To the Editor: Nut allergy is one of the most common and severe food allergies in children. ...understanding the causes of nut allergy is essential to establishing primary preventive measures to ...avoid the onset of this condition. Brough et al6,7 showed that environmental exposure to peanut in early life was associated with greater risk of both peanut sensitization and allergy in atopic children or children with a filaggrin loss-of-function mutation and that this risk was higher the greater the concentration of peanut proteins in household dust. ...the authors showed that the effect was greater in children with AD and those with more severe forms of this disorder, suggesting that exposure to peanuts through skin with an altered barrier function could be a sensitization pathway.
Background Cow's milk is the main cause of food allergy in children. Patients allergic to food frequently experience accidental exposure. There are few studies analyzing this problem, most of them ...concerning peanut allergy. Objective We sought to calculate the frequency of accidental exposure reactions in children allergic to cow's milk during a 12-month period, to analyze the clinical characteristics and circumstances surrounding the reactions, and to identify risk factors for severe reactions. Methods Eighty-eight children allergic to cow's milk (44 boys; median age, 32.5 months) were included in the study. A systematized questionnaire about accidental exposure was used. Reactions were classified as mild, moderate, and severe. Cow's milk– and casein-specific IgE antibody titers were determined. Results Thirty-five (40%) children had 53 reactions in the previous year (53% mild, 32% moderate, and 15% severe). Most reactions took place at home (47%) under daily life circumstances (85%). Specific IgE levels to cow's milk were higher in children with severe reactions than in those with moderate (median, 37.70 vs 7.71 KUA/L; P = .04) or mild (3.37 KUA/L; P = .04) reactions. The frequency of severe reactions was 10-fold higher in asthmatic children (odds ratio, 10.2; 95% CI, 1.13-91.54). Conclusions Reactions to accidental exposure are frequent in children with cow's milk allergy. The proportion of severe reactions was 15%. The risk factors for such reactions included very high levels of specific IgE to cow's milk and casein and asthma.
Methods Forty-six children <=18 months with clinical history of food allergy or atopic dermatitis (AD) were included. Gender, age, AD, breast feeding and first-degree family history of allergic ...disease were analyzed.
Specific IgE to Ara h 2 has been shown to be useful in the diagnosis of peanut allergy, whereas the peanut lipid transfer protein, Ara h 9, has been suggested to be responsible for peanut allergy in ...the Mediterranean population.
To better characterize peanut allergy in children from a Mediterranean area and determine the value of specific IgE to Ara h 6 (conglutinin, 2S albumin) for the diagnosis of peanut allergy.
Ninety-one children with suspected allergy to edible vegetables were included in the study. They were classified as allergic or tolerant to peanut. Specific IgE to peanut allergens was measured by a commercially available microarray (ImmunoCAP ISAC 112, ThermoFisher, Uppsala, Sweden).
Patients allergic to peanut showed positive specific IgE changes to peanut seed storage proteins (Ara h 1, Ara h 2, Ara h 3, and Ara h 6) more frequently than tolerant subjects. Ara h 9 showed a similar frequency of reactivity in the 2 groups. Ara h 6 was the allergen most frequently recognized by patients with allergy. Four patients with allergy were found to be mono-sensitized to Ara h 6. Ara h 2 and Ara h 6 showed similar diagnostic accuracy (areas under the curve 0.792 and 0.852). A combined cutoff point for Ara h 2 (≥0.1 ISU) and Ara h 6 (≥2 ISU) yielded the best diagnostic performance (sensitivity 0.77, specificity 0.97, positive predictive value 0.89, negative predictive value 0.93).
Peanut allergy cannot be ruled out without obtaining a negative determination of Ara h 6.
Summary
Background Bexarotene is the first synthetic retinoid X receptor‐selective retinoid (rexinoid) approved for the treatment of cutaneous T‐cell lymphoma (CTCL). However, little is known about ...the signalling pathways by which it exerts its anticarcinogenic effect.
Objectives To characterize the effects of bexarotene in CTCL cell lines and elucidate the underlying molecular pathways of its antineoplastic effect.
Methods The cell lines Hut‐78, HH and MJ were used. Cell viability was assessed with the XTT assay. The self‐renewal potential of cells after bexarotene treatment was studied with the methylcellulose clonogenic assay. Flow cytometry was used to analyse the effects on cell cycle, Ki‐67 expression and apoptosis induction. Cell cycle and apoptosis‐related protein expression were determined by Western blot and immunofluorescence.
Results Bexarotene induced a loss of viability and more pronounced inhibition of clonogenic proliferation in HH and Hut‐78 cells, whereas the MJ line exhibited resistance. Bexarotene upregulated and activated Bax in sensitive lines, although not enough to signal significant apoptosis. Instead, all data point to the inhibition of proliferation, rather than apoptosis, as the main mechanistic action of the rexinoid. Bexarotene signals both G1 and G2/M arrest by the modulation of critical checkpoint proteins. We further found that bexarotene activates p53 by phosphorylation at Ser15, which influences the binding of p53 to promoters for cell cycle arrest, induces p73 upregulation, and, in concordance, also modulates some p53/p73 downstream target genes, such as p21, Bax, survivin and cdc2. Bexarotene‐mediated ataxia telangiectasia mutated protein (ATM) activation in all studied lines suggests that ATM is likely to be the p53/p73 upstream activator.
Conclusions Our data indicate for the first time that bexarotene exerts its effect in CTCL mainly by triggering the p53/p73‐dependent cell cycle inhibition pathway, probably by upstream ATM activation. Therefore, bexarotene‐modulated genes represent potential biomarkers to assess the response to treatment of patients with CTCL.
Oral desensitization in children allergic to cow's milk proteins is not risk free. The analysis of factors that may influence the outcome is of utmost importance.
To analyze the efficacy and safety ...of the oral desensitization according to specific IgE (sIgE) level and adverse events during the maintenance phase.
Thirty-six patients allergic to cow's milk (mean age, 7 years) were included in an oral desensitization protocol. Patients were grouped according to sIgE levels (ImmunoCAP) into groups 1 (sIgE <3.5 kU/L), 2 (3.5-17 kU/L), and 3 (>17-50 kU/L). Nineteen children were included as a control group. Serum sIgE levels to cow's milk and its proteins were determined at inclusion and 6 and 12 months after finishing the desensitization protocol.
Thirty-three of 36 patients were successfully desensitized (200 mL): 100% of group 1 and 88% of groups 2 and 3. Desensitization was achieved in a median of 3 months (range, 1-12 months); 90% of the patients in group 1, 50% of the patients in group 2, and 30% of the patients in group 3 achieved tolerance in less than 3 months (P = .04). In the control group only 1 child tolerated milk in oral food challenge after 1 year. During the induction phase, there were 53 adverse events in 27 patients (75%). Patients of groups 2 and 3 had more severe adverse events compared with group 1. During the maintenance phase, 20 of 33 patients (60%) had an adverse event.
Oral desensitization is efficacious. Tolerance is achieved earlier when sIgE is lower. Severe adverse events are frequent, especially in patients with higher sIgE levels.
In our previous works, we have demonstrated that terfenadine (TEF) induces DNA damage and apoptosis in human melanoma cell lines. In this present work, we have studied the effect of histamine on ...viability of A375 human melanoma cells and the cell-signalling pathways through which TEF may induce its apoptotic effect. We have found that exogenous histamine stimulates A375 melanoma cell proliferation in a dose- and time-dependent manner. Moreover, TEF-induced apoptosis seems to occur via other cellular pathways independent of the histamine-signalling system since co-treatment of histamine with TEF did not protect melanoma cells from the cytotoxic effect of TEF, and alpha fluoromethylhistidine did not induce the same cytotoxic effect of TEF. In addition, we have observed that knocking down the H1 histamine receptor (HRH1) by small interference RNA approach protects melanoma cells only slightly from TEF-induced apoptosis. To explore the molecular mechanisms responsible for histamine and TEF effect on the cell growth, we analysed intracellular cyclic nucleotides and Ca2+ levels. TEF did not modify intracellular levels of cyclic adenosine 3′,5′-monophosphate and cyclic guanine 3′,5′-monophosphate; however, TEF induced a very sharp and sustained increase in cytosolic Ca2+ levels in A375 melanoma cells. On the contrary, histamine did not modulate intracellular Ca2+. TEF-induced Ca2+ rise and apoptosis appear to be phospholipase C (PLC) dependent since neomycin and U73122, two inhibitors of PLC, abolished cytosolic Ca2+ increase and protected the cells completely from cell death. Furthermore, inhibition of tyrosine kinase activity by genistein blocked cytosolic Ca2+ rise and TEF-induced apoptosis. These results suggest that TEF modulates Ca2+ homeostasis and induces apoptosis through other cellular pathways involving tyrosine kinase activity, independently of HRH1.
Serum soluble interleukin-2 receptor (sIL-2R), intercellular adhesion molecule-1 (sICAM-1) and interleukin-10 (IL-10) have each been reported as useful markers for melanoma progression. To evaluate ...the clinical relevance of these three markers, we simultaneously analysed their serum levels in patients with melanoma. A longitudinal study with a 3-year follow-up was performed and different stages of the disease were considered. Mean values of sIL-2R were significantly higher than in normal controls in all stages and correlated with the disease progression. The prognosis of patients with levels > 529 U/ml of sIL-2R was significantly poorer than in patients with sIL-2R levels < 529 U/ml. Levels of sICAM-1 were also elevated in melanoma patients, specially at the time of the metastatic disease. Serum IL-10 levels were more frequently detectable in the patients that developed metastasis during follow-up, and the prognosis of patients with detectable IL-10 levels was significantly poorer than in those patients with IL-10 undetected levels. Statistical analysis based on Logistic and Cox regression models showed that only sex, stage and sIL-2R value are factors significantly associated with metastatic progression. Moreover, high levels of sIL-2R could be a risk factor for malignant progression in melanoma.
Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I–II patients may still develop metastasis during follow‐up. The ...aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow‐up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease‐free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early‐stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival.
What's new?
The discovery of serum biomarkers capable of predicting metastatic risk during post‐operative follow‐up in early‐stage primary melanoma patients could significantly benefit patient prognosis and survival. The present study identifies two promising biomarker candidates: vitronectin and dermcidin. Analysis and comparison of serum proteins in melanoma patients who either remained disease‐free or developed metastases in the years after surgery to remove primary tumors revealed a strong association between metastatic progression of early‐stage melanomas (AJCC stage III) and vitronectin and dermcidin serum levels. Further study of these proteins could open up new opportunities in the effort to improve long‐term survival among melanoma patients.
Melanoma incidence has continued to rise in the latest decades, and the forecast is not optimistic. Non-invasive diagnostic imaging techniques such as optical coherence tomography (OCT) are largely ...studied; however, there is still no agreement on its use for the diagnosis of melanoma. For dermatologists, the differentiation of non-invasive (junctional nevus, compound nevus, intradermal nevus, and melanoma in-situ) versus invasive (superficial spreading melanoma and nodular melanoma) lesions is the key issue in their daily routine.
This work performs a comparative analysis of OCT images using haematoxylin-eosin (HE) and anatomopathological features identified by a pathologist. Then, optical and textural properties are extracted from OCT images with the aim to identify subtle features that could potentially maximize the usefulness of the imaging technique in the identification of the lesion's potential invasiveness.
Preliminary features reveal differences discriminating melanoma in-situ from superficial spreading melanoma and also between melanoma and nevus subtypes that pose a promising baseline for further research.
Answering the final goal of diagnosing non-invasive versus invasive lesions with OCT does not seem feasible in the short term, but the obtained results demonstrate a step forward to achieve this.
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