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The role of ferroptosis and chemokine profiles in DLBCL
Get PDFAbstract
Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma. The disease is aggressive by nature, and the average age of presentation is 65. Despite multiple studies with targeted therapies, no substantial improvements have been achieved, and intensive, highly toxic chemotherapeutics remain central to first-line DLBCL treatment.
Despite being in use for half a century, the exact mechanism of action of these drugs is still partially enigmatic. This research explores the role of ferroptosis in chemotherapeutic agent action. During ferroptosis excessive oxidative stress damages the cell membrane which then extrudes outwards. We demonstrated that the ferroptosis-inducing drugs auranofin, erastin, and buthionine sulfoximine induce this morphological change, whereas known inhibitors reduce or delay the effect.
Our novel approach demonstrates that the unique morphology of ferroptosis in vitro can be detected with a convolutional neural network (CNN) based image detection model. Our model performance was robust enough to allow us to screen multiple chemotherapeutic agents for their ferroptosis-inducing ability. We were able to demonstrate that cyclophosphamide and cisplatin also induce similar morphological changes associated with ferroptosis, but doxorubicin, carboplatin, etoposide, cytarabine, or vincristine did not. We hypothesized that cyclophosphamides toxic metabolite acrolein mediate ferroptotic activity through glutathione depletion. This highlights the toxicity profile of cyclophosphamide, as acrolein causes unique urinary tract toxicity during cancer treatment.
Centran nervous system (CNS) dissemination is a devastating event with an abysmal prognosis. Testicular DLBCL has an increased risk of CNS relapse. Chemokines offer a biologically plausible theory as chemokines relay the chemotaxis signal on cells during embryogenesis and inflammation. They have been implicated in solid cancer metastasis. Our pilot study examined the role of CXCR4 and CXCR5 routes in ptDLBCL CNS tropism. Compared to systemic disease, we saw a decrease in membranous CXCR5 expression in primary testicular DLBCL. Theoretically, the lower activity of CXCR5 could imply increased activity of the CXCR4 route, which might attract cancer cells towards CNS vasculature. CXCR4 ligand CXCL12 is expressed in CNS perivasculature as a chemokine barrier for immune cells. Original papers Kotkaranta, P., Chan, M., Vuolio, T., Miinalainen, I., Kuitunen, H., Turpeenniemi-Hujanen, T., Teppo, H.-R., Kuittinen, O., & Kuusisto, M. E. L. (2025). DLBCL cells with ferroptosis morphology can be detected with a deep convolutional neural network. Biomedicine & Pharmacotherapy, 182, 117785. https://doi.org/10.1016/j.biopha.2024.117785 https://doi.org/10.1016/j.biopha.2024.117785 Self-archived version Kotkaranta P., Kontiainen, P., Chan, M., Kuitunen H., Turpeenniemi-Hujanen T., Teppo H.-R., Kuittinen O., Kuusisto M. E. L. (2025). Commonly used chemotherapy agents induce ferroptosis in DLBCL cell lines. Manuscript in preparation. Ollikainen, R. K., Kotkaranta, P. H., Kemppainen, J., Teppo, H.-R., Kuitunen, H., Pirinen, R., Turpeenniemi-Hujanen, T., Kuittinen, O., & Kuusisto, M. E. L. (2021). Different chemokine profile between systemic and testicular diffuse large B-cell lymphoma. Leukemia & Lymphoma, 62(9), 2151–2160. https://doi.org/10.1080/10428194.2021.1913150 https://doi.org/10.1080/10428194.2021.1913150 Self-archived version Tiivistelmä
Diffuusi suurisoluinen B-solulymfooma on yleisin non-Hodgkin-lymfooma. Tauti on luonteeltaan aggressiivinen ja keskimääräinen sairastumisikä on 65 vuotta. Taudin hoidon kulmakivi on intensiivinen ja toksinen yhdistelmäsytostaattihoito. Useista tutkimushankkeista huolimatta merkittävästi parempia ja haitattomampia hoitoja ei ole löydetty.
Sytostaattien tarkat vaikutusmekanismit ovat yhä osittain tuntemattomia yli 70 vuoden käyttökokemuksista huolimatta. Tutkimuksessamme tarkastelemme ferroptoosin roolia solunsalpaajien vaikutusmekanismeissa. Ferroptoosissa oksidatiivinen stressi vaurioittaa solukalvoja, mikä johtaa ionitasapainon menettämiseen ja nesteen siirtymiseen kalvorakanteen yli. Pystyimme osoittamaan, että ferroptoosia indusoivat lääkkeet auranofiini, erastiini ja butioniinisulfoksidi, aiheuttavat ferroptoosiin liittyvän morfologisen muutoksen, mikä on estettävissä ferroptoosin inhibiittoreilla.
Osoitimme että ferroptoosin tyypillinen morfologia voidaan havaita in vitro konvoluutioneuroverkkoon perustuvalla kuvantunnistusmallilla. Selvitimme mallin avulla lymfooman hoidossa käytettyjen sytostaattien ferroptoottista vaikutusta. Syklofosfamidi ja sisplatiini aiheuttivat ferroptoottisen solukuoleman, kun taas doksorubisiini, karboplatiini, etoposidi, sytarabiini tai vinkristiini eivät. Syklofosfamidin toksinen metaboliatuote akroleiini voi aiheuttaa ferroptoosia vähentämällä glutationin määrää soluissa.
DLBCL:n leviäminen keskushermostoon heikentää ennustetta merkittävästi ja levinneen syövän hoitaminen on haastavaa. Kiveksen DLBCL:ään liittyy suurentunut riski taudin leviämiselle keskushermostoon. Kemokiinit tarjoavat biologisesti mielekkään selityksen, sillä niiden fysiologinen rooli on ohjata solujen liikkumista. Kemokiinen on osoitettu liittyvän kiinteiden kasvainten etäpesäkkeiden muodostumiseen. Tarkastelimme CXCR4- ja CXCR5-reittien roolia kivesperäisen DLBCL:n CNS-hakuisuudessa. Havaitsimme, että kivesperäisessä DLBCL:ssä CXCR5:n määrä solukalvolla oli vähentynyt verrattuna systeemiseen tautiin. Teoriassa CXCR5:n vähentynyt aktiivisuus voisi viitata lisääntyneeseen CXCR4-reitin aktiivisuuteen, mikä puolestaan voisi houkutella syöpäsoluja kohti keskushermoston verisuonistoa. CXCR4:n ligandin, CXCL12:n, tiedetään esiintyvän CNS:n verisuonirakenteissa ja toimivan immuunisoluja rajoittavana esteenä tulehdusten aikana. Osajulkaisut Kotkaranta, P., Chan, M., Vuolio, T., Miinalainen, I., Kuitunen, H., Turpeenniemi-Hujanen, T., Teppo, H.-R., Kuittinen, O., & Kuusisto, M. E. L. (2025). DLBCL cells with ferroptosis morphology can be detected with a deep convolutional neural network. Biomedicine & Pharmacotherapy, 182, 117785. https://doi.org/10.1016/j.biopha.2024.117785 https://doi.org/10.1016/j.biopha.2024.117785 Rinnakkaistallennettu versio Kotkaranta P., Kontiainen, P., Chan, M., Kuitunen H., Turpeenniemi-Hujanen T., Teppo H.-R., Kuittinen O., Kuusisto M. E. L. (2025). Commonly used chemotherapy agents induce ferroptosis in DLBCL cell lines. Manuscript in preparation. Ollikainen, R. K., Kotkaranta, P. H., Kemppainen, J., Teppo, H.-R., Kuitunen, H., Pirinen, R., Turpeenniemi-Hujanen, T., Kuittinen, O., & Kuusisto, M. E. L. (2021). Different chemokine profile between systemic and testicular diffuse large B-cell lymphoma. Leukemia & Lymphoma, 62(9), 2151–2160. https://doi.org/10.1080/10428194.2021.1913150 https://doi.org/10.1080/10428194.2021.1913150 Rinnakkaistallennettu versio Academic dissertation to be presented with the assent of the Doctoral Programme Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium 3 of Oulu University Hospital (Kajaanintie 50), on 5 September 2025, at 12 noonAbstract
Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma. The disease is aggressive by nature, and the average age of presentation is 65. Despite multiple studies with targeted therapies, no substantial improvements have been achieved, and intensive, highly toxic chemotherapeutics remain central to first-line DLBCL treatment.
Despite being in use for half a century, the exact mechanism of action of these drugs is still partially enigmatic. This research explores the role of ferroptosis in chemotherapeutic agent action. During ferroptosis excessive oxidative stress damages the cell membrane which then extrudes outwards. We demonstrated that the ferroptosis-inducing drugs auranofin, erastin, and buthionine sulfoximine induce this morphological change, whereas known inhibitors reduce or delay the effect.
Our novel approach demonstrates that the unique morphology of ferroptosis in vitro can be detected with a convolutional neural network (CNN) based image detection model. Our model performance was robust enough to allow us to screen multiple chemotherapeutic agents for their ferroptosis-inducing ability. We were able to demonstrate that cyclophosphamide and cisplatin also induce similar morphological changes associated with ferroptosis, but doxorubicin, carboplatin, etoposide, cytarabine, or vincristine did not. We hypothesized that cyclophosphamides toxic metabolite acrolein mediate ferroptotic activity through glutathione depletion. This highlights the toxicity profile of cyclophosphamide, as acrolein causes unique urinary tract toxicity during cancer treatment.
Centran nervous system (CNS) dissemination is a devastating event with an abysmal prognosis. Testicular DLBCL has an increased risk of CNS relapse. Chemokines offer a biologically plausible theory as chemokines relay the chemotaxis signal on cells during embryogenesis and inflammation. They have been implicated in solid cancer metastasis. Our pilot study examined the role of CXCR4 and CXCR5 routes in ptDLBCL CNS tropism. Compared to systemic disease, we saw a decrease in membranous CXCR5 expression in primary testicular DLBCL. Theoretically, the lower activity of CXCR5 could imply increased activity of the CXCR4 route, which might attract cancer cells towards CNS vasculature. CXCR4 ligand CXCL12 is expressed in CNS perivasculature as a chemokine barrier for immune cells.Tiivistelmä
Diffuusi suurisoluinen B-solulymfooma on yleisin non-Hodgkin-lymfooma. Tauti on luonteeltaan aggressiivinen ja keskimääräinen sairastumisikä on 65 vuotta. Taudin hoidon kulmakivi on intensiivinen ja toksinen yhdistelmäsytostaattihoito. Useista tutkimushankkeista huolimatta merkittävästi parempia ja haitattomampia hoitoja ei ole löydetty.
Sytostaattien tarkat vaikutusmekanismit ovat yhä osittain tuntemattomia yli 70 vuoden käyttökokemuksista huolimatta. Tutkimuksessamme tarkastelemme ferroptoosin roolia solunsalpaajien vaikutusmekanismeissa. Ferroptoosissa oksidatiivinen stressi vaurioittaa solukalvoja, mikä johtaa ionitasapainon menettämiseen ja nesteen siirtymiseen kalvorakanteen yli. Pystyimme osoittamaan, että ferroptoosia indusoivat lääkkeet auranofiini, erastiini ja butioniinisulfoksidi, aiheuttavat ferroptoosiin liittyvän morfologisen muutoksen, mikä on estettävissä ferroptoosin inhibiittoreilla.
Osoitimme että ferroptoosin tyypillinen morfologia voidaan havaita in vitro konvoluutioneuroverkkoon perustuvalla kuvantunnistusmallilla. Selvitimme mallin avulla lymfooman hoidossa käytettyjen sytostaattien ferroptoottista vaikutusta. Syklofosfamidi ja sisplatiini aiheuttivat ferroptoottisen solukuoleman, kun taas doksorubisiini, karboplatiini, etoposidi, sytarabiini tai vinkristiini eivät. Syklofosfamidin toksinen metaboliatuote akroleiini voi aiheuttaa ferroptoosia vähentämällä glutationin määrää soluissa.
DLBCL:n leviäminen keskushermostoon heikentää ennustetta merkittävästi ja levinneen syövän hoitaminen on haastavaa. Kiveksen DLBCL:ään liittyy suurentunut riski taudin leviämiselle keskushermostoon. Kemokiinit tarjoavat biologisesti mielekkään selityksen, sillä niiden fysiologinen rooli on ohjata solujen liikkumista. Kemokiinen on osoitettu liittyvän kiinteiden kasvainten etäpesäkkeiden muodostumiseen. Tarkastelimme CXCR4- ja CXCR5-reittien roolia kivesperäisen DLBCL:n CNS-hakuisuudessa. Havaitsimme, että kivesperäisessä DLBCL:ssä CXCR5:n määrä solukalvolla oli vähentynyt verrattuna systeemiseen tautiin. Teoriassa CXCR5:n vähentynyt aktiivisuus voisi viitata lisääntyneeseen CXCR4-reitin aktiivisuuteen, mikä puolestaan voisi houkutella syöpäsoluja kohti keskushermoston verisuonistoa. CXCR4:n ligandin, CXCL12:n, tiedetään esiintyvän CNS:n verisuonirakenteissa ja toimivan immuunisoluja rajoittavana esteenä tulehdusten aikana
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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