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Coming dissertations at MedFak

  • Studies of sympathetic nerve activity in cutaneous nerves in healthy subjects using intraneural microneurography : The relationship between nerve activity and effector organ response Author: Pirkko Hynninen Link: Publication date: 2020-06-10 10:01

    The aim of the research presented in this thesis is to gain new knowledge of the characteristic features of sympathetic nerve activity of cutaneous nerves in healthy adult humans using intraneural microneurography. One further goal is to study the relationship between nerve activity and effector organ response.

    The study has three main aims: I) to study temperature regulating mechanisms in human subjects, rhythm generating mechanism of nerve activity and the relationship between nerve activity and effector organs, including sweat glands and blood vessels, II) to study regional similarities and differences in sympathetic nerve activity recorded from different cutaneous nerves, III) to study effector organ response, without central nervous system influences, through intraneural stimulation after proximal nerve blocking.

    The most important results are as follows: 1) By exposing a human subject to warm and cold environments, it is possible to obtain selective activation of either the sudomotor or vasoconstrictor neural system. 2) Bursts of both sudomotor and vasoconstrictor activity occur at certain intervals and several types of rhythmic activity can be observed. 3) Sudomotor bursts have a shorter duration compared to vasoconstrictor bursts. 4) The rhythm generating mechanisms may help to restrict the firing rates of individual nerve fibres to low ranges, which provides high gain in the neuroeffector transfer function. 5) Simultaneous double nerve recordings provide evidence that in the distal glabrous skin area the thermoregulatory functions are mainly executed via vasoconstrictor nerve fibres. Instead, sudomotor fibres are brought into action only at relatively high temperatures. In the hairy skin of forearm and hand reflex thermoregulation is to large extent executed via sudomotor nerve fibres. 6) Intraneural electrical stimulation of sympathetic postganglionic axons in human skin nerves after proximal nerve blocking shows differences between sudomotor and vasoconstrictor effector organ responses.

    These results improve our knowledge of the function of the sympathetic nervous system in healthy human subjects.

  • Algorithmic discovery, development and personalized selection of higher-order drug cocktails : A label-free live-cell imaging & secretomics approach Author: Efthymia Chantzi Link: Publication date: 2020-06-02 14:25

    An upward trend in clinical pharmacology is the use of multiple drugs to combat complex and co-occurring diseases due to better efficacy, decreased toxicity and reduced risk of evolving resistance. Despite high late-stage attrition rates and the need for multi drug treatments, most drug discovery and development efforts are still mainly focused on new one-size-fits-all monotherapies. This is unfortunate given the complex, heterogeneous and often only partially understood pathophysiology of many diseases. In this context, polypharmacotherapies hold strong potential, especially when patient tailored. However, as of today, the personalized combination therapy area remains vastly unexplored. A major reason is lack of standardized and robust tools that allow systematic in vitro drug combination sensitivity testing of different disease models and patient derived cells.

    This thesis fills in this lack by introducing two methodological frameworks, namely COMBImageDL and COMBSecretomics, designed to enable systematic second- and higher-order drug combination studies within and beyond cancer pharmacology. They include advanced quality control procedures, non-parametric resampling statistics to quantify uncertainty and a data driven methodology to evaluate response patterns and discern higher- from lower- and single-drug effects. Both are based on a standardized and reproducible format that could be employed with any experimental platform that provides the required raw data. COMBImageDL searches exhaustively for drug cocktails that induce changes in cell viability and time evolving cell culture morphology by employing conventional endpoint synergy analyses jointly with quantitative label-free live-cell imaging. Deep neural network learning, MapReduce parallel processing and method-specific parameter tuning are key components of the design. The purely phenotypic functionality of COMBImageDL is extended by COMBSecretomics, which searches exhaustively for drug cocktails that can modify, or even reverse malfunctioning secretomic patterns. It processes complex datasets involving drug treated cells observed before and after being stimulated by relevant proteins. Finally, the highest single agent method is generalized for higher-order drug combination analysis and adjusted for secreted protein profiles.

    The frameworks were used in five pharmacological studies being industrial, academic and clinical collaborations in areas where novel and personalized multi drug regimens are highly needed; oncology (acute myeloid leukemia and glioblastoma multiforme) and osteoarthritis. These studies demonstrate intriguing drug combination findings and in general the great potential of tools like COMBImageDL and COMBSecretomics to accelerate the discovery and development of novel potent polypharmacotherapeutic candidates.

  • Internet-based Psychosocial Support : Design, Effects and User Experience in the Cancer Setting Author: Anna Hauffman Link: Publication date: 2020-05-20 08:42

    Background and Aim Being diagnosed with cancer is often described as a major loss of control leading to severe psychological distress and symptoms of anxiety and depression can continue to affect the individual in the long term. The cancer and its treatment may influence all dimensions of health, thus the psychosocial support provided needs to be multifaceted and easy accessed. Internet-based interventions may be one way to provide such support, but evidence is limited. This thesis aimed to investigate the design, effects, and experiences of internet-based psychosocial support in cancer.

    Methods and Results Study 1 encompassed a co-creation development process resulting in the interactive support provided as the first step in an internet-based stepped care intervention (iCAN-DO). The effects of iCAN-DO were investigated in a randomised controlled trial, targeting individuals newly diagnosed with cancer and concurrent self-reported symptoms of anxiety and depression (according to the Hospital Anxiety and Depression Scale). Step 1 had a psycho-educative content involving self-care strategies and was available to the intervention group during the ten-month study period. Step 2 comprised a guided internet-based cognitive behavior therapy (iCBT) program and was offered those without improvement in anxiety and depression after using Step 1. The results showed that iCAN-DO improved symptoms of depression compared with standard care, while symptoms of anxiety were largely unaffected. Most participants used Step 1, while only a few used Step 2.

    In Study 2, aspects of usefulness, relevance, and usability in iCAN-DO were explored through qualitative interviews, analysed using content analysis. Results showed that standard healthcare did not meet the individuals' needs and iCAN-DO was used as complement, providing access to relevant, trustworthy information and support. Usability was affected by the perceived usefulness and ease of use of the intervention, as well as by the user´s circumstances in life and consequences of the cancer. The co-creation process in the development of Step 1 added relevance, but both steps 1 and 2 would have gained from being provided earlier, integrated into standard healthcare and more adaptable to the individual.

    Conclusion The thesis concluded that the internet-based intervention had positive effects on symptoms of depression in individuals newly diagnosed with cancer. Individuals with cancer experience several unmet needs in standard healthcare and since psycho-educative support including self-care advice seems feasible in this group, efforts are needed to incorporate internet-based support in regular oncology care. Since the intervention did not target all symptoms (i.e. anxiety) further research is needed on how to enhance efficacy and how to make iCBT more feasible for this group.