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Spatial modulation of the cervical immune landscape by HIV risk factors
No full textThe female genital tract is the first line of defense against any sexually transmitted infections, including viruses, bacteria, or fungi, playing a critical role in maintaining reproductive and overall health. Among these infections, HIV remains a significant global public health concern, particularly in sub-Saharan Africa, where it is one of the leading causes of death. Women and girls in this region account for the majority of new cases, highlighting the need to understand the molecular mechanism that influence HIV susceptibility in the female genital tract, in order to develop effective interventions and preventive strategies.The overreaching aim of this thesis is to identify modulations in the transcriptional landscape of the cervical mucosa, first by bulk transcriptomics (paper I and III) on the larger cohort, then at higher resolution by spatial transcriptomics (paper II and IV) on a smaller subset of samples. Specifically, in paper I and II we looked at the effect of the contraceptive compound DMPA and in paper III and IV at different compositions of the vaginal microbiome.The injectable contraceptive compound DMPA has been suggested to induce an increased risk for HIV acquisition. This is concerning as it is a popular contraceptive choice in many HIV endemic areas.In paper I we found long-term DMPA use associated with a significant disruption of the epithelial barrier and an enhanced immunological profile. These are factors associated with heightened HIV susceptibility, on the other hand there was no link between DMPA use and differences in microbiome profiles at either clinical or molecular level. In paper II we determined the spatial location of processes identified in paper I as well as identifying a mucosal-wide immunoglobulin gene upregulation verified by staining. The heightened resolution revealed that markers of epithelial barrier disruption not only stemmed from the epithelium but also from the submucosa. Specifically, the submucosa exhibited extracellular matrix dysfunction.In paper III we compared the 16S rRNA taxonomical composition of cervicovaginal samples with paired tissue biopsy samples as well as correlating these with the tissue host-transcriptome. The tissue microbiome profile was similar although distinct from the cervico-vaginal microbiota. We hypothesize that the difference could stem from some bacteria's ability to adhere to the tissue lining and form biofilm, thus showing up at higher abundance in the tissue biopsy compared to the fluid samples. In paper IV we, similarly to paper III, identified that more diverse microbiome profiles associated with increased innate immune responses and epithelial barrier structure remodeling. We found that the microbiota profile defined by high microbial diversity (L4) had the largest shift in host transcriptome compared to the other three groups (L1-L3). This shift in gene expression was dominated by downregulation of genes in the clusters closest to the basal membrane.In conclusion, this thesis provides novel insights into the transcriptional and spatial dynamics of the cervical mucosa in response to hormonal contraceptive use and variations in vaginal microbiota composition. Additionally, we are the first to extensively characterize the whole-transcriptome landscape across the ectocervical mucosa at high spatial resolution.Together these results contribute to our understanding of the mechanisms underlying HIV and STI susceptibility. These insights could inform the development of more effective prevention strategies and targeted interventions aimed at improving reproductive health and reducing STI risk, particularly for women in high-risk settings.List of scientific papersI. Multi-omics analysis of the cervical epithelial integrity of women using depot medroxyprogesterone acetate. Bradley F, Franzén Boger M, Kaldhusdal V, Åhlberg A, Edfeldt G, Lajoie J, Bergström S, Omollo K, Damdimopoulos A, Czarnewski P, Månberg A, Oyugi J, Kimani J, Nilsson P, Fowke K, Tjernlund A, Broliden K. PLoS Pathogens, 2022, 18(5):e1010494. https://doi.org/10.1371/journal.ppat.1010494II. Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users. Kaldhusdal V, Franzen Boger M, Tjernlund A, Burgener A, Bradley F, Lajoie J, Omollo K, Kimani J, Fowke K, Czarnewski P, Broliden K. Scientific Reports 2025 15:1, 15(1), 1-16. https://doi.org/10.1038/s41598-024-83775-9III. Distinct cervical tissue-adherent and luminal microbiome communities correlate with mucosal host gene expression and protein levels in Kenyan sex workers. Edfeldt G, Kaldhusdal V, Czarnewski P, Bradley F, Bergström S, Lajoie J, Xu J, Månberg A, Kimani J, Oyugi J, Nilsson P, Tjernlund A, Fowke K, Kwon D*, Broliden K *. Microbiome, 2023, 11(1):67. https://doi.org/10.1186/s40168-023-01502-4 * Shared senior authorsIV. Spatially restricted host transcriptional signatures across the human ectocervical mucosa in response to different cervicovaginal microbiome compositions. Kaldhusdal V, Edfeldt G, Franzen Boger M, Burgener A, Lajoie J, Omollo K, Kimani J, Tjernlund A, Fowke K, Kwon D, Broliden K. [Manuscript]</p
Biomarkers for understanding the pathophysiology and risk assessment in subclinical and manifest coronary artery disease
No full textIntroductionCoronary artery disease (CAD) is a progressive disease, and mechanisms of coronary atherosclerosis and plaque rupture are incompletely covered. This thesis aimed to examine biomarkers at different stages of CAD including evaluation of: (I) the relationships between high-sensitivity C-reactive protein (hsCRP) and coronary atherosclerosis, (II) the associations between protein and metabolite biomarkers and subclinical CAD in two groups with different cardiovascular disease (CVD) risk, (III) ST-elevation myocardial infarction (STEMI) mechanisms using gene expression (GE) techniques without the influence of the acute inflammatory response during the event and (IV) the importance of inflammatory biomarkers sampled in a stable phase for prediction of long-term CVD events in young MI patients.Methods and resultsIn study I, associations between hsCRP and coronary computed tomography angiography (CCTA)-detected CAD were examined in 25,408 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). HsCRP >2.3 mg/L, compared to hsCRP In study II, the relative importance of 409 biomarkers (184 proteins and 225 metabolites) for prediction of subclinical CAD, was evaluated by machine learning, random forest (RF), models. Two study groups from SCAPIS with different CVD risk were included: one low-risk group with a systematic coronary risk evaluation 2 (SCORE2) below 5% (n=2,063) and one high-risk group with SCORE2 above 7.5% (n=576). In the low-risk group, branched-chain amino acids (BCAAs) were predictive of subclinical CAD, while high-density lipoprotein (HDL) metabolites, except for phospholipids (PL), were protective biomarkers. In the high-risk group, proteins involved in inflammatory processes were negatively associated with subclinical CAD, while HDL metabolites did not have any protective effect. Renin and Matrix metalloproteinase (MMP)-12 were identified as risk markers of subclinical atherosclerosis in both CVD risk groups.In study III, mixed linear models were used to examine GE in 51 STEMI patients sampled at three time points, in the acute phase before primary percutaneous coronary intervention (P1), after 24-48 hours (P2) and after three months (P3). Up- or downregulated genes between P1 and P2 were assumed to reflect the acute inflammatory response and therefore excluded. Seven genes had a differential GE at P1 compared to P3: ATP-binding cassette, sub-family G (WHITE), member 1 (ABCG1), RAB20, member RAS oncogene family (RAB20) and Transmembrane protein 2 (TMEM2) were upregulated, whereas four genes were downregulated: activin A receptor, type I (ACVR1), nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2 interacting protein (NFATC2IP), Sad1 and UNC84 domain containing 1 (SUN1) and tetratricopeptide repeat domain 9C (TTC9C).In study IV, nine inflammatory biomarkers (hsCRP, interleukin (IL)-6, IL-18, monocyte chemoattractant protein-1, MMP-1, MMP-3, MMP-9, serum amyloid A and tumor necrosis factor-alpha) were sampled in 382 MI patients below 60 years of age between 1996 and 2000. RF models were used to analyse the relative importance of biomarkers for prediction of CVD events after 20 years of follow-up. IL-6 was the most important biomarker for prediction of the composite endpoint of all-cause death, hospitalisation for MI or heart failure (HF) (hazard ratio (HR) 1.91, 95% CI 1.31-2.79), all-cause death (HR 2.38, 95% CI 1.42- 3.98) and HF hospitalisation (HR 2.70, 95% CI 1.32-5.50) after adjustment for CVD risk factors. IL-18 was the most important biomarker for MI hospitalisation.ConclusionsHsCRP was not associated with CCTA-detected coronary atherosclerosis in a large population-based cohort, although there was a weak association between hsCRP and noncalcified plaques, which are more prone to rupture. Different biomarker patterns were associated with subclinical CAD in a low versus a high CVD risk group. Increased BCAAs were associated with subclinical CAD, while HDL metabolites, with the exception of PL, were associated with less subclinical CAD in low-, but not in high-risk individuals. Renin and MMP-12 were associated with subclinical CAD regardless of the baseline CVD risk. ABCG1, involved in reversed cholesterol transport, was upregulated in the acute phase in STEMI patients and may be essential in initiation of an MI. IL-6 was the most important predictor of long-term CVD outcome, when nine inflammatory biomarkers were sampled in a stable clinical phase in young MI patients.List of scientific papersThe present thesis is based on the following studies, which will be referred to by their Roman numerals.I. Sofia Cederström, Pia Lundman, Joakim Alfredsson, Emil Hagström, Annica Ravn-Fischer, Stefan Söderberg, Troels Yndigegn, Per Tornvall, Tomas Jernberg. Association between high-sensitivity C-reactive protein and coronary atherosclerosis in a general middle-aged population. Scientific Reports. 2023;13(1):12171. https://doi.org/10.1038/s41598-023-39051-3II. Sofia Cederström, Yunzhang Wang, Pia Lundman, Joakim Alfredsson, Göran Bergström, Gunnar Engström, Lars Lind, Stefan Söderberg, Per Tornvall, Tomas Jernberg. Different plasma biomarker patterns associated with coronary atherosclerosis in low- versus high-risk individuals. [Submitted]III. Sofia Cederström, Pia Lundman, Lasse Folkersen, Gabrielle Paulsson-Berne, Glykeria Karadimou, Per Eriksson, Kenneth Caidahl, Anders Gabrielsen, Tomas Jernberg, Jonas Persson, Per Tornvall. New candidate genes for ST-elevation myocardial infarction. Journal of Internal Medicine. 2020;287(1):66-77. https://doi.org/10.1111/joim.12976IV. Sofia Cederström, Tomas Jernberg, Ann Samnegård, Fredrik Johansson, Angela Silveira, Per Tornvall, Pia Lundman. Inflammatory biomarkers and long-term outcome in young patients three months after a first myocardial infarction. Cytokine. 2024;182:156696. https://doi.org/10.1016/j.cyto.2024.156696</p
Epidemiological studies on the interplay between inflammatory bowel disease and kidney diseases
No full textInflammatory bowel disease (IBD) and chronic kidney disease (CKD) are chronic conditions with a bidirectional relationship influenced by immune dysregulation, chronic inflammation, and gut-kidney axis interactions. IBD, characterized by persistent gastrointestinal inflammation, is associated with kidney complications such as nephrolithiasis and interstitial nephritis, often stemming from systemic effects or adverse drug reactions. Colectomy, a surgical intervention frequently required in severe IBD cases, can lead to dehydration and electrolyte imbalances, increasing the risk of kidney damage. While biologic therapies have transformed IBD treatment by targeting specific immune pathways to reduce inflammation and induce remission, they carry potential risks, including rare kidney complications like drug-induced interstitial nephritis. The intricate interplay between IBD and CKD remains underexplored, underscoring the need for comprehensive research to improve patient care and outcomes.This thesis aims to advance our understanding of the bidirectional relationship between IBD and kidney diseases through large-scale epidemiological studies utilizing real-world data.Study I investigated the relationship between reduced kidney function, measured by estimated glomerular filtration rate (eGFR), and the risk of developing IBD in a large adult population. Over nearly a decade of follow-up, reduced eGFR was associated with a higher risk of IBD, particularly Crohn's disease, with stronger associations observed in women. These findings suggest that impaired kidney function may predispose individuals to IBD.Study II examined the association between IBD and kidney-related complications, including CKD and acute kidney injury (AKI). Over a median 9-year follow-up, IBD patients were found to have significantly increased risks of CKD and AKI compared to non-IBD individuals. More than 10% of IBD patients developed CKD within 10 years of diagnosis, emphasizing the importance of regular kidney function monitoring and timely nephrological care.Study III explored the relationship between colectomy and the risk of AKI and kidney failure in patients with biopsy-confirmed IBD within a large Swedish nationwide population. During a median follow-up of 14 years, colectomy was associated with increased risks of these kidney outcomes, particularly in patients with total colectomy, prolonged stoma periods, or ulcerative colitis. These findings highlight the need for targeted kidney function monitoring in high-risk IBD populations undergoing colectomy.Study IV assessed the risk of kidney complications in IBD patients treated with vedolizumab compared to infliximab or adalimumab. Adapting a target trial emulation framework, the study revealed that vedolizumab was associated with higher risks of AKI and CKD compared to infliximab, with elevated but less pronounced risks compared to adalimumab. Younger patients were particularly vulnerable to AKI. These findings underscore the importance of close kidney function monitoring in IBD patients initiating vedolizumab therapy.In conclusion, this thesis provides robust real-world evidence on the complex interplay between IBD and kidney diseases. The findings emphasize a critical need for vigilant kidney function monitoring in IBD patients, particularly those undergoing colectomy or initiating vedolizumab therapy, to improve clinical outcomes and patient care.List of scientific papersI. Yang Y, Ludvigsson JF, Olen O, Sjölander A, Carrero JJ. Estimated Glomerular Filtration Rate and the Risk of Inflammatory Bowel Disease in Adults: A Swedish Population-Based Study. Inflammatory Bowel Diseases. 2024;30(5):718-725. https://doi.org/10.1093/ibd/izac267II. Yang Y, Ludvigsson JF, Olen O, Sjölander A, Carrero JJ. Absolute and Relative Risks of Kidney and Urological Complications in Patients With Inflammatory Bowel Disease. American Journal of Gastroenterology. 2024;119(1):138-146. https://doi.org/10.14309/ajg.0000000000002473III. Yang Y, Ludvigsson JF, Forss A, Faucon AL, Faye AS, Olen O, Sjölander A, Carrero JJ. Risk of Kidney Failure in Patients With Inflammatory Bowel Disease Undergoing Colectomy: A Nationwide Cohort Study. Clinical Gastroenterology and Hepatology. 2024;22(11):2291-2298.e17. https://doi.org/10.1016/j.cgh.2024.05.010IV. Yang Y, Forss A, Voghera S, Ludvigsson JF, Faucon AL, Sjölander A, Olén O, Carrero JJ. Adverse kidney events in patients with inflammatory bowel disease initiating biologics with vedolizumab, infliximab or adalimumab. [Manuscript]</p
Group cognitive behavioral therapy for ADHD inattentive presentation : feasibility, patients' perspectives and effectiveness
No full textAttention-Deficit/Hyperactivity Disorder (ADHD) in adults is a common condition characterized by difficulties in regulating attention, activity, and goal- directed behavior. These challenges are particularly associated with inattentive symptoms, which can lead to significant impairments in daily life. Cognitive behavioral therapy (CBT) is recommended as a psychosocial intervention for ADHD and is often delivered in a uniform format, regardless of the predominant symptomatology. However, as inattention and hyperactivity/impulsivity present distinct challenges, there is reason to believe that presentation-specific treatments could be more effective. CBT for ADHD-Inattentive Presentation (CADDI) is specifically designed to address inattention and includes skills training in organizing and initiating activity and coping with procrastination and passivity. In addition, mindfulness meditation is practiced throughout treatment. The aim of this thesis was to evaluate the feasibility, patient perspectives, and effectiveness of CADDI in routine outpatient clinics.Study I investigated feasibility and preliminary effects of CADDI. Feasibility was evaluated through several measures, treatment adherence, attrition and acceptability. Method: In an open trial design, 39 adult patients with ADHD-I were included. Participants underwent 14 sessions of the CADDI protocol, at four outpatient settings. Results: The CADDI protocol proved feasible in terms of session completion and treatment acceptability. However, adherence in terms of home-assignment completion was low, and attrition was high.Study II explored participants perception of treatment according to the CADDI protocol. Methods: Participants were recruited from treatment groups following the protocol of CADDI, at three psychiatric outpatient units in Stockholm, Sweden. Individual semi-structured interviews, lasting on average 44,6 minutes, were conducted with 14 adults after the completion of CADDI. Interviews explored participants' perceptions of CADDI, its usefulness, and asked for suggestions for improvement. Interviews were conducted by independent interviewers, transcribed and analyzed using reflexive thematic analysis. The analysis generated three themes: "Factors of importance for change", with the subthemes; the group, therapeutic components, structure of treatment, and motivation, "Gains in treatment", with the subthemes; insight and understanding, increased attention, and planning and acting, and "Challenges with ADHD-I and remaining needs", with the subthemes; ADHD as a lifelong condition, maintaining gains in treatment, and wish for further support.Study III Investigated the effectiveness of CADDI in a multicenter superiority trial comparing the effectiveness of CADDI with regular CBT treatment for ADHD. Method: A multicenter, pragmatic, randomized controlled trial compared CADDI to Hesslinger's dialectical behavior therapy protocol. The study included 108 participants from six psychiatric outpatient clinics in Stockholm. Self-reported scales were used in assessment pre- and post-intervention. Primary outcome measure were behavioral activation and procrastination, secondary outcomes were symptoms of ADHD, depression, quality of life and functional impairment. Between and within-group effects were calculated following intention-to-treat analysis using multilevel modeling.Results: Between-group analysis showed that participants in the CADDI group had significantly greater improvement on the primary outcome measure of activation at post assessment (p = . 045, d = 0.49). No significant between-group effects were found on the other outcome measures, even though within-group analyses showed larger effect sizes in the CADDI condition relative to the control condition on several measures. Even though the results indicated differences in within-group effects, larger studies are needed to discern if the CADDI protocol is more effective than standard treatment on these measures. Adherence was good and attrition within normal range in both conditions, despite effects of the pandemic. Participants and therapists reported significantly higher satisfaction with CADDI as compared to the control group.Conclusions This thesis evaluated the CADDI protocol in three separate studies and found the protocol to be feasible, useful and acceptable when offered in routine outpatient psychiatric clinics. After revision of the protocol between Study I and Study III, adherence increased. Participants expressed contentment with the protocol and its mode of delivery, while highlighting the therapeutic value of group therapy. Further, the CADDI protocol proved to outperform standard treatment in increasing behavioral activation, thereby suggesting a potential advantage of an intervention specifically targeting ADHD-I over generic CBT for ADHD. Future research with larger samples and long-term follow-ups is recommended to validate and expand upon these results.List of scientific papersI. Strålin EE, Thorell LB, Szybek K, Lundgren T, Bölte S, Bohman B. Cognitive-behavioral group therapy for ADHD predominantly inattentive presentation: A feasibility study of a new treatment protocol. Nordic psychology. 2022;74(4):325-39. http://doi.org/10.1080/19012276.2021.2020683Il. Strålin EE, Sunnhed R, Thorell LB, Lundgren T, Bölte S, Bohman B. "It was very nice to be in a room where everyone had ADD-that's kind of VIP": Exploring clients' perceptions of group CBT for ADHD inattentive presentation. PloS one. 2024;19(6):e0299060. http://doi.org/10.1371/journal.pone.0299060III. Strålin EE, Thorell LB, Lundgren T, Bölte S, Bohman B. Cognitive Behavioral Therapy for ADHD predominantly inattentive presentation: randomized controlled trial of two psychological treatments. [Manuscript]</p
Copper & protein aggregation in neurodegenerative diseases
No full textNeurodegenerative diseases such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are on the rise and so far, only disease modifying treatments are clinically available and there is no established cure. There is a pressing need to further understand the exact causes of these diseases from which we can develop methods to treat them. One interesting set of features that connects these neurodegenerative diseases are neuroinflammation, protein aggregation and copper dyshomeostasis. For instance, Amyloid beta (AB), and Tubulin associated unit (Tau), which are important factors associated with AD that when aggregated can be sources of inflammation for the central nervous system (CNS). Interestingly both bind copper.Copper is a trace element that is essential for life with unique redox properties which allows it to form the catalytic domain for a number of enzymes including superoxide dismutase 1 (SOD1) for cellular antioxidant defence, mitochondrial cytochrome C oxidase (CcO) complex IV for oxidative respiration, ceruloplasmin (CP) for ferroxidase activity governing iron export from cells, dopamine beta hydroxylase (DBH) for noradrenaline (NA) synthesis. It also plays a role in protein aggregation either by stabilizing the protein structure in specific circumstances or more commonly induce protein aggregation due to its affinity to amino acids such as cysteine, histidine and tyrosine. Under oxidative conditions, this redox capacity can generate reactive oxygen species (ROS) if uncontrolled. Under reducing conditions or hypoxia, the Cult state is favoured that can accelerate protein aggregation. Due to this aggregation inducing nature we decided to look at methods of inhibiting this effect by using an endogenous copper binding tripeptide Gly-His-Lys (GHK) that can reduce the redox activity of copper once bound in STUDY I. Here we demonstrate that GHK can attenuate the redox activity of copper and prevent copper induced cell death in vitro and prevent copper- induced protein aggregation in a model using BSA. We continue with some further experiments outside of the published study using either GHK or GHK-Cu in a mouse model of multiple sclerosis called experimental autoimmune encephalomyelitis (EAE) which models aspects of autoimmunity and neuroinflammation, although we did not have success in attenuating the disease.However, although copper can cause protein aggregation, it is tempting to associate it with a negative light in the context of neurodegeneration. STUDY II is a literature review regarding copper, protein aggregation and ALS whose aim was to broadly survey the various research fields from the molecular scale involving the aggregation of proteins such as SOD1, to the higher order observations such as mitochondrial dysfunction, vascular dysfunction and to connect them with epidemiological evidence and disparate clinical observations from cases that bear very similar features as ALS. Intriguingly, copper deficiency seems likely as it underpins these functions. Furthermore, environmental factors are investigated which points to heavy metals, algal neurotoxins such as ß-Methylamino-L-alanine, (BMAA), formaldehyde and herbicides such as paraquat being strong risk factors. I hypothesize that the link between these factors coalesces in the disruption of copper homeostasis and cuproenzyme function that is central to ALS that reveals itself in a copper mis-partitioning whereby copper is shunted away from the neurons which suffer from deficiency, into microglia which require it for an elevated immune response. The conclusion from this study is a mis-partitioning of copper with functional deficiency and excess in other areas.In STUDY III we focus our attention on AD. In this review we aimed at unifying the roles of major AD risk factors into a comprehensive understanding. Amyloid beta (AB), tubulin associated unit (Tau) and apolipoprotein E (ApoE) all have alternative functions as antimicrobial peptides that are modulated by their aggregation propensity. Rather than aggregation being a fault, it appears to be a function to be called upon as a primitive arm of the innate immune response available to many cells including non-immune specialized cells such as neurons as a factor capable of neutralizing viruses, bacteria and fungi, both intracellularly and extracellularly. This appears to answer in part how non-immune specialized cells can defend themselves from invasion. AB, Tau and ApoE can all bind copper, and it may be possible that copper could be used to accelerate the aggregation of these proteins, for instance in the lysosomes. Copper also accumulates inside microglia, especially inside lysosomes for immune function and could represent a copper sink. Furthermore, AB may also act as a copper sink especially since copper accumulates in the AB rich plaques. As in ALS, clinical data reveal that AD bears signs of copper deficiency (brain-wide) which would in turn reflect in the loss of cuproprotein function such as mitochondrial deficiencies and iron accumulation. Furthermore, I present a compilation of evidence that links microbial infection in the CNS of AD patients that suggests that chronic parasitization of specially adapted pathogens such as herpes viruses, anaerobic spirochetes and biofilm- forming bacteria can insidiously enter the brain and trigger a long-lasting immune response that diverts AB, Tau and ApoE to a defensive aggregative role that over time leads to progressive loss of copper homeostasis and neurodegeneration. Overall, I provide evidence from STUDIES II & III to support the role of copper dyshomeostasis being key to neurodegeneration that can be induced by a variety of factors.STUDY IV characterizes a novel use of the AB stain thioflavin-T (THT) that describes use as a rapid and easy fluorescent Nissl stain allowing detection of brain structures, neuronal populations and nucleoli that can also be used in vitro in live cells. We also characterize the photochemical properties upon blue light exposure that leads to a photo-enhancement of areas stimulated by this light. This allowed us to develop a protocol that is compatible with fluorescent immunohistochemistry that also avoids the complications of this effect. Furthermore, we refine the protocol into two variants that allows for THT to be used as a Nissl stain or an amyloid stain.Preliminary Studies have also been included as a record of other work I have spent significant time on during my PhD. They mainly focus on microglial depletion and repopulation with anti-inflammatory microglial like cells (MLCs) as a method to target neuroinflammation. We characterize the effect of old age on the depletion and repopulation kinetics of microglia using the colony stimulating factor receptor (CSF-1R) inhibitor Plexidartinib (PLX3397) and investigate microglial depletion in the spinal cords. This basic work indicated that microglial depletion is not complete, which represents a challenge as replacement of the microglial with external microglia-like cells (MLCs) requires additional factors to facilitate successful engraftment of donor cells. To do this we attempted to load exosomes with the myeloablative drug busulfan that could hopefully attenuate the resident microglial repopulation long enough to give MLCs a better engraftment rate, but this experiment failed in the developmental stage. We also investigated the effects of different activation states of microglia and astrocytes on the phagocytosis of microglial debris that will be inevitably left over after depletion. One aspect that was recognized through these studies was the autofluorescence of CNS structures. This led to testing whether autofluorescence could be used as a label-free marker for inflammatory changes in fresh blood using flow cytometry, which provided interesting preliminary results. Finally, I document the preliminary work regarding the role of transforming growth factor beta 1 (TGF-β1) depletion in microglia by breeding of a transgenic strain and characterizing the basic pathological phenotype.List of scientific papersI. Min J, Sarlus H, Harris RA. Glycyl-l-histidyl-l-lysine prevents copper- and zinc-induced protein aggregation and central nervous system cell death in vitro. Metallomics 2024 2;16(5):mfae019. https://doi.org/10.1093/mtomcs/mfae019II. Min J, Sarlus H, Harris RA. Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS Front. Mol. Neurosci Volume 17 - 2024. https://doi.org/10.3389/fnmol.2024.1408159III. Min J, Sarlus H, Harris RA. MAD-microbial (origin of) Alzheimer's disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems. Front. Neurosci., Volume 18 - 2024.https://doi.org/10.3389/fnins.2024.1467333IV. Min J, Sarlus H, Sho Oasa, Robert A Harris, Thioflavin-T: application as a neuronal body and nucleolar stain and the blue light photo enhancement effect. Sci Rep. 22;14(1):24846. https://doi.org/10.1038/s41598-024-74359-8</p
Working hours and recovery in crisis : insights from the Swedish healthcare sector during the COVID-19 pandemic
No full textBackground and aimThe COVID-19 pandemic contributed to increased pressure on healthcare systems, which impacted the working conditions of healthcare workers. Recovery may be a key factor for maintaining health and safety during periods characterized by high stress, as insufficient recovery can lead to fatigue and impaired health over time. Recovery can however be disturbed or deprioritized during stressful periods, which has been referred to as the recovery paradox. Working hours can be an important determinant for recovery, as long working hours for example limit the time for recovery outside work, while night work and quick returns (MethodsSemi-structured interviews were conducted with HR representatives working in the Swedish healthcare sector during the pandemic. 19 HR representatives from 16 out of 21 Swedish regions were included. Interviews were also conducted with 22 registered nurses/certified nursing assistants who had worked with COVID-19 patients across four hospitals during the pandemic. Data was analyzed using reflexive thematic analysis. Furthermore, objective working hour data from nursing staff working in 24/7 operations between December 2018 - September 2023 was extracted from one Swedish region. Paired t-tests were conducted to compare working hours before and after the onset of the COVID-19 pandemic.ResultsThe results showed that, at the organizational level, working hours were maximized by implementing new scheduling solutions, limiting vacation, and providing economic compensation for employees to work more. Reorganization of employees, care and HR also took place, where employees were redeployed, some types of care was downscaled, and work at the HR level went from being mostly strategic to more operative. Different support functions were implemented, such as crisis support in the workplace. Issues relating to working hours, recovery and employee well-being were mainly attributed to first-line management. Insufficient staffing and skill mix contributed to the need to maximize working hours, reorganizing employees, care, and HR, and limited the ability to provide recovery for employees. At the employee level, results showed that the organization of working hours was perceived as suboptimal, which was related to demanding working hours, little room for recovery and poor management of working hours. Nursing staff also experienced loss of control in terms of lost influence over working hours, unpredictability in relation to working hours and the new schedules, and blurred boundaries between work and leisure. Participants described declining health and well-being in terms of impaired sleep, mental and physical changes, and extreme fatigue. Analyses of objective working hour data from one Swedish region showed that, at group level, there were few changes in working hours following the onset of the pandemic compared to before. However, the use of a new scheduling solution, which followed a continuous pattern of two day shifts, two evening shifts and two days off, increased the proportion of weekend work, and decreased the proportion of quick returns and single free days (i.e., having only one day off between work periods).ConclusionsThe findings from the present thesis suggest that at the organizational level, short- term solutions such as maximizing working hours and redeploying staff were used to manage the situation at hand. While organizations may be particularly dependent on their human capital during a crisis, the use of short-term solutions could deplete the human capital by contributing to for example fatigue, sick leave, and turnover, creating an organizational recovery paradox.How working hours interact with employee's private life and recovery processes during free time may be important to consider during crises, as for example on- call duties and weekend work could be a hindrance for important recovery activities and processes. Furthermore, maintaining some level of employee influence over working hours could be important during a crisis. Other important aspects relate to individual prerequisites and contextual factors. It could for example be problematic for individuals with poor tolerance to night work to be scheduled to work night shifts, and high workload could impact individuals' capacity to work long shifts. Given that the working conditions of healthcare workers worsened during the pandemic, previous research relating to working hours may not be directly applicable in this new context.Overall, having a more holistic approach to working hours and recovery in the Swedish healthcare sector could be important. Much of the responsibility for working hours, recovery and employee well-being was allocated to first-line management, and there was little follow up of working hours at higher organizational levels. This suggests that the support to first-line management has to be strengthened, especially during a crisis, but also that there may be a need to take more responsibilities for working hours and recovery at the organizational level. This could include both more guidance on how working hours and recovery should be managed, but also to evaluate how working hours influence fatigue, health, and safety. To increase preparedness for future crises, long term strategic efforts towards increasing staffing levels and skill mix could be important, and the software solutions for scheduling working hours may need to be improved. It could also be beneficial to develop a plan for how to manage working hours and recovery during crises, preferably with involvement from employees.List of scientific papersI. Hernandez, I., Arakelian, E., Rudman, A., & Dahlgren, A. (2024). An Organizational Recovery Paradox in Managing Working Hours, Staffing, and Recovery During the COVID-19 Pandemic-A Qualitative Study. Scandinavian Journal of Work and Organizational Psychology, 9(1), 6. https://doi.org/10.16993/sjwop.286II. Hernandez, I., Söderström, M., Rudman, A., & Dahlgren, A. (2024). Under pressure - Nursing staff's perspectives on working hours and recovery during the COVID-19 pandemic: A qualitative study. International Journal of Nursing Studies Advances, 7, 100225. https://doi.org/10.1016/j.ijnsa.2024.100225III. Hernandez, I., Rudman, A., Tucker, P., Kecklund, G. & Dahlgren, A. (2024). A Longitudinal Study of Nursing Staffs' Shift Schedules during the COVID-19 Pandemic. [Submitted]</p
Pathway to becoming a specialist nurse : from educational choice to professional practice
No full textBackground: Specialist nursing education is essential to address the growing complexity of healthcare and ensure high-quality patient care. Despite its importance, Sweden and many other countries face persistent shortages of specialist nurses. Understanding why registered nurses choose to pursue specialist education, how they select a speciality, and how they experience the transition into specialist roles is critical for addressing these challenges.Aim: The overall aim of these studies was to explore factors influencing registered nurses' decisions to pursue specialist education, their choice of speciality, and their perceptions of the relevance and impact of specialist education on clinical practice and professional development.Methods: This thesis consists of four studies using mixed methods. Studies I and III used surveys to examine motivational factors, perceived barriers, and speciality preferences among first-year specialist nursing students (n = 227) and registered nurses (n = 193). Studies II and IV used qualitative interviews with specialist nursing students (n = 20) and newly graduated specialist nurses (n = 30) to explore motives for specialisation and experiences of transitioning into specialist roles. Quantitative data were analysed using descriptive statistics, while qualitative data were analysed using content analysis.Results: Decisions to pursue specialist education were shaped by genuine motivation, financial considerations, perceived status, prior experience, and work-life balance. Wage benefits and career opportunities were central motivators. At the same time, previous exposure to specific fields influenced the choice of speciality. Status perceptions reinforced preferences for acute and technically complex areas, whereas interest in long-term care areas often reflected a desire for regular schedules and improved work-life balance. Transitioning into specialist roles was complex and frequently marked by feelings of insecurity and a temporary return to novice level, despite prior expertise. Confidence developed gradually through experience and was strongly influenced by workplace culture and support systems. Lack of clear role differentiation and organisational strategies sometimes undermined the perceived value of specialist education. While the education provided a solid foundation, participants highlighted gaps in depth, misalignment with role demands, and variability in skills preparation.Conclusions: Specialist education introduces a non-linear trajectory of professional growth, involving cyclical movement between competence stages and identity reconstruction. Combining Benner's model of skill acquisition with Transition Theory offers a nuanced understanding of this process. To address these issues, a stepwise educational model is proposed that enables greater specialisation. This model could consist of a common one-year master's program providing general advanced-level competence, followed by a specialisation in a specific area leading to a master's degree and, for those who wish, further progression to a doctoral degree. This structure would enhance clarity, flexibility, and alignment with international standards, ensuring that specialist nurses are prepared for evolving healthcare demands.Keywords: specialist nurse, nursing education, career choice, transition, Benner's model, Transition Theory, workforce development.List of scientific papersI. Factors affecting nurses' decision to undergo a specialist education and to choose a specialty.Tiliander A, Olsson C, Kalén S, Ponzer SS, Fagerdahl AM. Nurs Open. 2023 Jan;10(1):252-263. Epub 2022 Aug 8. PMID: 35941100; PMCID: PMC9748047. https://doi.org/10.1002/nop2.1300II. Exploring career choices of specialist nurse students: Their decision-making motives. A qualitative study Tiliander A, Olsson C, Kalén S, Ponzer S, Fagerdahl A. Nurs Open. 2024 Jul;11(7):e2241. PMID: 39032132; PMCID: PMC11259742. https://doi.org/10.1002/nop2.2241III. Motivation, Career Choice, and Decision Making in Specialist Nurse Education and Specialisation: A Cross-Sectional Study. Tiliander A, Olsson C, Kalén S, Ponzer S, Fagerdahl A. [Submitted]IV. Specialist nurses' perceptions of postgraduate education: a qualitative study. Tiliander A, Olsson C, Kalén S, Ponzer S, Fagerdahl A. [Submitted]</p
Specific phobia in dentistry : origin, prevalence, and treatment for children and adolescents
No full textBackground: Dental phobia (DP) in youth constitutes a distinct and impairing anxiety disorder with significant implications for oral health and psychosocial functioning. Despite its clinical salience, empirical knowledge remains limited; research in pediatric dentistry has predominantly addressed dental fear and anxiety (DFA), a broader and often developmentally normative construct, leaving DP insufficiently described and understood.Aims: This thesis, in four studies, explores DP across prevalence, development mechanisms, and treatment. Study I estimated the point prevalence of clinically assessed DP at age 16 and examined the comorbidity profile and psychological correlates. Study II employed qualitative methodology to describe the development patterns and perceived etiological pathways of blood-injection-injury (BII) phobia. Study III tested the efficacy of psychologist-guided internet-based cognitive behavioral therapy (ICBT) for DP and injection phobia (IP) in terms of diagnostic remission and ability to undergo dental procedures, compared with a waitlist control. Study IV evaluated the durability of ICBT effects at one-year follow-up and identified predictors of therapeutic response.Materials and methods: Studies I-II utilized data from the Trondheim Early Secure Study (TESS), a prospective, population-based cohort initiated in 2007 in Trondheim, Norway. TESS comprises a stratified random sample of 1,250 children born in 2003-2004, who are assessed biennially from age four onward using structured psychiatric interviews. In Study I, diagnostic items for DP and intra-oral injection phobia (I-OIP) were incorporated into the clinical interviews at age 16; associations were analyzed using multivariate models and population weighting. Study II analyzed audio recordings of all TESS interviews yielding BII diagnoses between ages 4-18 via deductive content analysis.Studies III-IV implemented a 12-week, psychologist-guided, exposure-based ICBT protocol for children aged 8-15 with DP and IP, using parents as coaches and visits to local dental clinics for in vivo exposures. The treatment included psychoeducation, cognitive strategies, relapse prevention, and a toolkit to support the graded exposures. Primary outcomes included diagnostic remission of DP/IP and the ability to undergo dental procedures; secondary outcomes included changes in DFA, negative cognitions, injection fear, and self-efficacy. Both studies used intention-to-treat analyses.Study III employed a two-arm, randomized controlled trial (RCT) comparing the treatment group to a wait-list control. Study IV pooled participants from a prior pilot study and the RCT, including individuals from the control group who, after the 12-week waiting list, were offered the treatment, and assessed outcomes at baseline, post-treatment, and one-year follow-up.Results: Study I showed that at age 16, DP point prevalence was 3.7%, and I-OIP prevalence was 8.0%, with substantial overlap. Adjusted analysis, indicated that DP was associated with female sex (OR=2.44), lower verbal intelligence (OR=0.91), and comorbid with social anxiety disorder (OR=2.46), ADHD hyperactive-impulsive symptoms (OR=1.31), I-OIP (OR=37.82), and other BII phobias (OR=13.14); however, DP was not associated to other anxiety or mood disorders, personality traits, executive functioning, or socioeconomic position. In Study II, the distribution of BII phobia in the sample exhibited an inverted U-shaped age distribution, peaking at age 10 and then resurging at age 18. Sex differences emerged post-puberty; around age 12, the initial occurrence in females increased relative to males, and a marked predominance of female BII cases was observed from age 16 onward. IP was the most frequent subtype, and direct conditioning was the heavily dominating etiological attribution. DP unvaryingly showed a lifetime comorbidity with IP and high comorbidity with other BII subtypes.In Study III, 65% of treated participants achieved remission of at least one diagnosis, compared with 0% in controls (p Study IV demonstrated sustained clinical benefits at one year (remission: DP 53%, IP 46%), with maintenance of the ability to undergo dental procedures and in secondary outcomes. Older age was associated with higher remission rates; male sex and greater treatment adherence were associated with greater improvements in selected child- and parent-rated outcomes; no adverse events were reported.Conclusions: Across designs, DP in youth emerges as a low-prevalence but clinically consequential disorder, etiologically distinct from DFA. DP in is characterized by a strong linkage to IP and BII mechanisms and etiology, with selective comorbidity (notably social anxiety and ADHD hyperactivity-impulsivity), and sensitivity to language-mediated demands, supporting a learning-contingent, context-specific model rather than a generalized anxiety trait. Developmental analyses identify possible critical windows (ages 8-10; late-adolescence in females), although replication in population-weighted trials is needed. They highlight direct conditioning from invasive procedures as the principal acquisition pathway, informing preventive strategies that emphasize anticipatory communication, autonomy-supportive pacing, and optimized behavioral support in dental, vaccination, and venipuncture settings.Therapist-guided, parent-supported ICBT, incorporating in vivo exposure administered by untrained general dental personnel, produces sustained remission and significant functional improvements in children and adolescents. This approach presents a scalable, safe, and readily implementable intervention for pediatric DP/IP within routine dental practices. It adds to the extensive body of evidence supporting the use of exposure-based Cognitive Behavioral Therapy (CBT) for specific phobias.These findings collectively underscore the imperative to elevate DP as a priority in pediatric dental research. They advocate for the development of stepped-care models that integrate systematic screening, preventive strategies, and exposure-based CBT interventions tailored to developmental risk profiles and resource constraints. Crucially, implementing evidence-based treatments for youth with DP, currently underserved in dental care, represents not only a clinical necessity but an ethical mandate to transform current routine practice into a framework that ensures equitable access to effective care.List of scientific papersI. Prevalence and comorbidity of dental phobia in a representative population of 16-year-olds in Norway. Schibbye R, Wichstrøm L, Steinsbekk S, Dahllöf G. International Journal of Paediatric Dentistry. 2025 1-11. https://doi.org/10.1111/ipd.70065II. Distribution and Perceived Acquisition of Blood-Injection-Injury Phobias Ages 4-18: Qualitative Analysis of Longitudinal Diagnostic Interviews. Schibbye R, Wichstrøm L, Steinsbekk S, Dahllöf G. [Submitted]III. Internet-Based Cognitive Behavioral Therapy for Children and Adolescents with Dental or Injection Phobia: Randomized Controlled Trial. Schibbye R, Hedman-Lagerlöf E, Kaldo V, Dahllöf G, Shahnavaz S. Journal of Medical Internet Research. 2024 Feb 21;26:e42322. https://doi.org/10.2196/42322IV. Internet-Based Cognitive Behavioral Therapy for Children and Adolescents with Dental or Injection Phobia: 1-year Follow-Up Assessment. Schibbye R, Hedman-Lagerlöf E, Kaldo V, Dahllöf G, Shahnavaz S. JMIR Pediatrics and Parenting. 2025;8:e80376. https://doi.org/10.2196/80376</p
Coronary microvascular dysfunction : a unifying pathophysiological mechanism of non-obstructive myocardial ischemia?
No full textIn this thesis, we explored presence of coronary microvascular dysfunction (CMD) by utilizing multiparametric stress perfusion cardiovascular magnetic resonance imaging (CMR) in several patient populations. Microvascular impairment has been observed in different vascular beds in a variety of different diseases and conditions, but possible pathophysiological mechanisms are not fully understood. Moreover, whether these share common disease pathways or represent different pathophysiological entities is not known.In the heart, CMD may manifest as chest pain with or without obstructive coronary artery disease (CAD) and mainly affects women. Although known to increase risk of unfavorable outcome, including both morbidity and mortality, CMD remains poorly understood. CMD is challenging to diagnose, and evidence-based treatments are limited. However, CMD may be identified using stress perfusion CMR, as CMD is indicated by reduced myocardial stress perfusion and/or reduced myocardial perfusion reserve (MPR). Moreover, CMR may characterize cardiac anatomy, function and tissue properties, thereby providing a comprehensive evaluation of possible myocardial pathology. In addition, CMR is radiation-free, has excellent spatial and temporal resolution, and excellent reproducibility. In this thesis, we used CMR to evaluate patients at follow-up after myocardial infarction with non-obstructive coronary arteries (MINOCA), after severe coronavirus disease 2019 (COVID-19), Wilson's disease (WD), and Takotsubo syndrome (TTS). The aim was to evaluate presence of CMD, cardiac dysfunction or myocardial tissue alterations, with the underlying aim to provide pathophysiological insights and thereby identify possible mechanisms for future therapies.In study I, we examined MINOCA patients with initial normal CMR at hospitalization with thus unexplained MINOCA presentation, at 5 years follow-up, showing suspected CMD by lower stress perfusion. In study II, we examined patients previously hospitalized due to severe COVID-19 at approximately 10 months follow-up, showing impaired stress perfusion and systolic function as assessed by global longitudinal and circumferential strain (GLS, GCS). Moreover, we did not find differences in perfusion between COVID-19 patients with or without cardiac risk factors or cardiac symptoms, thus suggesting CMD as result of severe COVID-19. In study III, we examined stable WD patients without cardiac symptoms, showing lower stress perfusion and MPR, as well as higher extracellular volume, indication both CMD and diffuse fibrosis. Moreover, systolic function was mildly affected, as assessed by left ventricular ejection fraction and GCS. In study IV, we examined TTS patients at hospitalization and 6 months follow-up and showed signs of global and regional edema and systolic dysfunction, with overall improvements to follow- up. Moreover, improvement in edema (as assessed by native T1) correlated to improved systolic function (as assessed by circumferential and longitudinal strain). While perfusion mapping was not available at the time of the study, this study was hypothesis-generating, and the research group is now undertaking a perfusion CMR study in acute MINOCA patients, including patients with TTS.In conclusion, we have shown reduced perfusion in different patient populations, both with and without chest pain, and in some populations also shown signs of fibrosis and systolic dysfunction. These findings suggest presence of CMD across different conditions, perhaps indeed a unifying pathophysiological mechanism of non-obstructive myocardial ischemia. However, further research is needed into the clinical phenotype, pathophysiology and potential therapies in CMD.List of scientific papersI. Steffen Johansson R, Tornvall P, Sörensson P, Nickander J. Reduced stress perfusion in myocardial infarction with nonobstructive coronary arteries. Sci Rep. 2023 Dec 13;13(1):22094. https://doi.org/10.1038/s41598-023-49223-wII. Steffen Johansson R, Loewenstein D, Lodin K, Bruchfeld J, Runold M, Ståhlberg M, Xue H, Kellman P, Caidahl K, Engblom H, Nickander J. Long-Term Coronary Microvascular and Cardiac Dysfunction After Severe COVID-19 Hospitalization. JAMA Netw Open. 2025 Jun 2;8(6):e2514411. https://doi.org/10.1001/jamanetworkopen.2025.14411III. Steffen Johansson R, Fogarasi C, Kellman P, Kindmark A, Nickander J. Increased extracellular volume, reduced stress perfusion and worse systolic function in Wilson's disease. [Accepted]IV. Steffen Johansson R, Ekenbäck C, Bascovics Brolin E, Jensen J, Sundqvist M, Y-Hassan S, Henareh L, Caidahl K, Spaak J, Sigfridsson A, Kellman P, Ugander M, Tornvall P, Sörensson P, Nickander J. Decreasing myocardial edema correlate with functional recovery in Takotsubo syndrome. [Submitted]</p
Defining the roles of antioxidants and a chemokine ligand in cancer
No full textReactive oxygen species (ROS) are involved in many cellular processes, from modulating intracellular signaling to mediating immune responses. Antioxidants neutralize ROS and maintain intracellular redox balance, because ROS in high concentrations can induce oxidative stress. While ROS can contribute to cancer development, oxidative stress has also been shown to limit tumor progression and metastasis. Previously, it has been discovered that antioxidant supplementation with N-acetylcysteine (NAC) and vitamin E accelerates tumor growth and metastasis in lung cancer mouse models. Similar effects have been observed in mice with melanoma, where NAC accelerated metastasis to the lymph nodes. Yet, it is unclear whether other compounds share the pro-metastatic properties of NAC and vitamin E, and whether antioxidants affect tumor angiogenesis— another critical characteristic of tumor progression.Chemokines are another group of essential signaling molecules that orchestrate cell migration and mediate immune responses. Among those, C-C motif chemokine ligand 28 (CCL28) is expressed in mucosal tissues and has been found to be involved in tumor-associated processes, such as angiogenesis and immune evasion. However, little is known about its functional significance in melanoma and lung tumor progression.The aim of this thesis is to investigate antioxidant effects and underlying molecular mechanisms in melanoma and lung tumor progression, and to explore the role of the chemokine CCL28 in both cancer types.In Study I, we screened 104 redox-modulating compounds and identified 18 that concurrently reduced ROS levels and increased melanoma cell migration. Four compounds typically found in foods and dietary supplements were further tested in vivo: vitamin C, b-carotene, canthaxanthin, and retinyl palmitate. Supplementing the diet with these compounds increased the numbers of metastatic lymph nodes in a BRAF-driven melanoma mouse model. Transcriptomic profiling of human melanoma cells incubated with the four antioxidants indicated that BTB and CNC homolog 1 (BACH1) is involved in mediating antioxidant-induced effects in melanoma. In addition, Bach1 knockout reduced experimental melanoma metastasis to the liver and lymph nodes in mice.In Study II, we investigated the effects of antioxidants on lung tumor angiogenesis in 3D lung tumor cell and xenograft models. Vitamin C, vitamin E and NAC increased the expression of the transcription factor BACH1, which regulated angiogenesis gene expression. In addition, antioxidants induced hypoxia- inducible factor 1-alpha (HIF1a) expression, and antioxidant-induced BACH1 upregulation was found to be dependent on HIF1a under normoxia. However, the BACH1-mediated upregulation of angiogenesis genes was not dependent on HIF1a. BACH1 expression also increased under hypoxia and prolyl hydroxylase (PHD) inhibitors stabilized BACH1 protein levels in both HIF1a-expressing and HIF1A- knockout cells. In mice, antioxidant supplementation of the diet increased tumor vascularity in BACH1-expressing but not BACH1-deficient lung tumors. Moreover, BACH1 expression correlated with a wide range of angiogenesis genes, and both vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR2) in lung tumors from patients. In line with this, high BACH1 expression sensitized xenograft lung tumors to a VEGFR2-blocking agent.In Study III, we explored the functional role of CCL28 in melanoma and lung cancer. Doxycycline-inducible CCL28 knockdown in human melanoma and lung cancer cells reduced colony formation and proliferation, while increasing apoptosis in a tumor cell-autonomous fashion. In immunodeficient mice, doxycycline-inducible CCL28 knockdown reduced subcutaneous tumor growth and inhibited experimental metastasis. Incubating melanoma and lung cancer cells with a recombinant CCL28 did not restore colony formation. In immunocytochemistry and cell fractionation experiments, CCL28 predominately localized to the cell nucleus. It was also enriched in DNA-binding protein fractions from melanoma and lung cancer cells. In addition, CCL28 expression was elevated in melanoma and lung tumors from patients compared to normal tissues, and high CCL28 expression was associated with poor overall survival in melanoma. In contrast to observations in human melanoma and lung cancer cells, Ccl28 expression was nearly undetectable in lung tumor cells from mice with KRAS-driven lung cancer, and its loss did not affect survival in these mice.In conclusion, these findings provide novel insights into antioxidant effects in tumor progression and metastasis, and the role of the chemokine ligand CCL28 in melanoma and lung cancer.List of scientific papersI. ROS-lowering doses of vitamin C and A accelerate malignant melanoma metastasis. Muhammad Kashif, Haidong Yao, Sarah Schmidt, Xue Chen, Michelle Truong, Elin Tüksammel, Yiran Liu, Martin O. Bergo (2023). Redox Biology, 60, 102619. https://doi.org/10.1016/j.redox.2023.102619II. Antioxidants stimulate BACH1-dependent tumor angiogenesis. Ting Wang, Yongqiang Dong, Zhiqiang Huang, Guoqing Zhang, Ying Zhao, Haidong Yao, Jianjiang Hu, Elin Tüksammel, Huan Cai, Ning Liang, Xiufeng Xu, Xijie Yang, Sarah Schmidt, Xi Qiao, Susanne Schlisio, Staffan Strömblad, Hong Qian, Changtao Jiang, Eckardt Treuter, and Martin O. Bergo (2023). The Journal of Clinical Investigation, 133(20), e169671. https://doi.org/10.1172/JCI169671III. Nuclear CCL28 sustains tumor cell survival and metastasis in melanoma and lung cancer. Sarah Schmidt, Nina Spagone-Wolf, Mirja Simon, Jan Schlegel, Xiufeng Xu, Xi Qiao#, and Martin O. Bergo#. [Manuscript]# Co-corresponding authors</p