Biomarkers predicting the controller dose of omalizumab in patients with chronic spontaneous urticaria.

BACKGROUND: Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response. METHODS: CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer. RESULTS: Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10-42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/µL (OR 13.33; 95% CI 3.32-52.63; p < .001) and the absence of hypothyroidism (OR 3.65; 95% CI 0.78-16.95; p = .099) were identified as predictive factors to achieve control with 300 mg/4 weeks. Twelve patients were able to stop OMA during the study (responders in remission, RR). RR had received OMA for a median of 29 months (12-53 months). Conversely, 32 patients had been on OMA for >29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30-100 months). There were no significant differences in clinical or analytical factors between RR and AR patients. CONCLUSIONS: Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients.

Flow-based basophil activation test in immediate drug hypersensitivity. An EAACI task force position paper.

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.

From MASK-air and SILAM to CATALYSE (Climate Action To Advance HeaLthY Societies in Europe).

Plant species vary under different climatic conditions and the distribution of pollen in the air. Trends in pollen distribution can be used to assess the impact of climate change on public health. In 2015, the Mobile Airways Sentinel networK for rhinitis and asthma (MASK-air®) was launched as a project of the European Innovation Partnership on Active and Healthy Ageing (EIP-on-AHA, DG Santé and DG CONNECT). This project aimed to develop a warning system to inform patients about the onset of the pollen season, namely, the System for Integrated modeLling of Atmospheric coMposition (SILAM). A global-to-meso-scale dispersion model was developed by the Finnish Meteorological Institute (FMI). It provides quantitative information on atmospheric pollution of anthropogenic and natural origins, particularly on allergenic pollens. Impact of Air Pollution on Asthma and Rhinitis (POLLAR, EIT Health) has combined MASK-air clinical data with SILAM forecasts. A new Horizon Europe grant (Climate Action to Advance HeaLthY Societies in Europe [CATALYSE]; grant agreement number 101057131), which came into force in September 2022, aims to improve our understanding of climate change and help us find ways to counteractit. One objective of this project is to develop early warning systems and predictive models to improve the effectiveness of strategies for adapting to climate change. One of the warning systems is focused on allergic rhinitis (CATALYSE Task 3.2), with a collaboration between the FMI (Finland), Porto University (Portugal), MASK-air SAS (France), ISGlobal (Spain), Hertie School (Germany), and the University of Zurich (Switzerland). It is to be implemented with the support of the European Academy of Allergy and Clinical Immunology. This paper reports the planning of CATALYSE Task 3.2.

Approach for delabeling beta-lactam allergy in children.

A considerable number of pediatric patients treated with beta-lactam (BL) antibiotics develop delayed onset of skin rashes during the course of treatment. Although the most frequent cause of these symptoms is infectious, many cases are labeled as allergic reactions to these drugs. BL allergy labels could have a negative impact, as they imply avoidance of this group of drugs and the use of second-line antibiotics, leading to a potential increase in adverse effects and the utilization of less effective therapies. This constitutes a major public health concern and economic burden, as the use of broad-spectrum antibiotics can result in multidrug-resistant organisms and prolonged hospital stays. Therefore, it is crucial to delabel patients during childhood to avoid false labeling in adult life. Although the label of BL allergy is among the most frequent causes of allergy referral, its management remains controversial, and new diagnostic perspectives are changing the paradigm of managing BL allergies in children. Traditionally, drug provocation testing (DPT) was exclusively performed in patients who had previously obtained negative results from skin tests (STs). However, the sensitivity of STs is low, and the role of in vitro testing in the pediatric population is not well defined. Recent studies have demonstrated the safety of direct DPT without prior ST or serum tests for pediatric patients who report a low-risk reaction to BLs, which is cost-effective. However, there is still a debate on the optimal allergic workup to be performed in children with a benign immediate reaction and the management of children with severe cutaneous adverse drug reactions. In this review, we will discuss the impact of the label of BL allergy and the role of the different tools currently available to efficiently address BL allergy delabeling in children.

Organ-specific allergen challenges in airway allergy: Current utilities and future directions.

Atopy has been long used as the screening method for airway allergy. Nevertheless, aeroallergens can trigger respiratory symptoms not only in atopic patients (atopic respiratory allergy, ARA), but also in non-atopic subjects (local respiratory allergy, LRA). Moreover, ARA and LRA can coexist in the same patient, and this clinical scenario has been called dual respiratory allergy (DRA). When the clinical history cannot determine the relevance of sensitizations in ARA patients, nasal, conjunctival or bronchial allergen challenges (NAC, CAC, and BAC, respectively) should be conducted. Moreover, these tests are required to identify patients with LRA and DRA. The clarification of the allergic triggers of airway diseases has a profound impact on the management strategies the patients can be offered. Importantly, allergen immunotherapy (AIT) remains as the only disease-modifying intervention for ARA. Recent data indicate that AIT might have a similar effect on LRA patients. Nevertheless, AIT success relies largely on the correct phenotyping of allergic individuals, and NAC, CAC, and BAC are very helpful tools in this regard. In this review, we will summarize the main indications and methodology of CAC, NAC, and BAC. Importantly, the clinical implementation of these tests might translate into precision medicine approaches and better health outcomes for patients with airway allergy.

Deconstructing adverse reactions to Amoxicillin-Clavulanic Acid: the importance of time of onset.

BACKGROUND: Amoxicillin-clavulanic acid (AX-CL) is the most consumed betalactam antibiotic worldwide. We aimed to establish the different phenotypes of betalactam allergy in those referring a reaction with AX-CL and to investigate the differences between immediate and non-immediate onset. METHODS: Cross-sectional retrospective study performed at Hospital Clínico San Carlos (HCSC) and Hospital Regional Universitario de Málaga (HRUM) in Spain. Patients reporting reactions with AX-CL who completed the allergy workup between 2017 and 2019 were included. Data of reported reaction and allergy workup were collected. Reactions were classified as immediate and non-immediate with 1hour cut-off point. RESULTS: We included 372 patients (HCSC 208, HRUM 164). There were 90 (24.2%) immediate, 252 (67.7%) non-immediate reactions, and 30 (8.1%) with unknown latency. Allergy to betalactams was ruled-out in 266 (71.5%) and confirmed in 106 patients (28.5%). The final main diagnosis in the overall population were allergy to aminopenicillins (7.3%), to CL (7%), to penicillin (6.5%) and to betalactams (5.9%). Allergy was confirmed in 77.2% and 14.3% of immediate and non-immediate reactions respectively, with a relative risk of 5.06 (95%CI 3.64-7.02) of an allergy diagnosis in those reporting immediate reactions. Only 2/54 patients with late-positive intradermal test (IDT) to CL were diagnosed of CL allergy. CONCLUSION: Allergy diagnosis was confirmed in a minority of the whole study population, but 5 times more frequently in those reporting immediate reactions, making this classification useful in risk stratification. Late-positive IDT for CL has no diagnostic value and its late reading could be retrieved from the diagnosis work-up.

Corrigendum: Approach for delabeling beta-lactam allergy in children.

[This corrects the article DOI: 10.3389/falgy.2023.1298335.].

Role of sCD40L in the prediction of super response to cardiac resynchronization therapy / Rol de sCD40L en la predicción de súper respuesta a la terapia de resincronización cardiaca

Background: The aim of this paper is to analyze the roleof the biomarkers Interleukin 6, Tumoral Necrosis Factor α,sCD40L, high sensitive Troponin T, high sensitive C-ReactiveProtein and Galectin-3 in predicting super response (SR) toCardiac Resynchronization Therapy (CRT), as they have notbeen studied in this field before. Methods: Clinical, electrocardiographic and echocardiographic data was obtained preimplant and after one year.SR was defined as reduction in LVESV ≥ 30% at one yearfollow-up. Blood samples were extracted preimplant. Multivariate logistic regression and ROC curves were performed. Results: 50 patients were included, 23 (46%) were SR. Characteristics related to SR were: female (35 vs. 11%, p = 0.04),suffering from less ischemic cardiomyopathy (13 vs. 63%,p < 0.0001) and lateral (0 vs. 18%, p = 0.03), inferior (4 vs.33%, p = 0.01) and posterior infarction (0 vs. 22%, p = 0.01);absence of mitral regurgitation (47% vs. 22%, p = 0.04), wider QRS width (157.7 ± 22.9 vs. 140.8 ± 19.2ms, p = 0.01), higher concentrations of sCD40L (6.9 ± 5.1 vs. 4.4 ± 3.3 ng/mL,p = 0.02), and left ventricular lead more frequent in lateralmedial position (69 vs. 26%, p = 0.002). QRS width, lateralmedial position of the lead and absence of mitral regurgitation were independent predictors of SR. sCD40L showeda moderate direct correlation with SR (r = 0.39, p = 0.02) andwith the reduction of LVESV (r = 0.44, p = 0.02). Conclusion: sCD40L correlates significantly with SR to CRT.QRS width, absence of mitral regurgitation and lateral medial position of the lead are independent predictors of SRin this cohort.(AU)

Fundamento: Analizar los biomarcadores Interleuquina 6,factor de necrosis tumoral α, sCD40L, troponina T hipersensible, proteína Creactiva hipersensible y galectina-3 en lapredicción de súper-respuesta (SR) a la terapia de resincronización cardiaca (TRC), ya que no han sido valorados conanterioridad. Material y métodos: Se recopilaron datos clínicos, electrocardiográficos y ecocardiográficos preimplante y al año.Se definió SR como disminución del VTSVI ≥ 30% al añode seguimiento. Las muestras sanguíneas fueron extraídaspreimplante. Se realizó regresión logística multivariante ycurvas ROC. Resultados: Se incluyeron 50 pacientes, 23 (46%) fueronSR.Las características relacionadas con la SR fueron: ser mujer (35 vs. 11%, p = 0,04), sufrir menos cardiopatía isquémica(13 vs. 63%, p < 0,0001) e infarto lateral (0 vs. 18%, p = 0,03),inferior (4 vs. 33%, p = 0,01) y posterior (0 vs. 22%, p = 0,01); ausencia de insuficiencia mitral (47% vs. 22%, p = 0,04), mayor anchura del QRS (157,7 ± 22,9 vs. 140,8 ± 19,2 ms, p = 0,01), mayorconcentración de sCD40L (6,9 ± 5,1 vs. 4,4 ± 3,3 ng/mL, p = 0,02),y electrodo ventricular izquierdo más frecuentemente en posición lateral media (69 vs. 26%, p = 0,002). El QRS, la posiciónlateral media del electrodo y la ausencia de insuficiencia mitral fueron predictores independientes de SR. sCD40L mostróuna correlación moderada directa con SR (r = 0,39, p = 0,02) ycon la disminución del VTSVI (r = 0,44, p = 0,02). Conclusiones: sCD40L se correlaciona significativamentecon SR a la TRC. El QRS, la ausencia de insuficiencia mitraly la posición lateral media del electrodo son predictores independientes de SR en esta cohorte.(AU)

Role of sCD40L in the prediction of super-response to cardiac resynchronization therapy.

BACKGROUND: The aim of this paper is to analyze the role of the biomarkers Interleukin 6, Tumoral Necrosis Factor a, sCD40L, high sensitive Troponin T, high sensitive C-Reactive Protein and Galectin-3 in predicting super response (SR) to Cardiac Resynchronization Therapy (CRT), as they have not been studied in this field before. METHODS: Clinical, electrocardiographic and echocardiographic data was obtained preimplant and after one year. SR was defined as reduction in LVESV = 30% at one year follow-up. Blood samples were extracted preimplant. Multivariate logistic regression and ROC curves were performed. RESULTS: 50 patients were included, 23 (46%) were SR. Characteristics related to SR were: female (35 vs. 11%, p?=?0.04), suffering from less ischemic cardiomyopathy (13 vs. 63%, p?

Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID hypersensitivity, genetic factors are believed to be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. OBJECTIVES: To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. METHODS: Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID-exacerbated respiratory disease (NERD). A set of tagging single-nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. RESULTS: The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1; rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34-2·14; Pcorrected = 2·83 × 10-4 ) and 2·19 for rs28395868 (95% CI 1·43-3·36; Pcorrected = 0·002). CONCLUSIONS: Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light on their genetic basis.

Hypersensitivity Reactions to Cancer Chemotherapy: Practical Recommendations of ARADyAL for Diagnosis and Desensitization.

Rapid drug desensitization has enabled first-line therapies in patients with drug hypersensitivity reactions to chemotherapeutic drugs including monoclonal antibodies. Desensitization is a safe and highly effective procedure, not only for IgE-mediated reactions, but also for those mediated by non-IgE mechanisms. The likelihood of breakthrough reactions during desensitization is low, and most are mild; in fact, moderate-to-severe reactions are infrequent. In this document, 16 allergy departments belonging to the Spanish research network ARADyAL present a review of the available scientific evidence and provide general guidelines for the diagnosis and management of drug hypersensitivity reactions to chemotherapeutic drugs and monoclonal antibodies. Emphasis is placed on the desensitization procedure.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases.

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy. (AU)

Las Redes Temáticas de Investigación Cooperativa en Salud (RETICS) son unas estructuras organizativas promovidas por el Instituto de Salud Carlos III del Ministerio de e Sanidad, Consumo y Bienestar Social con el objetivo de llevar a cabo proyectos de investigación colaborativos que aborden desafíos de interés general para la sociedad en el campo de la salud. La RETICS de Asma, Reacciones Adversas a Fármacos y Alérgicas (ARADyAL) comenzó en 2016 y fue financiada por un periodo de 5 años (2017-2021). ARADyAL integra la investigación básica y clínica en diferentes áreas de conocimiento, alergia, inmunología, genética, nanomedicina, farmacología y química, con especial interés en la investigación de nuevos biomarcadores, y el diseño y evaluación de nuevas estrategias de intervención para pacientes alérgicos con fenotipos graves. El consorcio está compuesto por 28 grupos de toda España, que incluyen 171 investigadores clínicos y básicos: 17 grupos clínicos que cubren a más de 10.000.000 de pacientes de todas las edades y de áreas tanto urbanas como rurales; 11 grupos básicos que desarrollan sus actividades principalmente en universidades e institutos de investigación. ARADyAL propone un programa de investigación organizado en tres áreas diferentes centradas en la medicina de precisión: Programa 1. Mecanismos y predicción de reacciones adversas a medicamentos y enfermedades alérgicas; Programa 2. Hacia un diagnóstico preciso de enfermedades alérgicas; y Programa 3. Predicción de intervenciones en enfermedades alérgicas. Además, hay un programa transversal dedicado a la formación. La red cuenta con un Comité de Dirección y un Comité Científico Asesor Externo, que asesoran a la coordinadora de la red la cual tiene experiencia reconocida en el campo. ARADyAL es un punto de encuentro único para médicos y científicos básicos que ya están trabajando en alergias.

PPARß/δ-dependent MSC metabolism determines their immunoregulatory properties.

Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARß/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARß/δ on MSC metabolic activity and the relevance of PPARß/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARß/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARß/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARß/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

Statement of the Spanish Society of Allergology and Clinical Immunology on Provocation Tests With Aspirin/Nonsteroidal Anti-inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. They are frequently involved in hypersensitivity reactions, which range from local or mild reactions to systemic and severe reactions. Consequently, it is necessary to perform an exhaustive study of patients in order to make an accurate diagnosis, search for safe procedures in the case of severe reactions, and identify alternative treatment options. Various guidelines and protocols address the management of hypersensitivity to NSAIDs, although these vary widely from country to country. The Committees of Asthma, Rhinoconjunctivitis, and Drug Allergy of the Spanish Society of Allergy and Clinical Immunology (SEAIC) propose the present position statement on available options for provocation testing with aspirin/NSAIDs. This document is the fruit of an exhaustive review of current evidence and is based on recent publications addressing the diagnosis of patients with hypersensitivity to NSAIDs and on a consensus-oriented discussion among a group of experts from the SEAIC. The main objective was to draft an easy-toread, practical guideline for health care professionals in specialist areas who assess and manage patients with suspected hypersensitivity to NSAIDs. Furthermore, indications, contraindications, and procedures for oral, bronchial, and nasal provocation tests with aspirin/NSAIDs have been updated.

Local allergic rhinitis: Implications for management.

A significant proportion of rhinitis patients without systemic IgE-sensitisation tested by skin prick test and serum allergen-specific IgE (sIgE) display nasal reactivity upon nasal allergen provocation test (NAPT). This disease phenotype has been termed local allergic rhinitis (LAR). LAR is an underdiagnosed entity affecting children and adults from different parts of the world, with moderate-to-severe symptoms, impairment of quality of life and rapid progression to symptom worsening. LAR is a stable phenotype and not merely an initial state of AR. Allergic rhinitis and LAR share many clinical features including a positive NAPT response, markers of type 2 nasal inflammation including sIgE in nasal secretions and a significant rate of asthma development. LAR should be considered as a differential diagnosis in those subjects of any age with symptoms suggestive of AR but no evidence of systemic atopy. Although LAR pathophysiology is partially unknown, in some patients sIgE can be demonstrated directly in the nasal secretions and/or indirectly via positive responses in basophil activation test (BAT). LAR can coexist with other rhinitis phenotypes, especially AR. The diagnosis currently relies on the positivity of NAPT to a single or multiple allergens. NAPT has high sensitivity, specificity and reproducibility, and it is considered the gold standard. BAT and the measurement of nasal sIgE can also contribute to LAR diagnosis. LAR patients benefit from the same therapeutic strategies than AR individuals, including the avoidance of allergen exposure and the pharmacotherapy. Moreover, several recent studies support the effectiveness and safety of allergen immunotherapy for LAR, which opens a window of treatment opportunity in these patients.

Silencing of the transcriptional factor ZEB1 alters the steroidogenic pathway, and increases the concentration of testosterone and DHT in DU145 cells.

Prostate cancer (PCa) is the second most common type of male malignancy worldwide. The transcription factor zinc finger E­box binding homeobox 1 (ZEB1) is associated with epithelial­mesenchymal transition and is also involved in regulation of androgen receptor (AR) expression, the main ligands of which are testosterone and dihydrotestosterone (DHT). These androgens are synthesized through the steroidogenic pathway within the prostate, and their synthesis is altered in PCa. The present study aimed to determine the ZEB1­induced alterations in androgen synthesis and AR expression in the DU145 PCa cell line. Reverse transcription­quantitative polymerase chain reaction, western blotting and immunocytochemistry were used to determine the mRNA and protein expression levels, and cellular localization of steroidogenic pathway enzymes in the DU145 cell line in response to ZEB1 silencing. Furthermore, the concentrations of testosterone and DHT were detected in cell culture medium using ELISA. ZEB1­silenced cells exhibited an increase in testosterone and DHT production, an increase in AR expression and an alteration in the steroidogenic pathway. In particular, steroidogenic acute regulatory protein and 5α­reductase 2 expression levels were decreased, whereas cytochrome P450 family 17 subfamily A member 1, 5α­reductase 1, aldo­keto reductase family 1 member D1 and aldo­keto reductase family 1 member C2 expression levels were increased. In conclusion, the present study provided novel information regarding the regulation of intratumoral androgen production in PCa, which is relevant for the progression of the disease to a castration­resistant form.