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Coming dissertations at MedFak

  • Hippocampal circuit dynamics in learning and value processing of sensory cues : A study into the function of hippocampal microcircuits involving OLMα2 cells Author: Samer Siwani Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439659 Publication date: 2021-05-07 12:00

    The anatomical signatures of the mnemonic/emotional processes share many brain structures, one of which seems to constitute a bridge, the hippocampus. It functions as a structure that consolidates engrams. It is connected to the prefrontal cortex, nucleus accumbens and amygdala, structures that provide emotional salience. This is, from an evolutionary perspective, likely a selection of fitness relevant engrams. Inputs from such structures to the hippocampus increase the likelihood of engram consolidation and behavioral response into long-term deposits. The hippocampal input pathways appear to be of importance for encoding and retrieval processes. During first encounters, entorhinal temporoammonic inputs are necessary for identifying probable threats and encoding of environmental cues. We find that artificial silencing of gate keeper neurons, named oriens lacunosum-moleculare (OLM) cells, increases approach and memory recall of novel cues in several tasks. Further, silencing of OLM cells mediates effective learning by increasing promiscuity in pyramidal cells in response to incoming sensory and/or emotional value inputs from other limbic structures, such as the basolateral amygdala. Depending on the dorsoventral position of the OLM cells, different phenotypes can be observed in different tasks. This is likely, at least in part, because of dorso-ventral differences in the connections between the hippocampus and other structures. In addition, OLM cells can control the specific oscillation frequency theta II (6-8 Hz), which appears in the ventral hippocampus and facilitates approach to predator odors. In conclusion, we show that the hippocampal circuit involving a subtype of OLM cells, is processing value of sensory cues through the temporoammonic pathway, and possibly affecting the basolateral amygdala inputs.

  • Unresolved Controversies in Child Pneumonia in low and middle income Countries. Author: Nick Brown Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439329 Publication date: 2021-05-04 12:09

    There has been a fall globally in pneumonia-related fatality in children during the Millennium Development and early Sustainable Development Goal era.

    However, pneumonia remains the single largest contributor to mortality with issues including antibiotic resistance, pollution, a change in infective epidemiology, equipoise over effects of adjunctive treatments and identification of sick, decompensating children. 

    This thesis examines 4 of these controversies as original research.

    Theme 1; two papers, 1 and 2: The first discusses the background motivation. The second a large randomized, non-inferiority controlled trial undertaken (‘RETAPP’) in a suburban slum area of Karachi, Pakistan. Oral amoxicillin treatment was compared with placebo, in the treatment of WHO-defined, uncomplicated, fast breathing pneumonia.

    Theme 2 (paper 3) The role of indoor air pollution and poverty in recurrent fast breathing pneumonia: a nested case control study.

    Theme 3 (paper 4). The role of adjunctive use of zinc to standard treatment in children with severe pneumonia: a systematic review and meta-analysis of randomised controlled trials.

    Theme 4 (paper 5). Recognition of the child with severe respiratory illness using the Clinical Respiratory Score in the emergency department 

    Results: In the RETAPP study, 4,002 randomised children were enrolled. There was a significant difference in treatment failure rates in the amoxicillin and placebo groups (2.6 % vs 4.9 %). The number needed to treat was high at 44, and mortality very low and similar in both groups, discussion points for policy makers.

    There does not appear to be an enhanced risk with Indoor Air Pollution in recurrence of pneumonia. The only predictor was household poverty: external pollution could be a factor.

    Adjunctive zinc confers no additional advantage to children with severe pneumonia.

    The clinical respiratory score is a highly sensitive, but non-specific marker for severe illness.

    Conclusions: The small, though significant, differences in treatment failure rates in fast breathing pneumonia are likely to have implications for setting of management.

    The role of environmental predictors needs to turn to poverty and external pollution.

    Zinc has no role as an adjunctive treatment. The clinical respiratory score has excellent predictive value for severe illness.

  • Antibody-based Cancer Immunotherapy : Personalization, response prediction and safety considerations Author: Mohamed Eltahir Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439220 Publication date: 2021-04-29 11:46

    Antibody-based therapeutics have remarkably improved the field of immuno-oncology. Multiple monoclonal antibodies (mAbs) are approved for clinical use, and numerous antibodies are under clinical development. The scope of this thesis is to study the personalization of antibody-based immunotherapeutics and tools to predict their efficacy and safety.

    In paper I, we investigated a new method for predicting immune toxicity related to mAbs infusion, the whole blood loop assay (WBLA). The assay recapitulates the in vivo setting and harmonizes well with clinically validated cytokine release assays (CRAs) following agonistic mAbs infusion. We also demonstrated the robustness of the assay in studying complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).

    Rituximab, the first approved mAb for an oncology indication, is known to induce CRS occasionally. In paper II, the WBLA was used to profile the chronic lymphocytic leukemia (CLL) patients’ specific responses to rituximab infusion. We demonstrated rituximab-induced CRS profile and complement activation in blood from CLL patients but not in blood from healthy donors. We also noted that NK cells were a significant source of the rituximab-induced cytokine release. Using Fc mutant versions of rituximab, the mode-of-action of rituximab in whole blood with respect to CDC and ADCC was elaborated.

    In paper III, we presented a novel flexible peptide cancer vaccine platform based on an anti-CD40 agonistic antibody. The platform consists of a bispecific antibody targeting CD40 and peptide-tagged antigens. The bispecific antibody retained the agonistic activity of anti-CD40 and was superior to parental anti-CD40 mAb in targeting antigen cross-presentation and stimulating both CD8+ and CD4+ T cell responses.

    In paper IV, we investigated the feasibility of proximity-extension assay (PEA) plasma proteomic analysis in predicting response to checkpoint inhibitors (CPIs) in non-small cell lung cancer patients. CPIs show great success in the clinic. However, not all patients benefit from CPIs. Using an immuno-oncology protein panel, we demonstrated that high plasma levels of T cell activation proteins were associated with better survival. We also identified an association between the pre-CPI plasma levels of CXCL9, CXCL10, IL-15, ADA and Casp8 and the response to CPI therapy. 

    In conclusion, this thesis demonstrates the feasibility of using the WBLA to assess antibody infusion efficacy and safety, as well as PEA plasma proteomics to predict response to CPI therapy. Additionally, it presents a novel approach for personalized therapeutic cancer vaccine delivery.

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