Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis

Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy

Cultural Heritage led Growth: Regional evidence from Greece (1998-2016)

This paper brings empirical evidence on the relationship between cultural heritage assets and economic growth. The case of Greece over the period 1998-2016 is taken as an example. Regional growth is approached through the formulation of a neoclassical growth model augmented with cultural heritage factors. Using panel methods of estimation, the empirical results reveal a positive impact of cultural heritage on regional growth, thus supporting a culture-led growth hypothesis for the Greek economy. In addition, a significant influence of other growth drivers such as physical and human capital, fertility and unemployment on regional growth is evidenced. Our results leave ample room for smart, inclusive and sustainable national, regional and EU policies to operate for the promotion of economic growth

Cultural Heritage led Growth: Regional evidence from Greece (1998-2016)

This paper brings empirical evidence on the relationship between cultural heritage assets and economic growth. The case of Greece over the period 1998-2016 is taken as an example. Regional growth is approached through the formulation of a neoclassical growth model augmented with cultural heritage factors. Using panel methods of estimation, the empirical results reveal a positive impact of cultural heritage on regional growth, thus supporting a culture-led growth hypothesis for the Greek economy. In addition, a significant influence of other growth drivers such as physical and human capital, fertility and unemployment on regional growth is evidenced. Our results leave ample room for smart, inclusive and sustainable national, regional and EU policies to operate for the promotion of economic growth

Population dynamics of Staphylococcus aureus and Salmonella Typhimurium in a laboratory medium and rocket extract

In the present study, the growth of Staphylococcus aureus and Salmonella Typhimurium on different growth media was studied. For this purpose, a growth medium (Luria – Bertani broth, LB) and extract from rocket, were inoculated with Staphylococcus aureus strain COL (MRSA) and Salmonella Typhimurium (CDC 6516-60). After the inoculation, the samples were incubated at 20°C

Identification of meat spoilage gene biomarkers in Pseudomonas putida using gene profiling

While current food science research mainly focuses on microbial changes in food products that lead to foodborne illnesses, meat spoilage remains as an unsolved problem for the meat industry. This can result in important economic losses, food waste and loss of consumer confidence in the meat market. Gram-negative bacteria involved in meat spoilage are aerobes or facultative anaerobes. These represent the group with the greatest meat spoilage potential, where Pseudomonas tend to dominate the microbial consortium under refrigeration and aerobic conditions. Identifying stress response genes under different environmental conditions can help researchers gain an understanding of how Pseudomonas adapts to current packaging and storage conditions. We examined the gene expression profile of Pseudomonas putida KT2440, which plays an important role in the spoilage of meat products. Gene expression profiles were evaluated to select the most differentially expressed genes at different temperatures (30 °C and 10 °C) and decreasing glucose concentrations, in order to identify key genes actively involved with the spoilage process. A total of 739 and 1269 were found to be differentially expressed at 30 °C and 10 °C respectively; of which 430 and 568 genes were overexpressed, and 309 and 701 genes were repressed at 30 °C and 10 °C respectively

Ability of Salmonella enterica and Staphylococcus aureus to develop biofilm community on stainless steel and colonize rocket tissue

In the present study, the ability of S. Typhimurium (CDC 6516-60) and S. aureus strain COL (MRSA) to both develop a biofilm community on stainless steel (SS) and colonize rocket tissue was investigated (incubation at 20°C for 144 h). In parallel, the planktonic growth of these pathogens in Brain Heart Infusion (BHI) broth, was followed

Appeal No. 0781: Boardman Local School District Board of Education v. Division of Mineral Resources Management

Chief\u27s Order 2007-40 (Ohio Valley Energy Systems

Targeted gene expression study of Salmonella enterica during biofilm formation on rocket leaves

In the present study, the ability of Salmonella Typhimurium to form biofilm community on rocket leaves and rocket extract at 10 C and 20 C was investigated. This goal was achieved with the study of expression of genes associated with biofilm formation and other functional roles. The obtained results showed that Salmonella growth was inhibited when cultured in rocket extract (liquid and solid state) and when grew directly to rocket leaves. The observed inhibition might be attributed to nutrient starvation to the specific growth media because of plant leaves's variability, cell physiology and antimicrobial compounds of rocket. In addition, gene expression study using Real-Time PCR showed that biofilm was formatted on solid media, while the entrance and adhesion of the microorganism within the plant held more strongly through the stomata of the plant leaves. Furthermore, genes associated with managing stress situations were overexpressed at 20 C. From these results, it is indicated that further studies are needed to better determine the survival and/or growth of the pathogen as “real” biofilm cells on plants. In addition, the study on development and gene expression of biofilm cells is necessary in order to eliminate the specific pathogen and reduce the food-borne diseases it causes

Η σημασία της μικροδορυφορικής αστάθειας (MSI) σε χαμηλής διαφοροποίησης αδενοκαρκινώματα του ενδομητρίου

Η ανεπάρκεια επιδιόρθωσης της αναντιστοιχίας (Mismatch repair deficiency- MMRd) ως αποτέλεσμα δυσλειτουργίας των γονιδίων που είναι υπεύθυνα για την επιδιόρθωση βλαβών του DNA, δηλαδή των MLH1, PMS2, MSH2 και MSH6, οδηγεί στην ανάπτυξη μικροδορυφορικής αστάθειας (Microsatellite instability- MSI). Τα καρκινώματα με μικροδορυφορική αστάθεια αποτελούν έναν από τους τέσσερις μοριακούς υπότυπους καρκίνου ενδομητρίου, σύμφωνα με την νέα ταξινόμηση από την ομάδα του Άτλαντα Γονιδιώματος του Καρκίνου (The Cancer Genome Atlas - TCGA) και αφορούν σε περίπου 30% των περιπτώσεων ενδομητρικού καρκίνου, θεωρούνται δε καρκινώματα ενδιάμεσης επιθετικότητας. Δεδομένου ότι τα χαμηλής διαφοροποίησης (grade 3) καρκινώματα έχουν συχνότερα επιθετική βιολογική συμπεριφορά και μεγαλύτερη πιθανότητα να εμφανίσουν μεταστατική νόσο, θεωρήσαμε σημαντικό να μελετήσουμε τη μικροδορυφορική αστάθεια στην ομάδα αυτή των καρκινωμάτων συμπεριλαμβάνοντας όλους τους ιστολογικούς τύπους που την απαρτίζουν, αλλά και να συγκρίνουμε την έκφραση των MMR πρωτεϊνών με την παρουσία ή όχι μεταλλαγμένου p53. Στόχος είναι να διαπιστώσουμε εάν η παρουσία μικροδορυφορικής αστάθειας αλλά και σε σχέση και με την έκφραση του p53, επηρεάζει την βιολογική συμπεριφορά των χαμηλής διαφοροποίησης ενδομητρικών καρκινωμάτων. Επιπλέον, είναι πολύ πιθανό οι ασθενείς αυτές να μπορούσαν να ωφεληθούν από μία θεραπεία που θα στόχευε στην αναστολή της δράσης των μορίων που σχετίζονται με τον προγραμματισμένο κυτταρικό θάνατο. Μεθοδολογία Υποψήφιες να συμπεριληφθούν στο παρόν ερευνητικό πρωτόκολλο ήταν γυναίκες που είχαν διαγνωστεί και αντιμετωπιστεί με χαμηλής διαφοροποίησης (grade 3) καρκίνο ενδομητρίου από το 2001 έως το 2017 στο εξειδικευμένο Τμήμα Γυναικολογικής Ογκολογίας της Γυναικολογικής Κλινικής ΙΑΣΩ. Πραγματοποιήθηκε η συλλογή και ανάλυση ποικίλων κλινικών και παθολογοανατομικών χαρακτηριστικών καθώς και η αξιολόγηση της ανοσοϊστοχημικής έκφρασης των τεσσάρων πρωτεϊνών επιδιόρθωσης (MMR protein expression) MLH1, PMS2, MSH2 και MSH6 αλλά και του p53. Η στατιστικές συσχετίσεις πραγματοποιήθηκαν με το στατιστικό πρόγραμμα SPSS version 23.0 (Armonk, NY). Αποτελέσματα Ο τελικός πληθυσμός της μελέτης αποτελείτo από 101 περιστατικά από τα οποία τα 41 περιστατικά αφορούσαν σε ενδομητριοειδή, ενώ τα 60 σε μη-ενδομητριοειδή καρκινώματα. Η πλειοψηφία των όγκων με μικροδορυφορική αστάθεια (MMRd-deficient) ήταν ενδομητριοειδούς τύπου (73,3%), ενώ οι όγκοι χωρίς μικροδορυφορική αστάθεια (MMRp- proficient) ήταν κυρίως μη ενδομητριοειδούς ιστολογικού τύπου (73,8%) (p<0,001). Αναλύοντας ξεχωριστά τους ιστολογικούς υπότυπους, μόνο οι ενδομητριοειδείς MMRd όγκοι βρέθηκαν να συσχετίζονται στατιστικά σημαντικά με αυξημένο βάθος διήθησης μυομητρίου, λεμφαδενικές μεταστάσεις και προχωρημένο στάδιο νόσου (p=0,035, p=0,011 και p=0,028, αντίστοιχα). Η ανάλυση επιβίωσης δεν ανέδειξε στατιστικά σημαντική διαφορά μεταξύ της έκφρασης πρωτεϊνών επιδιόρθωσης και επιβίωσης. Η επικουρική θεραπεία δεν βρέθηκε να επηρεάζει την πρόοδο της ασθένειας. Κατά την μελέτη των πρωτεϊνών επιδιόρθωσης ξεχωριστά, η απώλεια έκφρασης της MSH6 βρέθηκε να συσχετίζεται στατιστικά σημαντικά με λεμφαδενικές μεταστάσεις (p=0,04), ενώ η απώλεια έκφρασης των PMS2 και MLH1 με αυξημένο βάθος διήθησης του μυομητρίου (p=0,019 και p=0,036, αντίστοιχα). Τέλος, η παρουσία μεταλλαγμένου p53 δεν φαίνεται να επηρεάζει αρνητικά τη βιολογική συμπεριφορά των MMRd dή MMRp καρκινωμάτων. Συμπεράσματα Στη μελέτη μας, παρατηρήθηκε στατιστικά σημαντική συσχέτιση της απουσίας έκφρασης των πρωτεϊνών επιδιόρθωσης του DNA (MMR deficiency) με τον ενδομητριοειδή ιστότυπο σε σχέση με τους μη- ενδομητριοειδείς όγκους. Επιπρόσθετα, τα ενδομητριοειδή MMRd καρκινώματα φαίνεται να σχετίζονται με χαρακτηριστικά επιθετικής νόσου χωρίς όμως να παρουσιάζουν χειρότερη επιβίωση όταν συγκρίνονται με τα MMRp καρκινώματα. Ο έλεγχος μόνο των δύο πρωτεϊνών, των PMS2 και MSH6, φαίνεται ότι μπορεί να χρησιμοποιηθεί για τον εντοπισμό MMRd με ακρίβεια ισοδύναμη με τον έλεγχο και των τεσσάρων πρωτεϊνών. Η μη αναγνώριση αρνητικής προγνωστικής σημασίας σε p53 μεταλλαγμένα MMRd καρκινώματα είναι συμβατή με το αναμενόμενο βάσει της θεωρίας των «πολλαπλών ταξινομητών».Purpose Mismatch repair deficiency (MMRd) as a result of dysfunction of the genes responsible for DNA repair damage, namely MLH1, PMS2, MSH2 and MSH6, leads to the development of microsatellite instability (MSI). Carcinomas with microsatellite instability are one of the four molecular subtypes of endometrial cancer, according to the new classification by the Cancer Genome Atlas (TCGA) group, and they represent about 30% of endometrial cancer cases and are considered carcinomas of intermediate risk. Given that grade 3 carcinomas have more often an aggressive biological behaviour and a higher probability of metastatic disease, we considered it important to study microsatellite instability in this group of carcinomas. We also found important to include all histological types that consist this group, and to compare the expression of MMR proteins with the presence of wild type or abnormal p53 expression. The aim is to determine whether microsatellite instability alone or in relation to p53 expression could affect the biological behaviour of poorly differentiated endometrial carcinomas. In addition, it is very possible that these patients could benefit from a treatment targeting to inhibit the action of molecules associated with programmed cell death. Methods Candidates for inclusion in the present research protocol were women who had been diagnosed and treated with poorly differentiated (grade 3) endometrial cancer from 2001 to 2017 at the specialized Gynaecological Oncology Department of IASO Gynaecology Hospital. The collection and analysis of a variety of clinical and pathologic characteristics was carried out, following by the evaluation of the immunohistochemical expression of the four mismatch repair proteins, MLH1, PMS2, MSH2 and MSH6, as well as the expression of p53. Statistical analysis was performed with the statistical program SPSS version 23.0 (Armonk, NY). Results The final population of the study consists of 101 cases, of which 41 cases were endometrioid, while 60 were non-endometrioid carcinomas. The majority of MMRd tumors were of endometrioid type (73.3%), while MMR proficient (MMRp) cases were mainly of non-endometrioid histological type (73.8%) (p<0.001). Analysing histological types separately, endometrioid MMRd tumors were found to be statistically significantly associated with increased depth of myometrial invasion, lymph node metastases and advanced stage of disease (p=0.035, p=0.011 and p=0.028, respectively). Survival analysis revealed no statistically significant difference between MMR protein expression and outcome. Adjuvant therapy was not found to affect disease progression. When examining the MMR proteins separately, loss of MSH6 expression was found to be statistically significantly associated with lymph node metastases (p=0.04), while loss of expression of PMS2 and MLH1 with increased depth of myometrial invasion (p=0.019 and p =0.036, respectively). Finally, the presence of mutated p53 does not seem to negatively affect the biological behaviour of MMRd carcinomas. Conclusions In our group of high-grade endometrial car¬cinomas, MMR deficiency was statistically significantly more frequent in endometrioid than in non-endometrioid cancers. In addition, endometrioid MMRd carcinomas appear to be associated with features of aggressive disease but do not show worse survival when compared to MMRp carcinomas. Our findings support the two-protein testing algorithm compared to staining of all four proteins. The failure to identify a negative prognostic significance in p53 mutated MMRd carcinomas is compatible with what would be expected based on the “multiple classifier” theory