ATF2 knockdown reinforces oxidative stress-induced apoptosis in TE7 cancer cells

Abstract Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress-based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21 WAF1 , but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21 WAF1 protein expression, suggesting p21 WAF1 transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2-binding sequence in the p21 WAF1 promoter. p-ATF2 was found to interact with p-c-Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21 WAF1 downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4-dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti-cancer therapies. Keywords: oxidative stress-induced DNA damage cell cycle arrest ATF2 knockdown increase in apoptosis sensitivities combined treatment p21 WAF

Anaphylaxis in Elderly Patients-Data From the European Anaphylaxis Registry

Background: Elicitors and symptoms of anaphylaxis are age dependent. However, little is known about typical features of anaphylaxis in patients aged 65 years or more. Methods: The data from the Network for Online Registration of Anaphylaxis (NORA) considering patients aged ≥65 (elderly) in comparison to data from adults (18–64 years) regarding elicitors, symptoms, comorbidities, and treatment measures were analyzed. Results: We identified 1,123 elderly anaphylactic patients. Insect venoms were the most frequent elicitor in this group (p < 0.001), followed by drugs like analgesics and antibiotics. Food allergens elicited less frequently anaphylaxis (p < 0.001). Skin symptoms occurred less frequently in elderly patients (77%, p < 0.001). The clinical symptoms were more severe in the elderly (51% experiencing grade III/IV reactions), in particular when skin symptoms (p < 0.001) were absent. Most strikingly, a loss of consciousness (33%, p < 0.001) and preexisting cardiovascular comorbidity (59%, p < 0.001) were more prevalent in the elderly. Finally, adrenaline was used in 30% of the elderly (vs. 26% in the comparator group, p < 0.001) and hospitalization was more often required (60 vs. 50%, p < 0.001). Discussion and Conclusion: Anaphylaxis in the elderly is often caused by insect venoms and drugs. These patients suffer more often from cardiovascular symptoms, receive more frequently adrenaline and require more often hospitalization. The data indicate that anaphylaxis in the elderly tends to be more frequently life threatening and patients require intensified medical intervention. The data support the need to recognize anaphylaxis in this patient group, which is prone to be at a higher risk for a fatal outcome

Peanut‐induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. Results 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). Conclusions The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition

Triggers and Treatment of Anaphylaxis An Analysis of 4000 Cases From Germany, Austria and Switzerland

Background: Anaphylaxis is the most severe manifestation of a mast cell-dependent immediate reaction and may be fatal. According to data from the Berlin region, its incidence is 2-3 cases per 100 000 persons per year. Methods: We evaluated data from the anaphylaxis registry of the German-speaking countries for 2006-2013 and data from the protocols of the ADAC air rescue service for 2010-2011 to study the triggers, clinical manifestations, and treatment of anaphylaxis. Results: The registry contained data on 4141 patients, and the ADAC air rescue protocols concerned 1123 patients. In the registry, the most common triggers for anaphylaxis were insect venom (n = 2074; 50.1%), foods (n = 1039; 25.1%), and drugs (n = 627; 15.1%). Within these groups, the most common triggers were wasp (n = 1460) and bee stings (n = 412), legumes (n = 241), animal proteins (n = 225), and analgesic drugs (n = 277). Food anaphylaxis was most frequently induced by peanuts, cow milk, and hen's egg in children and by wheat and shellfish in adults. An analysis of the medical emergency cases revealed that epinephrine was given for grade 3 or 4 anaphylaxis to 14.5% and 43.9% (respectively) of the patients in the anaphylaxis registry and to 19% and 78% of the patients in the air rescue protocols. Conclusion: Wasp and bee venom, legumes, animal proteins, and analgesic drugs were the commonest triggers of anaphylaxis. Their relative frequency was age-dependent. Epinephrine was given too rarely, as it is recommended in the guidelines for all cases of grade 2 and above