Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression

Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer : final results of a randomised phase 2 clinical trial

The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). Vx-001 could induce specific CD8 immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. Clinical trial registration: NCT0193515

Actions of substance p on cellular responses during neurogenic inflammation

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Η εμπειρία των επαγγελματιών υγείας του Γενικού Νοσοκομείου Μυτιλήνης "Βοστάνειο" κατά τη φροντίδα προσφύγων και μεταναστών

Εισαγωγή: Τα δυο τελευταία χρόνια, πλήθος ανθρώπων από περιοχές της Μέσης Ανατολής και της Αφρικής αποτόλμησαν το δύσκολο και επικίνδυνο ταξίδι μέχρι την Ευρώπη. Μία από τις πύλες εισόδου στη χώρα ήταν και το νησί της Λέσβου. Σκοπός: Η διερεύνηση των εμπειριών των επαγγελματιών υγείας του Γενικού Νοσοκομείου Μυτιλήνης που επωμίστηκαν το φορτίο υγειονομικής περίθαλψης και φροντίδας μεταναστών και προσφύγων το 2015-2016. Υλικό – Μέθοδος: Το δείγμα απετέλεσαν 150 επαγγελματίες υγείας με ποσοστό ανταπόκρισης 81,9%. Η συλλογή των δεδομένων πραγματοποιήθηκε με τη χρήση ερωτηματολογίου βασισμένου στις θεματικές ενότητες: α) Γλώσσα – Επικοινωνία, β) Κουλτούρα, γ) Θρησκεία δ) Γενικές στάσεις. Αποτελέσματα: Οι επαγγελματίες αντιμετώπισαν γλωσσικά εμπόδια και επισήμαναν την αναγκαιότητα της διερμηνείας. Αναγνωρίζουν τις διαφορετικές απόψεις περί ασθενείας, την ανάγκη φροντίδας από άτομο του ίδιου φύλου αλλά και την επίδραση της θρησκείας στα πρότυπα φροντίδας. Συμπεράσματα: Τα αποτελέσματα μπορούν να θεωρηθούν χρήσιμα για τον προγραμματισμό κατάλληλων παρεμβάσεων για κάθε επαγγελματική ομάδα, με σκοπό τη βελτίωση της ποιότητας των υπηρεσιών φροντίδας υγείας. Λέξεις-Κλειδιά: Επαγγελματίες υγείας, πρόσφυγες, μετανάστες, επικοινωνία, κουλτούρα, θρησκεία.Introduction: During the last two years, a vast majority of people attempted to travel from Middle East countries as well as Africa towards Europe. One of the entrance gates was Lesvos. Purpose: The purpose of the study was to explore the experience of healthcare providers of General hospital of Mytilene during refugee and immigrant care. Method: The sample was consisted of 150 healthcare professionals with 81,9% participation. The collection of data was formulated via a questionnaire based on the following topics: a) Language -Communication b) Culture c) Religion d) General Attitudes. Results: Healthcare providers faced a lot of communication problems, they recognize the need of interpretation services as well as the effect of cultural and religious beliefs on health care. They are also aware of the need for gender matching. Conclusions: The results can be found useful in designing appropriate interventions for healthcare providers, in order to improve the quality of care services. Key Words: healthcare providers, refugees, immigrants, communication, culture, religion

Άστεγοι στην Αθήνα: προφίλ υγείας & εμβολιαστική κάλυψη

Σε παγκόσμιο επίπεδο, το πρόβλημα της αστεγίας, έχει τεράστεις διαστάσεις και χαρακτηριστικά πολυπαραγοντικού ζητήματος Δημόσιας Υγείας. Με προέχοντες τους κοινωνικούς προσδιοριστές και δευτερευόντως ατομικά αίτια, οι άστεγοι ορίζονται και αντιμετωπίζονται διαφορετικά στις διάφορες χώρες του ανεπτυγμένου αλλά και του αναπτυσσόμενου κόσμου. Στην Ελλάδα, το φαινόμενο της έλλειψης κι επισφάλειας στέγης είναι σχετικά πρόσφατο. Τα πολλαπλά προβλήματα που βιώνουν οι άστεγοι, είναι υγείας, κοινωνικά, οικονομικά και ψυχολογικά, όλα προερχόμενα από, αλλά και προκαλώντας τον κοινωνικό αποκλεισμό. Καθώς η πολυνοσηρότητα είναι κοινή στους άστεγους, η προσιτή και διαθέσιμη πρωτοβάθμια φροντίδα υγείας αποτελεί προϋπόθεση για αποτελεσματικές παρεμβάσεις στον τομέα της υγείας. Έγινε προσπάθεια για μια εκτίμηση του υγεινομικού προφίλ των αστέγων που πήραν μέρος στην ποιοτική μελέτη, της σχέσης τους με τις δομές υγείας και τη διενέργεια εμβολιασμών για τέσσερα κοινά νοσήματα, με υψηλή επίπτωση στον πληθυσμό αυτό.At an international level, the problem of homelessness has enormous dimensions and features of a multifactorial Public Health’s issue. Social determinants are primary causes and individual-personal causes are secondary, for people’s homelessness, which is defined and treated in a different way among the countries of the developed and the developing world. In Greece, the phenomenon is relatively recent. The huge amount of problems faced by the homeless are about health, social, economic and psychological reasons, all deprived of and provoking social exclusion. As multimorbidity is common among the homeless, accessible and affordable primary health care is a prerequisite for effective health interventions. An effort has been made to assess: the health profile of the homeless people who took part in this qualitative study, their relationship with health structures and the possible implementation of vaccinations against four common diseases, particularly dangerous for this population

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while simultaneously they can recruit T regulatory cells to further promote immunosuppression, thus shielding tumor cells against the immune defenses. In addition, they were shown to support tumor invasion and metastasis by inducing vascularization. Yet again, in order to exert their angiogenic activities, they do have at their disposal a variety of occasionally overlapping mechanisms, mainly driven by VEGF/JAK/STAT signaling. In this concept, they have risen to be a rather attractive target for therapies, including depletion or maturation, so as to overcome cancer immunity and suppress angiogenic activity. Even though, many studies have been conducted to better understand these cells, there is much to be done yet. This article hopes to shed some light on the paradoxal complexity of these cells, while elucidating some of the key features of MDSCs in relation to immunosuppression and, most importantly, to the vascularization processes, along with current therapeutic options in cancer, in relation to MDSC depletion

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

Myeloid-derived suppressor cells (MDSCs) constitute a vast population of immature myeloid cells implicated in various conditions. Most notably, their role in cancer is of great complexity. They exert immunosuppressive functions like hampering cancer immunity mediated by T lymphocytes and natural killer cells, while simultaneously they can recruit T regulatory cells to further promote immunosuppression, thus shielding tumor cells against the immune defenses. In addition, they were shown to support tumor invasion and metastasis by inducing vascularization. Yet again, in order to exert their angiogenic activities, they do have at their disposal a variety of occasionally overlapping mechanisms, mainly driven by VEGF/JAK/STAT signaling. In this concept, they have risen to be a rather attractive target for therapies, including depletion or maturation, so as to overcome cancer immunity and suppress angiogenic activity. Even though, many studies have been conducted to better understand these cells, there is much to be done yet. This article hopes to shed some light on the paradoxal complexity of these cells, while elucidating some of the key features of MDSCs in relation to immunosuppression and, most importantly, to the vascularization processes, along with current therapeutic options in cancer, in relation to MDSC depletion