Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer

SummaryChromosomal instability in human breast cancer is known to take place before mammary neoplasias display morphological signs of invasion. We describe here the unexpected finding of a tumor cell population with normal karyotypes isolated from bone marrow of breast cancer patients. By analyzing the same single cells for chromosomal aberrations, subchromosomal allelic losses, and gene amplifications, we confirmed their malignant origin and delineated the sequence of genomic events during breast cancer progression. On this trajectory of genomic progression, we identified a subpopulation of patients with very early HER2 amplification. Because early changes have the highest probability of being shared by genetically unstable tumor cells, the genetic characterization of disseminated tumor cells provides a novel rationale for selecting patients for targeted therapies

Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery

Background: Roux-en-Y gastric bypass (RYGB) surgery is associated with weight loss, improved insulin sensitivity and glucose homeostasis, and a reduction in co-morbidities such as diabetes and coronary heart disease. To generate further insight into the numerous metabolic adaptations associated with RYGB surgery, we profiled serum metabolites before and after gastric bypass surgery and integrated metabolite changes with clinical data. Methodology and Principal Findings: Serum metabolites were detected by gas and liquid chromatography-coupled mass spectrometry before, and 3 and 6 months after RYGB in morbidly obese female subjects (n = 14; BMI = 46.261.7). Subjects showed decreases in weight-related parameters and improvements in insulin sensitivity post surgery. The abundance of 48 % (83 of 172) of the measured metabolites changed significantly within the first 3 months post RYGB (p,0.05), including sphingosines, unsaturated fatty acids, and branched chain amino acids. Dividing subjects into obese (n = 9) and obese/ diabetic (n = 5) groups identified 8 metabolites that differed consistently at all time points and whose serum levels changed following RYGB: asparagine, lysophosphatidylcholine (C18:2), nervonic (C24:1) acid, p-Cresol sulfate, lactate, lycopene, glucose, and mannose. Changes in the aforementioned metabolites were integrated with clinical data for body mass index (BMI) and estimates for insulin resistance (HOMA-IR). Of these, nervonic acid was significantly and negatively correlated with HOMA-IR (p = 0.001, R = 20.55)

An upper limit to the photon fraction in cosmic rays above 10^19 eV from the Pierre Auger Observatory

An upper limit of 16% (at 95% c.l.) is derived for the photon fraction in cosmic rays with energies above 10^19 eV, based on observations of the depth of shower maximum performed with the hybrid detector of the Pierre Auger Observatory. This is the first such limit on photons obtained by observing the fluorescence light profile of air showers. This upper limit confirms and improves on previous results from the Haverah Park and AGASA surface arrays. Additional data recorded with the Auger surface detectors for a subset of the event sample, support the conclusion that a photon origin of the observed events is not favoured

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

Gutachten Baukultur in ländlichen Räumen Brandenburgs

Baukultur in ländlichen Räumen ist Alltagsbaukultur, die von vielen Akteuren mitgeprägt wird. Ein großer Teil der Verantwortung für das baukulturelle Erscheinungsbild liegt auf kommunaler und regionaler Ebene. Baukultur in ländlichen Räumen kann nicht allein auf das Thema regionstypisches und historisches Bauen reduziert werden und bezieht sich nicht nur auf die Architektur des Gebäudes. Das baukulturelle Leitbild ist weiter gefasst und bezieht die Infrastruktur, die öffentlichen Räume sowie die Kulturlandschaft mit ein. Baukultur im ländlichen Raum ist ein Gemeinschaftswerk Vieler. Um das landesweite Spektrum widerzuspiegeln, wurden Praxisbeispiele aus Kleinstädten (max. 10.000 Einwohner) und Dörfern aus unterschiedlichen Regionen Brandenburgs untersucht. Im Fokus der Betrachtung steht vor allem die Alltagsbaukultur. Von Interesse sind alle strategischen, planerischen und prozessuale Ansätze, die sich ums Planen und Bauen in ländlichen Räumen drehen und für die zukünftige Entwicklung von Leitbildern, Methoden und Verfahren von Bedeutung sein könnten. Zielsetzung der Untersuchung ist die Erarbeitung eines Leitfadens für die Stärkung der Baukultur im ländlichen Raum. Die Zielgruppe des Leitfadens sind die Akteure der Baukultur in kleineren Städten und Kommunen der ländlichen Regionen Brandenburgs. Der Leitfaden soll jedoch nicht nur als Dokumentation der Ergebnisse dienen. Der Schwerpunkt wird darin liegen, den Prozess aufzuzeigen, der zu einer gelungenen Baukultur geführt hat. Welche Akteurs- und Trägerkonstellationen, welche Instrumente, rechtliche Grundlagen, Beteiligungsverfahren oder Finanzierung sind bei der Umsetzung zur Anwendung gekommen und können anderen Kommunen als Vorbild dienen

Role of LRP-1 in cancer cell migration in 3-dimensional collagen matrix

International audienc

Alarming Upward Trend in Multidrug-Resistant Bacteria in a Large Cohort of Immunocompromised Children: A Four-Year Comparative Study

Documenting bacteremia at the onset of fever in immunosuppressed children is challenging; therefore, it leads to the early administration of broad-spectrum antibiotics. We aimed to analyse the evolution of antibiotic resistance profiles of bacterial bloodstream infections (BSI) and gut colonisations in a large cohort of immunocompromised children carrying a central venous catheter, in comparison with a prior, similar study conducted in our centre from 2014 to 2017. A retrospective, observational cohort study was conducted from January 2018 to December 2021, in a tertiary centre for paediatric immuno-haematology and oncology. Empirical antibiotic therapy was adapted to the immunosuppression risk group and prior bacterial colonisation. There was a mean of 6.9 BSI/1000 patient bed days. Multidrug-resistant bacteria (MDRB) associated BSI accounted for 35/273 (12.8%). The incidence of MDRB gum/gut colonisation and MDRB associated BSI increased annually and correlated with the level of immunosuppression (p = 0.024). One third (34.7%) of the BSI episodes were not associated with neutropenia. As compared to the previous study, an alarming emergence of MDRB responsible for gut colonisations and BSI in immunosuppressed children was reported over the last four years. The degree of immunosuppression directly correlates with the risk of having an MDRB gut colonisation or MDRB BSI