Mast cells protect from skin tumor development and limit tumor growth during cutaneous de novo carcinogenesis in a Kit‐dependent mouse model

Epidermal tumors belong to the most frequent type of neoplasms, and tumor‐associated accumulation of mast cells (MCs) has first been observed more than a century ago. Therefore, MCs have been implicated in tumor development and growth; however, the results regarding the role of MC in cutaneous de novo carcinogenesis are still controversially discussed. Here, we subjected MC‐deficient Kit^W/Kit^W?v mice to chemical skin carcinogenesis. Tumors were induced using the carcinogen 7,12‐dimethylbenz[a]‐anthracene and subsequent treatment with the tumor promoter 12‐tetradecanoyl‐phorbol‐13‐acetat. The treatment resulted in pronounced inflammatory cell infiltrates that were diminished in MC‐deficient animals. Unexpectedly, tumor development and growth was significantly increased in MC‐deficient Kit^W/Kit^W?v mice. The repair of their MC deficiency by local adoptive transfer of MCs normalized tumor incidence and growth. The recruitment of skin‐infiltrating immune cells, particularly of F4/80+ monocytes, Gr‐1+ granulocytes, B220+ B cells and CD8+ T lymphocytes, to sites of tumor development was, in part, also controlled by MCs. Recent evidence indicated the importance of local antitumor tissue immunity which prevents tumor development. These findings suggest a critical role for MCs in mediating these host antitumor immune responses in the skin.     

An internet survey on self‐reported food allergy in Greece: clinical aspects and lack of appropriate medical consultation

Background Food allergy (FA) represents a common and worldwide disorder but in publications referring to FA the reported diagnosis is rarely confirmed. Consequently, the subjectively assessed FA may negatively affect the quality of life of patients and their families. Objective We have conducted this internet survey in order to estimate the self‐reported perception of FA in Greece. Methods A standard anonymous questionnaire was posted for a 3‐month period on http://www.in.gr , a Greek popular Internet portal. Each individual could participate only once. Participants were screened for the presence or history of FA by a key question and were then asked to provide information on symptoms, course and management. Results A total of 3673 adult subjects (mean age 34.2 years, range 18–74, females 61.3%), reporting FA were included in analysis. Most reported reactions were related to fruits (14.9%), seafood (10.7%) and nuts (9.2%). The first episode occurred principally during the second (29.2%) and third (30.9%) decade within 3 h from consumption (82.2%). Predominant symptoms were urticaria and oral allergy syndrome (almost 25% each one). Nearly half of the participants sought no medical advice, while 31.4% asked for an allergist’s consultation. Almost 21% of reactors were hospitalized; nuts, severity of symptoms (lower respiratory and/or cardiovascular), onset in lower age, previous exercise and concomitant alcohol and/or aspirin intake were positively associated with hospitalization. Conclusion Although FA causes severe anaphylactic episodes, almost 50% of individuals who experience symptoms perceived as FA do not seek medical advice. Awareness programmes must be carried out in order to increase consciousness about this potentially fatal medical condition.     

Randomized,double‐blind,placebo‐controlled study of safety and efficacy of miltefosine in antihistamine‐resistant chronic spontaneous urticaria

Background Chronic spontaneous urticaria (CSU), a mast cell‐driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo. Objective To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard‐dosed antihistamines. Methods In this investigator‐initiated multicentre, randomized, double‐blind, placebo‐controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150‐mg miltefosine (n = 47) or placebo (n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. Results After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine‐treated patients (?6.3 vs. ?3.5 in placebo‐treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine‐treated patients vs. placebo‐treated patients (P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. Conclusions The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard‐dosed antihistamines.     

Membrane‐bound stem cell factor is the major but not only driver of fibroblast‐induced murine skin mast cell differentiation

The maintenance and modulation of cutaneous mast cell (MC) numbers is held to be important for skin immune responses to allergens and pathogens. The increase in MC numbers in the skin is achieved by proliferation and the differentiation of precursor to mature MCs. Fibroblast‐derived SCF is thought to be the major skin MC growth factor and it potently induces MC proliferation. The mechanisms of fibroblast‐induced skin MC differentiation, including the role of SCF, however, remain insufficiently characterized and understood. Using cocultures of immature murine MCs and fibroblasts, we found that the adhesion of immature MCs to fibroblasts via VCAM‐1 and α₄β₇ integrin is very important for subsequent differentiation, which is driven by fibroblast membrane‐bound SCF and additional fibroblast‐derived membrane‐bound signals. Thus, our results show that fibroblast‐induced MC differentiation is induced by direct cell–cell contact and involves both Kit‐dependent and Kit‐independent pathways. Our findings add to the understanding of how immature mast cells mature in murine skin and encourage further analyses of the underlying mechanisms, which may result in novel targets for the modulation of skin mast cell driven diseases.     

Biologic basis for interleukin-1 in disease

To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL- 1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.     

Erythroid marrow function in anemic patients

Erythropoietic activity is known to be closely associated with marrow iron uptake. A modification of the standard measure of plasma iron turnover has been developed in which erythron transferrin uptake (ETU) rather than iron uptake has been calculated. The ETU has the advantage of providing a parameter of erythroid marrow activity independent of change produced by plasma iron and transferrin saturation. Measurements in 80 patients with anemia were compared to the normal value of 60 +/- 12 mumol/L whole blood/d. The mean ETU for ten patients with severe aplastic anemia and for six patients with pure red-cell aplasia were 12 +/- 8 and 12 +/- 11 mumol/L whole blood/d, respectively. In ten transfusion-dependent patients with renal failure under dialysis therapy, the mean value was 35 +/- 11, while ten other dialyzed patients who were transfusion independent had a mean ETU of 73 +/- 21 mumol/L whole blood/d. Sixteen patients with hemolytic anemia had an average ETU of 400 +/- 130, while 28 patients with ineffective erythropoiesis had a mean value of 474 +/- 147 mumol/L whole blood/d. While patients with hypoproliferative anemia showed no relation between the severity of anemia and ETU, those with hyperproliferative erythroid marrow showed increasing values as the anemia became more severe. Sequential measurements in patients with aplastic anemia under treatment and in thalassemic patients under transfusion therapy showed the value of this measurement in monitoring the effects of treatment on erythroid marrow activity. It is concluded that the measurement of ETU provides a more direct ferrokinetic evaluation of erythroid activity in anemic states.