Matrix rigidity control of breast cancer cell malignancy

The extracellular matrix (ECM) is a dynamic and essential scaffold that orchestrates tissue architecture and cellular behavior through a complex interplay of biochemical and biomechanical cues. In breast cancer, the ECM undergoes extensive remodeling, characterized by increased deposition and cross-linking of collagen fibers. This remodeling leads to a progressively stiffer microenvironment, a hallmark of many solid tumors, which disrupts normal tissue homeostasis and drives malignant transformation. Despite the recognized importance of ECM stiffness in tumor progression, the molecular mechanisms by which mechanical cues regulate breast cancer cell phenotypes remain incompletely understood.This thesis systematically investigates the role of ECM stiffness in modulating breast cancer cell behavior, employing an integrated multi-omic approach that combines quantitative proteomics, kinome profiling, and functional genetic screens. Utilizing the high-grade breast cancer cell line MCF10CA1a, we confirmed that an increase in matrix stiffness induces a phenotypic transition from a ductal carcinoma in situ (DCIS)-like state observed on compliant matrices, reflective of normal mammary gland architecture, to an invasive ductal carcinoma (IDC)-like phenotype on rigid matrices, recapitulating the mechanical properties of malignant breast tissue.In Study I, quantitative mass spectrometry revealed that matrix stiffening upregulates several enzymes of the mevalonate pathway, particularly Hydroxymethylglutaryl-CoA Synthase 1 (HMGCS1), at the protein level without corresponding changes in mRNA, indicating post-transcriptional regulation. Functional assays demonstrated that HMGCS1 is essential for the stiffness-induced malignant phenotype, and its synthesis is regulated by integrin and Rac1 signaling pathways. Notably, HMGCS1 expression was also elevated in human breast tumor tissues and correlated with collagen organization, underscoring the clinical relevance of these findings.Study II employed peptide chip arrays to profile kinase activity across stiffness-dependent cellular states, identifying the inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) and mitogen-activated protein kinase 8 (MAPK8) as key mediators of the stiffness-induced IDC phenotype. Both siRNA-mediated knockdown and pharmacological inhibition of IKBKE and MAPK8 successfully reverted the invasive phenotype to a DCIS-like state, suggesting that targeting these kinases could offer new therapeutic strategies for breast cancer.In Study III, integration of proteomic, kinomic, and transcriptomic data, followed by a targeted RNAi screen, identified several critical regulators of stiffness-induced malignancy, including FES proto-oncogene-tyrosine kinase (FES), Heat Shock Protein Family B (Small) Member 8 (HSPB8), Pyruvate dehydrogenase kinase 1 (PDK1), and Tensin-4 (TNS4). Of particular interest, TNS4 was consistently upregulated at the protein level in response to stiff ECM across multiple breast cancer cell lines. Importantly, at a stiffness resembling breast cancer, TNS4 predominantly localizes in hemidesmosomes (HDs) and is essential for the assembly of HDs. Moreover, disruption of TNS4 or the HD-linked keratin network abrogated the stiffness-induced malignant phenotype.Collectively, these findings provide novel insights into the molecular pathways by which the matrix stiffness regulates breast cancer cell behaviors and highlight potential targets for therapeutic intervention aimed at disrupting the biomechanical drivers of malignancy.List of scientific papersI. Sara Göransson, Helene Olofsson, Henrik J. Johansson, Feifei Yan, Christos Vogiatzakis, Shuo Liang, Hermano Martins Bellato, Laia Masvidal, Inci Aksoylu, Johan Hartman, Glaucia NM Hajj, Ola Larsson, Janne Lehtio, Staffan Stromblad. Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis. MATRIX BIOLOGY. 2025;140:1-15. https://doi.org/10.1016/j.matbio.2025.05.005II. Feifei Yan*, Sara Göransson*, Helene Olofsson, Christos Vogiatzakis, Anagha Acharekar, Staffan Stromblad. Matrix stiffness-induced IKBKE and MAPK8 signaling drives a phenotypic switch from DCIS to invasive breast cancer. CELL COMMUNICATION AND SIGNALING. 2025;23(1):269. https://doi.org/10.1186/s12964-025-02276-yIII. Feifei Yan, Sara Göransson, Jianjiang Hu, Staffan Strömblad. Matrix rigidity control of hemidesmosomes governs breast cancer cell malignancy. [Manuscript]*: Equal contribution</p

Seizures in the neonatal period : neurological outcomes, mortality and treatment

Background: In childhood, the risk of seizures is greatest during the neonatal period, affecting 1-5 per 1000 live newborns. Seizures in the neonate are most often acute provoked and are easily misinterpreted even by experienced healthcare professionals. Registration of brain activity with electroencephalogram (EEG) or amplitude-integrated EEG (aEEG) is of major importance to clarify whether the symptoms are central nervous system (CNS)- induced or not. To date, larger, population-based studies on postneonatal neurological outcomes and mortality after EEG/aEEG-verified neonatal seizures of any cause are scarce. Also, knowledge-gaps exist concerning the use of anti- seizure medications (ASMs) during neonatal hospitalization and to what extent children are discharged with ongoing ASM treatment from neonatal care at a national level. In Sweden, several health care registries exist that constitute valuable tools in conducting such epidemiological research.Aims: To investigate the accumulated evidence of adverse neurological outcomes and mortality after EEG/aEEG-verified neonatal seizures. To validate the Swedish Neonatal Quality Register (SNQ) regarding its "CNS-induced seizures" variable in addition to other neurological variables, seizure-related diagnoses, ASMs during neonatal hospitalization and at discharge. To investigate the risk of postneonatal epilepsy (PNE) and mortality after EEG/aEEG-verified neonatal seizures on a population-based level. Also, to study what types of ASMs are used during neonatal hospitalization and to what extent infants are discharged with ASM from neonatal care in Sweden. To investigate the risk of developmental delay (DD), intellectual disability (ID), autism, attention-deficit hyperactivity disorder (ADHD), and cerebral palsy (CP) after EEG/aEEG verified neonatal seizures on a population-based level and to explore prescription patterns of medications in individuals with ADHD.Materials and methods: In Study I, inclusion and exclusion criteria were decided prior to database searches in Medline, Embase, and Web of Science. Outcomes of interest were PNE, DD, ID, autism, ADHD, CP, and mortality in children with EEG/aEEG-verified neonatal seizures. Double-blinded screening of abstracts followed by full-text reading of scientific articles were performed. Methodology was according to the checklist of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.In Study II, children born between January 1, 2009, and December 31, 2016, admitted to a neonatal unit in the Stockholm region, and with the checkbox "CNS-induced seizures" marked in the SNQ Register were included. Neurological variables and seizure-related P90 diagnoses according to the 10th Swedish edition of International Statistical Classification of Diseases and Related Health Problems (ICD-10-SE) codes were validated against medical charts. Coherence of ASMs used during neonatal hospitalization and validity of ASM at discharge were explored. Positive predictive values (PPVs) with 95% confidence intervals (CIs) were investigated.In Studies III and IV, children diagnosed with P90.9A (seizures with EEG/aEEG- verification) of any cause in the SNQ Register with a simultaneous tick in the checkbox for "CNS-induced seizures" and born between January 1, 2009, and December 31, 2020, constituted the exposed group. Controls were obtained from the National Medical Birth Register, negative for the P90.9A diagnosis in the National Patient Register (NPR) and matched for year of birth, sex, and gestational age (completed weeks) at a ratio of 1:5 (exposed:controls). Information on diagnoses were obtained from the NPR, mortality data from the National Cause of Death Register, and information on medical drug prescriptions from the National Prescribed Drug Register. The follow-up period was from January 1, 2009, to December 31, 2021, except for medical drug prescription, where data were obtained until the end of 2022. Cumulative incidences and adjusted hazard ratios (aHRs) of PNE, DD, ID, autism, ADHD, CP, and mortality were investigated with 95% CIs. The use of ASMs during neonatal hospitalization and their continuation at discharge from neonatal care were explored, as well as the medical drug prescription in ADHD diagnosis.Results: In Study I, 5518 records were screened, 260 read in full text and 31 studies were finally included. The reported cumulative incidences of PNE varied between 5-84%, for DD: 9-67%, for ID: 24-39%, for CP: 9-78%, and for mortality: 1-62%. In children with neonatal status epilepticus, the incidence of PNE was 46- 83%. In Study II, 351 study subjects with a total of 385 hospitalizations were included. The P90.9A diagnosis had a PPV of 89.8% (95% CI: 85.4-93.0%). The PPV for hypoxic-ischemic encephalopathy grade 2-3 was 94.4% (95% CI: 88.4- 97.4%), for CNS infarction: 80.0% (95% CI: 67.7-88.4%), and for CNS hemorrhage: 56% (95% CI: 38.6-72.0%). The PPV for ASM at discharge was 72.6% (95% CI: 66.1-78.3%), and 67.0% of the ASMs registered in the SNQ Register had total coherence with the electronic medical charts. In Study III, the cumulative incidence of PNE in children with neonatal seizures was 15.7% (95% CI: 13.5-18.9) at 2 years and 22.4% (95% CI: 19.8-25.2) at 7 years of age. The aHR for PNE was 50.3 (95% CI: 33.5-75.5) and the aHR for mortality was 8.37 (95% CI: 4.94-14.0). Phenobarbital was the most commonly used ASM during neonatal hospitalization. The proportion of infants discharged with ASM from neonatal care decreased during the study period, from 77.1% to 8.7% while the risk of PNE remained unchanged. In Study IV, the greatest cumulative incidence in children with neonatal seizures was found for CP: 21.9% (95% CI: 19.4-24.6%) at 10 years of age, followed by ID: 14.7% (95% CI: 12.0-17.6%) at the corresponding age. The greatest aHR of 42.6 (95% CI: 26.3-69.1) was shown for CP, followed by an aHR of 18.9 (95% CI: 11.8-30.4) for ID. Methylphenidate was the most commonly prescribed medication for children with ADHD diagnosis.Conclusions: The overall evidence regarding adverse neurological outcomes and mortality following EEG/aEEG-verified neonatal seizures demonstrates a wide range of reported risks. The SNQ Register has a high validity of the P90.9A diagnosis when the "CNS-induced seizures" checkbox is ticked. On a nationwide level, the risk of adverse neurological outcomes and mortality is significantly greater in children with EEG/aEEG-verified neonatal seizures compared to controls. Standardized follow-up programs for affected children are essential to enable timely implementation of appropriate interventions when adverse neurological outcomes are identified. In the future, additional large-scale studies investigating neonatal seizures in the light of etiologies are warranted. Thereby, an enhanced understanding about seizure related impact on neurological outcomes could be generated and potentially enable a more individualized follow-up.List of scientific papersI. Westergren H, Finder M, Marell-Hesla H, Wickström R. Neurological outcomes and mortality after neonatal seizures with electroencephalographical verification. A systematic review. Eur J Paediatr Neurol. 2024 Mar;49:45-54. Epub 2024 Feb 12. PMID: 38367369. https://doi.org/10.1016/j.ejpn.2024.02.005II. Westergren H, Marell Hesla H, Altman M, Wickström R. Validation of central nervous system-induced seizures and other neurological variables in the Swedish Neonatal Quality Register. Acta Paediatr. 2022 Jul;111(7):1331-1337. Epub 2022 Mar 27. PMID: 35298855; PMCID: PMC9314797. https://doi.org/10.1111/apa.16336III. Westergren H, Hesla HM, Altman M, Freyland S, Wickström R. Epilepsy After Electroencephalographically Verified Neonatal Seizures: A Swedish Population-Based Matched Cohort Study. Pediatr Neurol. 2026 Jan;174:29-36. Epub 2025 Oct 8. PMID: 41166784. https://doi.org/10.1016/j.pediatrneurol.2025.10.003IV. Westergren H, Marell Hesla H, Altman M, Wickström R. Neurological outcomes beyond epilepsy following electroencephalographically verified neonatal seizures: A Swedish nationwide cohort study. Neuroepidemiology. 2026 Feb 16:1-16. Epub ahead of print. PMID: 41697907. https://doi.org/10.1159/000551055</p

Myasthenia gravis epidemiology : from environmental risk factors to quality of life

Myasthenia gravis is an autoimmune disease associated with a variable degree of muscular weakness and fatigability. Over the past decades, several studies have found increasing incidence rates, especially among men and higher age groups, although the underlying reasons are unknown. On the other hand, mortality rates have changed dramatically over the past century so that MG patients now have almost the same life expectancy as people free of MG. However, it is not known to what degree this is also paralleled by a similar improvement in quality of life among people living with MG. The objective of this PhD thesis was to explore both possible environmental risk factors impacting MG risk, as well as to determine how residual disease symptoms correlate with quality of life scores by using questionnaire and registry data.In study I we described the Genes and Environment in MG (GEMG) - study population. We estimated that almost half the patients at inclusion had an unacceptable symptom state indicating an unmet need of improved disease control.In study II we used the nationwide MG registry to assess how disease activity and quality of life measurements covaried. We concluded that at already low disease activity patients reported significantly decreased quality of life indicating a need for improved treatment algorithms or treatments.In study III we explored the impact of smoking, snuff use and alcohol consumption on MG disease risk using the GEMG questionnaire. We found that, alcohol consumption was negatively associated with developing MG in all subgroups. Further smoking or snuff use at onset was positively associated with developing early onset MG. In study IV we explored the impact of body mass index (BMI), physical activity and fish consumption on MG disease risk using the GEMG questionnaire. We found that BMI significantly impacted the risk of MG. When estimating population attributable fraction, we found a specifically high impact in male patients, which we hypothesize could explain part of the observed incidence increase. Physical activity was not associated with MG, while at least weekly fish consumption at age 20 was associated with a decreased risk of MG.List of scientific papersI. Petersson M, Feresiadou A, Jons D, Ilinca A, Lundin F, Johansson R, Budzianowska A, Roos AK, Kågström V, Gunnarsson M, Sundström P, Piehl F, Brauner S. Patient-Reported Symptom Severity in a Nationwide Myasthenia Gravis Cohort: Cross- sectional Analysis of the Swedish GEMG Study. Neurology, 2021. PMID: 34376512. https://doi.org/10.1212/wnl.0000000000012604II. Petersson M, Wu J, Berggren F, Schager I, Piehl F, Brauner S. Impact of disease activity on quality of life and EQ-5D-3L score in myasthenia gravis: results from the Swedish MG registry. Journal of Neurology, 2025. PMID: 40775536. https://doi.org/10.1007/s00415-025-13298-4III. Petersson M, Jons D, Feresiadou A, Ilinca A, Lundin F, Johansson R, Budzianowska A, Roos AK, Kågström V, Gunnarsson M, Sundström P, Klareskog L, Olsson T, Kockum I, Piehl F, Alfredsson L, Brauner S. Nicotine, Alcohol Consumption, and Risk of Myasthenia Gravis: Results From the Swedish Nationwide GEMG Study. Neurology, 2025. PMID: 40493875. https://doi.org/10.1212/wnl.0000000000213771IV. Petersson M, Ilinca A, Jons D, Feresiadou A, Lundin F, Johansson R, Budzianowska A, Roos AK, Kågström V, Gunnarsson M, Sundström P, Kockum I, Klareskog L, Olsson T, Piehl F, Alfredsson L, Brauner S. Body mass index, physical activity, fish consumption and association to Myasthenia gravis: Results from the Swedish GEMG-study. [Submitted]</p

High-definition likelihood framework for local genetic architecture and proteome-informed target discovery

Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but translating these association signals into actionable biology remains a challenge. This is largely because most GWAS signals are non-coding, often reflect multiple correlated variants in linkage disequilibrium (LD), and rarely identify the effector gene, tissue, or mechanism. Large-scale plasma proteomics can help bridge this gap by providing molecular mediators that are closer to pharmacological intervention and can be anchored to genetic variation through protein quantitative trait loci (pQTL). However, integrative analyses that connect pQTLs to disease genetics are often unstable at the locus level due to polygenicity, allelic heterogeneity, and imperfect LD information, leading to overconfident or inconsistent conclusions. In addition, most studies focus on protein monomers, yet proteins rarely act in isolation but instead interact with other proteins to form complexes and pathways that collectively execute cellular functions. This thesis develops likelihood-based methodologies that make local genetic architecture a practical unit for inference and evidence integration, and applies them to regional genetic analysis, protein-disease colocalization, and complexlevel target discovery. In Study I, we introduce HDL-L, a high-dimensional, fulllikelihood framework for estimating local SNP heritability and local genetic covariance from summary association statistics. Across extensive simulations, HDL-L provides well-calibrated regional inference, yielding more consistent local heritability estimates and more efficient genetic correlation estimates than LAVA over a wide range of genetic architectures. Applied to 30 UK Biobank phenotypes, HDL-L identified 109 significant local genetic correlations with a substantial computational advantage. In Study II, we extend the likelihood framework to perform colocalization analysis (HDL-C) of plasma proteins with complex diseases. Leveraging large-scale proteomic and GWAS resources, we prioritize protein-disease pairs driven by shared genetic effects and evaluate robustness using a cross-sex reproducibility design. Integrating genetically supported signals with drug knowledge bases distinguishes validated targets, repurposing opportunities, and novel hypotheses: among the top 50 HDL-C prioritized protein-disease pairs in male and female UK Biobank cohorts, we recover 40 previously validated drug-protein-disease relationships with approved indications and identify 62 additional relationships with repurposing potential, alongside 63 new protein-disease candidates for therapeutic follow-up. In Study III, we move beyond protein monomers to protein complexes by combining genetically informed protein-protein interactions with structural modeling to uncover targetable protein complexes. We identify 3,370 significant cis-trans protein pairs from 2,864 pQTLs, including 633 supported by STRING and 262 supported by experimental evidence, enriched for coherent functional modules such as apolipoprotein- and CD22-centered networks. Using AlphaFold3, we show that genetically supported interactions are enriched for high-confidence assemblies relative to matched controls. By using machine learning models, druggability analyses further reveal 25 complex-specific binding pockets across seven complexes that are absent in isolated monomers, highlighting opportunities for complex-selective pharmacological modulation, exemplified by SERPINA1-CTRL and HSBP1-WASHC3 within the WASH-Arp2/3 pathway. Overall, these studies position local shared-architecture inference as a robust layer of evidence for moving from genetic association signals to biological insight. Rather than stopping at the observation that traits are genetically related, the framework developed in this thesis helps localize where that sharing occurs in the genome and links it to specific genes, proteins, and pathways that may underlie disease mechanisms. In this way, the thesis provides both statistical tools and an analytical workflow that integrates regional genetic inference, proteomic data, and structural protein information. This combination makes it possible to move from broad genomic findings to more concrete and testable hypotheses, thereby supporting biomarker discovery, clarifying disease biology, and prioritizing therapeutic targets.List of scientific papersThe articles will be referred to in the text by their Roman numerals, and are reproduced in full at the end of the thesis. I. Li, Y., Pawitan, Y., & Shen, X. (2025). An enhanced framework for local genetic correlation analysis. Nature Genetics, 57(4), 1053 – 1058. https://doi.org/10.1038/s41588-025-02123-3II. Li, Y., Zhai, R., Yang, Z., Li, T., Pawitan, Y., & Shen, X. (2026). High-definition likelihood inference of genetic colocalization reveals protein biomarkers for human complex diseases. GigaScience, 15, giaf155. https://doi.org/10.1093/gigascience/giaf155III. Li, Y., Wang, Q., Zhai, R., Vu, T. N., Pawitan, Y., & Shen, X. (2026). A statistical genetics framework for discovering druggable protein complexes in human plasma. [Manuscript]</p

Early-onset breast cancer in East Africa : genetics, tumor characteristics and clinical management

Background: Breast cancer is a leading cause of cancer-related mortality among women worldwide, with particularly poor outcomes in many low-and middle- income countries. In East Africa, patients are often young at diagnosis, present with advanced disease, and face major barriers to accessing timely and comprehensive cancer care. Knowledge about the underlying tumor biology and hereditary predisposition in these settings remains limited.Aim: The overarching aim of this thesis was to evaluate the biological and genetic landscape of breast cancer, and access to breast cancer care in Ethiopia and Uganda, with a specific focus on early-onset disease among women.Methods: This thesis comprises four studies. Study I was a multicenter retrospective observational study of breast cancer surgery in 29 hospitals across Uganda, used to estimate the national breast cancer surgery rate and unmet surgical need. Study II was a cross-sectional study including women aged 18-39 years and men >18 years with invasive breast cancer from Ethiopia (n = 100) and a comparable patient cohort from Sweden (n = 100), focusing on stage at diagnosis and tumor subtypes. In Study III, the Ethiopian cohort underwent multigene panel testing for 12 established breast cancer susceptibility genes to assess the type and prevalence of germline pathogenic variants. Study IV was a prospective observational study following the Ethiopian cohort for one year to evaluate initiation and completion of recommended multimodal treatment, as well as early recurrence and mortality.Results: In Study I, after correction for missing data using multiple imputation, the annual breast cancer surgery rate was estimated at 137 procedures, corresponding to 5.7% of the national breast cancer incidence. Assuming that 80% of incident cases should receive surgery, the unmet surgical need was 92.9%. Most operations were performed at the National Referral Hospital by specialist surgeons.In Study II, Ethiopian patients presented with substantially more advanced disease compared with Swedish patients. Ethiopian and Swedish participants were diagnosed in tumor stage I (3.3% vs 27.0%), stage II (33.7% vs 45.0%), stage III (44.6% vs 23.0%) and stage IV (18.5% vs 5.0%), representing a significant difference in stage distribution between the groups (p In Study III, genetic analysis was successfully performed in 89 Ethiopian patients. In total, 22 germline pathogenic variants were identified. Over one-fifth (21.3%) harbored a pathogenic variant in a high-risk gene (BRCA1, BRCA2 or PALB2), including seven BRCA1, eight BRCA2 and four PALB2 variants.In Study IV, among patients with non-metastatic disease at diagnosis (n = 76), initiation of surgery and systemic therapy was relatively high, but only 20% completed the full recommended multimodal treatment. Early outcomes were poor: 29.2% of stage I-Ill patients experienced recurrence within one year, and among those with primary metastatic disease, the one-year mortality rate was 58.3%, with substantial loss to follow-up.Conclusions: This thesis reveals gaps in access to surgical and multimodal breast cancer care in East Africa, alongside a substantial burden of advanced- stage and hereditary disease. In Uganda, only a small fraction of women and men with breast cancer undergo surgery, leaving the vast majority of cases untreated. In Ethiopia, patients present with markedly more advanced disease than patients in Sweden, despite estrogen receptor-positive tumors being the most common subtype in both regions and both cohorts being unscreened populations. A high proportion of Ethiopian patients carried germline pathogenic variants in high-risk breast cancer susceptibility genes, underscoring the importance of hereditary predisposition in the target population.Major barriers to completing multimodal treatment, together with very limited access to radiotherapy and targeted therapies, likely contribute to high rates of early recurrence and mortality, highlighting an urgent need for strengthened cancer services in the region.List of scientific papersI. Ekdahl Hjelm T, Matovu A, Mugisha N, Löfgren J. Breast cancer care in Uganda: A multicenter study on the frequency of breast cancer surgery in relation to the incidence of breast cancer. PLoS One 14:e0219601, 2019. https://doi.org/10.1371/journal.pone.0219601II. Ekdahl Hjelm T*, Gebremariam TY*, Weldearegay MF, Sori M, Bauer M, Ayele BG, Assefa M, Anberber E, Mohammed HY, Kantelhardt EJ, Margolin S, Lindblom A, Ashenafi S, Lofgren J. Stage at diagnosis and tumor characteristics among young women and men with breast cancer, in Ethiopia and Sweden, a descriptive cross- sectional study. BMC Cancer 25:1222, 2025. https://doi.org/10.1186/s12885-025-14614-xIII. Ekdahl Hjelm T*, Gebremariam TY*, Weldearegay MF, Ayele BG, Assefa M, Anberber E, Kvist A, Törngren T, Borg Å, Margolin S, Lindblom A, Ashenafi S, Löfgren J. Germline pathogenic variants in breast cancer predisposing genes among early-onset female and male breast cancer in Ethiopia. JCO Global Oncology. [Accepted]IV. Ekdahl Hjelm T, Gebremariam TY, Weldearegay MF, Zenebe Y, Assefa M, Margolin S, Lindblom A, Ashenafi S, Löfgren J. Initiation of recommended oncological treatment in a cohort of young female and male breast cancer patients in Ethiopia: A one-year follow-up study. [Submitted]* Shared first authorship.</p

Ascending aortic aneurysm : implications of aortic valve phenotype

BACKGROUND: An ascending aortic aneurysm (AscAA) is a silent, potentially fatal condition, as it increases the risk of aortic wall failure through dissection or rupture. With an increasing prevalence, aortic disease now occupies the position of the 19th leading cause of death in the United States. Surgical intervention is indicated when the diameter exceeds 55 mm, or at smaller diameters in the presence of comorbidities or high-risk clinical features. While elective surgical treatment is prophylactic, many who present with catastrophic acute aortic failure do so at diameters below these surgical criteria. As current guideline thresholds rely primarily on aortic diameter, these strategies remain blind to the underlying aortic biology that determines rates of disease progression. Furthermore, there is currently no targeted medical treatment.AscAA encompasses multiple aetiologies with the same clinical manifestation - a dilatation of the ascending aortic segment. Discernible aetiologies, including syndromic disease and familial thoracic aortopathies, are increasingly found in clinical practice but are at the present time expected to make up 20-23% of surgical cohorts. The two most prevalent forms of AscAA are the degenerative AscAA, and the form manifesting in patients with a bicuspid aortic valve (BAV) - the most common (about 0.5-1.4% of the general population) congenital malformation of the heart valves. While the mechanisms of disease for these two forms are not fully known, multiple lines of evidence suggest different molecular and histopathological phenotypes.AIMS: This thesis aims to develop new insights into AscAA pathogenesis from molecular, cellular, and translational perspectives, with a focus on degenerative and BAV-associated forms. Specifically, the thesis aims to characterise endothelial-to-mesenchymal transition (EndMT) in degenerative and BAV-associated aortopathy. Additional aims include identification of drivers of fibrotic and inflammatory remodelling, investigation of mechanisms linking aortic valve disease to early aortic wall pathology, and evaluation of whether transcriptomic subtypes of ascending aortic tissue inform post-operative clinical heterogeneity.MATERIALS AND METHODS: Across all studies, investigations were primarily conducted in two cohorts of patients undergoing open heart surgery for either ascending aortic surgery, aortic valve replacement or both at the Karolinska University Hospital in Solna, Sweden. For the first cohort, operated between 2007 and 2013, patients were recontacted to inquire about participation in a 10-year radiological follow-up. For the majority of patients in this cohort, retrospective information on death and aortic events was collected through the medical records. The second cohort was started in 2012 and is still ongoing. In both cohorts, biological samples were collected from dilated and non-dilated ascending aortas, as well as plasma and whole blood. Human aortic tissue was used for transcriptomic exon arrays, spatial transcriptomics, proteomics, and primary cell isolation. In-house data on physiological rat aortic expression was used, and external single-cell matrices were produced from cohorts in Munich, Germany for cellular deconvolution.RESULTS: In study I we found that EndMT processes specific to BAV-associated AscAA had similar characteristics to embryonic EndMT, and we found a loss of canonical endothelial function in BAV-associated aortas even in the absence of dilatation, as evidenced by loss of CD31, decreased endothelial laminin y1, and subintimal accumulation of albumin as a proxy for endothelial permeability. In study II, the EndMT process was seemingly driven by osteopontin, in part expressed by CD68-positive cells. The expression of osteopontin may be regulated by distal enhancers affected by the transcription factor ETS1, in the context of inflammatory cells. This regulatory function could further be validated by cellular perturbations and in degenerative AscAA tissue. In study III, following up on the inflammatory phenotype of degenerative AscAA, we observed an association of nascent subintimal oxLDL and endothelial activation in non-dilated aortas of patients with aortic regurgitation, with potential downstream effects exacerbating inflammatory activity by CD68-positive cells. When following a subset of patients having undergone aortic valve replacement, we found that those who were operated for aortic regurgitation did not continue to grow, but patients with aortic stenosis (who rarely develop degenerative AscAA) did grow. Data from the follow-up on patients undergoing aortic valve and/or ascending aortic surgery was then leveraged in study IV to identify context-agnostic transcriptomic subtypes of aortic expression associated with late aortic events. We identified a subset of degenerative AscAA with a particularly inflammatory gene expression profile, which was associated with a significantly higher risk of residual disease through aneurysm development in the remaining ascending aorta. This subtype may be distinguishable from other degenerative AscAA through blood-borne plasma proteins.CONCLUSIONS: This thesis demonstrates that AscAA comprises biologically distinct disease processes linked to aortic valve phenotype. Endothelial dysfunction emerges as an early and central feature in both BAV-associated and degenerative AscAA; however, the underlying disease programs differ. BAV-associated aortopathy is characterised by features consistent with developmental endothelial dysfunction, whereas degenerative AscAA is more closely associated with endothelial activation, inflammation, and fibrotic degeneration. In degenerative AscAA, inflammatory activity may persist beyond the resected aortic segment and be associated with residual post-operative aortic risk. Collectively, these findings suggest that biologically informed approaches may complement current diameter-based guidelines in the future management of AscAA.List of scientific papersI. David Freiholtz; Otto Bergman; Karin Lång; Flore-Anne Poujade; Valentina Paloschi; Carl Granath; Jan H Lindeman; Christian Olsson; Anders Franco-Cereceda; Per Eriksson; Hanna M. Björck. Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability. Journal of Molecular Medicine. 2023 Jul;101(7):801-811. https://doi.org/10.1007/s00109-023-02316-5II. David Freiholtz; Otto Bergman; Sailendra Pradhananga; Karin Lång; Flore-Anne Poujade; Carl Granath; Christian Olsson; Anders Franco-Cereceda; Pelin Sahlén; Per Eriksson; Hanna M. Björck. SPP1/osteopontin: a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm? Journal of Molecular Medicine. 2023 Oct;101(10):1323-1333. https://doi.org/10.1007/s00109-023-02370-zIII. David Freiholtz; Claudia Reyes-Goya; Karin Lång; Otto Bergman; Christian Olsson; Malin Granbom Koski; Michael Dismorr; Cecilia Österholm; Kenneth Caidahl; Anders Franco-Cereceda; Per Eriksson; Anton Gisterå; Hanna M Björck. Tricuspid aortic valve regurgitation associates with ascending aortic aneurysm through endothelial activation and lipoprotein infiltration. Arteriosclerosis, Thrombosis, and Vascular Biology. 2025 Sep;45(9):1636-1647. https://doi.org/10.1161/atvbaha.125.323112IV. David Freiholtz; Otto Bergman; Joscha Buech; Christian Olsson; Anders Franco-Cereceda; Per Eriksson; Hanna M. Björck. Transcriptional states of the ascending aorta predict post-surgical aortic enlargement and clinical outcomes. [Manuscript]</p

Norms and values as barriers and enablers to global sexual and reproductive health and rights

Background: Sexual and reproductive health and rights (SRHR) are interdependent and framed as universal rights as per the 2018 Guttmacher- Lancet Commission's (GLC) definition, yet their realisation remains uneven and context-dependent. Social norms, gender inequality, and structural factors (e.g. policy, laws, resources etc) shape whether rights on paper become rights-in-practice. Perceived reproductive agency - the capacity to decide if, when, and how many children to have - offers a person-centred lens linking rights to lived experience. This research is important in sub-Saharan Africa given that the region has experienced important SRHR gains and changes in the past three decades while both urgent and complex needs still remain. Also, most country-comparative analyses of unintended pregnancy and abortion focus on legislation alone, leaving out social norms - which differentiates the formal environment (what should be available) from the lived environment (what is socially acceptable and practically attainable) - underexplored. To address these gaps, we (i) developed a comprehensive SRHR & Gender Module aligned with the GLC SRHR definition; (ii) constructed population-level indices for SRHR-supportive attitudes; (iii) analysed their associations with perceived reproductive agency and subjective well-being (SWB); and (iv) examined how abortion norms and laws relate to rates of unintended pregnancy and abortion among women who do not want to be pregnant across countries and over time.Aim: To improve the understanding of norms and values toward SRHR and gender equality, and study how these serve as barriers or enablers to SRHR outcomes globally, with a particular focus on individual perceptions and country-level outcomes.Methods: Together with the World Values Survey (WVS), we developed and piloted an SRHR and Gender Module to capture a broad range of SRHR domains in line with the GLC definition. The module was piloted in Nigeria (2017-2018), then fielded in a revised version in Ethiopia, Kenya, and Zimbabwe during WVS Wave 7 (2017-2021; N = 4,948) in nationally representative samples. Study I (Ethiopia, Kenya, Zimbabwe; n = 3,711) used exploratory factor analysis of 58 module items to derive five subscales and an overall SRHR Support Index. Adjusted regression models examined sociodemographic correlates of the index, stratified by country and sex. Study II (Ethiopia, Kenya, Zimbabwe; n= 3,096) assessed how SRHR attitudes (Index and subindices) and gender-equality values (WVS Equality Index) related to perceived reproductive agency measured by respondents rating their level of freedom of choice and control over their family planning (i.e. if, when and how many children to have) using a 1-10 Likert scale with higher numbers representing higher agency. We compared values and attitudes among respondents of high vs. low perceived agency (using the median as a cut-off) using descriptive statistics, bivariate tests, and multivariable logistic regression, stratified by country and sex. Study III (all four countries; N = 4,302) examined associations between perceived reproductive agency and SWB captured by four items where respondents rated their life satisfaction (Likert scale; 1-10), overall life agency (Likert scale; 1-10), health status (Likert scale; 1-5), and happiness (Likert scale; 1-4). Using bivariate and multivariable logistic regressions, we analysed how SWB differed among respondents of high vs. low perceived reproductive agency stratified by country and sex. Study IV combined WVS and European Values Survey data on population level abortion norms with country-year measures of abortion legislation (restrictive: prohibited altogether/save life/preserve health; vs. broadly legal: on request/broad socioeconomic grounds) and Guttmacher Institute estimates of unintended pregnancy and abortion rates per 1,000 women wanting to avoid pregnancy, and percent of unintended pregnancies ending in abortion (88 countries; 1990-2019). We conducted five country case analyses of major policy changes (Poland, South Africa, Spain, Uruguay, India) to contextualise quantitative patterns.Results: In study I, a 23-item, five-factor solution captured norms toward: (1) sexual and reproductive rights, (2) neighbourhood sexual safety, (3) gender-equitable relationships, (4) equitable masculinity norms, and (5) SRHR interventions. The sub-indices performed well across countries and subgroups and were combined into a comprehensive SRHR Support Index (1-100 scale; mean = 39.19, SD = 15.27; a = 0.80), with higher scores indicating more supportive SRHR attitudes. Mean scores for the Index were highest in Kenya, then Ethiopia and lowest in Zimbabwe, with different scores for the sub-indices. Higher education and being single were associated with more supportive attitudes (except Ethiopia). Younger age and urban residence were associated with higher support among men only. In study II, we found that, respondents rated their reproductive agency high (median =9, IQR=6-10). Country, education, subjective social class, and religion were associated with reproductive agency. Adjusted analyses indicated associations between supportive attitudes towards Equitable Masculinity Norms, SRHR Interventions Norms and Gender Equality, with high reproductive agency. In study III, we found that among the 4,302 respondents, 55% perceived their reproductive agency as high, 66% reported high life satisfaction; 51% high overall life agency, and 75% rated themselves healthy and happy. Higher perceived reproductive agency was associated with higher overall life agency and among women greater life satisfaction. In study IV, we found that more supportive norms toward abortion and lower rates of unintended pregnancy and abortion were found in countries where abortion was broadly legal. By contrast, low public support for abortion clustered with higher rates of unintended pregnancy and abortion. The share of unintended pregnancies ending in abortion was highest in countries where abortion was liberal in law but low in public support. Country case analyses showed that shifts in policy, norms, and outcomes are highly context-specific.Conclusions: Norms and values toward SRHR are associated with SRHR outcomes, examined at both the individual and country levels. In addition to legislation and policies, SRHR supportive norms and gender equitable values appear crucial to ensuring that people - particularly women, can exercise their sexual and reproductive rights and realise not only better sexual and reproductive health, but well-being at large.List of scientific papersI. Svallfors S*, Båge K*, Ekström AM, Dessie Y, Wado YD, Fagbemi M, Larsson EC, Litorp H, Puranen B, Sundewall J, Uthman OA, Kågesten AE. Support for sexual and reproductive health and rights in Sub- Saharan Africa: a new index based on World Values Survey data. Reprod Health. 2024 Jun 25;21(1):90. PMID: 38918832; PMCID: PMC11197335. https://doi.org/10.1186/s12978-024-01820-2II. Båge K, Kågesten A, Uthman O, Salazar M, Puranen B, Svallfors S, Ekström AM, Litorp H. Attitudes toward sexual and reproductive health and rights and their associations with reproductive agency: a population-based cross-sectional study in Ethiopia, Kenya, and Zimbabwe. Sex Reprod Health Matters. 2024 Dec;32(1):2444725. Epub 2025 Feb 21. PMID: 39803831; PMCID: PMC11849024. https://doi.org/10.1080/26410397.2024.2444725III. Båge K, Kågesten A, Fagbemi M, Uthman O, Arunda M. O, Puranen B, Ekström AM, Litorp H. Is reproductive agency associated with subjective well-being? A population-based cross-sectional study among men and women in four sub-Saharan African countries using the World Values Survey. Critical Public Health. 2026 36(1). https://doi.org/10.1080/09581596.2025.2604450IV. Båge K, Bearak J, Cleeve A, Larsson EC, Puranen B, Gemzell- Danielsson K, Ekström AM, Litorp H, Svallfors S, Kågesten AE. Variations in abortion attitudes and reproductive outcomes by abortion legislation globally: an ecological analysis. [Submitted]*Shared first author</p

FAPI PET in pancreatic cancer

Pancreatic cancer remains one of the most lethal malignancies, largely due to late diagnosis, complex tumor biology, and limitations of conventional imaging in early detection, lesion characterization, and treatment response assessment. A defining biological feature of pancreatic ductal adenocarcinoma is its dense desmoplastic stroma, dominated by cancer-associated fibroblasts that express fibroblast activation protein. Targeting this stromal component offers a biologically distinct imaging signal compared with conventional morphologic or metabolic approaches and may improve biological lesion characterization in diagnostically challenging settings.The overall aim of this thesis was to evaluate the clinical utility of [68Ga]Ga-FAPI- 46 positron emission tomography/computed tomography (PET/CT) for imaging- based assessment of pancreatic cancer in selected clinically relevant decision- making contexts. Four substudies, embedded within a prospective Phase II clinical trial, investigated tumor characterization and diagnostic performance, temporal uptake behavior and differentiation from inflammatory disease, optimization of acquisition protocols and image quality, as well as evaluation of treatment response following neoadjuvant therapy.Paper I investigated the diagnostic accuracy of FAPI PET/CT in patients with suspected pancreatic or periampullary tumors scheduled for surgical exploration. FAPI PET/CT demonstrated high sensitivity and excellent lesion conspicuity for malignant disease, with particular value in cases where conventional imaging was equivocal. Quantitative uptake thresholds enabled reliable differentiation between malignant and benign pathology in this surgically verified cohort, supporting the role of stromal-targeted imaging as a complementary diagnostic tool in preoperative scenarios with high diagnostic uncertainty.Paper II addressed methodological optimization by evaluating whether PET acquisition time could be reduced without compromising image quality or quantitative reliability. Visual grading and quantitative analyses showed that three-minute acquisitions preserved diagnostic image quality, standardized uptake values, and lesion-to-background ratios, supporting the feasibility of streamlined protocols suitable for routine clinical implementation and advanced imaging strategies.Paper III explored temporal uptake patterns to improve differentiation between pancreatic cancer and chronic pancreatitis. While early single-time-point uptake demonstrated overlap between malignant and inflammatory lesions, relative changes in uptake over time provided superior discrimination. Relative SUVmax change achieved the highest diagnostic performance, with delayed imaging offering incremental value. A 60-minute relative change metric retained high discriminatory performance at a clinically practical and patient-convenient time point.Paper IV evaluated the role of post-neoadjuvant FAPI PET/CT for treatment response assessment and perivascular evaluation in a clinically responder- selected cohort. No significant associations were observed between whole- tumor FAPI uptake and histopathological TRG, reflecting both cohort characteristics and the biological persistence of stromal activation after therapy. However, exploratory vessel-level analyses demonstrated a directional relationship between perivascular FAPI uptake and histopathologic vascular involvement, suggesting potential complementary value in evaluating equivocal vascular findings after neoadjuvant treatment.In conclusion, [68Ga]Ga-FAPI-46 PET/CT provides high diagnostic sensitivity and conspicuity in untreated pancreatic cancer, particularly in cases where routine clinical imaging is inconclusive. Acquisition time optimization supports practical clinical implementation, and temporal imaging enhances lesion characterization where fibro-inflammatory overlap limits specificity. Conversely, isolated post- therapy FAPI PET snapshots may struggle to accurately reflect histopathologic regression, indicating the importance of baseline or longitudinal imaging strategies in response assessment. Together, the findings define clinically relevant contexts in which stromal-targeted PET adds value to current pancreatic cancer imaging pathways and establish a foundation for future prospective and longitudinal studies.List of scientific papersI. Rasinski P, af Buren S, Holstensson M, Nilsson T, Loizou L, Tran TA, Sparrelid E, Löhr JM, Axelsson R. Tumor Characterization by [68Ga]FAPI-46 PET/CT Can Improve Treatment Selection for Pancreatic Cancer Patients: An Interim Analysis of a Prospective Clinical Trial. J Nucl Med 2023; 64: 1232-1237. https://doi.org/10.2967/jnumed.123.265481II. Nilsson T, Rasinski P, Smedby Ö, af Buren S, Sparrelid E, Löhr JM, Tran TA, Blomgren A, Tzortzakakis A, Axelsson R, Holstensson M. Acquisition Duration Optimization Using Visual Grading Regression in [68Ga]FAPI-46 PET Imaging of Oncologic Patients. J Nucl Med Technol 2024; 52: 221-228. https://doi.org/10.2967/jnmt.123.267156III. Rasinski P, Nilsson T, Peillon A, Holstensson M, Tzortzakakis A, Moro CF, Tran TA, Sparrelid E, Löhr JM, Axelsson R. Timing is Everything: Unmasking Pancreatic Cancer with Dual and Multiple-Timepoint [68Ga]Ga-FAPI-46 PET Imaging [Submitted] IV. Rasinski P, Loizou L, Molina Centelles MF, Tzortzakakis A, Peillon A, Søreide K, Sparrelid E, Axelsson R, Ghorbani P. Post-Neoadjuvant FAPI PET/CT in Pancreatic Cancer: Response Assessment and Perivascular Evaluation [Manuscript]</p

Modulating fibroblasts in hard-to-heal wounds and skin ageing : roles of circRNAs and dermal injectables

Human skin wound healing is a complex and tightly regulated biological process comprising four sequential yet overlapping phases: hemostasis, inflammation, proliferation and remodeling. The process is initiated by tissue injury and bleeding, followed by clot formation to rapidly restore vascular integrity. Subsequently, the inflammation phase is characterized by the recruitment of immune cells to the wound environment, driven by the release of pro-inflammatory mediators. This phase is followed by the proliferation phase, during which fibroblasts, key effector cells of the skin dermis, become activated, accompanied by keratinocyte migration, neovascularization and angiogenesis. The final remodeling phase culminates in wound closure and tissue maturation, involving reorganization of the extracellular matrix, scar formation and a gradual restoration of tensile strength. Despite this highly coordinated process, wound healing can become impaired or dysregulated, resulting in delayed repair and the development of chronic, hard- to-heal wounds. In parallel, physiological ageing is associated with a progressive decline in skin integrity, elasticity and regenerative capacity.Owing to an incomplete understanding of the underlying pathophysiological mechanisms governing chronic wounds, effective therapeutic strategies remain limited. In recent years, circular RNA (circRNA), a distinct class of non-coding RNA, have emerged as important regulators of gene expression. Their covalently closed structure confers stability, rendering them as promising candidates for novel therapeutics. In contrast, dermal injectables are widely used in clinical and aesthetic medicine to restore lost volume and counteract visible signs of skin ageing, although their molecular and cellular effects on skin homeostasis remains incompletely characterized. Accordingly, this doctoral thesis aims to investigate circular RNAs as potential therapeutic targets in chronic wound healing, while also exploring the differential cellular and tissue-level effects of dermal injectables in the context of skin ageing. To this end, the work is based on analyses of healthy skin and acute wound tissue obtained from healthy volunteers, as well as biopsies derived from patients with chronic wounds. Through this approach, the thesis seeks to advance the understanding of non-coding RNA-mediated mechanisms in skin repair and to provide insights into innovative therapeutic strategies for both impaired wound healing and skin ageing.In Paper I, we investigate CircGLIS3(2), a circular RNA with a unique ability to undergo translation, prompting an exploration of how its coding and non-coding function influence human dermal fibroblasts behavior. CircGLIS3(2) is transiently upregulated in wound fibroblasts in response to injury-associated cues, including IL-la, TGF-B, hypoxia, and ER stress, which collectively drive its expression and translation. Functionally, CircGLIS3(2) exerts a dual role: its RNA promotes fibroblast activation by stabilizing the protein PCOLCE, while its translated protein enhances fibroblast proliferation through interaction with BTF3. Together, CircGLIS3(2) RNA and protein facilitates key reparative processes and ultimately improves wound healing.Paper II centers on mitochondria encoded circular RNA (mecciRNA) CircMT- RNR2, in the context of diabetic foot ulcers (DFU), where its expression is markedly reduced. Given the well-established association between mitochondrial dysfunction, oxidative stress, and DFUs, we identify CircMT-RNR2 as a key regulator of mitochondrial redox homeostasis in dermal fibroblasts. CircMT-RNR2 enhances fibroblast migration, proliferation and extracellular matrix production. Mechanistically, this mecciRNA exerts its protective effects through direct interaction with PRDX3, a mitochondrial antioxidant protein, thereby stabilizing redox balance. Collectively, these findings position CircMT-RNR2 as a potential therapeutic target to improve wound repair in DFU.In Paper III, we explore the role of CircASH1L(4,5) in wound healing, with a particular focus on its interaction with the microRNA (miRNA) miR-129-5p. We demonstrate that CircASH1L(4,5) enhances the stability of miR-129-5p by protecting it from target-directed miRNA degradation. Functionally, the coordinated actions of CircASH1L(4,5) and miR-129-5p enhance epidermal keratinocyte growth and motility, facilitating efficient wound re-epithelialization. This study uncovers a previously unrecognized function of circRNAs as stabilizing scaffolds for miRNAs and highlights their importance in skin repair.In Paper IV, the focus shifts to combating skin ageing through the use of dermal injectables. In this comparative study, we investigate the cellular and molecular effects of two poly-L-lactic acid (PLLA) dermal injectables with distinct particle design, PLLA microspheres and PLLA microflakes, in human dermal fibroblasts or skin tissue. Our findings demonstrate that particle design is a critical determinant of biological outcome. Specifically, PLLA microspheres enhance fibroblast function by promoting cell migration, extracellular matrix (ECM) production and wound contraction, whereas PLLA microflakes trigger a pronounced inflammatory response. Transcriptomic profiling further revealed that PLLA microspheres upregulate genes associated with adipogenic differentiation, while PLLA microflakes suppress regenerative signaling pathways. Taken together, the results provide a foundation for the rational design of more efficient and safer dermal injectables for skin rejuvenation.Collectively, the findings presented in this doctoral thesis provide novel insights into the role of circular RNAs and dermal injectables as modulators of fibroblast function in hard-to-heal wounds and skin ageing. This deepens our understanding on wound repair and skin regeneration, paving the way for future clinical interventions aimed at improving wound healing and promoting skin health.List of scientific papersI. Collaborative duality of CircGLIS3(2) RNA and protein in human wound repair. Guanglin Niu*, Maria A. Toma*, Jennifer Geara, Xiaowei Bian, Yongjian Chen, Lihua Luo, Qizhang Wang, Yunting Xiao, Manika Vij, Minna Piipponen, Zhuang Liu, Sho Oasa, Letian Zhang, Dörte Schlesinger, Ákos Végvári, Dongjing Li, Aoxue Wang, Vladana Vukojevíc, Simon J Elsässer, Pehr Sommar, and Ning Xu Landen Advanced Science, 2025 Jul; 12(25): e2416784. https://doi.org/10.1002/advs.202416784II. Mitochondrial CircRNA CircMT-RNR2 safeguards antioxidant defense to support fibroblast functions in wound repair Guanglin Niu*, Jennifer Geara*, Yongjian Chen, Yanwei Xiao, Zhuang Liu, Pehr Sommar, Aoxue Wang, Xiaowei Zheng and Ning Xu Landen Advanced Science, 2026 Feb 8: e17141. https://doi.org/10.1002/advs.202517141III. Circular RNA CircASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing Qizhang Wang, Guanglin Niu, Zhuang Liu, Maria A. Toma, Jennifer Geara, Xiaowei Bian, Letian Zhang, Minna Piipponen, Dongqing Li, Aoxue Wang, Pehr Sommar, and Ning Xu Landen British Journal of Dermatology, 2025 Feb 18; 192(3): 468-480. https://doi.org/10.1093/bjd/ljae405IV. Poly-L-Lactic Acid Microspheres Promote Skin Rejuvenation via Enhanced Fibroblast Function Jennifer Geara, Lihua Luo, Onur Parlak, Pehr Sommar, and Ning Xu Landén Journal of Biomedical Materials Research Part A, 2025 Nov; 113(11): e38017. https://doi.org/10.1002/jbm.a.38017*Co-first authors</p

Treatment of hyper- and hypothyroidism : Lugol’s iodine and liothyronine

BackgroundHyper- and hypothyroidism are commonly treated according to well- established guidelines. However, subsets of patients are treated with non- standard therapies. In hyperthyroid conditions, preoperative management with Lugol's iodine is occasionally used, while in autoimmune hypothyroidism, liothyronine is prescribed to selected patients with persistent symptoms despite adequate thyroxine treatment. The clinical impact, safety, and consequences of these non-standard treatment approaches remain incompletely understood.ObjectiveThe objective of this thesis was to evaluate non-standard treatments in thyroid disease, focusing on preoperative Lugol's iodine in hyperthyroid conditions and liothyronine in autoimmune hypothyroidism. Specifically, the aims were to assess clinical outcomes of preoperative Lugol's iodine in Graves' disease, evaluate the safety and tolerability of short-term Lugol's iodine in toxic nodular thyroid disease, examine the association between preexisting psychiatric morbidity and subsequent liothyronine use, and investigate psychiatric outcomes following liothyronine exposure in autoimmune hypothyroidism.MethodsThis thesis comprises four studies using different designs. Retrospective population-based observational studies and a prospective interventional study were conducted. Surgical outcomes following rescue preoperative Lugol's iodine were assessed using the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery in a regional cohort of patients undergoing thyroidectomy. The short-term safety and hormonal effects of Lugol's iodine in patients with toxic nodular thyroid disease were examined in an open-label pre-post intervention trial. Nationwide register-based retrospective cohort studies were used to investigate associations between psychiatric morbidity and liothyronine treatment in autoimmune hypothyroidism, including both predictors of liothyronine use and subsequent psychiatric outcomes after exposure to liothyronine. Data from the National Patient Register and the National Prescribed Drug Register were analyzed using regression and time-to- event models adjusted for key covariates.ResultsPreoperative Lugol's iodine was associated with an increased short-term need for calcium and active vitamin D supplementation following thyroidectomy; these differences did not persist at later follow-up. In patients with toxic nodular thyroid disease, short-term Lugol's iodine treatment resulted in reduced thyroid hormone concentrations without any signs of aggravated thyrotoxicosis or deterioration in quality of life. In the nationwide register- based analyses on liothyronine, preexisting affective or anxiety-related psychiatric morbidity was associated with an increased likelihood of subsequent liothyronine treatment in autoimmune hypothyroidism. Furthermore, liothyronine exposure was associated with an increased risk of later incident psychiatric morbidity, including affective or anxiety morbidity, and possibly psychotic morbidity, with consistent findings across most sex and age strata, except in individuals aged 75 years or older, where no associations were found.ConclusionsThis thesis highlights clinical considerations regarding non-standard treatments in thyroid disease. The findings support heightened postoperative vigilance when Lugol's iodine is used before thyroidectomy in a rescue setting and suggest that short-term Lugol's iodine may be a feasible preoperative option in toxic nodular thyroid disease when antithyroid drugs are unsuitable. In autoimmune hypothyroidism, the results underscore the importance of awareness of poor mental well-being and psychiatric vulnerability, both before and during treatment of this condition.List of scientific papersI. Surgical outcome after thyroidectomy due to Graves' disease and Lugol iodine treatment: a retrospective register-based cohort study. Hedberg F, Falhammar H, Calissendorff J, Bränström R. Endocrine. 2024 Jul;85(1):272-278. Epub 2024 Feb 2. PMID: 38306008 https://doi.org/10.1007/s12020-024-03708-4Il. Assessing the Impact of short-term Lugol's solution on toxic nodular thyroid disease: A pre-post-intervention study. Hedberg F, Cramon PK, Bränstrom R, Falhammar H, Calissendorff F. Front Endocrinol (Lausanne). 2024 Jul 25;15:1420154. eCollection 2024. PMID: 39119004 https://doi.org/10.3389/fendo.2024.1420154III. Influence of Preexisting Psychiatric Morbidity on Liothyronine Use in Hypothyroidism: A Swedish Nationwide Cohort Study. Hedberg F, Lindh JD, Mannheimer B, Planck T, Skov J, Lehtihet M, Falhammar H, Calissendorff J. J Clin Endocrinol Metab. 2025 Jun 7:dgaf337. Online ahead of print. PMID: 40482039 https://doi.org/10.1210/clinem/dgaf337IV. Psychiatric Morbidity Following Liothyronine Exposure in Autoimmune Hypothyroidism: A Swedish Nationwide Cohort Study. Hedberg F, Lind JD, Mannheimer B, Planck T, Skov J, Falhammar H, Calissendorff J. [Submitted]</p