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Modelling multiple time-scales with flexible parametric survival models : with applications to myeloproliferative neoplasms
No full textSurvival models are often based on only one time-scale for the analysis. However, when analysing time-to-event data, it may be important to model multiple time-scales. The objectives of this thesis are to assess bias from modelling only one time-scale, and to describe and apply a novel method for modelling multiple time-scales in time-to-event data within the framework of flexible parametric survival models (FPM).Study I investigates the bias in estimates when only one time-scale is used. Using simulated data with two time-scales and a binary covariate, we fitted FPM on the log-hazard scale with one time-scale. Our findings indicate slight bias in survival proportions for most scenarios and large bias in log hazard ratios when non-proportional hazards existed on the second time-scale. This highlights the importance of considering multiple time-scales and exploring non-proportional hazards in the model.Study II presents a novel FPM approach that incorporates multiple time-scales without time-splitting the data. This method's flexibility arises from using a linear relationship between time-scales, simplifying the modelling process. We demonstrated this with two case studies, comparing it to the Poisson rate model and showcasing various graphical representations of survival and hazard rates.Study III applies FPM on the log-hazard scale to estimate thrombosis rates in patients with myeloproliferative neoplasms (MPN) over both attained age and time since diagnosis. Results show the highest thrombosis rates within the first two years post-diagnosis, with subsequent rates more influenced by attained age. Hazard ratios for thrombosis remained consistently above one when comparing MPN patients with matched population controls Study IV estimates hazard rates and cumulative incidence functions (CIF) for transformation to acute myeloid leukaemia or myeloidisplastic syndromes in MPN patients over both attained age and time since diagnosis. Transformation rates and CIF showed a stronger dependence on time since diagnosis, though this dependence varied greatly across attained ages by subtype and outcome.In conclusion, this thesis demonstrates the effectiveness of FPM in modelling multiple time-scales, providing a robust tool for complex time-to-event data analysis, particularly in the context of myeloproliferative neoplasms.List of scientific papersI. Batyrbekova N, Bower H, Dickman PW, Szulkin R, Lambert PC, Andersson TML. Potential bias introduced by not including multiple time-scales in survival analysis: a simulation study. Communications in Statistics - Simulation and Computation. 2022;0(0):1-14. https://doi.org/10.1080/03610918.2022.2038626II. Batyrbekova N, Bower H, Dickman PW, Ravn-Landtblom A, Hultcrantz M, Szulkin R, Lambert PC, Andersson TML. Modelling multiple time-scales with flexible parametric survival models. BMC Medical Research Methodology. 2022;22(1):290. https://doi.org/10.1186/s12874-022-01773-9III. Batyrbekova N, Hultcrantz M, Ravn-Landtblom A, Szulkin R, Dickman P, Andersson TML, Syriopoulou E. Do thrombosis rates for MPN patients increase with both age and time since diagnosis? A nationwide register-based matched-cohort study. [Submitted]IV. Batyrbekova N, Ravn-Landtblom A, Hultcrantz M, Szulkin R, Dickman P, Andersson TML. Risk of transformation to acute myeloid leukemia and myelodysplastic syndromes in patients with myeloproliferative neoplasms over attained age and time since diagnosis: a nationwide cohort study. [Manuscript]</p
Metabolic Profile and Long-Term Risk of Depression, Anxiety, and Stress-Related Disorders.
No full textIMPORTANCE: Biomarkers of lipid, apolipoprotein, and carbohydrate metabolism have been previously suggested to be associated with the risk for depression, anxiety, and stress-related disorders, but results are inconsistent. OBJECTIVE: To examine whether the biomarkers of carbohydrate, lipid, and apolipoprotein metabolism are associated with the risk of depression, anxiety, and stress-related disorders. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study with longitudinal data collection assessed 211 200 participants from the Apolipoprotein-Related Mortality Risk (AMORIS) cohort who underwent occupational health screening between January 1, 1985, and December 31, 1996, mainly in the Stockholm region in Sweden. Statistical analysis was performed during 2022 to 2023. EXPOSURES: Lipid, apolipoprotein, and carbohydrate biomarkers measured in blood. MAIN OUTCOMES AND MEASURES: The associations between biomarker levels and the risk of developing depression, anxiety, and stress-related disorders through the end of 2020 were examined using Cox proportional hazards regression models. In addition, nested case-control analyses were conducted within the cohort, including all incident cases of depression, anxiety, and stress-related disorders, and up to 10 control individuals per case who were individually matched to the case by year of birth, sex, and year of enrollment to the AMORIS cohort, using incidence density sampling. Population trajectories were used to illustrate the temporal trends in biomarker levels for cases and controls. RESULTS: A total of 211 200 individuals (mean [SD] age at first biomarker measurement, 42.1 [12.6] years; 122 535 [58.0%] male; 188 895 [89.4%] born in Sweden) participated in the study. During a mean (SD) follow-up of 21.0 (6.7) years, a total of 16 256 individuals were diagnosed with depression, anxiety, or stress-related disorders. High levels of glucose (hazard ratio [HR], 1.30; 95% CI, 1.20-1.41) and triglycerides (HR, 1.15; 95% CI, 1.10-1.20) were associated with an increased subsequent risk of all tested psychiatric disorders, whereas high levels of high-density lipoprotein (HR, 0.88; 95% CI, 0.80-0.97) were associated with a reduced risk. These results were similar for male and female participants as well as for all tested disorders. The nested case-control analyses demonstrated that patients with depression, anxiety, or stress-related disorders had higher levels of glucose, triglycerides, and total cholesterol during the 20 years preceding diagnosis, as well as higher levels of apolipoprotein A-I and apolipoprotein B during the 10 years preceding diagnosis, compared with control participants. CONCLUSIONS AND RELEVANCE: In this cohort study of more than 200 000 participants, high levels of glucose and triglycerides and low levels of high-density lipoprotein were associated with future risk of depression, anxiety, and stress-related disorders. These findings may support closer follow-up of individuals with metabolic dysregulations for the prevention and diagnosis of psychiatric disorders
Lung-function trajectories: relevance and implementation in clinical practice.
No full textLung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.</p
The effect of neuromuscular electrical stimulation on the human skeletal muscle transcriptome.
No full textAIM: The influence on acute skeletal muscle transcriptomics of neuromuscular electrical stimulation (NMES), as compared to established exercises, is poorly understood. We aimed to investigate the effects on global mRNA-expression in the quadriceps muscle early after a single NMES-session, compared to the effects of voluntary knee extension exercise (EX), and to explore the discomfort level. METHODS: Global vastus lateralis muscle gene expression was assessed (RNA-sequencing) in 30 healthy participants, before and 3 h after a 30-min session of NMES and/or EX. The NMES-treatment was applied using textile electrodes integrated in pants and set to 20% of each participant's pre-tested MVC mean (±SD) 200 (±80) Nm. Discomfort was assessed using Visual Analogue Scale (VAS, 0-10). The EX-protocol was performed at 80% of 1-repetition-maximum. RESULTS: NMES at 20% of MVC resulted in VAS below 4 and induced 4448 differentially expressed genes (DEGs) with 80%-overlap of the 2571 DEGs of EX. Genes well-known to be up-regulated following exercise, for example, PPARGC1A, ABRA, VEGFA, and GDNF, were also up-regulated by NMES. Gene set enrichment analysis demonstrated many common pathways after EX and NMES. Also, some pathways were exclusive to either EX, for example, muscle tissue proliferation, or to NMES, for example, neurite outgrowth and connective tissue proliferation. CONCLUSION: A 30-min NMES-session at 20% of MVC with NMES-pants, which can be applied with an acceptable level of discomfort, induces over 4000 DEGs, of which 80%-overlap with DEGs of EX. NMES can induce exercise-like molecular effects, that potentially can lead to health and performance benefits in individuals who are unable to perform resistance exercise
Essential care of critical illness
No full textBackground:Critical illness is a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and the potential for reversibility. Patients of any age can become critically ill due to any underlying diagnosis and in any location. The critically ill patients require urgent support of failing vital organs - critical care - to improve their chance of survival.Substantial unmet needs of critical care have been reported from hospitals both in high- and low-resource settings. Yet, most health policy attention is directed towards the care of specific diagnoses. Moreover, the policy attention in critical care is mostly directed towards advanced technology and high-cost intensive care. To be equitable and effective, however, critical care systems should focus on the most feasible lifesaving interventions - the essential care of critical illness. Such interventions can ensure that patients with critical illness are identified and that they are provided with urgent critical care.There is surprisingly little epidemiological evidence to guide policy makers about the priority of critical illness and health systems require strategies for effective delivery of critical care.Aim:To assess the burden of critical illness in different global settings and to develop, evaluate and reach consensus around strategies to facilitate implementation of essential care of critical illness.Methods:Four studies were conducted in different global settings. To estimate the burden of critical illness, a novel method was applied in prospective point-prevalence and cohort studies in hospitals in Malawi, Sri Lanka and Sweden, and in the population of the whole Sörmland region of Sweden. The Vital-Signs Directed Therapy (VSDT) protocol for task-sharing critical care was implemented in an intensive care unit (ICU) in Tanzania and studied with a before-and-after design. The content of the Essential Emergency and Critical Care (EECC) concept to guide health system priorities, was specified in a large, diverse and global Delphi consensus. Statistical methods included univariate and multivariate regression models and Chi2-tests.Results:Critical illness was found in 12% of all hospital in-patients across the settings. In the substudy in Sörmland region, the population prevalence of critical illness was 19 per 100,000 people. Among hospital in-patients across all setting, critical illness was strongly associated with mortality (OR 7.5) and 19% died in hospital. More than 90% of the critically ill patients were cared for outside ICUs, in low- staffed general wards.Implementation of VSDT increased acute treatments of critical illness and reduced mortality among patients presenting with shock from 92% to 69%, but not among all patients. The specified EECC package contains 40 lifesaving clinical processes that are effective, low-cost and feasible to implement in any hospital ward in the world, and the 66 resources that are required for providing this care.Conclusions:The results challenge three common misconceptions that have substantial consequences for patients around the world. First, critical illness is not uncommon - it is common. Second, critically ill patients are not always in ICUs - most critically ill patients are cared for in low-staffed general wards. Third, critical care is not limited to expensive and technologically sophisticated interventions. The work in this thesis has shown that critical care can be feasible and low-cost to be provided where most critically ill patients are cared for - in low-staffed or low-resourced settings. The findings can be used to inform priorities in health systems so critical care can be provided more effectively and reach more patients. A new focus on essential care of critical illness has potential to reduce mortality across medical disciplines.List of scientific papersI. Vital Signs Directed Therapy: Improving Care in an Intensive Care Unit in a Low-Income Country. Baker T, Schell CO, Lugazia E, Blixt J, Mulungu M, Castegren M, Eriksen J, Konrad D .. PLoS One. 2015 Dec 22;10(12):e0144801. https://doi.org/10.1371/journal.pone.0144801II. The burden of critical illness among adults in a Swedish region-a population-based point-prevalence study. Schell CO, Wellhagen A, Lipcsey M, Kurland L, Bjurling-Sjöberg P, Stålsby Lundborg C, Castegren M, Baker T. European Journal of Medical Research. 2023 Sep 7;28(1):322. https://doi.org/10.1186/s40001-023-01279-0III. The hospital burden of critical illness across global settings: a point-prevalence and cohort study in Malawi, Sri Lanka and Sweden. Carl Otto Schell, Raphael Kayambankadzanja, Abigail Beane, Andreas Wellhagen, Chamira Kodippily, Anna Hvarfner, Grace Banda-Katha, Nalayini Jegathesan, Christoffer Hintze, Wageesha Wijesiriwardana, Martin Gerdin Warnberg, Sujeewa Jayasingha Arachchilage, Mtisunge Kachingwe, Petronella Bjurling-Sjoberg, Iasaac Mbingwani, Annie Kalibwe Mkandawire, Hampus Sjostedt, Wezzie Kumwenda-Mwafulirwa, Surenthirakumaran Rajendra, Odala Kamandani, Cecilia Stalsby Lundborg, Samson Kwazizira Mndolo, Miklos Lipcsey, Rashan Haniffa, Lisa Kurland, Markus Castegren, Tim Baker. [Manuscript]IV. Essential Emergency and Critical Care: a consensus among global clinical experts. Schell CO, Khalid K, Wharton-Smith A, Oliwa J, Sawe HR, Roy N, Sanga A, Marshall JC, Rylance J, Hanson C, Kayambankadzanja RK, Wallis LA, Jirwe M, Baker T; EECC Collaborators. BMJ Glob Health. 2021 Sep;6(9):e006585. https://doi.org/10.1136/bmjgh-2021-006585</p
Statistical and computational methodologies for omics data analyses and drug response prediction
No full textWith the availability of valuable omics data from recent high-throughput sequencing technologies, and a deeper understanding of the pathophysiology of multiple diseases, researchers can now focus on precision medicine to improve the effectiveness of current diagnosis and treatment methods. Unlike traditional treatment, which was largely subjective and based on clinicians' experience, modern treatment for complex diseases can be guided by the precision medicine approach, such as through the molecular classification of diseases of patients. However, despite the early promising outcomes of precision medicine, analyzing omics data to tailor effective treatments for patients and explore the biological mechanisms of diseases remains highly challenging. This is not only due to the heterogeneity of the disease but also the complexity of the omics data.In this thesis, we aim to develop statistical and computational methodologies for multi-omics data analyses and drug response prediction. The methodologies are applied for both simulated and real datasets from different diseases, with a particular focus on acute myeloid leukemia (AML) and amyotrophic lateral sclerosis (ALS). Through critical evaluation and validation analyses, we demonstrate that our methods perform well against competing methods.In study I, we propose a pathway activation score (PAS) and apply it to identify and validate druggable cancer-specific pathways (DCSP) from pan-cancer datasets. Our hypothesis is that cancers with activated DCSPs are more likely to respond to the corresponding drug. In analysis, we identified and validated 4,794 DCSPs across 23 cancers. Further focusing on AML, we show that tumor samples with higher PAS exhibit stronger drug responses, supporting our hypothesis.In study II, we develop MDREAM, a prediction model for drug response in AML patients. We first train MDREAM on the BeatAML cohort using gene expression, mutation profiles, and drug response data. We further validate MDREAM in the test set of the BeatAML dataset and externally validate it in a Swedish AML dataset and a relapsed leukemia dataset. Our results demonstrate the robust and consistent performance of MDREAM across datasets. We also propose a confidence score metric to compute prediction uncertainty and illustrate its application within the MDREAM framework.In study III, we implement DIPx, a machine learning model for personalized drug synergy prediction based on PAS. DIPx is trained and validated using the AstraZeneca-Sanger (AZS) DREAM Challenge dataset. Our validation results show that DIPx achieves higher accuracy than the top-performing method from the challenge. Additionally, we demonstrate how PAS can suggest potential biological mechanisms by identifying activated pathways that mediate drug synergy interactions.In study IV, we introduce MegaFun, a computational method for quantifying the functional aspects of the microbiome from metagenomics data. MegaFun utilizes gene clusters based on sequence similarities at both the pangenome and isolate levels. To quantify functional abundance, it employs an alternating EM algorithm which is applied to a bilinear model capturing the complexity of the microbiome at the isolate level. In a simulated dataset, MegaFun outperforms HUMAN, a state-of-the-art method for functional quantification. We also apply MegaFun to analyze a real metagenomics dataset from ALS patients.In summary, we have developed novel statistical and computational methods to analyze omics data and responses of drugs. The results demonstrate that these methods perform well against existing methodologies. We hope that our work will advance omics data analysis and drug response prediction, and aid researchers in uncovering biological insights.List of scientific papersI. Quang Thinh Trac, Tingyou Zhou, Yudi Pawitan, and Trung Nghia Vu. Discovery of druggable cancer-specific pathways with application in acute myeloid leukemia. Gigascience. 11:giac091 (2022).https://doi.org/10.1093/gigascience/giac091II. Quang Thinh Trac, Yudi Pawitan, Tian Mou, Tom Erkers, Päivi Östling, Anna Bohlin, Albin Österroos, Mattias Vesterlund, Rozbeh Jafari, Ioannis Siavelis, Helena Bäckvall, Santeri Kiviluoto, Lukas M. Orre, Mattias Rantalainen, Janne Lehtio, Sören Lehmann, Olli Kallioniemi, and Trung Nghia Vu. Prediction model for drug response of acute myeloid leukemia patients. npj Precis. Onc. 7, 32 (2023).https://doi.org/10.1038/s41698-023-00374-zIII. Quang Thinh Trac*, Yue Huang*, Tom Erkers, Päivi Östling, Anna Bohlin, Albin Osterroos, Mattias Vesterlund, Rozbeh Jafari, loannis Siavelis, Helena Bäckvall, Santeri Kiviluoto, Lukas M. Orre, Mattias Rantalainen, Janne Lehtio, Sören Lehmann, Olli Kallioniemi, Yudi Pawitan and Trung Nghia Vu. Pathway activation model for personalized prediction of drug synergy. eLife13:RP100071 (2024). (* Contributed equally)https://doi.org/10.7554/eLife.100071.1IV. Quang Thinh Trac, Emily Joyce, Fredrik Boulund, Fang Fang, Yudi Pawitan and Trung Nghia Vu. Functional quantification of microbiome from metagenomics. [Manuscript]</p
Systemic inflammation and neuroimmunity in surgical trauma
No full textTissue injury due to surgery or trauma initiates the release of damage associated molecular patterns (DAMPs), which in turn triggers a cascade of immune cell activation and the release of inflammatory mediators. Although the inflammatory process often begins locally, it may grow out of local capacities and require systemic involvement. While this potent evolutionary response is aimed to limit damage and facilitate repair, it must be carefully regulated to prevent further harm. Patients undergoing elective surgery may develop several complications arising from excessive or impaired immune responses such as cognitive impairment, systemic inflammatory response syndrome (SIRS) or infection. Neuroimmune regulatory mechanisms, based on autonomic nervous control of peripheral inflammation, have been found to attenuate and resolve inflammation in acute and chronic experimental as well as clinical settings. This thesis aims to explore the role and relevance of 'neuroimmunity', a concept involving neural sensing and regulation of immune responses, in the context of surgical trauma.Paper I explores the carotid body (CB) as a putative sensor and mediator of systemic inflammation triggered by surgery. Rat CBs were excised and exposed ex vivo to DAMPs, such as high mobility group box protein 1 (HMGB1), S100A8/A9, or conditioned plasma obtained from a surgical model in rats. Release of neurotransmitters, indicating CB activation, as well as transcriptional changes were analyzed. Results show that CBs express DAMP receptors (RAGE, TLR4 and CXCR4), and that both DAMPs and conditioned plasma trigger CB neurotransmitter release and evoke multiple changes in CB gene expression.Paper II is a temporal characterization of the molecular immune response to surgery, concurrent changes in heart rate variability (HRV) and cognitive capacity. Male patients (n=25) scheduled for abdominal surgery were sequentially evaluated before and up to 6 months after surgery. Blood samples and recordings of HRV were retrieved at multiple timepoints. Cognitive testing was performed pre-operatively and repeated 3-5 days and 6-8 weeks post- surgery. Cellular and molecular analyses revealed systemic molecular response patterns to surgery in line with previous experimental findings. Further, distinct patient-specific HRV-patterns were identified and these observations correlated with inflammatory protein trajectories in proteomic analyses.Cognitive changes showed a trend toward significance, where patients with high HRV performed better cognitively compared to those with low HRV.Paper III focuses on the systemic cellular response to surgery. Pre-operative (baseline) HRV and cellular immune status were assessed in male surgical patients (n=40) and followed with serial blood samples up to 6 months, complementing paper II. In-depth cellular and molecular analyses of the leukocyte proteomic response to lipopolysaccharide (LPS) ex vivo were performed. Temporal differences in subsets of polymorphonuclear cells (PMNs) and peripheral blood mononuclear cells (PBMCs) after surgery as well as changes in protein expression after surgery and whole blood LPS stimulation associated with baseline HRV.In conclusion, the works of this thesis establish that the carotid body contains the molecular machinery necessary for sensing inflammation and transmitting inflammatory information to the brain. Furthermore, human studies demonstrate that heart rate variability (HRV) is a key patient characteristic associated with the inflammatory response to surgery, indicating the involvement of neuroimmune regulatory mechanisms in maintaining immune homeostasis after sterile trauma. A deeper understanding of temporal immune trajectories and their associated regulatory capacities is essential for guiding future patient- centered care and reducing the risk of immune-related complications following surgery.List of scientific papersI. The impact of damage-associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body.Mkrtchian S, Kåhlin J, Gómez-Galán M, Ebberyd A, Yoshitake T, Schmidt S, Kehr J, Hildenborg M, Jonsson Fagerlund M, Erlandsson Harris H, Eriksson LI.Exp Physiol. 2020 Sep;105(9):1634-1647 https://doi.org/10.1113/EP088705II. The neuroimmune response to surgery - an exploratory study of trauma-induced changes in innate immunity and heart rate variability.Hildenborg M, Kåhlin J, Granath F, Schening A, Granström A, Ebberyd A, Klevenvall L, Zetterberg H, Han J, Schlegel TT, Harris R, Harris HE, Eriksson LI.Front Immunol. 2022 Jul 7;13:911744 https://doi.org/10.3389/fimmu.2022.911744III. Patient neuroimmune properties and the cellular immune response to surgical trauma.Hildenborg M, Filipovic I, Sun D, Kahlin J, Schening A, Granström A, Klevenvall L, Erlandsson Harris H, Schlegel TT, Bjorkstrom N, Eriksson LI.[Manuscript]</p
Hemiplegic cerebral palsy : clinical presentation and aetiology
No full textCerebral palsy is an umbrella term for motor impairments that share features of a non-progressive brain injury, acquired during the early stages of its development. These motor impairments can have different aetiologic backgrounds, occurring in the prenatal, perinatal or postnatal period. Cerebral palsy is the most common cause of childhood onset, lifelong disability in many countries. The motor impairment is classified as unilateral/ hemiplegic or bilateral. It is often associated with visual- and hearing deficits as well as epilepsy and cognitive impairment. These associated impairments can be more disabling than the motor disturbance itself. Epilepsy is common in cerebral palsy, present in 30-40 % of cases. Epilepsy is related to the underlying brain lesion. Children with cerebral palsy, epilepsy and intellectual disability constitute a large patient group in paediatric neurology.This thesis contains five clinical studies. The first part of the thesis comprises three clinical studies in which we described the motor impairments, and associated impairments, in a population-based group of children with hemiplegia/unilateral cerebral palsy after cerebral infection. In study I we found a high frequency of epilepsy and intellectual disability among the participants. In study II six children and 15 caregivers in this group were interviewed regarding the child`s ability to participate in age-related activities. All reported great difficulties participating in age-related activities. Hygiene issues hindered children with a non-Swedish cultural background from participating in camps or swimming. In study III the severity of the motor disability in these children was assessed using the Movement Assessment Battery for Children and the Paediatric Disability Inventory. Balance and hand function were impaired in all. Motor difficulties dominated during pre-school years, difficulties with social and communication skills predominated in school-age children.For the second part of the thesis we studied a population-based group of hemiplegic children, with different aetiologic backgrounds. In study IV we investigated both aetiologic background factors, clinical presentation including brain imaging, electroencephalogram (EEG) and epilepsy found in each child. Risk factors for cerbral palsy were present in 16 of the 21 participants. Risk factors are important for early identification. Any child with these risk factors should be offered a check-up by a paediatrician or paediatric neurologist. Epilepsy was common and associated with combined grey and white matter injuries. In study V we investigated intellectual disability and its association with epilepsy and brain imaging in this population-based group of hemiplegic children. Intellectual disability was present in 38 % and uneven cognitive profiles in 57%. Nine of the children developed epilepsy.Together, these studies show that epilepsy, intellectual disability and uneven cognitive profiles are common in hemiplegic cerebral palsy. Individual cognitive assessment is recommended before school start.List of scientific papersI. Elsa Tillberg, Ulrika Radell and Per mark. (2008). Postnatal cerebral infection leading to hemiplegic cerebral palsy: Clinical description of 13 children in Stockholm, Sweden. Disability and Rehabilitation. 30:5, 338-347. https://doi.org/10.1080/09638280701463829 II. Ulrika Radell, Elsa Tillberg, Eva Mattsson and Per mark. (2008). Participation in age-related activities and influence of cultural factors - comments from youth and parents of children with postnatal post infectious hemiplegia in Stockholm, Sweden. Disability and Rehabilitation. 30:11,891-897. https://doi.org/10.1080/09638280701403999 III. Ulrika Radell, Elsa Tillberg, Eva Mattsson and Per mark. (2008). Postnatal cerebral infection leading to hemiplegic cerebral palsy: Functional limitations and disability of 13 children in Sweden. Disability and Rehabilitation. 30:25, 1910-1919. https://doi.org/10.1080/09638280701673641 IV. Elsa Tillberg, Bengt Isberg, Jonas K.E. Persson. (2020). Hemiplegic (unilateral) cerebral palsy in northern Stockholm: clinical assessment, brain imaging, EEG, epilepsy and aetiologic background factors. BMC Pediatrics. (2020: (1) 20:116. https://doi.org/10.1186/s12887-020-1955-z V. Elsa Tillberg, Jonas K.E. Persson. (2024). Hemiplegic (unilateral) cerebral palsy in northern Stockholm: Intellectual disability and epilepsy. Seizure. 120. 110-115. https://doi.org/10.1016/j.seizure.2024.06.012 </p
Genome and prognosis models : towards the personalized therapy for patients with B-cell lymphoma
No full textB-cell lymphoma is a heterogeneous cancer derived from B lymphocytes, with over 60 subtypes classified by the World Health Organization (WHO). Common subtypes include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). Several factors have been suggested to be associated with lymphomagenesis and inferior outcomes, such as different types of genetic alternations, viral infection, and tumor microenvironment. Using high-throughput sequencing on the genome and transcriptome of tumors at the bulk tissue or single-cell levels, we investigated the factors contributing to lymphomagenesis and disease progression across various types of B-cell lymphomas. Furthermore, leveraging data from multiple cohorts, we developed a prognostic tool to predict outcomes for DLBCL patients.In study I, we investigated the genetic and transcriptomic profiles of 2805 DLBCL patients, focusing on those with early disease progression within two years after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment. We observed distinct mutational patterns in patients with poor outcomes, including enriched mutations in TP53, MYD88, SPEN, MYC, and unique expression profiles characterized by dysregulation of cell migration, T-cell activation, PI3K, and NF-kB signaling. Additionally, we developed a robust and independent prognostic tool based on the expression of 24 genes to identify DLBCL patients with early disease progression. This tool can also be combined with cell-of-origin subtypes and DNA molecular subtypes to further stratify patients.In study II, we explored the association between chronic hepatitis B virus (HBV) infection and FL in the Chinese population using the data derived from genomic and transcriptomic sequencing. Compared to HBV surface antigen negative (HBsAg-) FL patients, HBsAg+ FL patients were younger, had higher histology grades, and poorer prognoses. Their tumors exhibited enhanced mutagenesis and distinct genetic profiles, characterized by a lack of IGH/BCL2 translocations and CREBBP mutations but more mutations in another set of genes (TNFAIP3, FAS, HIST1H1C, TP53, PIM1, etc.). Transcriptomic analyses showed that HBsAg+ FLs exhibited expression signatures similar to those of activated B-cell-like DLBCL (ABC-DLBCL). These data suggest that HBsAg+ FLs may represent a distinct FL subtype.In study III, we studied tumor evolution and microenvironment of MCL from primary to relapse by integrating data from whole-genome sequencing (WGS), single-cell RNA sequencing (scRNA-seq), and single-cell B-cell receptor sequencing (scBCR-seq). We observed significant inter-patient, intra-patient, and intra-tumor heterogeneity in MCL. Additionally, MCL cells may receive survival signals from T cells via CD40-CD40L and CD70-CD27 interactions and from myeloid cells via BAFF-mediated signals. Furthermore, we demonstrated divergent clonal evolution patterns through disease progression in individual patients. Our results indicate that intra-tumor heterogeneity is likely a key factor contributing to MCL relapse, complicating therapeutic eradication. Subsequently, residual tumor clones may acquire new mutations and copy number changes, or migrate into favorable tissue microenvironments, promoting tumor cell proliferation and leading to disease relapse.In study IV, we conducted a systematic characterization of mutational signatures using WGS data from 929 tumors across nine subtypes of B-cell malignancies. We identified 16 single-base substitution (SBS), four double-base substitution (DBS), and three indel signatures, including three lymphoid-specific signatures and several associated with DNA repair deficiencies and specific tumor types. Additionally, we extracted 6,040 kataegis events (highly clustered mutations) and confirmed three previously identified kataegis signatures associated with activation-induced cytidine deaminase (AID), polymerase h (POLH), and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) activities. Our extensive cohort further revealed that the AID-mediated kataegis signature was linked those subtypes with poorer prognostic outcomes.In conclusion, our extensive genomic and transcriptomic studies provide valuable insights into the complex mechanisms driving lymphomagenesis and disease progression in different types of B-cell lymphoma. Our findings have the potential to advance the development of personalized medicine for lymphoma patients.List of scientific papersI. Genetic and transcriptomic analyses of diffuse large B-cell lymphoma patients with poor outcomes within two years of diagnosis. Ren W*, Wan H*, Own S*, Berglund M, Wang X, Yang M, Li X, Liu D, Ye X, Sonnevi K, Enblad G, Amini R, Sander B, Wu K, Zhang H., Wahlin B, Smedby K, PanHammarstršm Q. Leukemia. 2024, 38(3), 610Đ620. *shared first authors. https://doi.org/10.1038/s41375-023-02120-7 II. Distinct clinical and genetic features of hepatitis B virus-associated follicular lymphoma in Chinese patients. Ren W*, Wang X*, Yang M*, Wan H, Li X, Ye X, Meng B, Li W, Yu J, Lei M, Xie F, Jiang W, Kimby E, Huang H, Liu D, Li Z, Wu K, Zhang H, Pan-Hammarstršm Q. Blood Advances. 2022;6(9):2731-2744. *shared first authors. https://doi.org/10.1182/bloodadvances.2021006410 III. Tumor evolution and immune microenvironment dynamics in primary and relapse mantle cell lymphoma. Wan H, Ren W, Yang M, Li X, Wasik A, Du L, de Campos-Mata L, Nie M, Yang C, Ye X, Yang Z, Ansell S, Liu D, van der Burg M, Wu K, Sander B, Pan-Hammarstršm Q. [Submitted]IV. Mutational signature analysis of nine types of B-cell malignancies. Wan H*, Ren W*, Yang M, Ye X, Nie M, Li X, Liu D, Wang X, Sander B, Li W, Maura F, Wu K, Li Z, Zhang H, Yeap L, Pan-Hammarstršm Q. *shared first authors. [Manuscript]</p
Functional characterization of protective antibodies in murine models of rheumatoid arthritis
No full textRheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease, characterized by chronic, erosive polyarthritis and by the presence of various autoantibodies in serum and synovial fluid. There are many different types of arthritogenic antibodies present in patients who suffer from RA. Among them, there are RFs (rheumatoid factors), ACPAs (anti-citrullinated protein antibodies) and anti-CarP (anti-carbamylated protein antibodies). Additionally, antibodies against collagen type II (COL2) are also found in some patients. However, we will see in this thesis that not all autoantibodies have arthritogenic properties. Some of them can have regulatory properties and even confer protection.In paper I, recombinant ACPA antibodies derived from human RA patient B cell clones were generated using Expi293F cells and we efficacy characterized them in different mouse models of RA. We found that some of these ACPA clones were non-reactive when administered individually to mouse or in combination with other known anti-COL2 pathogenic antibodies. To our surprise, one clone (E4) not only was non-reactive, but also conferred protection in collagen antibody induced arthritis (CAIA) and glucose-6-phosphate isomerase arthritis (GPIA) mouse models. Furthermore, we observed that E4 forms immune complexes with alpha enolase (ENO1) in the synovium interacting with synovial macrophages promoting IL10 secretion through FCGR2B. This is of vital importance because it is the first time that an ACPA antibody isolated from RA patients shows outstanding protection in several murine models of rheumatoid arthritis.In paper II, antibodies against the F4 specific epitope on COL2 were generated using a phage display library, and a group of candidate antibodies with high affinity for the F4 epitope were selected (together with other criteria). Some of these protective antibodies have been chosen and validated in the collagen antibody induced arthritis (CAIA) mouse model. Furthermore, we observed that R69-4 binds to a wide range of targets in the synovium (including C1q) and dampens the neutrophil signal by downregulating neutrophil FCGR3. We selected a good candidate antibody (R69-4) that could be used for prospective clinical trials in humans and possibly diminish the acute phase inflammation in patients suffering from RA.In paper III, we discovered that Fcgr2b and Fcgr3 are important regulators of collagen antibody induced arthritis in mice. Using FCGR2B knock-out mice, we observed that it induces severe arthritis very rapidly, even outweighing the resistance from the deficiency of complement C5. On the other hand, when there is deficiency of FCGR3, mice are completely resistant to arthritis.In paper IV, the protective antibody candidate described in paper II (R69-4) was tested in different mouse models of rheumatoid arthritis in the widely used strain DBA/1 with promising results. Interestingly, it protects against the T cell dependent and COL2 independent glucose-6-phosphate isomerase (GPIA) mouse model during early time points. Furthermore, we found that R69-4 antibody follows an alternative pathway for protection by decreasing activating FCGRs in macrophages and increasing the surface expression of FCGR2B, thus promoting a macrophage anti-inflammatory phenotype compared to isotype and pathogenic antibody controls.In paper V, we studied the effect of Fc sialylation in anti-COL2 pathogenic antibodies. Fc sialylation has been associated with anti-inflammation and some studies indicate that it might have a potential as a treatment. We have engineered known arthritogenic anti-COL2 antibodies so that they have a high degree of sialylation in the Fc glycan fraction. These engineered antibodies were injected into mice, but they were only effective in attenuating the signs of arthritis in collagen-induced arthritis (CIA) and not in collagen antibody-induced arthritis (CAIA). Additionally, their efficacy depended on the antibody Fc isotype.List of scientific papersI. A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis. Yibo He, Changrong Ge, Alex Moreno-Giro, Bingze Xu, Christian M. Beusch, Katalin Sandor, Jie Su, Lei Cheng, Erik Lšnnblom, Christina Lundqvist, Linda M. Slot, Dongmei Tong, Vilma Urbonaviciute, Bibo Liang, Taotao Li, Gonzalo Fernandez Lahore, Mike Aoun, Vivianne Malmstrom, Theo Rispens, Patrik Ernfors, Camilla I. Svensson, Hans Ulrich Scherer, RenŽ E M Toes, Inger Gjertsson, Olov Ekwall, Roman A. Zubarev, Rikard Holmdahl. (2023). Nature Communications. https://doi.org/10.1038/s41467-023-36257-x II. A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils. Zhongwei Xu, Bingze Xu, Susanna Lundstršm, Alex Moreno-Giro, Danxia Zhao, Myriam Martin, Erik Lšnnblom, Qixing Li, Alexander KrŠmer, Changrong Ge, Lei Cheng, Bibo Liang, Dongmei Tong, Roma Stawikowska, Anna Blom, Gregg Fields, Roman Zubarev, Rikard Holmdahl. (2023). Nature Communications. https://doi.org/10.1038/s41467-023-41561-7 III. Fcgr2b and Fcgr3 are the major genetic factors for antibody mediated arthritis development, which also override the effect of Hc encoding complement C5. Zhongwei Xu; Alex Moreno-Gir—; Danxia Zhao; Alexander KrŠmer, Bingze Xu, Rajan Kumar Pandey, Susanna Lundstršm, Rikard Holmdahl. (2024). European Journal of Immunology. https://doi.org/10.1002/eji.202350659 IV. Protection against arthritis by a collagen type II epitope specific antibody through various Fc gamma receptors on macrophages. Alex Moreno- Gir—, Bingze Xu, Gregg Fields, Zhongwei Xu, Rikard Holmdahl. [Manuscript]V. Fc sialylation has no effect on pathogenicity of arthritogenic antibodies. Alexander KrŠmer, Ëlex Moreno-Gir—, Susanna L Lundstršm, Taotao Li, Ana Coelho, Zhongwei Xu, Bingze Xu, Roman A. Zubarev, Rikard Holmdahl. [Manuscript]</p