The Clinical Relevance of Circulating Tumor Cells in Early Breast Cancer

Circulating tumor cells (CTCs) are considered to be evading cancer cells that have been shed or actively invaded from the primary tumor into the blood circulation or lymphatic system and which may finally extravasate to found metastases. CTCs as “liquid biopsy” hold great promise to be a powerful non-invasive real-time measurable biomarker for predicting clinical outcomes and cancer treatment response. Several studies evaluated the role of CTC presence and count in the neoadjuvant and adjuvant setting of early breast cancer (EBC) and revealed their significant prognostic value. In this chapter, we highlight the clinical relevance of CTCs in early breast cancer (EBC) and state the urgency for further research in this field to definitely translate this marker from bench to bedside

Treatment planning comparison for head and neck cancer between photon, proton, and combined proton-photon therapy - From a fixed beam line to an arc

BACKGROUND AND PURPOSE: This study investigates whether combined proton-photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments. MATERIAL AND METHODS: Five HNC patients with a planning CT and multiple (4-7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared. RESULTS: The target coverage for CPPT without adaptation is insufficient (average V95%=88.4 %), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5 %) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are -2.7 %/-3.4 %/-5.0 % for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are + 0.8 %/-0.9 %/-4.3 %. CONCLUSION: CPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined

Treatment planning comparison for head and neck cancer between photon, proton, and combined proton-photon therapy - from a fixed beam line to an arc.

BACKGROUND AND PURPOSE This study investigates whether combined proton-photon therapy (CPPT) improves treatment plan quality compared to single-modality intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) for head and neck cancer (HNC) patients. Different proton beam arrangements for CPPT and IMPT are compared, which could be of specific interest concerning potential future upright-positioned treatments. Furthermore, it is evaluated if CPPT benefits remain under inter-fractional anatomical changes for HNC treatments. MATERIAL AND METHODS Five HNC patients with a planning CT and multiple (4-7) repeated CTs were studied. CPPT with simultaneously optimized photon and proton fluence, single-modality IMPT, and IMRT treatment plans were optimized on the planning CT and then recalculated and reoptimized on each repeated CT. For CPPT and IMPT, plans with different degrees of freedom for the proton beams were optimized. Fixed horizontal proton beam line (FHB), gantry-like, and arc-like plans were compared. RESULTS The target coverage for CPPT without adaptation is insufficient (average V95%=88.4%), while adapted plans can recover the initial treatment plan quality for target (average V95%=95.5%) and organs-at-risk. CPPT with increased proton beam flexibility increases plan quality and reduces normal tissue complication probability of Xerostomia and Dysphagia. On average, Xerostomia NTCP reductions compared to IMRT are -2.7%/-3.4%/-5.0% for CPPT FHB/CPPT Gantry/CPPT Arc. The differences for IMPT FHB/IMPT Gantry/IMPT Arc are +0.8%/-0.9%/-4.3%. CONCLUSION CPPT for HNC needs adaptive treatments. Increasing proton beam flexibility in CPPT, either by using a gantry or an upright-positioned patient, improves treatment plan quality. However, the photon component is substantially reduced, therefore, the balance between improved plan quality and costs must be further determined

Stofffluss- und Akteursmodell als Grundlage für ein aktives Ressourcenmanagement im Bauwesen von Baden-Württemberg „StAR-Bau“ - Schlussbericht des Forschungsvorhabens

Dieser Bericht untersucht aktuelle und zukünftige Stoffströme in einem integrierten, regionalen Stoffstrom- und Akteursmodell für Gebäude und Straßeninfrastrukturen. Die drei Maßnahmen Besteuerung von Primärrohstoffen, Erhöhung von Deponiegebühren und Anpassung von Ausbildungsinhalten ergeben in den Modellberechnungen ein mittleres Ressourcenschonungspotenzial von 30,8 % für Baden-Württemberg bis 2030, also eine Verringerung der kumulierten Stoffstrombilanzen von 119 auf 82 Mio. Tonnen

Transverse Polarisation of Quarks in Hadrons

We review the present state of knowledge regarding the transverse polarisation (or transversity) distributions of quarks. After some generalities on transverse polarisation, we formally define the transversity distributions within the framework of a classification of all leading-twist distribution functions. We describe the QCD evolution of transversity at leading and next-to-leading order. A comprehensive treatment of non-perturbative calculations of transversity distributions (within the framework of quark models, lattice QCD and QCD sum rules) is presented. The phenomenology of transversity (in particular, in Drell-Yan processes and semi-inclusive leptoproduction) is discussed in some detail. Finally, the prospects for future measurements are outlined.Comment: small changes, references added, as finally published in Physics Report

Tip- and laser-based 3D nanofabrication in extended macroscopic working areas

The field of optical lithography is subject to intense research and has gained enormous improvement. However, the effort necessary for creating structures at the size of 20 nm and below is considerable using conventional technologies. This effort and the resulting financial requirements can only be tackled by few global companies and thus a paradigm change for the semiconductor industry is conceivable: custom design and solutions for specific applications will dominate future development (Fritze in: Panning EM, Liddle JA (eds) Novel patterning technologies. International society for optics and photonics. SPIE, Bellingham, 2021. https://doi.org/10.1117/12.2593229). For this reason, new aspects arise for future lithography, which is why enormous effort has been directed to the development of alternative fabrication technologies. Yet, the technologies emerging from this process, which are promising for coping with the current resolution and accuracy challenges, are only demonstrated as a proof-of-concept on a lab scale of several square micrometers. Such scale is not adequate for the requirements of modern lithography; therefore, there is the need for new and alternative cross-scale solutions to further advance the possibilities of unconventional nanotechnologies. Similar challenges arise because of the technical progress in various other fields, realizing new and unique functionalities based on nanoscale effects, e.g., in nanophotonics, quantum computing, energy harvesting, and life sciences. Experimental platforms for basic research in the field of scale-spanning nanomeasuring and nanofabrication are necessary for these tasks, which are available at the Technische Universität Ilmenau in the form of nanopositioning and nanomeasuring (NPM) machines. With this equipment, the limits of technical structurability are explored for high-performance tip-based and laser-based processes for enabling real 3D nanofabrication with the highest precision in an adequate working range of several thousand cubic millimeters

Endogenous tumor suppressor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia

Purpose Dysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML. Methods We profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo. Results miR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio 6 standard error, 20.56 6 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1. Conclusion The tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms

Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration. Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology, we established a ChAc patient-derived induced pluripotent stem cell model and an efficient differentiation protocol providing a large population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc. Patient-derived MSNs displayed enhanced neurite outgrowth and ramification, whereas synaptic density was similar to controls. Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs. Treatment with the F-actin stabilizer phallacidin or the Src kinase inhibitor PP2 resulted in the significant reduction of disinhibited synaptic currents to healthy control levels, suggesting a Src kinase- and actin-dependent mechanism. This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs. These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function

Pharmacogenetic Associations of MMP9 and MMP12 Variants with Cardiovascular Disease in Patients with Hypertension

MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested. = 0.015). for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions