Browsing by Subject "Cancer"

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  • Arasu, Uma Thanigai; Deen, Ashik Jawahar; Pasonen-Seppänen, Sanna; Heikkinen, Sami; Lalowski, Maciej; Kärnä, Riikka; Härkönen, Kai; Mäkinen, Petri; Lazaro-Ibañez, Elisa; Siljander, Pia R-M; Oikari, Sanna; Levonen, Anna-Liisa; Rilla, Kirsi (2020)
    Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
  • Salaspuro, Mikko (2017)
    Ethanol is neither genotoxic nor mutagenic. Its first metabolite acetaldehyde, however, is a powerful local carcinogen. Point mutation in ALDH2 gene proves the causal relationship between acetaldehyde and upper digestive tract cancer in humans. Salivary acetaldehyde concentration and exposure time are the two major and quantifiable factors regulating the degree of local acetaldehyde exposure in the ideal target organ, oropharynx. Instant microbial acetaldehyde formation from alcohol represents >70% of total ethanol associated acetaldehyde exposure in the mouth. In the oropharynx and achlorhydric stomach acetaldehyde is not metabolized to safe products, instead in the presence of alcohol it accumulates in saliva and gastric juice in mutagenic concentrations. A common denominator in alcohol, tobacco and food associated upper digestive tract carcinogenesis is acetaldehyde. Epidemiological studies on upper GI tract cancer are biased, since they miss information on acetaldehyde exposure derived from alcohol and acetaldehyde present in 'non-alcoholic' beverages and food. (C) 2017 Published by Elsevier Ltd.
  • Hiltunen, Anukka (Helsingfors universitet, 2010)
    The major problem in cancer treatment is toxic side effects of the chemotherapy. Typically less than 1 % of the administered free drug reaches target cells while the rest damages non-diseased cells. Toxic side effects often limit dose escalation of anticancer drugs which leads to incomplete tumor response, early disease relapse and possible the development of drug resistance. Liposomes can be targeted in cancer tissue with passive or active targeting. In passive targeting the liposomes accumulate in abnormally formed cancer tissue through the process of extravasation and enhance the concentration of liposomal drug in solid tumor. To further improve the anticancer efficiency of passive targeted liposomes is to couple a targeting ligand to the surface of the drug carrier (i.e. active targeting). The ligand specifically binds to a surface epitope on the target cell leading to the accumulation of the liposomal drug inside the tumor cells. The aim of this study was to investigate the cytotoxicity of targeted immunoliposomes. In experimental part the liposomes were constructed using cetuximab (C225, Erbitux®) antibody and evaluated for specific cellular uptake and cytotoxicity in vitro. Cetuximab antibody is specific and selective inhibitor of HER-1 -protein (ErbB-1, EGFR, epidermal growth factor receptor). HER1 -protein is frequently expressed in high levels in human carcinomas (for example in lung and colorectal cancers, head, neck and breast cancers and in pancreatic, ovarian, prostate and bladder carcinomas). Specific immunoliposome uptake and cytotoxicity were studied in SKOV-3cells (ovarian adenocarsinoma cell line) which overexpress the EGF -receptor. Monkey kidney epithelial cells (CV-1) were used as a control cell line which represents non-diseased cells. Active targeting and cellular uptake of liposomes were investigated in cell uptake studies. Non-targeted pegylated liposomes were used as control liposomes. Specific binding of the cetuximab antibody to EGF -receptor was noticed in competition studies. The in vitro cytotoxicity of doxorubicin containing immunoliposomes was studied with Alamar Blue® cell viability assay. Liposome size was determined at intervals of about two weeks during the experimental part. In conclusions, antibody targeted immunoliposomes showed greater cellular uptake and cytotoxicity in EGFRoverexpressing target cells (SKOV-3) than the corresponding non-targeted liposomal drug. Immunoliposomes showed greater cytotoxicity after five days incubation, which can be a consequence of liposome formulation and slow rate of release of doxorubicin. In contrast, antibody targeted liposomes did not show specific cellular uptake or cytotoxicity in CV-1 control cell line. In clinical cancer therapy actively targeted liposomes could improve the therapeutic effectiveness of the liposomal preparations. Many studies have shown that ligand-bearing liposomes will selectively bind to target cells in vitro, but only few studies have shown the possibility in vivo.
  • Karlsson, Elin (Helsingin yliopisto, 2020)
    LAPTM4B är ett transmembranprotein som finns i lysosomer och sena endosomer. En isoform av proteinet, LAPTM4B-35 är ofta överuttryckt i flera cancerformer och det främjar bland annat cancercellernas proliferation och migration samt reglerar cellernas endocytos. Proteinet påverkar intracellulär cellsignalering genom flera olika rutter. LAPTM4B påverkar cellernas sfingolipid-metabolism som också har en central roll för cancercellers proliferation och migration. I detta projekt undersöktes effekten av LAPTM4B-knockout på uttrycket av sfingosin 1-fosfat receptorer i A431-celler och resultaten jämfördes med uttrycket av samma receptorer i LAPTM4B-överuttryckande A431-celler. Vi kunde se ett minskat uttryck av sfingosin 1-fosfat receptor 1 (S1PR1) i LAPTM4B-knockout celler. I projektet undersöktes även hur dessa cellers migration påverkades då de stimulerades av sfingosin 1-fosfat (S1P). Ett tydligt tecken var att varje gång cellerna stimulerades med S1P blev migrationen av cellerna mindre. Effekten var lägre i LAPTM4B-knockout celler jämfört med i vild typs A431-celler. I projektet ingick en undersökning av halten glutation i LAPTM4B-knockout celler jämfört med i LAPTM4B-överuttryckande celler. Resultaten från dessa experiment var att LAPTM4B-knockout celler innehåller lägre halter av glutation än LAPTM4B-överuttryckande celler. Detta projekt understöder att det finns interaktioner mellan sfingolipid-signalering och LAPTM4B och ger ny information om endosomala signaleringsmekanismer.
  • Elovainio, Marko; Lumme, Sonja; Arffman, Martti; Manderbacka, Kristiina; Pukkala, Eero; Hakulinen, Christian (2021)
    Lack of social contacts has been associated with an increased risk of cancer mortality, but it is not known whether living alone increases the risk of cancer incidence or case fatality. We examined the association between living alone with cancer incidence, case-fatality and all-cause mortality in eight most common cancers. All patients with their first cancer diagnosis in 2000-2017 were identified from the nationwide Finnish Cancer Registry. Information on living arrangements was derived from Statistics Finland. The incidence analyses were conducted using Poisson regression. The total Finnish population served as the population at risk. Fine-Gray model was used to estimate case-fatality and Cox proportional regression model all-cause mortality. In men, we found an association between history of living alone and excess lung cancer incidence but living alone seemed to be associated with lower incidence of prostate cancer and skin melanoma. In women, living alone was more consistently associated with higher incidence of all studied cancers. Cancer patients living alone had an 11%-80% statistically significantly increased case-fatality and all-cause mortality in all studied cancers in men and in breast, colorectal and lung cancer in women. Living alone is consistently associated with increased cancer incidence risk in women but only in some cancers in men. Both men and women living alone had an increased risk of all-cause mortality after cancer diagnosis.
  • Salaspuro, Mikko (2020)
    Background:Alcohol consumption and ethanol in alcoholic beverages are group 1 carcinogens, that is, carcinogenic to humans. However, ethanol itself is neither genotoxic nor mutagenic. Based on unique gene-epidemiologic and gene-biochemical evidence, the first metabolite of ethanol oxidation - acetaldehyde (ACH) - acts as a local carcinogen in the oropharynx. This review is focused on those facts, which highlight the importance of the oropharynx and local ACH in the pathogenesis of alcohol-related oropharyngeal cancer.Summary:The strongest evidence for the local carcinogenicity of ACH in man provides a point mutation in the aldehyde dehydrogenase 2 (ALDH2) gene, which has randomized millions of alcohol consumers to markedly increased ACH exposure via saliva. This novel human cancer model is associated with manifold risk for oropharyngeal cancer and most importantly it is free from confounding factors markedly hampering epidemiological studies on alcohol-related cancer. The oropharynx is an ideal target organ for the cancer risk assessment of ACH. There is substantial epidemiological data on alcohol-related oropharyngeal cancer risk and also on salivary ACH concentrations among major risk groups for oropharyngeal cancer. Normal human saliva does not contain measurable levels of ACH. However, alcohol ingestion results within seconds in a concentration-dependent accumulation of ACH in saliva, which continues for up to 10-15 min after each sip of alcoholic beverage. This instant ACH exposure phase is followed by a long-term phase derived from ethanol diffused back to saliva from blood circulation. Microbes representing normal oral flora play a major role in local ACH formation from ethanol. In ALDH2-deficient subjects excess ACH during the long-term ACH exposure phase is most probably derived from salivary glands.Key Message:ALDH2gene mutation proves the causal relationship between local ACH exposure via saliva and oropharyngeal cancer and provides new means for the quantitative assessment of local ACH exposure in relation to oropharyngeal cancer risk. Instant ACH formation from ethanol represents approximately 70-100% of total local ACH exposure. Ethanol present in "non-alcoholic" beverages and food forms an epidemiological bias in studies on alcohol-related upper digestive tract cancer.Responses:One should quit smoking, adopt sensible drinking habits, and maintain good oral hygiene. Genetic risk groups could be screened and educated. Consumption of beverages and foodstuffs containing low ethanol levels as well as alcoholic beverages containing high ACH levels should be minimized. To that aim, labelling of alcohol and ACH concentrations of all beverages and foodstuffs should be mandatory.
  • Bolomsky, Arnold; Vogler, Meike; Kose, Murat Cem; Heckman, Caroline A.; Ehx, Gregory; Ludwig, Heinz; Caers, Jo (2020)
    Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Bolomsky, Arnold; Vogler, Meike; Köse, Murat C; Heckman, Caroline A; Ehx, Grégory; Ludwig, Heinz; Caers, Jo (BioMed Central, 2020)
    Abstract Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Long, Maeve; McWilliams, Thomas G. (2020)
    Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.
  • Ylivinkka, Irene; Keski-Oja, Jorma; Hyytiainen, Marko (2016)
    Netrins form a family of secreted and membrane-associated proteins, netrin-1 being the prototype and most investigated member of the family. The major physiological functions of netrin-1 lie in the regulation of axonal development as well as morphogenesis of different branched organs, by promoting the polarity of migratory/invasive front of the cell. On the other hand, netrin-1 acts as a factor preventing cell apoptosis. These events are mediated via a range of different receptors, including UNC5 and DCC-families. Cancer cells often employ developmental pathways to gain survival and motility advantage. Within recent years, there has been increasing number of observations of upregulation of netrin-1 expression in different forms of cancer, and the increased expression of netrin-1 has been linked to its functions as a survival and invasion promoting factor. We review here recent advances in the netrin-1 related developmental processes that may be of special interest in tumor biology, in addition to the known functions of netrin-1 in tumor biology with special focus on cancer cell migration. (C) 2016 Elsevier GmbH. All rights reserved.
  • Lopes, Alessandra; Feola, Sara; Ligot, Sophie; Fusciello, Manlio; Vandermeulen, Gaëlle; Préat, Véronique; Cerullo, Vincenzo (BioMed Central, 2019)
    Abstract Background DNA vaccines against cancer held great promises due to the generation of a specific and long-lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally. Methods Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7–9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection. Results The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups. Conclusions This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic.
  • Lopes, Alessandra; Feola, Sara; Ligot, Sophie; Fusciello, Manlio; Vandermeulen, Gaëlle; Préat, Véronique; Cerullo, Vincenzo (2019)
    Background: DNA vaccines against cancer held great promises due to the generation of a specific and long lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally. Methods: Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7-9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection. Results: The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups. Conclusions: This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic.
  • Hemminki, Otto; dos Santos, João M; Hemminki, Akseli (BioMed Central, 2020)
    Abstract In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains. As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors. Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
  • Hemminki, Otto; dos Santos, Joao Manuel; Hemminki, Akseli (2020)
    In this review, we discuss the use of oncolytic viruses in cancer immunotherapy treatments in general, with a particular focus on adenoviruses. These serve as a model to elucidate how versatile viruses are, and how they can be used to complement other cancer therapies to gain optimal patient benefits. Historical reports from over a hundred years suggest treatment efficacy and safety with adenovirus and other oncolytic viruses. This is confirmed in more contemporary patient series and multiple clinical trials. Yet, while the first viruses have already been granted approval from several regulatory authorities, room for improvement remains. As good safety and tolerability have been seen, the oncolytic virus field has now moved on to increase efficacy in a wide array of approaches. Adding different immunomodulatory transgenes to the viruses is one strategy gaining momentum. Immunostimulatory molecules can thus be produced at the tumor with reduced systemic side effects. On the other hand, preclinical work suggests additive or synergistic effects with conventional treatments such as radiotherapy and chemotherapy. In addition, the newly introduced checkpoint inhibitors and other immunomodulatory drugs could make perfect companions to oncolytic viruses. Especially tumors that seem not to be recognized by the immune system can be made immunogenic by oncolytic viruses. Logically, the combination with checkpoint inhibitors is being evaluated in ongoing trials. Another promising avenue is modulating the tumor microenvironment with oncolytic viruses to allow T cell therapies to work in solid tumors. Oncolytic viruses could be the next remarkable wave in cancer immunotherapy.
  • Ranta, Amanda Katrianna (Helsingin yliopisto, 2020)
    Ex vivo drug sensitivity testing is used widely in studies aiming at personalizing medicine for acute myeloid leukemia (AML) patients. However, different conditions, such as cytokines used in media and cryopreservation of cells, as well as varying readout methods can affect primary cell viability, cell composition and sensitivity results. Such affects have been previously studied in some AML treatments, however, not with flow cytometry or with venetoclax. In this thesis, we studied the responses of AML patients to venetoclax using ex vivo drug sensitivity testing with various settings. We first tested three media and two sensitivity readout methods on 29 fresh primary AML samples to determine the optimal media and method for determining ex vivo drug sensitivity. We then tested these same variables on 16 cryopreserved samples and compared these results to their fresh counterparts. Finally, we applied our platform to clinical use and tested its capability to predict in vivo responses to venetoclax in ten AML patients. Our platform was able to predict venetoclax responses in nine out of ten patients using condition media coupled with a flow cytometry-based method, determined as optimal in the first phase. Sensitivity results as well as cell composition obtained after cryopreservation differed from their fresh counterparts and, therefore, we conclude that cryopreserved samples should not be used in guiding treatment ex vivo. Our results give valuable information about sources of error associated with ex vivo drug sensitivity testing. Consideration of these results when designing preclinical studies will enhance their reliability and relevance. Ex vivo testing could be in the future implemented into clinical practice in guiding treatment, saving society and patients from costs and unnecessary adverse effects.
  • Rodriguez-Wallberg, Kenny A.; Tanbo, Tom; Tinkanen, Helena; Thurin-Kjellberg, Ann; Nedstrand, Elizabeth; Kitlinski, Margareta Laczna; Macklon, Kirsten T.; Ernst, Erik; Fedder, Jens; Tiitinen, Aila; Morin-Papunen, Laure; Einarsson, Snorri; Jokimaa, Varpu; Hippelainen, Maritta; Lood, Mikael; Gudmundsson, Johannes; Olofsson, Jan I.; Andersen, Claus Yding (2016)
    Introduction. The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. Material and methods. A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. Results. Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1: 3). Conclusions. Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.
  • Rebane, Anni (Helsingin yliopisto, 2015)
    Given the success of first-line treatment in chronic myeloid leukemia (CML), the prevalence of the disease is estimated to increase and more patients are expected to develop resistance to therapy. Thus, even relatively rare point mutations are likely to become more common. In CML, the uncontrollable division of myeloid cells is caused by a reciprocal translocation of chromosomes 9 and 22, resulting in the Philadelphia chromosome. At the meeting point of the two chromosomes, breakpoint cluster region (BCR) and Abelson proto-oncogene 1 (ABL1) fuse together to form the chimeric fusion oncogene BCR-ABL1, the latter of which, the non-receptor tyrosine kinase ABL1, is the driver of the disease. Since the tyrosine kinase inhibitor (TKI) imatinib became available in 2001, the success of first-line therapy has significantly improved the prognosis of CML patients. However, up to 50% of patients with imatinib-refractory disease develop resistance due to point mutations in ABL1, and the most common mutation to emerge is BCR-ABL1 T315I. The broad-range TKI ponatinib is the only approved TKI that inhibits the kinase activity of BCR-ABL1 T315I, but adverse side effects leave patients with this mutation in need of a better, safer, and more effective treatment. The kinase inhibitor axitinib was shown to be selective for BCR-ABL1 T315I, but mutations that emerge as a consequence of axitinib-resistance have yet to be explored. Moreover, patients with the T315I mutation treated with ponatinib have been reported to develop highly drug-resistant mutations in BCR-ABL1 such as T315M and the E255V/T315I compound mutation. The purpose of this study was to identify mutations that enable cells to develop resistance to the kinase inhibitor axitinib and to find new, potential inhibitors for cells expressing the drug-resistant mutations BCR-ABL1 T315I, BCR-ABL1 T315M, and BCR-ABL1 E255V/T315I. To this end, mouse hematopoietic cell lines were constructed prior to determining cell viability in response to inhibitors in combinations and as independent agents. As a novel finding, cells stably expressing T315M were found to exhibit sensitivity to inhibitors of topoisomerase II and mTOR. Moreover, synthetic lethality occurred in these cells in response to the combined treatment of the allosteric inhibitor asciminib and the TKI ponatinib, although not in clinically relevant doses. The highly resistant cells expressing BCR-ABL1 E255V/T315I, like cells expressing T315I and T315M, showed sensitivity to conventional chemotherapy. Notably, however, three SMAC mimetics displayed selectivity to cells expressing BCR-ABL1 E255V/T315I over cells expressing only the single T315I mutation. Considering that CML is expected to become increasingly prevalent, more patients are estimated to develop resistance to therapy. As even relatively rare mutations in BCR-ABL1 become more common, finding an effective treatment for cells expressing these highly resistant mutations takes us one step closer to identifying a safe and effective treatment for CML patients carrying those mutations.
  • Torssander, Jenny; Moustgaard, Heta; Peltonen, Riina; Kilpi, Fanny; Martikainen, Pekka (2018)
    Because people tend to marry social equals – and possibly also because partners affect each other’s health – the social position of one partner is associated with the other partner’s health and mortality. Although this link is fairly well established, the underlying mechanisms are not fully identified. Analyzing disease incidence and survival separately may help us to assess when in the course of the disease a partner’s resources are of most significance. This article addresses the importance of partner’s education, income, employment status, and health for incidence and survival in two major causes of death: cancer and cardiovascular diseases (CVD). Based on a sample of Finnish middle-aged and older couples (around 200,000 individuals) we show that a partner’s education is more often connected to incidence than to survival, in particular for CVD. Once ill, any direct effect of partner’s education seems to decline: The survival chances after being hospitalized for cancer or CVD are rather associated with partner’s employment status and/or income level when other individual and partner factors are adjusted for. In addition, a partner’s history of poor health predicted higher CVD incidence and, for women, lower cancer survival. The findings suggest that various partner’s characteristics may have different implications for disease and survival, respectively. A wider focus on social determinants of health at the household level, including partner’s social resources, is needed.
  • Rinta-aho, Maija (Helsingin yliopisto, 2019)
    Tausta: Tutkielman tavoitteena oli selvittää onkologisille ja hematologisille potilaille vuonna 2016 tehdyn kyselytutkimuksen vapaakenttävastauksien avulla heidän näkemyksiänsä ja toiveitansa hoitonsa suhteen. Avoimia kysymyksiä potilailta kysymällä on mahdollista tunnistaa potilaille tärkeitä ja potilastyytyväisyyttä parantavia seikkoja, jotka eivät välttämättä lääkärin näkökulmasta nousisi oleellisiksi. Maailmalla potilaskokemuksia ja -tyytyväisyyttä avoimin kysymyksin tutkittaessa potilaille tärkeiksi asioiksi on aiemmissa tutkimuksissa noussut muun muassa kommunikaatioon, viiveisiin hoidossa, sairaalaympäristöön, hoidon jatkuvuuteen ja saavutettavuuteen liittyvät teemat. Menetelmät: Menetelmänä oli vapaakenttävastausten läpikäyminen ja laadullinen pohdinta. Tähän kuului vastauksissa toistuvien teemojen tunnistaminen ja niiden mukaan vastausten ryhmittely, sekä merkittävimpien vastaajaryhmien ja kahden sairaalan vastausten erojen tarkempi tarkastelu. Tulokset: Potilaille tärkeimmäksi teemaksi nousi vapaakenttävastauksissa kommunikaatio, jota reilu kolmasosa vastauksista käsitteli. Seuraavaksi eniten potilaiden kommentit olivat yleistä positiivista palautetta hoitavia yksiköitä kohtaan. Muita tärkeiksi nousseita teemoja olivat toiveet omalääkäristä tai omahoitajasta, sairaalakäyntiaikataulut, suoraan hoitoon liittyvät asiat ja sairaalaympäristö. Pohdinta: Potilaiden vapaissa vastauksissa esiin nousseet kommentit ja toiveet olivat samansuuntaisia kuin aiemmissakin vastaavissa kyselyissä. Kommunikaation näkökulmasta vastausten perusteella yksittäisen lääkärin kohdalla hyvään vuorovaikutukseen ja riittävään tiedonjakamiseen panostaminen olisi tärkeää, kun taas hoitoprosesseja isommassa mittakaavassa suunnitellessa tulisi ottaa huomioon helpompi yhteydenottomahdollisuus hoitopaikkaan. Potilaille on tärkeää myös välttää turhaa odotusaikaa, saada kokemus kiireettömästä vastaanottotilanteesta, tarkoituksenmukainen sairaalaympäristö sekä mahdollisuus saada tavata samat tutut hoitajat ja lääkärit.
  • de Hoogt, Ronald; Estrada, Marta F.; Vidic, Suzana; Davies, Emma J.; Osswald, Annika; Barbier, Michael; Santo, Vitor E.; Gjerde, Kjersti; van Zoggel, Hanneke J. A. A.; Blom, Sami; Dong, Meng; Narhi, Katja; Boghaert, Erwin; Brito, Catarina; Chong, Yolanda; Sommergruber, Wolfgang; van der Kuip, Heiko; van Weerden, Wytske M.; Verschuren, Emmy W.; Hickman, John; Graeser, Ralph (2017)
    Two-dimensional (2D) culture of cancer cells in vitro does not recapitulate the three-dimensional (3D) architecture, heterogeneity and complexity of human tumors. More representative models are required that better reflect key aspects of tumor biology. These are essential studies of cancer biology and immunology as well as for target validation and drug discovery. The Innovative Medicines Initiative (IMI) consortium PREDECT (www.predect.eu) characterized in vitro models of three solid tumor types with the goal to capture elements of tumor complexity and heterogeneity. 2D culture and 3D mono-and stromal cocultures of increasing complexity, and precision-cut tumor slice models were established. Robust protocols for the generation of these platforms are described. Tissue microarrays were prepared from all the models, permitting immunohistochemical analysis of individual cells, capturing heterogeneity. 3D cultures were also characterized using image analysis. Detailed step-by-step protocols, exemplary datasets from the 2D, 3D, and slice models, and refined analytical methods were established and are presented.