluoropyrimidines (P=0.0055). CONCLUSIONS: In our cohort, DPYD*9A variant was the most common diagnosed variant. The correlation between DPYD*9A genotype and DPD deficiency in clinical phenotype was noticeable in patients who received full dose fluoropyrimidines as they all experienced grade 3-4 toxicities (diarrhea).

Propiedades biológicas de los alérgenos inhalatorios y su relación con la respuesta inmunitaria / Biological properties of inhalant aeroallergens and their relation to immune responses

IgE-binding studies show that many of the common causes of inhalant allergy such as grass, olive, ragweed and birch pollen, house dust mites and some fungi have one or a few principal allergens that can account for most of the allergic response. The IgE binding to allergens from other sources can be more evenly spread amongst different proteins or, as indicated in cat allergy, varies with clinical presentation. The biological properties of nearly all of the principal allergens can now be predicted from the knowledge of their structures and they point to likely interactions with the innate immune system, as well as possible interactions with hormonal regulators of immunity. As found for pectate lyases and the Ole e1-like proteins, biologically similar proteins can be principal allergens for many species while the Dermatophagoides spp. and Blomia tropicalis allergens show that allergens with the same biological properties reveal interspecies variation in allergen hierarchy. These properties show that the interactions of allergens with innate immunity and immuno-regulators will be different for different allergens, and this concurs with the evidence that immune responses to allergens from the same source are regulated independently, as are responses to co-presented allergenic and non-allergenic proteins

Los estudios de unión con la IgE demostraron que muchas de las causas comunes de alergia inhalatoria, como a las gramíneas, el olivo, la ambrosía, el polen de abedul, los ácaros del polvo doméstico y algunos hongos, tienen uno o unos pocos de los alérgenos principales que pueden representar la mayoría de las respuestas alérgicas. La IgE que se une a los alérgenos de otras fuentes puede diseminarse entre diferentes proteínas o, como indica la alergia al gato, varía con la presentación clínica. Las propiedades biológicas de casi todos los alérgenos principales pueden actualmente predecirse a partir del conocimiento de sus estructuras e indican las interacciones probables con el sistema inmunitario innato, así como las interacciones posibles con los reguladores hormonales de la inmunidad. Como se encontró para las pectato liasas y las proteínas similares a Ole e1, las proteínas biológicamente similares pueden ser los alérgenos principales para muchas especies, mientras que los alérgenos Dermatophagoides spp. y Blomia tropicalis muestran que los alérgenos con las mismas propiedades biológicas tienen variación entre las especies en la jerarquía alergénica. Estas propiedades demuestran que las interacciones de los alérgenos con la inmunidad innata y los inmunorreguladores serían diferentes para los distintos alérgenos, y esto coincide con las pruebas que indican que las respuestas inmunes a los alérgenos de la misma fuente sufren una regulación por aumento (upregulation), independientemente de si son respuestas a las proteínas co-presentadas alergénicas y no alergénicas

Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale.

The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high-frequency administration may be more appropriate.

Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series.

INTRODUCTION: Knee osteoarthritis is associated with persistent joint pain, stiffness, joint deformities, ligament damage, and surrounding muscle atrophy. The complexity of the disease makes treatment difficult. There are no therapeutic drugs available to halt the disease progression, leaving patients dependent on pain medication, anti-inflammatory drugs, or invasive joint replacement surgery. CASE PRESENTATIONS: Four patients with a history of unresolved symptomatic knee osteoarthritis were investigated for the therapeutic outcome of combining an exercise rehabilitation program with intra-articular injections of autologous StroMed (ie, stromal vascular fraction cells concentrated by ultrasonic cavitation from lipoaspirate) and platelet-rich plasma (PRP). The Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) was administered along with physical function tests over a 12-month period. The first patient achieved a maximum therapeutic outcome of 100 in all five KOOS subscales (left knee), and 100 for four subscales (right knee). The second patient scored 100 in all five KOOS subscales (left knee), and greater than 84 in all subscales (right knee). Treatment of the third patient resulted in improved outcomes in both knees of >93 for four KOOS subscales, and 60 for the Function in Sport and Recreation subscale. The fourth patient improved to 100 in all five KOOS subscales. In all patients, the physical function "Get-up and Go" test and "Stair Climbing Test" returned to normal (a value of zero). CONCLUSION: This case series indicates that improved outcomes may be obtained when autologous stromal vascular fraction (StroMed) cell therapy is combined with traditional exercise practices and PRP for osteoarthritis. Of the seven joints treated: all patients' scores of pain improved to >96; and quality of life scores to >93. Functional performance measures of mobility returned to normal. This simple treatment appears to be extremely effective for osteoarthritis disorders that have no drug treatment to halt disease progression.

Improving immunity to Haemophilus influenzae in children with chronic suppurative lung disease.

BACKGROUND: Endobronchial infections related to non-typeable Haemophilus influenzae (NTHi) are common in children and adults with suppurative airway disease such as bronchiectasis and COPD. Impaired cell mediated immune responses to NTHi have been described in these patients. Currently there are no interventions known to correct the deficiency in cell mediated immune responses to NTHi. The aim of this study was to determine if receipt of a conjugate vaccine containing protein D from H. influenzae is associated with improvement in NTHi-specific cytokine responses in children with chronic suppurative lung disease. METHODS: Blood mononuclear cells from 107 young children with chronic suppurative lung disease and 32 healthy control children were stimulated in vitro with NTHi. We compared the cytokine production of stimulated mononuclear cells from children who had received the pneumococcal H. influenzae protein D conjugate vaccine with cells from children who received pneumococcal vaccines without protein D. Protein D-specific IgG1 was quantified in plasma. RESULTS: Children with chronic suppurative lung disease who received ≥ 3 doses of the protein D conjugate vaccine produced significantly more IFNγ than children who received the alternative vaccines without protein D (median 939 versus 338 pg/ml; p = 0.007). Importantly, the amount of IFNγ produced by those vaccinated with the conjugate vaccine approached the levels observed in cells from healthy children. The conjugate vaccine was also associated with small but significant increases in IL-13 (p < 0.001) and IL-5 (p = 0.007). Protein D-specific IgG1 levels correlated with the number of PHiD-CV doses (p = 0.02). CONCLUSION: Vaccination with PHiD-CV is associated with improvements in NTHi-specific cell-mediated and humoral immune responses in children with chronic suppurative lung disease.

Migraine and tension-type headache treated with stromal vascular fraction: a case series.

INTRODUCTION: Chronic migraines and tension-type headaches are debilitating diseases affecting 1.4 to 2.2% of the population with both quality of life and economic implications. To date, the pain associated with migraine and tension-type headaches has been controlled with a range of medications, with varying levels of success. In addition, the side-effect profile of these medications, as well as their potential for addiction, has been a cause for concern for both patients and physicians. CASE PRESENTATIONS: Four women with long histories of migraine or frequent tension-type headache that meet the International Classification of Headache Disorders criteria for Chronic Migraine or Tension-type Headaches were given a systemic treatment(s) of autologous stromal vascular fraction or autologous 'StroMed' isolated from lipoaspirate. StroMed is stromal vascular fraction cells prepared by ultrasonic cavitation. Two of the four patients, both of whom are Arab women aged 40 and 36 years, ceased having migraines after 1 month, for a period of 12 to 18 months. The third patient, a Slavic woman aged 43 years, had a significant decrease in the frequency and severity of migraines with only seven migraines over 18 months. The fourth patient, an Asian woman aged 44 years, obtained a temporary decrease for a period of a month and was retreated 18 months later and has been free of migraines to date for 1 month. Pain medication was typically reduced from prescribed opioid analgesia to non-steroidal anti-inflammatory drugs and paracetamol. CONCLUSIONS: This case series is the first to provide evidence of the efficacy of autologous StroMed and stromal vascular fraction in the treatment of migraine and tension-type headache. The treatment of this disease by stromal vascular fraction adds a new dimension to its clinical applicability and suggests a relatively simple treatment that may help address the symptoms of the disease. Given what is known about the components of the stromal vascular fraction and how they act, the information presented in this case series may also further our knowledge of the etiology and pathophysiology of migraine and tension-type headaches. This treatment is simple, looks to be extremely effective and has been life changing for these patients.

Species-specific and cross-reactive IgG1 antibody binding to viral capsid protein 1 (VP1) antigens of human rhinovirus species A, B and C.

BACKGROUND: Human rhinoviruses (HRV) are associated with upper and lower respiratory illnesses, including severe infections causing hospitalization in both children and adults. Although the clinical significance of HRV infections is now well established, no detailed investigation of the immune response against HRV has been performed. The purpose of this study was to assess the IgG1 antibody response to the three known HRV species, HRV-A, -B and -C in healthy subjects. METHODS: Recombinant polypeptides of viral capsid protein 1 (VP1) from two genotypes of HRV-A, -B and -C were expressed as glutathione S-transferase (GST) fusion proteins and purified by affinity and then size exclusion chromatography. The presence of secondary structures similar to the natural antigens was verified by circular dichroism analysis. Total and species-specific IgG1 measurements were quantitated by immunoassays and immunoabsorption using sera from 63 healthy adults. RESULTS: Most adult sera reacted with the HRV VP1 antigens, at high titres. As expected, strong cross-reactivity between HRV genotypes of the same species was found. A high degree of cross-reactivity between different HRV species was also evident, particularly between HRV-A and HRV-C. Immunoabsorption studies revealed HRV-C specific titres were markedly and significantly lower than the HRV-A and HRV-B specific titres (P<0.0001). A truncated construct of HRV-C VP1 showed greater specificity in detecting anti-HRV-C antibodies. CONCLUSIONS: High titres of IgG1 antibody were bound by the VP1 capsid proteins of HRV-A, -B and -C, but for the majority of people, a large proportion of the antibody to HRV-C was cross-reactive, especially to HRV-A. The improved specificity found for the truncated HRV-C VP1 indicates species-specific and cross-reactive regions could be defined.

Hypoallergenic Der p 1/Der p 2 combination vaccines for immunotherapy of house dust mite allergy.

BACKGROUND: More than 50% of allergic patients have house dust mite (HDM) allergy. Group 1 and 2 allergens are the major HDM allergens. OBJECTIVE: We sought to produce and perform preclinical characterization of a recombinant hypoallergenic combination vaccine for specific immunotherapy of HDM allergy. METHODS: Synthetic genes coding for 2 hybrid proteins consisting of reassembled Der p 1 and Der p 2 fragments with (recombinant Der p 2 [rDer p 2]/1C) and without (rDer p 2/1S) cysteines were expressed in Escherichia coli and purified to homogeneity by means of affinity chromatography. Protein fold was determined by using circular dichroism analysis, allergenic activity was determined by testing IgE reactivity and using basophil activation assays, and the presence of T-cell epitopes was determined based on lymphoproliferation in allergic patients. Mice and rabbits were immunized to study the molecules' ability to induce an allergic response and whether they induce allergen-specific IgG capable of inhibiting allergic patients' IgE binding to the allergens, respectively. RESULTS: rDer p 2/1C and rDer p 2/1S were expressed in large amounts in E coli as soluble and folded proteins. Because of the lack of disulfide bonds, rDer p 2/1S did not form aggregates and was obtained as a monomeric protein, whereas rDer p 2/1C did form aggregates. Both hypoallergens lacked relevant IgE reactivity and had reduced ability to induce allergic inflammation and allergic responses but induced similar T-cell proliferation as the wild-type allergens. Immunization with the hypoallergens (rDer p 2/1S > rDer p 2/1C) induced IgG antibodies in rabbits that inhibited the IgE reactivity of patients with HDM allergy to Der p 1 and Der p 2. CONCLUSION: The preclinical characterization indicates that particularly rDer p 2/1S can be used as a safe hypoallergenic molecule for both tolerance and vaccination approaches to treat HDM allergy.

Varying allergen composition and content affects the in vivo allergenic activity of commercial Dermatophagoides pteronyssinus extracts.

BACKGROUND: Diagnosis and immunotherapy of house-dust mite (HDM) allergy is still based on natural allergen extracts. The aim of this study was to analyze commercially available Dermatophagoides pteronyssinus extracts from different manufacturers regarding allergen composition and content and whether variations may affect their allergenic activity. METHODS: Antibodies specific for several D. pteronyssinus allergens (Der p 1, 2, 5, 7, 10 and 21) were used to analyze extracts from 10 different manufacturers by immunoblotting. Sandwich ELISAs were used to quantify Der p 1 and Der p 2 in the extracts. Mite-allergic patients (n = 45) were skin-tested with the extracts and tested for immunoglobulin E (IgE) reactivity to a panel of 10 mite allergens (Der p 1, 2, 4, 5, 7, 8, 10, 14, 20 and 21) by dot blot. RESULTS: Only Der p 1 and Der p 2 were detected in all extracts but their concentrations and ratios showed high variability (Der p 1: 6.0-40.8 µg ml(-1); Der p 2: 1.7-45.0 µg ml(-1)). At least 1 out of 4 allergens (i.e. Der p 5, 7, 10 and 21) was not detected in 8 of the studied extracts. Mite-allergic subjects showed different IgE reactivity profiles to the individual mite allergens, the extracts showed different allergenic activity in skin-prick tests and false-negative results. CONCLUSIONS: Commercially available D. pteronyssinus extracts lack important allergens, show great variability regarding allergen composition and content and some gave false-negative diagnostic test results in certain patients.

Sensitizing and Th2 adjuvant activity of cysteine protease allergens.

BACKGROUND: Innate properties that enhance immune responses might increase the propensity of certain allergens to induce allergic sensitization. Either a direct adjuvant effect or the increased immune response to the allergen could then increase allergic responses to bystander antigens. Here, we report on a model that does not use Th2-skewing adjuvants and yet achieves sensitization solely via the nasal mucosa. METHODS: Animals were sensitized with either enzymatically active, inactive or non-activated cysteine proteases via the nasal mucosa. Following two sensitization phases, mice were challenged with a higher dose of allergen. For bystander sensitization, mice received recombinant Der p 2 at sensitization in conjunction with the cysteine protease and were challenged with rDer p 2 alone. Sensitization was determined by measuring allergen-specific antibody responses and cytokine and cellular infiltrates into the lungs following challenge. RESULTS: Sensitization for Th2-type lung hypersensitivity for both the cysteine protease and bystander antigens was readily achieved and both were dependent on the proteolytic activity of the allergen. Bystander adjuvant activity was demonstrated for mice that were low IgE responders to the cysteine protease, showing a response independent from the immune response to the enhancing cysteine protease. Airway hyperreactivity was induced in the susceptible NOD strain of mouse, and mice subjected to prolonged administration of papain maintained the ability to produce lung hypersensitivity and Th2-type responses. CONCLUSIONS: These experiments demonstrate that cysteine protease activity at low doses can be an adjuvant for respiratory Th2 responses for themselves and bystander antigens in the absence of another adjuvant.

SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.

House dust mite allergens in asthma and allergy.

IgE antibodies in house dust mite (HDM) allergy follow a predictable pattern. Half are directed against two dominant allergens and the remainder largely against four midpotency allergens. This hierarchical pattern is not changed by the titre of the IgE response or severity of disease. The structures of these allergens are known and they can be produced as authentic recombinant allergens. There is also evidence that the allergenicity is augmented by the biological activity of the key allergens, validating them as targets for vaccination. Collectively, these developments should facilitate the development of new diagnostics, improve immunotherapy and allow vaccination with defined reagents. Highly purified recombinant polypeptides representing the important mite allergens are now available so that informative and reproducible experiments can be performed with mite allergens in place of poorly defined and variable extracts.

Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children.

Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated "exhausted" phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcepsilonR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R(+) alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-alpha can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.

The estrogen-responsive B box protein (EBBP) restores retinoid sensitivity in retinoid-resistant cancer cells via effects on histone acetylation.

Retinoids have significant clinical activity in several human cancers, yet the factors determining retinoid sensitivity in cancer cells are still unclear. Retinoid-induced expression of retinoic acid receptor (RAR) beta(2) is a necessary component of the retinoid anticancer signal in cancer cells. We have previously identified the Estrogen-responsive B Box Protein (EBBP), a member of the Tripartite Motif (TRIM) protein family, as a novel RARbeta2 transcriptional regulator in the retinoid signal. Here we examined the mechanism of the EBBP effect on the retinoid anticancer signal. We assessed retinoid-responsive RARbeta2 transcription in retinoid-resistant breast and lung cancer cells in the presence of chromatin modifying agents. A histone deacetylase (HDAC) inhibitor alone, or in combination with retinoid, was more effective than a demethylating agent in restoring RARbeta2 transcription in resistant cells. Overexpression of EBBP alone markedly increased histone acetylation. The effect of EBBP on retinoid-responsive transcription appeared to be limited to genes with the retinoic acid response element (betaRARE) regulatory sequence, such as CYP26A1. EBBP inhibited cell growth by effects on cyclin D1 and Phospho-Rb, and, reduced cell viability in retinoid-resistant cancer cells. The viability of non-cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARbeta2 and CYP26A1, by modifying histone acetylation in retinoid-resistant cancer cells, and, is an important target for drug discovery in retinoid-resistant cancers.

Molecular mimicry as the key to the dominance of the house dust mite allergen Der p 2.

Evaluation of: Trompette A, Divanovic S, Visintin A et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585-588 (2009). The majority of complex sources of allergen contain a small number of dominant allergens that bind at least half of the IgE antibodies of allergic subjects. For the house dust mite Dermatophagoides pteronyssinus, these allergens are Der p 1 and Der p 2. There is evidence that the cysteine-protease activity of Der p 1 imparts adjuvant activity to the allergen. It has now been shown that Der p 2 mimics the activity of its fellow ML-domain protein, MD-2, by presenting lipopolysaccharide to Toll-like receptor-4 for the activation of inflammatory genes. In accord with this, Der p 2 presented with lipopolysaccharide also induced enhanced type 1 allergic sensitization of mice, even when they were deficient in MD-2. The mimicry of MD-2 can thus also self adjuvant Der p 2 to enhance it allergenicity. This not only describes an intriguing mechanism for enhancing allergenicity but also, since both of the dominant mite allergens have intrinsic adjuvant activity, exemplifies an important principle for driving allergic sensitization.

ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma.

Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower-risk tumors, suggesting that this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor alpha-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically engineered mice (TH-MYCN) extended tumor latency and survival in homozygous mice and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments antitumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and shows initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors.