SMAC Mimetic BV6 Induces Cell Death in Monocytes and Maturation of Monocyte-Derived Dendritic Cells

Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NFkB system and TNF signaling. In view of the overwhelming importance of the NFkB transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings: BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NFkB pathway, but it also diminished the stronger NFkB-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12. Significance: The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies

Дослідження структури порушених відкритою розробкою земель й пошук шляхів вдосконалення рекультивації залишкових виробок кар'єрів

Стаття присвячена дослідженням структури порушених земель, на ділянках з видобутку корисних копалин відкритим способом. Наведено площі порушень земель при розробці основних видів корисних копалин. Проаналізовано ризики, що виникають із несвоєчасною рекультивацією земель гірничого відводу, а також від покинутих гірничих виробок старих кар'єрів. Паралельно розглянуті обсяги відходів гірничого виробництва та їх повторне використання в якості заповнювача для залишкових вироблених просторів кар'єрів.The article is devoted to the research of land violation indicators at the extraction of minerals by surface mining method. Data gives about the land violations area at the mining key minerals. Ana-lyzed the risks from the not-on-time reclamation of the mining clam and abandoned excavations of the old quarries. In parallel considered the volumes of mining wastes and their reuse as aggregate for filling residual spaces of surface mines.Статья посвящена исследованиям площадей нарушения земель, связанных с добычей полезных ископаемых открытым способом. Приведены площади нарушений земель при разработке основных видов полезных ископаемых. Проанализированы риски, представляемые несвоевременной рекультивацией земель горного отвода, а также заброшенными горными выработками старых карьеров. Параллельно рассмотрены объемы отходов горного производства и их повторное использование в качестве заполнителя для остаточных выработанных пространств карьеров

The international EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria

Publisher Copyright: © 2021 GA²LEN. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA(2)LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.Peer reviewe

The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA(2)LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria

A Differentiation-Based Phylogeny of Cancer Subtypes

Histopathological classification of human tumors relies in part on the degree of differentiation of the tumor sample. To date, there is no objective systematic method to categorize tumor subtypes by maturation. In this paper, we introduce a novel computational algorithm to rank tumor subtypes according to the dissimilarity of their gene expression from that of stem cells and fully differentiated tissue, and thereby construct a phylogenetic tree of cancer. We validate our methodology with expression data of leukemia, breast cancer and liposarcoma subtypes and then apply it to a broader group of sarcomas. This ranking of tumor subtypes resulting from the application of our methodology allows the identification of genes correlated with differentiation and may help to identify novel therapeutic targets. Our algorithm represents the first phylogeny-based tool to analyze the differentiation status of human tumors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Definition of new MHC-class-I epitopes from the tumor-associated antigen MUC1 and the role of T-cell responses against tumor-associated antigens in the immune reconstitution after allogeneic stem cell transplantation

Der mit allogener Stammzelltransplantation (SCT) assoziierte "Graft-Versus-Leukemia"-Effekt war bis vor kurzem ein zum Großteil rein klinisch beschriebenes Phänomen. Besonders interessant ist hier das Potential tumorspezifischer T-Zellantworten gegen sogenannte "Selbst" -Antigene wie beispielsweise die in dieser Arbeit untersuchten Tumor-assoziierten Antigene MUC1, Proteinase 3 oder WT1. Die Definition von immer mehr Tumor-assoziierten Antigenen (TAA) erweitert den "Pool" an potentiellen Zielstrukturen für immuntherapeutische Impfstrategien. Es ist jedoch von großer Bedeutung, sich bei der steten Zunahme neuer Antigene nicht nur auf wenige HLA-Restriktionen zu beschränken, sondern ein breit gefächertes Angebot an Vakzine-Kandidaten zur Verfügung zu haben (wie in dieser Arbeit am Beispiel von MUC1 gezeigt), um die Immunantworten gegen ein möglichst breites Spektrum von HLA-Restriktionen überprüfen zu können und bei einem eventuellen zukünftigen klinischen Einsatz möglichst vielen Patienten diese Therapien zu ermöglichen. MHC-Klasse-I Peptidepitope aus dem Tumor-assoziierten Antigen MUC1 wurden hierzu für die HLA-Restriktionen HLA-A*68, B*0702, B*2705 und B*4402 vorhergesagt sowie synthetisiert. Für diese Restriktionen konnten Epitope nachgewiesen werden, die bei Patienten im untersuchten Kollektiv direkt ex vivo eine Peptid-spezifische IFN-g-Produktion in zytotoxischen T-Lymphozyten (CTL) induzieren. Zusätzlich konnte für jedes dieser insgesamt 5 Peptide eine Induzierbarkeit spezifischer T-Zellen in ex vivo negativen Spendern nachgewiesen und ein Funktionsnachweis dieser Zellen durch Peptid-spezifische IFN-g-Produktion erbracht werden. Insgesamt erwies sich das Screening vorhergesagter Peptide in einem geeigneten Patientenkollektiv mittels IFN-g-Nachweis als sehr gute und schnelle Methode, um neue T-Zell-Epitope zu definieren. In sieben von 19 Patienten nach allogener SCT konnten spezifische T-Zellen gegen Tumor-assoziierte Antigene (MUC1, WT1, Proteinase 3) detektiert werden. Interessanterweise zeigte sich in 85,7% der Fälle bei diesen Patienten eine Remission. Demgegenüber ließ sich in der Gruppe ohne spezifische T-Zellen für die untersuchten Antigene nur in 50% der Patienten eine Rezidivfreiheit beobachten. Nach Durchführung von Fishers exaktem Test konnte jedoch keine statistische Signifikanz dieser Ergebnisse festgestellt werden (p=0,29). Die fehlende Signifikanz dieser Ergebnisse ergibt sich möglicherweise aus der zu kleinen Anzahl untersuchter Patienten, da ebenso kein signifikanter Zusammenhang zwischen Auftreten einer "Graft-versus-Host Disease" (GVHD) und einem vermehrten Vorkommen von Remissionen bei den untersuchten Patienten (p=0,59) existierte, was im Gegensatz zu Literaturdaten weitaus größerer Untersuchungen steht.The Graft-versus-Leukemia (GVL) effect after allogeneic hematopoetic stem cell transplantation (SCT) is one of the most prominent examples showing the ability of the immune system to eliminate malignant diseases. First, this effect was a strictly clinically described phenomenon. However, in the last years T cell responses against tumor associated antigens (such as WT1, proteinase-3 or MUC1) could be detected and partly set in correlation with clinical benefit. The availability of new tumor-associated antigens (TAA) increased the number of potential targets for immunotherapeutic approaches; furthermore it is very important to define new MHC-class-I epitopes from known TAA to have a broad repertoire available for both T-cell monitoring and a possible vaccine development. MHC-class-I peptide epitopes from the TAA MUC1 were predicted by computer algorithms and synthesized (HLA restrictions A*68, B*0702, B*2705; B*4402). For each of these HLA restrictions, at least one MHC-class-I restricted peptide epitope was found to induce specific IFN-g production in cytotoxic T lymphocytes (CTL) of patients. In addition, we could demonstrate an induction of peptide-specific CTL in healthy donors and perform functional analysis. In 7/19 patients after allogeneic SCT, CTL directed against at least one of the TAA MUC1, WT1 or proteinase-3 could be detected. Interestingly, 85.7 % of these patients had not developed a relapse of their underlying disease at the time of analysis in contrast to the patients without TAA-specific CTL (only 50 %). The observed trend to a lower risk of relapse in patients with TAA-specific CTL was not statistically significant when performing Fishers exact test ( p = 0.29 ). Furthermore, no correlation between the occurrence of graft-versus-host disease (GVHD) and relapse in our small cohort of patients was found ( p = 0.59 ). Since the correlation between GVHD and a decreased risk of relapse was demonstrated in studies with more patients recruited, one could assume that our cohort was too small for an adequate statistical evaluation. To evaluate the importance of T-cell responses against TAA in allogeneic stem cell transplantation, further studies have to be performed

Intensified neoadjuvant chemotherapy with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX in a patient with locally advanced unresectable pancreatic cancer

The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial