13,028 research outputs found
Recommended from our members
Ensuring Access to Safe and Nutritious Food for All Through the Transformation of Food Systems
Identifizierung prädiktiver und prognostischer Biomarker in unterschiedlichen Tumorkompartimenten des ösophagealen Adenokarzinoms
Das ösophageale Adenokarzinom zeigt eine global steigende Inzidenz und hat mit einer 5-Jahres-Überlebensrate von weniger als 25% eine schlechte Prognose. Personalisierte Therapieansätze sind selten und prognostische/prädiktive Biomarker des Tumormikromilieus sind unzureichend charakterisiert. Die kumulative Promotion nähert sich dieser Problematik in drei unterschiedlichen Schwerpunkten. 1. Zur Identifizierung Kompartiment-spezifischer Biomarker wurde eine Methode entwickelt, welche als kostengünstige Alternative zum sc-Seq Expressionsprofile individueller Zelltypen generiert. Dabei erfolgt die Extraktion der RNA nicht aus Einzelzellen, sondern aus flowzytometrisch-getrennten Zellkompartimenten. Die Separation der Proben in Epithelzellen, Immunzellen und Fibroblasten wurde durch verschiedene Verfahren validiert und eine suffiziente Ausbeute an RNA auch für kleine Gewebemengen gezeigt. 2. Biomarker des Immunzellkompartiments als therapeutische Angriffspunkte wurden in einem Patientenkollektiv von bis zu 551 Patienten auf ihre Bedeutung beim EAC überprüft. Es zeigte sich eine Expression der Immuncheckpoints LAG3, VISTA und IDO auf TILs durch IHC und RNA-Sonden basierte Verfahren in einem relevanten Anteil (LAG3: 11,4%, VISTA: 29%, IDO: 52,6%). Es konnte eine prognostisch günstige Bedeutung der VISTA, LAG3 und IDO Expression gezeigt werden. Durch den Vergleich von Genexpressionsprofilen aus therapienaiven und vorbehandelten Tumoren konnte zudem ein immunsuppressiver Effekt von neoadjuvanten Therapiekonzepten auf das Tumormikromilieu des EACs gezeigt werden. Dabei kam es zur verminderten Expression von Checkpoints und Anzahl TILs nach (Radio-) Chemotherapie. 3. Im Tumorzellkompartiment wurde die Rolle von Amplifikationen in ErbB-Rezeptor abhängigen Signalwegen durch FISH-Technik und Immunhistochemie evaluiert. Es fanden sich KRAS Amplifikationen in 17,1%, PIK3CA Amplifikationen in 5% sowie eine HER2/neu-Überexpression in 14,9% der untersuchten Tumore
Subsidiary Entrepreneurial Alertness: Antecedents and Outcomes
This thesis brings together concepts from both international business and entrepreneurship to develop a framework of the facilitators of subsidiary innovation and performance. This study proposes that Subsidiary Entrepreneurial Alertness (SEA) facilitates the recognition of opportunities (the origin of subsidiary initiatives). First introduced by Kirzner (1979) in the context of the individual, entrepreneurial alertness (EA) is the ability to notice an opportunity without actively searching. Similarly, to entrepreneurial alertness at the individual level, this study argues that SEA enables the subsidiary to best select opportunities based on resources available. The research further develops our conceptualisation of SEA by drawing on work by Tang et al. (2012) identifying three distinct activities of EA: scanning and search (identifying opportunities unseen by others due to their awareness gaps), association and connection of information, and evaluation and judgement to interpret or anticipate future viability of opportunities. This study then hypothesises that SEA leads to opportunity recognition at the subsidiary level and further hypothesises innovation and performance as outcomes of opportunity recognition. This research brings these arguments together to develop and test a comprehensive theoretical model.
The theoretical model is tested through a mail survey of the CEOs/MDs of foreign subsidiaries within the Republic of Ireland (an innovative hub for foreign subsidiaries). This method was selected as the best method to reach the targeted respondent, and due to the depth of knowledge the target respondent holds, the survey can answer the desired question more substantially. The results were examined using partial least squares structural equation modelling (PLS-SEM). The study’s findings confirm two critical aspects of subsidiary context, subsidiary brokerage and subsidiary credibility are positively related to SEA. The study establishes a positive link between SEA and both the generation of innovation and the subsidiary’s performance. This thesis makes three significant contributions to the subsidiary literature as it 1) introduces and develops the concept of SEA, 2) identifies the antecedents of SEA, and 3) demonstrates the impact of SEA on subsidiary opportunity recognition. Implications for subsidiaries, headquarters and policy makers are discussed along with the limitations of the study
A scoping review of natural language processing of radiology reports in breast cancer
Various natural language processing (NLP) algorithms have been applied in the literature to analyze radiology reports pertaining to the diagnosis and subsequent care of cancer patients. Applications of this technology include cohort selection for clinical trials, population of large-scale data registries, and quality improvement in radiology workflows including mammography screening. This scoping review is the first to examine such applications in the specific context of breast cancer. Out of 210 identified articles initially, 44 met our inclusion criteria for this review. Extracted data elements included both clinical and technical details of studies that developed or evaluated NLP algorithms applied to free-text radiology reports of breast cancer. Our review illustrates an emphasis on applications in diagnostic and screening processes over treatment or therapeutic applications and describes growth in deep learning and transfer learning approaches in recent years, although rule-based approaches continue to be useful. Furthermore, we observe increased efforts in code and software sharing but not with data sharing
Recommended from our members
The Epidemiology and Genetic Architecture of Vitamin D Deficiency in African Children
Vitamin D deficiency is a common public health problem worldwide. However, little is known about the epidemiology of vitamin D deficiency in Africa. In this thesis, I aimed to determine: 1) the prevalence of and risk factors associated with vitamin D deficiency in studies conducted in Africa; 2) the prevalence and predictors of vitamin D deficiency in African children; 3) the association between vitamin D and iron deficiency in African children; and 4) genetic variants that influence vitamin D status in Africans.
In a systematic review and meta-analyses of previous vitamin D studies in Africa, the average prevalence of low vitamin D status was 18.5%, 34.2% and 59.5% using cut-offs of 25-hydroxyvitamin D (25(OH)D) levels of <30 nmol/L, <50 nmol/L and <75 nmol/L, respectively. Populations at risk of vitamin D deficiency included newborns, women, and people living in high latitudes or urban areas.
In an epidemiological study of young children living in Africa, the prevalence of low vitamin D status was 0.6%, 7.8% and 44.5% using cut-offs of 25(OH)D levels of GC2 variant of the group-specific component (GC) gene, which encodes vitamin D binding protein.
Vitamin D deficiency was also associated with 80% higher odds of iron deficiency in these children. Adjusted regression models revealed that vitamin D deficiency was associated with higher ferritin and hepcidin levels suggesting lower iron status, and reduced sTfR and transferrin levels and increased TSAT and serum iron levels suggesting improved iron status.
Genome-wide association study (GWAS) in Africans revealed genetic variants that influence vitamin D status in vitamin D metabolism genes: DHCR7/NADSYN1, CYP2R1 and GC. However, the majority of SNPs from previous European GWASs did not replicate in the current GWAS.
Findings from this thesis indicate that vitamin D deficiency is prevalent in many African populations and should be considered in public health strategies in Africa
In vitro investigation of the effect of disulfiram on hypoxia induced NFκB, epithelial to mesenchymal transition and cancer stem cells in glioblastoma cell lines
A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.Glioblastoma multiforme (GBM) is one of the most aggressive and lethal cancers with a poor prognosis. Advances in the treatment of GBM are limited due to several resistance mechanisms and limited drug delivery into the central nervous system (CNS) compartment by the blood-brain barrier (BBB) and by actions of the normal brain to counteract tumour-targeting medications. Hypoxia is common in malignant brain tumours such as GBM and plays a significant role in tumour pathobiology. It is widely accepted that hypoxia is a major driver of GBM malignancy. Although it has been confirmed that hypoxia induces GBM stem-like-cells (GSCs), which are highly invasive and resistant to all chemotherapeutic agents, the detailed molecular pathways linking hypoxia, GSC traits and chemoresistance remain obscure. Evidence shows that hypoxia induces cancer stem cell phenotypes via epithelial-to-mesenchymal transition (EMT), promoting therapeutic resistance in most cancers, including GBM.
This study demonstrated that spheroid cultured GBM cells consist of a large population of hypoxic cells with CSC and EMT characteristics. GSCs are chemo-resistant and displayed increased levels of HIFs and NFκB activity. Similarly, the hypoxia cultured GBM cells manifested GSC traits, chemoresistance and invasiveness. These results suggest that hypoxia is responsible for GBM stemness, chemoresistance and invasiveness. GBM cells transfected with nuclear factor kappa B-p65 (NFκB-p65) subunit exhibited CSC and EMT markers indicating the essential role of NFκB in maintaining GSC phenotypes. The study also highlighted the significance of NFκB in driving chemoresistance, invasiveness, and the potential role of NFκB as the central regulator of hypoxia-induced stemness in GBM cells. GSC population has the ability of self-renewal, cancer initiation and development of secondary heterogeneous cancer. The very poor prognosis of GBM could largely be attributed to the existence of GSCs, which promote tumour propagation, maintenance, radio- and chemoresistance and local infiltration.
In this study, we used Disulfiram (DS), a drug used for more than 65 years in alcoholism clinics, in combination with copper (Cu) to target the NFκB pathway, reverse chemoresistance and block invasion in GSCs. The obtained results showed that DS/Cu is highly cytotoxic to GBM cells and completely eradicated the resistant CSC population at low dose levels in vitro. DS/Cu inhibited the migration and invasion of hypoxia-induced CSC and EMT like GBM cells at low nanomolar concentrations.
DS is an FDA approved drug with low toxicity to normal tissues and can pass through the BBB. Further research may lead to the quick translation of DS into cancer clinics and provide new therapeutic options to improve treatment outcomes in GBM patients
RNA pull-down-confocal nanoscanning (RP-CONA), a novel method for studying RNA/protein interactions in cell extracts that detected potential drugs for Parkinson’s disease targeting RNA/HuR complexes
MicroRNAs (miRNAs, miRs) are a class of small non-coding RNAs that regulate gene expression through specific base-pair targeting. The functional mature miRNAs usually undergo a two-step cleavage from primary miRNAs (pri-miRs), then precursor miRNAs (pre-miRs). The biogenesis of miRNAs is tightly controlled by different RNA-binding proteins (RBPs). The dysregulation of miRNAs is closely related to a plethora of diseases. Targeting miRNA biogenesis is becoming a promising therapeutic strategy.
HuR and MSI2 are both RBPs. MiR-7 is post-transcriptionally inhibited by the HuR/MSI2 complex, through a direct interaction between HuR and the conserved terminal loop (CTL) of pri-miR-7-1. Small molecules dissociating pri-miR-7/HuR interaction may induce miR-7 production. Importantly, the miR-7 levels are negatively correlated with Parkinson’s disease (PD).
PD is a common, incurable neurodegenerative disease causing serious motor deficits. A hallmark of PD is the presence of Lewy bodies in the human brain, which are inclusion bodies mainly composed of an aberrantly aggregated protein named α-synuclein (α-syn). Decreasing α-syn levels or preventing α-syn aggregation are under investigation as PD treatments. Notably, α-syn is negatively regulated by several miRNAs, including miR-7, miR-153, miR-133b and others. One hypothesis is that elevating these miRNA levels can inhibit α-syn expression and ameliorate PD pathologies.
In this project, we identified miR-7 as the most effective α-syn inhibitor, among the miRNAs that are downregulated in PD, and with α-syn targeting potentials. We also observed potential post-transcriptional inhibition on miR-153 biogenesis in neuroblastoma, which may help to uncover novel therapeutic targets towards PD.
To identify miR-7 inducers that benefit PD treatment by repressing α-syn expression, we developed a novel technique RNA Pull-down Confocal Nanoscaning (RP-CONA) to monitor the binding events between pri-miR-7 and HuR. By attaching FITC-pri-miR-7-1-CTL-biotin to streptavidin-coated agarose beads and incubating them in human cultured cell lysates containing overexpressed mCherry-HuR, the bound RNA and protein can be visualised as quantifiable fluorescent rings in corresponding channels in a confocal high-content image system. A pri-miR-7/HuR inhibitor can decrease the relative mCherry/FITC intensity ratio in RP-CONA. With this technique, we performed several small-scale screenings and identified that a bioflavonoid, quercetin can largely dissociate the pri-miR-7/HuR interaction. Further studies proved that quercetin was an effective miR-7 inducer as well as α-syn inhibitor in HeLa cells.
To understand the mechanism of quercetin mediated α-syn inhibition, we tested the effects of quercetin treatment with miR-7-1 and HuR knockout HeLa cells. We found that HuR was essential in this pathway, while miR-7 hardly contributed to the α-syn inhibition. HuR can directly bind an AU-rich element (ARE) at the 3’ untranslated region (3’-UTR) of α-syn mRNA and promote translation. We believe quercetin mainly disrupts the ARE/HuR interaction and disables the HuR-induced α-syn expression.
In conclusion, we developed and optimised RP-CONA, an on-bead, lysate-based technique detecting RNA/protein interactions, as well as identifying RNA/protein modulators. With RP-CONA, we found quercetin inducing miR-7 biogenesis, and inhibiting α-syn expression. With these beneficial effects, quercetin has great potential to be applied in the clinic of PD treatment. Finally, RP-CONA can be used in many other RNA/protein interactions studies
School-based interventions to increase physical activity and reduce cardiometabolic risk in children
Walking with the Earth: Intercultural Perspectives on Ethics of Ecological Caring
It is commonly believed that considering nature different from us, human beings (qua rational, cultural, religious and social actors), is detrimental to our engagement for the preservation of nature. An obvious example is animal rights, a deep concern for all living beings, including non-human living creatures, which is understandable only if we approach nature, without fearing it, as something which should remain outside of our true home. “Walking with the earth” aims at questioning any similar preconceptions in the wide sense, including allegoric-poetic contributions. We invited 14 authors from 4 continents to express all sorts of ways of saying why caring is so important, why togetherness, being-with each others, as a spiritual but also embodied ethics is important in a divided world
- …