Organoids as preclinical cancer models of hepatocellular carcinoma to study doxorubicin response

Background & Aims: Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). However, the response rate to TACE varies, and the molecular mechanisms underlying variable responses are poorly understood. Patient-derived HCC organoids (HCCOs) offer a novel platform to investigate variability of doxorubicin responses, the impact of hypoxia on tumor cell proliferation, and the molecular mechanisms underlying doxorubicin resistance. Methods: We evaluated the effects of hypoxia and doxorubicin on cell viability and cell cycle distribution in twenty patient-derived HCCO models. We also identified HCCO-intrinsic determinants of doxorubicin response by comparing the transcriptomes of sensitive to resistant HCCOs. To validate candidate genes, we used small molecule inhibition and quantified intracellular doxorubicin levels. Results: Hypoxia reduced the proliferation of HCCOs and increased the number of cells in the G0/G1 phase of the cell cycle, while decreasing the number in the S phase. The IC50s of the doxorubicin response varied widely, from 29nM to >1μM. Doxorubicin and hypoxia did not exhibit synergistic effects but were additive in some HCCOs. Doxorubicin reduced the number of cells in the G0/G1 and S phases and increased the number in the G2 phase under both normoxia and hypoxia. Genes related to drug metabolism and export, most notably ABCB1, were differentially expressed between doxorubicin-resistant and sensitive HCCOs. Small molecule inhibition of ABCB1 increased intracellular doxorubicin levels and decreased drug tolerance in resistant HCCOs. Conclusions: The inhibitory effects of doxorubicin treatment and hypoxia on HCCO proliferation are variable, suggesting an important role of tumor-cell intrinsic properties in doxorubicin resistance. ABCB1 is a determinant of doxorubicin response in HCCOs

Strengthening vaccine pharmacovigilance in low- and middle-income countries using a multi-centre hospital based prospective surveillance approach

The capacity to rapidly detect and respond to emerging vaccine safety signals is critical for assuring public confidence in vaccination programmes. Clinical trials, despite their increasing size, cannot detect very rare or long-term adverse events following immunization (AEFIs) and do not represent the diversity of real-world populations, highlighting the need for effective post-licensure safety surveillance of vaccines. Spontaneous reporting remains the mainstay of vaccine safety monitoring in low- and middle-income countries (LMICs). Such passive surveillance systems are susceptible to under- and biased reporting and lack the capacity to identify long-term sequelae following vaccinations. The present thesis aims to evaluate the potential of multi-centre hospital-based active surveillance approaches towards strengthening capacity for vaccine pharmacovigilance in LMICs. To achieve these objectives, the thesis established two prospective observational active vaccine safety surveillance networks across seven countries. The two large, multi-centre studies underpinning this thesis, collectively screened a cohort of over 160,000 individuals and identified over 40,000 serious perinatal, neonatal and paediatric adverse outcomes, syndromes and diseases in one primary, five secondary and 32 tertiary care hospitals across seven countries, over a span of 34 months. By generating background rates of adverse perinatal, neonatal, and paediatric conditions across diverse geographies and healthcare settings, it shows that hospitals in resource-constrained settings can effectively classify adverse outcomes and vaccine exposures using standardized definitions. The thesis demonstrates the feasibility and potential of tailored multi-centre hospital-based active surveillance systems in India and other LMICs. These findings offer operational and scientific guidance for building robust and responsive post-licensure active vaccine safety surveillance systems in the future

Bridging the Gap: Wirkung von langjährigem funktionellen Krafttraining auf die Beinkraft von Jugendlichen mit Zerebralparese

Hintergrund: Bisherige Untersuchungen zeigen, dass Trainingsinterventionen die Kraft bei Ju-gendlichen mit zerebraler Parese (CP) steigern können, sie im Vergleich zu gesunden Gleich-altrigen dennoch signifikant schwächer sind. Diese Studie wurde initiiert, um zu erforschen, ob regelmässiges hochintensives funktionelles Krafttraining im Gruppensetting eine Chance bie-tet, Defizite in Bezug auf die Beinkraft der neuromuskulären Krankheit bei Jugendlichen mit CP zu verringern oder auf ein vergleichbares Kraft-Niveau zu ihren gesunden Peers zu bringen. Methoden: In dieser Querschnittsstudie wurde die Auswirkung von Trainingsstatus und CP-Diagnose auf die Maximalkraft (Fmax) und die Kraftentwicklungsrate (RFD) untersucht. Ver-glichen wurden fünf trainierte Jugendliche (im Alter von 14 bis 23 Jahren) mit CP, die über 2.5 Jahre am Trainingsangebot togetherfit teilnahmen, mit vier untrainierten CP-Jugendlichen so-wie 18 gesunden Gleichaltrigen (9 trainiert, 9 untrainiert). Die Messungen erfolgten mit dem IsoMed® 2000-Dynamometer. Die gesunden, untrainierten Jugendlichen dienten als Referenz-gruppe zur Berechnung der "Health Distance" zu den anderen Gruppen. Ergebnisse: Das Training verbessert die Beinkraft bei Jugendlichen mit CP, wobei besonders in der RFD des dominanten Beins höhere Werte als bei gesunden trainierten Altersgenossen er-reicht wurden. Die "Health Distance" zwischen trainierten CP-Jugendlichen und gesunden Gleichaltrigen ist im dominanten Bein deutlich reduziert im Vergleich zu untrainierten CP-Ju-gendlichen. Schlussfolgerungen: Obwohl das Kraftniveau der trainierten CP-Jugendlichen nicht das der ge-sunden Vergleichsgruppe erreicht (Ausnahme RFD), verdeutlichen die Ergebnisse eine Annä-herung und unterstreichen damit die Effektivität und den Wert des Trainings. Das Angebot to-getherfit dient als wirksame Therapieform bei CP. Zukünftige Studien sollten die zugrundelie-genden neuromuskulären Mechanismen weiter erforschen und prüfen, ob diese Effekte auch in grösseren Stichproben signifikant sind

Welches Potential hat Sensomotoriktraining zur Symptomreduktion neuropathischer Symptome nach einer neurotoxischen Chemotherapie? – ein Case Report

Die Chemotherapie-induzierte periphere Polyneuropathie (CIPN) ist eine zentrale Nebenwir-kung der Krebstherapie, die sich in vielen Bereichen negativ auf die Gesundheit und die Le-bensqualität der Patient:innen auswirkt. Bei Erwachsenen gibt es viel Evidenz, die für ein Sen-somotoriktraining (SMT) zur Linderung der CIPN spricht. Untersuchungen im pädiatrischen Bereich fehlen jedoch noch. Das SMT scheint aber auch bei ihnen eine wirkungsvolle Behand-lungsmethode zu sein. Aus diesem Anlass absolvierte eine 16-jährige CIPN-Patientin regel-mässig ein SMT. Die Auswirkungen davon werden in dieser Arbeit analysiert. Methode Aufgrund der relativ limitierten Patientenzahl in der pädiatrischen Onkologie wird in dieser Ar-beit über eine einzelne Patientin berichtet, was einem klassischen Case-Report entspricht. Die Patientin besuchte vier Monate lang regelmässig ein spielerisches SMT und führte zusätzlich zwei- bis dreimal wöchentlich Übungen zuhause durch. Arztberichte und Assessments doku-mentierten den Verlauf ihrer CIPN und dessen Einfluss auf die Gleichgewichtsfähigkeit, Dor-salflexion der Füsse und Gehfähigkeit. Die Resultate wurden mit einer gesunden Referenz-gruppe verglichen. Die Lebensqualität wurde mittels Fragebögen erfasst. Ergebnisse Das SMT führte zu einer Verbesserung des Ganges, des Gleichgewichts und des Bewegungs-umfangs der Dorsalflexion der Füsse. Der Achilles- und Patellarsehenreflex waren wieder aus-lösbar. Das SMT wirkte sich auch positiv auf die Lebensqualität aus. Schlussfolgerung Ein regelmässiges, spielerisches SMT mit einer 16-jährigen CIPN-Patientin ist gut durchführ-bar. Es könnte für krebskranke Kinder und Jugendliche eine vielversprechende Behandlungs-methode der CIPN sein

"To walk between the raindrops": the role of rabbis in bioethical decision-making : Orthodox and Reform Jewish practice in the United States and Israel

Bioethics as an interdisciplinary examination of dilemmas regarding all forms of life began in the United States of the postwar era. As medical science advanced, medical interventions became increasingly technical and intellectual resources outside of the medical profession were pertinent to deal with new arising questions. Since issues of life, death, and social justice were questions long pondered by philosophers and theologians, their approaches to answering those unprecedented problems became an integral part of the new evaluation of medical practice. Thus, thinkers and scholars from all branches of Judaism have long participated in intellectual and inter-religious exchange on the problematization of bioethical issues. Designed as a qualitative comparative study of Israel and the United States, this research project investigates the role(s) of rabbis and chaplains involved in bioethical decision-making and is concerned with a close examination of the interrelationship of rabbinic discourse and practice regarding bioethical issues. Pierre Bourdieu’s concepts of the logic of practice and habitus offer the theoretical framework for evaluating the rabbis’ professional role at the intersection of objective structure, i.e. religious tradition and rabbinic discourse, and the social encounter with congregants and patients. The following pages aim to show that Jewish moral spheres of action are always located at and realized within institutional, social, and cultural contexts. Description regarding social backgrounds and national idiosyncrasies is provided at length due to the fact that bioethical decisions do not occur within a socio-cultural vacuum. Thus, descriptions of Orthodox Judaism and the Reform Movement in the United States and Israel serve as the cultural and historical basis for evaluating rabbinic discourses and practice. The main part elaborates on the type of questions rabbis receive, the professional networks they rely on, and the main forms of social exchange with congregants and patients. In order to frame the relational dynamic of such exchange, a model was developed. Based on the descriptions given by altogether 52 interview partners, four main constellations, or role types, have emerged from the data. Namely, spiritual-authority, normative-authority, spiritual-resource, and normative-resource. It captures behaviour prevalent either in Orthodox religious cultures, Reform Jewish settings, or both. The last two chapters of this dissertation deliver profund argumentative discourse analyses on two bioethical issues, brain death and organ donation, including their relevance and use in rabbinical decision-making and counselling. This study contributes to the breadth of research that deals with bioethics and religious traditions. With its practice-oriented, empirical approach, this research project takes into account the social and institutional situatedness of bioethical decision-making processes at the interface of state, healthcare, patient and religious institutions

Cell type-focused compound screen in human organoids reveals molecules and pathways controlling cone photoreceptor death

Human organoids that mirror their corresponding organs in cell-type diversity present an opportunity to perform large-scale screens for compounds that protect disease-affected or damage healthy cell types. However, such screens have not yet been performed. Here, we generated 20,000 human retinal organoids with GFP-labeled cone photoreceptors. Since degeneration of cones is a leading cause of blindness, we induced cone death and screened 2,707 compounds with known targets, for those that saved cones or those that further damaged cones. We identified kinase inhibitors that protected cones in both the short and longer term, HSP90 inhibitors that saved cones in the short term but damaged them in the longer term, and broad HDAC inhibition by many compounds that significantly damaged cones. This resource provides a database for cone-damaging compounds, and it describes compounds that can be starting points to develop neuroprotection for cones in diseases such as macular degeneration

Intermolecular interactions of macrocyclic, supramolecular, and mechanically interlocked structures accessible via 1,3-butadiyne synthesis.

This PhD thesis is the result of several scientific projects, in which macrocyclic and mechanically interlocked structures have been designed and synthesized in order to study strong and weak intermolecular interactions. While their investigation relied on different experimental techniques, the use of acetylene couplings played a crucial role for the successful synthesis of these challenging targets and draws a common theme throughout the chapters of this thesis