KI Open Archive Karolinska Institutet
Not a member yet
10598 research outputs found
Sort by
Aspects on hereditary gastric cancer
No full textGastric cancer has a poor prognosis, as it is often diagnosed at an advanced stage. Identifying individuals at high risk is essential in order to offer surveillance, early treatment or preventive measures, including prophylactic gastrectomy.Familial clustering of gastric cancer is observed in approximately one in ten cases, and hereditary gastric cancer with well-known genetic susceptibility accounts for around three percent of all gastric cancer cases, including Hereditary Diffuse Gastric Cancer (HDGC), Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) and Familial Intestinal Gastric Cancer (FIGC). The risk of gastric cancer is also elevated in several other hereditary cancer syndromes, such as Lynch syndrome (disease-causing variants in one of the DNA mismatch repair genes), Li-Fraumeni syndrome (TP53), Familial Adenomatous Polyposis (APC), Peutz-Jeghers syndrome (STK11), MUTYH-associated polyposis, Juvenile Polyposis (SMAD4 or BMPR1A) and Hereditary Breast or Ovarian Cancer syndrome (BRCA1 or BRCA2). Yet, many families do not carry any recognised genetic cause.Over the past few decades, it has become clear that cancer is a disease with complex traits. Instead of focusing entirely on high-penetrance, single-gene variants, many current studies use multi-genic models to investigate associations between single variants or combinations of them, called haplotypes, across the genome, as seen in Genome Wide Association Studies (GWAS). Several GWAS on cancer have been carried out over the past decades, and many candidate regions (loci) and risk alleles have been associated with gastric cancer. However, few of these suggested variants are functional, and further studies are required to explore their biology. Lately, there has been an increased focus on loci that predispose individuals to more than one type of cancer, reflecting pleiotropy. Both pleiotropic and cancer-specific loci identified through GWAS have considerably expanded the list of genes influencing cancer risk. Nevertheless, it remains challenging to fully translate the results from GWAS into clinical practice, particularly in terms of prevention programmes or potential therapeutic targets.The overall aim of this thesis was to examine different aspects on hereditary gastric cancer, explore associations between gastric cancer and other malignancies, and investigate potential shared genetic predisposing factors for these tumours.In Paper I, a retrospective cohort study was conducted including 107 individuals previously diagnosed with gastric cancer. Cancer cases in close family members were recorded. The proportions of different cancer types among first- and second-degree relatives of the included patients were compared to those in the general Swedish population. The main finding was that both uterine cancer and gastric cancer were overrepresented compared to the reference population.Equivalent to Paper I, Paper II investigated cancer occurrences among close relatives of gastric cancer patients, but this time in a prospective setting. A total of 134 patients with newly diagnosed gastric cancer were included. The relative occurrence of different cancer types among first- and second-degree relatives was estimated and compared to the general Swedish population. Similar to Paper I, the relative occurrence of gastric cancer was higher than in the reference population. Among first-degree relatives, cancer of the small intestine was more common, while among second-degree relatives, the relative occurrence of both cervical cancer and bone cancer was higher than in the reference population. A lower relative occurrence was observed for prostate cancer and urinary tract cancer among both first- and second-degree relatives.In Paper III, a GWAS was conducted, consisting of 685 colorectal cancer cases, whose relatives had gastric and/or prostate cancer, and 4780 healthy controls from the Swedish Twin Registry. A sliding window haplotype analysis was undertaken using a logistic regression model. Candidate loci on ten chromosomal regions were suggested, most of which included protein-coding genes previously shown to be involved in cancer. Sequencing of DNA was then carried out on colorectal cancer patients with gastric and/or prostate cancer among their close relatives to search for candidate variants within these haplotype loci. Finally, the suggested candidate variants were investigated in a case-control study of colorectal cancer cases and healthy controls. Although no statistically significant results were noted in the final association study, the paper demonstrated proof of principle strategy to identify risk variants found by haplotype GWAS.Analogous to Paper III, in Paper IV a GWAS was undertaken with the same 685 cases, but with different controls. A total of 1642 controls, consisting of spouses of the cases and healthy blood donors from the same geographical region as the cases, were selected. Similar to Paper III, a sliding window haplotype analysis was conducted using a logistic regression model. The ten candidate loci identified in Paper III were replicated in the analysis, and 50 novel candidate loci were suggested, two of which were the same as in Paper III. DNA sequencing and a subsequent case-control study were carried out in the same manner and with the same cases and controls as in Paper III. One variant on locus 10q11.21 reached statistical significance. Further studies are required to determine the actual risk associated with the suggested loci.List of scientific papersI. Increased risk for uterine cancer among first-degree relatives to Swedish gastric cancer patients Samola Winnberg J, Rudd E, Keränen A, Lagerstedt-Robinson K, Lindblom A, Nilsson M, Lindblad M and Sjödahl K. Hereditary Cancer in Clinical Practice. 2020;18:12. https://doi.org/10.1186/s13053-020-00145-yII. Cancer among first- and second-degree relatives to Swedish patients diagnosed with gastric cancer Samola Winnberg J, Nilsson M, E. Vossen L, Lindblom A and Lindblad M. [Manuscript]III. A genome-wide association study in Swedish colorectal cancer patients with gastric- and prostate cancer in relatives Samola Winnberg J, Vermani L, Liu W, Soller V, Thutkawkorapin J, Lindblad M and Lindblom A. Hereditary Cancer in Clinical Practice. 2024;22(1):25. https://doi.org/10.1186/s13053-024-00299-zIV. A haplotype GWAS in syndromic familial colorectal cancer Vermani L, Samola Winnberg J, Liu W, Soller V, Sjödin T, Lindblad M and Lindblom A. International Journal of Molecular Sciences. 2025;26(2). https://doi.org/10.3390/ijms26020817</p
Ischemic stroke in working ages : large vessel occlusion, work capacity and outcome after thrombectomy
No full textThis thesis examines outcomes of ischemic stroke patients of working age. Stroke patients of working age risk permanent or long-term disability, which in turn affects many aspects of their individual lives.Large vessel occlusions are a cause of severe stroke, however, the prevalence is widely varying depending on the method and definition. We determined the prevalence in a Swedish untriaged setting (Study I). We found a lower prevalence than previously described, 11.3% of all ischemic stroke events. The reason could be related to clinical practice regarding detection at the time, as computer tomography angiography was not performed in half of the patients. Patients of working ages did not have more large vessel occlusions compared to older patients.Patients with large vessel occlusions are eligible for thrombectomy treatment. Mechanical thrombectomy is the technique of retrieving the thrombus through manual extraction. The histological components of the extracted thrombi were analyzed in Study II. We found that pharmaceutical therapies such as anticoagulants alter the thrombus composition, however antiplatelet therapy did not. There was no age-related difference in thrombus composition.The outcomes after thrombectomy treatment have been very encouraging, however, due to limited statistical power it remains unclear whether thrombectomy is beneficial in ages below 50. Study III investigated the nationwide outcomes of working-aged patients. We found that the outcome of working-aged patients was better, and the risk of subsequent brain hemorrhage and mortality was lower compared to older patients.The ability to work is often regarded as one of the most important matters for stroke patients in rehabilitation. We performed a nationwide study on sickness absence and disability pension on stroke patients of working ages (Study IV). Over time, stroke patients demonstrate lowered rates of sickness absence and disability pension. Still, in the year before stroke onset, stroke patients showed elevated absence rates compared to matched references with similar socioeconomic backgrounds. These absence days were mostly related to mental and musculoskeletal disorders.Patients treated with thrombectomy risk severe stroke outcomes. For these patients, work-related outcomes are underexamined. Study V investigates the sickness absence and disability pension of all treated patients, showing that one third of patients are not sickness absent at 30 days after treatment, with increasing rates at follow-up. These results supplement traditional stroke outcomes such as functional independence after stroke.List of scientific papersI. Prevalence of large vessel occlusions in an unselected hospital- based stroke cohort in Sweden. Roland M, Markaki I, Arnberg F, Klironomos S, Sjöstrand C. Frontiers in Neurology. (2025). https://doi.org/10.3389/fneur.2025.1549537II. Anticoagulants and other predictors of thrombus composition in patients treated with thrombectomy. Roland M, Aspegren O, Sjöstrand C, Arnberg F. [Manuscript]III. Mechanical thrombectomy in stroke patients of working age: Real-world outcomes in Sweden. Roland M, Markaki I, Andersson T, Arnberg F, Sjöstrand C. European Stroke Journal. (2022). https://doi.org/10.1177/23969873211067883IV. Sickness absence and disability pension before and after ischemic stroke: a Swedish longitudinal cohort study with matched references. Roland M, Rudberg AS, Alexanderson K, Sjöstrand C. European Stroke Journal. (2024). https://doi.org/10.1177/23969873241261011V. Sickness absence and disability pension in stroke patients treated with mechanical thrombectomy. Roland M, Rudberg AS, Arnberg F, Alexanderson K, Sjöstrand C. Journal of Stroke and Cerebrovascular Diseases. (2025). https://doi.org/10.1016/j.jstrokecerebrovasdis.2025.108236</p
Identification of dental anxiety
No full textDental anxiety is common, and dental clinicians can use several different techniques to manage its symptoms. However, before giving any anxiety-alleviating treatment, the dental staff must first understand that their patient is indeed suffering from dental anxiety. This thesis aims to enhance our understanding of how dental anxiety is identified.Study I aimed to assess how dental clinicians rate dental anxiety. One hundred four clinicians from 24 public dental clinics in Östergötland, Sweden, evaluated 1,128 adult patients returning for routine check-ups. Patients expressed their levels of dental anxiety on the Modified Dental Anxiety Scale and a Visual Analog Scale. The clinicians assessed the patients' anxiety levels using a Visual Analog Scale. The correlation (rs) between the anxiety ratings given by the clinicians and those provided by patients was found to be 0.45. Notably, among patients with high dental anxiety, no correlation was observed between the ratings of the clinicians and those of the patients. Generally, the clinicians tended to rate dental anxiety lower than their patients, particularly in cases of high anxiety.Study II aimed to identify, describe, and develop concepts regarding how dental professionals perceive dental anxiety. Eleven semi-structured interviews were performed with public dental clinicians in Östergötland, Sweden. A purposive and theoretical sampling method was employed, and theoretical saturation was achieved after eight interviews. The recorded interviews were transcribed verbatim. Classical grounded theory was utilized for data analysis through a method known as constant comparative analysis. The primary finding (the core category) was The clinical eye, which refers to clinicians recognizing behaviors that may indicate dental anxiety based on their knowledge, experiences, or intuition. This core category includes five categories: Sympathetic activation, Patient- reported anxiety, Controlling behaviors, Avoidance, and Accomplishment. Initially, there is often doubt about whether a specific behavior is a result of dental anxiety. To gain more certainty, clinicians must recognize a stressor within the dental environment by observing a behavioral change during the anticipation, presence, or removal of that stressor.Study III aimed to understand how patients experience the dental staff identifying them as dentally anxious. Semi-structured interviews were performed with ten people who considered themselves to be dentally anxious. The methodology was consistent with that of Study II, reaching theoretical saturation after eight interviews. The core category that emerged was hope for Fingerspitzengefühl from dental staff, which refers to an intuitive understanding of a situation and the appropriate response. This concept also encompasses tact and sensitivity from the dental staff. The dentally anxious were reluctant to confide their dental anxiety to the staff due to embarrassment and guilt, thus placing the responsibility for noticing on the staff. The participants hoped that the dental staff would detect their anxiety, acknowledge their feelings of embarrassment, and take meaningful steps to help alleviate their distress.Study IV aimed to adapt the English version of the Modified Dental Anxiety Scale (MDAS) for use in Sweden and to validate it within the Swedish context. The process followed recommended guidelines for cross-cultural adaptation and validation. Field testing of the Swedish MDAS (MDAS-S) involved 246 adults attending routine dental check-ups and seven individuals diagnosed with dental phobia. The MDAS-S scores were significantly higher (p List of scientific papersI. Evaluation of the ability of dental clinicians to rate dental anxiety. Höglund M, Bågesund M, Shahnavaz S, Wårdh I. Eur J Oral Sci. 2019 Oct;127(5):455-461. https://doi.org/10.1111/eos.12648II. Dental clinicians recognizing signs of dental anxiety: a grounded theory study. Höglund M, Wårdh I, Shahnavaz S, Berterö C. Acta Odontol Scand. 2023 Jul;81(5):340-348. https://doi.org/10.1080/00016357.2022.2154263III. Dental professional recognition of dental anxiety from a patient perspective: a grounded theory study. Höglund M, Wårdh I, Shahnavaz S, Berterö C. Acta Odontol Scand. 2024 Dec 18;83:696-701. https://doi.org/10.2340/aos.v83.42447IV. Cross-cultural adaptation and validation of the Swedish version of the Modified Dental Anxiety Scale. Höglund M, Göranson E, Wårdh I, Larsson P. Acta Odontol Scand. 2024 Dec 16;83:666-671. https://doi.org/10.2340/aos.v83.42436</p
Development of translational models and identification of novel therapeutic targets for medulloblastoma
No full textMedulloblastoma (MB), the most frequent malignant brain cancer in children, has traditionally been studied using established cell lines, patient-derived xenografts, engineered mouse models, and orthotopic transplants. While these models have been instrumental in advancing our understanding of MB pathogenesis, they predominantly represent later stages of tumor development, failing to adequately capture the early events of tumor initiation and progression. Moreover, many preclinical in vivo models are unable to fully recapitulate human tumor pathogenesis due to species differences in development and organ structures. Additionally, despite the discovery of numerous molecular therapeutic strategies over recent decades, only a small fraction of drugs demonstrating preclinical efficacy have translated successfully into human clinical trials. This further underscores the need for innovative approaches to model tumorigenesis. Modeling early tumor development has become possible with the emergence of induced pluripotent stem cell (iPSC) technology, thereby opening new avenues for the discovery of potential therapeutic targets. This thesis describes the development of novel, disease-relevant model systems that integrate patient- derived iPSCs and zebrafish xenografts to faithfully recapitulate the early stages of MB tumorigenesis. The overall aim of this thesis was to develop both in vitro and in vivo models that mimic MB initiation and progression, thereby facilitating mechanistic studies and the identification of novel therapeutic targets.In Paper I, we established a new human model system for sonic hedgehog (SHH)- driven MB by utilizing neuroepithelial stem (NES) cells derived from non- cancerous Gorlin syndrome patient iPSCs. Re-transplantation of these cells leads to a more malignant phenotype and accelerated tumor formation, providing a robust platform for studying the molecular changes during tumor development. Importantly, this study identified LGALS1 (galectin-1) as a direct GLI target gene that is upregulated in SHH MB, recognizing it as a promising novel therapeutic target. Furthermore, we describe the development of an orthotopic zebrafish- based xenograft model for MB in Paper II. In this model, MB cells exhibited intrinsic homing to the hindbrain region of developing zebrafish embryos upon blastula- stage transplantation, a process further enhanced by in vitro neural stem cell culture conditions. The blastula-stage zebrafish xenografts not only recapitulated tumor growth and neurotropism across MB subgroups but also serve as an efficient in vivo system for rapid drug testing. This provides a scalable alternative to traditional mouse models. Both of these novel model systems have been used to elucidate the role of galectins in SHH-driven MB (Paper III). This study demonstrated that LGALS3 (galectin-3) is highly expressed in these tumors and plays a crucial role in maintaining primary cilia structures, thereby facilitating canonical SHH signaling. Functional studies revealed that loss or inhibition of galectin-3 reduces tumorigenicity by impairing cell proliferation, migration and overall tumor progression in vivo. Additionally, galectin-3 modulates amino acid uptake, particularly arginine, through a TGF-B-mediated transcriptional mechanism on the activity of its solute carrier (SLC) transporters. All of this highlights its potential as a therapeutic target for SHH-driven MB. Lastly, we present the development of a human in vitro iPSC-derived cerebellar organoid model to explore their potential as a model system for MB (Paper IV). These organoids, generated from both control and Gorlin syndrome patient-derived iPSCs, recapitulated critical aspects of cerebellar development. Notably, Gorlin- derived organoids displayed accelerated growth, increased proliferation, and a higher abundance of PAX6-positive cells compared to controls. This makes them an invaluable, all-human system for further exploration of MB pathogenesis.In conclusion, this thesis significantly advances MB research by developing innovative in vitro and in vivo models that more accurately mirror the early stages of MB tumor initiation and progression. Additionally, we demonstrate that these model systems enable the discovery of novel therapeutic targets for SHH-driven MB, holding promise for translational research.List of scientific papersI. Susanto E, Marin Navarro A, Zhou L, Sundström A, van Bree N, Stantic M, Moslem M, Tailor J, Rietdijk J, Zubillaga V, Hübner JM, Weishaupt H, Wolfsberger J, Alafuzoff I, Nordgren A, Magnaldo T, Siesjö P, Johnsen JI, Kool M, Tammimies K, Darabi A, Swartling FJ, Falk A, Wilhelm M. Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells. Proc Natl Acad Sci U S A. 2020 Aug 18; 117(33) : 20127-20138. https://doi.org/10.1073/pnas.1920521117II. van Bree N, Oppelt AS, Lindstrom S, Zhou L, Boutin L, Coyle B, Swartling FJ, Johnsen JI, Brautigam L, Wilhelm M. Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing. Neuro Oncol. 2025 Mar; 27(3) : 779-794. https://doi.org/10.1093/neuonc/noae210III. van Bree N, Oppelt AS, Zimmer E, Wiesinger ML, Kvastad L, Escudero Morlanes J, Marques R, Bell N, Boutin L, Dias J, Zetterberg F, Nilsson U, Schäfer S, Zhou L, Teixeira A, Wilhelm M. Galectin-3 supports tumorigenesis in SHH-driven medulloblastoma by coordinating ciliary signaling and amino acid transport. [Manuscript]IV. van Bree N, Haazen L, Falk A, Magnaldo T, Wilhelm M. Generation of Gorlin syndrome patient iPSC-derived cerebellum organoids as a model system for SHH-driven medulloblastoma. [Manuscript]</p
Connecting charge, structure, and biomolecular interactions with native mass spectrometry
No full textUnderstanding biomolecular interactions is crucial for advancing our fundamental knowledge of biological processes and for aiding pharmaceutical development to target diseases effectively. This thesis aims to investigate how protein properties and biomolecular interactions influence the charging mechanisms during electrospray ionization (ESI) in native mass spectrometry (nMS). We then use the insigths from these studies to investigate the structure-function relationship of membrane protein-lipid complexes.Paper I examines the role of ionizable residues in ESI charging using protein engineering across three different systems. We find that in the absence of ionizable residues, proteins can still charge according to their surface area, but exhibit a lower proton affinity and gas-phase stability. The position of these residues also affects protein stability due to Coulombic destabilization.Paper II rigorously investigates how the choice of detergents impacts the final charge state of membrane proteins. The study highlights the role of the detergent headgroup's proton affinity in membrane protein charging and suggests a charge equilibration mechanism during detergent removal in the gas-phase. This equilibration occurred through the transfer of protons from the detergent headgroup to the transmembrane region of the protein in the vacuum environment. This process thus be modulated to stabilize labile protein complexes for nMS analysis.Paper III explores the structure-charge state relationships of protein-DNA complexes reported in the literature. While DNA complexes exhibit slightly lower charges compared to proteins, they both follow a power-law relationship. The charge state distributions vary significantly for protein-DNA complexes. We observe that the final charge state differs depending on whether the DNA is bound centrally or peripherally, which can be explained by the higher density and gas- phase compaction of DNA molecules.Paper IV investigates the influence of low-complexity domains on protein ionization. Using both designed and naturally occurring proteins containing a mixture of folded and low-complexity domains, the study elucidates their roles in the charging mechanism, facilitating better interpretation of these processes.Paper V focuses on an artificial membrane protein system to identify the fundamental principles of lipid binding and lipid-mediated stabilization. By combining nMS with molecular dynamics simulations, the study uncovers key features, including residue positioning and dynamics involved in lipid-mediated stabilization. Additionally, it led to the discovery of a novel cardiolipin binding site in a membrane-bound protease, which plays a role in the protein's allosteric regulation.Togheter, the findings from these five studies shed light on the fundamental mechanisms of ESI and demonstrate how protein engineering, alongside biomolecular interactions, can be leveraged to gain deeper insights into protein structure and function.List of scientific papersI. MIA L. ABRAMSSON, Cagla Sahin, Jonathan T. S. Hopper, Rui M. M. Branca, Jens Danielsson, Mingming Xu, Shane A. Chandler, Nicklas Österlund, Leopold L. Ilag, Axel Leppert, Joana Costeira-Paulo, Lisa Lang, Kaare Teilum, Arthur Laganowsky, Justin L. P. Benesch, Mikael Oliveberg, Carol V. Robinson, Erik G. Marklund, Timothy M. Allison, Jakob R. Winther & Michael Landreh. Charge engineering reveals the roles of ionizable side chains in electrospray ionization mass spectrometry. JACSAu. 2021, 1, 2385-2393. https://pubs.acs.org/doi/10.1021/jacsau.1c00458II. Hsin-Yung Yen, MIA L. ABRAMSSON, Mark T. Agasid, Dilraj Lama, Joseph Gault, Idlir Liko, Margit Kaldmäe, Mihkel Saluri, Abdul Aziz Qureshi, Albert Suades, David Drew, Matteo T. Degiacomi, Erik G. Marklund, Timothy M. Allison, Carol V. Robinson & Michael Landreh. Electrospray ionization of native membrane proteins proceeds via a charge equilibration step. RSC Advances. 2022, 12, 9671-9680. https://doi.org/10.1039/d2ra01282kIII. MIA L. ABRAMSSON, Louise J. Persson, Frank Sobott, Erik G. Marklund & Michael Landreh. Charging of DNA Complexes in Positive-Mode Native Electrospray Ionization Mass Spectrometry. J. Am. Soc. Mass. Spectrom. 2024, 35, 12, 3157-3162. https://doi.org/10.1021/jasms.4c00335IV. Hannah Osterholz, Alexander Stevens, MIA L. ABRAMSSON, Dilraj Lama, Anna Rising, Erik G Marklund, Arne Elofsson, Sebastian Deindl, Axel Leppert & Michael Landreh. Native mass spectrometry captures the conformational plasticity of proteins with low-complexity domains. JACSAu. 2025. https://doi.org/10.1021/jacsau.4c00961V. MIA L. ABRAMSSON, Robin A. Corey, Jan Škerle, Louise J. Persson, Olivia Anden, Abraham O. Oluwole, Rebecca J. Howard, Erik Lindahl, Carol V. Robinson, Kvido Strisovsky, Erik G. Marklund, David Drew, Phillip J. Stansfeld & Michael Landreh. Engineering cardiolipin binding to an artificial membrane protein reveals determinants for lipid-mediated stabilization. eLife [Manuscript Preprint] https://doi.org/10.7554/eLife.104237.1</p
Immune responses to mRNA vaccines : characteristics & the impact of host immune status
No full textmRNA vaccines played a critical role in combating the SARS-CoV-2 pandemic and are progressing toward wider clinical use. However, much of how mRNA vaccines act upon the immune system to induce protection remains incompletely understood. This thesis explores how mRNA vaccines interact with the cells of the immune system, focusing on B cell immunity, early inflammation, and host-specific factors.In study I, we compared a preclinical nucleoside-unmodified mRNA vaccine candidate against an antigen-matched inactivated virus vaccine. We found that two doses of unmodified mRNA vaccine induced higher peak neutralizing antibody titers and bone marrow plasma cell counts, while showing similar memory B cell somatic hypermutation and diversity. Antibody titers were cross- neutralizing and stabilized at a higher plateau at 1 year after mRNA compared to inactivated virus vaccination.In study II, we investigated how prior SARS-CoV-2 influence the early innate immune responses to nucleoside-modified mRNA vaccination in humans. We showed that mRNA vaccination induces a transient inflammatory response including moderate systemic release of proinflammatory cytokines, upregulation of type I interferon associated genes, and proportional expansion of circulating monocyte populations. In individuals with known prior SARS-CoV-2 infection, the magnitude of the innate response to the prime vaccination was increased compared to SARS-CoV-2 naïve controls. Correlation analysis associated innate immune activation to levels of pre-existing adaptive immunity.In study III, we investigated the B cell response to SARS-CoV-2 mRNA vaccination in hematopoietic stem cell transplant recipients. While those vaccinated within 12 months post-transplant had reduced antibody and memory B cell levels, the responses that did occur were functional in terms of neutralization and accumulation of somatic hypermutation in the B cell receptor. Lower responses were associated with elevated fractions of immature transitional B cells.In summary, this thesis provides insights into both the early and long-term immune responses elicited by mRNA vaccines and underscores the influence of individual host factors, such as prior antigen experience and immune repertoire composition, on vaccine responsiveness.List of scientific papersI. Hellgren F*, Cagigi A*, Arcoverde Cerveira R*, Ols S, Kern T, Lin A, Eriksson B, Dodds MG, Jasny E, Schwendt K, Freuling C, Müller T, Corcoran M, Karlsson Hedestam GB, Petsch B, Loré K. Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses. Nature Communications. 2023 Jun 22;14(1):3713. https://doi.org/10.1038/s41467-023-39421-5II. Hellgren F*, Rosdahl A*, Arcoverde Cerveira R, Lenart K, Ols S, Gwon YD, Kurt S, Delis AM, Joas G, Evander M, Normark J, Ahlm C, Forsell MN, Cajander S, Loré K. Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans. JCI Insight. 2024 May 8;9(9):e175401. https://doi.org/10.1172/jci.insight.175401III. Hellgren F, Arcoverde Cerveira R, Lindgren G, Chen P, Lenart K, Ols S, Cagigi A, Rocavert Barranco M, Shaloom Vitus E, Corcoran M, Gwon Y-D, Forsell MNE, Evander M, COVAXID Study group, Bergam P, Buggert M, Ljunggren H-G, Aleman S, Karlsson Hedestam GB, Björklund A, Nordlander A, Ljungman P, Mielke S*, Loré K *. The impact of B cell reconstitution on mRNA vaccine responses in allogeneic stem cell transplant recipients. [Manuscript]*= Equal contribution.</p
Sex-specific white matter alterations in children exposed to high pregestational BMI
No full textObjective: This study investigated whether exposure to high pregestational BMI (≥ 25 kg/m2) is associated with alterations in white matter microstructure in early childhood, explored sex-specific effects, and examined associations with cognitive performance.Methods: A total of 90 children from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort underwent diffusion tensor imaging between ages 2 and 7 years. Data were processed using ExploreDTI to obtain mean fractional anisotropy (FA) and mean diffusivity (MD). Pregestational weight was self-reported by pregnant individuals, height was measured at enrollment, and child cognitive outcomes were assessed at ages 3 to 4 years using the Wechsler Preschool and Primary Scale of Intelligence.Results: Children exposed to high pregestational BMI had lower FA, but not higher MD, in the superior longitudinal fasciculus and in the body and splenium of the corpus callosum compared with unexposed children (BMI 18.5-24.9 kg/m2). This association persisted when analyzing pregestational obesity and overweight categories separately. Altered FA in splenium of the corpus callosum was associated with poorer cognitive outcomes in exposed children. Exposed male children had higher FA in the fornix, whereas female children had lower FA in the body and splenium of the corpus callosum compared with unexposed peers.Conclusions: High pregestational BMI was associated with alterations in white matter microstructure during early childhood in a sex-specific manner. Promoting healthy lifestyles and weight management among individuals of childbearing age is crucial.</p
Association of preterm birth and birth size status with neurodevelopmental and psychiatric disorders in spontaneous births
No full textPreterm birth (PTB) or small birth size are risk factors for certain neurodevelopmental disorders. The magnitude of these associations in spontaneous births, and of associations for combined PTB and birth size status on neurodevelopmental and psychiatric disorders is unexplored. We investigated whether PTB and small/large for gestational age (SGA/LGA), separately or combined, in spontaneous births, are associated with a wide spectrum of neurodevelopmental and psychiatric disorders. In this population-based registry cohort study, all singleton spontaneous births in Finland from 1996 to 2014 were followed until 2018 (n = 819 764). We show that PTB across gestational ages, and SGA, were associated with higher risks for anxiety disorders, intellectual disabilities, specific developmental disorders (SDD), autism spectrum disorders (ASD), attention-deficit/hyperactivity disorders (ADHD) and other emotional and behavioural disorders (F98). Most of these associations were not attributed to familial factors. Larger effect sizes were observed with lower gestational ages. Extremely PTB was associated at highest risks with intellectual disabilities (HR, 10.70 [95%CI, 8.69-13.17]) and SDD (HR, 8.91 [95%CI, 8.18-9.71]). Moreover, very preterm birth combined with SGA was associated with a higher risk for SDD (HR, 7.55 [95%CI, 6.61-8.62]) than that of very preterm or SGA birth alone. Conversely, LGA birth lowered the risk for SDD and other emotional and behavioural disorders among individuals born very preterm. In conclusion, PTB along with SGA is associated with higher risks for SDD than one exposure alone, whereas LGA lowers the risks for SDD and other emotional and behavioural disorders in individuals born spontaneously.</p
Investigating the interplay of social defeat stress and personality in male and female zebrafish
No full textPsychological stress is now a known cause for many aspects of health deterioration or worsening of already existing health conditions. The way individuals interact with their environment and potential stressors depends on many factors including their personality background, upbringing, social experience, sex or age. This can translate into different coping strategies and different health consequences. In this thesis, the response to a stressful social experience and the effects of the resulting chronic stress are investigated using zebrafish (Danio rerio) as a model. A protocol of social defeat stress induced through dyadic fights was applied, and to better understand the interaction between social experience and personality, two lines of zebrafish were used, characterized by different coping styles, reactive and proactive (and hence different personality trait phenotypes, namely shy and bold). Sex differences were also considered, and the experiments were executed with both male and female individuals. A variety of parameters were measured to assess the consequences of social defeat stress and the overall health status of the animal: body condition, behavioral response (mirror test, zMCSF), and gene expression in the brain, intestine and skin (RNA sequencing). In summary, we showed that in both males and females inherited coping styles (personality) had a stronger effect on the response to social stress at various levels than the acquired social rank. Nevertheless, the lower social rank of subordinate/loser fish enhanced those effects, and those individuals appeared more vulnerable to subsequent health impairments, notably with signs of higher inflammation in the gut or signs of potential injuries and wound healing in the skin. Together, the data highlights the complexity of the response to stressors and the benefits of including unusual but very influential factors such as inherited personality traits in the experimental design. The data also supports previous findings showing that chronic stress can lead to potential impairment of health.List of scientific papersI. Hubená, P., Benrejdal, L., Brodin, D., Axling, J., Sarma, O.S., Bergman, P., Winberg, SEffects of Stress Coping Styles and Social Defeat on Zebrafish Behaviour and Brain TranscriptomicsNeuroscience Bulletin, Sep. 2025https://doi.org/10.1007/s12264-025-01506-0II. Benrejdal, L., Hubená, P., Brodin, D., Morales Castro, R.A., Rekha, R.S., Winberg, S., Bergman, P.Personality and repeated social defeat affect health condition and gene expression in the skin and intestines in zebrafishProgress in Neuro-Psychopharmacology and Biological Psychiatry, Sep. 2025, p. 111487https://doi.org/10.1016/j.pnpbp.2025.111487III. Hubená, P .* , Benrejdal, L .* , Brodin, D., Morales Castro, R.A., Bergman, P., Winberg, S.Coping with Stress: Behavioural and Transcriptomic Profiles Across Tissues in Female Zebrafish [Manuscript]*Equal contribution</p
