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Improving organ dose sparing in left-sided breast cancer with yaw-limited volumetric modulated arc therapy : a dosimetric comparison to conventional and intensity modulated radiation therapy approaches
Full text linkBackground:
To assess the dose-sparing capabilities of a yaw-limited volumetric modulated arc therapy (YL_VMAT) beam setup for adjacent organs at risk (OAR) in comparison with 3D-conventional radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT) and conventional VMAT for radiation therapy in left-sided breast cancer patients.
Methods:
In total, 80 treatment plans for 20 patients, of which 10 patients underwent CT-scans in deep inspiration breath-hold (DIBH) and 10 patients in free-breathing (FB) technique. Besides generally tangential-weighted static and IMRT beams, VMAT treatment plans with approximately 270° arc length have been compared and analyzed to a multi-field, yaw-adapted, unconventional partial VMAT technique retrospectively. The prescription dose was set to 40.05 Gy in 15 fractions.
Results:
We achieved a more pronounced steeper dose falloff directed from the thoracic wall to the adjacent lung tissue resulting in a significantly better ipsilateral lung and considerably cardiac dose sparing using the YL_VMAT method in general. Compared with standard techniques (IMRT, VMAT, 3D-CRT), YL-VMAT in combination with DIBH can achieve lower mean doses for the heart (1.05 Gy vs. 1.73 Gy, 2.16 Gy and 1.44 Gy), the left anterior descending (LAD) artery (3.68 Gy vs. 6.53 Gy, 5.13 Gy and 8.64 Gy) and the left lung (3.59 Gy vs. 5.39 Gy, 4.79 Gy and 5.87 Gy), respectively. Also with FB, the corresponding mean doses for the left lung and cardiac structures were lower with the YL-VMAT method than with IMRT (heart: 1.70 Gy vs. 2.44 Gy; LAD: 6.50 Gy vs. 11.97 Gy; left lung: 3.10 Gy vs. 4.72 Gy), VMAT (heart: 1.70 Gy vs. 2.52 Gy; LAD: 6.50 Gy vs. 9.06 Gy; left lung: 3.10 Gy vs. 4.46 Gy) and 3D-CRT (heart: 1.70 Gy vs. 2.78 Gy; LAD: 6.50 Gy vs. 15.09 Gy; left lung: 3.10 Gy vs. 5.77 Gy). In addition, we found out superiority of YL_VMAT for the V5, V10, and V20 Gy to the left lung. For DIBH and FB, all differences for the left lung were significant, with p < 0.05.
Conclusions:
With the YL_VMAT technique, dose exposures to radiosensitive OARs like the lung, heart and LAD artery can be reduced considerably to very low values in comparison to already established planning methods. The benefits must be weighed against the potential risks induced by an increased dose exposure to the contralateral breast
Interdisziplinäre Fragilitäts-Bewertungsinstrumente und deren prädiktiver Voraussagewert auf das perioperative Outcome betagterer Patientinnen mit Endometriumkarzinom - Eine explorative hypothesengenerierende retrospektive Kohortenstudie
Full text link65 Seiten ; Illustratione
Histologische Subklassifikation, Manifestationsmuster und Therapieergebnisse von Patienten mit Marginalzonenlymphom an der Universitätsmedizin Mainz im Zeitraum von 2003 bis 2019
Full text linkVI, 79 Seiten ; Diagramm
Ethische Dilemmata in der Anästhesie : die Frage der Bluttransfusionen bei Zeugen Jehovas trotz religiöser Ablehnung – kann eine bindende Festlegung getroffen werden?
Full text linkIV, 80 Seiten ; Diagramm
Tuning connectivity in a three-component assembly of metal–organic cage-cross-linked polymer networks
Full text linkNetwork connectivity strongly influences the dynamics and mechanical properties of materials such as natural tissues and hydrogels, which are known for their adaptability and self-healing. Metal–organic cages (MOCs), with modular structures and reversible coordination, provide a versatile platform to engineer connectivity in polymer networks. Here, we use an octahedral MOC to form transient poly(ethylene glycol) (PEG)-based hydrogels and investigate their viscoelastic behavior by varying the junction functionality and polymer architecture. A distinct low-frequency relaxation mode emerges after annealing, reflecting the interplay between cage formation and a mixture of homo- and heteroleptic metal complexes. Cage formation is undermined at both high and low polymer concentrations due to steric hindrance and chain overstretching, respectively. At an optimal polymer concentration, reducing cage content preserves the cage integrity and reveals a transition from phantom to affine network behavior. In contrast, replacing polymeric ligands with small-molecule equivalents results in misconnectivity and a lower modulus. Kinetics analysis at the microscale using Fluorescence Resonance Energy Transfer (FRET) shows that incorporation into polymer networks destabilizes the cage, likely due to chain dynamics. DFT calculations further reveal that only Pd2+, among several tested transition metal ions, provides the appropriate coordination environment and bond stability for robust cage formation. Despite this, the high junction functionality enables rapid and efficient self-healing. This work examines how tuning connectivity in transient networks can guide the design of materials with tailored properties such as recyclability, self-healing, and stimuli-responsiveness
Patient needs in the context of gynecologic oncology and breast cancer : a validation study
Full text linkMedical advancements and therapeutic innovations are progressing rapidly, necessitating corresponding adaptations in the delivery of patient-centered care. This study explores the needs of women diagnosed with gynecologic and breast cancers, using the frameworks of the National Academy of Medicine and the Picker Institute as reflective lenses. We conducted a qualitative, single-center study employing grounded theory methodology. Semi-structured interviews were carried out with 20 patients undergoing treatment for gynecologic malignancies and breast cancer at a university medical center. Interviews covered multiple phases of illness, including treatment initiation, adaptation, abstention, and future-oriented decisions. Data were analyzed inductively using constant comparative methods. Findings largely affirmed the relevance of the eight established domains of patient-centered care - personal values, clear information and education, emotional support, involvement of family and friends, physical comfort, coordinated care, continuity, and access to treatment. Three additional insights emerged: needs vary according to illness phase and tend to taper over time; they are grounded in ethical dimensions, including social identity, epistemic agency, and moral distress; and they are interdependent, requiring holistic rather than isolated responses. These results highlight that effective patient-centered care must account not only for the content of care but also for its timing, context and ethical significance, warranting integration into standard oncological practice
Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1
Full text linkIon transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling – resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms
Sequelae of preterm birth over the lifespan : an exploratory analysis of behavioral problems in childhood and increased risk of major depression and anxiety in adulthood from a cohort study
Full text linkBackground:
Existing research has shown that prematurity and low birth weight are associated with mental health in children and adolescents, but their impact on mental health in adulthood and the mechanisms involved have been less studied. This study investigated the impact of prematurity and abnormal fetal growth, as a marker for fetal growth restriction, on mental health outcomes in adulthood.
Methods:
This retrospective cohort study examined adults aged 18–52 years, categorized by gestational age (extremely preterm: ≤28 weeks; very preterm: 29–32 weeks; moderately preterm: 33–36 weeks; term: ≥37 weeks). The cohort consists of individuals who were either born preterm or at term from 1969 to 2002. Data collection occurred between 2019 and 2021. This exploratory analysis used multivariable logistic regression to assess the impact of prematurity and fetal growth restriction on adult mental health outcomes (measured by the “Patient Health Questionnaire”), adjusting for age, gender, and socioeconomic status. The study also explored the relationship between childhood behavioral problems, retrospectively described by the mothers of the participants (2–4 years), and adult mental health, with separate analyses for preterm and term births.
Findings:
The multivariable logistic regression analysis of 606 participants (average age 28·96 ± 8·9 years, 326 females) indicated that a low gestational age of ≤28 weeks was independently associated with an increased prevalence of major depressive disorder (OR = 4·14, CI: 1·43–11·77, p = 0·01) and anxiety disorder (OR = 5·17, CI: 1·51–17·37, p = 0·01) in adulthood compared to a gestational age of ≥37 weeks. A low birth weight percentile was not associated with mental disorders. Further regression analysis revealed that peer problems and emotional problems in childhood were significantly associated with major depression in adulthood in participants born preterm. The sensitivity analysis revealed that the previously observed association between the gestational age group of ≤28 weeks and major depressive disorder was no longer statistically significant (OR = 2·84, CI: 0·85–9·07, p = 0·08) when the model was adjusted for maternal smoking and alcohol consumption during pregnancy. The association between the extreme preterm group and generalized anxiety disorder remained significant (OR = 4·63, CI: 1·27–16·22, p = 0·02).
Interpretation:
This study provides exploratory insights into the complex impact of prematurity on mental health in adulthood, highlighting the vulnerability of the extremely preterm group (≤28 weeks) from a multi-informant, lifespan perspective. It emphasizes the importance of continuous monitoring and psychosocial support for those born extremely preterm, from infancy through adulthood, to mitigate potential adverse mental health outcomes.
Funding:
The Gutenberg Prematurity Study was supported by the Ernst und Berta-Grimmke Stiftung, Stufe 1 support of the UM and the Else Kröner-Fresenius-Stiftung
prm-PASEF-based quantification and isomeric model for extended coverage of human plasma lipidome in Parkinson’s disease
Full text linkThis study introduces a clinical lipidomics platform leveraging fragment-based quantification on parallel reaction monitoring (PRM)-parallel accumulation serial fragmentation (PASEF) for lipid quantification. An isomeric model, termed “SN regression model”, built on specific PASEF-fragment ion patterns, was developed for the quantification of coeluting sn positional isomers without prior derivatization. This PASEF-isomeric lipidomics aids in the resolution and quantification of 176 lipid isomers coeluting in chromatography and/or ion mobility dimensions, expanding the lipidome quantitative coverage to 481 plasma lipids covering 14 lipid subclasses with CV <40% for 32 plasma replicates. We demonstrated the method’s advantage for clinical research by detailed quantitative lipidomic phenotyping of patients with Parkinson’s disease, enabling the delineation of new biochemical pathways affected by the disorder and stratification of patients. The method’s amenability for high-throughput deep quantitative coverage of highly structurally resolved lipidome has implications for improving the diagnosis and understanding of the distinct metabolic alterations in Parkinson’s disease subgroups and, generally, for disorders associated with lipid dysregulation
Targeting Leishmania: exploring novel antileishmanial compounds and drug targets in the context of parasite cell death
Full text linkLeishmaniasis is a neglected tropical disease with limited therapeutic options. This
thesis employed two complementary approaches and human primary cell models to
identify novel biological concepts which may contribute to therapeutic advancements.
In a series of phenotypic screenings, pateamines and arylmethylaminosteroids were identified
as chemical entities eliciting in vitro antileishmanial effects. While pateamines
exhibited excessive cytotoxicity towards host macrophages, both arylmethylaminosteroids
could significantly reduce intracellular parasite burden. Based on their activity,
authorized compounds fulfilling pharmacophore criteria were tested for antileishmanial
activity with an extraordinary hit rate. Repurposing of established drugs is a pragmatic
strategy to accelerate the development of new antiparasitic therapies.
As a second approach, putative drug targets in Leishmania major linked to cell death
were investigated. Many cellular processes in these parasites remain poorly characterized.
Programmed cell death is a potential drug target, as not only regulates parasite
survival and death but also facilitates immunosuppressive mechanisms. Genome editing
was employed to delete candidate genes hypothesized to be associated with this
process. However, no links to cell death pathways were discovered.
Instead, a quantitative proteomics study identified p1/s1, a 3’-nucleotidase/nuclease,
as enriched in sub-lethal stress and potentially involved in DNA degradation. Extensive
characterization of this versatile ecto-enzyme revealed no link to cell death,
but its dual activity was confirmed in an inducible knockout system. Degradation of
free 3’-nucleotides and nucleic acids by p1/s1 provides L. major with essential purines
while simultaneously facilitating immune evasion. Specifically, during in vitro infection,
3’-AMP hydrolysis led to decreased pro-inflammatory TNFα secretion and reduced
T cell proliferation via the generation of immunomodulatory adenosine. Furthermore,
p1/s1-mediated endonuclease activity enabled L. major to degrade and escape neutrophil
extracellular traps.
In summary, this thesis provides new insights into the molecular biology of Leishmania
and outlines several novel antileishmanial strategies, highlighting potential directions
for the development of future therapeutics.Leishmaniose ist eine vernachlässigte Tropenkrankheit mit begrenzten therapeutischen
Möglichkeiten. Diese Dissertation nutzt zwei komplementäre Herangehensweisen und
humane Primärzellmodelle, um neue biologische Konzepte zu identifizieren, die zu therapeutischen
Fortschritten beitragen können.
In phänotypischen Testungen wurden Pateamine und Arylmethylaminosteroide als Substanzklassen
identifiziert, die in vitro antileishmaniale Effekte hervorrufen. Wohingegen
Pateamine übermäßige Zytotoxizität auf Makrophagen zeigten, konnten beide Arylmethylaminosteroide
die intrazelluläre Parasitenlast signifikant reduzieren. Basierend auf
deren Aktivität wurden bereits zugelassene Wirkstoffe, die Pharmakophor-Kriterien
erfüllen, mit außergewöhnlich hoher Trefferquote auf antileishmaniale Aktivität getestet.
Die Umwidmung von etablierten Medikamenten stellt einen pragmatischen Ansatz
dar, um die Entwicklung neuer antiparasitärer Therapien zu beschleunigen.
Als zweiter Ansatz wurden mutmaßliche Wirkstoff-Zielproteine in Leishmania major
untersucht, die in Verbindung mit Zelltod stehen könnten. Viele zelluläre Prozesse
dieser Parasiten sind nur unzureichend charakterisiert. Programmierter Zelltod in Leishmanien
ist ein potenzielles Ziel für Wirkstoffe, da er Überleben und Tod der Parasiten
steuert, aber auch immunsuppressive Mechanismen ermöglicht. Mittels Genom-
Editierung wurden Kandidatengene deletiert, die in Verbindung mit diesem Prozess
stehen könnten. Allerdings wurden keine direkten Verbindungen zu Zelltod gezeigt.
Stattdessen identifizierte eine quantitative Proteomstudie die 3’-Nukleotidase/Nuklease
p1/s1, die unter subletalem Stress an DNA Abbau beteiligt sein könnte. Eine umfangreiche
Charakterisierung dieses vielseitige Ektoenzyms zeigte keine Verbindung zu Zelltod
auf. Dagegen wurde dessen duale Aktivität durch eine induzierte Gendeletion bestätigt.
Der Abbau von freien 3’-Nukleotiden und Nukleinsäuren durch p1/s1 versorgt L. major
mit essentiellen Purinen, ermöglicht aber auch Mechanismen der Immunevasion. Insbesondere
führte die Hydrolyse von 3’-AMP während in vitro Infektionen durch Generierung
von immunmodulatorischem Adenosin zu verminderter Sekretion von proinflammatorischem
TNFα und T-Zell Proliferation. Weiterhin erlaubte die p1/s1-induzierte
Endonuklease-Aktivität den Abbau von Neutrophilen Extrazellulären Fallen und damit
den Austritt aus solchen.
Zusammengefasst bietet diese Thesis neue Erkenntnisse in der Molekularbiologie von
Leishmanien und beschreibt mehrere neuartige antileishmaniale Strategien, die potenzielle
Ansätze für die Entwicklung zukünftiger Therapien aufzeigen.xviii, 171 Seiten ; Illustrationen, Diagramm