Browsing by Subject "RESISTANCE"

Sort by: Order: Results:

Now showing items 21-40 of 173
  • Lavoginal, Darja; Samuel, Kulli; Lavrits, Arina; Meltsovl, Alvin; Soritsa, Deniss; Kadastik, Ulle; Peters, Maire; Rinken, Ago; Salumets, Andres (2019)
    Research question: Endometriosis is a common gynaecological disease defined by the presence of endometrium-like tissue outside the uterus. This complex disease, often accompanied by severe pain and infertility, causes a significant medical and socioeconomic burden; hence, novel strategies are being sought for the treatment of endometriosis. Here, we set out to explore the cytotoxic effects of a panel of compounds to find toxins with different efficiency in eutopic versus ectopic cells, thus highlighting alterations in the corresponding molecular pathways. Design: The effect on cellular viability of 14 compounds was established in a cohort of paired eutopic and ectopic endometrial stromal cell samples from 11 patients. The biological targets covered by the panel included pro-survival enzymes, cytoskeleton proteins, the proteasome and the cell repair machinery. Results: Protein kinase inhibitors GSK690693, ARC-775 and sorafenib, proteasome inhibitor bortezomib, and microtubuledepolymerizing toxin monomethyl auristatin E were more effective in eutopic cells. In contrast, 10 mu mol/l of the anthracycline toxin doxorubicin caused cellular death in ectopic cells more effectively than in eutopic cells. The large-scale sequencing of mRNA isolated from doxorubicin-treated and control cells indicated different survival strategies in eutopic versus ectopic endometrium. Conclusions: Overall, the results confirm evidence of large-scale metabolic reprogramming in endometriotic cells, which underlies the observed differences in sensitivity towards toxins. The enhanced efficiency of doxorubicin interfering with redox equilibria and/or DNA repair mechanisms pinpoints key players that can be potentially used to selectively target ectopic lesions in endometriosis.
  • Badeau, Robert M.; Honka, Miikka-Juhani; Bucci, Marco; Iozzo, Patricia; Eriksson, Johan G.; Nuutila, Pirjo (2017)
    Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. The circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: Thirty-seven elderly women were separated into elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using proton nuclear magnetic resonance (1H-NMR) and insulin-dependent tissue-specific glucose uptake in skeletal muscle was assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the docosahexaenoic acid percentage of the total long-chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (p = 0.015). DHA/FA associated significantly with skeletal muscle glucose uptake (GU) (p = 0.031) and the metabolizable glucose value derived from hyperinsulinemic-euglycemic clamp technique (M-value) in the OLM group only (p = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and this association is significantly weakened in the offspring of obese mothers.
  • Prabhakar, Neeraj; Merisaari, Joni; Le Joncour, Vadim; Peurla, Markus; Sen Karaman, Didem; Casals, Eudald; Laakkonen, Pirjo; Westermarck, Jukka; Rosenholm, Jessica M. (2021)
    Glioblastoma (GB) is the most frequent malignant tumor originating from the centralnervous system. Despite breakthroughs in treatment modalities for other cancer types, GB remainslargely irremediable due to the high degree of intratumoral heterogeneity, infiltrative growth, andintrinsic resistance towards multiple treatments. A sub-population of GB cells, glioblastoma stem cells(GSCs), act as a reservoir of cancer-initiating cells and consequently, constitute a significant challengefor successful therapy. In this study, we discovered that PEI surface-functionalized mesoporoussilica nanoparticles (PEI-MSNs), without any anti-cancer drug, very potently kill multiple GSClines cultured in stem cell conditions. Very importantly, PEI-MSNs did not affect the survival ofestablished GB cells, nor other types of cancer cells cultured in serum-containing medium, even at25 times higher doses. PEI-MSNs did not induce any signs of apoptosis or autophagy. Instead, asa potential explanation for their lethality under stem cell culture conditions, we demonstrate thatthe internalized PEI-MSNs accumulated inside lysosomes, subsequently causing a rupture of thelysosomal membranes. We also demonstrate blood–brain-barrier (BBB) permeability of the PEI-MSNs in vitroandin vivo. Taking together the recent indications for the vulnerability of GSCs for lysosomaltargeting and the lethality of the PEI-MSNs on GSCs cultured under stem cell culture conditions,the results enforcein vivotesting of the therapeutic impact of PEI-functionalized nanoparticles infaithful preclinical GB models.
  • Pietilä, Elina A.; Gonzalez-Molina, Jordi; Moyano-Galceran, Lidia; Jamalzadeh, Sanaz; Zhang, Kaiyang; Lehtinen, Laura; Turunen, S. Pauliina; Martins, Tomas A.; Gultekin, Okan; Lamminen, Tarja; Kaipio, Katja; Joneborg, Ulrika; Hynninen, Johanna; Hietanen, Sakari; Grenman, Seija; Lehtonen, Rainer; Hautaniemi, Sampsa; Carpen, Olli; Carlson, Joseph W.; Lehti, Kaisa (2021)
    Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and beta 1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naive, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting. Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.
  • Menden, Michael P.; Wang, Dennis; Mason, Mike J.; Szalai, Bence; Bulusu, Krishna C.; Guan, Yuanfang; Yu, Thomas; Kang, Jaewoo; Jeon, Minji; Wolfinger, Russ; Nguyen, Tin; Zaslavskiy, Mikhail; Abante, Jordi; Abecassis, Barbara Schmitz; Aben, Nanne; Aghamirzaie, Delasa; Aittokallio, Tero; Akhtari, Farida S.; Al-lazikani, Bissan; Alam, Tanvir; Allam, Amin; Allen, Chad; de Almeida, Mariana Pelicano; Altarawy, Doaa; Alves, Vinicius; Amadoz, Alicia; Anchang, Benedict; Antolin, Albert A.; Ash, Jeremy R.; Aznar, Victoria Romeo; Ba-alawi, Wail; Bagheri, Moeen; Bajic, Vladimir; Ball, Gordon; Ballester, Pedro J.; Baptista, Delora; Bare, Christopher; Bateson, Mathilde; Bender, Andreas; Bertrand, Denis; Wijayawardena, Bhagya; Boroevich, Keith A.; Bosdriesz, Evert; Bougouffa, Salim; Bounova, Gergana; Brouwer, Thomas; Bryant, Barbara; Calaza, Manuel; Calderone, Alberto; Calza, Stefano; Capuzzi, Stephen; Carbonell-Caballero, Jose; Carlin, Daniel; Carter, Hannah; Castagnoli, Luisa; Celebi, Remzi; Cesareni, Gianni; Chang, Hyeokyoon; Chen, Guocai; Chen, Haoran; Chen, Huiyuan; Cheng, Lijun; Chernomoretz, Ariel; Chicco, Davide; Cho, Kwang-Hyun; Cho, Sunghwan; Choi, Daeseon; Choi, Jaejoon; Choi, Kwanghun; Choi, Minsoo; Cock, Martine De; Coker, Elizabeth; Cortes-Ciriano, Isidro; Cserzö, Miklós; Cubuk, Cankut; Curtis, Christina; Daele, Dries Van; Dang, Cuong C.; Dijkstra, Tjeerd; Dopazo, Joaquin; Draghici, Sorin; Drosou, Anastasios; Dumontier, Michel; Ehrhart, Friederike; Eid, Fatma-Elzahraa; ElHefnawi, Mahmoud; Elmarakeby, Haitham; van Engelen, Bo; Engin, Hatice Billur; de Esch, Iwan; Evelo, Chris; Falcao, Andre O.; Farag, Sherif; Fernandez-Lozano, Carlos; Fisch, Kathleen; Flobak, Asmund; Fornari, Chiara; Foroushani, Amir B. K.; Fotso, Donatien Chedom; Fourches, Denis; Friend, Stephen; Frigessi, Arnoldo; Gao, Feng; Gao, Xiaoting; Gerold, Jeffrey M.; Gestraud, Pierre; Ghosh, Samik; Gillberg, Jussi; Godoy-Lorite, Antonia; Godynyuk, Lizzy; Godzik, Adam; Goldenberg, Anna; Gomez-Cabrero, David; Gonen, Mehmet; de Graaf, Chris; Gray, Harry; Grechkin, Maxim; Guimera, Roger; Guney, Emre; Haibe-Kains, Benjamin; Han, Younghyun; Hase, Takeshi; He, Di; He, Liye; Heath, Lenwood S.; Hellton, Kristoffer H.; Helmer-Citterich, Manuela; Hidalgo, Marta R.; Hidru, Daniel; Hill, Steven M.; Hochreiter, Sepp; Hong, Seungpyo; Hovig, Eivind; Hsueh, Ya-Chih; Hu, Zhiyuan; Huang, Justin K.; Huang, R. Stephanie; Hunyady, László; Hwang, Jinseub; Hwang, Tae Hyun; Hwang, Woochang; Hwang, Yongdeuk; Isayev, Olexandr; Don’t Walk, Oliver Bear; Jack, John; Jahandideh, Samad; Ji, Jiadong; Jo, Yousang; Kamola, Piotr J.; Kanev, Georgi K.; Karacosta, Loukia; Karimi, Mostafa; Kaski, Samuel; Kazanov, Marat; Khamis, Abdullah M.; Khan, Suleiman Ali; Kiani, Narsis A.; Kim, Allen; Kim, Jinhan; Kim, Juntae; Kim, Kiseong; Kim, Kyung; Kim, Sunkyu; Kim, Yongsoo; Kim, Yunseong; Kirk, Paul D. W.; Kitano, Hiroaki; Klambauer, Gunter; Knowles, David; Ko, Melissa; Kohn-Luque, Alvaro; Kooistra, Albert J.; Kuenemann, Melaine A.; Kuiper, Martin; Kurz, Christoph; Kwon, Mijin; van Laarhoven, Twan; Laegreid, Astrid; Lederer, Simone; Lee, Heewon; Lee, Jeon; Lee, Yun Woo; Lepp_aho, Eemeli; Lewis, Richard; Li, Jing; Li, Lang; Liley, James; Lim, Weng Khong; Lin, Chieh; Liu, Yiyi; Lopez, Yosvany; Low, Joshua; Lysenko, Artem; Machado, Daniel; Madhukar, Neel; Maeyer, Dries De; Malpartida, Ana Belen; Mamitsuka, Hiroshi; Marabita, Francesco; Marchal, Kathleen; Marttinen, Pekka; Mason, Daniel; Mazaheri, Alireza; Mehmood, Arfa; Mehreen, Ali; Michaut, Magali; Miller, Ryan A.; Mitsopoulos, Costas; Modos, Dezso; Moerbeke, Marijke Van; Moo, Keagan; Motsinger-Reif, Alison; Movva, Rajiv; Muraru, Sebastian; Muratov, Eugene; Mushthofa, Mushthofa; Nagarajan, Niranjan; Nakken, Sigve; Nath, Aritro; Neuvial, Pierre; Newton, Richard; Ning, Zheng; Niz, Carlos De; Oliva, Baldo; Olsen, Catharina; Palmeri, Antonio; Panesar, Bhawan; Papadopoulos, Stavros; Park, Jaesub; Park, Seonyeong; Park, Sungjoon; Pawitan, Yudi; Peluso, Daniele; Pendyala, Sriram; Peng, Jian; Perfetto, Livia; Pirro, Stefano; Plevritis, Sylvia; Politi, Regina; Poon, Hoifung; Porta, Eduard; Prellner, Isak; Preuer, Kristina; Pujana, Miguel Angel; Ramnarine, Ricardo; Reid, John E.; Reyal, Fabien; Richardson, Sylvia; Ricketts, Camir; Rieswijk, Linda; Rocha, Miguel; Rodriguez-Gonzalvez, Carmen; Roell, Kyle; Rotroff, Daniel; de Ruiter, Julian R.; Rukawa, Ploy; Sadacca, Benjamin; Safikhani, Zhaleh; Safitri, Fita; Sales-Pardo, Marta; Sauer, Sebastian; Schlichting, Moritz; Seoane, Jose A.; Serra, Jordi; Shang, Ming-Mei; Sharma, Alok; Sharma, Hari; Shen, Yang; Shiga, Motoki; Shin, Moonshik; Shkedy, Ziv; Shopsowitz, Kevin; Sinai, Sam; Skola, Dylan; Smirnov, Petr; Soerensen, Izel Fourie; Soerensen, Peter; Song, Je-Hoon; Song, Sang Ok; Soufan, Othman; Spitzmueller, Andreas; Steipe, Boris; Suphavilai, Chayaporn; Tamayo, Sergio Pulido; Tamborero, David; Tang, Jing; Tanoli, Zia-ur-Rehman; Tarres-Deulofeu, Marc; Tegner, Jesper; Thommesen, Liv; Tonekaboni, Seyed Ali Madani; Tran, Hong; Troyer, Ewoud De; Truong, Amy; Tsunoda, Tatsuhiko; Turu, Gábor; Tzeng, Guang-Yo; Verbeke, Lieven; Videla, Santiago; Consortium, AstraZeneca-Sanger Drug Combination DREAM (2019)
    The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
  • Kurki, Tuuli; Brunila, Kristiina; Lahelma, Elina (2019)
    The focus of this paper is to examine how immigrants become constituted as ideal care workers in educational settings. By analysing the everyday practices in two educational contexts in the Helsinki metropolitan area, Finland, the authors explore how these practices that are influenced by the national and transnational immigration and integration policy, regardless of their well-meant actions, can gender and racialise students with immigrant status.
  • Anttila, Jani V.; Shubin, Mikhail; Cairns, Johannes; Borse, Florian; Guo, Qingli; Mononen, Tommi; Vazquez-Garcia, Ignacio; Pulkkinen, Otto; Mustonen, Ville (2019)
    A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains. Author summary Cells and organisms evolve to better survive in their environments and to adapt to new challenges. Such dynamics manifest in a particularly problematic way with the evolution of drug resistance, which is increasingly recognized as a key challenge for global health. Thus, developing therapy paradigms that factor in evolutionary dynamics is an important goal. Using a minimal mathematical model of a cancer cell population we contrast cytotoxic (increasing death rate) and cytostatic (decreasing birth rate) treatments while keeping the effect of the therapy on the net growth reduction constant. We then quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates and the details of cell competition. Most importantly, we identify specific cell population dynamics under which a certain treatment could be significantly better than the alternative.
  • Heikkilä, Riie; Katainen, Anu (2021)
    In qualitative interviews, challenges such as deviations from the topic, interruptions, silences or counter-questions are inevitable. It is debatable whether the researcher should try to alleviate them or consider them as important indicators of power relations. In this methodological article, we adopt the latter view and examine the episodes of counter-talk that emerge in qualitative interviews on cultural practices among underprivileged popular classes by drawing on 49 individual and focus group interviews conducted in the highly egalitarian context of Finland. Our main aim is to demonstrate how counter-talk emerging in interview situations could be fruitfully analysed as moral boundary drawing. We identify three types of counter-talk: resisting the situation, resisting the topic, and resisting the interviewer. While the first type unites many of the typical challenges inherent to qualitative interviewing in general (silences, deviations from the topic and so forth), the second one shows that explicit taste distinctions are an important feature of counter-talk, yet the interviewees mostly discuss them as something belonging to the personal sphere. Finally, the third type reveals how the strongest counter-talk and clearest moral boundary stemmed from the interviewees' attitudes towards the interviewer herself. We argue that counter-talk in general should be given more importance as a key element of the qualitative interview. We demonstrate that all three types of counter-talk are crucial to properly understanding the power relations and moral boundaries present in qualitative interviews and that cultural practices are a particularly good topic to tease them out.
  • Sheppard, Samuel K.; Cheng, Lu; Meric, Guillaume; De Haan, Caroline P. A.; Llarena, Ann-Katrin; Marttinen, Pekka; Vidal, Ana; Ridley, Anne; Clifton-Hadley, Felicity; Connor, Thomas R.; Strachan, Norval J. C.; Forbes, Ken; Colles, Frances M.; Jolley, Keith A.; Bentley, Stephen D.; Maiden, Martin C. J.; Hänninen, Marja-Liisa; Parkhill, Julian; Hanage, William P.; Corander, Jukka (2014)
  • Nikinmaa, Sakari; Podonyi, Anna; Raivio, Peter; Meurman, Jukka; Sorsa, Timo; Rantala, Juha; Kankuri, Esko; Tauriainen, Tuomas; Pätilä, Tommi (2021)
    New means to reduce excessive antibiotic use are urgently needed. This study tested dual-light aPDT against Staphylococcus aureus biofilm with different relative ratios of light energy with indocyanine green. We applied single-light aPDT (810 nm aPDT, 405 aBL) or dual-light aPDT (simultaneous 810 nm aPDT and 405 nm aBL), in both cases, together with the ICG photosensitizer with constant energy of 100 or 200 J/cm(2). Single-dose light exposures were given after one-day, three-day, or six-day biofilm incubations. A repeated daily dose of identical light energy was applied during biofilm incubations for the three- and six-day biofilms. Using 100 J/cm(2) light energy against the one-day biofilm, the dual-light aPDT consisting of more than half of aBL was the most effective. On a three-day maturated biofilm, single-dose exposure to aPDT or dual-light aPDT was more effective than aBL alone. With total light energy of 200 J/cm(2), all dual-light treatments were effective. Dual-light aPDT improves the bactericidal effect on Staphylococcus aureus biofilm compared to aPDT or aBL and provides a sustained effect. An increase in the relative ratio of aBL strengthens the antibacterial effect, mainly when the treatment is repeatedly applied. Thus, the light components' energy ratio is essential with dual-light.
  • 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/.
  • Pour-Aboughadareh, Alireza; Poczai, Péter (2021)
    The dataset herein indicated the novelty of the article entitled “Dataset on the use of MGIDI in screening drought-tolerant wild wheat accessions at the early growth stage”. Data were gathered during 2018-2019 on a set of wild wheat germplasm under two control and water deficit stress conditions. One hundred and forty-six accessions belonging to Ae. tauschii, Ae. cylindrica, and Ae. crassa were assessed under optimal glasshouse conditions to screen the drought-tolerant samples at the early growth stage. Nine drought tolerance and susceptibility indices along with the multi-trait genotype-ideotype distance index (MGIDI) were used to visualize the dataset. The obtained data can highlight the potential of the MGIDI index in accelerating screening of a large number of plant materials using multiple traits or selection indices in crop breeding programs, especially at the early growth stage.
  • Sivaranjani, Murugesan; Leskinen, Katarzyna; Aravindraja, Chairmandurai; Saavalainen, Päivi; Pandian, Shunmugiah Karutha; Skurnik, Mikael; Ravi, Arumugam Veera (2019)
    Background: Alpha-mangostin (alpha-MG) is a natural xanthone reported to exhibit rapid bactericidal activity against Gram-positive bacteria, and may therefore have potential clinical application in healthcare sectors. This study sought to identify the impact of alpha-MG on Staphylococcus epidermidis RP62A through integrated advanced omic technologies. Methods: S. epidermidis was challenged with sub-MIC (0.875 mu g/ml) of alpha-MG at various time points and the differential expression pattern of genes/proteins were analyzed in the absence and presence of alpha-MG using RNA sequencing and LC-MS/MS experiments. Bioinformatic tools were used to categorize the biological processes, molecular functions and KEGG pathways of differentially expressed genes/proteins. qRT-PCR was employed to validate the results obtained from these analyses. Results: Transcriptomic and proteomic profiling of alpha-MG treated cells indicated that genes/proteins affected by alpha-MG treatment were associated with diverse cellular functions. The greatest reduction in expression was observed in transcription of genes conferring cytoplasmic membrane integrity (yidC2, secA and mscL), cell division (ftsY and divlB), teichoic acid biosynthesis (tagG and dltA), fatty-acid biosynthesis (accB, accC, fabD, fabH, fabl, and fabZ), biofilm formation (icaA) and DNA replication and repair machinery (polA, polC, dnaE, and uvrA). Those with increased expression were involved in oxidative (katA and sodA) and cellular stress response (clpB, clpC, groEL, and asp23). The qRT-PCR analysis substantiated the results obtained from transcriptomic and proteomic profiling studies. Conclusion: Combining transcriptomic and proteomic methods provided comprehensive information about the antibacterial mode of action of alpha-MG. The obtained results suggest that alpha-MG targets S. epidermidis through multifarious mechanisms, and especially prompts that loss of cytoplasmic membrane integrity leads to rapid onset of bactericidal activity.
  • Koskenniemi, Aino (2021)
    In the past decades, numerous disciplines have investigated so-called ethical and alternative forms of consumption. This has led to confusion about what terms to use and how to interpret the multiple ways in which people act within and upon the market. This article presents the first comprehensive review of the main concepts used in these discussions. Then, drawing on critical theory, in particular on Marcuse and Horkheimer, the article argues that the current debate over consumption lacks critical self-reflection with regard to the uses of these concepts. The second part of the article shows how the analytic structure of the debate over consumption creates an artificial difference between forms of consumption deemed deviant and those judged normal. By disregarding this artificiality, the article argues, research normalizes individual consumption as the sphere of political action and ends up legitimating forms of consumption it critiques.
  • Narvi, Elli; Vaparanta, Katri; Karrila, Anna; Chakroborty, Deepankar; Knuutila, Sakari; Pulliainen, Arto; Sundvall, Maria; Elenius, Klaus (2018)
    Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
  • Pietarinen, Paavo O.; Eide, Christopher A.; Ayuda-Duran, Pilar; Potdar, Swapnil; Kuusanmaki, Heikki; Andersson, Emma I.; Mpindi, John P.; Pemovska, Tea; Kontro, Mika; Heckman, Caroline A.; Kallioniemi, Olli; Wennerberg, Krister; Hjorth-Hansen, Henrik; Druker, Brian J.; Enserink, Jorrit M.; Tyner, Jeffrey W.; Mustjoki, Satu; Porkka, Kimmo (2017)
    Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.
  • Vuorinen, Katariina; Zamora, Olena; Vaahtera, Lauri; Overmyer, Kirk; Brosché, Mikael (2021)
    Plants require interaction between signaling pathways to differentiate and integrate stress responses and deploy appropriate defenses. The hormones ethylene, salicylic acid (SA), and jasmonic acid (JA) are important regulators of plant defenses. Numerous interactions between these signaling pathways are the cornerstone of robust plant immunity. Additionally, during the early response to pathogens, reactive oxygen species (ROS) act as signaling molecules. Here, we examined the extent of signal interaction in the early stages of Botrytis cinerea infection. To enable a comparison between B. cinerea infection with ROS signaling, we subjected plants to ozone treatment, which stimulates an apoplastic ROS burst. We used a collection of single, double, and triple signaling mutants defective in hormone signaling and biosynthesis and subjected them to B. cinerea infection and ozone treatment at different timepoints. We examined lesion size, cell death, and gene expression (both quantitatively and spatially). The two treatments shared many similarities, especially in JA-insensitive mutants, which were sensitive to both treatments. Unexpectedly, a B. cinerea- susceptible JA-insensitive mutant (coil), became tolerant when both SA biosynthesis and signaling was impaired (coil npr1 sid2), demonstrating that JA responses may be under the control of SA. Extensive marker gene analysis indicated JA as the main regulator of both B. cinerea and ozone defenses. In addition, we identified the transcription factor SRI_ as a crucial regulator of PLANT DEFENSIN expression and cell-death regulation, which contributes to resistance to B. cinerea. Overall, our work further defines the context of ROS in plant defense signaling.
  • Nordlund, Jessica; Backlin, Christofer L.; Zachariadis, Vasilios; Cavelier, Lucia; Dahlberg, Johan; Ofverholm, Ingegerd; Barbany, Gisela; Nordgren, Ann; Overnas, Elin; Abrahamsson, Jonas; Flaegstad, Trond; Heyman, Mats M.; Jonsson, Olafur G.; Kanerva, Jukka; Larsson, Rolf; Palle, Josefine; Schmiegelow, Kjeld; Gustafsson, Mats G.; Lonnerholm, Gudmar; Forestier, Erik; Syvanen, Ann-Christine (2015)
  • Stenroth, Lauri; Sefa, Sandra; Arokoski, Jari; Töyräs, Juha (2019)
    This study investigated the reliability of Achilles and patellar tendon cross-sectional area (CSA) measurement using ultrasound imaging (USI) and magnetic resonance imaging (MRI). Fifteen healthy adults were imaged twice on two occasions, interrupted by a tendon loading protocol. Tendon CSA segmentations were conducted by an experienced and an inexperienced rater blinded to information regarding subject, session and loading status. USI provided good test-retest reliability (intra-class correlation coefficient [ICC] 2,1 > 0.85, standard error of measurement [SEM] 5%-6%), while with MRI it was excellent (ICC 2,1 > 0.92, SEM 4%) for the experienced rater. This study suggests that MRI provides superior reliability for tendon CSA measurements compared with USI. However, the difference in reliability between the methods was small, and the results were inconclusive regarding objectivity and sensitivity to change when assessed based on the effect of loading. We concluded that both methods can be used for reliable CSA measurements of the Achilles and patellar tendons when using a highly standardized measurement protocol and when conducted by an experienced rater. (C) 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved.
  • Mäkelä, Pirjo; Vaarala, L; Rajalahti, R; Rajala, A; PeltonenSainio, P (1997)