Faculty of Medicine


Recent Submissions

  • Vasilescu, Catalina (Helsingin yliopisto, 2020)
    Next-Generation Sequencing (NGS) technologies enabled the characterization of the human genome and its variation in great detail within large cohorts. The current medical research aims towards personalized medicine, whereby identifying the causal disease mechanisms in each individual will promote more tailored forms of treatment. In genetic studies, NGS technologies involve targeted sequencing panels of known disease genes, whole-exome sequencing (WES) covering the genome's protein-coding part, and whole-genome sequencing (WGS). Our study applied targeted panels and WES for the genetic diagnosis of severe childhood disorders, starting with a progressive neurological syndrome and continuing with a cohort of 66 children diagnosed with cardiomyopathy, a leading cause of pediatric heart transplants. We made substantial progress in understanding the molecular basis of the studied disorders. First, we strengthen the evidence that heat shock response is a novel mechanism underlying leukoencephalopathy. Second, we characterized genetically a cohort of early-onset severe cardiomyopathies (KidCMP), representing the whole of Finland for patients evaluated for cardiac transplantation or receiving inotropic support. Third, we characterized a novel disease gene causing childhood cardiomyopathies, an important step in further deciphering the genetic landscape of these severe heart disorders. Altogether, this thesis highlights the power of novel technologies in identifying causal genetic variants and characterizing novel disease genes. Our findings enhance knowledge of the underlying molecular mechanisms and potentially aid in developing new therapeutic interventions. For families, the genetic diagnosis enables a causative recognition of the disease and identifying individuals at risk. Our cardiomyopathy project also contributed to establishing a protocol for systematic genetic testing of patients and families at the Pediatric Cardiology Department of the University of Helsinki Central Hospital.
  • Ollila, Aino Maria (Helsingin yliopisto, 2020)
    Perioperative myocardial ischemia and infarction are frequent and serious complications, especially in elderly patients with cardiovascular risk factors who are undergoing major non-cardiac surgery. As the population in high-income countries is rapidly aging, the incidence and significance of perioperative cardiac complications will likely increase in the future. The objectives of this study were to determine the incidence and prognosis of perioperative myocardial infarction in patients undergoing non-cardiac surgery in a Finnish tertiary care hospital, to investigate the pathophysiology of this complication, and to review the current literature for preventive strategies. Study I was a prospective observational study that investigated the incidence and 90-day mortality of perioperative myocardial infarction in 385 patients, aged 50 years or older, undergoing non-cardiac surgery in Meilahti Hospital. The performance of the Gupta cardiac risk calculator in non-American patient population was tested as well. Study II investigated the incidence of postoperative myocardial ischemia and its potential association with development of myocardial infarction. The prospective cohort included 51 high cardiac risk patients undergoing vascular surgery. The patients were postoperatively monitored with continuous electrocardiography and cumulative ischemic load was calculated. Study III aimed to further expand the current knowledge of the pathophysiology of perioperative myocardial infarction. The laboratory substudy included 75 patients from the first cohort and investigated the potential association of systemic inflammation and perioperative endothelial glycocalyx injury with development of perioperative myocardial infarction. Study IV was a systematic review and meta-analysis about the safety and efficacy of intravenous esmolol for perioperative cardiac protection. The review included 3 studies and 196 patients. The incidence of perioperative myocardial infarction was 7%, and it was associated with a fivefold increase in 90-day mortality. Gupta cardiac risk calculator performed fairly in predicting myocardial infarction. Postoperative ischemic electrocardiographic changes were common in high cardiac risk patients, with an incidence of 33%. Despite being mostly asymptomatic, cumulative ischemic load predicted perioperative myocardial infarction with an AUC of 0.87 (95% CI: 0.75-0.99). Systemic inflammation, reflected by elevated plasma interleukin-6 levels, was associated with perioperative troponin release and myocardial infarction. None of the measured endothelial glycocalyx injury markers (soluble thrombomodulin, syndecan-1, and vascular adhesion protein-1) was associated with perioperative myocardial infarction. Intravenous esmolol reduced the incidence of perioperative myocardial ischemia (RR =0.43, 95% CI: 0.21-0.88). No association with clinically significant bradycardia and hypotension could be confirmed. The studies included in the review were too few and too small to provide conclusive evidence regarding other clinically relevant outcomes, such as mortality. Based on the data of the two prospective patient cohorts from a large Finnish tertiary care hospital, perioperative myocardial ischemia and infarction are frequent complications in surgical patients and are associated with poor prognosis. Without systematic perioperative ischemia monitoring, most of these complications remain undiagnosed. Future studies are needed to determine the pathophysiological mechanisms of perioperative myocardial ischemia and infarction, and to identify safe and efficient treatment strategies. Keywords: Perioperative myocardial infarction, myocardial ischemia, non-cardiac surgery, cardiac troponin T, endothelial glycocalyx, prevention, esmolol
  • Cervera Taboada, Alejandra (Helsingin yliopisto, 2020)
    Cancer is a collection of diseases that combined are one of the leading causes of deaths worldwide. Although great strides have been made in finding cures for certain cancers, the heterogeneity caused by both the tissue in which cancer originates and the mutations acquired in the cell’s DNA results in unsuccessful treatments for some patients. The genetic alterations caused by carcinogenics or by random mutations acquired during normal cell division promotes changes in the cell’s metabolism. These changes are usually reflected in abnormal gene expression that can be studied to understand the underlying mechanisms giving rise to cancer as well as suggest treatments that can exploit each tumor’s specific vulnerabilities. RNA-Seq is a technology that allows the identification and quantification of the genes that are being expressed inside the cell in a given moment. RNA-Seq has several characteristics and advantages that allow a diversity of applications to exist. For example, apart from quantifying gene expression, it can be used to detect different variants of the same gene, has base pair resolution which is informative of the gene sequence, and can also be used to quantify other RNA molecules besides messenger RNA (mRNA), such as microRNAs. The two main aims of this work are to provide computational methods for data analysis of RNA-Seq and to show specific applications of RNA-Seq that can shed light into cancer mechanisms. In Publications I and IV we developed the Sequence Processesing Integration and Analysis (SePIA) and the Fusion Gene Integration (FUNGI) toolsets that facilitate the creation of reproducible pipelines for investigating different aspects of the cancer transcriptome. SePIA’s utility is showcased with the analysis of datasets from two public data repositories. One of the analysis shows a standard RNA-Seq analysis, while the second one produced a pipeline for mRNA-microRNA integration. The second toolset, FUNGI, is aimed specifically at finding reliable gene fusions with oncogenic potential. To demonstrate FUNGI’s features, we analyzed 107 in-house samples and processed over 400 public samples from a public data repository. FUNGI allowed us to detect fusions in ovarian cancer with a higher prevalence than previously recognized. Additionally, we identified a fusion gene that has not been reported before in ovarian cancer, but that can be targeted with a drug currently in clinical trials. In Publication II we investigated the role of alternative splicing in diffuse large B-cell lymphoma and were able to show that isoform-level instead of gene-level is better at discriminating between subtypes. Additionally, specific isoforms, such as APH1A, KCNH6, and ABCB1, were correlated with survival. In Publication III, we used RNA-Seq to complement the phasing of genetic variants with somatic mutations in tumor suppressor genes. In this study we found enrichment of haplotype combinations that suggest that haploinsufficiency of tumor suppressor genes is enriched in cancer patients. SePIA and FUNGI are tools that can be used by the community to explore their datasets and contribute to the acquisition of knowledge in the field of cancer genetics with next generation sequencing. The applications of RNA-Seq studies included in this dissertation showed that RNA-Seq can be effectively used to aid in the classification of cancer subtypes, and that RNA-Seq can be used in combination with DNA sequencing to explore gene expression mediated by genetic variation in cancer.
  • Raivisto, Teija (Helsingin yliopisto, 2020)
    Periodontitis and dental caries are common chronic diseases, even adolescents suffer not only from caries but also from early stage of periodontitis, subclinical periodontitis. Both diseases are influenced by environmental, host-derived, and genetic factors. Recognition of these factors may reveal susceptibility to disease at an early stage, thus enabling preventive interventions. Oral fluids contain many potential biomarkers for periodontitis. Matrix metalloproteinase (MMP)-8 and especially its active form aMMP-8 seems to be key biomarkers for periodontitis. The level of aMMP-8 in oral fluids can be measured by the specific aMMP-8 chairside test. The triggering receptor expressed on myeloid cells 1 (TREM-1) together with its ligand peptidoglycan recognition protein 1 (PGLYRP1) are recently recognized salivary biomarkers amplifying proinflammatory processes in periodontal diseases. Studies were carried out at Kotka Health Center in Eastern Finland in 2004-2005 and/or 2014-2015 and at the Hämeenlinna Health Center in Southern Finland in 2017-2018. Participants were 14-17 years old. Altogether 501 participants in 2004-2005 and 47 in 2014-2015 consented to the study. With their permission DNA analyses were performed on 47 participants in 2004-2005 and on all participants (n=47) in 2014-2015. In 2017-2018 altogether 125 participants consented to the study and the mouth rinse analyses. The aMMP-8 chairside mouth rinse test identified and alerted adolescents with poor oral hygiene at risk for subclinical periodontitis without detectable and visible manifestations of the illness. Periodontal treatment and preventive intervention decreased aMMP-8 levels assessed by a change in test stick result from positive (+) to negative (-) during the monitoring period. Young patients at risk must be identified to enable early preventive interventions and treatment. Genetic polymorphisms of MMP3 and VDR genes are linked to subclinical periodontitis in Finnish adolescents. Only tentative genetic aetiology for dental caries could be observed. Elevated PGLYRP1 levels in adolescents with gingivitis and subclinical periodontitis and its positive correlation with TREM-1 and aMMP-8 may indicate an association of PGLYRP1 with early stages of periodontal disease. However, it has a lower discriminating capacity and is therefore a less reliable marker alone in the diagnosis of subclinical periodontitis in adolescents.
  • Kaivola, Karri (Helsingin yliopisto, 2021)
    In neurodegenerative diseases neurons gradually die leading to various symptoms based on the affected nervous region. Often memory, movements or both are affected, and the symptoms worsen over time greatly affecting the quality of life. Neurodegenerative diseases are often caused by many factors, both intrinsic and environmental. Genetics often play an important role in neurodegenerative diseases and genetic research can help to elucidate disease mechanisms. Since many neurodegenerative diseases share overlapping mechanisms, insights in one disease can elucidate the mechanisms of other diseases as well. The aim of this thesis was to study the genetics of three neurodegenerative diseases: amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and the closely related dementia with Lewy bodies (DLB). ALS is characterized by a progressive loss of voluntary movements that leads to respiratory failure. AD and DLB lead to dementia but DLB patients often also have parkinsonism and visual hallucinations. In Publication I, we determined the C9orf72 GGGGCC hexanucleotide repeat length of 3142 Finns. The C9orf72 hexanucleotide expansion is the most common cause of ALS and frontotemporal lobar degeneration (FTLD) in populations of European ancestry, but the exact pathogenic repeat length and the role of intermediate length alleles in disease is unclear. Often 30 repeats is used as the expansion threshold. We presented the distribution of C9orf72 repeat length in older individuals and found that 0.38% have 30-45 repeats. However, these individuals had no apparent accumulation of neurodegenerative or psychiatric symptoms. We found no association with intermediate repeat length alleles (7-45 or 20-45) and AD or cognitive impairment. Intermediate-length alleles with ≥20 repeats were found to be more common in Finland than elsewhere. In Publication II, we utilized the same cohorts from the first study as controls and additionally determined the repeat lengths of 750 Finnish ALS patients and additional 800 younger controls aged 18-65 years. There have been mixed results on the association of intermediate repeat length alleles with ALS so we tested the association using several thresholds: 7-45, 17-45, 21-45, 24-45 and 24-30. None of these intermediate repeats associated with ALS when only the effect of the longer allele was considered. However, carrying two copies of intermediate-length alleles was associated with ALS especially when the longer allele was over 17 repeats (p=0.002, OR 5.32, 95% CI 2.02-14.05). In Publication III, we studied the distribution of Lewy-related pathology (LRP) in the Vantaa 85+ population cohort. Our results confirmed that LRP progresses caudo-rostrally in 64% individuals with LRP, whereas a third have amygdala-based progression pattern. Moreover, the amygdala-based progression pattern was associated with AD pathology and APOE ε4. Our findings suggest that DLB should not be viewed as a single entity, but two. In Publication IV, we studied the association of previously identified genetic risk loci for AD with the different neuropathological features of AD. These features were amyloid β deposition (CERAD score), tau pathology (Braak staging), cerebral amyloid angiopathy and capillary amyloid β. We identified risk loci for every neuropathological feature including capillary amyloid β for which there were no previously identified risk loci. Our findings help to match known AD loci to neuropathological changes elucidating the role of each gene in AD pathogenesis.
  • Aalto, Ulla (Helsingin yliopisto, 2020)
    Drugs with anticholinergic properties (DAPs) are known to have a large spectrum of adverse effects affecting both the peripheral and central nervous system. Older multimorbid people in declining health as regards cognitive and physical performance are especially vulnerable to these adverse effects, such as dizziness, confusion and cognitive decline. Cumulative DAP use, reflecting a greater anticholinergic burden, increases the risks of adverse outcomes. There are several international criteria concerning DAPs and anticholinergic burden. However, there are relatively few studies comparing various criteria and their prognostic value. In addition, the relationship of DAPs with Quality of Life (QOL) among older people has received very little attention. The aim of this study was to explore the use of DAPs in long-term care facilities (LTCFs), and their associated factors, in particular psychological well-being (PWB), Health-related Quality of Life (HRQOL), and mortality. Furthermore, the relationships between anticholinergic burden and associated factors were also investigated by comparing three internationally well-established anticholinergic scales. In addition, temporal trends in DAP use were studied over a 14-year period. The study comprises four cross-sectional sub-studies conducted in 2003, 2007, 2011, and 2017 in LTCFs in Helsinki. All background data on demographic factors, medication use, and diagnoses of chronic and acute medical conditions were retrieved from medical records. Trained study nurses performed the assessments needed, using the same structured study protocol at each time point. The medications were classified according to WHO Anatomical Therapeutic Chemical (ATC) criteria. DAP use and anticholinergic burden were defined by using the Anticholinergic Risk Scale (ARS) (Studies I, III and IV), and by comparing three scales, the ARS, Chew’s list, and the Anticholinergic Drug Scale (ADS) (Study II). Of all residents living in nursing homes (NHs) and assisted living facilities (ALFs) in Helsinki, 2432 were included in Studies I and II. PWB was assessed by using a validated questionnaire. Mortality data was retrieved from central registers. In Study III, all residents living in NHs and ALFs in Helsinki in 2017 were invited to participate, and after exclusions, 2474 remained. DAP use was defined by the ARS score and HRQOL was assessed by use of the 15D instrument, separately among people with and without cognitive decline, according to their nutritional status, and functioning. In Study IV, temporal trends of DAP use defined by the ARS were investigated from 2003 to 2017 in three NH cohorts in 2003 (n=1979), in 2011 (n=1568), and in 2017 (n=750), and in three ALF cohorts in 2007 (n=1336), in 2011 (n=1556), and in 2017 (n=1673). In Studies I and II the residents in long-term care facilities were about 84 years of age and mostly female. DAP use was very common, since about half of the participants (51%) used at least one DAP according to the ARS (Study I). When defining DAP use by combination of the three scales, as many as 85% of participants were identified as DAP users (Study II). The three scales included partly the same, but mostly different drugs, and the scales only partly overlapped each other. DAP users were in general younger and had better cognition than non-users. A higher number of drugs used regularly was associated with DAP use (mean range 8.8–10.1) compared with non-users (mean 7.1, p for trend <0.001) (Study I). In NHs no significant trend in DAP use was observed over 14 years (52–46–52%, p for trend =0.19), whereas in ALFs an increasing trend in DAP use was observed over the years (41–51–54%, p for trend <0.001) (Study IV). In Study I an association between DAP use and poorer psychological well-being, measured by PWB score ranging from 0 to 1, was observed. Those not using DAPs had a significantly higher PWB score (mean 0.73) than those using them, and the PWB score had a decreasing trend along with increasing number of DAPs used (mean range 0.67-0.67-0.62, p for trend <0.001). The association remained in further analyses, irrespective of possible underlying depression or dependency in functioning. In Study II, when comparing how the three scales predicted PWB, Chew’s list alone, or combinations of two or three lists together showed an association with poorer PWB. Using a higher number of DAPs was also associated with poorer PWB. In 1-year follow-up no association between mortality and DAP use was seen, compared with not using any DAPs. However, an association between a higher number of DAPs used and an increased risk of mortality was observed. In Study III HRQOL measured by the 15D instrument showed an increasing trend along with higher ARS scores (mean 15D score 0.596–0.629, p linearity <0.001). However, after stratification according to cognitive and functional status, no significant differences in HRQOL between the ARS-score groups were any longer seen. Overall, residents with dementia, poor nutritional status, and dependency on another person’s assistance had lower HRQOL than those without dementia, those well-nourished or not dependent. Interactions between ARS score and dementia (p<0.001 for dementia and p=0.021 for interaction), and ARS score and dependency emerged (p<0.001 for dependency and p=0.017 for interaction). Despite clinical guidelines which advise against the use of DAPs, they have remained widely used in this frail population of older adults in long-term care, as roughly one in two residents in LTCFs use them. DAPs seem to be prescribed to younger individuals and those with better cognition, whereas the cognitively more impaired are spared them. Some favorable trends concerning DAP use in LTCFs during recent years, such as decrease of ARS scores in NHs, or disappearance of certain high potential DAPs, were observed. However, concerning results emerged as regards residents in ALFs, where an increasing trend in DAP use was observed. Although the three DAP scales investigated have certain similarities, they overlap only partly and seem to predict different outcomes. The results showing an association between anticholinergic burden and poorer PWB are worrisome, and further studies are warranted to investigate this topic.
  • Banerjee, Joanna (Helsingin yliopisto, 2020)
    Posterior reversible encephalopathy syndrome (PRES) and other central nervous system (CNS) toxicities not only complicate the treatment of acute lymphoblastic leukaemia (ALL) in children, but may lead to treatment modifications and long-term effects which increase morbidity and even mortality. Although recognition of these complications has improved in the last decades thanks to the increased availability of brain magnetic resonance imaging (MRI) in clinical practice, data on exact incidence rates, treatment strategies in different complications, and impact on outcomes are limited. Cranially irradiated leukaemia survivors are at risk of brain tumours, but the incidence rates of brain tumours after long latency periods need to be defined. In this thesis, the occurrence and spectrum of CNS symptoms, clinical characteristics and impact on prognosis and neurological outcome were determined during and after ALL therapy, as well as the significance for neurotoxicity of low dosing of folinic acid after high-dose methotrexate. In addition, the risk of secondary brain tumours in cranially irradiated leukaemia survivors after long latency periods was defined. For the first and second study, data were gathered on 643 children treated in Finland in accordance with the protocols of the Nordic Society of Paediatric Haematology and Oncology (NOPHO ALL 1992 and NOPHO ALL2000). The NOPHO leukaemia registry provided data on patient and treatment characteristics. Thorough reviews were performed of all medical records and the detailed data on CNS symptoms from all patients. In the first study, acute CNS symptoms occurred in 86 patients (13%) during the first two months of the treatment. PRES was the most common CNS complication. Cerebrovascular events occurred in 10 patients (1.6%), hypertensive encephalopathy in six (1.0%), and methotrexate-related stroke-like syndrome in one (0.2%). CNS symptoms due to systemic or unclear conditions, particularly sepsis, were important for differential diagnosis, and occurred in thirty-six (5.6%) children. No CNS symptom was characteristic for specific CNS complications and diagnosis in most cases required a combination of imaging, laboratory tests, and clinical judgement. CNS leukaemia was an independent risk factor for defined CNS complications in a multivariable logistic regression analysis. Defined CNS complications other than PRES were not associated with lower event-free or overall survival. Epilepsy was a common sequela. However, a majority of these sequelae occurred in patients with PRES. In the second study, a total of 29 (4.5%) patients developed PRES, almost exclusively during the induction treatment. All patients presented with seizures. Hyponatremia was a common finding in patients with PRES, and significant hypertension, constipation, and > 2 weeks of alkalinisation hydration was associated with PRES in a multivariable binary logistic regression analysis. PRES was associated with long-term neurological morbidity, as one third of the patients with PRES developed epilepsy. In addition, relapses were more common in PRES group and PRES was associated with lower overall survival. In the third study, data on high-dose methotrexate treatment were gathered from patients treated with NOPHO ALL2000 standard or intermediate risk protocols at Oulu and Kuopio University Hospitals. In over half (n = 181) of the 351 high-dose methotrexate courses, methotrexate clearance was fast, leading to low dosing of folinic acid. Despite low folinic acid previously having been suggested to associate with increased neurotoxicity, no neurotoxicity was seen in a cohort of forty-four patients. In the fourth study, all cranially irradiated adult leukaemia survivors (with a minimum of 10 years after end of therapy) from Oulu University Hospital were invited to a follow-up brain MRI, if not recently imaged due to neurologic symptoms. The cohort consisted of 60 patients; however, only 49 patients participated in the study. Of these leukaemia survivors, eleven (22%) developed a meningioma after an exceptionally long latency period, mean 25 years (range 14–34 years). The incidence of meningiomas continued to increase 20 years after the treatment, unlike that of gliomas, which typically develop with shorter latency periods. Four patients were symptomatic at the time of diagnosis, three had multiple meningiomas, and two had recurrent disease. Eight meningiomas were operated on, with a World Health Organization (WHO) I histology in seven patients and WHO II (atypical) in one patient. No other brain tumours were seen. In conclusion, the studies included in this thesis showed that CNS complications are common during and after ALL therapy. PRES in particular is a significant complication of the treatment associated with long-term morbidity (epilepsy) and poor prognosis. It was not clear whether the negative impact on outcome was due to PRES itself or a result of suboptimal therapy. The role of hyponatremia in the pathogenesis of PRES requires further studies. Although CNS complications can usually be cured, some are life-threatening. Accurate diagnostics of symptoms is crucial for proper treatment. In patients with fast clearance, a low dose of folinic acid after high-dose methotrexate was sufficient to prevent neurotoxicity. It was observed that meningiomas developed with a long latency, which is today a known feature of radiation-induced meningiomas.
  • Laukkanen, Erika (Helsingin yliopisto, 2020)
    Root canal treatment (RCT) is a common procedure in dentistry that aims to heal and prevent a root canal infection. The evidence on the outcome of RCT is primarily based on studies from controlled settings, such as teaching clinics, but little is known about the outcome in general dental practice. The aim of this study was to investigate and compare the radiographic outcome of non-surgical RCT in two distinct treatment settings and operators: RCTs by dental students in the University Dental Clinic of the City of Helsinki in 2008–2011 and by general dental practitioners (GDPs) in Health Centres of the City of Helsinki in 2010–2011. Furthermore, the study aimed to assess the impact of various factors, such as tooth type, quality of root filling, and systemic diseases on the outcome of RCT. This study is based on patient records, including digital radiographs. The first dataset consisted of 640 permanent teeth, root-canal-treated by dental students, in 504 patients. These treatments followed a strict protocol and were supervised by specialised endodontists. The second dataset was scrutinised using stratified random sampling by tooth type amongst RCTs by GDPs; the sample included equal numbers of teeth per tooth type (n = 71), resulting in 426 teeth in 426 patients. The clinical protocol for these treatments was not standardised. The periapical index (PAI) was utilised for the evaluation of success of RCT. Only the latest follow-up radiograph was included for each case. The follow-up periods were 6–71 months and 6–105 months for RCTs by dental students and GDPs, respectively. Both healthy and healing cases were considered successful. The quality of root fillings varied by type of tooth; adequate root fillings were least frequent in molars. Root fillings by dental students were more often optimal than root fillings by GDPs. The success rate of RCTs was favourable and comparable to previous studies for RCTs by dental students; 84% of cases were successful. For RCTs by GDPs, success was achieved in 67% of cases, thus less often than when performed by dental students. Success was more likely for teeth without preoperative apical periodontitis. Type of tooth influenced the outcome of RCT; success was more likely in non-molars than molars. Diabetic patients experienced poorer RCT outcomes than healthy patients, especially in teeth with apical periodontitis prior to treatment. Other systemic diseases seemed to have no impact on the outcome. In conclusion, the outcome of RCT achieved by dental students was up to par, whereas the outcome by GDPs was unsatisfactory, especially in molars. The outcome of RCT varies according to tooth-based and patient-related factors, thus the prognosis should be estimated separately for each tooth and patient. RCTs are successful when performed following guideline standards, consequently reinforcing the necessity of the continuous education of dentists, and the option of referral of more complex cases, such as molars, to endodontic specialists.
  • Mroueh, Rayan (Helsingin yliopisto, 2021)
    In Studies I and II, we investigated the treatment modalities and outcomes for 360 oral tongue squamous cell carcinoma (OTSCC) patients treated at the five Finnish University hospitals from 2005 to 2009 and compared results with the earlier cohort from 1995 to 1999. Additionally, we assessed the non-curative treatment regimens and survival among 82 OTSCC patients treated at the HUS Helsinki University Hospital from 2005 to 2016. During 2005–2009, OTSCC diagnosis typically occurred at an early stage (78% were clinically T1 or T2 tumors), which undeniably eventuates in better outcomes. The disease recurrence rate for OTSCC patients diagnosed during 2005–2009 was 27%. Overall survival (OS) and disease-specific survival (DSS) rates for patients treated with curative intent were 61% and 76%. Five-year-recurrence-free survival (RFS) for OTSCC has improved from 47% in our previous series to 65% in the current series (P < .001). Regarding patients treated with non-curative intent, survival is decimal (median survival 72 days following the decision of non-curative treatment), and one can consider long the treatment delay (average 19–25 days). For the second part of the research (Studies III and IV), we utilized the Finnish cancer registry (FCR), which includes all new primary cancers diagnosed in Finland since 1953. Study III consisted of 6,602 oral squamous cell carcinoma (OSCC) patients with no previous cancers. We confirmed that OSCC patients carry an 85% excess risk of developing a second primary cancer (SPC) compared with the cancer incidence rates in the Finnish population and the risk persisted even after five years. Patients with a primary tumor in the floor of mouth had the highest standardized incidence ratio (SIR) for SPC (SIR 2.38, 95%-CI: 2.04–2.77, P < .001) when compared to the general population. The respiratory and intrathoracic organs (22% of all SPCs), and digestive organs (21%) were the commonest sites for SPCs. In Study IV, we aimed to elucidate the proportion of HNC cases revealing familial clustering and estimate the relative risk of HNC for family members and spouses of a proband diagnosed with early‐onset HNC. We retrieved from the FCR a total of 923 probands diagnosed with early-onset HNC (≤ 40-year-old) from 1970 to 2012. In this patient cohort, over 97% of HNC cases were sporadic. We detected no increased risk of HNC or other malignancies in first‐ or second‐degree relatives of a proband diagnosed with early‐onset HNC when compared with the general population’s cancer risk. Our study emphasizes that the contribution of shared familial factors, such as inherited genetic mutations, or early HPV‐exposure, to early‐onset HNC, is, in the Finnish population, insignificant and, at most, a minor proportion of early-onset HNC cases is solely attributable to germline mutations.
  • Sanaksenaho, Galina (Helsingin yliopisto, 2020)
    Background. Although extensively studied in experimental models, human data on intestinal adaptation in short bowel syndrome (SBS) is very limited. Aim of the study. We studied mucosal homeostasis of the duodenum in children with intestinal failure (IF) both during parenteral nutrition (PN) and after achieving intestinal autonomy by weaning off PN in relation to controls. Patients and methods. In total, 58 patients with IF aged from 0.5 to 23 years and 43 controls matched for age and gender without intestinal pathology were included. Duodenal biopsies obtained during clinically indicated gastroscopies were collected. We evaluated duodenal disaccharidase activities, inflammation, structural mucosal hyperplasia, proliferation, apoptosis, epithelial barrier function and nutrient transport by using the glucose oxidase method, histology, immunohistochemistry, and quantitative real-time polymerase chain reaction (qPCR) for 52 genes. Dilatation of the small bowel was assessed from a contrast small bowel series. Results. Activities of maltase and sucrase were 1.6 times lower and mucosal inflammation more frequent (22% vs 3%) in patients on current PN in comparison with controls (P˂0.05 for both). Disaccharidase activities in patients who had weaned off PN were comparable with controls. In the evaluation of mucosal morphology, proliferation, and apoptosis, PN-dependent and weaned off patients showed similar results to controls. Compared to controls, SBS patients showed a statistically significant (P<0.005 for PN-dependent and weaned off patients) increase in mucosal mRNA expression of Transforming growth factor (TGF)β2 and Caveolin1 (CAV1). In addition, compared to controls, patients on PN demonstrated elevated mRNA expression of Claudin 1 (CLDN1), Mucin 2 (MUC2) and Glucose transporter, GLUT1 (SLC2A1) and decreased expression of NLR family CARD containing 4 (NLRC4) (P<0.005 for all). Weaned-off patients showed increased histologic inflammation of the lamina propria and elevated Tumor necrosis factor (TNF) and TGF-β2 (P<0.05 for all) mRNA expression when compared to controls. Pathologic small bowel dilatation was associated with shorter crypts (P=0.045) and decreased mRNA expression of Interleukin (IL)-6 (P=0.008). Conclusions. In children with IF, current PN was associated with decreased disaccharidase activities and increased inflammation, suggesting that PN requirement negatively affects intestinal adaptation. Duodenal mucosal hyperplasia seemed to have only a limited role in intestinal adaptation after extensive bowel resection in children with SBS and despite weaning off PN, patients showed mucosal inflammation and molecular signs of altered epithelial permeability.
  • Jouhi, Susanna (Helsingin yliopisto, 2020)
    The first part of this thesis summarizes the current literature on small choroidal melanomas (CMs). Although the aetiology of this disease remains unknown, many risk factors have been reported. Differentiation from the more common choroidal naevi is generally clinical, and several typical characteristics of the malignant tumour have been used as a diagnostical tool. When the differentiation cannot be made clinically or by biopsy, the remaining option is to observe for growth that signals malignancy. Small posterior tumours, in particular, have frequently been observed for growth because treatment would most likely affect vision. However, observation before treatment might increase the risk for metastases. Small CMs are typically treated conservatively, and enucleation is no longer a generally accepted alternative, partly because these tumours are thought to be able to micrometastasise years before diagnosis. The primary aims when managing small malignant CMs are to destroy the tumour and prevent local recurrences that might be associated with an increased risk for metastases. Eye-preserving treatments frequently allow for the preservation of useful vision as well. Several options are available for treating small CMs. In Finland, the majority of CMs are treated with episcleral plaque brachytherapy. Ruthenium106 brachytherapy is an effective choice for small melanomas because the dose distribution is ideal for treating tumours with a thickness of up to 5.4 mm. The second and main part of this thesis summarizes the recent Finnish contributions to this field. The research presented in this thesis starts by retrospectively examining the treatment results from 10-mm ruthenium plaque (Study I), leading to a comparative study looking at the treatment results of both 10-mm round radioactive plaque (CCX) and 15-mm round radioactive plaque (CCA), with the aim to see whether and when it is safe to reduce vision- threatening radiation side-effects by using a smaller plaque (Study II) when treating small CMs less than 10 mm in their largest basal diameters (LBDs). The smallest 10-mm plaque delivers less scattered radiation compared with a 15-mm plaque or larger. Previously, it was not known whether a smaller radiation area and less scattered radiation could affect the recurrence rate, preservation of useful vision, and frequency of side-effects. This thesis found that the recurrence and complication rates were comparable between patients treated with the 10-mm or 15-mm plaque, but vision was more effectively preserved after treatment with the 10-mm plaque when the tumour was located close to the foveola. An eccentric location of the plaque was a risk factor for a local recurrence with both plaques. This study supports the treatment of small posterior CMs close to fovea with 10-mm rather than 15-mm plaque. The challenge of diagnosing small CMs before they have the capacity to disseminate led to the search for the smallest size of a CM that had been reported to metastasize and an attempt to find out whether melanomas that disseminated and melanomas that did not disseminate differed from each other clinically. As the Finnish population is not sufficiently large to collect data for this study, a retrospective collaboration study was done with the European Ocular Oncology Group (OOG) (Study III). Ten ocular oncology services submitted the data on all their patients with a CM of 3 mm or less in thickness and 9 mm or less in LBD who were treated and who subsequently developed metastases. This study found that CMs less than 3 mm in LBD are unlikely to metastasize. Observation without treatment beyond this limit might impair survival. Clinical characteristics of small fatal choroidal melanomas (SFCMs) did not differ from those of non-fatal CMs of a similar size: clinical characteristics predicting metastasis could not be identified. Due to inspiration from Study III, ways to alternatively diagnose small melanomas before they get the capacity to disseminate were examined. The growth rates and tumour doubling times (TDT) of incipient CMs were calculated (Study IV). Short TDT and a fast growth rate combined with the calculated age at tumour origin after puberty supported a melanoma diagnosis. These were the nine smallest presumed CMs reported at that point. The earlier diagnosis enabled treating these patients with less invasive transpupillary thermotherapy (TTT), of which preliminary results are shared in this thesis. The reported growth parameters could be employed as diagnostic criteria for the incipient melanomas.
  • Ahopelto, Kaisa (Helsingin yliopisto, 2020)
    Background: Cancer is the second most common cause of death nowadays. Gastrointestinal malignancies account for over 20% of cancer deaths globally. The prognosis in colorectal cancer has improved over the years while that of pancreatic and stomach has remained poor for the past decade. Biochemical tumor markers help in subtyping cancers to aim in choosing the best possible treatment for each individual. They are also helpful in follow-up and in determining prognosis. Cancer cells have metabolic features that differ from non-cancerous cells. One of these is the ability to use glycolysis as an energy source. Transketolase-like protein 1 (TKTL1) is a protein that catalyses cancer cells’ glucose production via the pentose phosphate pathway. This thesis consists of four studies that aimed to investigate the potential of TKTL1 as a prognostic marker in gastrointestinal cancers. Materials and methods: Study I included 840 colorectal patients treated in 1989-2000. The second study comprised 111 patients with colorectal cancer and liver metastases thereof. These patients were operated on in 1988-2007. Formalin-fixed samples were obtained from the primary tumor and liver metastases in 60 patients, the primary tumor only in 21 patients and liver metastases only in 30 patients. Study III included 313 patients with gastric cancer surgically treated in 2000-2009. Study IV on pancreatic ductal adenocarcinoma (PDAC) comprised 168 patients who were treated surgically in 2001-2011. All patients were treated at the Department of Surgery at Helsinki University Hospital. Clinicopathological data was gathered from patient records and causes of death from Statistics Finland. For all patients, tissue micro array (TMA) series were constructed including 3-6 tumor spots per patient. For study IV whole tissue samples were used in addition to TMA blocks. All tissue samples were stained for TKTL1 using immunohistochemistry. In study III also Glucose transporter 1 (GLUT1) staining was done. Results: TKTL1 immunostaining occurs mostly in cytoplasm although nucleus staining can also be seen. TKTL1 positivity is typical for cancer cells, but weak expression can occur in normal cells. In study I on colorectal cancer, TKTL1 associated with Dukes stage B through D, with left-sided disease, and with adenocarcinoma. Patients with high tissue expression of TKTL1 had poor prognosis but TKTL1 was not an independent prognostic factor. In study II, in the subgroup of patients with synchronous liver metastasis, the prognosis was poor in those with a high expression of TKTL1 in primary tumor tissue. In gastric cancer (study III), positive TKTL1 immunostaining associated with positive immunostaining of GLUT1, higher age, male gender, and advanced stage disease (stage II-IV and pT2-4). GLUT1 associated with intestinal type of cancer. TKTL1 served as a marker of poor prognosis in gastric cancer, but not independent, but GLUT1 did not have any prognostic value. Contradictory to previous findings in other cancer types, study IV showed that high expression of TKTL1 in PDAC was a marker of better prognosis in patients over 65 years old and those with distant metastasis, perivascular invasion and stage IV disease, but had no prognostic value in general. Conclusions: TKTL1 was a marker of poor prognosis among patients with colorectal cancer and also among those with synchronous liver metastases and those with intestinal or diffuse gastric cancer. TKTL1 cannot be used as a general prognostic marker in pancreatic ductal adenocarcinoma.
  • Rantala, Elina (Helsingin yliopisto, 2020)
    Objectives Primary uveal melanoma is the most common intraocular malignant tumour in adults. It metastasises in more than half of patients, and even 35 years after the diagnosis of the primary tumour, metastatic uveal melanoma is the leading cause of death. However, no consensus exists regarding either screening or treatment of metastatic disease. The aims of this study are to provide a systematic review and meta-analysis of the current literature regarding the survival of actively treated patients with metastatic uveal melanoma; to describe a national cohort with metastatic uveal melanoma; and by means of this cohort, to analyse both the agreement of imaging modalities in diagnosis of metastatic disease and the stage-stratified survival of patients who received best supportive care (BSC) and active treatment. Methods Study I was a systematic review and meta-analysis of original, peer-reviewed articles published between January 1, 1980 and March 29, 2017, reporting individual-level survival in Kaplan-Meier plot or numerical form. The survival graphs were digitised, and individual survival times were pooled. The median overall survival (OS) was calculated by treatment modality, and modalities were compared by the log-rank test and Cox regression, adopting conventional chemotherapy (CHT) as a reference. For Studies II–IV, a nationwide cohort of patients was identified, whose metastases were diagnosed between January 1, 1999 and December 31, 2016 after the primary tumour had been managed in the Ocular Oncology Service, Helsinki University Hospital, which is a national referral centre. If a computed tomography (CT) or magnetic resonance imaging (MRI) was performed within 60 days of the upper abdominal ultrasonography (US), then the agreement of findings was studied regarding the presence and number of metastases (Study II). To study the survival of patients who received BSC (Study III) or active treatment (Study IV), they were assigned to stages IVa, IVb, and IVc, corresponding to predicted median OS of ≥12 months, <12–6 months, and <6 months, by using the Helsinki University Hospital Working Formulation (WF), previously validated by the European Ophthalmic Oncology Group (OOG). The primary endpoint was OS. It was compared with the Kaplan-Meier product-limit method and Cox proportional hazards regression analysis against BSC and between active treatment modalities (Study IV). Results The meta-analysis included 2,494 patients from 78 studies, and the median OS was 13 months. Of the treatment modalities with >100 patients, the pooled median OS was 5–6 months longer with surgery and IHP and 4 months shorter with CPI than with CHT, for which the median OS was 11 months (P < 0.010, log-rank test). However, OS was subject to identifiable confounding factors related to the heterogeneity in the included studies. The nationwide cohort with metastatic uveal melanoma comprised 338 patients, of whom metastatic disease was diagnosed in 215 patients with US and CT/MRI within 60 days. The sensitivity of US in detecting metastases was 96% (95% confidence interval [CI], 92–98). Moreover, US detected metastases in 95% of the patients and agreed with a staging CT/MRI on their presence in 89% of patients, showing at least the same number of lesions as CT/MRI in 72% of patients, and in nine patients, it detected metastases that CT initially missed for various reasons. In the nationwide cohort, 108 patients who were analysed received BSC and 216 active treatment. Of the patients who received BSC, 24%, 19%, and 55% represented WF stages IVa, IVb, and IVc, respectively. The median OS shortened with increasing stages, and calculated from the treatment decision (i.e. BSC), it was 12 months (95% CI, 9.4–21) for stage IVa, 5.7 months (95% CI, 0.7–11) for stage IVb, and 0.6 months (95% CI, 0.3–0.9) for stage IVc (P < 0.001, log-rank test for trend). Of the 216 patients who received active treatment, 66%, 17%, and 15% represented WF stages IVa, IVb, and IVc, respectively. The median OS also shortened with increasing stages, and calculated from treatment decision, it was 18 months (95% CI, 16–21) for stage IVa, 6.9 months (95% CI, 4.8–9.7) for stage IVb, and 1.9 months (95% CI, 1.6–2.9) for stage IVc (P < 0.001, log-rank test for trend). In stage IVa, patients who received chemoimmunotherapy with interferon or interleukin (CIT) or local therapy, especially surgical resection, as their first-line treatment had a longer OS (18 and 27 months, respectively) than patients who received CHT (10 months) (P < 0.020). However, compared to BSC, OS after CIT in stage IVa was comparable (P > 0.99, corrected for multiple comparisons by stage), as was survival after selective internal radiation therapy (SIRT) (P = 0.58). Finally, we did not observe any convincing difference in OS relative to that after BSC in any comparison in stage-IVb or -IVc patients. Main conclusions The meta-analysis suggested no clinically significant difference by treatment modality, although for patients with solitary hepatic metastases, surgery might have been more effective than CHT. However, the studies reviewed were heterogeneous. In the nationwide cohort, hepatic US was a sensitive follow-up modality, supporting its continued use as the primary imaging method for this purpose. The median OS was comparable to that of BSC patients with main treatment modalities—except with CHT and surgery in stage IVa, the former being associated with shorter and the latter with longer survival. Surgical resection may be superior but is available only for a minority of patients. No current treatment that is available for most patients with metastatic uveal melanoma is likely to appreciably prolong OS. Furthermore, validated staging systems and proper historical control groups are crucial for correct interpretation of the outcomes in non-randomised trials. Keywords uveal melanoma; uveal neoplasms; melanoma; metastasis; treatment; best supportive care; chemotherapy; surgery; chemoimmunotherapy; immunotherapy; targeted therapy; selective internal radiation therapy; isolated hepatic perfusion; transarterial chemoembolisation; ultrasonography; magnetic resonance imaging; computed tomography; survival; staging; meta-analysis; retrospective study
  • Mattsson, Markus (Helsingin yliopisto, 2020)
    The role of human factors in crash causation is a central theme in traffic psychology. Human factors are often roughly categorized into cognitive errors and a tendency to break rules. In data analysis, these psychological properties are treated as measurable, continuous quantities, quite alike weight, length and temperature. Their existence is inferred based on covariation among individual traffic behaviors, which for their part function as measurements of the level of these properties: for instance, driving under the influence of alcohol and speeding are thought to reflect the tendency to break traffic rules. The thesis examines joint variation among traffic behaviors and compares two competing explanations for the phenomenon: 1) The latent variable view of errors and violations, according to which covariation among traffic behaviors is explained by latent, unobservable psychological properties that cause variation in them and 2) The network view, according to which traffic behaviors interact directly with one another, which makes it unnecessary to posit unobservable psychological properties as explanations of behavior. Within traffic psychology, questions such as these are usually not explicitly raised; rather, latent variable models are used as the default tool in data analysis. This practice entails certain assumptions, such as that of the latent variable models measuring the same unobservable properties in the same way across groups of respondents. Moreover, more fundamental questions, such as the theoretical status of latent variables in terms of realist vs. constructionist commitments and the nature of the relationship between latent and observed variables are seldom considered. The present thesis addresses these issues. Studies I and II examine a central property of latent variable models of driver behavior: whether the same psychological properties can be measured in the same way across different subgroups of drivers that are defined based on age, sex and nationality. Both studies utilize rigorous latent variable measurement equivalence analyses. Study I concludes that if the latent variable view is adopted, patterns of covariation among self-reported traffic behaviors are sufficiently different across subgroups of Finnish respondents formed based on age and gender that the latent variables may well be specific to the group in question. Study II reaches a similar conclusion concerning social behavior (breaking rules in traffic) based on a comparison of young Finnish and Irish drivers. On the other hand, it shows that cognitive errors can more readily be interpreted as being related to similar – but not identical – latent variables across countries. Study III assumes a novel point of view, and examines interactions among individual traffic behaviors using psychological network models. This shifts the focus from abstract psychological properties to potentially causal relationships between traffic behaviors: drivers who are more likely to exceed speed limits are also more likely to end up driving close to another vehicle, for instance. In other words, edges in the network models are interpreted as causal hypotheses. Study III also presents Poisson regression models that predict crashes from self-reported traffic behaviors instead of latent variables. This enables various self-reported traffic behaviors to have differential associations with crashes, which is intuitively plausible as, for instance, the violations range from driving under the influence of alcohol to honking at others. The models are built and tested in independent sets of data, making it possible to avoid overfitting the predictive models to data at hand. This procedure, together with selecting variables based on regularized regression, is argued to have useful properties in predicting crashes in traffic psychology. As a whole, the thesis presents two new interpretations for the relationship between individual traffic behaviors and the psychological properties investigated within traffic psychology. First, the psychological properties may reduce to nametags for behaviors that co-occur in certain kinds of contexts and have no causal power of their own. Second, they may prove to be emergent properties arising from the interaction among the behaviors. These alternatives are discussed together with an intermediate view that combines the latent variable view and the network view. The thesis, then, positions itself as a part of recent psychometric discussion in which psychological properties are seen as being formed through the interaction of different behaviors, thoughts and emotions without necessarily treating psychological properties as unidimensional, measurable quantities.
  • Thiede, Anja (Helsingin yliopisto, 2020)
    Developmental dyslexia is at the low end of a spectrum in reading and writing abilities, and may arise despite normal intelligence and education. It often is accompanied by difficulties in domains important for reading, such as phonological processing and verbal working memory. Neural impairments in speech processing are evident in the majority of dyslexic individuals and could be linked to phonological and temporal sampling problems. This thesis integrates four studies for which neuropsychological assessments, magnetoencephalography (MEG), electroencephalography (EEG), and magnetic resonance imaging (MRI) were conducted. The first study examined the influence of familial dyslexia risk on neural speech-sound discrimination in newborn infants (Study I). The second and third study investigated neural processing of speech-sound changes (Study II) and natural speech (Study III) in adult dyslexic and typical readers. The fourth study analyzed anatomical brain abnormalities in dyslexia (Study IV). In addition, the associations of neural measures to reading and related phonological-processing and working-memory skills were investigated (Studies II–IV). The main findings of this thesis were neural speech-processing impairments in newborns at risk of and adults with dyslexia, neuroanatomical abnormalities in adults with dyslexia, and links between the neural measures and skills relevant for reading. Specifically, newborns at risk of dyslexia compared to a group of low risk showed atypical neural speech discrimination responses that may be precursors of phonological deficits in dyslexia (Study I). However, neuromagnetic discrimination responses elicited by the same speech-sound changes suggested no abnormalities in adults with dyslexia, yet, the responses were associated with reading and working memory functions (Study II). Inter-subject correlation (ISC) to natural speech was weaker between dyslexic than typically-reading adults in delta- and high gamma-frequency bands, and stronger in the theta, beta, and low gamma bands, possibly reflecting temporal sampling deficits of natural speech features (Study III). The ISC strength was related to all three reading-relevant skills of interest. Structural abnormalities were observed in dyslexic adults as decreases in grey- and white-matter volumes in temporal, frontal, and subcortical structures important for reading (Study IV). Furthermore, grey- and white-matter volumes were associated with reading and working memory functions. Taken together, this thesis illuminates neural speech processing deficits in dyslexia and its risk at birth and pinpoints associations between reading skills and neurofunctional and -anatomical measures.
  • Arumilli, Meharji (Helsingin yliopisto, 2020)
    Since the annotation of the dog genome in 2005, dogs have emerged as excellent models of human disease. Many disease associations of variant alleles in homologous genes have been discovered in dogs, providing new therapeutic candidates to the corresponding human diseases as well as establishing preclinical large animal models. Significant progress in genetic studies has happened after moving from microarrays to next generation sequencing or combining the two approaches. This transition has required the development and application of novel bioinformatic approaches to facilitate genetics and genomics. This thesis established a variety of bioinformatic approaches and tools to facilitate canine genomics and disease gene discovery. In study I, the successful development and application of the bioinformatic pipelines resulted in the identification of causal variants of three new disease genes, SLC37A2, SCARF2 and FAM20C, of relevance to Caffey disease, van den Ende Gupta syndrome (VDEGS) and Raine syndrome in human, respectively. In study II, novel genomic content was discovered through de novo assembly of genomic reads of Border Collies, which didn’t map to the current canine genome reference. This study revealed sequences that filled the existing gaps in the reference genome and identified gene models that were missing from the reference. Overall, this study reveals novel genomic content to facilitate the improvement of upcoming canine genome reference for disease variant allele discovery in candidate genes. In study III, a novel bioinformatic tool, webGQT, was successfully developed and piloted to handle and filter large amounts of next generation sequencing (NGS) data. This tool is purported to non-bioinformatics users to mine genetic information from millions to billions of variants among thousands of genomes. This tool has been successfully utilized in various disease genetics projects. In summary, new bioinformatic approaches have been successfully developed and applied in this thesis to facilitate both the transition of the field to the NGS era and disease gene discovery and genomics in dogs. These findings in this thesis have implications to veterinary research, diagnostics and human medicine with novel candidate genes in three rare disorders.
  • Halonen, Pia (Helsingin yliopisto, 2020)
    Lichen sclerosus (LS) and lichen planus (LP) are dermatological diseases with similarities and differences. Both inflame the stratified squamous epithelial sites of the body, LS preferring the genitalia and LP the oral cavity and extragenital skin. The diseases are usually symptomatic – painful or itchy or both – and chronic with a capacity to cause complications and decrease the quality of life (QoL). LS diagnosis is usually straightforward, whereas that of LP can be tricky. Good symptomatic control is achieved with treatment, but the recommendations for long-term maintenance treatment and follow-up are ambiguous. Reports of cancers in LS and LP patients are scattered throughout the medical literature, but the associations remain unconfirmed. The effects of lichen on mortality are unknown. The lack of large-scale epidemiological studies of LS and LP motivated this thesis. Finnish nationwide registries are the source of the data for the studies. Two cohorts – one with 7 800 women with LS and the other with 13 400 women with LP – were used to assess the incidence of lichen, associated cancer risk, and mortality following a lichen diagnosis made in the specialized health care. LP was more common than LS in women: The incidence rates were 28 and 19/100 000 between 2003 and 2012. The incidence of LP stayed constant throughout the study period, but the incidence of LS rose from 14 in 2003 to 22/100 000 in 2012. Both lichens are mainly diagnosed in postmenopausal women with maximum incidence rates between 65 and 69 years for LP (64/100 000) and between 75 and 79 years for LS (53/100 000). A small peak in incidence of LS was observed in 5- to 9-year-old girls. Women with an LP diagnosis had an increased risk of cancers of the lip (standardized incidence ratio (SIR) 5.17, 95% confidence interval (CI) 3.06-8.16), tongue (SIR 12.4, 95% CI 9.45-16.0), oral cavity (SIR 7.97, 95% CI 6.79-9.24), larynx (SIR 3.47, 95% CI 1.13-8.10), esophagus (SIR 1.95, 95% CI 1.17-3.04), and vulva (SIR 1.99, 95% CI 1.18-3.13). Women with LS were at increased risk of cancers of the vulva (SIR 33.6, 95% CI 28.9-38.6) and vagina (SIR 3.69, 95% CI 1.01-9.44), whereas the risk of cancer of the cervix was reduced (SIR 0.00, 95% CI 0.00-0.70). The observed cancer risks reflect the different predilection sites of the lichens and confirm the associations between LS and LP and cancers. Women with an LS diagnosis had reduced mortality when compared to the population (standardized mortality ratio (SMR) 0.84, 95% CI 0.78-0.90). In contrast, the mortality of LP women was increased (SMR 1.07, 95% CI 1.02-1.11), with excess mortality from diseases of many organ systems (respiratory diseases (SMR 1.31, 95% CI 1.07-1.57), digestive diseases (SMR 1.39, 95% CI 1.09-1.75), infections (SMR 1.78, 95% CI 1.14-2.64)) and cancers (mouth cancer (SMR 6.50, 95% CI 4.32-9.39), Hodgkin lymphoma (SMR 6.37, 95% CI 1.83-17.2), non-Hodgkin lymphoma (SMR 1.68, 95% CI 1.11-2.44)). A systemic inflammation involvement could, in theory, explain this finding. Based on this thesis, an increased risk of cancers in women with LS and LP is confirmed. Both lichens are fairly common diseases presenting to many different specialties. Knowledge of the diseases’ effects outside the treating physician’s own specialty should be increased, especially for LP, given the increased patient mortality. Women with LP could benefit from care by multidisciplinary teams.
  • Pietikäinen, Johanna (Helsingin yliopisto, 2020)
    Background and Objective: Depression affects up to 10–15% of women during pregnancy and the first postnatal year. Insomnia during pregnancy is a risk factor for postnatal depression, but it is unclear which insomnia symptoms and at which stage of pregnancy we should screen for preventive purposes. While maternal perinatal depression and its consequences for children’s emotional development have received attention, the longitudinal pattern of both maternal and paternal depressive symptoms and the father’s contribution to the risk of emotional symptoms in the offspring is less clear. The aims of this doctoral study were to investigate a) how risk factors, including prenatal sleep, associate with postnatal depressive symptoms (PDS), b) how the accumulation of such risk factors increases the risk of PDS, c) the longitudinal pattern of maternal and paternal depressive symptoms from pregnancy until two years postnatally, and d) how persistent depressive symptoms associate with children’s emotional problems at the ages of 2 and 5 years Materials and methods: This thesis consists of four individual studies from two Finnish birth cohorts. Studies I, III and IV were based on the CHILD-SLEEP birth cohort (n = 1667 mothers, n = 1598 fathers in late pregnancy and n = 949 children at the age of 2 years) and Study II on the FinnBrain birth cohort (n = 3808 mothers in early pregnancy). In Studies I and II, logistic regression analysis was performed, with a higher level of depressive symptoms (CES-D ≥10 (CS) or EPDS ≥11 (FB)) as the dependent variable and various insomnia symptoms as independent variables. In addition, in Study II, odd ratios were calculated for various PDS risk factor combinations and heat maps were constructed to visualize the accumulation of the PDS risk. In Study III, latent trajectory analyses were performed to examine the longitudinal pattern of maternal and paternal depressive symptoms. In Study IV, associations of maternal and paternal depressive symptom trajectories with children’s emotional problems at the ages of 2 and 5 years were examined with a general linear model. Results: In Studies I and II, we found associations between several insomnia symptoms in late pregnancy and PDS after adjusting for background variables and prenatal depressive symptoms: poor general sleep quality, short sleep of ≤7 h and long sleep latency of >20 min. In addition, in the cumulative models of Study II, we found that long sleep latency (≥20 min) in early pregnancy, decreased functioning in middle pregnancy, and insufficient sleep time during late pregnancy associated with PDS. The accumulation of several risk factors such as a history of depression, anxiety and multiparity substantially increased the risk of PDS, and the best model comprising background variables as well as measurements from early, middle and late pregnancy was able to predict 21.2% of PDS (Nagelkerke 0.21). In Study III, three stable depressive symptom trajectories were found for both mothers and fathers: stable low (n = 1053, 63.1% mothers, n = 1201, 74.9% fathers), stable intermediate (n = 470, 28.1% mothers, n = 362, 22.6% fathers) and stable high (n = 147, 8.8% mothers, n = 41, 2.6% fathers). Depression in one parent also associated with increased depressive symptoms in the spouse (χ2 = 104.6, p < 0.001). In Study IV, we constructed combined parental depressive symptom trajectories and found a group with a higher level of persistent maternal depressive symptoms or depressive symptoms in both parents to associate with an increased risk of children’s emotional problems, whereas paternal depressive symptoms did not increase this risk for children if the mother was non-depressive. A higher level of maternal depressive symptoms was associated with a higher level of children’s emotional problems in a dose-dependent manner at the ages of both 2 and 5 years, whereas no such pattern was found in relation to a higher level of paternal depressive symptoms. Importantly, persistent subclinical maternal depressive symptoms increased the risk of externalizing and internalizing problems among both 2- and 5-year-olds. Conclusions: Long sleep latency in early pregnancy and several insomnia symptoms in late pregnancy might be vulnerability markers for an increased risk of PDS and thus potential screening items in order to better detect women at increased risk of PDS. The accumulation of risk factors in PDS should be taken into account when deciding when preventive interventions are necessary, and this study is the first to use heat maps to visualize such an accumulation. Maternal depressive symptoms should preferably be detected during pregnancy and treated with low threshold counselling and psychotherapeutic interventions as the first-line treatment. The screening of both parents is recommendable if one of them presents with depressive symptoms during the perinatal period. Individual, group and couple therapeutic interventions should be developed in the public sector in order to respond to the growing need for non-pharmacological treatments for perinatal mental health disorders.
  • Mustonen, Neea (Helsingin yliopisto, 2020)
    Background: The incidence of immune-mediated diseases, such as type 1 diabetes (T1D), celiac disease (CD), and allergic diseases, has been increasing since the 1950s. This trend has been particularly conspicuous in affluent Westernized countries. Etiologies behind these diseases are still poorly understood, but socioeconomic circumstances and environmental factors may play a crucial role in their pathomechanisms. The hygiene hypothesis aims to explain the rising trend in immune-mediated diseases by suggesting that children’s developing immune systems are vulnerable to malfunction in environments that provide inadequate microbial exposure early in life. Aims: This thesis aims to explore how early clinical infections, their medications, and allergic sensitization associate with the development of T1D, CD, and allergies in three geographically close areas in Finland, Estonia, and Russian Karelia. These neighboring countries have shown clear contrasts in the frequencies of immune-mediated diseases, standards of hygiene, and socioeconomic circumstances. Methods: As part of the DIABIMMUNE study, over 4500 children from Finland, Estonia, and Russian Karelia were prospectively followed either from birth to 3 years of age or from 3 to 5 years of age. Children attended regular clinical visits that comprised physical examinations and the collection of biological samples for the assessment of immune-mediated outcomes. Children’s parents prospectively reported all participating children’s illnesses, infections, medications, and allergic symptoms that appeared during the follow-up. Results: Regarding infectious illnesses, respiratory infections were most frequently reported, followed by gastrointestinal infections, unlocalized febrile episodes, and other localized infections. Compared to Russian Karelian and Estonian children, Finnish children experienced more infections and used more medications. Finnish children also had the highest frequency of T1D, CD, and allergic sensitization. In all, progression to T1D was associated with a higher number of infections, and progression to CD with a higher number of febrile infections. Of systemic antibiotics and antipyretic analgesics, penicillin and acetaminophen, respectively, were the most common. Children who progressed to T1D or CD and their unaffected peers used medications similarly. Children with and without allergic sensitization had similar frequencies of infectious diseases and their medications. Children carrying genetic risk for autoimmunity developed immunoglobulin E (IgE) sensitization more often than their general-population peers. Early IgE sensitization associated with an increased risk for the development of clinical allergy symptoms and CD, but not for T1D. The predictive value of the sensitization for clinical allergies was age-dependent, and in all, sensitization predicted allergy-related symptoms quite poorly. Sensitization tests predicted allergic symptoms caused by aeroallergens better than those caused by dietary allergens, and the results for aeroallergen sensitization were more consistent between serum and skin testing methods. Conclusions: Immune-mediated diseases, early-life infections, and the use of various medications were more common in Finland than in the neighboring areas of Estonia and Russian Karelia. The co-occurrence of allergic and autoimmune diseases may suggest that, to a certain extent, these diseases share some common pathomechanisms. Keywords: aeroallergen, allergy, antibiotic, antipyretic analgesic, atopy, autoimmunity, celiac disease, childhood infection, dietary allergen, Estonia, Finland, human leukocyte antigen, hygiene hypothesis, IgE sensitization, islet autoimmunity, Russian Karelia, skin prick test, type 1 diabetes.  
  • Cajuso Pons, Tatiana (Helsingin yliopisto, 2020)
    Colorectal cancer (CRC) is the third most common cancer type and a major cause for cancer deaths. Retrotransposons are transposable elements (TE) able to mobilize and insert via an RNA intermediate. Although germline retrotransposition can contribute to genetic diversity, uncontrolled retrotransposition can lead to genomic instability. Retrotransposons are normally repressed by promoter methylation however, they become highly active in many cancers, such as CRC. Since retrotransposons are difficult to detect, their role in tumorigenesis has remained considerably unexplored. The main goal of this thesis project was to further understand the impact of retrotransposition in colorectal tumorigenesis utilizing whole genome sequencing (WGS) and Nanopore sequencing. In study I, we detected an active reference long interspersed element-1 (LINE-1) located in the first intron of TTC28. This active LINE-1 led to the most frequent somatic structural rearrangement in our dataset, with a total of 83 somatic retrotranspositions in 92 CRCs. In study II, we applied long-distance inverse-PCR (LDI-PCR) with Nanopore sequencing to detect retrotranspositions arising from the active LINE-1 identified in study I. We identified 25 subclonal insertions in addition to 14 insertions previously detected by WGS, indicating active retrotransposition during the tumorigenic process. In study III, we characterized somatic retrotransposon insertions in 202 colorectal tumor whole genomes. Among recurrent insertions in fragile sites and cancer genes, we identified two insertions in exon 16 of APC, suggesting that retrotransposon insertions can contribute to tumor initiation. Furthermore, the number of somatic insertions correlated with the CpG island methylator phenotype (CIMP), the genomic fraction of allelic imbalance (AI), and poor CRC survival. These findings suggest that the clinical impact of retrotransposition in CRC might be more important than previously acknowledged, although several questions remain unanswered. Future work should shed light on the timing and novel mechanisms by which retrotransposition could influence tumorigenesis. The better understanding of the role of both somatic and germline retrotransposition could provide tools for patient stratification and cancer prevention.

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