Kohärente Dipol-Dipol-Kopplung in multichromophoren Makromolekülen und multimolekularen Nanopartikeln

Die Emission von Licht in konjugierten Molekülen, welche die Grundlage für organische Elektronik darstellen, hängt stark von der Ausrichtung der einzelnen Moleküle zueinander ab. Dies ist auf die zugrundeliegende kohärente Dipol-Dipol-Kopplung zurückzuführen, welche zu einer energetischen Aufspaltung des angeregten Zustandes führt. Die Besetzung wird dann durch die Anordnung der Moleküle bestimmt. So wird bei paralleler Ausrichtung eine sogenannte H-Kopplung begünstigt, während linear in Reihe ausgerichtete Moleküle eine J-Kopplung aufweisen. Auch lichtabsorbierende und -emittierende Segmente (Chromophore) eines einzelnen Makromoleküls, wie beispielsweise eines Polymers können miteinander koppeln und die Photolumineszenz des gesamten Systems beeinflussen. In dieser Arbeit wird das Zusammenspiel der beiden Kopplungsarten in verschiedenen Modellsystemen unterschiedlicher Größe, beginnend mit multichromophoren Makromolekülen definierter Ausdehnung und Struktur, untersucht. Die Herstellung multimolekularer Nanopartikel erlaubt es dann, die Kopplung mehrerer Makromoleküle zu untersuchen ohne dabei die starke Heterogenität eines Molekülfilms in Kauf nehmen zu müssen

Interplay between J- and H-type coupling in aggregates of π-conjugated polymers: a single-molecule perspective

Strong dipole–dipole coupling within and between π‐conjugated segments shifts electronic transitions, and modifies vibronic coupling and excited‐state lifetimes. Since J‐type coupling between monomers along the conjugated‐polymer (CP) chain and H‐type coupling of chromophores between chains of a CP compete, a superposition of the spectral modifications arising from each type of coupling emerges, making the two couplings hard to discern in the ensemble. We introduce a single‐molecule H‐type aggregate of fixed spacing and variable length of up to 10 nm. HJ‐type aggregate formation is visualized intuitively in the scatter of single‐molecule spectra

A double-blind randomized controlled trial of maternal postpartum deworming to improve infant weight gain in the Peruvian Amazon

Background : Nutritional interventions targeting the critical growth and development period before two years of age can have the greatest impact on health trajectories over the life course. Compelling evidence has demonstrated that interventions investing in maternal health in the first 1000 days of life are beneficial for both mothers and their children. One such potential intervention is deworming integrated into maternal postpartum care in areas where soil-transmitted helminth (STH) infections are endemic. Methodology/Principal Findings : From February to August 2014, 1010 mother-infant pairs were recruited into a trial aimed at assessing the effectiveness of maternal postpartum deworming on infant and maternal health outcomes. Following delivery, mothers were randomly assigned to receive either single-dose 400 mg albendazole or placebo. Participants were followed-up at 1 and 6 months postpartum. There was no statistically significant difference in mean weight gain between infants in the experimental and control groups (mean difference: -0.02; 95% CI: -0.1, 0.08) at 6 months of age. Further, deworming had no effect on measured infant morbidity indicators. However, ad hoc analyses restricted to mothers who tested positive for STHs at baseline suggest that infants of mothers in the experimental group had greater mean length gain in cm (mean difference: 0.8; 95% CI: 0.1, 1.4) and length-for-age z-score (mean difference: 0.5; 95% CI: 0.2, 0.8) at 6 months of age. Conclusions/Significance : In a study population composed of both STH-infected and uninfected mothers, maternal postpartum deworming was insufficient to impact infant growth and morbidity indicators up to 6 months postpartum. Among STH-infected mothers, however, important improvements in infant length gain and length-for-age were observed. The benefits of maternal postpartum deworming should be further investigated in study populations having higher overall prevalences and intensities of STH infections and, in particular, where whipworm and hookworm infections are of public health concern

Applicability of liquid biopsies to represent the mutational profile of tumor tissue from different cancer entities

Genetic investigation of tumor heterogeneity and clonal evolution in solid cancers could be assisted by the analysis of liquid biopsies. However, tumors of various entities might release different quantities of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) into the bloodstream, potentially limiting the diagnostic potential of liquid biopsy in distinct tumor histologies. Patients with advanced colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), and melanoma (MEL) were enrolled in the study, representing tumors with different metastatic patterns. Mutation profiles of cfDNA, CTCs, and tumor tissue were assessed by panel sequencing, targeting 327 cancer-related genes. In total, 30 tissue, 18 cfDNA, and 7 CTC samples from 18 patients were sequenced. Best concordance between the mutation profile of tissue and cfDNA was achieved in CRC and MEL, possibly due to the remarkable heterogeneity of HNSCC (63%, 55% and 11%, respectively). Concordance especially depended on the amount of cfDNA used for library preparation. While 21 of 27 (78%) tissue mutations were retrieved in high-input cfDNA samples (30-100 ng, N = 8), only 4 of 65 (6%) could be detected in low-input samples (<30 ng, N = 10). CTCs were detected in 13 of 18 patients (72%). However, downstream analysis was limited by poor DNA quality, allowing targeted sequencing of only seven CTC samples isolated from four patients. Only one CTC sample reflected the mutation profile of the respective tumor. Private mutations, which were detected in CTCs but not in tissue, suggested the presence of rare subclones. Our pilot study demonstrated superiority of cfDNA- compared to CTC-based mutation profiling. It was further shown that CTCs may serve as additional means to detect rare subclones possibly involved in treatment resistance. Both findings require validation in a larger patient cohort

Ein Online-Experiment zur Erforschung kognitiv-emotionstheoretischer Determinanten im unternehmerischen Entscheidungsprozess

Die Frage welche Rolle Emotionen und Kognitionen bei der Entscheidung, eine konkrete unternehmerische Gelegenheit auszunützen, spielen, ist bis heute nicht vollständig beantwortet und regt dementsprechend immer wieder Forschungsarbeiten an. Häufig setzen diese jedoch an nachdem eine unternehmerische Entscheidung getroffen wurde. Erst von wenigen Forschern wurde der Entscheidungsprozess bevor eine unternehmerische Gelegenheit ausgenützt wird, betrachtet (z. B. Lang-von Wins, 2004; Phan, Wong & Wang, 2002). Eine Onlinefragebogenstudie mit drei unterschiedlichen Stichproben von Angestellten, Studenten und Unternehmensgründern (N insgesamt = 578) unter Verwendung unterschiedlicher experimentell manipulierter Szenarios bestätigt die zentrale Annahme kognitiver Emotionstheorien, dass die subjektive Bewertung der objektiven unternehmerischen Gelegenheit die unternehmerische Entscheidung besser vorhersagt, als dies die Merkmale der unternehmerischen Situation zu leisten im Stande sind. Zudem zeigen unsere Ergebnisse, dass negativer und positiver Affekt den Zusammenhang zwischen Merkmalen der unternehmerischen Gelegenheit und unternehmerischen Entscheidung moderieren

Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema

Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD

Nanoscale π-conjugated ladders

It is challenging to increase the rigidity of a macromolecule while maintaining solubility. Established strategies rely on templating by dendrons, or by encapsulation in macrocycles, and exploit supramolecular arrangements with limited robustness. Covalently bonded structures have entailed intramolecular coupling of units to resemble the structure of an alternating tread ladder with rungs composed of a covalent bond. We introduce a versatile concept of rigidification in which two rigid-rod polymer chains are repeatedly covalently associated along their contour by stiff molecular connectors. This approach yields almost perfect ladder structures with two well-defined π-conjugated rails and discretely spaced nanoscale rungs, easily visualized by scanning tunnelling microscopy. The enhancement of molecular rigidity is confirmed by the fluorescence depolarization dynamics and complemented by molecular-dynamics simulations. The covalent templating of the rods leads to self-rigidification that gives rise to intramolecular electronic coupling, enhancing excitonic coherence. The molecules are characterized by unprecedented excitonic mobility, giving rise to excitonic interactions on length scales exceeding 100 nm. Such interactions lead to deterministic single-photon emission from these giant rigid macromolecules, with potential implications for energy conversion in optoelectronic devices

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Charakterisierung der molekularen Resistenzmechanismen gegen Radiochemotherapie beim Plattenepithelkarzinom im Kopf-Hals Bereich

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with an incidence of more than 650 000 cases per year and 330 000 cancer deaths worldwide. These tumors mainly arise in the squamous epithelium within the oral cavity, pharynx and salivary glands. Major risk factors are smoking, alcohol consumption and infection with human papilloma virus (HPV). Surgery or radiotherapy (RT) serve as a standard treatment for early stage tumors, while locoregionally advanced tumors are treated with radical surgery followed by subsequent adjuvant RT/chemoradiotherapy (CRT) or primary CRT. Despite advances in CRT, survival rates still remain poor with locoregional recurrences in up to 40% of patients. Novel therapeutic strategies like the administration of immune checkpoint inhibitors (ICI) in the recurrent and metastatic setting have been recently approved by the FDA. Tumor mutational burden (TMB) estimated from whole exome sequencing (WES) or comprehensive gene panels has previously been established as predictive factor of response to ICI. In the present study, TMB and its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI was investigated. The accuracy of TMB estimation by an in-house head and neck cancer-specific 327-gene panel was established in the Cancer Genome Atlas (TCGA) HNSCC WES dataset. A high accuracy of TMB estimation by the 327-gene panel could be observed. Subsequently, the interference of TMB with outcome after cCRTX was determined in a multicenter cohort including 158 patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing (tNGS) was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumor samples. In a subset of cases (n=40), tumor RNA was used for immune related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, HPV status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. In summary, it could be demonstrated that high TMB identifies HNSCC patients with poor outcome after cCRTX who might potentially benefit from CRTX-ICI combination.Das Plattenepithelkarzinom im Kopf-Hals Bereich zählt zu den sechs häufigsten bösartigen Tumoren weltweit mit einer Inzidenz von mehr als 650.000 Fällen pro Jahr und 330.000 Sterbefälle weltweit. Tumore, die sich in einem frühen Stadium befinden, werden primär operiert oder bestrahlt. Lokal fortgeschrittene Tumore werden mit einer radikalen Resektion, gefolgt von einer adjuvanten Radiotherapie (RT)/ Radiochemotherapie (RCT) oder einer primären RCT behandelt, wobei die lokoregionäre Rezidivrate bei 40% liegt. Die Gabe von Immuncheckpoint-Inhibitoren (ICI) stellt derzeit einen neuen Therapieansatz für Patienten mit rezidivierender, metastasierter Erkrankung dar. Ein wichtiger prädiktiver Faktor für das Ansprechen auf diese Therapie ist die Tumormutationslast (TML), welche entweder mittels Whole-Exome Sequenzierung (WES) oder Gen-Panels bestimmt werden kann. In der vorliegenden Studie wurde der prädiktive Wert der TML für die Wirksamkeit einer definitiven Radiochemotherapie (cCRTX-englisch: concurrent chemoradiation), welche als potentieller Kombinationspartner von ICI gesehen werden kann, untersucht. Ein 327 Gene umfassendes und spezifisch für die Analyse von Tumoren im Kopf-Hals Bereich (HNSCC – englisch: head and neck squamous cell carcinoma) designtes Gen Panel wurde im Rahmen dieser Arbeit etabliert. Um die Präzision der TML Berechnung mittels eines Gen-Panels zu bestimmen, wurde zuerst der WES HNSCC Datensatz aus dem Cancer Genome Atlas (TCGA) verwendet. Anhand des 327-Gen Panel konnte die TML mit einer hohen Präzision berechnet werden. In einer multizentrischen Kohorte von Patienten mit lokal fortgeschrittenem HNSCC, welche einheitlich mittels cCRTX behandelt wurde, wurde die Interferenz der TML mit der Wirksamkeit einer cCRTX bestimmt. Von den insgesamt 158 Patienten konnten 101 Formalin-fixierte Paraffin-eingebettete (FFPE) Tumorproben, welche vor der Behandlung entnommen wurden, mittels gezielter Next Generation Sequenzierung (tNGS) analysiert werden. In 40 Fällen wurde zudem aus der Tumor RNA ein Genexpressionsprofil von Immun-assoziierten Genen mittels der nanoString Plattform erstellt. Die TML wurde mit dem TP53 Genotyp, dem HPV-Status, der Immun-Expressions- Signatur und verschiedenen Überlebensparametern korreliert. Auch für die Validierung der Ergebnisse wurde die TCGA HNSCC Kohorte verwendet. Eine hohe TML zeigte eine signifikante Assoziation mit einer erhöhten Prävalenz von Mutationen im TP53 Gen und Immungen-Expressionsmustern, welche unabhängig vom inflammatorischen T-Zell Genexpressionsprofil waren. Außerdem zeigte sich eine signifikante Reduktion im Gesamtüberleben in der Patientengruppe mit hoher TML, was auch im multivariaten Modell bestätigt werden konnte. Der prognostische Wert der TML konnte in der TCGA HNSCC Kohorte bestätigt werden. Zusammenfassend konnte in dieser Doktorarbeit gezeigt werden, dass HNSCC Patienten mit hoher TML eine schlechte Wirksamkeit der cCRTX aufweisen und womöglich von einer CRTX-ICI Kombinationsbehandlung profitieren würden

Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa cells were cultured alone or with PCa-associated fibroblasts (CAFs). Notably, the ratio of PCa cells to CAFs significantly increased in time in favor of the tumor cells within the spheroids strongly mimicking PCa in vivo. Despite this loss of CAFs, the stromal cells, which were not sensitive to androgen and even stimulated by the anti-androgens, significantly influenced the sensitivity of PCa cells to androgen and to the anti-androgens bicalutamide and enzalutamide. In particular, DuCaP cells lost sensitivity to enzalutamide when co-cultured with CAFs. In LAPC4/CAF and LNCaP/CAF co-culture spheroids the impact of the CAFs was less pronounced. In addition, 3D spheroids exhibited a significant increase in E-cadherin and substantial expression of vimentin in co-culture spheroids, whereas AR levels remained unchanged or even decreased. In LNCaP/CAF spheroids we further found increased Akt signaling that could be inhibited by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002, thereby overcoming the anti-androgen resistance of the spheroids. Our data show that CAFs influence drug response of PCa cells with varying impact and further suggest this spheroid model is a valuable in vitro drug testing tool