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Endometrial regeneration and uterine disorders : cellular and molecular studies
No full textThe human endometrium, a unique mucosal tissue, exhibits remarkable regenerative capacity, undergoing monthly cycles of breakdown and renewal. Such a dynamic remodeling process is hypothesized to be initiated and orchestrated by putative stem/progenitor cells residing in the basalis layer. However, precise characterization of these stem cell populations and their regulatory networks remains elusive due to limited access to full-thickness endometrial specimens and insufficient exploration of tissue heterogeneity at single-cell resolution. Many pathological factors can disrupt normal endometrial remodeling, leading to various common uterine disorders, including endometriosis, adenomyosis, intrauterine adhesions, and thin endometrium, therefore extensively affecting women’s reproductive health. Elucidating the spatial and temporal dynamics of endometrial tissue heterogeneity at single-cell resolution is therefore essential for understanding the cellular and molecular mechanisms governing endometrial regeneration, thereby enhancing our mechanistic insight into the pathogenesis of various uterine disorders and facilitating the development of more targeted therapeutics.In Study I, we explored the therapeutic action of vaginal bromocriptine for adenomyosis. Our findings revealed that bromocriptine treatment exerted anti-proliferative effects on eutopic endometrium from adenomyosis both ex vivo and in vitro, potentially acting by regulating certain microRNAs and signaling pathways linked to cell proliferation.In Study II, we investigated the role of microRNAs in endometriosis through small RNA sequencing. Comparative analysis between women with and without endometriosis identified 14 differentially expressed microRNAs. Through integrated analysis combining target gene prediction, mRNA sequencing, experimental validation, and bioinformatic analysis, we characterized two key microRNAs and their potential target genes that may contribute to endometriosis development through modulation of cell migration and relevant pathways.In Study III, we analyzed transcriptional profiles of placental tissues from SARS-CoV-2 - infected and non-infected women during the third trimester of pregnancy. Despite the absence of detectable viral load in placental tissue, we observed significant downregulation of nine immunoglobulin superfamily genes in the maternal compartment of actively infected cases, suggesting potential molecular mechanisms underlying the increased risks of pregnancy complications associated with COVID-19 infection.In Study IV, utilizing high-resolution spatial transcriptomics(Visium HD), we mapped cellular heterogeneity within full-thickness endometrium across three distinct time points during the proliferative phase. Our results provide a highly resolved spatial transcriptional atlas of the proliferative endometrium that aligns well with tissue morphology, revealing pronounced spatial cellular heterogeneity and dynamic molecular change during endometrial regeneration.In conclusion, this thesis advances our understanding of basic endometrial biology and provides mechanistic insights into several endometrial pathologies through integrated multi?scale analyses spanning histological, cellular, and molecular investigations. By applying cutting-edge next-generation sequencing technologies across four distinct studies, we have explored both physiological and pathological aspects of human endometrial tissue. The insights gained in the thesis will lead to future research in regenerative medicine and the development of targeted therapies for uterine disorders, ultimately improving women’s fertility and reproductive health.List of scientific papersI. Tang Y† , Ponandai-Srinivasan S† , Frisendahl C, Andersson JK, Pavone D, Stewart EA, Lalitkumar PGL, Korsching E, Bogavarappu NR, Gemzell-Danielsson K. Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis. Front Endocrinol (Lausanne). 2023 Mar 9;14:1026168. https://doi.org/10.3389/fendo.2023.1026168II. Frisendahl C† , Tang Y† , Peters, M., Bogavarappu, N. R., Lalitkumar, P. G., Piltonen, T., Arffman, R.K., Salumets, A., Gotte, M., Korsching, E., Gemzell-Danielsson, K. miR-193b-5p and miR-374b-5p are aberrantly expressed in endometriosis and suppress cell migration in vitro. Biomolecules. 2024;14(11):1400. https://doi.org/10.3390/biom14111400III. Tang Y† , Boggavarapu NR† , Aronsson A, Gemzell-Danielsson K, Lalitkumar PG. Global transcriptomic analysis of placentas from women with gestational SARS-CoV-2 infection during the third trimester of pregnancy. Int J Mol Sci. 2024; Jan 28;25(3):1608. https://doi.org/10.3390/ijms25031608IV. Tang Y† , Frisendahl C† , Nair K, Boggavarapu NR, Flam F, Kopp Kallner H, Papaikonomou K, Lalitkumar PG, Gemzell-Danielsson K. Spatio-temporal transcriptome of the human proliferative endometrium at single-cell scale. [Manuscript]† Shared first author</p
Aspects of aspirin in colorectal cancer development and prognosis
No full textColorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and its incidence continues to rise. Despite advancement in treatment, CRC survival remains around 60%. Since the first study in 1988 reported aspirin's potential role in CRC prevention, extensive research has been conducted to explore its impact on both CRC prevention and prognosis. However other areas remain unexplored. Aspirin's widespread availability, low cost, and well-documented safety profile make it an attractive candidate for further investigation, particularly if new therapeutic benefits can be identified. The aim of this thesis was to explore under-investigated aspects of aspirin's impact on CRC. This includes examining its effects on survival outcomes, metastatic risk, interactions with metformin, and mutation profiles. By addressing these areas, this research offers new insights into aspirin's role in CRC development and prognosis.Study I investigated the association between low-dose aspirin use and CRC outcomes in 32,195 non-metastatic CRC, aged 18-85 years, diagnosed between 2007 and 2016, who underwent curative-intended surgery. Using data from the Colorectal cancer database (CRCBaSe) Sweden, the study found no significant association between aspirin use at the time of surgery and 5-year all-cause mortality (adjusted HR 1.03, 95% CI: 0.97–1.08), CRC-specific mortality (adjusted HR 0.99, 95% CI: 0.91–1.07) or relapse-free survival (adjusted HR 1.01, 95% CI: 0.96- 1.06). This represents the largest observational study to date on aspirin use and CRC outcomes, suggesting no clear survival benefit from aspirin use in non?metastatic CRC patients, while also being one of the few studies to investigate the risk of recurrence.Study II examined the impact of type 2 diabetes mellitus (T2DM) and metformin use on CRC outcomes, along with the potential synergistic effect of combining metformin and aspirin, in a nationwide cohort of 33,028 non-metastatic CRC patients aged ≥18 years, diagnosed between 2007 and 2016 using CRCBaSe. The study found no significant association between T2DM or metformin use and time to recurrence or CRC-specific mortality (adjusted HR 0.95, 95% CI: 0.87–1.05 for T2DM; adjusted HR 0.98, 95% CI: 0.85–1.13 for metformin users). Additionally, no synergistic effect was observed between metformin and aspirin use in relation to CRC outcomes.Study III explored the relationship between low-dose aspirin use and the risk of synchronous distant CRC metastasis in 88,960 patients diagnosed between 2007 and 2021 aged ≥18 years, using CRCBaSe. The study revealed that current and past aspirin users had a reduced risk of synchronous distant metastases in right-sided colon cancer (adjusted OR 0.87, 95% CI: 0.80–0.94 for current users; adjusted OR 0.83, 95% CI: 0.73–0.95 for past users), particularly among long-term users (adjusted OR 0.84, 95% CI: 0.76–0.92 for ≥5 years of use and adjusted OR 0.78, 95% CI: 0.68–0.90 for ≥1825 pills of use). No such association was observed for rectal cancer.Study IV explored the relationship between aspirin use and mutation profiles in 3,030 non-metastatic CRC patients who were screened for the ALASCCA trial. Aspirin users had a lower probability of PIK3CA mutations (0.18, 95% CI 0.14–0.22) compared to non-users (0.25, 95% CI 0.23–0.26). Among MSI-high tumors, aspirin users exhibited higher probabilities of BRAF and PTEN mutations but lower probabilities of KRAS and PIK3CA mutations. No significant differences were observed in microsatellite stable tumors. These findings highlight potential molecular mechanisms through which aspirin may influence CRC development.This thesis sheds light on several underexplored aspects of aspirin's role in CRC. Aspirin use demonstrates potential in reducing metastatic risk, only in colon cancer, and influences specific molecular profiles associated with tumor development. It is associated with a lower probability of PIK3CA mutations and distinct mutation patterns in MSI-high tumors, such as increased BRAF and PTEN mutations and decreased KRAS mutations. However, aspirin does not confer a clear survival benefit in non-metastatic CRC, and its interaction with metformin has no impact on CRC outcomes. These findings highlight the complex role of aspirin in CRC and underscore the need for further biomarker-driven studies to clarify its therapeutic potential.List of scientific papersI. Low-dose aspirin use and colorectal cancer survival in 32,195 patients – A national cohort study. Shahrivar M, Weibull CE, Ekström Smedby K, Glimelius B, Syk I, Matthiessen P, Nordenvall C, Martling A. Cancer Medicine 2023 Jan; 12(1):315-324. https://doi.org/10.1002/cam4.4859II. Type II diabetes and metformin use does not affect colorectal cancer prognosis. Shahrivar M, Dietrich CE, Glimelius B, Saraste D, Martling A, Buchli C, Nordenvall C. International Journal of Cancer 2024 Nov. 27. Online ahead of print. https://doi.org/10.1002/ijc.35266III. Low-dose aspirin use and the risk of synchronous metastatic colorectal cancer: results from a population-based cohort study. Shahrivar M, Dietrich CE, Glimelius B, Martling A, Nordenvall C. [Submitted]IV. Aspirin use and mutation profile in non-metastatic colorectal cancer. Shahrivar M, Nordenvall C, Mayrhofer M, Dietrich CE, Bergström R, Myrberg IH, Lindberg J, Martling A. [Manuscript]</p
Exploration of new therapeutic approaches and genetic and non-genetic adaptations in Plasmodium falciparum
No full textInfections with malaria are a major health burden that impacts global society and economy alike. The most dominant and lethal malaria-causing parasite is Plasmodium falciparum, which exhibits a high multiplication rate, efficient host cell invasion, potent cytoadherence, unique abilities to avoid the host's immune response, and countering treatment measures. The increasing occurrence of artemisinin-based combination therapy (ACT) treatment failure in P. falciparum stresses the discovery of new compounds that can either replace artemisinin as the first-line treatment, counter existing drug resistance, or function as a novel combination partners. Therefore, extensive evaluation of drugs and their targets is required to elucidate the full potential of treatment opportunities.To increase our understanding of the parasite's opportunities to develop drug resistance, we evaluated the formation of resistance in P. falciparum, based on the heat shock protein 90 (Hsp90) inhibitor geldanamycin. Cyclic selection with incremental concentrations revealed a highly mutable geldanamycin target site, causing rapid adaptation to drug pressure. Interestingly, increased drug resistance was associated with the revertible upregulation of clag transcription, possibly allowing the parasite to elevate its resistance phenotype at a minimal fitness cost.We further investigated the potential of nitric oxide (NO) donors for malaria treatment and evaluated the antiparasitic potential of the novel drug candidate PDNO in vitro. Our results demonstrated antiparasitic features of NO donors and uncovered enhanced properties for PDNO. These findings were elevated by an irreversible cytostatic effect upon repeated treatment, emphasizing its potential as an adjunct treatment option. However, we also revealed an antagonistic effect towards dihydroartemisinin and offer a mechanistic explanation, which suggests an incompatibility of NO donors for use in ACTs.Collectively, these studies improve our understanding of drug resistance development in P. falciparum and emphasize the fitness-dependent interplay of genetic mutations and non-genetic alterations. Moreover, we describe the potential of a drug candidate and offer insight into the antagonistic mechanism of NO donors in combination with artemisinin.</p
Physical activity, intensive exercise, and mechanisms for muscle impairment in patients with idiopathic inflammatory myopathies
No full textIdiopathic inflammatory myopathies (IIM), or myositis, are chronic, heterogenous systemic inflammatory diseases, characterized by low muscle strength and muscle endurance as hallmark symptoms. Patients are often left with sustained disability and reduced physical function and quality of life. The cause of the reduced muscle function is yet unknown, and levels of inflammation correlates poorly with muscle strength. Several mechanisms have been proposed, one of them being impaired mitochondrial function leading to reduced work capacity of the muscles. Today, physical exercise is a central adjuvant treatment to combat the disease, however, it is still unknown how these patients can exercise early in the disease to try to avoid the deterioration and maintain function and strength instead of trying to recover it.The aim of this thesis was threefold; to investigate the role of physical activity on quality of life, anxiety, and depression, to investigate possible mechanisms causing muscle impairment, and to investigate the efficacy on aerobic capacity, and safety regarding disease activity, of high-intensity interval training in recent onset IIM.Questionnaires on self-reported level of physical activity, anxiety and depression was given to patients, additional data were obtained from the Swedish Rheumatology Quality Registry (SRQ). As much as 82 % of the 246 participants reported sufficient physical activity according to recommendations. Logistic regression models revealed the possible protective role of physical activity on depression with a reduced risk of 77 %, and that for every millimeter increase of fatigue, the risk of anxiety increased by 2 % and for depression by 3 % (Paper I). By incubating muscle from healthy mice with patient sera, a reduced force production across stimulation frequencies was seen after 24 hours of incubation in both 10 % and 50 % serum concentration. There were no negative effects on force production when incubating with sera from healthy controls or isolated IgG from autoantibody positive patients. Further, tetanic [Ca2+] in mechanically isolated muscle fiber was not affected by patient sera. For the first time, patient serum has been demonstrated to induce muscle weakness in mouse skeletal muscle, suggesting non-cellular factors within the systemic circulation may contribute to impaired muscle function in IIM (Paper II). In a randomized controlled multicenter trial, the efficacy and safety of high-intensity interval training was investigated in recent-onset IIM. Participants were randomly allocated, by a blinded person, to either HIIT or control (CON). Clinical assessments, blood test, maximal exercise test, and patient-reported outcomes (e.g., quality of life, pain, and fatigue) were performed at inclusion and 12-week follow-up. HIIT comprised six 30-45-seconds intervals per session with 2 minutes of active rest in- between), with three weekly supervised sessions. CON did a low-to-moderate home-based exercise protocol with eight exercises of ten reps each and a 15- minute-walk, five times weekly. HIIT outperformed CON regarding oxygen uptake (VO2peak), as well as peak power and time-to-exhaustion in the maximal exercise test. Further HIIT had higher levels of mitochondrial proteins at follow-up (Paper III). HIIT did not increase inflammation or disease activity in any measure. It did not outperform CON in improving disease activity, however, HIIT did improve self- reported physical function and general health. Tere were no statistically significant difference between the groups in rating of fatigue or pain. The HIIT group significantly reducing the daily prednisone dosage (Paper IV).Overall, this thesis highlights the importance of physical activity and patient- reported outcomes. Further, we have demonstrated that non-cellular factors in systemic circulation could impair muscle function, but not autoantibodies or [Ca2+]. Lastly, our results demonstrate that HIIT is more effective in improving aerobic capacity, mitochondrial function and physical function compared to standard home exercise in recent-onset IIM, while not increasing inflammation or disease activity.List of scientific papersPapers included in this thesis listed below with roman numerals.I. Self-reported physical activity and fatigue and its associations to anxiety and depression in adult patients with idiopathic inflammatory myopathies: a MIHRA psychological impact and MIHRA exercise and rehabilitation scientific working groups collaboration. Kristofer M Andreasson, Fabricio Espinosa-Ortega, Helene Sandlund, Helene Alexanderson. Clin Exp Rheumatol. 2024 Sep 10. Epub ahead of print. PMID: 39263797. doi: https://doi.org/10.55563/clinexprheumatol/5u5ah3.II. Serum from patients with idiopathic inflammatory myopathy induces skeletal muscle weakness. Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson. Ann Rheum Dis. 2024 Nov 14;83(12):1796-1797. PMID: 39197873. doi: https://doi.org/10.1136/ard-2024-225912.III. High-Intensity Interval Training Outperforms Moderate Exercise to Improve Aerobic Capacity in Patients with Recent-Onset Idiopathic Inflammatory Myopathies: A Multicenter Randomized Controlled Trial. Kristofer M Andreasson, Cecilia Leijding, Maryam Dastmalchi, Antonella Notarnicola, Stefano Gastaldello, Takashi Yamada, Heléne Sandlund, Dag Leonard, Håkan Westerblad, Ingrid E Lundberg, Daniel C Andersson Helene Alexanderson. medRxiv 2024.12.05.24318130; doi: https://doi.org/10.1101/2024.12.05.24318130 [Manuscript Preprint]IV. High-Intensity Interval Training in Recent-Onset Idiopathic Inflammatory Myopathies Does Not Increase Inflammation but Improves Self-Reported Physical Function: A multicenter randomized controlled trial. Kristofer M Andreasson, Maryam Dastmalchi, Antonella Notarnicola, Helene Sandlund, Dag Leonard, Håkan Westerblad, Daniel C Andersson, Ingrid E Lundberg, Helene Alexanderson. [Manuscript]</p
Early cancer detection through symptoms and signs
No full textEarly cancer detection is critical for improving survival rates, yet it requires a careful balance between minimising missed diagnoses and avoiding over- investigation. Primary care plays a central role in this process. This thesis aims to enhance understanding of the complexities involved in early cancer detection by analysing symptoms and signs, with the goal of contributing to the development of risk assessment and prediction tools to identify cancer at an early stage within primary care.This thesis is based on five quantitative studies conducted within the Swedish healthcare system. Study I examined symptoms reported by referred patients via questionnaires at the Department of Pulmonary Medicine at Karolinska University Hospital. It investigated whether machine learning could predict which patients subsequently received a lung cancer diagnosis, stratified by smoking status. Studies II and III focused on comprehensive diagnostic data and coded symptoms from primary care to facilitate early detection of non-metastatic colorectal cancer, with Study II conducted in Region Stockholm and Study III in Region Västra Götaland. Studies IV and V used comprehensive clinical and laboratory data from the entire adult population of Stockholm County. Study IV presents a cohort description, while Study V examines the association and discriminatory capacity of newly developed anaemia as an indicator for cancer.In Study I, the findings demonstrate that predictive models, using machine learning, exhibit good discriminatory ability for patients who either never smoked or were current smokers. In Study II, an existing Swedish risk assessment tool was validated by replicating it in a different region, with consistent results across regions. In Study III, a new predictive model was developed using machine learning to analyse all diagnostic data for identifying non-metastatic colorectal cancer. Study IV introduces the extensive STEADY-CAN (Stockholm early detection of cancer study) cohort, providing opportunities to analyse early cancer detection patterns. Study V investigates the association between newly developed anaemia and cancer risk within the STEADY-CAN cohort, revealing a significant impact on risk assessment.These findings collectively address the value of improved risk stratification in primary care by leveraging existing data to better identify patients at elevated risk of having cancer. The results highlight key themes in early detection- predictive accuracy, risk stratification, clinical utility, and applicability across populations-and identify areas where current evidence has been limited or inconclusive. Future research should prioritise the validation of novel diagnostic approaches and the development of systems that support clinical decision- making, while upholding the principles of accessible, patient-centred care. Keywords: Early cancer detection, Primary care, Machine learning, Colorectal cancer, Lung cancer, Risk assessment tools, Anaemia, STEADY-CAN.List of scientific papersI. Nemlander E, Rosenblad A, Abedi E, Ekman S, Hasselström J, Eriksson LE, Carlsson AC. Lung cancer prediction using machine learning on data from a symptom e-questionnaire for never smokers, formers smokers and current smokers. PLoS One. 2022 Oct 21;17(10):e0276703. PMID: 36269746; PMCID: PMC9586380.https://doi.org/10.1371/journal.pone.0276703Erratum for: PLoS One. 2022 Oct 21;17(10):e0276703. PMID: 38060550; PMCID: PMC10703334. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0295780 II. Nemlander E, Rosenblad A, Abedi E, Hasselström J, Sjövall A, Carlsson AC, Ewing M. Validation of a diagnostic prediction tool for colorectal cancer: a case-control replication study. Fam Pract. 2023 Jan 5:cmac147. PMID: 36611019. https://doi.org/10.1093/fampra/cmac147III. Nemlander E, Ewing M, Abedi E, Hasselström J, Sjövall A, Carlsson AC, Rosenblad A. A machine learning tool for identifying non- metastatic colorectal cancer in primary care. European Journal of Cancer. 2023 Jan 11. https://doi.org/10.1016/j.ejca.2023.01.011IV. Nemlander E, Abedi E, Ljungman P, Hasselström J, Carlsson AC, Rosenblad A. The Stockholm Early Detection of Cancer Study (STEADY-CAN): rationale, design, data collection, and baseline characteristics for 2.7 million participants. https://doi.org/10.1007/s10654-024-01192-8V. Nemlander E, Rosenblad A, Abedi E, Hasselström J, Ljungman P, Carlsson AC. Newly developed anaemia predicts incident cancer and death within 18 months: Findings from 1.1 million patients in the Stockholm Early Detection of Cancer Study (STEADY-CAN) cohort. [Manuscript]</p
Host adaptation of Plasmodium falciparum translational control
No full textMalaria, caused by the intracellular protozoan parasite Plasmodium falciparum, continues to be a significant global health challenge. One of the major difficulties in combating the disease is the parasite's ability to constantly respond and adapt to changes in its human host environment. Alterations in host environment are tightly linked to disease progression in the intraerythrocytic development cycle (IDC), which is why the parasite has developed unique metabolic adaptation strategies. However, it remains unclear how the parasites sense such changes and regulate protein synthesis, particularly given its lack of the canonical TOR pathway. Thus, understanding how the parasite controls its translation under conditions of limited nutrient availability is crucial for gaining deeper insights into host-parasite interactions and adaptation, which may ultimately aid the development of more effective antimalarial therapies.Notably, P. falciparum can serve as a unique model system for studying translational control as it presents the extremely AT-rich genome, skewed codon and amino acid (AA) usage, but a non-redundant set of tRNA genes. These features raise important questions regarding the ways in which the parasite offsets its codon usage bias to maintain efficient translation, and whether these evolutionary outcomes are neutral or represent adaptive strategies of the parasite to its host.Therefore, this thesis explores how P. falciparum adapts to the human host environment through the lens of tRNA regulation, focusing on tRNA expression dynamics, aminoacylation and tRNA modifications. In Project I and II, by optimizing the tRNA sequencing protocol, we systematically explored the tRNA profiles in P. falciparum across various developmental stages and under different stress stimuli. In Project III, using multi-omics analysis, we elucidated a novel feature of host metabolic adaptation which underlies translational control.We provide evidence that the biased AA usage in the P. falciparum genome is adaptive to host hemoglobin (HB), the primary internal source of AAs. Notably, we show that highly expressed transcripts have a lower requirement and hence dependency on AAs that are scarce or entirely absent, such as Isoleucine (Ile), which cannot be obtained through HB digestion and must be acquired from the external host environment.Through comprehensive tRNA profiling in P. falciparum, we discovered a discordance between anticodon and codon pools. Specifically, tRNA responsible for decoding AAs that are scarce in HB exhibit lower expression levels, suggesting varied decoding efficiency for different AAs. Interestingly, genes associated with lipid synthesis and proliferation have adapted to incorporate a high level of HB- rare AAs such as Ile in their encoded proteins. This adaptation enables the parasite to regulate its proliferation by selectively repressing the protein synthesis of these genes during the periods of nutrient scarcity. Furthermore, by exposing parasites to AA deprivation, we revealed a non-canonical stress sensing mechanism facilitated by the regulation of Ile-tRNA aminoacylation . This, in turn, triggers selective ribosome stalling on Ile-rich transcripts, thereby selectively regulating the translation of these genes. Remarkably, this mechanism is unique as it is independent of kinase-mediated signaling cascades, enabling a decentralized resource allocation that is directly governed by the availability and need for nutrients.By analyzing other metabolically relevant pathways, we suggest that the adaptative strategies used by P. falciparum may have evolved similarly in other intracellular parasites. Our study provides insights that metabolic constrains play an essential role in shaping the protein primary sequence and amino acid composition, challenging the prevailing view that functional constrains are the primary evolutionary drivers. This perspective offers new insights into protein and genome evolution, in particular, it may serve as an interesting model to explore the role of mutation bias in adaptive evolution.This thesis presents three related projects:Project I: We optimized tRNA sequencing techniques to provide a comprehensive view of the tRNA profiling in P. falciparum, focusing on tRNA abundance, aminoacylation levels as well as a variety of nucleotide modifications.Project II: We explored tRNA modifications during stage transitions and under different stress conditions.Project III: By employing multi-omics analysis, we uncovered a novel layer of metabolic adaptation in P. falciparum characterized by its highly biased AA usage in its proteome and is coupled to a regulated tRNA expression program.List of scientific papersI. Qian Li, Leonie Vetter, Ylva Veith, Elena Christ, Ákos Végvári, Cagla Sahin, Ulf Ribacke, Mats Wahlgren, Johan Ankarklev, Ola Larsson, Sherwin Chun-Leung Chan. tRNA regulation and amino acid usage bias reflect a coordinated metabolic adaptation in Plasmodium falciparum (iScience). https://doi.org/10.1016/j.isci.2024.111167II. Qian Li, Ylva Veith, Elena Christ, Mats Wahlgren, Johan Ankarklev, Ola Larsson, Sherwin Chun-Leung Chan. tRNA base methylation identification and quantification in Plasmodium falciparum. [Manuscript]</p
Investigating drug effects on aging and alzheimer's disease using causal inference approaches
No full textThe geroscience hypothesis offers a compelling approach to extending human lifespan and healthspan by targeting fundamental aging mechanisms. Recent advances in biomarkers for biological aging (BA biomarkers) present promising tools for measuring the aging process in humans and may serve as valuable endpoints for assessing the impact of interventions, including pharmacological treatments, on aging. Alzheimer's disease (AD), one of the most prevalent age- related diseases, imposes immense suffering on patients and families and poses significant healthcare burdens in aging societies. While recent amyloid-targeted immunotherapies show progress in slowing cognitive decline in early-stage AD, emerging evidence suggests that combined therapies targeting multiple pathological pathways, as well as early interventions in preclinical or earlier stages, may hold the greatest promise for preventing or managing AD progression. This doctoral thesis evaluates the effects of various drugs on aging and AD onset, aiming to provide insights into drug candidates with repurposing potential as anti-aging agents or AD-modifying treatments.Studies I and II employed a longitudinal design using conditional generalized estimating equation (cGEE) models to analyze within-individual variations across two aging cohorts from Sweden and the United States. A broad range of BA biomarkers-spanning molecular, physiological, and functional levels-served as outcome measures. Multiple drug classes were evaluated for associations with BA biomarker changes, identifying calcium channel blockers, vitamin D analogues, bisphosphonates, thyroid hormone replacements, thiazides, and proton pump inhibitors as associated with reductions in one or more BA biomarkers.Study III utilized a Mendelian randomization design to investigate the genetically predicted effects of antidiabetic drugs on AD risk. Findings suggested that the genetically predicted effects of sulfonylureas and glucagon-like peptide-1 (GLP- 1) analogues were associated with approximately 60% and 70% reductions in AD risk per 1 mmol/L decrease in blood glucose levels, respectively.Study IV evaluated the effects of GLP-1 analogues, sulfonylureas, and dipeptidyl peptidase-4 (DPP-4) inhibitors on dementia onset in a real-world setting using Swedish register data specifically comparing their effectiveness among old individuals with type 2 diabetes mellitus (T2DM). Results indicated that GLP-1 analogues were associated with 30 and 23% reduced risks of dementia compared to sulfonylureas and DPP-4 inhibitors, respectively.In conclusion, Studies I and II identified several drug classes that may benefit certain aspects of human aging, though these findings are exploratory and warrant further validation in larger, diverse populations. Studies III and IV highlighted the potential neuroprotective effects of sulfonylureas and GLP-1 analogues. The limited brain penetration of current sulfonylureas suggests an avenue for future research into the neuroprotective role of sulfonylurea targets in the brain. While GLP-1 analogues emerge as the most promising candidates for neuroprotection from these studies, their effects may vary between individuals with and without type 2 diabetes. Future randomized controlled trials are essential to clarify the neuroprotective effects of GLP-1 analogues across these populations.List of scientific papersI. Tang B, Li X, Wang Y, Sjölander A, Johnell K, Thambisetty M, Ferrucci L, Reynolds CA, Finkel D, Jylhävä J, Pedersen NL, Hägg S. Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging. Geroscience. 2023 Jun;45(3):2065-2078. https://doi.org/10.1007/s11357-023-00784-8II. Tang B, Kuo P, Moore A, Thambisetty M, Ferrucci L, Hägg S, Longitudinal Associations Between Medication Use and Phenotypic Aging: Insights from the Baltimore Longitudinal Study of Aging. [Submited]III. Tang B, Wang Y, Jiang X, Thambisetty M, Ferrucci L, Johnell K, Hägg S. Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study. Neurology. 2022 Aug 16;99(7):e650-e659. https://doi.org/10.1212/wnl.0000000000200771IV. Tang B, Sjölander A, Wastesson J, Maura G, Blotiere P-O, Szilcz M, Mak JK, Qin C, Alvarsson M, Religa D, Johnell K, Hägg S. Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study. eClinicalMedicine. 2024 Jun 1;73:102689. https://doi.org/10.1016/j.eclinm.2024.102689</p
In hospital cardiac arrest – from aetiology to clinical outcomes : the role of vasopressin and corticosteroids
No full textEvery year in Sweden, around 2,500 patients experience an in-hospital cardiac arrest (IHCA) in which cardiopulmonary resuscitation is initiated, and about one third survive to hospital discharge. In contrast to cardiac arrest occurring outside hospital, the causes of IHCA are more heterogeneous. The cause of the cardiac arrest is usually based on knowledge of the most common aetiology and clinical signs preceding cardiac arrest. The aetiology of IHCA affects outcomes, and understanding the underlying factors is essential not only for prevention but also for identifying reversible causes and guiding treatment. Treatment algorithms for IHCA are largely extrapolated from out-of-hospital cardiac arrest, even though there are substantial differences in patient characteristics, aetiologies, and the considerably shorter time from cardiac arrest to advanced cardiac life support, which may influence the response to pharmacological therapy. The optimal pharmacological treatment for IHCA remains uncertain, including the role of vasopressin and corticosteroids in addition to adrenaline. Following the change in Swedish legislation in 2022, which now allows drug trials to include patients unable to provide prior consent, new opportunities for clinical research have emerged in this critically ill patient group.This thesis comprises four studies (I-IV). The aims were to investigate the distribution of IHCA aetiologies and their association with survival, to evaluate patients' attitudes and motives towards participation in a randomised controlled drug trial in the event of a cardiac arrest, and to assess the feasibility and safety of conducting a pilot study, in which IHCA patients were randomised to either vasopressin, corticosteroids, and adrenaline or standard treatment with adrenaline only.MethodsStudy I and II were registry-based observational studies using the Swedish Registry for Cardiopulmonary Resuscitation. In Study I, patients with IHCA due to pulmonary aspiration of gastric content were compared with those with other respiratory causes. In Study II, data from the Swedish Registry for Cardiopulmonary Resuscitation were merged with the National Patient Register and the Cause of Death Register. Patients were compared according to their registered aetiology. The primary outcome for Studies I and II was 30-day survival.Study III was a prospective survey and a predefined substudy of Study IV, where hospitalised adult patients were asked for informed consent to participate in a randomised controlled drug trial in the event of a cardiac arrest during their hospital stay. A subgroup was also asked about their motives for accepting or declining inclusion. The primary outcome was patients' willingness to participate.Study IV, the VAST-A pilot study, was a randomised, double blind, clinical drug trial. Witnessed IHCAs meeting criteria for adrenaline administration were randomised 1:1 to receive adrenaline, combined with vasopressin, and corticosteroids (intervention) or adrenaline and placebo (standard care). Outcomes included feasibility and safety assessments.ResultsStudy I: IHCA due to pulmonary aspiration occurred more frequently on general wards among unmonitored patients compared with cardiac arrest due to other respiratory causes. Cardiac arrest due to aspiration were associated with significantly lower 30-day survival (8% versus 18%). In the adjusted analysis, the odds ratio for 30-day survival was 0.46 (95% CI 0.19-0.94) in IHCAs due to aspiration compared with those with other respiratory aetiologies.Study II: Among 4,320 IHCA patients, approximately 50% had a cardiac cause and 50% a non-cardiac cause. The three most common causes were myocardial ischaemia, other cardiac causes, and pulmonary causes. Patients with a cardiac cause had the highest proportion of 30-day survival, whereas those with haemorrhage or infection had the lowest.Study III: Of 1,064 patients approached, 85% approved a potential inclusion in the IHCA drug trial. In the subgroup of 411 patients asked about their motives, the main reason for accepting inclusion was to contribute to research (328 patients, 84%), while the main reason for declining was concern about receiving the drug treatment.Study IV: During December 2022 to June 2024, 39 IHCA patients were randomised. The median time from cardiac arrest to adrenaline administration was 7 minutes (intervention) versus 5 minutes (standard care), and to vasopressin administration 10:30 versus 9:00 minutes. Four patients had a protocol deviation at the scene of the arrest and three in the intensive care unit.ConclusionCardiac causes of IHCA have the highest proportion of 30-day survival and cardiac arrest due to pulmonary aspiration, haemorrhage, and infection has the lowest. These findings emphasise the importance of improved monitoring and preventive strategies among high-risk patients, as well as the need for an internationally standardised system for reporting IHCA aetiologies. The vast majority of approached patients were willing to participate in the emergency randomised drug trial in case of a cardiac arrest, indicating that patients' attitudes are not a major barrier to emergency research. Randomisation and drug administration during cardiac arrest were safe, however, the inclusion rate was low and there was a delay in drug administration. Protocol adjustments are needed to streamline the study drug administration and randomisation process to ensure sufficient enrolment in the VAST-A main trial. These findings underscore the value of conducting a pilot study prior to a main randomised control trial.List of scientific papersI. Malin Albert, Johan Herlitz, Araz Rawshani, Mattias Ringh, Andreas Claesson, Therese Djärv, Per Nordberg. Cardiac arrest after pulmonary aspiration in hospitalised patients: a national observational study. BMJ Open. 2020 volume 10 Issue 3. Pages e032264. https://doi.org/10.1136/bmjopen-2019-032264II. Malin Albert, Johan Herlitz, Araz Rawshani, Sune Forsberg, Mattias Ringh, Jacob Hollenberg, Andreas Claesson, Meena Thuccani, Peter Lundgren, Martin Jonsson, Per Nordberg. Aetiology and outcome in hospitalized cardiac arrest patients. European Heart Journal Open, 2023, Volume 3 Issue 4, Pages oead066. https://doi.org/10.1093/ehjopen/oead066III. Malin Albert1, Marie Thonander1, Sune Forsberg, Frida Lindgren, Meena Thuccani, Annika Odell, Kristofer Skoglund, Niklas Bergh, Jacob Hollenberg, Mattias Ringh Martin Jonsson, Per Nordberg, Peter Lundgren. Hospitalized patients' attitudes towards participating in a randomized control trial in case of a cardiac arrest. Resuscitation plus, 2024, Volume 18, pages 100645. https://doi.org/10.1016/j.resplu.2024.100645IV. Malin Albert1, Sune Forsberg1, Mattias Ringh, Frida Lindgren, Marie Thonander, Meena Thuccani, Araz Rawshani, Therese Djärv, Jacob Hollenberg, Leif Svensson, Johan Herlitz, Martin Jonsson, Per Nordberg, Peter Lundgren. Vasopressin and Steroids in addition to adrenaline in cardiac arrest (VAST-A) - A randomised pilot study. Resuscitation, 2025, Volume 210, pages 110593. https://doi.org/10.1016/j.resuscitation.2025.1105931 These authors contributed equally to this work.</p
Associations of estrogen with modifiable and non-modifiable risk factors for dementia: A narrative review.
No full textFemale sex is associated with higher incidence and risk of dementia. Estrogen may represent one important mechanism contributing to the increase in incidence rates. In this review, we synthesize narratively the evidence for associations between estrogen-across the life course from menarche to menopause, estrogen-containing hormonal contraception and hormone replacement therapies, and pregnancy-with potential modifiable risk factors for dementia. These include education, hearing loss, traumatic brain injury, hypertension, alcohol use, obesity, smoking, depression, physical inactivity, diabetes, low-density lipoprotein (LDL) cholesterol, social isolation, air pollution, and untreated visual loss, as well as apolipoprotein E ε4. In addition, evidence is summarized for associations with sleep, diet, and stress. Evidence suggests that estrogen is associated with some of these modifiable risk factors for dementia, particularly LDL cholesterol, smoking, and depression. Research needs to further define these associations and understand whether interventions targeting estrogen levels at key life stages could offer intervention opportunities to reduce future risk of dementia in women. HIGHLIGHTS: Higher dementia risk in women may be associated with estrogen. Estrogen is associated with some of the modifiable risk factors for dementia. However, significant gaps exist in the literature for most risk factors.</p
Metastatic colorectal cancer from an epidemiological and immunological perspective
No full textColorectal cancer (CRC) is the third most common type of cancer and around 8000 persons in Sweden get the diagnosis each year. One in five will have metastases at diagnosis, i.e., synchronous, and almost as many will develop metastases during follow up, i.e., metachronous. Median survival after diagnosis of metastatic CRC (mCRC) is 1-1.5 years. The most common metastatic locations are the liver, lungs, and peritoneum. When the extent of tumour spread in these organs is limited, surgical resection of the metastases may be feasible. Only a fraction of patients is treated with metastatic site surgery. The treatments are imperfect and puts the patient's body under major strain and risk. Despite this, prognosis of mCRC is largely dependent on if the primary tumour and metastases can be surgically removed or not.There is a need to increase our understanding of who benefits from the surgical treatments and who does not. Furthermore, previous research has shown that access to metastatic site surgery may be unequal. Lastly, a deeper understanding of the immune system's role in CRC could be crucial, as it influences disease progression and may be central to the discovery of novel treatment options. The overarching aim of this thesis is to improve the prognosis of patients with mCRC by deepening our understanding of the disease and its treatment through epidemiological and immunological approaches.Study I investigated overall survival of 131 patients with CRC and peritoneal metastases (PM) undergoing direct (without neoadjuvant chemotherapy) cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with complete cytoreduction (CCO-1), between 2012 and 2019. The patients' PM were confirmed by histopathological examination, and potential extraperitoneal metastases treated before end of follow-up. The median overall survival was 40.3 months. In a multivariable model including potential prognostic factors, peritoneal carcinomatosis index > 16 was the only factor studied associated with decreased survival. The study showed that overall survival, from an institution with direct surgery as the standard, was similar to reported median overall survival from other recent cohorts where neoadjuvant chemotherapy was standard.Study II examined the association between hospital volume and metastatic site surgery for 9,968 adult patients diagnosed with synchronous mCRC in 2009- 2016, registered in the Swedish CRC database linkage CRCBaSe. Patients at high-volume hospitals were more often treated with metastatic site surgery. When adjusting for that high-volume hospitals were more often university hospitals, in addition to adjustment of identified confounders, only hospital level remained associated with chance of metastatic site surgery. In summary, being cared for at a hospital with proximity to metastatic site surgery, i.e., a university hospital increased the odds of receiving metastatic site surgery.In study III the association between sex and metastatic site surgery was investigated for 12,201 patients with synchronous mCRC diagnosed in 2007- 2016 and registered in CRCBaSe. Women received 23% less metastatic site surgery for mCRC despite adjusting for factors affecting patient selection, e.g., age, comorbidities, and primary tumour location. Furthermore, the effect of sex on receival of metastatic site surgery was modulated by hospital level and year of diagnosis. This indicates that non-biological reasons contribute to the sex- based differences observed in metastatic site surgery rates.In study IV the impact of patient income on cancer-specific survival after diagnosis of synchronous or metachronous mCRC was evaluated. In total, 33,498 patients diagnosed with CRC in 2007-2021 were identified using CRCBaSe, including follow-up throughout 2022. Patient income was associated with relative survival and the effect was time-varying with the largest impact in the first years after metastasis diagnosis. Furthermore, we found no support for a temporal trend affecting the impact of income on mCRC survival. Thus, patient income continues to be a factor associated with inferior survival after mCRC diagnosis.In study V we explored innate lymphoid cells (ILCs)' transcriptional patterns and differentiation capacities in tissue samples of primary colon cancer, PM from CRC, and macroscopically unaffected colon. Patients undergoing direct surgery for primary colon cancer and/or PM from CRC at Karolinska University Hospitals from 2020 were recruited. Single cell RNA sequencing of tissue samples from 11 patients revealed that primary colon cancer and CRC-PM are infiltrated by 14 transcriptionally different clusters of ILCs. In all three tissue types, two clusters of immature ILCs were present, annotated early NK cells and naïve ILCs. The naïve ILCs in tumours had more transcriptional similarities to ILCs type 1 (ILC1s) and tissue-resident natural killer cells, than ILCs from unaffected colon. We used a flow cytometry panel, based on the gene expression and surface protein signatures of the immature cells. Thereby, we could confirm the existence of the immature cell clusters in another patient population of eight patients contributing with seven primary tumours and seven colon tissue samples. The differentiation capacity of the immature cells was investigated using in vitro differentiation assays of an additional 14 patients contributing with paired primary tumour and unaffected colon samples. The experiments showed that naïve ILCs from primary colon tumours had an increased capacity to generate cells with a ILC1 or tissue-resident natural killer cell phenotype. Our findings contribute to the understanding of ILCs role in CRC and provides insights that could potentially be used in future therapies aiming to increase the innate immune response in CRC.List of scientific papersI. Direct surgery with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for patients with Colorectal Peritoneal Metastases. Ljunggren M, Nordenvall C, Palmer G. Eur J Surg Oncol. 2021 Nov;47(11):2865-2872. https://doi.org/10.1016/j.ejso.2021.05.046II. Hospital factors and metastatic surgery in colorectal cancer patients, a population-based cohort study. Ljunggren M, Weibull CE, Rosander E, Palmer G, Glimelius B, Martling A, Nordenvall C. BMC Cancer. 2022 Aug 19;22(1):907. https://doi.org/10.1186/s12885-022-10005-8III. Sex differences in metastatic surgery following diagnosis of synchronous metastatic colorectal cancer. Ljunggren M, Weibull CE, Palmer G, Osterlund E, Glimelius B, Martling A, Nordenvall C. Int J Cancer. 2023 Feb 1;152(3):363-373. https://doi.org/10.1002/ijc.34255IV. Low income has a negative effect on survival following diagnosis of metastatic colorectal cancer – a population-based cohort study Ljunggren M, Dietrich CE, Merk C, Palmer G, Martling A, Nordenvall C. Cancer Med. [Accepted]V. Tumor-infiltrating immature innate lymphoid cells in colorectal cancer and peritoneal metastases are dysregulated and biased towards tissue-resident NK cell differentiation. Marchalot A, Ljunggren M, Weigel W, Stamper C, Tibbitt C, Meninger I, Vinay Pandey R, Franklin M, Ahlberg M, Lindforss U, Jansson-Palmer G, Nordenvall C, Mjösberg J. [Manuscript]</p