The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has ...largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.
This rapid review summarizes the most up to date evidence about the risk factors for severe food‐induced allergic reactions. We searched three bibliographic databases for studies published between ...January 2010 and August 2021. We included 88 studies and synthesized the evidence narratively, undertaking meta‐analysis where appropriate. Significant uncertainties remain with respect to the prediction of severe reactions, both anaphylaxis and/or severe anaphylaxis refractory to treatment. Prior anaphylaxis, an asthma diagnosis, IgE sensitization or basophil activation tests are not good predictors. Some molecular allergology markers may be helpful. Hospital presentations for anaphylaxis are highest in young children, yet this age group appears at lower risk of severe outcomes. Risk of severe outcomes is greatest in adolescence and young adulthood, but the contribution of risk taking behaviour in contributing to severe outcomes is unclear. Evidence for an impact of cofactors on severity is lacking, although food‐dependent exercise‐induced anaphylaxis may be an exception. Some medications such as beta‐blockers or ACE inhibitors may increase severity, but appear less important than age as a factor in life‐threatening reactions. The relationship between dose of exposure and severity is unclear. Delays in symptom recognition and anaphylaxis treatment have been associated with more severe outcomes. An absence of prior anaphylaxis does not exclude its future risk.
Food challenges Ballmer-Weber, Barbara K.; Beyer, Kirsten
Journal of allergy and clinical immunology,
January 2018, 2018-01-00, 20180101, Letnik:
141, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Discuss this article on the JACI Journal Club blog:www.jaci-online.blogspot.com.Because there is no in vitro test that can accurately predict the clinical relevance of a sensitization to food, the ...oral food challenge still remains the most reliable procedure to confirm or exclude food allergy and to assess the development of tolerance in children with potentially transient food allergies, such as to cow's milk, hen's egg, wheat, or soy.In case of a very severe (ie, anaphylactic) reaction by history, the benefit of a challenge has to be carefully weighed against the risk....food challenges are often necessary in infants and children with eczema and food sensitization (based on skin testing or IgE measurement in vitro) if the food has thus far not been introduced into the diet and might cause immediate-type symptoms or has already been eaten but is highly suspected of causing worsening of eczema.When to stop an oral food challenge The oral food challenge should be stopped if objective symptoms occur (eg, generalized urticaria); subjective symptoms are usually not a criterion for stopping the challenge.1 When in doubt about the challenge result being positive, the time interval between the doses can be extended before the next dose is given....the same dose can be repeated instead of increasing the amount.Appendix Table I Dosing regimen with adequate amounts (for use, please recalculate with actual protein amount) Dose Protein (g) Pasteurized or baked whole hen's egg (g) Fresh whole cow's milk (g) Peanut flour (g) Wheat gluten (g) 1 0.003 0.023 0.1 0.006 0.004 2 0.01 0.078 0.3 0.02 0.014 3 0.03 0.23 1 0.06 0.04 4 0.1 0.78 3 0.2 0.14 5 0.3 2.3 10 0.6 0.4 6 1 7.8 30 2 1.4 7 3 23.4 100 6 4 Cumulative dose (on another day) 4.4 35 144 9 6 Table II Subjective and objective symptoms observed under challenge Organ Subjective symptoms Objective symptoms Skin Itch Flushing, erythema, hives, angioedema Oral mucosa Itch Blisters, redness, swelling Gastrointestinal tract Nausea, pain, cramps Vomiting, diarrhea Nose Itch Bursts, sniffing, rhinorrhea Eyes Itch Reddening, edema of conjunctiva Lung Tightness, chest pain, dyspnea Wheezing, use of accessory muscles, reduction of lung function Larynx Throat tightness Dry cough, stridor, hoarseness Cardiovascular or neurologic system Dizziness, vertigo, weakness Tachycardia, decrease in blood pressure, collapse, loss of consciousness Table E1 Drugs contraindicated for challenges (and treatment interval before challenge) Antihistamines (3 d) except hydroxyzine and dexclorpheniramine (10 d) Systemic corticosteroids (2 wk) Tricyclic antidepressants (5 d) Immunosuppressive treatment β-Blocking agents (24 h) Angiotensin-converting enzyme inhibitors (2 d) Table E2 Required medical skills and appropriate equipment for implementation of food challenges Medical staff trained in evaluation of allergic responses and treatment of allergic diseases, including anaphylaxis Skills in inserting infusion lines and material for infusion lines Team particularly trained in resuscitation on call: facilities for hospitalization and day clinic for postchallenge observation Laryngoscope, intubation tube, ventilation bag, oxygen Heart defibrillator Peak flow meter, spirometric device β2-Agonist inhaler, epinephrine inhaler, or epinephrine in a nebulizer Antihistamines and corticosteroids administered orally and intravenously, epinephrine administered intramuscularly (or intravenously if needed in intensive care settings) 1 H.A. Sampson, R. Gerth van Wijk, C. Bindslev-Jensen, S. Sicherer, S.S. Teuber, A.W. Burks, Standardizing double-blind, placebo-controlled oral food challenges:
Background Patients with birch pollen allergy often develop allergic reactions to plant foods. Objective To evaluate the prevalence, main symptoms, and triggers of birch pollen–related food allergy ...and the role of food-specific IgG4 antibodies in food tolerance. Methods Food-induced symptoms were evaluated in 225 individuals with birch pollen allergy by using a standardized questionnaire. IgE and IgG4 levels specific for the major birch pollen allergen Bet v 1 and birch profilin Bet v 2 and the Bet v 1 homologs in apple (Mal d 1) and hazelnut (Cor a 1) were quantified by ImmunoCAP. Mock-treated and IgG-depleted sera from patients tolerating hazelnuts in food challenges were compared for their inhibitory activity for binding of Cor a 1–IgE complexes to B cells. Results In total, 73% of the study population experienced food allergy, which was perennial in 86% of the affected individuals. The oral allergy syndrome was the main clinical manifestation. However, more than 58% of the patients also experienced food-induced rhinoconjunctivitis. Apples and hazelnuts were identified as the most frequent triggers. Food allergy correlated with IgE reactivity to Bet v 1 but not to Bet v 2. Mal d 1–specific and Cor a 1–specific IgG4 /IgE ratios were significantly higher in food-tolerant individuals than individuals with food allergy. Sera from IgG4 -positive food-tolerant patients possessed IgG-dependent IgE-inhibitory activity. Conclusion Birch pollen–related food allergy is highly prevalent and often perennial. High food allergen–specific IgG4 /IgE ratios seem associated with food tolerance, potentially because specific IgG4 blocks IgE binding to food allergens. Thus, the presence of food allergen–specific IgG4 antibodies is no diagnostic marker for birch pollen–related food allergy.
Background
Essential oils (EOs) are widely used in cosmetics, perfumes, massage fluids, aroma therapy and natural medicine. Some EOs contain contact sensitizers.
Objectives
To describe the frequency ...of sensitization to EOs in dermatitis patients presenting in skin clinics including concomitant reactions, to evaluate the EO patch test preparations and to identify patient groups with an increased risk of EO sensitization.
Patients and methods
Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2010–2019.
Results
Twelve EOs were patch tested in an aimed manner in 10 930 patients, of whom 908 (8.3%) reacted to at least 1 EO. Only 6 EOs elicited more than 1% positive patch test reactions: ylang ylang (I + II) oil (3.9%), lemongrass oil (2.6%), jasmine absolute (1.8%), sandalwood oil (1.8%), clove oil (1.6%) and neroli oil (1.1%). Concomitant reactions among EOs or to EOs and fragrances were frequent. Among EO‐positive patients, women, leg dermatitis patients, patients aged 40 years or more, masseurs and cosmeticians were over‐represented.
Conclusions
Sensitization to EOs occurs, albeit infrequently in most cases. Masseurs and cosmeticians have an increased risk of sensitization to EOs.
Allergic reactions to most EOs mostly cannot be traced back to single fragrance components, are often accompanied by contact allergy to other fragrances/EOs, and occur preferably in women, patients aged 40+, leg dermatitis patients, masseurs and cosmeticians.
Background Soybean is considered an important allergenic food, but published data on soybean allergens are controversial. Objective We sought to identify relevant soybean allergens and correlate the ...IgE-binding pattern to clinical characteristics in European patients with confirmed soy allergy. Methods IgE-reactive proteins were identified from a soybean cDNA expression library, purified from natural soybean source, or expressed in Escherichia coli . The IgE reactivity in 30 sera from subjects with a positive double-blind, placebo-controlled soybean challenge (n = 25) or a convincing history of anaphylaxis to soy (n = 5) was analyzed by ELISA or CAP-FEIA. Results All subunits of Gly m 5 (β-conglycinin) and Gly m 6 (glycinin) were IgE-reactive: 53% (16/30) of the study subjects had specific IgE to at least 1 major storage protein, 43% (13/30) to Gly m 5 , and 36% (11/30) to Gly m 6. Gly m 5 was IgE-reactive in 5 of 5 and Gly m 6 in 3 of 5 children. IgE-binding to Gly m 5 or Gly m 6 was found in 86% (6/7) subjects with anaphylaxis to soy and in 55% (6/11) of subjects with moderate but only 33% (4/12) of subjects with mild soy-related symptoms. The odds ratio ( P < .05) for severe versus mild allergic reactions in subjects with specific IgE to Gly m 5 or Gly m6 was 12/1. Conclusion Sensitization to the soybean allergens Gly m 5 or Gly m 6 is potentially indicative for severe allergic reactions to soy.
Background
Peanut allergy is a type‐I hypersensitivity immune reaction mediated by the binding of peanut allergens to IgE‐FcεRI complexes on mast cells and basophils and by their subsequent cellular ...degranulation. Of all major peanut allergens, Ara h 2 is considered the most anaphylactic. With few options but allergen avoidance, effective treatment of allergic patients is needed. Passive immunotherapy (herein called PIT) based on prophylactic administration of peanut‐specific monoclonal antibodies (mAbs) may present a promising treatment option for this under‐served disease.
Method
Fully human recombinant anti‐peanut IgG mAbs were tested in mice sensitized to peanut allergen extract. Allergic mice received intravenous immunotherapy with anti‐peanut Ara h 2‐specific IgG1 or IgG4 mAbs cocktails, and were then challenged by a systemic injection of high‐dose peanut allergen extract. The protection from allergic anaphylaxis was measured by monitoring the core body temperature.
Results
PIT with peanut‐specific mAbs was associated with a significant and dose‐dependent reduction of anaphylactic reactions in peanut‐sensitized mice challenged with peanut allergen extract. Complete protection was observed at doses approximately 0.3–0.6 mg mAbs. Mixtures of mAbs were more effective than single mAbs, and effective treatment could be obtained with mAbs of both IgG1 and IgG4 subclasses. The therapeutic effect of anti‐Ara h 2 mAbs was based on allergen neutralization and independent of the Fcγ receptor and mast‐cell inhibition.
Conclusion
This is the first report that shows that human‐derived anti‐peanut mAbs can prevent allergic anaphylaxis in mice. The study demonstrates that neutralizing allergenic epitopes on Ara h 2 by mAbs may represent a promising treatment option in peanut‐allergy.
Anti‐Ara h 2 IgG1/IgG4 mAbs from peanut‐allergic patients were cloned and recombinantly produced. Preclinical testing was performed in peanut‐sensitized mice receiving passive immunotherapy prior to an allergen challenge. Anti‐Ara h 2 mAbs prevent allergic anaphylaxis by neutralizing peanut allergens before they bind to IgE and induce a FcɛRI‐mediated degranulation of mast cells and basophils.Abbreviations: AUC, area under the curve; FcɛRI, Fc epsilon receptor I; Ig, immunoglobulin; mAbs, monoclonal antibodies; PIT, passive immunotherapy; temp., temperature
MicroRNAs (miRNAs) are small RNA molecules that control gene expression by inhibition of protein translation or by degradation of cognate target mRNAs. Even though strict developmental and ...tissue-specific regulation appears to be critical for miRNA function, very little is known about the mechanisms governing miRNA gene expression. Several recent studies have shown that miRNA genes can be regulated by DNA methylation and other epigenetic mechanisms. The observation of altered miRNA gene methylation patterns in human cancers also suggested that miRNA gene methylation is functionally relevant for tumorigenesis. We have now performed a comprehensive analysis of miRNA genes and found that about half of these genes are associated with CpG islands and thus represent candidate targets of the DNA methylation machinery. An expanded analysis of several miRNA-associated CpG islands in five cell lines indicated that miRNA gene methylation is detectable at high frequencies, both in normal and malignant cells. Possible explanations for this phenomenon include the specific structure of miRNA genes and/or their requirement for strict expression regulation.
This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE‐mediated food allergy and was developed using the Grading of Recommendations, ...Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy‐focused clinical history followed by tests to determine IgE sensitization, such as serum allergen‐specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen‐sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.
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