Browsing by Subject "Cancer"

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  • Pisano, Michele; Zorcolo, Luigi; Merli, Cecilia; Cimbanassi, Stefania; Poiasina, Elia; Ceresoli, Marco; Agresta, Ferdinando; Allievi, Niccolo; Bellanova, Giovanni; Coccolini, Federico; Coy, Claudio; Fugazzola, Paola; Martinez, Carlos Augusto; Montori, Giulia; Paolillo, Ciro; Penachim, Thiago Jose; Pereira, Bruno; Reis, Tarcisio; Restivo, Angelo; Rezende-Neto, Joao; Sartelli, Massimo; Valentino, Massimo; Abu-Zidan, Fikri M.; Ashkenazi, Itamar; Bala, Miklosh; Chiara, Osvaldo; de' Angelis, Nicola; Deidda, Simona; De Simone, Belinda; Di Saverio, Salomone; Finotti, Elena; Kenji, Inaba; Moore, Ernest; Wexner, Steven; Biffl, Walter; Coimbra, Raul; Guttadauro, Angelo; Leppäniemi, Ari; Maier, Ron; Magnone, Stefano; Mefire, Alain Chicom; Peitzmann, Andrew; Sakakushev, Boris; Sugrue, Michael; Viale, Pierluigi; Weber, Dieter; Kashuk, Jeffry; Fraga, Gustavo P.; Kluger, Ioran; Catena, Fausto; Ansaloni, Luca (2018)
    Obstruction and perforation due to colorectal cancer represent challenging matters in terms of diagnosis, life-saving strategies, obstruction resolution and oncologic challenge. The aims of the current paper are to update the previous WSES guidelines for the management of large bowel perforation and obstructive left colon carcinoma (OLCC) and to develop new guidelines on obstructive right colon carcinoma (ORCC). Methods: The literature was extensively queried for focused publication until December 2017. Precise analysis and grading of the literature has been performed by a working group formed by a pool of experts: the statements and literature review were presented, discussed and voted at the Consensus Conference of the 4th Congress of the World Society of Emergency Surgery (WSES) held in Campinas in May 2017. Results: CT scan is the best imaging technique to evaluate large bowel obstruction and perforation. For OLCC, selfexpandable metallic stent (SEMS), when available, offers interesting advantages as compared to emergency surgery; however, the positioning of SEMS for surgically treatable causes carries some long-term oncologic disadvantages, which are still under analysis. In the context of emergency surgery, resection and primary anastomosis (RPA) is preferable to Hartmann's procedure, whenever the characteristics of the patient and the surgeon are permissive. Rightsided loop colostomy is preferable in rectal cancer, when preoperative therapies are predicted. With regards to the treatment of ORCC, right colectomy represents the procedure of choice; alternatives, such as internal bypass and loop ileostomy, are of limited value. Clinical scenarios in the case of perforation might be dramatic, especially in case of free faecal peritonitis. The importance of an appropriate balance between life-saving surgical procedures and respect of oncologic caveats must be stressed. In selected cases, a damage control approach may be required. Medical treatments including appropriate fluid resuscitation, early antibiotic treatment and management of co-existing medical conditions according to international guidelines must be delivered to all patients at presentation. Conclusions: The current guidelines offer an extensive overview of available evidence and a qualitative consensus regarding management of large bowel obstruction and perforation due to colorectal cancer.
  • Adhikari, Sadiksha (Helsingin yliopisto, 2020)
    Structural variants comprise a large number of variations occurring in the human genome and are detected in many diseases including cancers. To a limited extent, whole exome sequencing (WES) is capable of detecting structural variations (SVs) using algorithms and tools utilizing local assembly, split-reads, discordant read-pairs and read depth methods. However, due to the significantly large size of SVs compared to the reads produced and the presence of repetitive regions in the genome, identification of SVs presents a major challenge. 10X Genomics has developed a technology that requires very low amounts of DNA and uses a linked-reads approach to produce long reads. Recently, linked-read technology has shown promising results in resolving complex SVs. In this thesis, we aimed to assess whether linked-read exome sequencing is able to infer more comprehensive information in SVs compared to WES in multiple myeloma (MM). The disease model was chosen based on the presence of high numbers of SVs in MM patient tumor cells. Here, we report that linked-read sequencing has led to the identification of a potential novel translocation t(1; 14) that significantly impacts the change in expression of genes and could potentially have impact on the prognosis and treatment of multiple myeloma patients. By Long Ranger analysis we detected t(1;14) in six out of eight samples. Further, to study whether the translocation differentially affects the expression levels of any genes, differential gene expression was performed between t(1;14) positive versus t(1;14) wild type samples. The analysis resulted in 107 differentially expressed genes where 4 upregulated and 103 downregulated genes were found in the translocation positive samples. Among the downregulated genes, we found S100A8 and S100A9 genes which are previously shown to be associated with chemoresistance to PAD (bortezomib, doxorubicin and dexamethasone) therapy. The related breakpoints of the event were identified by Manta tool (SV caller) using both linked-read and WES. Therefore, linked-read information does not appear necessary to detect this event. In this study, we found that linked-read sequencing has certain advantages over WES such as low input DNA, increased number and quality of calls and breakpoint information. However, linked-read sequencing technique is limited to the detection of certain SV types in addition to increased cost of sequencing. These two factors must be considered before choosing linked-read sequencing over WES. Somatic mutations and clinically relevant SV were detected equally efficiently by both techniques.
  • Lachenmeier, Dirk W.; Salaspuro, Mikko (2017)
    Humans are cumulatively exposed to acetaldehyde from various sources including alcoholic beverages, tobacco smoke, foods and beverages. The genetic-epidemiologic and biochemical evidence in ALDH2-deficient humans provides strong evidence for the causal relationship between acetaldehyde-exposure due to alcohol consumption and cancer of the upper digestive tract. The risk assessment has so far relied on thresholds based on animal toxicology with lower one-sided confidence limit of the benchmark dose values (BMDL) typically ranging between 11 and 63 mg/kg bodyweight (bw)/day dependent on species and endpoint. The animal data is problematic for regulatory toxicology for various reasons (lack in study quality, problems in animal models and appropriateness of endpoints - especially cancer - for transfer to humans). In this study, data from genetic epidemiologic and biochemical studies are reviewed. The increase in the daily exposure dose to acetaldehyde in alcohol-consuming ALDH2-deficients vs. ALDH2-actives was about twofold. The acetaldehyde increase due to ALDH2 inactivity was calculated to be 6.7 mu g/kg bw/day for heavy drinkers, which is associated with odds ratios of up to 7 for head and neck as well as oesophageal cancer. Previous animal toxicology based risk assessments may have underestimated the risk of acetaldehyde. Risk assessments of acetaldehyde need to be revised using this updated evidence. (C) 2017 The Authors. Published by Elsevier Inc.
  • Autio, Karoliina P. M.; Ruotsalainen, Janne J.; Anttila, Marjukka O.; Niittykoski, Minna; Waris, Matti; Hemminki, Akseli; Vähä-Koskela, Markus J. V.; Hinkkanen, Ari E. (2015)
    Background: Dogs suffer from spontaneous tumors which may be amenable to therapies developed for human cancer patients, and dogs may serve as large-animal cancer models. A non-pathogenic Semliki Forest virus vector VA7-EGFP previously showed promise in targeting human tumor xenografts in mice, but the oncolytic capacity of the virus in canine cancer cells and the safety of the virus in higher mammals such as dogs, are not known. We therefore assessed the oncolytic potency of VA7-EGFP against canine cancer cells by infectivity and viability assays in two dog solid tumor cell lines. Furthermore we performed a 3-week safety study in two adult Beagles which received a single intravenous injection of similar to 2 x 10(5) plaque forming units of parental A7(74) strain. Results: VA7-EGFP was able to replicate in and kill both canine cancer cell lines tested. No adverse events were observed in either of the two virus-injected adult Beagles and no infective virus could be recovered from any of the biological samples collected over the course of the study. Neutralizing antibodies to Semliki Forest virus became detectable in the dogs at 5 days post infection and remained elevated until study termination. Conclusions: Based on these results, testing of the oncolytic potential of attenuated Semliki Forest virus in canine cancer patients appears feasible.
  • Andersson, Therese M-L.; Engholm, Gerda; Lund, Anne-Sofie Q.; Lourenco, Sofia; Matthiessen, Jeppe; Pukkala, Eero; Stenbeck, Magnus; Tryggvadottir, Laufey; Weiderpass, Elisabete; Storm, Hans (2019)
    Background: Physical activity has been shown to reduce the risk of colon, endometrial and postmenopausal breast cancer. The aim of this study was to quantify the proportion of the cancer burden in the Nordic countries linked to insufficient levels of leisure time physical activity and estimate the potential for cancer prevention for these three sites by increasing physical activity levels. Methods: Using the Prevent macrosimulation model, the number of cancer cases in the Nordic countries over a 30-year period (2016-2045) was modelled, under different scenarios of increasing physical activity levels in the population, and compared with the projected number of cases if constant physical activity prevailed. Physical activity (moderate and vigorous) was categorised according to metabolic equivalents (MET) hours in groups with sufficient physical activity (15+ MET-hours/week), low deficit (9 to Results: If no one had insufficient levels of physical activity, about 11,000 colon, endometrial and postmenopausal breast cancer cases could be avoided in the Nordic countries in a 30-year period, which is 1% of the expected cases for the three cancer types. With a 50% reduction in all deficit groups by 2025 or a 100% reduction in the group of high deficit, approximately 0.5% of the expected cases for the three cancer types could be avoided. The number and percentage of avoidable cases was highest for colon cancer. Conclusion: 11,000 cancer cases could be avoided in the Nordic countries in a 30-year period, if deficit in physical activity was eliminated. (C) 2019 Elsevier Ltd. All rights reserved.
  • Nevala, Aapeli (Helsingin yliopisto, 2020)
    Thanks to modern medical advances, humans have developed tools for detecting diseases so early, that a patient would be better off had the disease gone undetected. This is called overdiagnosis. Overdiagnosisisaproblemespeciallycommoninacts,wherethetargetpopulationofanintervention consists of mostly healthy people. Colorectal cancer (CRC) is a relatively rare disease. Thus screening for CRC affects mostly cancerfree population. In this thesis I evaluate overdiagnosis in guaiac faecal occult blood test (gFOBT) based CRC screening programme. In gFOBT CRC screening there are two goals: to detect known predecessors of cancers called adenomas and to remove them (cancer prevention), and to detect malign CRCs early enough to be still treatable (early detection). Overdiagnosis can happen when detecting adenomas, but also when detecting cancers. This thesis focuses on overdiagnosis due to detection of adenomas that are non-progressive in their nature. Since there is no clinical means to make distinction between progressive and non-progressive adenomas, statistical methods must be applied. Classical methods to estimate overdiagnosis fail in quantifying this type of overdiagnosis for couple of reasons: incidence data of adenomas is not available, and adenoma removal results in lowering cancer incidence in screened population. While the latter is a desired effect of screening, it makes it impossible to estimate overdiagnosis by just comparing cancer incidences among screened and control populations. In this thesis a Bayesian Hidden Markov model using HMC NUTS algorithm via software Stan is fitted to simulate the natural progression of colorectal cancer. The five states included in the model were healthy (1), progressive adenoma (2), screen-detectable CRC (3), clinically apparent CRC (4) and non-progressive adenoma (5). Possible transitions are from 1 to 2, 1 to 5, 2 to 3 and 3 to 4. The possible observations are screen-negative (1), detected adenoma (2), screen-detected CRC (3), clinically manifested CRC (3). Three relevant estimands for evaluating this type of overdiagnosis with a natural history model are presented. Then the methods are applied to estimate overdiagnosis proportion in guaiac faecal occult blood test (gFOBT) based CRC screening programme conducted in Finland between 2004 and 2016. The resulting mean overdiagnosis probability for all the patients that had an adenoma detected for programme is 0.48 (0.38, 0.56, 95-percent credible interval). Different estimates for overdiagnosis in sex and age-specific stratas of the screened population are also provided. In addition to these findings, the natural history model can be used to gain more insight about natural progression of colorectal cancer.
  • Fontana, Flavia; Bartolo, Raquel; Santos, Helder A. (Springer International Publishing AG, 2021)
    Advances in Experimental Medicine and Biology
    During the last 20+ years, research into the biomedical application of nanotechnology has helped in reshaping cancer treatment. The clinical use of several passively targeted nanosystems resulted in improved quality of care for patients. However, the therapeutic efficacy of these systems is not superior to the original drugs. Moreover, despite extensive investigations into actively targeted nanocarriers, numerous barriers still remain before their successful clinical translation, including sufficient blood-stream circulation time and efficient tumor targeting. The combination of synthetic nanomaterials with biological elements (e.g., cells, cell membranes, and macromolecules) is presently the cutting-edge research in cancer nanotechnology. The features provided by the biological moieties render the particles with prolonged bloodstream circulation time and homotopic targeting to the tumor site. Moreover, cancer cell membranes serve as sources of neoantigens, useful in the formulation of nanovaccines. In this chapter, we will discuss the advantages of biohybrid nanosystems in cancer chemotherapy, immunotherapy, and combined therapy, as well as highlight their preparation methods and clinical translatability.
  • Hou, Mi; Eriksson, Emma; Svechnikov, Konstantin; Jahnukainen, Kirsi; Soder, Olle; Meinhardt, Andreas; Savendahl, Lars (2014)
  • GBD 2015 Eastern Mediterranean Reg (2018)
    To estimate incidence, mortality, and disability-adjusted life years (DALYs) caused by cancer in the Eastern Mediterranean Region (EMR) between 2005 and 2015. Vital registration system and cancer registry data from the EMR region were analyzed for 29 cancer groups in 22 EMR countries using the Global Burden of Disease Study 2015 methodology. In 2015, cancer was responsible for 9.4% of all deaths and 5.1% of all DALYs. It accounted for 722,646 new cases, 379,093 deaths, and 11.7 million DALYs. Between 2005 and 2015, incident cases increased by 46%, deaths by 33%, and DALYs by 31%. The increase in cancer incidence was largely driven by population growth and population aging. Breast cancer, lung cancer, and leukemia were the most common cancers, while lung, breast, and stomach cancers caused most cancer deaths. Cancer is responsible for a substantial disease burden in the EMR, which is increasing. There is an urgent need to expand cancer prevention, screening, and awareness programs in EMR countries as well as to improve diagnosis, treatment, and palliative care services.
  • Endén, Kira; Tainio, Juuso; Nikkilä, Atte; Helanterä, Ilkka; Nordin, Arno; Pakarinen, Mikko P.; Jalanko, Hannu; Jahnukainen, Kirsi; Jahnukainen, Timo (2020)
    Background The prevalence of malignancies after pediatric solid organ transplantation was evaluated in a nationwide study. Methods All patients who had undergone kidney, liver, or heart transplantation during childhood between the years 1982 and 2015 in Finland were identified. The inclusion criteria were age under 16 years at transplantation and age over 18 years at the last follow-up day. A total of 233 (137 kidney, 53 liver, and 43 heart) transplant recipients were enrolled. Controls (n = 1157) matched by the year of birth, gender, and hometown were identified using the Population Register Center registry. The cancer diagnoses were searched using the Finnish Cancer Registry. Results Altogether 26 individuals diagnosed with cancer were found, including 18 transplant recipients. Cancer was diagnosed at a median of 12.0 (IQR 7.8-17.8) years after the transplantation. The transplant recipients' risk for cancer was significantly higher when compared with the controls (HR 14.7; 95% CI 6.4-33.9). There was no difference for different graft types. Sixty-one percent of cancers among the transplant recipients were diagnosed at age older than 18 years. Conclusion The risk for cancer is significantly higher among young adults having undergone solid organ transplantation during childhood in comparison with population controls. Careful follow-up and attention to prevent cancers throughout adulthood are warranted.
  • Candido, Marcus V; Syrjä, Pernilla; Kilpinen, Susanne; Spillmann, Thomas (BioMed Central, 2018)
    Abstract Background Gastric carcinoma (GC) is a rather rare pathological finding in dogs, with the exception of some breeds which seem predisposed. The etiopathogenesis is largely unknown in dogs, whereas in humans GC often develops from gastric mucosal metaplasia and dysplasia. This study investigates whether dogs of certain breeds are more often subject to gastroduodenoscopy (GDS), and diagnosed with GC, mucosal metaplasia or dysplasia. A retrospective clinical database search was performed at the Veterinary Teaching Hospital at the University of Helsinki, Finland. The following inclusion criteria were applied to estimate relative risk for metaplasia/dysplasia and GC: dogs from pure breeds with at least five individuals subject to GDS with histopathology of gastric biopsies. Results Between 2006 and 2016, from a total of 54945 canine patients presented, 423 dogs underwent GDS. Inclusion criteria were met in 180 dogs of 20 different pure breeds. Eight dogs had GCs (mean age = 9.8 ± 1.7 years): Belgian Tervuren (n = 4), Collie (n = 2), Golden Retriever (n = 1) and Jack Russel Terrier (n = 1). Fourteen dogs of eight breeds had gastric mucosal metaplasia or dysplasia. A log-binomial statistical model revealed that dogs in the following breeds had a significantly higher probability to undergo GDS than the others in the study population: Australian Terrier, Belgian Tervuren, Cairn Terrier, Collie and Siberian Husky. Belgian Tervuren was found at higher risk to be diagnosed with GC [RR = 19 (5.7–63.9; P < 0.0001)], as well as mucosal metaplasia/dysplasia [RR (7.6; 2.95–19.58; P < 0.0001)], as compared to the other breeds included. Shetland Sheepdog had an increased RR (5.83; 1.75–19.45; P = 0.0041) for metaplasia. Conclusions The results indicate a very low incidence of GC in dogs. The Belgian Tervuren, however, appears as predisposed. The histopathologic descriptions of mucosal changes such as metaplasia and dysplasia were also rare, but were more frequent in the Belgian Tervuren. Previous reports of these changes in dogs are very scarce, but they might be presumably related to GC in dogs, as they are in humans. Future research should investigate the possible role of metaplasia and dysplasia in the development of GC in dogs, especially those of predisposed breeds.
  • Candido, Marcus Vinicius; Syrjä, Pernilla; Kilpinen, Susanne; Spillmann, Thomas (2018)
    Background: Gastric carcinoma (GC) is a rather rare pathological finding in dogs, with the exception of some breeds which seem predisposed. The etiopathogenesis is largely unknown in dogs, whereas in humans GC often develops from gastric mucosal metaplasia and dysplasia. This study investigates whether dogs of certain breeds are more often subject to gastroduodenoscopy (GDS), and diagnosed with GC, mucosal metaplasia or dysplasia. A retrospective clinical database search was performed at the Veterinary Teaching Hospital at the University of Helsinki, Finland. The following inclusion criteria were applied to estimate relative risk for metaplasia/dysplasia and GC: dogs from pure breeds with at least five individuals subject to GDS with histopathology of gastric biopsies. Results: Between 2006 and 2016, from a total of 54945 canine patients presented, 423 dogs underwent GDS. Inclusion criteria were met in 180 dogs of 20 different pure breeds. Eight dogs had GCs (mean age = 9.8 +/- 1.7 years): Belgian Tervuren (n = 4), Collie (n = 2), Golden Retriever (n = 1) and Jack Russel Terrier (n = 1). Fourteen dogs of eight breeds had gastric mucosal metaplasia or dysplasia. A log-binomial statistical model revealed that dogs in the following breeds had a significantly higher probability to undergo GDS than the others in the study population: Australian Terrier, Belgian Tervuren, Cairn Terrier, Collie and Siberian Husky. Belgian Tervuren was found at higher risk to be diagnosed with GC [RR = 19 (5.7-63.9; P <0.0001)], as well as mucosal metaplasia/dysplasia [RR (7.6; 2.95-19.58; P <0.0001)], as compared to the other breeds included. Shetland Sheepdog had an increased RR (5.83; 1.75-19.45; P = 0.0041) for metaplasia. Conclusions: The results indicate a very low incidence of GC in dogs. The Belgian Tervuren, however, appears as predisposed. The histopathologic descriptions of mucosal changes such as metaplasia and dysplasia were also rare, but were more frequent in the Belgian Tervuren. Previous reports of these changes in dogs are very scarce, but they might be presumably related to GC in dogs, as they are in humans. Future research should investigate the possible role of metaplasia and dysplasia in the development of GC in dogs, especially those of predisposed breeds.
  • Wibroe, Morten; Cappelen, Johan; Castor, Charlotte; Clausen, Niels; Grillner, Pernilla; Gudrunardottir, Thora; Gupta, Ramneek; Gustavsson, Bengt; Heyman, Mats; Holm, Stefan; Karppinen, Atte; Klausen, Camilla; Lönnqvist, Tuula; Mathiasen, Rene; Nilsson, Pelle; Nysom, Karsten; Persson, Karin; Rask, Olof; Schmiegelow, Kjeld; Sehested, Astrid; Thomassen, Harald; Tonning-Olsson, Ingrid; Zetterqvist, Barbara; Juhler, Marianne (2017)
    Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.
  • Magnussen, Synnove Norvoll; Hadler-Olsen, Elin; Costea, Daniela Elena; Berg, Eli; Jacobsen, Cristiane Cavalcanti; Mortensen, Bente; Salo, Tuula; Martinez-Zubiaurre, Inigo; Winberg, Jan-Olof; Uhlin-Hansen, Lars; Svineng, Gunbjorg (2017)
    Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - beta 1 (TGF-beta 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real- time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-beta 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF-beta 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.
  • 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/.
  • Uoti, Arttu (Helsingin yliopisto, 2021)
    Background and objectives: Cancer is one of the leading causes of death worldwide, and resistance to current treatments demands the continuous development of novel cancer therapies. Cancer immunotherapy aims to induce anticancer immune responses that selectively target cancer cells. Viruses can also be harnessed to elicit tumor-specific immune responses and to improve the response rates of other concomitant cancer therapies. The purpose of this study was to develop a novel viral vector-based cancer vaccine for intratumoral immunotherapy. By using the previously developed PeptiENV cancer vaccine platform, the vector viruses were coated with cell-penetrating peptide (CPP) sequence-containing tumor peptides in an attempt to further drive the immune responses elicited by the vector against cancer cells. The efficacy of the PeptiENV complex as a cancer vaccine was assessed by following its effects on tumor growth and the development of local and systemic antitumor immune responses. Methods: The PeptiENV complex formation was assessed by a surface plasmon resonance (SPR) analysis. Dendritic cell (DC) activation and antigen cross-presentation were studied using the murine JAWS II dendritic cell line. The development of cellular immune responses against tumor antigens was first studied by immunizing mice with the PeptiENV complex. The antitumor efficacy and immunity of intratumoral PeptiENV administration were then studied using the murine melanoma models B16.OVA and B16.F10.9/K1. In addition to intratumoral PeptiENV treatment, some of the B16.F10.9/K1-implanted mice were also treated with an anti-PD-1 immune checkpoint inhibitor (ICI) to study the PeptiENV complex as a biological adjuvant for ICIs. Results: The SPR analysis confirmed that CPP-containing peptides can be stably anchored onto the viral envelope of the viral vector. The in vitro results showed that the PeptiENV complex does not hamper the presentation of antigens at the surface of DCs. Additionally, the viral vector was found to activate DCs seen as a change in the cells’ morphology and surface protein expression. Immunizing mice with the PeptiENV complex induced a robust antigen-specific cytotoxic T cell response. Upon intratumoral administration in vivo, the PeptiENV cancer vaccine was not capable of inducing tumor growth control against B16.OVA melanoma, although it did still elicit robust systemic and local antitumor T cell responses. In the treatment of B16.F10.9/K1 melanoma, however, the PeptiENV complex induced efficient tumor growth control, which resulted in a significant survival benefit. Additionally, co-administration of anti-PD-1 resulted in an additive therapeutic effect. Discussion and conclusions: The present study describes a novel, highly immunogenic viral vector-based cancer vaccine that has the potential to be used as an adjuvant treatment for ICI therapy. Subsequent studies could be conducted to gain a deeper understanding of the immunological mechanisms underlying the antitumor efficacy of the cancer vaccine complex. Moreover, this novel PeptiENV complex could also be further developed as an infectious disease vaccine platform against emerging pandemics. However, the effects of pre-existing antiviral immunity on the efficacy of the cancer vaccine should be explored in future studies.
  • Mäkinen, Lotta (Helsingin yliopisto, 2017)
    Granulosa cell tumor (GCT) is a rare ovarian malignancy, which is considered to be of low malignant potential but has a tendency to recurrence. In this study, we studied the variation of estrogen receptors in adult type GCTs in correlation with clinical data. A tumor tissue microarray containing 194 AGCT tumor samples was immunostained with antibodies against ER-β and GPER1. 93% of the tumors expressed ER-β in either their nucleus (47%) or cytoplasm (78%), and 94% of tumors expressed GPER1. The cytoplasmic expressions of ER-β and GPER1 correlated positively. Nuclear expression of ER-β was more abundant than cytoplasmic expression in tumors from premenopausal women, when compared to tumors from postmenopausal women. Overall survival tended to be worse for patients with high GPER1 expression. On the basis of these findings, we prove that AGCTs have different estrogen receptor profiles that may have an impact on clinical findings.
  • Aho, Joonas; Helenius, Mikko; Vattulainen-Collanus, Sanna; Alastalo, Tero-Pekka; Koskenvuo, Juha (2016)
    Cell damage can lead to rapid release of ATP to extracellular space resulting in dramatic change in local ATP concentration. Evolutionary, this has been considered as a danger signal leading to adaptive responses in adjacent cells. Our aim was to demonstrate that elevated extracellular ATP or inhibition of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) activity could be used to increase tolerance against DNA-damaging conditions. Human endothelial cells, with increased extracellular ATP concentration in cell proximity, were more resistant to irradiation or chemically induced DNA damage evaluated with the DNA damage markers gamma H2AX and phosphorylated p53. In our rat models of DNA damage, inhibiting CD39-driven ATP hydrolysis with POM-1 protected the heart and lung tissues against chemically induced DNA damage. Interestingly, the phenomenon could not be replicated in cancer cells. Our results show that transient increase in extracellular ATP can promote resistance to DNA damage.
  • Biancari, Fausto; Dahlbacka, Sebastian; Juvonen, Tatu; Virtanen, Marko P.O.; Maaranen, Pasi; Jaakkola, Jussi; Laakso, Teemu; Niemelä, Matti; Tauriainen, Tuomas; Vento, Antti; Husso, Annastiina; Savontaus, Mikko; Laine, Mika; Mäkikallio, Timo; Raivio, Peter; Eskola, Markku; Rosato, Stefano; Anttila, Vesa; Airaksinen, Juhani; Valtola, Antti (2020)
    Aim The aim of this study was to assess the outcome of transcatheter aortic valve replacement (TAVR) in patients with cancer. Methods This is a retrospective study from the nationwide FinnValve registry on 2130 consecutive patients who underwent TAVR for severe AS from January 2008 to October 2017. Results In this cohort, 417 patients (19.6%) had history of cancer and 113 (5.3%) had an active malignancy at the time of TAVR. Patients with any malignancy had similar late mortality than patients without any malignancy (at 7 years, 65.1% vs. 59.3%, adjusted HR 1.105, 95%CI 0.892–1.369). At 7 years, cancer-related mortality was 22.5% among patients with preoperative cancer, and 11.0% in those without preoperative cancer (p 
  • Saari, H.; Lisitsyna, Ekaterina S.; Rautaniemi, K.; Rojalin, T.; Niemi, L.; Nivaro, O.; Laaksonen, T.; Yliperttula, M.; Vuorimaa-Laukkanen, E. (2018)
    In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes. By FLIM, we show distinct cellular uptake mechanisms of different EV subtypes, exosomes and microvesicles, loaded with anti-cancer agent, paclitaxel. We demonstrate differences in intracellular behavior and drug release profiles of paclitaxel-containing EVs. Exosomes seem to deliver the drug mostly by endocytosis while microvesicles enter the cells by both endocytosis and fusion with cell membrane. This research offers a new real-time method to investigate EV kinetics with living cells, and it is a potential advancement to complement the existing techniques. The findings of this study improve the current knowledge in exploiting EVs as next-generation targeted drug delivery systems.