Cyclometallated Au(III) dithiocarbamate complexes: synthesis, anticancer evaluation and mechanistic studies

A series of cationic mixed cyclometallated (C^N)Au(III) dithiocarbamate complexes has been synthesized in good yields [HC^N = 2-(p-t-butylphenyl)pyridine]. The crystal structure of [(C^N)AuS2CNEt2]PF6 (3) has been determined. The cytotoxic properties of the new complexes have been evaluated in vitro against a panel of human cancer cell lines and healthy cells and compared with a neutral mixed (C^C)Au(III) dithiocarbamate complex (C^C = 4,4′-di-t-butylbiphenyl-2,2′-diyl). The complexes appeared to be susceptible to reduction by glutathione but were stable in the presence of N-acetyl cysteine. The potential mechanism of action of this class of compounds has been investigated by measuring the intracellular uptake of some selected complexes, by determining their interactions with higher order DNA structures, and by assessing the ability to inhibit thioredoxin reductase. The complexes proved unable to induce the formation of reactive oxygen species. The investigations add to the picture of the possible mode of action of this class of complexes

Five-years surveillance of invasive aspergillosis in a university hospital

<p>Abstract</p> <p>Background</p> <p>As the most common invasive fungal infection, invasive aspergillosis (IA) remains a serious complication in immunocompromised patients, leading to increased mortality. Antifungal therapy is expensive and may result in severe adverse effects.</p> <p>The aim of this study was to determine the incidence of invasive aspergillosis (IA) cases in a tertiary care university hospital using a standardized surveillance method.</p> <p>Methods</p> <p>All inpatients at our facility were screened for presence of the following parameters: positive microbiological culture, pathologist's diagnosis and antifungal treatment as reported by the hospital pharmacy. Patients fulfilling one or more of these indicators were further reviewed and, if appropriate, classified according to international consensus criteria (EORTC).</p> <p>Results</p> <p>704 patients were positive for at least one of the indicators mentioned above. Applying the EORTC criteria, 214 IA cases were detected, of which 56 were proven, 25 probable and 133 possible. 44 of the 81 (54%) proven and probable cases were considered health-care associated. 37 of the proven/probable IA cases had received solid organ transplantation, an additional 8 had undergone stem cell transplantation, and 10 patients were suffering from some type of malignancy. All the other patients in this group were also suffering from severe organic diseases, required long treatment and experienced several clinical complications. 7 of the 56 proven cases would have been missed without autopsy. After the antimycotic prophylaxis regimen was altered, we noticed a significant decrease (p = 0.0004) of IA during the investigation period (2003-2007).</p> <p>Conclusion</p> <p>Solid organ and stem cell transplantation remain important risk factors for IA, but several other types of immunosuppression should also be kept in mind. Clinical diagnosis of IA may be difficult (in this study 13% of all proven cases were diagnosed by autopsy only). Thus, we confirm the importance of IA surveillance in all high-risk patients.</p

Expression of Stem Cell Markers in the Human Fetal Kidney

In the human fetal kidney (HFK) self-renewing stem cells residing in the metanephric mesenchyme (MM)/blastema are induced to form all cell types of the nephron till 34th week of gestation. Definition of useful markers is crucial for the identification of HFK stem cells. Because wilms' tumor, a pediatric renal cancer, initiates from retention of renal stem cells, we hypothesized that surface antigens previously up-regulated in microarrays of both HFK and blastema-enriched stem-like wilms' tumor xenografts (NCAM, ACVRIIB, DLK1/PREF, GPR39, FZD7, FZD2, NTRK2) are likely to be relevant markers. Comprehensive profiling of these putative and of additional stem cell markers (CD34, CD133, c-Kit, CD90, CD105, CD24) in mid-gestation HFK was performed using immunostaining and FACS in conjunction with EpCAM, an epithelial surface marker that is absent from the MM and increases along nephron differentiation and hence can be separated into negative, dim or bright fractions. No marker was specifically localized to the MM. Nevertheless, FZD7 and NTRK2 were preferentially localized to the MM and emerging tubules (<10% of HFK cells) and were mostly present within the EpCAMneg and EpCAMdim fractions, indicating putative stem/progenitor markers. In contrast, single markers such as CD24 and CD133 as well as double-positive CD24+CD133+ cells comprise >50% of HFK cells and predominantly co-express EpCAMbright, indicating they are mostly markers of differentiation. Furthermore, localization of NCAM exclusively in the MM and in its nephron progenitor derivatives but also in stroma and the expression pattern of significantly elevated renal stem/progenitor genes Six2, Wt1, Cited1, and Sall1 in NCAM+EpCAM- and to a lesser extent in NCAM+EpCAM+ fractions confirmed regional identity of cells and assisted us in pinpointing the presence of subpopulations that are putative MM-derived progenitor cells (NCAM+EpCAM+FZD7+), MM stem cells (NCAM+EpCAM-FZD7+) or both (NCAM+FZD7+). These results and concepts provide a framework for developing cell selection strategies for human renal cell-based therapies

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

Nine-Years Surveillance of invasive Aspergillosis in a University Hospital

Graf K, Weiner V, Ott E, Albrecht U-V, Ziesing S, Chaberny IF. Nine-Years Surveillance of invasive Aspergillosis in a University Hospital. In: DGHM 2012. International Journal of Medical Microbiology. Vol 302. Elsevier; 2012

Analyse von nosokomialen Ausbrüchen mit multiresistentem Acinetobacter baumannii

Hintergrund: In deutschen Krankenhäusern treten, besonders auf Intensivstationen, immer häufiger Ausbrüche mit multiresistentem Acinetobacter baumannii (MR-AB) auf. Trotz umgehend initiierter Isolierungsmaßnahmen kommt es jedoch häufig zu weiteren Übertragungen. Methode: Um über die Isolierungsmaßnahmen hinaus ggf. weitere Präventionsmaßnahmen vorschlagen zu können, wurden sieben Ausbrüche an drei Universitätsklinika mit insgesamt 59 betroffenen Patienten analysiert. Ergebnisse: Es zeigte sich, dass ein Teil der Indexpatienten als Intensivverlegungen aus Ländern aufgenommen wurden, in denen Infektionen durch multiresistente gramnegative Bakterien weit verbreitet sind. In einem Fall gab es bei dem vermutlichen Indexpatienten einen Vorbefund mit MR-AB, es war aber kein Alert-System etabliert. Für einige Übertragungen auf Patienten auf räumlich zum Teil weit entfernt liegenden Stationen konnten epidemiologische Hinweise dafür gefunden werden, dass diese durch einmalige Kontakte von Personal, das stationsübergreifend tätig ist, erfolgt sein könnten. Auch wurden Ausbrüche durch die Verlegung von Patienten auf weitere Stationen ausgeweitet. Schlussfolgerung: Zur Prävention von Ausbrüchen durch MR-AB ist zu überlegen, Intensivpatienten, die aus Ländern mit hoher Prävalenz multiresistenter Erreger übernommen werden, präventiv zu isolieren und ein Aufnahmescreening auf multiresistente gramnegative Bakterien durchzuführen. Dabei ist zu beachten, dass MR-AB unter wirksamer antibiotischer Therapie möglicherweise nicht nachweisbar sind. Des Weiteren ist ein Alert-System bei Wiederaufnahme von Patienten mit MR-AB zu empfehlen. Schulungen hinsichtlich der Prävention von Übertragungen sollten gerade bei diesem Erreger auch stationsübergreifend tätiges Personal einbeziehen.Background: There have been numerous descriptions of outbreaks with multidrug resistant Acinetobacter baumannii (MR-AB) in German hospitals in recent years. Despite the immediate implementation of isolation precautions further transmissions were frequently observed. Method: In this study seven outbreaks including 59 patients at three university hospitals were analysed to propose additional prevention measures.Results: Some of the index patients had been transferred from countries where infections due to multidrug resistant Gram negative bacteria are widespread. In one case the probable index case had been tested positive for MR-AB during a previous hospital stay, and an alert system on readmission had not been established. This study showed epidemiological evidence that a single contact to staff working in different areas of the hospital could have been effectual for transmissions to patients in distant wards. Additionally, outbreaks spread to other wards through patient transfer. Conclusion: To prevent outbreaks with MRAB we propose a screening for multidrug resistant Gram negative bacteria (MDR-GN) in patients transferred from countries with a high prevalence of MDR-GN at admission and to keep them under preventive isolation precautions. We further recommend the establishment of an alert system on readmission of patients with MR-AB. Education on infection prevention measures has to include staff working on different wards and departments of the hospital

Roadmap for Edge AI:a Dagstuhl perspective

Based on the collective input of Dagstuhl Seminar (21342), this paper presents a comprehensive discussion on AI methods and capabilities in the context of edge computing, referred as Edge AI. In a nutshell, we envision Edge AI to provide adaptation for data-driven applications, enhance network and radio access, and allow the creation, optimization, and deployment of distributed AI/ML pipelines with given quality of experience, trust, security and privacy targets. The Edge AI community investigates novel ML methods for the edge computing environment, spanning multiple sub-fields of computer science, engineering and ICT. The goal is to share an envisioned roadmap that can bring together key actors and enablers to further advance the domain of Edge AI.Comment: for ACM SIGCOMM CC

Roadmap for edge AI : A Dagstuhl Perspective

Funding Information: The work is partially supported by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101021808, by CHIST-ERA grant CHIST-ERA-19-CES-005, and by the Austrian Science Fund (FWF): I 5201-N. Funding Information: The discussions leading to this editorial were initiated in Dagstuhl Seminar 21342 on Identifying Key Enablers in Edge Intelligence, and we thank all participants for their contributions. The work is partially supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 101021808, by CHIST-ERA grant CHIST-ERA-19-CES-005, and by the Austrian Science Fund (FWF): I 5201-N. Publisher Copyright: © 2022 Copyright is held by the owner/author(s).Based on the collective input of Dagstuhl Seminar (21342), this paper presents a comprehensive discussion on AI methods and capabilities in the context of edge computing, referred as Edge AI. In a nutshell, we envision Edge AI to provide adaptation for data-driven applications, enhance network and radio access, and allow the creation, optimisation, and deployment of distributed AI/ML pipelines with given quality of experience, trust, security and privacy targets. The Edge AI community investigates novel ML methods for the edge computing environment, spanning multiple sub-fields of computer science, engineering and ICT. The goal is to share an envisioned roadmap that can bring together key actors and enablers to further advance the domain of Edge AI.Non peer reviewe

Roadmap for edge AI: A Dagstuhl Perspective

Based on the collective input of Dagstuhl Seminar (21342), this paper presents a comprehensive discussion on AI methods and capabilities in the context of edge computing, referred as Edge AI. In a nutshell, we envision Edge AI to provide adaptation for data-driven applications, enhance network and radio access, and allow the creation, optimisation, and deployment of distributed AI/ML pipelines with given quality of experience, trust, security and privacy targets. The Edge AI community investigates novel ML methods for the edge computing environment, spanning multiple sub-fields of computer science, engineering and ICT. The goal is to share an envisioned roadmap that can bring together key actors and enablers to further advance the domain of Edge AI.Information and Communication TechnologyDistributed System