Development and characterization of a linear ion trap for an improved optical clock performance

Single ion frequency standards have demonstrated in several experiments excellent results and are approaching fractional frequency uncertainties of 10^-18. As dominant contributions to the uncertainty are linked to the ion trap properties a further reduction would be possible by an improved ion trap. Due to the interrogation of a single ion these frequency standards are currently limited by the intrinsically low signal-to-noise ratio and require long averaging times on the order of several days. This limitation is critical for various applications that require a high frequency resolution on short timescales. One possibility to improve the clock stability is to increase the number of clock ions. However, this approach further increases the requirements for the ion trap. Therefore, for the realization of a multi-ion clock that aims at simultaneously reducing the frequency stability and uncertainty the control over the characteristics of the ion trap is crucial. This thesis continues previous work towards the realization of a multi-ion optical clock based on ion Coulomb crystals of 115In+ ions which are sympathetically cooled by 172Yb+ ions. The existing design for a segmented linear ion trap has been refined and a reliable trap manufacturing process for a trap based on gold coated aluminium nitride wafers has been developed. Manufacturing tolerances below 10 μm allowed to reduce the axial micromotion amplitudes substantially. For a region of more than 300 μm the uncertainty contribution of the three-dimensional micromotion amplitude is shown to be below 10^-19. Additionally the radial ion heating rate of the trap has been measured to be 1.1 phonons/s for a trap frequency of 490 kHz. The time dilation shift due to the heating rate on the radial trap axis is found to be (2.1 ± 0.3) x 10^-20 1/s. The trap design has also been optimized for a low trap temperature rise due to the applied rf voltage. Trap temperature measurements with Pt100 sensors installed on the trap showed a maximum temperature increase of 1.21 K at an rf voltage amplitude of 1 kV. By comparing the measurement results to FEM simulations the uncertainty contribution of the trap temperature to the black-body radiation shift has been deduced to be 2.4 x 10^-20. As the ion trap provides a high level of control on Coulomb crystals it also provides an ideal test bed for studying atomic many-body systems. This work presents results of the investigations on topological defects in two-dimensional Coulomb crystals. The emphasis was placed on the effects of mass defects and external electric fields on the stability of the topological defects. It is shown that these effects can be used to manipulate and create topological defects deterministically.In mehreren Experimenten haben Frequenzstandards auf der Basis von einzelnen Ionen hervorragende Ergebnisse erzielt und nähern sich einer relativen Frequenzunsicherheit von 10^-18 an. Eine weitere Reduzierung der Frequenzunsicherheit wäre durch eine verbesserte Ionenfalle möglich, da dominante Beiträge der Frequenzunsicherheit auf die Eigenschaften der Ionenfalle zurückzuführen sind. Aufgrund der Abfrage eines einzelnen Ions sind diese Frequenznormale zur Zeit durch das intrinsisch niedrige Signal-Rausch-Verhältnis limitiert und benötigen lange Mittelungszeiten in der Größenordnung von mehreren Tagen. Diese Limitierung ist für verschiedene Anwendungen, die eine hohe Frequenzauflösung nach kurzen Mittelungszeiten erfordern, ein kritischer Punkt. Die Frequenzstabilität kann durch eine höhere Anzahl von Uhrenionen verbessert werden. Allerdings werden durch diesen Ansatz auch die Anforderungen an die Ionenfalle weiter erhöht. Aus diesem Grund ist für die Realisierung einer Multi-Ionen Uhr, die gleichzeitig die Frequenzstabilität und -unsicherheit weiter verringern soll, die Kontrolle über die Eigenschaften der Ionenfalle von entscheidender Bedeutung. Diese Dissertation setzt frühere Arbeiten zur Realisierung einer optischen Multi-Ionen-Uhr auf der Basis von Coulomb-Kristallen aus 115In+-Ionen, die durch 172Yb+-Ionen sympathisch gekühlt werden, fort. Das existierende Design einer segmentierten linearen Ionenfalle wurde optimiert und es wurde ein zuverlässiger Herstellungsprozess basierend auf goldbeschichteten Aluminiumnitrid-Wafern entwickelt. Durch Fertigungstoleranzen von weniger als 10 μm konnte die axiale Mikrobewegungsamplitude deutlich reduziert werden. Es wird gezeigt, dass in einem Bereich von über 300 μm der Beitrag der dreidimensionalen Mikrobewegung zur Frequenzunsicherheit unterhalb von 10^-19 ist. Zusätzlich wurde die radiale Heizrate der Falle mit 1,1 Phononen/s bei einer Fallenfrequenz von 490 kHz bestimmt. Die Frequenzverschiebung durch Zeitdilatation durch die Heizrate der radialen Fallenachse beträgt damit (2,1 ± 0,3) x 10^-20 1/s. Das Fallendesign wurde ebenso auf einen geringen Anstieg der Fallentemperatur durch die angelegte HF-Spannung optimiert. Die Messungen der Fallentemperatur mit den auf der Falle installierten Pt100 Sensoren zeigten einen maximalen Temperaturanstieg von 1,21 K bei einer HF-Spannungsamplitude von 1 kV. Durch den Vergleich der Messergebnisse mit FEM-Simulationen wurde der Beitrag der Fallentemperatur zur Frequenzverschiebung durch die Schwarzkörperstrahlung mit 2,4 x 10^-20 bestimmt. Da die Ionenfalle eine sehr gute Kontrolle über Coulomb-Kristalle bietet, eignet sie sich auch hervorragend für Experimente mit atomaren Vielteilchensystemen. Hierzu werden in dieser Arbeit Untersuchungen topologischer Defekte in zweidimensionalen Coulomb-Kristallen vorgestellt. Der Schwerpunkt lag dabei auf der Analyse des Einflusses von Massendefekten und externen elektrischen Feldern auf die Stabilität der topologischen Defekte. Es wird gezeigt wie dieser Einfluss genutzt werden kann, um die Defekte gezielt zu manipulieren und sie deterministisch zu produzieren

A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/− nab-paclitaxel in elderly pancreatic cancer patients (GrantPax)

Background: In the group of elderly patients (≥70 years) with metastatic pancreatic ductal adenocarcinoma (mPDAC), it is not known who benefits from intensive 1st line nab-paclitaxel/gemcitabine (nab-p/gem) combination chemotherapy or who would rather suffer from increased toxicity. We aim to determine whether treatment individualization by comprehensive geriatric assessments (CGAs) improves functional outcome of the patients. Methods/Design: GrantPax is a multicenter, open label phase 4 interventional trial. We use a CGA to stratify elderly patients into three parallel treatment groups (n = 45 per arm): 1) GOGO (nab-p/gem), 2) SLOWGO (gem mono) or 3) FRAIL (best supportive care). After the 1st cycle of chemotherapy (or 4 weeks in FRAIL group) another CGA and safety assessment is performed. CGA-stratified patients may not decline in their CGA performance in response to the first cycle of chemotherapy (primary objective), measured as a loss of 5 points or less in Barthels activities of daily living. Based on the second CGA, patients are re-assigned to their definite treatment arm and undergo further CGAs to monitor the course of treatment. Secondary endpoints include CGA scores during the course of therapy (CGA1–4), response rates, safety and survival rates. Discussion: GrantPax is the first trial implementing a CGA-driven treatment to personalize therapy for elderly patients with pancreatic cancer. This may lead to standardization of therapy decisions for elderly patients and may optimize standard of care for this increasing group of patients. Trial registration: NCT02812992 , registered 24.06.2016

A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA)

Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. Methods: RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. Discussion: The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. Trial registration: EudraCT Number 2017–002056-86; NCT03416244, registered: 31.1.2018

Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001, n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments

Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mitigate these beneficial effects by promoting a negative feedback-loop comprising extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated kinase kinase 1/2 (MEK1/2)-dependent inactivation of PPARγ. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARγ. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARγ. Synthetic peptides were designed resembling the regulatory coiled-coil (CC) domain of MTMR7, and their activities studied in human cancer cell lines and C57BL6/J mice. MTMR7 formed a complex with PPARγ and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. MTMR7-CC peptides mimicked PPARγ-activation in vitro and in vivo due to LXXLL motifs in the CC domain. Molecular dynamics simulations and docking predicted that peptides interact with the steroid receptor coactivator 1 (SRC1)-binding site of PPARγ. Thus, MTMR7 is a positive regulator of PPARγ, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARγ.ISSN:2157-902