Biomedicum Helsinki Foundation Grantees 2024

The board of the Biomedicum Helsinki Foundation has granted a total of 260 000 euros of research grants in the year 2024. Assigned grants have been awarded from the following specific funds within the Foundation: Borrelia Fund, Timo Lehtonen Urology fund, Brain Cancer Fund, Marketta Helenius Fund for Health Sciences,Cardiovascular Fund, Neurological and Cerebrovascular Disorder Fund or from the Cancer and Cell Based Cancer Research Fund.

Clinical Post-Doctoral Grant

Hakemus VJ (lisätieto) - First name	Hakemus (lisätieto) - Title of research proposal	Hakemus VJ (lisätieto) - Last name	Hakemus (lisätieto) - Abstract of research proposal	Name	Title	Abstract of research proposal	Hakemus (lisätieto) - Fund	Fund	Amount
				Markus Haapanen	Delirium as a risk factor for incident institutionalization	Institutional care for the elderly deteriorates quality of life, increases mortality, and raises costs. Delirium, a common, life-threatening, and preventable condition, is characterized by sudden disturbances in attention and cognition. Although delirium has recently been shown to be causally related to the onset of dementia, its significance for institutionalization is not well understood. This research project aims to investigate the role of aims to provide evidence supporting its significance as a factor leading to institutionalization. The anticipated results could help prevent or delay institutional care, reduce healthcare costs, and improve quality of life. Conducted under the supervision of a global leader in geriatric research, this study will broaden my researchscope, benefit my specialization in geriatrics, and aid my development as a leading expert in the field.delirium as a risk factor for institutionalization in both healthy and demented patients. The central hypothesis is that delirium alone predisposes individuals to institutional care, and its occurrence in dementia further strengthens this association. We will test this hypothesis using an Australian longitudinal population-baseddataset, encompassing over 12 million care episodes over 19 years. Since delirium is preventable, this study aims to provide evidence supporting its significance as a factor leading to institutionalization. The anticipated results could help prevent or delay institutional care, reduce healthcare costs, and improve quality of life. Conducted under the supervision of a global leader in geriatric research, this study will broaden my research scope, benefit my specialization in geriatrics, and aid my development as a leading expert in the field.		No specific grant area	50,000 €

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Young Investigators´ Grants

Hakemus VJ (lisätieto) - First name	Hakemus VJ (lisätieto) - Last name	Name	Title	Abstract of research proposal	Fund	Amount	Kokouskäsittely - Päätös
Bassel	Alsaed	Alsaed Bassel	Targeting primary immunotherapy resistance in non-small cell lung caner patients carrying EGFR mutation	Immunotherapies have been revolutionizing cancer care and promising in some lung cancer patients, but not all patients respond to these novel treatments. In this study, we use patient-derived material, such as tumor resections and matching blood samples to tackle an important clinical question: “Why are lung cancer patients with EGFR alterations not responsive to immunotherapy?”. Here, and by utilizing single-cell sequencing and CRISPR screening we aim to discover a list of potential genes that contribute to the primary immunotherapy resistance in EGFR mutated non-small cell lung cancers (NSCLC). The results of this study might lead to the discovery of novel treatments or combinations of immunotherapy drugs that would benefit NSCLC patients carrying EGFR mutations. Furthermore, there is a lack of predictive biomarkers for immunotherapy. Hence, clinicians are hesitant to prescribe the new and expensive immune-oncology (IO) drugs. There is also a lack of pre-clinical platforms that could predict which patient would benefit from the current immunotherapies. Current drug testing models such as humanized mice lack high reproducibility and are expensive, non-personalized 2D cell lines lack three-dimensionality and 3D organoids miss the immune context. Therefore, one aim of this study is to develop a patient-derived immuno-oncology microfluidic platform with a novel set-up to screen for immunotherapy and combination therapy responses in lung cancer patients.	Cancer and Cell Based Cancer Research	4,000 €	+
Anna	Äyräväinen	Äyräväinen Anna	Myomectomies: Tumor Characteristics and Clinical Implications	The thesis project aims at widening our understanding of the molecular and clinical factors underlying uterine leiomyomas in women of fertile age. We have already shown that the distribution of the three established driver alterations is comparable in young (median age 34 years) and middle-aged women. As a novel finding, we have shown that MED12 mutations and biallelic FH inactivation occur also in a subset of adenomyomas. Our results on the study of molecular and clinical risk factors for reinterventions confirm the earlier findings that leiomyoma related reinterventions after myomectomy are common (20% of women in our study underwent a reintervention). The number of leiomyomas removed at the index operation was a risk factor for reintervention. Age at index operation and postoperative parity decreased the risk. We identified a clonal relationship between the index and recurrent leiomyomas in 3/33 patients (9%). Our results also highlight the significancy of germ line FH mutations (i.e. HLRCC syndrome) as a risk factor for repeated leiomyoma operations. Finally, we show that quality of life improves after both laparoscopic and abdominal myomectomy. Although MED12 mutations in leiomyomas are related to multiple number of tumors, they do not associate with the surgical approach of myomectomy. Further, quality of life of myomectomy patients was comparable irrespective of the MED12 mutation status in the removed leiomyomas.	No specific grant area	4,000 €	+
Sarianna	Barron-Linnankoski	Barron-Linnankoski Sarianna	Kognitiivis-behavioraalinen ryhmäinterventio neuro/psykiatrisesti oireilevien lasten hoidossa	Lasten psykiatrinen oireilu on kasvussa mutta mielenterveyspalveluista on maailmanlaajuinen pula. Tässä tutkimuksessa tarkastellaan, miten psykiatrisesti monioireiset lapset hyötyvät kognitiivis-behavioraalisesta (CBT) ryhmäinterventiosta. Tutkimme intervention vaikutuksia lasten käytös- ja uniongelmiin, elämänlaatuun ja stressioireisiin. Lisäksi tutkimme lasten elämänlaadun ja vanhempien hyvinvoinnin välisiä yhteyksiä sekä hiuskortisolin käyttöä käytös- ja uniongelmien biomarkkerina. Tutkimukseen osallistui 109 psykiatrisesti monioireista 6-12-vuotiasta lasta. Yli 70 prosentilla lapsista oli useampi kuin yksi psykiatrinen diagnoosi. Lapset osallistuivat 12 kerran CBT-ryhmäinterventioon osana erikoissairaanhoidon lastenpsykiatrista hoitoa. Tutkimus toteutettiin kyselylomakkeilla, jotka lapset, vanhemmat ja opettajat täyttivät 4 eri ajankohtana. Lapsilta otettiin myös hiusnäytteet kortisolitasojen seuraamiseksi. Tulokset osoittivat, että lasten käytösoireet vähenivät ja itsetunto parani tilastollisesti merkitsevästi ryhmäintervention myötä välittömästi ja pitkällä aikavälillä. Lasten kaverisuhteet olivat keskeisiä sekä lasten että heidän vanhempiensa hyvinvoinnin kannalta. Hiuskortisolin ei havaittu olevan yhteydessä käytös- tai uniongelmiin, eikä se näyttänyt liittyvän käytösoireiden vähenemiseen CBT-hoidon myötä. Tulosten pohjalta voidaan kehittää lastenpsykiatrisia hoitokäytäntöjä, ja niillä on merkitystä yhteiskunnallisesti kustannustehokkuuden ja työvoimapulan kannalta.	No specific grant area	6,000 €	+
Saru	Basnet	Basnet Saru	Revolutionizing cancer treatment by uniting oncolytic adenoviruses with T cell engagers to prevent T cell exhaustion in ovarian ascites samples	Genetically modified oncolytic adenoviruses infect and selectively kill cancer cells while leaving healthy cells unharmed. They specifically target cancer cells, replicating within them and causing their destruction. When used as a monotherapy, oncolytic virotherapy holds some limitations, such as limited tumor penetration, limited systemic distribution, clearance by the immune system, etcetera. One effective way to gain robust therapeutic effects from the oncolytic virus is to combine it with several other immunotherapies, such as bispecific T cell engagers (BsTe). BsTe are special fusion proteins designed to recruit the body's immune system, specifically T cells, to attack cancer cells. BsTe binds to T cells and cancer cells and bring them in a close proximity and destroy the cancer cells. Combining oncolytic adenovirus with BsTe could result in significantly better tumor killing and improved targeted attack. The combination therapy will harnesses the power of both viruses and the immune system to target and destroy cancer cells more effectively. This project has characterized the novel oncolytic adenovirus (Ad5/3-E2F-d24-aMUC1aCD3-IL2) in vitro, ex vivo and in vivo using human patient derived ovarian cancer samples. We have effectively assessed the functionality of this novel virus by assessing its replication, cytotoxicity, T cell activation and cytokine secretion profiles using and gain insights into its potential therapeutic applications in clinical settings.	Cancer and Cell Based Cancer Research	4,000 €	+
Cinzia	Bessone	Bessone Cinzia	Analysis of Prox1 transcription factor in intestinal differentiation and maintenance of the tumor stem cell pool	Colorectal cancer (CRC) is one of the most common cancers in the Western world. A crucial initiating step in the development of most CRCs is a mutation in the adenomatous polyposis coli (APC) gene, which leads to the formation of benign adenomas via the Wnt/beta-catenin signaling pathway. This pathway is activated in approximately 90% of CRC cases. The prospero homeobox 1 (PROX1) transcription factor is a specific target of the abnormally activated Wnt downstream pathway in the intestinal epithelium. Our lab has previously shown that PROX1 regulates the proliferation and tumor-initiating properties of cells expressing the intestinal stem cell (ISC) marker leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). Since tumor stem cells have been considered essential for tumor development, metastasis, and treatment resistance, I aim to define the function of Prox1 in such cells. Our results so far show that Prox1 is a crucial tumor stem cell marker that identifies radioresistant clonogenic cells that repopulate the tumor after radiation in intestinal tumors of ApcMin/+ mouse model. Moreover, our results show that many of the DNA damage repair (DDR) transcripts are expressed more robustly in Prox1+ tumor cells. Considering that many studies are now focused on defining the mechanisms by which Prox1 drives CRC, I aim to analyze the effect of Prox1 deletion in Lgr5+ tumor stem cells. My results may provide new druggable targets to eradicate CRC stem cells.	Cancer and Cell Based Cancer Research	4,000 €	+
Rim	Bouslama	Bouslama Rim	NOVEL MECHANISTIC INSIGHTS INTO DIABETIC KIDNEY DISEASE: THE ROLE OF ADAPTOR PROTEIN PACSIN2	The number of people with diabetes quadrupled in the world since 1980. One third of individuals with diabetes develop its kidney complication. In 2019, diabetes and diabetic kidney disease (DKD) caused an estimated 2 million deaths. Yet, the mechanisms leading to DKD are not well understood. Our previous studies have shown that protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2) increases with DKD and regulates key cell functions in the kidneys. However, it remained unclear whether the role of PACSIN2 in DKD was protective or harmful. To answer this query, we generated mice genetically modified to lack PACSIN2. We hypothesized that the absence of PACSIN2 leads to kidney damage and predisposes to DKD due to a flawed inflammatory response. The study described in this application aims to understand the function of PACSIN2 in the kidneys of both healthy and diabetic mice, and characterize the involvement of PACSIN2 in the kidney’s inflammatory response, using PACSIN2-deficient mice. Our investigations of PACSIN2 provide a novel contributor to kidney health and inflammation in diabetes. These findings offer a better understanding of the complex machinery behind DKD, which will ultimately help improve the available diagnostic means and lead to new treatments.	Urological research	4,000 €	+
Luz Eneida	Cabrera Lara	Cabrera Lara Luz Eneida	Innate immune responses in viral infections: Exploring the roles of neutrophils and monocytes in vascular permeability	Zoonotic diseases significantly threaten human health. This research focuses on innate immune responses to viral infections, particularly involving neutrophils and monocytes. These myeloid cells play crucial roles in pathogen clearance and vascular interactions, which can influence disease outcomes by disrupting vascular permeability and leading to severe complications. Using COVID-19 and orthohantavirus-caused diseases as models, we employed in vitro studies, flow cytometry, and clinical correlations to examine these processes. We identified a significant increase in low-density granulocytes (LDGs) in COVID-19 patients, linked to emergency myelopoiesis and immunosuppressive capacities. In acute Puumala orthohantavirus (PUUV) infection, LDGs were associated with thrombocytopenia but lacked immunosuppressive ability. We also described neutrophil inflammasome formation during COVID-19, mediated by type I interferons, highlighting a novel aspect of neutrophil function. Additionally, we found that increased heparanase (HPSE) levels in urine during PUUV infection correlated with disease severity, suggesting a mechanism for endothelial glycocalyx degradation and vascular permeability disruption. We further investigated monocyte involvement in glycocalyx breakdown during PUUV infection. This research enhances our understanding of host immune responses to viruses, focusing on the roles of neutrophils, monocytes, and the endothelial glycocalyx in viral pathogenesis.	No specific grant area	4,000 €	+
Yingjia	Chen	Chen Yingjia	Prediction of selective and synergistic drug combinations in relapsed AML using single-cell transcriptomics	In this study, we will develop a precision medicine pipeline that makes use of ex vivo drug sensitivity profiles and single-cell RNA sequencing (scRNA-seq) data from longitudinal patient samples, at various disease stages, to effectively identify drug combinations for relapsed patients. Based on a cohort of 5 paired diagnosis-relapse acute myeloid leukemia (AML) patient samples, patient-specific machine learning (ML) models will be developed to identify drug combinations with maximal synergistic effects in relapsed samples, while showing minimal effects in diagnostic samples. We will further investigate subclonal heterogeneity through scRNA-seq profiles of primary cells from the AML patient cohort, and the differences between the diagnostic and relapsed stages in response to disease progression and treatment regimens. Additionally, the model predictions will identify patient-specific combinations with high synergy and potency in co-inhibiting AML cells in the relapsed stage, that show non-synergistic effects in the non-malignant cells. These predictions will be validated using flow cytometry-based cell population-level drug combination assays.	Cancer and Cell Based Cancer Research	4,000 €	+
James	Clubb	Clubb James	The critical role of antibody producing cells in regulating the anti-tumour response to oncolytic adenovirotherapy	Immunotherapies such as immune checkpoint inhibitors and oncolytic viruses (OVs) have made significant impact on clinical outcome for patients with solid tumours. Mechanistically OVs selectively replicate in cancer cells, causing cell lysis and can be engineered to express immunomodulatory transgenes to induce a local and systemic immune response against cancer cells. Efficacy of OVs is impaired by the immune response against virus, including complement and neutralizing antibodies (nAbs), which prevent virus infecting cells and expressing immunomodulatory transgenes. In contrast, antibody-producing cells, mainly plasma and B cells are emerging as critical mediators in orchestrating the response to immunotherapies in solid tumours. In this study, we develop animal models of head and neck cancer and pancreatic cancer, to characterize the intratumoral antibody response induced by an oncolytic adenovirus expressing IL2 and TNFa (TILT-123). We also characterize antibody-producing cells, and nAbs from ovarian cancer patients enrolled in a phase I clinical trial with TILT-123, to identify prognostic and predictive biomarkers of response and overall survival. Identification of biomarkers will improve patient stratification and better clinical outcomes for patients whilst also contributing to the development of novel OVs with more potent anti-tumour efficacy. The research project is progressing well with first two articles published, one in submission and one other ongoing.	Cancer and Cell Based Cancer Research	4,000 €	+
Jun	Dai	Dai Jun	Tracing back intrinsic chemo-resistance in HGSC organoids via ReSisTrace	High-grade serous carcinoma (HGSC), the deadliest ovarian cancer subtype, initially responds well to chemotherapy but eventually becomes resistant, leading to poor survival rates. Recent research highlights non-genetic heterogeneity as a key driver of treatment resistance in various cancers. Our group and others have identified pre-existing cellular states, such as the stress-associated state, linked to drug resistance. To address this, we've developed ReSisTrace, a lineage-tracing method that predicts resistance-prone states using shared transcriptomic features among sister cells. Initially applied to cancer cell line, it identified vulnerable patient groups and novel neo-adjuvant therapies. Now, we're extending our work to HGSC organoids and aiming to uncover intrinsic carboplatin-resistant states and pre-sensitize cells before carboplatin treatment. From my preliminary results, we observed that the organoid sample represented original clinical patient sample well. Second, stress-associated transcription factors (JUNB, FOS) were enriched in the carboplatin pre-resistant organoid population, and JUNB or FOSB upregulated Kuramochi cell line is more resistant to carboplatin. Furthermore, the pre-resistant signature identified by ReSisTrace is associated with poor patient survival in ovarian cancer TCGA cohort. Interestingly, we found that pevonedistat down-regulates stress-associated genes (JUNB, JUND, FOS, FOSB) in Kuramochi cell line and sensitizes organoids to carboplatin.	Cancer and Cell Based Cancer Research	6,000 €	+
Sofie	Ekroos	Ekroos Sofie	The role of hormonal contraception in prevention of anemia in premenopausal women	Blood donation has been decreasing year-by-year, culminating in an acute shortage of blood during the SARS-CoV-2 pandemic. Despite blood donor selection processes to ensure donor safety, donors are at risk of developing iron deficiency anemia (IDA). Despite young women being at high risk for developing IDA, they are proportionally overrepresented among blood donors. My PhD project aims to identify menstruation-related factors that can be used in donation interval prediction for this vulnerable population, which would allow donors with greater capacity to donate more frequently and extend donation intervals for donors needing more time to recover. In my previous study (DOI 10.1111/AOGS.14890; in press, accepted to Acta Obstetricia et Gynecologica Scandinavica 27.5.2024), we identified hormonal contraceptives as the most influential protective factor of donor iron stores. For the third project as part of my PhD, I aim to quantify the effect of hormonal contraception use on anemia in the Finnish normal population. The work will be an extension of FinOCC, a large register-based study of hormonal contraceptive use in Finland (described elsewhere by Toffol et al., 2020).	No specific grant area	4,000 €	+
Marja	Hakkarainen	Hakkarainen Marja	Hematopoietic stem cell transplantation for ERCC6L2 disease	ERCC6L2 disease results from biallelic germline mutations in the ERCC6L2 gene. In the early stages, affected individuals are susceptible to bone marrow failure (BMF). As the disease progresses, high-risk TP53-mutated hematological malignancies (HM) with erythroid predominance develop. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure for ERCC6L2 patients. We previously discovered that timing of HSCT is critical; patients transplanted in early stages perform better than those with HM. However, ERCC6L2's role in DNA repair raises concerns about treatment-related toxicities (TRT) and mortality, common in DNA repair defects. Earlier studies also link ERCC6L2 defects to radiosensitivity and immunoglobulin abnormalities. Thus, exploring factors impacting HSCT is crucial, especially given the poor prognosis for ERCC6L2 patients with HM. In this global multicenter study, we aim to optimize the path of HSCT for ERCC6L2 patients by a comprehensive investigation of the detailed characteristics of HSCT, TRT, and outcomes of this patient group. We present extensive detailed data for 35-40 ERCC6L2 patients. Our preliminary results support better prognosis if HSCT is performed before disease progression to HM. Additionally, ERCC6L2 patients exhibit a higher risk of endothelial damage than other patients. Individual assessment of HSCT timing is essential, and this study will aid in managing and following up this challenging patient population.	Cancer and Cell Based Cancer Research	6,000 €	+
Sandra	Harjuhaahto	Harjuhaahto Sandra	Unraveling the disease mechanisms of spinal muscular atrophy Jokela type using multiple new disease models	Spinal muscular atrophy Jokela type (SMAJ) is a late-onset motor neuron disease in which the neurons of the spinal cord degenerate. It is caused by dominant founder variant p.G66V in coiled-coil helix coiled-coil helix 10 gene (CHCHD10) and belongs to the Finnish Disease Heritage. SMAJ has a remarkably high carrier frequency for a dominant disease mutation in Finland. The disease causes significant disability but does not typically shorten lifespan. Currently, there is no cure for SMAJ. CHCHD10 is a mitochondrial intermembrane space protein of unknown exact function. It has been linked to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD) and mitochondrial myopathy. The pathogenic mechanisms in CHCHD10-related disorders as well as the normal function of CHCHD10 protein in mitochondria are incompletely understood. The aim of my research is to understand the pathophysiology of SMAJ using a combination of in vitro and in vivo models. I have studied patient serum samples and skin fibroblasts, as well as motor neurons differentiated from patient-specific and genome-edited induced pluripotent stem cells (iPSC), and a novel knock-in mouse model. My findings suggest that SMAJ dysregulates energy metabolism, leading to altered energy buffering by creatine metabolism. We propose that changes in creatine metabolism are caused by mitochondrial dysfunction. These findings offer potential avenues for treatment trials.	Neurological and Cerebrovascular Disorder	6,000 €	+
Aino	Heikkinen	Heikkinen Aino	Enhancing mitochondrial biogenesis to slow biological aging in human skeletal muscle	Aging is accompinied by a decline in mitochondrial metabolism, impairing cellular function and contributing to loss in muscle function. Vitamin B3 derivatives, such as nicotinamide riboside (NR), enhance mitochondrial biogenesis by increasing NAD levels. Previous research demonstrated NR’s role in boosting mitochondrial biogenesis in human muscle tissue. However, its potential to reduce biological aging and combat age-related muscle loss remains unclear. This research hypothesises that enhancing mitochondrial biogenesis with NR will reduce biological aging, measured using epigenetic clocks, in human myotubes. We will quantify and compare mitochondrial DNA quantity and biological age, estimated using epigenetic clocks, between NR-treated and control human skeletal muscle cells. We explore, in a fully controlled setting, NR’s capability to slow biological aging by enhancing mitochondrial biogenesis. This research will contribute to a deeper understanding of the interaction between mitochondria and biological aging in muscle, which could provide a basis for potential therapeutic strategies to prevent age-related loss in muscle function in the future.	No specific grant area	4,000 €	+
Sami	Jalil	Jalil Sami	Advancing Genetic Therapies: Developing Precision CRISPR Editing for Finnish Founder Pathogenic Variants	Over the last decade, tens of clinical trials have leveraged the gene-editing power of the CRISPR system to improve the lives of patients with sickle cell disease, junctional epidermolysis bullosa, Duchenne muscular dystrophy, and many others. However, considerable work remains to address the estimated 10,000 monogenic diseases. In this project, we have designed different CRISPR methods for correcting monogenic diseases in vitro, with a special emphasis on Finnish founder mutations. We developed an in vitro model to study the metabolic disease Argininosuccinate Lyse Deficiency (ASLD) by differentiating patient-derived hiPSC into hepatocytes and studying their metabolomic profile. Then, we optimised a lipid nanoparticle-delivered base editing method, which efficiently corrected the ASLD variant and restored the levels of the hallmark metabolites related to the disease. We have published our findings and made our tools available to the scientific community through international non-profit repositories. For the final phase of our project, we will further optimise the lipid nanoparticle delivery system to correct the ASLD variant in a mouse model that we have developed carrying the Finnish founder pathogenic variant. Following the gene correction, we expect to observe a restoration of the metabolomic profile in the plasma, a reduction in the ammonia levels and a mitigation of the neurodegeneration observed in the patients and the ASLD mice.	No specific grant area	4,000 €	+
Ilja	Kalashnikov	Kalashnikov Ilja	In-depth epidemiological, molecular, and genetic characterization of nodular lymphocyte-predominant Hodgkin´s lymphoma and T-cell/histiocyte rich large B-cell lymphoma	Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy with few malignant cells in a diverse tumor microenvironment (TME). The TME's histological composition significantly influences outcomes; nodular B-cell rich TME is linked to an indolent disease, while T-cell infiltration or diffuse growth may resemble and transform into aggressive T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). The molecular features distinguishing NLPHL and THRLBCL remain unclear, and there are no established molecular prognostic biomarkers for identifying high-risk patients or those at risk of transformation. Moreover, due to its low incidence, population-based data on NLPHL's epidemiology and transformation are limited. The aims of this PhD thesis is 3-fold: 1. To enhance NLPHL and THRLBCL surveillance in Finland, we will conduct a nationwide assessment of cases diagnosed between 1995 and 2018, focusing on incidence, transformation rates, survival, causes of death, and temporal trends. 2. To identify potential targets for novel diagnostic and therapeutic strategies in NLPHL and THRLBCL patients by characterizing driver mutations and transcriptomic features using advanced whole transcriptome and exome sequencing technologies. 3. To identify potential prognostic biomarkers in NLPHL and THRLBCL patients by performing a detailed spatial characterization of the TME using cyclic immunofluorescence imaging (CyCIF).	Cancer and Cell Based Cancer Research	4,000 €	+
Sara	Khamaiseh	Khamaiseh Sara	Molecular Characterization of Uterine Leiomyomas and Leiomyosarcomas Through Omics Analyses	Uterine leiomyomas, also known as fibroids, are common benign tumors that can significantly impact women's quality of life. Severe symptomatic leiomyomas are primarily treated by surgery. A subset of leiomyomas resembles their malignant counterpart, uterine leiomyosarcomas, which are rare aggressive cancers. Preoperative diagnosis is difficult as symptoms between these benign and malignant tumors highly overlap. This PhD thesis aims to systematically characterize both leiomyomas and leiomyosarcomas to identify the molecular defects driving their tumorigenesis. We utilize our unique sample collection of unique leiomyomas with various histopathologies and abnormal growth patterns, along with leiomyosarcomas. Methods include various omics analyses and bioinformatics tools. Early detection of tumors with malignant potential can even prevent cancer. Thesis includes four subprojects: 1) We have shown that 3 ́RNA sequencing accurately classifies paraffin embedded leiomyomas (published), 2) We provided molecular evidence for lung metastasis and malignant transformation of a uterine leiomyoma (published), 3) we reveal the molecular and clinical risk factors for recurrent leiomyomas after myomectomy (manuscript is under review in AJOG), and 4) We found distinct dysregulation of the retinoblastoma pathway in leiomyosarcomas compared to leiomyomas, including potential biomarkers to distinguish benign from malignant tumors (analysis is ongoing).	No specific grant area	6,000 €	+
Anne	Koivuholma	Koivuholma Anne	Pään ja kaulan kolmiulotteinen mallintaminen - kuvantaminen, leikkauspreparaatti ja histopatologia	Suusyöpätapauksia todetaan Suomessa noin 400 vuodessa, kielisyöpä on suuontelon syövistä yleisin. Tutkimusaineistomme on rajattu käsittämään juuri kielisyöpiä. Vaikka tutkimus tehdään Helsingin yliopistossa, sen tulokset koskettavat jokaista kielisyöpäpotilasta maassamme. Tutkimuksen tavoitteena on tuottaa menetelmä, jolla voidaan luoda kolmiulotteinen malli kielikasvaimen histologisista näytteistä sekä kasvaimen magneettikuvantamislöydöksistä ja jota voidaan käyttää avuksi kliinisessä työssä. Toisena päätavoitteena on liittää histologisista näytteistä muodostettu 3D malli potilaasta otettuihin magneettikuviin. Tutkimuskokonaisuus koostuu neljästä osatyöstä: I. Osatyön tavoitteena on kehittää menetelmä, jossa leikkausresekaattia kuvataan makroskooppisesti ilman histologiaa 3D:nä. II. Osatyön tavoitteena on tuottaa 3D malli histologisista näytteistä resekaatin sisällä. III. Osatyön tavoitteena on luoda kuvafuusio yhdistämällä magneettikuvista luotu kolmiulotteinen malli ja histologisista leikkeistä luotu malli sekä verrata todellista histologisesti todettua kasvainta magneettikuvauksessa nähtyihin muutoksiin. IV. Osatyön tavoitteena on luoda 3D mallit sekä histopatologiasta että magneettikuvista 9 eri kasvaimesta ja arvioida menetelmän virhelähteitä sekä kudoskäsittelyn vaikutuksia mittoihin.	No specific grant area	4,000 €	+
Kristiina	Kumar	Kumar Kristiina	Modeling disorders of hypothalamic-pituitary-gonadal axis	The onset of puberty is a complex process governed by hypothalamic-pituitary-gonadal (HPG) -axis. The activation of the HPG-axis is regulated by multiple internal and external cues like nutritional and social status of the individual. Pulsatile release of gonadotropin releasing hormone (GnRH) by hypothalamic GnRH neurons stimulates pituitary gonadotropes to release Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). These activate the production of gonadal steroids that regulate the maturation of secondary sex characteristics. During embryonic development GnRH neurons are first observed near the developing olfactory epithelium. They then migrate to the hypothalamus along the olfactory-derived axons and terminal nerve. Defects in the development or migration of GnRH neurons or pituitary can lead to congenital hypogonadotropic hypogonadism (CHH) characterized by absent or delayed puberty with low levels of LH, FSH and sex steroids. When CHH is associated with defected olfaction, it is called Kallmann Syndrome (KS). At least 60 genes are now implicated in CHH and KS, but still majority of the patients remain without genetic diagnosis of their condition. In my dissertation, I have developed tools for studying the function of human GnRH-neurons and modelled novel variants underlying CHH and KS in relevant in vitro cellular models. I am here applying funding for the completion of the Summarizing report of my dissertation.	No specific grant area	4,000 €	+
Atte	Lahtinen	Lahtinen Atte	Germline variants in severe hematological diseases and their effect on hematopoietic stem cell transplantation outcomes and comorbidities	Hematopoieettinen kantasolusiirto on ainoa parantava hoitovaihtoehto pahanlaatuisia verisairauksissa. Hoitojen kehityksestä huolimatta niiden vaikutusta ei voida rajoittaa verisoluihin ja ne vaikuttavat myös muihin kudoksiin. Hoitojen sivuvaikutukset vaikuttavat potilaan ennusteeseen ja huonontavat elämänlaatua. Perinnöllisten tekijöiden on tunnistettu lisäävän riskiä haittavaikutuksille, mutta näiden merkitys on suurelta osin vielä tuntematon. Tunnistamalla näitä ennen hoitoa voimme parantaa kalliiden ja kuormittavien hoitojen tuloksia yksilöllistämällä hoitoa ja seurantaa hoitojen jälkeen. Tutkimuksessa hyödynnetään eksomisekvensointidataa, jota analysoidaan yhdessä potilaista kerättyjen kliinisten tietojen kanssa. Aineisto koostuu n. 1000 potilaasta, jolla on todettu verisairaus, ja näistä on kuhunkin osatyöhön valittu soveltuvat. Ensimmäisessä (akuutti lymfaattinen leukemia -potilaat) ja toisessa (kantasolusiirtopotilaat) tutkittiin hematologisia sairauksia sekä muita syöpäsairauksia aiheuttavien varianttien esiintymistä potilailla. Näiden tulokset on julkaistu v. 2022. Kolmannessa osatyössä tutkitaan näiden ituratavarianttien vaikutusta kantasolusiirron lopputulokseen. Neljännessä osatyössä tutkitaan kantasolusiirtopotilaiden siittiöiden tuotantoa tavoitteena turvata lisääntymiskyky kuormittavien hoitojen jälkeen. Potilaiden sukusolunäytteiden tiedot yhdistetään muihin tietoihin ja analysoidaan ituratavarianttien, sairauden ja annettujen hoitojen vaikutusta näihin.	Cancer and Cell Based Cancer Research	4,000 €	+
Jaakko	Leskelä	Leskelä Jaakko	Oral Health in Cryptogenic Ischemic Stroke	Stroke is a life-threatening state, where circulation in a part of the brain is compromised. Periodontitis is an inflammatory disease initiated by microbial dysbiosis. The association between periodontitis and stroke is well known, but the underlying mechanisms remain unclear - although inflammatory processes may be one conjunctive. The high proportion of cryptogenic (unknown etiologies) cases among the younger population is likely to reflect uncharacterized risk factors, of which some might be related to oral health. The study SECRETO-ORAL is a substudy of SECRETO, an international prospective multicenter case-control study of young adults (age 18-49) presenting with an imaging-positive first-ever acute IS of unexplained etiology i.e., cryptogenic ischemic stroke (CIS). The oral status was examined, and serum, saliva, and subgingival samples were collected and a panoramic tomograph was taken from all participants. First results showed that periodontitis and recent dental procedures are associated with CIS independently from common confounders. The grant applicant has been involved in this project since 2014, including sample collection, data analysis, organizing of the data and samples, contacting the study participants, digitalization of the study data, and analysis of the panoramic tomographs. All statistical analysis has been done by the grant applicant. The study is part of the PhD thesis which is planned to be ready for examination at the beginning of 2025.	No specific grant area	4,000 €	+
Jing	Liang	Liang Jing	Transcription stress-induced remodeling of RNA polymerase II-complex affects chromatin-accessibility	Transcriptional cyclin-dependent kinases (CDK) phosphorylate RNA polymerase II (RNA Pol II) to regulate transcription initiation (CDK7), to release the polymerase (CDK9) and to sustain elongation on the long genes (CDK12). Inactivation of CDK12 is associated with aggressive disease characteristics in prostate cancer (PC). CDK12 promotes transcription elongation, and cancer cells in general have high levels of transcription. It is therefore unexpected that the loss of CDK12 activity would confer a proliferative advantage to cancer cells. In my PhD Tenure (start Sep 2022), I will explain why PC cells become more aggressive when they lose CDK12 using three approaches: 1. Transcriptional / splicing effects (published in 2024). 2. Epigenetic-remodeling due to loss of CDK12 (in submission). 3. Remodeling of RNA Pol II interactome and chromatin-accessibility. I hypothesize that the decrease in the activity of transcriptional kinases remodels RNA Pol II interactome to open chromatin and thereby allow transcription factor binding to compensate for the decrease in kinase activity. Indeed, my ATAC-seq data revealed that depleting the activities of any of the major transcriptional kinases leads to chromatin-relaxation. Having confirmed my hypothesis on chromatin-accessibility, I will use the Biomedicum-grant to establish if this relaxation is due to remodeling of the RNA Pol II complex itself and present my findings in the EACR-2025 meeting.	Urological research	4,000 €	+
Riikka	Mustonen	Mustonen Riikka	The impact of screen time and parental linguistic support on the language development of children aged 2.5 to 4.2 years	There is variability in language skills among typically developing children. Besides genetics, environmental factors may have a role in explaining individual differences. We aim to study whether children’s and parent’s screen time and parental reading/singing/storytelling in a home environment are associated with the language development of preschool-aged children, and if an association is found, to which language domain (lexicon, grammar, general language ability) particularly. This doctoral study also includes an international comparison study on screen time, parental attitudes towards it, and whether they are associated with children’s language development in Finland, Norway, Estonia, Croatia, and Poland. The Finnish participants are 164 preschool-aged (2;6 – 4;1, year; month; 50 % boys) Finnish-speaking children and their parents. Parents report how much they and their children use screen time, and how much they support their children’s language development at home (book reading/storytelling/singing). Children’s language skills will be tested using the validated tests with the Finnish norming sample. Information on children’s screen time, parental attitudes towards screen time, and language skills will also be collected in four other countries (Estonia, Norway, Croatia, and Poland; 335 children aged 3 to 3,5 years; 50 % boys). Information derived from this research can be used by professionals (i.e., speech therapists, nurses, psychologists) in the clinical context.	No specific grant area	4,000 €	+
Kristen Michelle	Nader	Nader Kristen Michelle	A fast and automated identification of disease-specific malignant and healthy cells using single-cell transcriptomics	Tumor heterogeneity presents a significant therapeutic challenge. Heterogeneity arises from genetic, epigenetic, and environmental factors, often leading to more aggressive disease and reduced drug sensitivity. Effective therapy must target cancer subclones with distinct genotypes and phenotypes. However, identifying patient-specific treatments that selectively target these subclones is challenging, as the number of possible drug-dose combinations far exceeds what can be tested with limited patient cells. To address this, we developed scTherapy (doi: 10.1101/2023.06.26.546571), a machine learning framework that leverages single-cell transcriptomic profiles to prioritize treatment options for individual patients with cancer. This method predicts specific drug-dose combinations for each subclone, guiding in vitro testing and maximizing the use of scarce patient samples. Currently available tools cannot sufficiently distinguish malignant from healthy clusters in single-cell transcriptomics data. To overcome this, we repurposed scType (doi: 10.1038/s41467-022-28803-w) with a custom marker dataset of malignant and healthy cell marker genes specific to the cancer in question. However, this process is time-consuming for users who need to find their own disease-specific marker genes for use with scType. Therefore, I aim to develop a novel computational method to accurately distinguish disease-specific malignant and healthy clusters in single cell transcriptomics data.	Cancer and Cell Based Cancer Research	4,000 €	+
Mai	Nguyen	Nguyen Mai	Novel integrative analysis of cell-free DNA based features and tissue omics for Monitoring Treatment Response and Tracking Cancer Evolution in High Grade Serous Ovarian Carcinoma	Circulating tumor DNA (ctDNA), comprising free DNA released into the bloodstream by cancer cells, presents a promising non-invasive biomarker for the early detection and monitoring of cancer. However, the clinical utility of ctDNA is currently limited by challenges such as low tumor fraction and interference from hematopoietic mutations. This research aims to overcome these obstacles and enhance the application of ctDNA in cancer treatment through a comprehensive study with two primary objectives: - Prognostic Value of ctDNA: Investigate the tumor-related factors influencing ctDNA release by integrating matched DNA and RNA data at diagnosis. Understanding these factors will elucidate the mechanisms behind ctDNA release and its prognostic significance. - Epigenetic Features During Treatment: Analyze changes in nucleosome features extracted from ctDNA during treatment with carboplatin, paclitaxel, and bevacizumab. This analysis will provide insights into the effects of these drugs through longitudinal sampling. By understanding the biological characteristics of ctDNA release, particularly in patients with very low ctDNA fractions, this study will offer robust references for unmet clinical criteria. Longitudinal tracking of ctDNA fragment profiles will complement genomic changes, aiding in treatment monitoring and understanding cancer evolution. Ultimately, this research aims to pave the way for more precise and personalized treatment strategies.	Cancer and Cell Based Cancer Research	6,000 €	+
Petra	Nygren	Nygren Petra	High-throughput drug screening to identify enhancers of NK cell immunotherapy in advanced phase chronic myeloid leukemia	Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified SMAC mimetics as potent enhancers of NK cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. We were able to validate our results in primary CML patient samples, indicating that SMAC mimetics could have potential in the combination treatment of blast-phase CML with NK cell based immunotherapies. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML. Further investigations are planned and ongoing.	No specific grant area	6,000 €	+
Linda	Ottensmann	Ottensmann Linda	Lipidomics and its link to genetics, cardio-metabolic disease risk, and lifestyle factors	Cardiovascular diseases (CVD) lead to 31% of global deaths. Known risk factors include lifestyle factors and plasma lipids. Plasma lipids such as LDL-Cholesterol are routinely measured to assess CVD risk. Recent technological advances in lipidomics allow measuring plasma lipid species, improving CVD risk assessment. However, the impact of genetics and lifestyle factors on lipid species remains poorly understood. We characterize the genetic architecture of the human plasma lipidome and inspect its link to disease risk and lifestyle by analyzing lipidomics data from the GeneRISK cohort. The cohort consists of 7302 Finnish individuals for which 179 plasma lipid species were measured by mass spectrometry. These data combined with genotype data, blood lipids, physical examination data, and information about health status and lifestyle provide a unique opportunity to assess the impact of genetics and lifestyle on lipidome profiles. Objective 1: To characterize the genetic architecture of the human plasma lipidome we performed genome-wide association studies of 179 lipid species measured in GeneRISK. We identified 56 genetic loci, including 8 novel loci. Objective 2: We are assessing whether lipid species have a causal effect on CVD and comorbidities by applying Mendelian Randomization analyses. Objective 3: We will calculate the effects of lifestyle on lipid species level and analyze whether genetic loci are associated with lipid species through interaction with lifestyle factors.	Cardiovascular	4,000 €	+
Aino	Peura	Peura Aino	Microenvironmental stiffness regulates luminal breast cancer cell immunity and resistance	Luminal breast cancer, the most common subtype worldwide, exhibits favorable 5- and 10-year survival rates. However, 40-50% of these cancers eventually metastasize decades after diagnosis. Recent research highlights epigenetic regulation as the driving force behind late-breaking metastasis. Yet, preventing or targeting these dormant cancer cells remains a challenge. Our previous research, alongside other studies, reveals that breast tumor microenvironment stiffness significantly influences cancer cell identity. Traditionally, the stiffness of the tumor microenvironment has been linked to the progression of numerous cancer types. However, during tumorigenesis, tumor cells will encounter a more soft microenvironment, for instance during metastasis or as a result of intratumoral necrosis. Luminal breast cancer cells embedded in the soft microenvironment have been shown to dedifferentiate into an undifferentiated phenotype, while upregulating pathways associated to treatment resistance. Moreover, the softness of the microenvironment activates similar cellular identity epigenetic pathways as identified in the dormant cancer cells. Our project aims to uncover how these softness-induced dormant cells suppress antitumor immunity and develop resistance to breast cancer adjuvant therapies. By doing so, we contribute valuable insights into breast cancer cell dormancy and explore potential therapeutic approaches for patients	Cancer and Cell Based Cancer Research	6,000 €	+
Negar	Pourjamal	Pourjamal Negar	Antibody-drug conjugates in experimental models of HER2-positive gastric cancer and breast cancer with special reference to drug resistance	Most HER2-positive gastric and breast cancers develop resistance to the anti-HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Moreover, certain tumor cells, known as giant multinucleated drug-tolerant persister cancer cells (GM-DTPCs) survive treatments and cause tumor recurrence, yet their role in HER2-positive cancers remains unexplored. We compared the efficacy of T-DM1, T-DXd, and novel disitamab vedotin (DV) on cell survival in HER2-positive gastric or breast cancer cell lines and in xenograft/metastases models. Additionally, we investigated underlying resistance mechanisms. DV was highly effective in vitro and in vivo, even in cell lines and xenografts resistant to T-DM1 and T-DXd. Combinations of DV with T-DM1 or T-DXd showed greater efficacy than single agents. Moreover, we noted chromothripsis, resulting in HER2-containing extrachromosomal circular DNA, which was lost during GM-DTPC cycles, causing drug resistance. We impeded tumor regrowth by targeting Nectin-4, which was overexpressed in GM-DTPC cells, using enfortumab vedotin. Our findings support assessing DV alone or in combination with T-DM1 or T-DXd in trials for HER2-positive cancer patients who have progressed on T-DM1 or T-DXd. Our results also suggest that the study of GM-DTPC cells is a promising approach to overcoming tumor regrowth. In this phase of my PhD study, I kindly ask your support to complete my thesis, as my salaried position has ended.	Cancer and Cell Based Cancer Research	6,000 €	+
Siiri	Reinikka	Reinikka Siiri	Molecular landscape of endometrial tumors	Endometrial polyps are common tumor-like lesions affecting 10% of women. Polyps can cause pain and abnormal uterine bleeding, reduce fertility, and even undergo malignant transformation to endometrial cancer. Despite a high prevalence, very little research has been directed towards understanding the molecular mechanisms resulting in endometrial polyp development. Ergo, we conducted a comprehensive genomic profiling of endometrial polyps. We identified genomic alterations in HMGA1 and HMGA2 in 74% of the polyps (Reinikka, S., et al. in revision). The second study stems directly from our finding of frequent HMGA1 and HMGA2 alterations in polyps. Similar rearrangements have been reported also in uterine leiomyomas, another common gynecological tumor. Now, we analyze how similar HMGA1/2 alterations are within and between the tumor types. The aim is to evaluate whether these alterations could provide a novel treatment target for both tumor types. The third project focuses on endometrial cancer – the most common gynecological cancer in Europe. Endometrial cancers are highly versatile, and they can be divided into four molecular subgroups. One subgroup consists of tumors with no specific molecular profile (NSMP). In general, NSMP tumors have relatively good prognosis. However, some NSMP tumors are unexpectedly aggressive. We aim to identify the molecular factor(s) leading to aggressive behavior. Overall, our research aims to help a high number of women suffering from these tumors.	No specific grant area	6,000 €	+
Anna	Richardt	Richardt Anna	Ischemic Stroke during Pregnancy and Puerperium	Background: Ischemic strokes during pregnancy and puerperium are rare but potentially dangerous complications of pregnancy, that cause maternal mortality and significant morbidity for survivors. The incidence of ischemic strokes during pregnancy and childhood has been estimated to be 12.2/100,000 deliveries and it has been found to be rising. Objectives: The aim is to investigate the incidence, etiology, risk factors, treatment, prevention and risk of recurrence of ischemic strokes during pregnancy and puerperium, as well as the subsequent health status of patients in a national cohort covering 30 years. Materials and methods: We collected a retrospective national cohort of women who suffered ischemic stroke during pregnancy and puerperium in Finland from 1987–2016. The cases were identified from national registers, Medical Birth Register, Hospital Discharge Register and the Cause of Death register, using diagnosis or procedure codes referring to ischemic stroke. The research team obtained the medical records of the patients identified from the registers, verified the information about the diagnosis and its temporal connection to pregnancy, and collected data for the study. Significance: The aim of the dissertation is to produce information to support clinical decision-making, so that ischemic strokes during pregnancy and puerperium can be identified and treated better.	Neurological and Cerebrovascular Disorder	6,000 €	+
Rocio	Sartori Maldonado	Sartori Maldonado Rocio	A genetic engineering strategy to control cell proliferation for cell therapies.	Robust proliferation is a key feature of most cell lines used for scientific research. Induced pluripotent stem cells (iPSC) in particular, additionally hold a lot of promise for regenerative medicine and cell therapies, as they can differentiate into functional, potentially therapeutic tissues. However, cells that do not exit the cell cycle during the differentiation suppose a fundamental biological risk of unlimited or unwanted growth that hampers the use of these cells beyond the clinical trial stage. Here, we describe a metabolic safety system to prevent undesired proliferation. We genetically inactivated the enzyme in charge of the de novo thymidylate synthesis (TYMS) in iPSC, yielding cells that proliferate when supplemented with exogenous dTMP but fail to grow in its absence. As thymidine is needed for DNA, but not RNA synthesis, this approach targets only proliferative cells, without affecting postmitotic tissue. Thus, the method allows robust cell culture and manufacture while diminishing the risk of uncontrolled growth of transplanted cells. While supplemented, TYMS-/- iPSCs produce teratomas in vivo and differentiate normally into pancreatic beta cells. Implanting beta cell-progenitors leads to multiple cysts with the wildtype cells, while the TYMS-/- do not lose control of their proliferation. Implantation of terminal differentiated beta cells show they no longer require dTMP to remain functional, as seen by prolonged in vivo production of human insulin in mice.	No specific grant area	4,000 €	+
Mariel	Savelius	Savelius Mariel	Harnessing pro-apoptotic actions of metformin in novel combination therapeutic approaches for MYC-high breast cancer	Breast cancer (BC) continues to be the leading cause (15%) of cancer deaths among women. Among the most aggressive BC subtypes is triple-negative breast cancer (TNBC) that is lacking targetable receptors. There is an urgent unmet medical need to discover novel and safe treatment options for patients with advanced and/or difficult to treat BC. MYC-oncogene is overexpressed in half of the breast cancers. We have discovered a well tolerated drug combination therapy modality, which is based on synthetic lethal interaction with MYC. Our research suggests that metformin combined with BH3-mimetics induces immunogenic cell death in MYC-high cancer cells. Our combination had better efficacy in mice and was less toxic than chemotherapy that is currently offered for patients with metastatic TNBC. Therefore, targeting MYC-high tumors with synthetic lethal strategies may offer new efficient and safe treatment options for TNBC and new possibilities to use immunotherapies in the treatment of breast cancer. However, there are several open questions needed to be answered for optimal treatment. In my research, I will determine how metformin exerts its pro-apoptotic actions and identify the best MYC-syntehtic lethal BH3-mimetic combination treatment against MYC-high breast cancer. I will also determine the mechanism of action of this combination and what are the effects of the combination on immune cells – promoting or suppressing?	Cancer and Cell Based Cancer Research	4,000 €	+
Krista	Tuohinto	Tuohinto Krista	TARGETING SOX18 PIONEERING ACTIVITY IN ONCOGENIC HERPESVIRUS TUMORIGENESIS	Oncogenic Kaposi sarcoma (KS) herpesvirus (KSHV) infection leads to development of an endothelial tumors during periods of immune deficiencies. KS consist of spindle-shaped cells harboring viral DNA tethered to the host chromatin. Efficient viral DNA replication in host cells is crucial for the maintenance of infection, and for KS to develop. Chromatin modifications control the KSHV replication by providing access for the host replication machinery, recruited by a viral LANA protein, to the KSHV replication origin. KSHV reprograms lymphatic endothelial cell (LEC) identity to spindle cells with high amounts of viral DNA. We found that SOX18, a key developmental transcription factor of LEC, is widely co-expressed in KS tumors with LANA. SOX18 binds to the origins of KSHV replication, supporting viral DNA synthesis in LEC. Small molecule inhibitor of SOX18 dramatically decreased viral DNA and spindle cell phenotype in vivo, providing proof of SOX18 as a viable therapeutic target for KS. Ongoing research uncovers the mechanism how SOX18 supports the viral DNA genome replication. Our data suggests that KSHV hijacks SOX18 to promote chromatin accessibility to ensure efficient viral replication. This study shows interplay between LANA and host chromatin opening BAF complex recruited on viral DNA by SOX18, indicating novel function for SOX18 as pioneering factor. KSHV sensitizes host cells for SOX18 and BAF inhibition, revealing their potential as targets in virus-induced cancer.	Cancer and Cell Based Cancer Research	4,000 €	+
Essi	Viippola	Viippola Essi	Sex differences in the human plasma proteome	Genetic sex influences disease risk, with notable variation in clinical outcomes within each sex. While RNA sequencing studies have revealed extensive sex differences in gene expression (GEX), sex differences in protein expression (PEX) are less explored. We analyzed PEX in 2,919 proteins measured in plasma from 42,979 UK Biobank participants. We found that 69% of the proteins had sex-specific PEX. Genes with the most sex-biased GEX were also more likely to be sex-biased for PEX (r=0.55 for liver). In PEX, we found 187 protein pairs with large protein-protein correlation differences between sexes, with 75 % involving PAEP, FSHB, and RLN2 proteins, all expressed in female-specific tissues. Sex-specific correlations were more common in PEX than GEX. We developed a machine learning model to predict sex based on proteomic data and explore intra-sex variability. We identified 331 individuals showing PEX patterns resembling the opposite sex. Sex-proteome-atypical individuals were more likely to have sex aneuploidies, particularly XXY (p<1e-16), and PheWAS revealed associations with various diseases, such as chronic kidney disease. The proteomics-based sex predictor was replicated in Biobank Japan (AUC=0.995) and Japan COVID-19 Task Force (AUC=0.976) where we found that females with male-typical proteomic profiles were more likely to have severe COVID-19. These findings reveal complex patterns of sex-biased proteomic variability, providing insights into sex-specific health risks.	No specific grant area	4,000 €	+
Zhiyang	Wang	Wang Zhiyang	The relationship between the external and internal exposome linking to adolescent mental health	Adolescent mental health problems are a growing concern, with environmental factors playing a significant role in their etiology. The exposome framework encompasses the totality of the environment, providing a holistic perspective. The research will employ the internal exposome (multi-omics) to understand the biological pathways with causal potentials between the external exposome and adolescent mental health. The study includes participants from two cohorts: FinnTwin12 (Finland), and WALNUTs (Spain). A comprehensive external exposome is curated including greenery, social indicators, family relationships, and so on. The internal exposome consists of metabolomics and proteomics. There were 32 proteins, as strong biobanks of adolescent mental health from previous studies, composing the proteomics set in this study. An abundant and untargeted metabolite set is going to be generated. First, we will assess relationships between metabolites and proteins using repeated generalized linear regression. Second, we will explore how identified metabolites mediate or moderate the relationships between external exposures and proteins through a 4-way decomposition analysis. These exposure–protein relationships have proven links to adolescent mental health in previous analyses. This study will deliver evidence on the pathways from exposures, metabolites, proteins, and adolescent mental health with causal inference. We expected to provide implications in health policy and urban planning.	No specific grant area	4,000 €	+
Shivani	Yalala	Yalala Shivani	O-GlcNAcylation directly controls RNA polymerase II (RNA Pol II) activity	I started my PhD Tenure in University of Helsinki in December 2022, and my goal is to understand how transcriptional stress remodels prostate cancer (PC) cells and if this could be used as a basis for therapy. My Tenure is divided into three projects. My first project was published in April 2024 (Yalala & al., PMID: 38661032). In the second project, I have established the spatio-temporal remodeling of DNA replication program in response to CDK12 inactivation, which provides an explanation for the increased genomic instability and escape from the immune system for this sub-type of PC (manuscript in preparation). In the last project of my PhD Tenure, I will map how O-GlcNAcylation of any potential site of the RNA polymerase II (RNA Pol II) carboxy-terminal domain (CTD) affects its interactome and activity. I hypothesize that, similar to phosphorylation, O-GlcNAcylation patterns on the CTD regulate the polymerase's interactome and activity. Earlier, the lack of suitable reagents and sensitive assays to directly measure RNA Pol II-activity have prevented these experiments. By integrating my dual proteomics, ChIP-seq, and SLAM-seq data, I will establish the machinery, space and time, when the O-GlcNAcylation occurs with respect to proteome, gene body, and the nascent transcription. I apply for the Biomedicum Young Investigator’s grant to perform mass spectrometry-based characterization of the RNA Pol II interactome during hypo- and hyper-O-GlcNAcylation.	Urological research	4,000 €	+
Jie	Zhu	Zhu Jie	Optimizing Personalized Drug Combinations for Acute Myeloid Leukemia Subtypes Using Multi-Omics Data and Machine Learning	Over the past several years, many new therapies for patients with acute myeloid leukemia (AML) have entered clinical practice, including epigenetic therapies (e.g., 5-azacitidine), isocitrate dehydrogenase (IDH) inhibitors, and fms-like kinase 3 (FLT3) inhibitors, as well as combination therapies such as azacitidine with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Despite these advances, the initial therapy regimen of “7+3” cytarabine and daunorubicin has remained mainly unchanged since 1973. The complete remission (CR) rate is 70% in younger adults and 50% for older patients, but most patients relapse and suffer from lifelong toxicities of the treatment. Treatments promoting differentiation have shown great results in certain AML subtypes, but other subtypes still rely on non-targeted therapies. My research aims to address this by identifying tailored treatment options for different AML subtypes using multi-omics data and drug sensitivity profiles on the FIMM platform. This will involve: (1) Creating a machine learning model to predict optimal drug combinations for various AML subtypes, (2) Investigating the role of pathogenic genes in different AML subtypes using scRNA-seq and CRISPR-Cas9 technology, and (3) Testing the effect of these drug combinations in patient cells and mice models, and identifying drug combination targets using macromolecule interaction technology.	No specific grant area	4,000 €	+

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Start-Up Grants

Hakemus VJ (lisätieto) - First name	Hakemus VJ (lisätieto) - Last name	Name	Title	Abstract of research proposal	Fund	Amount
Camilla	Bergström	Bergström Camilla	Characterisation of the role of TrkB in glioblastoma neuroplasticity	Glioblastomas (GB) are the most frequent and aggressive brain cancers, with dismal survival and poor response to current therapies. Drug resistance is fueled by adaptive plasticity of GB cells, changing identity in response to microenvironmental changes. For instance, GB cell identity shift towards neuronal-like (NEU-GB), enables extensive invasion by integrating healthy neuronal networks. We first performed patient database analyses and transcriptomic profiling of patient cells. Our data show that the key regulator of neuroplasticity, tropomyosin receptor kinase B (TrkB), is a robust biomarker of NEU-GB, and likely promote neuronal mimicry during GB invasion. This study aims to elucidate the impact of TrkB activity (activation/inhibition) on GB plasticity and tumor progression by implementing optogenetics and gene silencing techniques on patient-derived GB cells in vitro. Additionally, pharmacological TrkB modulators, commonly used to treat other neuropathologies at the hospital, will be tested for their potential to reprogram GB into a more chemotherapy sensitive state. By uncovering the role of TrkB in GB, this research will identify new therapeutic targets, offering novel strategies to improve treatment outcomes for GB patients.	Brain Cancer	4,000 €
Vinaya	Dulipati	Dulipati Vinaya	Immune responses and evasion strategies of Borrelia spirochetes in neuroborreliosis.	Lyme disease (LB) is the most common tick-borne disease in the world and is caused by the Borrelia burgdorferi sl. Europe alone reports 360,000 cases in the last two decades, with the majority in Nordic countries. There is no vaccine available yet. In Europe, about 3%–38% of LB patients experience neurological symptoms, also known as Lyme neuroborreliosis (NB). It is unknown why and how Borrelia can penetrate the CNS to cause NB. A key virulence mechanism of Borrelia spirochetes is complement resistance. Host complement targets microbes at different levels: the opsonins C1q, C4b and C3b/iC3b target the bacteria for phagocytosis, C5b-9 complex forms injurious membrane pores for cell lysis, and the chemotaxins C3a and C5a attract inflammatory cells to the infection site. A key borrelial immunoevasion mechanism is to bind the complement inhibitor factor H (FH) that aids in C3b inactivation. The first identified FH-binding protein on Borrelia was the outer surface protein E (OspE). Literature also describes other borrelial FH-binding proteins, CspZ and CspA. Another borrelial surface protein, BBK32, has been shown to help in complement evasion by binding the C1 complex. In Dulipati V et al. 2024 SJI, we observed that serological footprint in NB patients includes strong antibody responses to OspE and BBK32. Both OspE and BBK32 are vaccine candidates. Analyses of immune responses to important borrelial virulence factors are crucial for both diagnostics and vaccine development.	Borrelia research	4,000 €
Emilia	Franzén	Franzén Emilia	Characteristics of above 65-years-olds with type 1 diabetes in the Finnish Diabetic Nephropathy Study	Ageing in people with type 1 diabetes is becoming common due to improved treatment. Ageing in type 1 diabetes is identified as a research gap. This study aims to identify ageing-related characteristics in people with type 1 diabetes, including protective factors and those linked to worse outcomes and poor survival. This study includes 864 participants aged 55 and older with type 1 diabetes from the Finnish Diabetic Nephropathy Study, grouped according to ages 50–55, 55–60, and above 65 years. All study participants underwent thorough clinical examination, diabetes history recording, blood and urine samples, and questionnaires. In our preliminary analyses the following factors showed independent association with age above 65 years: a higher diabetes onset age, higher pulse pressure, lower mean arterial pressure, lower daily insulin dose per kg, lower HbA1c, a history of retinal photocoagulation, a history of cardiovascular events, absence of diabetic kidney disease, and absence of current smoking. No association was found for variables related to obesity, lipids or lipoproteins, chronic low-grade inflammation, the use of antihypertensive or lipid lowering-medications, or presence of depression with above 65 years of age. Our preliminary results identified potential protective factors in those over 65, as well as factors linked to worse health outcomes. I am applying for 4,000 euros from the Biomedicum Helsinki Foundation to finalize my manuscript in autumn 2024.	No specific grant area	4,000 €
Olli	Heikkinen	Heikkinen Olli	Group B streptococcus virulence factors and their interaction with the complement system	Streptococcus agalactiae or Group B Streptococcus (GBS) is a leading cause of adverse pregnancy outcomes, neonatal sepsis, pneumonia, and meningitis. Despite the recent progress in the prevention of GBS meningitis via prophylactic antibiotic treatment, infected neonates still have a poor prognosis, indicating that we still don’t fully understand the mechanisms leading to neuronal damage. This study will elucidate these molecular mechanisms by finding novel host factors and GBS virulence factors associated with severe infections in newborns and GBS colonization in pregnancy. Earlier studies have shown that several GBS proteins interact with the innate immune system. Using bulk mRNA sequencing from 100 GBS-positive and 100 negative vaginal swabs obtained from pregnant women our group has identified several immune-related genes that are upregulated during GBS infection. By isolating secreted molecules from these clinical GBS strains we have identified a GBS-specific protein complex that activates the complement system and induces complement-receptor-specific inflammatory responses on phagocytic cells. In my master's thesis, I aim to find out whether this molecule complex alters the inflammatory pathways. I will identify molecular mechanisms on how this protein complex regulates the innate immune response and affects GBS colonization and pathogenicity. This project might open up new opportunities to develop targeted immunotherapeutic interventions against this infection.	No specific grant area	4,000 €
Eeva	Juselius	Juselius Eeva	Mechanisms of Aβ binding to microbial surfaces	Amyloid-beta (Aβ) peptides are toxic to neurons and are the key protein in Alzheimer’s disease (AD) pathology. Aβ is also shown to have antimicrobial properties and may play a role in fighting bacteria infecting the central nervous system (CNS), such as Borrelia. Oligomerization of Aβ is critical in disease progression in AD and it also enhances the antimicrobial activity of Aβ. Lyme disease Borrelia and relapsing fever Borrelia species can evade the immune response by binding complement regulator factor H (FH). In this master's thesis project, I aim to find out how Aβ attacks CNS-infecting bacteria despite the bacteria’s known ability to bind FH. I aim to demonstrate that Aβ binding to specific molecules on Borreliae surfaces will 1) reduce bacterial ability to bind FH, 2) increase complement attack against the bacteria and 3) increase Aβ oligomerization by using immunological and biochemical methods. Understanding how Aβ oligomerization is triggered could give more information about the disease mechanisms in Borrelia infections and AD and whether infection triggered neuroinflammation could be involved in the pathogenesis of AD.	Borrelia research	4,000 €
Jaakko	Ketola	Ketola Jaakko	Bile acids as mediators of metabolic improvement in adipose tissue after weight loss through bariatric surgery	Obesity associates with dysfunction of adipose tissue mitochondria. In contrast with dieting, weight loss through bariatric surgery shows potential for improving adipose tissue mitochondrial function. The beneficial effects of bariatric surgery may in part be mediated by the marked increases in fasting and postprandial plasma bile acid levels and their possible impact on tissue energy metabolism. Bile acids can influence tissue metabolism through bile acid receptors TGR5 and FXR, or by stimulating the secretion of hormones such as GLP-1 and FGF19 in the gut, which are known to enhance mitochondrial function in skeletal muscle and brown adipocytes. It is not yet known, how bile acid metabolism after surgery associates with adipose tissue transcriptomic and proteomic changes and which pathways can potentially mediate the beneficial effects of bile acids to tissue metabolism. The aim of my study is to elucidate the connections between circulating fasting and postprandial bile acids and subcutaneous adipose tissue transciptome and proteome and their links to metabolic improvement after bariatric surgery. I will study a surgical weight loss group of 45 patients, whose bile acid levels will be correlated to significantly differentially expressed genes using multivariate regression analyses. I will assess how the bile acids in plasma associate with adipose tissue gene and protein expression profiles and metabolic phenotypes of the patients.	No specific grant area	4,000 €
Kaarina	Rimpeläinen	Rimpeläinen Kaarina	Impact of pre-eclampsia and hypertensive disorders of pregnancy on the risk of cardiovascular disease and all-cause mortality in women with type 1 diabetes	The aim of our study is to assess whether a history of pre-eclampsia increases the risk of cardiovascular events or all-cause mortality in women with type 1 diabetes in comparison to women with type 1 diabetes with other or no hypertension during pregnancy. We also aim to assess, if the possible connection between pre-eclampsia and later cardiovascular disease is explained by concomitant diabetic retinopathy or diabetic kidney disease. The study is part of the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study, which is an observational follow-up study. The 190 women of this sub-study gave birth at the HUS Women’s Hospital between 1988 and 1996, and were enrolled to the FinnDiane Study in 2004. The participants were grouped into four groups. 1. No history of hypertension (n=95), 2. Pre-pregnancy hypertension (n=20), 3. Pregnancy-induced hypertension (n=32), and 4. Pre-eclampsia (n=43). Follow-up data is retrieved from the Hospital Discharge Registry Hilmo, Finnish Institute of Health and Welfare and from Cause of Death Registry, Statistics Finland, until on December 31, 2020, or until possible death. Median follow-up time is 27.9 years. Main outcomes are all-cause mortality (n=25) and a composite CV event (n=46), consisting of acute myocardial infarction, coronary revascularization, hospitalization due to heart failure, stroke, or cardiovascular death. We also include information on participant's kidney disease and retinopathy during follow-up to our analyses.	Cardiovascular	4,000 €
Ville	Väyrynen	Väyrynen Ville	Immune landscape and CLEVER-1 expression in hepatoblastoma	Hepatoblastoma (HB), the predominant primary liver malignancy in pediatric populations, is traditionally managed through surgical resection or liver transplantation, supplemented with chemotherapeutic regimens. Despite the advancements in surgical techniques and chemotherapeutics, approximately 20-30% of HB patients respond poorly to these interventions, and many endure lifelong complications. To mitigate unsatisfactory patient outcomes, research in immuno-oncology is investigating the therapeutic potential of exploiting the tumor immune microenvironment (TIME). The objective of this study is to elucidate the TIME of HBs and to investigate the expression of potential immunotherapeutic targets, such as CLEVER-1. We will employ multiplex immunofluorescence (mIHC) staining to map the distribution and localization of immune cells and prospective immuno-oncological targets within HB tissue samples. Subsequently, image analysis will be conducted using deep-learning neural networks to ensure precise and comprehensive data interpretation. To validate the findings from the mIHC experiments, we will utilize RNA sequencing and proteomics assays. Additionally, these methodologies will elucidate the transcriptomic and proteomic landscapes of HBs. Finally, we will correlate the results with clinical variables.	Cancer and Cell Based Cancer Research	4,000 €
Isabelle	Weert	Weert Isabelle	Humanizing mice for the study of schizophrenia patient-derived microglia-like cells	Schizophrenia (SCZ) is a neurodevelopmental disorder in which the aetiology remains poorly understood. Multiple aspects of the disorder and the patients quality of life makes for a need to develop proper tools to study this disorder. Some current hypotheses involve life events in which microglia are heavily implicated, maternal immune activation (MIA) being one of them. The Koistinaho lab has curated a unique library of induced pluripotent stem cells (iPSC) derived from monozygotic twins discordant for SCZ (SCZ twin, unaffected twin, and control) to study the complex interplay between genetic risk and clinical manifestation. The studies from this lab have shown interesting findings in vitro using these iPSCs to make microglia-like cells (iMGL), but fail to reach the level of maturity seen in microglia in vivo. To assess if the effects observed in vitro are translatable, an experimental design has been constructed in which iMGL progenitors will be transplanted into embryos (E14) of pregnant immunocompromised mice that express human CSF1. This way, we can study the iMGLs and their complex interplay with other cell types in a more physiologically relevant environment. Furthermore, by mimicking MIA conditions using poly(I:C), the effects of MIA on the iMGLs can be studied. By sacrificing the mice at different timepoints after the initial transplantation and poly(I:C)/saline treatment, we hope to discover morphological and functional differences between the different cell lines.	No specific grant area	4,000 €

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Biomedicum Helsinki Prize 2024

The Biomedicum Helsinki Foundation Prize 2024 for an exceptional publication in health sciences from the local community during the previous year was revorded to PhD Yilin Kang for the following publication: Ancestral allele of DNA polymerase gamma modifies antiviral tolerance Nature. 2024; 628(8009): 844–853)