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Targeting the IGF1R signaling for anti-cancer therapy
No full textActivation of Insulin-like growth factor -1 receptor (IGF1R) signaling is pivotal for development of many types of cancer and, therefore, strategies of targeting this pathway for cancer treatment represents a valid approach. However, such strategies have been largely undermined by the widespread resistance observed in tumor cells. One of the contributors to this resistance is the activation of non-canonical β-arr1/2 system downstream of IGF1R, which leads to differential effects depending on this system’s balance. It can facilitate protumorigenic, proliferative and survival signaling within tumor cells, and, on the other hand, could initiate/activate tumor-suppressor pathways.This thesis provides an extensive review of the IGF1R contributions to the maintenance of the malignant phenotype. The focus is on the insights into both the canonical pathways downstream of IGF1R as well as their relationship with the more recently identified non-canonical β-arr1/2 controlled pathways. Although a direct manipulation of β-arr1/2 system to develop therapeutic strategies remains challenging, this thesis discusses the potential of using such approach downstream IGF1R to improve management of cancer patients. Within the frame of targeting non-canonical β-arr1/2 controlled pathways, as a proof of- concept, the thesis specifically discussed three studies. Study I addresses the concept of shifting the balance towards the β-arr2 predominance. This was achieved in melanoma cells by either overexpressing β-arr2 and/or silencing β- arr1. In combination with a common treatment modality in melanoma (DTIC), this approach led to a significant inhibition of melanoma cell proliferation. This study suggests that a β-arr2-predominant status, in addition to downregulating IGF1R, provides context for p53 activation thereby suppressing tumor growth. Furthermore, this study provides rationale for combining p53-activating therapeutics with β-arr2-dominant conditions.The second study reviewed in this thesis describes the use of Paroxetine (PX), a GRK2 inhibitor, to create a β-arr1-predominant cellular environment. Under these conditions, the IGF1R is downregulated, which has by itself an antitumorigenic effect. However, shift towards β-arr1-predominant conditions can also activate some pro-tumorigenic effects, which were mitigated using inhibitors of the MAPK/PI3K downstream signaling pathway resulting in inhibition of tumor cell proliferation. This study provides rationale for combining targeted signaling therapeutics with β-arr1-dominant conditions. The third study reviewed in this thesis describes the cellular responses to different antibodies targeting IGF1R. The study analyzes the IGF1R degradation, internalization and also downstream signaling in connection to β-arr1/2 system activity. The study suggests the potential of different anti-IGF1R antibodies to produce a desired shift towards β-arr1 or β-arr2-dominant condition. In conclusion, this thesis provides new insights into the IGF1R signaling and β- arr1/2 involvement and highlights potential therapeutic strategies for overcoming resistance in cancer treatments targeting IGF1R.</p
Beta-blocker therapy after acute myocardial infarction with preserved ejection fraction : observational and clinical studies
No full textBackgroundCardiovascular disease, with its feared primary presentation of acute myocardial infarction (AMI), remains the leading cause of morbidity and mortality globally. Despite its routine use worldwide, the scientific evidence for beta-blocker therapy in patients with AMI and preserved left ventricular ejection fraction (LVEF) is surprisingly limited. Large, randomized trials are required to form a more solid base and to support recommendations.Methods and resultsStudy I. An observational study linking data from multiple Swedish national registries assessed dose-dependent effects of beta-blockers on death from any cause and new AMI. A total of 97,575 patients with first-time AMI were included, where 33,126 (33.9%) patients were discharged with >50% of the target beta- blocker dose, and 64,449 (66.1%) patients with 50% of the target dose had a similar risk of the composite endpoint (HR, 1.03; 95% CI, 0.99 to 1.08; P = 0.18) compared with patients on Study II. A register-based, randomized, parallel, open-label, multicentre trial that evaluated the effect of routine initiation of beta-blocker treatment, in patients with AMI and preserved LVEF, in reducing the risk of death from any cause, or new AMI. The trial was performed at 38 centres in Sweden, one in Estonia, and six in New Zealand. From September 2017 through May 2023, 5020 patients were randomly assigned to either long-term beta-blocker treatment or no beta- blocker treatment. Baseline characteristics were well balanced between the two groups, the median age of the population was 65 years and 22.5% were women. Unadjusted Cox proportional hazards regression analysis showed that beta- blocker treatment did not decrease the risk of the composite endpoint, including death from any cause or new AMI, compared with no beta-blocker treatment (HR, 0.96; 95% CI, 0.79 to 1.16; P=0.64).Study III. A pre-specified substudy of the trial described in Study II, designed to evaluate the effect of beta-blockers on health-related quality of life (HRQoL) in patients with AMI and preserved LVEF. Responses to EQ-5D questionnaires were obtained at 6-10 weeks and 11-13 months after AMI. A total of 4,080 patients answered the forms, out of which 2,023 (49.6%) patients were randomized to beta-blockers. Baseline characteristics were similar to those in the main trial. The study reported results from intention-to-treat (ITT) and on-treatment analyses using the Wilcoxon rank sum test and adjusted ordinal regression analyses. The main outcome, median EQ-5D index score, did not differ between the groups at follow-up one (6-10 weeks after the AMI) (OR, 1.00; 95% CI, 0.89 to 1.13; P = 0.94). At the second follow-up (11-13 months after AMI), the results remained unchanged (OR, 1.02; 95% CI, 0.90 to 1.15; P = 0.78). The findings were robust in on-treatment analyses and across relevant subgroups.Study IV. A pre-specified substudy of the trial described in Study II, where conventional echocardiographic parameters and global longitudinal strain (GLS) measurements were obtained from routine echocardiographic examinations during the index hospitalization at four participating centres. The analysis addressed the question of whether or not GLS measurement in addition to LVEF improves outcome prediction. A likelihood ratio (LR) test between models adjusted for age, sex, hypertension, smoking, diabetes, previous AMI, and multivessel disease was used to compare LVEF and GLS as prognostic methods. A Cox regression model was used to evaluate the impact of beta-blocker treatment on the composite endpoint of death from any cause, or new AMI. A total of 1,436 patients (28.6% of the total population) were included. The LR test showed no significant difference (P = 0.56) when comparing the combination of GLS and LVEF to LVEF alone. The results were robust when adding beta-blocker randomization status as an independent variable.ConclusionsThis thesis provides new evidence that routine initiation of beta-blockers in patients with AMI and preserved LVEF does not decrease the risk of death from any cause, or new AMI, compared with no beta-blocker use. Even when complemented with more advanced echocardiographic measurements, no additive prognostic value regarding these endpoints was found. In addition, beta-blockers do not seem to affect HRQoL in this patient population. If beta-blockers are used, it appears that higher doses are not associated with improved cardiovascular outcomes.List of scientific papersI. Mars K, Wallert J, Held C, Humphries S, Pingel R, Jernberg T, Olsson EMG, Hofmann R. Association between ß-blocker dose and cardiovascular outcomes after myocardial infarction: insights from the SWEDEHEART registry. Eur Heart J Acute Cardiovasc Care. 2020. https://doi.org/10.1093/ehjacc/zuaa002II. Yndigegn T, Lindahl B, Mars K, Alfredsson J, Benatar J, Brandin L, Erlinge D, Hallen O, Held C, Hjalmarsson P, Johansson P, Karlström P, Kellerth T, Marandi T, Ravn-Fischer A, Sundström J, Östlund O, Hofmann R, Jernberg T. Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2401479III. Mars K, Humphries S, Leissner P, Jonsson M, Karlström P, Lauermann J, Alfredsson J, Kellerth T, Ravn-Fischer A, Erlinge D, Lindahl B, Yndigegn T, Jernberg T, Held C, Olsson EMG, Hofmann R. Effects of beta-blockers on quality of life and well-being in patients with myocardial infarction and preserved left ventricular function - a prespecified substudy from REDUCE-AMI. Eur Heart J Cardiovasc Pharmacother. 2024. https://doi.org/10.1093/ehjcvp/pvae062IV. Mars K, Hofmann R, Jonsson M, Manouras A, Engvall J, Yndigegn T, Jernberg T, Shahgaldi K/ Sundqvist MG. The prognostic value of global longitudinal strain in patients with myocardial infarction and preserved ejection fraction - a prespecified substudy of the REDUCE-AMI trial. Eur Heart J Cardiovasc Imaging. 2025. https://doi.org/10.1093/ehjci/jeaf015</p
Modeling early human neural development using iPS cells
No full textHuman induced Pluripotent Stem Cells (iPSCs) have long been known for their great potential in disease and development modeling as well as their possible use for cell transplantations. This thesis investigates the advantages and limitations of human iPSCs. We investigated the fundamentals of neural lineage specifications during neural induction. In addition to modeling human neural development, we assessed the therapeutic efficiency of iPSCs derived neural epithelial stem (NES) cell doses in a pre-clinical study of spinal cord injury (SCI). Modeling development and the generation of cells for transplantations is dependent on the generation of standardized and trustable cells. NES cells are a great tool for both fields. They provide unlimited supply of neural progenitor cells and are able to generate into all major neural lineages. This thesis consists of one protocol for the standardized generation of NES cells, two studies using these cells for pre-clinical cell transplantation studies, and one paper to investigate the role of an adhesion molecule during early neural development. All included papers provide deeper insights into development in health and disease.In paper I we develop a protocol for the standardized and robust generation of NES cells. This neural induction protocol can be used to generate cells relevant for transplantations and for modeling human development in 2D.In paper II we prove that the generation of big batches of transplantable cells is possible and has many advantages. The cells have robust viability and keep differentiation potential even after prolonged periods of freezing. The quality of the cells can be assed prior to transplantation.In paper III off-the-shelf NES cell doses were transplanted into a rat SCI model. The cells were able to survive and differentiate into relevant neural cell types. Transplantation showed positive effects regarding regeneration tissue integrity.In paper IV we identified changes in relevant signaling pathways and early development in cells with bi-allelic NRXNla deletion. We thereby identified a possible mechanism of action for this adhesion molecule early in development. Developmental changes included change in regionalization, switch in cell fate, further progression in EMT, and higher levels of TGFB and BMP signaling.In total, this thesis provides methods and protocols for generation of possible cell transplantation products in the future. We also show that these cells can be used in disease modeling in 2D and to identify new roles of proteins beyond their known function.List of scientific papersI. Protocol for the derivation, culturing and differentiation of human iPS-cell-derived neuroepithelial stem cells to study neural differentiation in vitro. Javier Calvo-Garrido, Dania Winn, Camilla Maffezzini, Anna Wedell, Christoph Freyer, Anna Falk, Anna Wredenberg. STAR Protocols. (2021). https://doi.org/10.1016/j.xpro.2021.100528II. Pre-clinical evaluation of clinically relevant iPSC derived neuroepithelial stem cells as an off-the-shelf cell therapy for spinal cord injury. Dania Winn, Elias Uhlin, Malin Kele, Ilse Eidhof, Anna Falk Frontiers. Pharmacology. (2024). https://doi.org/10.3389/fphar.2024.1390058III. Multiple therapeutic effects of human neural stem cells derived from induced pluripotent stem cells in a rat model of post-traumatic syringomyelia. Tingting Xu, Xiaofei Li, Yuxi Guo, Elias Uhlin, Lena Holmberg, Sumonto Mitra, Dania Winn, Anna Falk, Eriks Sundström. eBioMedicine. (2022). https://doi.org/10.1016/j.ebiom.2022.103882IV. Multi-Omic Profiling reveals the Impact of NRXNa Deletion on early Neural Development in an iPSC Model. Dania Winn, Alireza Ghahramani, Sarfraz Shafiq, Yan Jiang, Ilse Eidhof, Nathalie Bérubé, Anna Falk. [Manuscript]</p
From CMV to cancer : the immunological power of adaptive NK cells
No full textNatural killer (NK) cells are key players in the immune response against many viral infections and malignancies, bridging innate and adaptive immunity. A subset of NK cells, adaptive NK (aNK) cells, display memory-like properties-such as the ability to respond more robustly upon re-exposure to stimuli-alongside enhanced cytotoxicity and metabolic adaptability, which refers to their capacity to reprogram energy usage depending on environmental cues. These features position aNK cells as promising candidates for cancer immunotherapy. This thesis explores the interplay between cytomegalovirus (CMV) and aNK cells, focusing on their role in inflammation and the tumor microenvironment of glioblastoma (GBM). GBM was chosen as a primary model due to its reported association with CMV, including the detection of CMV proteins within tumor tissues, which suggests a potential viral contribution to disease progression and immune modulation. GBM is an aggressive brain tumor with a highly immunosuppressive environment and a critical need for novel therapeutic approaches.In Paper I, we explore the role of CMV in shaping the inflammatory landscape of colorectal cancer. We demonstrate that CMV infection upregulates cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), key inflammatory mediators, thereby promoting tumor progression. Targeting both viral infection and inflammation using antiviral and anti-inflammatory agents reduced tumor cell proliferation, highlighting them for potential therapeutic strategies.Paper II investigates antigen-specific interactions between aNK cells and HLA-E- expressing dendritic cells (DCs). We identify novel CMV-derived peptides that stabilize HLA-E and enhance aNK cell activation via NKG2C. This study establishes aNK cells as antigen-responsive effectors with memory-like properties, providing insights into harnessing NKG2C-HLA-E interactions for cancer immunotherapy.In Paper III, we optimize an ex vivo expansion strategy for aNK cells using IL-15, IL- 21, two cytokines that have demonstrated to be important in NK cell proliferation and survival; and tumor lysates, enhancing their persistence and cytotoxic potential. Using a zebrafish xenograft model, we demonstrate that aNK cells exhibit superior anti-tumor activity compared to conventional NK (CNK) cells when they are culture in the presence of IL-15 and IL-21 together with K562E feeder cells loaded with tumor antigens, supporting their use in adoptive cell therapy.Paper IV explores the metabolic adaptability of aNK cells in GBM. We show that aNK cells maintain their infiltration of tumor spheroids and cytotoxicity in a suppressive TME. Unlike cNK cells, aNK cells can utilize different metabolic pathways for their activation, highlighting their superior metabolic flexibility.This thesis highlights the potential of aNK cells in cancer immunotherapy, focusing on their antigen recognition, metabolism, and role in solid tumors. By targeting viral-driven inflammation, enhancing NKG2C-HLA-E interactions, and improving metabolic adaptability, we propose strategies to boost NK cell therapies and counteract tumor immune suppression.List of scientific papersI. Pantalone MR, Martín Almazán N, Lattanzio R, Taher C, De Fabritiis S, Valentinuzzi S, Bishehsari F, Mahdavinia M, Verginelli F, Rahbar A, Mariani-Costantini R, Söderberg-Naucler C. Human cytomegalovirus infection enhances 5-lipoxygenase and cycloxygenase-2 expression in colorectal cancer. Int J Oncol. 2023 Nov;63(5):116. Epub 2023 Sep 1. https://doi.org/10.3892/ijo.2023.5564II. Martín Almazán N*, Sala BM*, Sandalova T, Sun Y, Resink T, Cichocki F, Söderberg-Naucler C, Miller JS, Achour A, Sarhan D. Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses. Front Immunol. 2023 Sep 21;14:1230718. https://doi.org/10.3389/fimmu.2023.1230718III. Martín Almazán N*, Román S*, Sun Y, Bräutigam L, Pantalone MR, Stragliotto G, Gultekin O, Söderberg-Nauclér C, Saheli S, Lehti K, Sarhan D. Advancing Adoptive Cell Therapy: Optimized Expansion of Adaptive NK Cells for Solid Tumors. BioRxiv 2024, Oct. [Manuscript Preprint] https://doi.org/10.1101/2024.10.02.616358IV. Martín Almazán N, Hahn P, Calvera A, Damdimopoulos A, Sarhan D* and Söderberg-Naucler C *. Study the immune metabolism and metabolic flexibility of adaptive NK cells in the glioblastoma tumor microenvironment. [Manuscript]</p
Breast and endometrial cancer susceptibility, genome-wide haplotype association studies
No full textThe heritability of BC and EC is partially understood; however, a significant portion of its genetic contribution remains to be identified. Haplotypes are frequently utilized as markers of ethnicity due to their preservation through generations and there are known Swedish, Icelandic and Jewish founder haplotypes in BRCA genes. In the past decade, germline variants for BC and EC have primarily been discovered through GWAS focusing on SNPs in large global populations. We have previously demonstrated that haplotype-based GWAS on Swedish samples, can reveal novel susceptibility loci for colorectal cancer, achieving promising results even with a relatively small study population. To build on earlier epidemiological findings of overrepresentation of EC cases in families affected of BC, the overall aim of this thesis was to identify novel genetic candidate risk loci for BC and EC, either separately or as a putative syndrome. Various strategies utilizing the haplotype-based GWAS approach were applied to Swedish samples that were previously included in the large BCAC (Breast Cancer Association Consortium) and ECAC (Endometrial Cancer Association Consortium).Study I identified one novel BC candidate risk locus at 8p21.2 (odds ratio (OR) 2.08; p 3.92x10-8) and confirmed three known BC susceptibility loci (10q26.13, 11q13.3, and 16q12.1) based on 3,200 unselected BC cases (both with and without family history) and 5,021 controls. Within the three known loci, relatively separated subloci were identified, indicating diverse variants may occur in the Swedish population in these regions. Subgroup analysis of familial cases in the four loci demonstrated higher OR in all four loci (non-significant for 8p21.2). Thus, haplotype-based GWAS is a robust method, and a novel BC locus could be detected. The selected familial analysis of the loci provided support for a direct genetic contribution to the association. Study II identified five novel BC candidate risk loci (9p24.3, 11q22.3, 15q11.2, 16q24.1, and Xq21.31) with OR ranging from 2.4 to 3.6 and confirmed three well-known BC susceptibility loci (10q26.13, 11q13.3, and 16q12.1) based on analysis of 650 familial BC cases and 5021 controls. Comparison of data from study I demonstrated higher OR in all eight loci for the familial analysis. Thus, selected analysis of familial cases (with enriched genetic contribution) could identify novel loci and again supported the direct genetic contribution for the association. Study III identified one novel risk locus at 12p11.21 (OR 1.42; p 4.55 x 10-8) and confirmed three well-known loci (10q26.13, 11q13.3, and 16q12.1, the latter with two separate haplotypes) based on 2,550 sporadic BC cases (without family history) and 5,021 controls. The novel locus on chromosome 12p11.21 exhibited a higher OR in the analysis of sporadic cases compared to familial cases and unselected cases (data from study I and II). Thus, the novel locus may represent a genetic effect-modifier, maybe influenced by environmental factors. Study IV identified 15 novel EC candidate risk loci (2q1.1, 4p16.1, 6q13, 7p21.1, 9p13.3, 10q26.3, 11q21, 12q13.11, 13q12.11, 15q13.3, 16q24.3, 19q13.32, 20p12.3 and 22q13.2) with OR ranging from 1.6 to 3.3 based on 1,116 EC cases and 5,021 controls. None of these loci were known. Therefore, a replication analysis of the novel Swedish loci was conducted using two smaller cohorts from Belgium (528 EC- cases; 1,266 controls) and Germany (221 EC-cases; 251 controls). Despite the modest sample sizes in the replication cohorts, there was support for most loci, which exhibited positive ORs. Furthermore, potential European founder haplotypes were suggested. Study V identified three candidate risk loci associated with shared risk for EC and BC at 8p21.2 (OR 2.05; p 1.58x10-8), 16q24.3 (OR 2.4; p 3.88x10-8) and 17q11.2 (OR 1.27; p 4.3x10-8) based on 4,316 EC cases and 5,021 controls.In conclusion, the five studies presented in this thesis identified novel susceptibility loci for BC and EC individually, as well as loci with shared genetic risks. Further studies are warranted to explore how these findings can be integrated into future preventive strategies. This knowledge contributes to the ongoing move towards more personalized prevention.List of scientific papersI. Barnekow, E., Hasslow, J., Liu, W., Bryant, P., Thutkawkorapin, J., Wendt, C., Czene, K., Hall, P., Margolin, S., & Lindblom, A. (2023). A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31. Int J Mol Sci, 24(5). https://doi.org/10.3390/ijms24054468II. Barnekow, E., Liu, W., Helgadottir, H. T., Michailidou, K., Dennis, J., Bryant, P., Thutkawkorapin, J., Wendt, C., Czene, K., Hall, P., Margolin, S., & Lindblom, A. (2022). A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16. Cancers (Basel), 14(5). https://doi.org/10.3390/cancers14051206III. Vermani, L., Barnekow, E., Liu, W., Wendt, C., Hall, P., Margolin, S., & Lindblom, A. (2024). Swedish Genome-Wide Haplotype Association Analysis Suggests Breast Cancer Loci with Varying Risk-Modifying Effects. Genes (Basel), 15(12). https://doi.org/10.3390/genes15121616IV. Barnekow, E., Liu, W., Andersson, E., Wang, X., Helgadottir, H. T., Thutkawkorapin, J., Barilla, S., Vermani, L., Mints, M., Tham, E., Fasching, P. A., Lambrechts, D., Amant, F., Spurdle, A. B., Hall, P., O'Mara, T. A., Margolin, S., & Lindblom, A. (2025). A Swedish genome-wide haplotype association analysis identifies novel candidate loci associated with endometrial cancer risk. PLoS One, 20(3). https://doi.org/10.1371/journal.pone.0316086V. Barnekow, E., Liu, W., Andersson Franko, M., von Wachenfeldt, A., Wendt, C., Tham, E., Mints, M., Tracy, A. O'Mara, Hall, P., Margolin, S., Lindblom A. Novel shared heritable candidate risk loci for breast and endometrial cancer, a Swedish haplotype genome-wide association study. [Manuscript]</p
Study protocol for a triple-blind randomised controlled trial evaluating a machine learning-based predictive clinical decision support tool for internet-delivered cognitive behaviour therapy (ICBT) for depression and anxiety.
No full textTherapist-supported internet-based Cognitive Behavioural Therapy (ICBT) has strong scientific support, but all patients are not helped, and further improvements are needed. Personalized medicine could enhance ICBT. One promising approach uses a Machine learning (ML) based predictive decision support tool (DST) to help therapists identify patients at risk of treatment failure and adjust their treatments accordingly. ICBT is a suitable clinical context for developing and testing such predictive DST's, since its delivery is quite flexible and can quickly be adapted for probable non-responders, for example by increasing the level and nature of therapist support, to avoid treatment failures and improve overall outcomes. This type of strategy has never been tested in a triple-blind randomised controlled trial (RCT) and has rarely been studied in ICBT.The aim of this protocol is to expand on previous registered protocols with more detailed descriptions of methods and analyses before analyses is being conducted. A triple blind RCT comparing ICBT with a DST (DST condition), to ICBT as usual (TAU condition). The primary objective is to evaluate if the DST condition is superior to the TAU condition in decreasing diagnose-specific symptoms among patients identified to be at risk of failure. Secondary objectives are to evaluate if the DST improves functioning, interaction, adherence, patient satisfaction, and therapist time efficiency and decreases the number of failed treatments. Additionally, we will investigate the therapists' experience of using the DST.Patients and therapists have been recruited nationally. They were randomised and given a sham rationale for the trial to ensure allocation blindness. The total number of patients included was 401, and assessments were administered pre-treatment, weekly during treatment, at post-treatment and at 12-month follow-up. Primary outcome is one of the three diagnosis-specific symptom rating scales for respective treatment and primary analysis is difference in change from pre- to post-treatment for at-risk patients on these scales. Informed consent to participate in the study was obtained from all participants. Both therapists and patients are participants in this trial. For patients, informed consent to participate in the study was obtained when they registered interest for the study via the study's secure web platform and carried out initial screening before the diagnostic and fit for treatment assessment, they first received the research subject information and were asked for consent by digitally signing that they had read and understood the information. For therapists who were part of the study, consent was requested after they had registered their interest. Therapists then received an email with a link to the study's secure web platform with the research person's information and were asked for consent by digitally signing that they had read and understood the information. All documents are stored in secure, locked filing cabinets on the clinic's premises or on a secure digital consent database. Approved by the Swedish Ethical Review Authority (SERA), record number 2020-05772.</p
Novel genetic causes of childhood cancer predisposition
No full textChildhood cancer predisposition syndromes (CPS) refer to rare diseases increasing the risk of developing pediatric cancer. Genomic studies have estimated that about 8-18% of children with cancer carry pathogenic variants in CPS genes. This broad diagnostic yield is caused by differences in study designs such as patient inclusion criteria, sequencing methods, number of genes analyzed, and the definition of positive findings. Moreover, the diagnosis of CPS can have important clinical implications for patients including adjusted diagnostic procedures, treatment, surveillance and genetic counselling.With the ultimate goal of increasing our knowledge on pediatric cancer predisposition, my thesis focused on the study of childhood CPS, using cross- disciplinary methods including register-based, genetic and molecular studies.In Study I, we compiled a broad pediatric CPS research panel with 881 genes and developed a ranking system that prioritizes genes with established or suspected evidence for their association with childhood cancer predisposition. This panel can be used as a tool for the discovery of known and novel childhood CPS in massively parallel sequencing studies of large pediatric cancer cohorts.In Studies II - IV, we report the occurrence of cancer in congenital syndromes with previously unknown cancer associations. Specifically, we describe multiple ovarian tumors in a 13-year-old girl with Prader-Willi syndrome (Study II), neuroblastoma in two female patients with Marfan syndrome (Study III), and a soft tissue sarcoma in a 17-year-old boy with Limb-girdle Muscular Dystrophy Recessive 1 (Study IV). Through these reports, we encourage further studies about the possible implication of these rare diseases in cancer development.In Studies II and V, we used the Swedish national registries to determine the cancer risk spectrum in some of the congenital syndromes mentioned above. In patients with Prader-Willi syndrome (Study II), although we did not find an increased risk of cancer overall, we observed a high frequency of pediatric cancer. Moreover, the low number of pediatric patients with cancer precluded further statistical testing. In individuals with muscular dystrophy (Study V), we found an increased risk of pediatric astrocytomas and other gliomas, as well as an increased risk of adult pancreatic and nonthyroid endocrine tumors. In myotonic dystrophy (Study V), pediatric patients had an increased risk of brain tumors, while adults presented an overall increased cancer risk, explained by various malignancies.In Study VI, we identified a homozygous variant in the FLCN gene as the genetic cause of a novel multisystemic syndrome in a boy with global developmental delay, short stature, severe immunodeficiency, and leukemia at 1-year of age. We showed that the FLCN p.G15S variant leads to nuclear retention of TFE3/TFEB, resulting in altered expression of genes involved in the lysosomal biogenesis and autophagy pathways. Further, we hypothesize that the FLCN p.G15S variant is hypomorphic, leading to this rare autosomal recessive syndrome.All in all, this thesis aimed to contribute to a better understanding of childhood CPS.List of scientific papersI. Assembling a gene panel for the discovery of novel pediatric cancer predisposition syndromes. Maya-González C, Tesi B, Poluha A, Lagerstedt-Robinson K, Nordgren A#, Taylan F#. [Submitted]II. Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation. Maya-González C, Wessman S, Lagerstedt-Robinson K, Taylan F, Tesi B, Kuchinskaya E, McCluggage WG, Poluha A, Holm S, Nergårdh R, Díaz De Ståhl T, Höybye C, Tettamanti G, Delgado-Vega AM, Skarin Nordenvall A, Nordgren A. Frontiers in Medicine, 2023. DOI: 10.3389/fmed.2023.1172565. https://doi.org/10.3389/fmed.2023.1172565III. Occurrence of cancer in Marfan syndrome: Report of two females with neuroblastoma and review of the literature. Maya-González C, Delgado-Vega AM, Taylan F, Lagerstedt Robinson K, Hansson L, Pal N, Fagman H, Puls F, Wessman S, Stenman J, Georgantzi K, Fransson S, Díaz De Ståhl T, Ek T, Palmer R, Tesi B, Kogner P#, Martinsson T#, Nordgren A#. American Journal of Medical Genetics Part A, 2024. DOI: 10.1002/ajmg.a.63812.https://doi.org/10.1002/ajmg.a.63812IV. Pediatric Soft Tissue Sarcoma in Limb-Girdle Muscular Dystrophy: Molecular Findings and Clinical Implications. Maya-González C, Díaz De Ståhl T, Wessman S, Taylan F, Tesi B, Lagerstedt- Robinson K, Tettamanti G, Dukic M, Poluha A, Ljungman G, Nordgren A. American Journal of Case Reports, 2024. DOI: 10.12659/AJCR.945715.https://doi.org/10.12659/AJCR.945715V. Cancer Risk in Patients With Muscular Dystrophy and Myotonic Dystrophy: A Register-Based Cohort Study. Maya-González C*, Tettamanti G*, Taylan F, Skarin Nordenvall A, Sejersen T, Nordgren A. Neurology, 2024. https://doi.org/10.1212/WNL.0000000000209883VI. Biallelic variants in the FLCN gene lead to a novel syndrome with global developmental delay, short stature and immunodeficiency. Maya-González C, Boeckemeier L, Ten Berk de Boer E, Eisfeldt J, Pozzani F, Mhashal A, Campbell T, Bobeck J, Ekholm K, Bryceson Y, Orellana L, Lindqvist A, Nordgren A#, Taylan F#. [Manuscript]* Shared first authors.# Shared senior authors.</p
Quality assessment of cognitive-behavioural therapy: competence, adherence, and clinical outcomes
No full textBackgroundQuality of care is essential in disseminating cognitive-behavioural therapy (CBT). Yet, little is known about how therapists acquire CBT competence, to what extent CBT is delivered as intended and with skill in routine psychiatric care, and if delivered CBT improve the health of patients with common psychiatric disorders, including depression, anxiety disorders, posttraumatic stress disorder, and obsessive-compulsive disorder.Research aimsThe aim was to examine the quality of CBT in practice. We formulated four main hypotheses: 1) therapists are competent in delivering CBT, both following training and in clinical practice, 2) therapists adhere to CBT procedures and techniques in routine psychiatric care, 3) CBT is delivered with desired clinical outcomes in terms of symptom reduction, functional ability, and global health, and 4) therapist competence and adherence is associated with clinical outcomes.MethodsWe conducted three observational studies, with longitudinal and cross-sectional designs. Competence was assessed by observers, based on sessions with standardised patients (Studies I and II). Adherence was assessed by observers, therapists, and patients (Study II), or patients only (Study III). Outcomes were based on patient reports of symptoms, function, and global health (Study II) or of perceived improvement and treatment satisfaction (Study III). Statistical analysis included non-parametric tests (Kruskal-Wallis, Mann-Whitney U, Spearman and Kendall's rank correlations), parametric tests (Pearson correlation, one-way ANOVA), reliable change index, and linear mixed models.ResultsFirst, we found that therapist competence improved after CBT training (Cohen's d effect size = 1.94). A competence threshold was passed by 72% (n = 46/64) after training and 76% (n = 22/29) in routine practice. More competent therapists tended to underestimate their performance, while less competent therapists made more accurate self-assessments.Second, therapist adherence was moderate to high in routine psychiatric care, across perspectives (patients, therapists, and observers), subscales, and diagnoses. Adherence ratings were higher from patients than therapists and for structure/conceptualisation than behavioural/cognitive techniques. Moreover, therapist adherence ratings were higher among patients treated for panic disorder compared to those treated for depression, generalised anxiety disorder, or obsessive-compulsive disorder.Third, patients improved significantly across outcomes (ds = 0.80 - 1.36) and 67% (n = 57/85) demonstrated reliable clinical improvement, while 5% reliably deteriorated (n = 5/85). Moreover, patients reported high degrees of perceived symptom improvement and treatment satisfaction.Finally, there was a moderate correlation between therapist adherence and patient-rated improvement (Kendall's ts rank correlation coefficient = . 37 -. 38, ps ConclusionIn conclusion, CBT was delivered with high quality. Overall, therapists demonstrated competence and adherence, and patients showed clinical improvements. However, there were exceptions, including instances of below- threshold competence, non-adherence, and nearly a third of patients who did not appear to benefit from treatment. The potential association between competence/adherence and patient improvement remains unclear, possibly due to methodological limitations including limited statistical power.List of scientific papersI. Bergvall, H., Ghaderi, A., Andersson, J., Lundgren, T., Andersson, G., & Bohman, B. (2023). Development of competence in cognitive behavioural therapy and the role of metacognition among clinical psychology and psychotherapy students. Behavioural and Cognitive Psychotherapy. https://doi.org/10.1017/S1352465822000686II. Bergvall, H., Linde, J., Alfonsson, S., Sunnhed, R., Barber, J. P., Lundgren, T., Andersson, G., & Bohman, B. (2024). Quality of cognitive-behavioural therapy in routine psychiatric care: therapist adherence and competence, and patient outcomes for depression and anxiety disorders. BMC Psychiatry, 24:887. https://doi.org/10.1186/s12888-024-06328-4III. Bergvall, H., Andersson, G., Lundgren, T., & Bohman, B. Therapist adherence to cognitive-behavioural therapy and quality of care from a patient perspective. [Submitted]</p
Investigating prenatal and early-life environmental causes of neurodevelopment, using genetically informative study designs
No full textNeurodevelopmental conditions such as autism and attention-deficit hyperactivity disorder (ADHD) emerge in childhood and persist throughout life, impacting multiple domains of functioning. Although a substantial body of research highlights the strong genetic basis of these conditions, environmental influences remain an area of investigation. In this work we explored associations between adverse life events (ALEs), psychosocial adversity during pregnancy and early childhood, neonatal jaundice, and the likelihood of autism and ADHD in children. To address potential biases from unmeasured familial confounding, we applied family-based study designs.Study I examined the association between psychosocial adversity in the family in the first year of life on autism and ADHD diagnoses in the child. While we observed an increased likelihood of autism and a dose-response relationship for ADHD in the general population, these associations weakened as the level of familial relatedness increased (cousin, half-sibling, and sibling comparisons), suggesting that the initial findings were influenced by unmeasured familial confounding.Study II investigated the association between ALEs during pregnancy on autism diagnoses and mother-rated autistic traits in offspring. The results indicated a higher likelihood of autism diagnosis and more pronounced autistic traits in the full sample. However, sibling comparisons revealed that these associations were largely explained by unmeasured familial confounding rather than a direct causal relationship.Study III assessed the association between severe, repeated exposure to ALEs in early childhood on autism diagnoses and mother-rated autistic traits at age 3. We found a dose-response relationship in the general population, but the associations attenuated in sibling comparisons, suggesting familial confounding. While we also observed an increased likelihood of an autism diagnosis, sibling comparisons lacked statistical power, therefore, this result should be interpreted with caution.Study IV evaluated the association between neonatal jaundice and autism diagnosis. Our findings indicated that this relationship was primarily confounded by perinatal factors, particularly gestational age, with little evidence for additional familial confounding.These results underscore the importance of accounting for familial confounding.List of scientific papersI. Kanina A, Larsson H, Sjölander A, Butwicka A, Taylor MJ, Martini MI, et al. Association between cumulative psychosocial adversity in the family and ADHD and autism: a family-based cohort study. Transl Psychiatry. 2023;13(1):282. https://doi.org/10.1038/s41398-023-02571-7II. Kanina A, Sjölander A, Martini MI, Butwicka A, Larsson H, Hughes A, Rádo MK, Taylor MJ, Havdahl A, Ask H, Rosenqvist M. Prenatal exposure to adverse life events and autism and autistic-like traits in children in the 1 Norwegian Mother, Father and Child Cohort Study (MoBa). 2024. [Accepted]III. Kanina A, Sjölander A, Martini MI, Butwicka A, Ronald A, Rádo MK, Larsson H, Ask H, Rosenqvist M, Taylor MJ. Early life exposure to severe adverse life events in the family and diagnosed autism and autistic traits at age 3 in children: a genetically informative study. [Manuscript]IV. Kanina A, Li Z, Rosenqvist M, Butwicka A, Larsson H, Johansson S, Rádo MK, Martini MI, Taylor MJ. The association between clinically diagnosed neonatal jaundice and autism: a Swedish register-based cohort study. [Manuscript]</p
Effects of mechanical load/stress on bone growth
No full textLeg length discrepancy (LLD) is a condition characterised by a difference in bone length, where one leg is shorter than the other. Surgical treatments for LLD are often associated with complications such as pain at the surgical site, infection, and delayed bone union. Thus, there is an ultimate need to establish noninvasive approaches to treat LLD. This thesis explores the use of mechanical loading as a potential noninvasive method to treat LLD.Study I focused on the creation of a portable, computer-controlled microloading device capable of delivering precise mechanical loading to small bone organs and animals, such as mice. Using this device, we tested the direct effects of mechanical forces on rat embryonic femur and metatarsal bones cultured ex vivo. These results revealed that mechanical loading at 0.4N significantly decreased growth in metatarsal bones (by approximately 1 mm) while significantly increasing growth in femurs (by approximately 4 mm). These findings suggest that the impact of mechanical forces on bone growth appears to be influenced by both the size and unique traits of the bones.Study II investigated the transcriptomic responses of adolescent growth plate cartilage to mechanical forces. RNA sequencing identified 15 significantly regulated genes and 6 associated signalling pathways in growth plate samples treated with mechanical loading. This represents the first report of the transcriptomic effects of mechanical forces on adolescent growth plate cartilage, filling a critical gap in our understanding of the interaction between human growth plate biology and mechanical loading.Study III extended these findings to young mice, where mechanical loading was applied to the joints of one hindlimb (both female and male, 4-week-old and 8-week-old). Mechanical loading significantly increased femur length, with the most pronounced effects observed in 4-week-old mice of both sexes. Furthermore, we identified PTGS2 (prostaglandin- endoperoxide synthase 2) as a key gene involved in the bone-lengthening effects of mechanical loading. PTGS2 expression was significantly elevated in the CD73+ and PTHrP+ skeletal stem cell niches of the growth plate in treated legs. Pharmacological inhibition of PTGS2 abolished the bone-lengthening effect, confirming its critical role. Furthermore, mechanical loading significantly increased both PTGS2 expression and the size of ex vivo cultured human growth plate cartilage.In conclusion, these findings indicate that mechanical loading offers a promising noninvasive treatment strategy to enhance bone growth and correct LLD in patients, paving the way for future clinical applications.List of scientific papersI. Zhengpei Zhang, Farasat Zaman, Tobia Sebastiano Nava, Tim R J Aeppli, Elena M Gutierrez-Farewik, Artem Kulachenko, Lars Sävendahl. Micromechanical Loading Studies in Ex Vivo Cultured Embryonic Rat Bones Enabled by a Newly Developed Portable Loading Device. Ann Biomed Eng. 2023 Oct;51(10):2229-2236. https://doi.org/10.1007/s10439-023-03258-2II. Zhengpei Zhang, Nageswara Rao Boggavarapu, Laila Sara Arroyo Muhr, Ainhoa Garcia-Serrango, Tim R J Aeppli, Tobia Sebastiano Nava, Yunhan Zhao, Elena M Gutierrez-Farewik, Artem Kulachenko, Lars Sävendahl #, Farasat Zaman #. Genomic Effects of Biomechanical Loading in Adolescent Human Growth Plate Cartilage: A Pilot Study. Cartilage. 2024 Dec 10:19476035241302954. https://doi.org/10.1177/19476035241302954III. Zhengpei Zhang #, Tim R J Aeppli #, Nageswara Rao Boggavarapu2, Laila Sara Arroyo Muhr, Yunhan, Zhao, Eva Pontén, Elena M Gutierrez-Farewik, Artem Kulachenko, Lars Sävendahl #, Farasat Zaman #. Mechanical Stimulation: A Non-invasive Treatment Strategy for Leg Length Discrepancy. [Manuscript]# Denotes equal last-author contribution</p