Browsing by Subject "MEDICINE"

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  • Gupta, Abhishekh; Gautam, Prson; Wennerberg, Krister; Aittokallio, Tero (2020)
    Accurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates, and experimental noise to better characterize drug-induced effects. We demonstrate an improved consistency and accuracy of NDR compared to existing metrics in assessing drug responses of cancer cells in various culture models and experimental setups. Notably, NDR reliably captures both toxicity and viability responses, and differentiates a wider spectrum of drug behavior, including lethal, growth-inhibitory and growth-stimulatory modes, based on a single viability readout. The method will therefore substantially reduce the time and resources required in cell-based drug sensitivity screening. Abhishekh Gupta et al. present a normalized drug response (NDR) metric for accurate quantification of drug sensitivity in cell-based high-throughput assays. They show that NDR captures both toxicity and viability responses to improve drug effect classification over existing methods.
  • Sturesson, L.; Lindstrom, V.; Castren, M.; Niemi-Murola, L.; Falk, A. -C. (2016)
    Background: Pain is one of the most common symptoms in the Emergency Department (ED) and is the cause of more than half of the visits to the ED. Several attempts to improve pain management have been done by using, for example, standards/guidelines and education. To our knowledge no one has investigated if and how different actions over a longitudinal period affect the frequency of pain documentation in the ED. Therefore the aim of this study was to describe the frequency of documented pain assessments in the ED. Method: A cross-sectional study during 2006-2012 was conducted. The care of patients with wrist/arm fractures or soft tissue injuries on upper extremities was evaluated. Result: Despite various actions our result shows that mandatory pain assessment in the patient's computerized medical record was the only successful intervention to improve the frequencies of documentation of pain assessment during care in the ED. During the study period, no documentation of reassessment of pain was found despite the fact that all patients received pain medication. Conclusion: To succeed in increasing the frequency of documented pain assessment, mandatory pain rating is a successful action. However, the re-evaluation of documented pain assessment was nonexisting. (C) 2016 Elsevier Ltd. All rights reserved.
  • Ranta, Jukka; Airaksinen, Manu; Kirjavainen, Turkka; Vanhatalo, Sampsa; Stevenson, Nathan J. (2021)
    Objective To develop a non-invasive and clinically practical method for a long-term monitoring of infant sleep cycling in the intensive care unit. Methods Forty three infant polysomnography recordings were performed at 1-18 weeks of age, including a piezo element bed mattress sensor to record respiratory and gross-body movements. The hypnogram scored from polysomnography signals was used as the ground truth in training sleep classifiers based on 20,022 epochs of movement and/or electrocardiography signals. Three classifier designs were evaluated in the detection of deep sleep (N3 state): support vector machine (SVM), Long Short-Term Memory neural network, and convolutional neural network (CNN). Results Deep sleep was accurately identified from other states with all classifier variants. The SVM classifier based on a combination of movement and electrocardiography features had the highest performance (AUC 97.6%). A SVM classifier based on only movement features had comparable accuracy (AUC 95.0%). The feature-independent CNN resulted in roughly comparable accuracy (AUC 93.3%). Conclusion Automated non-invasive tracking of sleep state cycling is technically feasible using measurements from a piezo element situated under a bed mattress. Significance An open source infant deep sleep detector of this kind allows quantitative, continuous bedside assessment of infant's sleep cycling.
  • FIDELITY Finnish Degenerative Meni; Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Itälä, Ari; Joukainen, Antti; Kalske, Juha; Nurmi, Heikki; Kumm, Jaanika; Sillanpää, Niko; Kiekara, Tommi; Turkiewicz, Aleksandra; Toivonen, Pirjo; Englund, Martin; Taimela, Simo; Järvinen, Teppo L. N. (2020)
    Objectives To assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up. Design Multicentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial. Setting Orthopaedic departments in five public hospitals in Finland. Participants 146 adults, mean age 52 years (range 35-65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised. Interventions APM or placebo surgery (diagnostic knee arthroscopy). Main outcome measures We used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade >= 1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function ( Western Ontario Meniscal Evaluation Tool (WOMET), Lysholm, and knee pain after exercise using a numerical rating scale). Results There was a consistent, slightly greater risk for progression of radiographic knee osteoarthritis in the APM group as compared with the placebo surgery group (adjusted absolute risk difference in increase in Kellgren-Lawrence grade >= 1 of 13%, 95% CI -2% to 28%; adjusted absolute mean difference in OARSI sum score 0.7, 95% CI 0.1 to 1.3). There were no relevant between-group differences in the three patient-reported outcomes: adjusted absolute mean differences (APM vs placebo surgery), -1.7 (95% CI -7.7 to 4.3) in WOMET, -2.1 (95% CI -6.8 to 2.6) in Lysholm knee score, and -0.04 (95% CI -0.81 to 0.72) in knee pain after exercise, respectively. The corresponding adjusted absolute risk difference in the presence of mechanical symptoms was 18% (95% CI 5% to 31%); there were more symptoms reported in the APM group. All other secondary outcomes comparisons were similar. Conclusions APM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.
  • Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Itälä, Ari; Joukainen, Antti; Nurmi, Heikki; Kalske, Juha; Ikonen, Anna; Järvelä, Timo; Järvinen, Tero A. H.; Kanto, Kari; Karhunen, Janne; Knifsund, Jani; Kröger, Heikki; Kääriäinen, Tommi; Lehtinen, Janne; Nyrhinen, Jukka; Paloneva, Juha; Päiväniemi, Outi; Raivio, Marko; Sahlman, Janne; Sarvilinna, Roope; Tukiainen, Sikri; Välimäki, Ville-Valtteri; Äärimaa, Ville; Toivonen, Pirjo; Järvinen, Teppo L. N.; FIDELITY Finnish Degenerative (2018)
    Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.
  • Gatej, Alexandra-Raluca; Lamers, Audri; van Domburgh, Lieke; Crone, Matty; Ogden, Terje; Rijo, Daniel; Aronen, Eeva; Barroso, Ricardo; Boomsma, Dorret I.; Vermeiren, Robert (2019)
    Background: Severe behavioural problems (SBPs(1)) in childhood are highly prevalent, impair functioning, and predict negative outcomes later in life. Over the last decade, clinical practice guidelines for SBPs have been developed across Europe to facilitate the translation of scientific evidence into clinical practice. This study outlines the results of an investigation into academic experts' perspectives on the current prevalence, implementation, and utility of clinical guidelines for SBPs in children aged 6-12 across Europe. Methods: An online semi-structured questionnaire was completed by 28 psychiatry and psychology experts from 23 countries. Results: Experts indicated that approximately two thirds of the included European countries use at least an unofficial clinical document such as textbooks, while nearly half possess official guidelines for SBPs. Experts believed that, although useful for practice, guidelines' benefits would be maximised if they included more specific recommendations and were implemented more conscientiously. Similarly, experts suggested that unofficial clinical documents offer a wide range of treatment options to individualise treatment from. However, they stressed the need for more consistent, evidence-based clinical practices, by means of developing national and European clinical guidelines for SBPs. Conclusions: This study offers a preliminary insight into the current successes and challenges perceived by experts around Europe associated with guidelines and documents for SBPs, acting as a stepping stone for future systematic, in-depth investigations of guidelines. Additionally, it establishes experts' consensus for the need to develop official guidelines better tailored to clinical practice, creating a momentum for a transition towards European clinical guidelines for this population. (c) 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • FINGER Study Grp; Stephen, Ruth; Liu, Yawu; Ngandu, Tiia; Antikainen, Riitta; Hulkkonen, Juha; Koikkalainen, Juha; Levälahti, Esko; Parkkola, Riitta; Pippola, Pauliina; Rinne, Juha; Strandberg, Timo; Tuomilehto, Jaakko; Vanninen, Ritva; Kivipelto, Miia; Soininen, Hilkka; Solomon, Alina (2019)
    BackgroundThe Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a multicenter randomized controlled trial that reported beneficial effects on cognition for a 2-year multimodal intervention (diet, exercise, cognitive training, vascular risk monitoring) versus control (general health advice). This study reports exploratory analyses of brain MRI measures.MethodsFINGER targeted 1260 older individuals from the general Finnish population. Participants were 60-77years old, at increased risk for dementia but without dementia/substantial cognitive impairment. Brain MRI scans were available for 132 participants (68 intervention, 64 control) at baseline and 112 participants (59 intervention, 53 control) at 2years. MRI measures included regional brain volumes, cortical thickness, and white matter lesion (WML) volume. Cognition was assessed at baseline and 1- and 2-year visits using a comprehensive neuropsychological test battery. We investigated the (1) differences between the intervention and control groups in change in MRI outcomes (FreeSurfer 5.3) and (2) post hoc sub-group analyses of intervention effects on cognition in participants with more versus less pronounced structural brain changes at baseline (mixed-effects regression models, Stata 12).ResultsNo significant differences between the intervention and control groups were found on the changes in MRI measures. Beneficial intervention effects on processing speed were more pronounced in individuals with higher baseline cortical thickness in Alzheimer's disease signature areas (composite measure of entorhinal, inferior and middle temporal, and fusiform regions). The randomization groupxtimexcortical thickness interaction coefficient was 0.198 (p=0.021). A similar trend was observed for higher hippocampal volume (groupxtimexhippocampus volume interaction coefficient 0.1149, p=0.085).ConclusionsThe FINGER MRI exploratory sub-study did not show significant differences between the intervention and control groups on changes in regional brain volumes, regional cortical thicknesses, or WML volume after 2years in at-risk elderly without substantial impairment. The cognitive benefits on processing speed of the FINGER intervention may be more pronounced in individuals with fewer structural brain changes on MRI at baseline. This suggests that preventive strategies may be more effective if started early, before the occurrence of more pronounced structural brain changes.Trial registrationClinicalTrials.gov, NCT01041989. Registered January 5, 2010.
  • Raj, R.; Bendel, S.; Reinikainen, M.; Hoppu, S.; Laitio, R.; Ala-Kokko, T.; Curtze, S.; Skrifvars, M. B. (2018)
    Background: Neurocritical illness is a growing healthcare problem with profound socioeconomic effects. We assessed differences in healthcare costs and long-term outcome for different forms of neurocritical illnesses treated in the intensive care unit (ICU). Methods: We used the prospective Finnish Intensive Care Consortium database to identify all adult patients treated for traumatic brain injury (TBI), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) and acute ischemic stroke (AIS) at university hospital ICUs in Finland during 2003-2013. Outcome variables were one-year mortality and permanent disability. Total healthcare costs included the index university hospital costs, rehabilitation hospital costs and social security costs up to one year. All costs were converted to euros based on the 2013 currency rate. Results: In total 7044 patients were included (44% with TBI, 13% with ICH, 27% with SAH, 16% with AIS). In comparison to TBI, ICH was associated with the highest risk of death and permanent disability (OR 2.6, 95% CI 2.1-3.2 and OR 1.7, 95% CI 1.4-2.1), followed by AIS (OR 1.9, 95% CI 15-23 and OR 1.5, 95% CI 1.3-1.8) and SAH (OR 1.8, 95% CI 1.5-2.1 and OR 0. 8, 95% CI 0.6-0.9), after adjusting for severity of illness. SAH was associated with the highest mean total costs ((sic)51,906) followed by ICH ((sic)47,661), TBI ((sic)43,916) and AIS ((sic)39222). Cost per independent survivor was lower for TBI ((sic)58,497) and SAH ((sic)96,369) compared to AIS ((sic)104,374) and ICH ((sic)178,071). Conclusion: Neurocritical illnesses are costly and resource-demanding diseases associated with poor outcomes. Intensive care of patients with TBI or SAH more commonly result in independent survivors and is associated with lower total treatments costs compared to ICH and AIS.
  • Louhimo, Riku i; Laakso, Marko; Belitskin, Denis; Klefstrom, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa (2016)
    Background: Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. Results: We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Conclusions: Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.
  • Liira, Helena; Koskela, Tuomas; Thulesius, Hans; Pitkala, Kaisu (2016)
    Objective: Research and PhDs are relatively rare in family medicine and primary care. To promote research, regular one-year research courses for primary care professionals with a focus on clinical epidemiology were started. This study explores the academic outcomes of the first four cohorts of research courses and surveys the participants' perspectives on the research course. Design: An electronic survey was sent to the research course participants. All peer-reviewed scientific papers published by these students were retrieved by literature searches in PubMed. Setting: Primary care in Finland. Subjects: A total of 46 research course participants who had finished the research courses between 2007 and 2012. Results: Of the 46 participants 29 were physicians, eight nurses, three dentists, four physiotherapists, and two nutritionists. By the end of 2014, 28 of the 46 participants (61%) had published 79 papers indexed in PubMed and seven students (15%) had completed a PhD. The participants stated that the course taught them critical thinking, and provided basic research knowledge, inspiration, and fruitful networks for research. Conclusion: A one-year, multi-professional, clinical epidemiology based research course appeared to be successful in encouraging primary care research as measured by research publications and networking. Activating teaching methods, encouraging focus on own research planning, and support from peers and tutors helped the participants to embark on research projects that resulted in PhDs for 15% of the participants.
  • Häikiö, Juha; Yli-Kauhaluoma, Sari; Pikkarainen, Minna; Iivari, Marika; Koivumäki, Timo (2020)
    The healthcare and wellness sector currently attempts to provide more proactive service models with data-driven solutions. This study examines the expectations and values related to personal data i.e. data valences from the perspective of service providers and individual users. The study is based on the analysis of extensive empirical material collected through interviews and a collaborative workshop. The data was collected in one cultural context, Finland. The results suggest that the potential service providers and users have similar expectations regarding self-evidence of data while the main differences concern the expectations of transparency. The results of the study propose some basic requirements for the development of personalised data-driven services in future. The study suggests that basic requirements for the development of future data driven services concern expectations to usable data visualisations, data as a motivator, data accuracy and data transparency. Even though there are varying expectations to personal health data and even some concerns, it can be seen that here different ecosystem actors primarily perceived the wider use of personal health and wellness data as a positive trend. It can be concluded that collaborative personal data-driven service ecosystems are an integral part of development towards proactive service models in healthcare.
  • Kvarnström, Kirsi; Westerholm, Aleksi; Airaksinen, Marja; Liira, Helena (2021)
    Introduction: Medication adherence continues to be a significant challenge in healthcare, and there is a shortage of effective interventions in this area. This scoping review studied the patient-related factors of medication adherence. Methods: We searched Medline Ovid, Scopus, and Cochrane Library from January 2009 to June 2021 to find the most recent original qualitative studies or systematic reviews that addressed the patient-related factors of medication adherence in treating chronic conditions. We used the PRISMA-ScR checklist to ensure the quality of the study. Results: The initial search revealed 4404 studies, of which we included 89 qualitative studies in the scoping review. We inductively organized the patient-related factors causing barriers, as well as the facilitators to medication adherence. The studies more often dealt with barriers than facilitators. We classified the factors as patient-specific, illness-specific, medication-related, healthcare and system-related, sociocultural, as well as logistical and financial factors. Information and knowledge of diseases and their treatment, communication, trust in patient-provider relationships, support, and adequate resources appeared to be the critical facilitators in medication adherence from the patient perspective. Discussion and conclusions: Patients are willing to discuss their concerns about medications. Better communication and better information on medicines appear to be among the critical factors for patients. The findings of this scoping review may help those who plan further interventions to improve medication adherence.
  • Snell, Karoliina (2019)
    In Finland, as well as all over the globe, great weight is put on the possibilities of large data collections and ‘big data’ for generating economic growth, enhancing medical research, and boosting health and wellbeing in totally new ways. This massive data gathering and usage is justified by the moral principle of improving health. The imperative of health thus legitimizes data collection, new infrastructures and innovation policy. It is also supported by the rhetoric of health promotion. New arrangements in health research and innovations in the health sector are justified, as they produce health, while the moral principle of health also obligates individual persons to pursue healthy lifestyles and become healthy citizens. I examine how, in this context of Finnish data-driven medicine, arguments related to privacy and autonomy become silenced when contrasted with the moral principle of health.
  • Kerminen, H.; Jamsen, E.; Jantti, P.; Huhtala, H.; Strandberg, T.; Valvanne, J. (2016)
    Introduction: Comprehensive geriatric assessment (CGA) is one of the most important evaluation tools in geriatrics, but there is variability in its use in different clinical settings. In this study we aimed to clarify how Finnish geriatricians apply CGA in their clinical practice. Methods: We organized a web-based survey among the members of Finnish Geriatricians (n = 248). The questionnaire included items about use and content of CGA. The evaluated domains were assessment of cognition, nutrition and functional ability, evaluation of depression, and measurement of orthostatic blood pressure. Results: Altogether 121 physicians (49%) responded, and the present analysis included 95 geriatricians performing clinical work. Majority of the respondents (94%) used CGA. Of them, 38% performed CGA to all new patients and 62% to selected patients only. Ten respondents (11%) incorporated all five domains into CGA whereas others selected domains according to their clinical judgment. Greater proportion of female than male physicians included evaluation of depression (39% vs. 16%, P = 0.045) and assessment of functional ability (48% vs. 24%, P = 0.01) always in CGA. Respondents, who applied CGA to all new patients, incorporated nutritional assessment (68% vs. 34%, P = 0.002) and measurement of orthostatic blood pressure (76% vs. 54%, P = 0.04) always into CGA more often than those who performed CGA to selected patients only. Respondents' working conditions were not associated with the application of CGA. Conclusions: Majority of the respondents performed CGA to their patients. The content of CGA varied between geriatricians. Incomplete evaluation may lead to inadequate detection of geriatric syndromes and other problems. (C) 2016 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
  • Aavik, Kadri (2021)
    This article examines institutional resistance to veganism, with a focus on the medical system. Based on a qualitative analysis of vegans’ accounts of medical encounters in Estonia, collected via an online questionnaire, I argue that the vegan body is socially constructed as a deviant entity by medical professionals. I suggest that the medical professionals’ perceptions of vegans are based less on the actual conditions of their bodies but more on ideas about what are socially and politically acceptable identities and (bodily) practices. Deviance is produced through association with the uneasy category of ‘vegan’. The experiences of vegans in the medical system illuminate the role of powerful social institutions in resisting transition towards more ethical and ecologically sustainable food practices and in endorsing human exploitation of other animals.
  • Skaga, Erlend; Kulesskiy, Evgeny; Fayzullin, Artem; Sandberg, Cecilie J.; Potdar, Swapnil; Kyttälä, Aija; Langmoen, Iver A.; Laakso, Aki; Gaal-Paavola, Emilia; Perola, Markus; Wennerberg, Krister; Vik-Mo, Einar O. (2019)
    BackgroundA major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naive glioblastoma stem cells (GSC) is unclear.MethodsWe cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation.ResultsAlthough tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p
  • He, Liye; Tang, Jing; Andersson, Emma I.; Timonen, Sanna; Koschmieder, Steffen; Wennerberg, Krister; Mustjoki, Satu; Aittokallio, Tero (2018)
    The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway cross-talk, personalized combination treatments targetingmultiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug-target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T-cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10 of 24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL. Significance: An integrated use of functional drug screening combined with genomic and molecular profiling enables patient-customized prediction and testing of drug combination synergies for T-PLL patients. (C) 2018 AACR.
  • Bruun, Jarle; Kryeziu, Kushtrim; Eide, Peter W.; Moosavi, Seyed; Eilertsen, Ina A.; Langerud, Jonas; Rosok, Bård; Totland, Max; Brunsell, Tuva; Pellinen, Teijo; Saarela, Jani; Bergsland, Christian H.; Palmer, Hector G.; Brudvik, Kristoffer; Guren, Tormod; Dienstmann, Rodrigo; Guren, Marianne G.; Nesbakken, Arild; Bjornbeth, Bjorn Atle; Sveen, Anita; Lothe, Ragnhild A. (2020)
  • Remes, Satu Maria; Leijon, Helena; Vesterinen, Tiina; Louhimo, Johanna; Pulkkinen, Ville; Ezer, Sini; Kere, Juha; Haglund, Caj; Arola, Johanna (2020)
    Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor-metastasis pairs, for PCSK2 expression with polymer-based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so-called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re-evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki-67 in well-differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.
  • Kaskinen, Anu; Ayeboa-Sallah, Benjamin; Teivaanmäki, Tiina; Wärnhjelm, Elina; Korhonen, Liisa; Helve, Otto (2018)
    Background: Pediatric physician-led Web-based chat services offer a novel, low-threshold communication channel between caregivers and physicians. Objective: Our aim was to describe chat conversations between caregivers and physicians in a Web-based chat service to determine the factors that should be considered when planning a similar chat service. We also aimed to evaluate whether caregivers considered the consultations helpful, whether physicians considered they could answer caregivers' questions, and whether further face-to-face medical contact was needed. Methods: In September 2015, a private medical center for children in the greater Helsinki area initiated a Web-based chat service, accessible via any device with an internet connection, open from 9 am to 9 pm local time. Four residents in pediatrics, who had performed at least 60% of their 6-year residency program, served as the physicians responsible for chat consultations with caregivers of children. Between October 2015 and March 2016, 343 consecutive consultations were immediately evaluated by a chat physician. On average, caregivers were followed up by email questionnaire 7-14 days later, which 98 caregivers answered a median of 11 (interquartile range, IQR, 7-20) days later. Results: The age of the children whose caregivers contacted the chat service was a median of 2.1 (IQR 0.83-4.69) years, and 29.8% (102/342) of the children were less than 1 year old. The majority (119/343, 34.7%) of the chat conversations took place from 9 am to noon, and infections were the most common concern in over half of cases (189/343, 55.1%). Chat physicians recommended a face-to-face appointment with a physician for that same day in 13.7% (47/343) of the cases. A face-to-face exam was recommended for that same day more often if the chat concerned infection (36/189, 19.0% cases) compared with other reasons (11/154, 7.1%, cases; P=. 001). Physicians felt capable of answering caregivers' questions in 72.6% (249/343) of the cases, whereas 93% (91/98) of caregivers considered physicians' answers helpful. Whether caregivers had to take their children to see a physician that same day or whether caregivers' main concern was infection was not found to be associated with whether caregivers considered physicians' answers helpful or not. However, physicians felt more capable of answering caregivers' questions when the main concern was infection. Conclusions: Parental consultations via Web-based chat service often take place before noon and focus on infection-related issues as well as on the health and illness of very young children. These factors should be considered when planning or setting up such a service. Based on the high satisfaction with the chat service by both physicians and caregivers, Web-based chat services may be a useful way to help caregivers with concerns about their child's health or illness.