Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes

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MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B- cell lymphoma

Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen-activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, PIP5K1 and IMPA1, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (n = 92 and n = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets.Peer reviewe

Microglial amyloid beta clearance is driven by PIEZO1 channels

Background Microglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (A beta) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of A beta. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored. Methods Here we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and A beta pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations. Results We show that PIEZO1 orchestrates A beta clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. A beta inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in A beta clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets. Conclusion These results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated A beta burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.Peer reviewe

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.Peer reviewe

Valohoito-opas ihotautia sairastavalle asiakkaalle

TIIVISTELMÄ Jäntti, Tanja ja Pesonen, Kirsi. Valohoito-opas ihotautia sairastavalle asiakkaalle. Helsinki, kevät 2012. Diakonia-ammattikorkeakoulu, Diak Etelä, Helsinki. Hoitotyön koulutusohjelma, sairaanhoitaja (AMK). Olemme tuottaneet opinnäytetyönä Ihopisteen asiakkaille valohoitoa koskevan oppaan. Oppaan tavoitteena on antaa tietoa valohoidosta ja sen toteutuksesta sekä tukea asiakkaan itsehoitoa. Oppaan tieto on koottu alan perusteoksista ja asiantuntija-artikkeleista. Valohoidot ovat osa erilaisten tulehduksellisten ihotautien hoitoa. Opas sisältää teoriaa ihon rakenteesta ja valohoidon vaikutuksesta ihoon sekä konkreettista ohjausta valohoidon toteutuksesta ja siihen liittyvistä valmisteluista. Opinnäytetyön raporttiosuudessa käsittelemme ihotauteja, niiden hoitoja sekä valohoitoa laajemmin kuin oppaassa. Ihotaudit vaikuttavat ihmisen kokonaisvaltaiseen hyvinvointiin, vaikka ne ovat harvoin terveydelle vaarallisia. Ihotautia sairastavan hoidon kulmakivi on itsehoidon tukeminen ja ohjaus. Ohjausvalmiudet ovat kiinteä osa sairaanhoitajan ammatillista ydinosaamista. Opas on toteutettu yhteistyössä Iholiiton kanssa. Iholiitto ry on valtakunnallinen edunvalvonta- ja potilasjärjestö, jonka toimintaan kuuluvat Ihopisteet Helsingissä, Tampereella ja Rovaniemellä. Ihopisteen hoitajat ovat antaneet oppaasta palautetta, minkä mukaan olemme muokanneet sen lopulliseen muotoonsa. Opas tulee kaikkien kolmen Ihopisteen käyttöön toukokuussa 2012. Asiasanat: ihotaudit, valohoito, potilasohjeet, oppaa

Enabling Transformative Change: Investigating Capabilities for Sustainability in City Management

Public organizations are increasingly struggling with sustainability challenges for various reasons. First, being complex and cross-cutting by nature (Dunlop and Russel 2012), sustainability extends to structures and processes in different levels and branches of organizations making it an issue of governance and management (Dinica 2018). While the pivotal role of public sector in promoting sustainability has been highlighted in previous literature (e.g., Jordan and Lenschow, 2009; Leuenberger and Bartle 2014; Fiorino 2010; Dunlop and Russel 2012), there is a lack of understanding and focus especially on the strategically critical role of local government in the field of sustainable development (e.g., Hoornweg et al. 2011; Krause, Feiock, and Hawkins 2016; Castán Broto, Trencher, Iwaszuk & Westman 2019). Secondly, promoting sustainability has been difficult for the dual role of cities in solving and contributing to sustainability challenges. This means that cities constitute both problems and solutions to sustainability challenges (Grimm et al. 2008). Cities are local scenes where the global ecological crises, e.g., forest fires, drought and pollution concretize, but they are also sites where innovative activity to mitigation and adaptation happens. For example, as Grimm et al. (2008) put it, the local nature of biodiversity loss and climate crisis make cities represent microcosms of global changes, making them interesting cases for understanding the dynamics of sustainability and responses to change. However, there is scarce understanding about how to promote these new aims in public management. Our study contributes by identifying a set of capabilities that enable a city to promote transformative change toward sustainability. Our findings are based on an investigation of an extensive development project, where the top management of the second biggest city in Finland, Espoo, developed a vision of a new management approach for comprehensive sustainability. Our empirical material includes workshop and individual interview data gathered during fall 2020 and spring 2021 during the impact-driven governance project. Participants in the workshops and interviews were the city mayor and other senior members from strategy, governance, data management and service development units. In total 151 pages of transcribed text was analysed. We analysed the text following the Gioia method (Gioia, et al., 2012). The Gioia method, especially used in management and organizational studies, is used to study people’s interpretations of event. Our findings suggest that promoting transformative change requires dynamic capabilities (Kattel & Mazzucato, 2018; Teece et al., 1997; Piening, 2013), which drive proactive change and agile adaptation to evolving circumstances. The emphasis on sustainability is associated with rapidly changing values, political priorities, and regulations. Furthermore, knowledge of environmental and social problems and solutions accumulates constantly (refs). In such conditions of ‘environmental turbulence’, ordinary efficiency-oriented capabilities are often found insufficient and public organizations should invest in developing dynamic capabilities for managing change processes to meet with new external demands (Piening, 2013), led by managerial efforts (Felin & Powell, 2016). Our finding suggest implementing a reflective management cycle, where sustainability goals are formulated, operationalized, implemented and continuously re-evaluated in light of new knowledge and diverse understandings of value

Hulluus kulttuurisena kysymyksenä

peerReviewe

Enabling Transformative Change: Investigating Capabilities for Sustainability in City Management

Public organizations are increasingly struggling with sustainability challenges for various reasons. First, being complex and cross-cutting by nature (Dunlop and Russel 2012), sustainability extends to structures and processes in different levels and branches of organizations making it an issue of governance and management (Dinica 2018). While the pivotal role of public sector in promoting sustainability has been highlighted in previous literature (e.g., Jordan and Lenschow, 2009; Leuenberger and Bartle 2014; Fiorino 2010; Dunlop and Russel 2012), there is a lack of understanding and focus especially on the strategically critical role of local government in the field of sustainable development (e.g., Hoornweg et al. 2011; Krause, Feiock, and Hawkins 2016; Castán Broto, Trencher, Iwaszuk & Westman 2019). Secondly, promoting sustainability has been difficult for the dual role of cities in solving and contributing to sustainability challenges. This means that cities constitute both problems and solutions to sustainability challenges (Grimm et al. 2008). Cities are local scenes where the global ecological crises, e.g., forest fires, drought and pollution concretize, but they are also sites where innovative activity to mitigation and adaptation happens. For example, as Grimm et al. (2008) put it, the local nature of biodiversity loss and climate crisis make cities represent microcosms of global changes, making them interesting cases for understanding the dynamics of sustainability and responses to change. However, there is scarce understanding about how to promote these new aims in public management. Our study contributes by identifying a set of capabilities that enable a city to promote transformative change toward sustainability. Our findings are based on an investigation of an extensive development project, where the top management of the second biggest city in Finland, Espoo, developed a vision of a new management approach for comprehensive sustainability. Our empirical material includes workshop and individual interview data gathered during fall 2020 and spring 2021 during the impact-driven governance project. Participants in the workshops and interviews were the city mayor and other senior members from strategy, governance, data management and service development units. In total 151 pages of transcribed text was analysed. We analysed the text following the Gioia method (Gioia, et al., 2012). The Gioia method, especially used in management and organizational studies, is used to study people’s interpretations of event. Our findings suggest that promoting transformative change requires dynamic capabilities (Kattel & Mazzucato, 2018; Teece et al., 1997; Piening, 2013), which drive proactive change and agile adaptation to evolving circumstances. The emphasis on sustainability is associated with rapidly changing values, political priorities, and regulations. Furthermore, knowledge of environmental and social problems and solutions accumulates constantly (refs). In such conditions of ‘environmental turbulence’, ordinary efficiency-oriented capabilities are often found insufficient and public organizations should invest in developing dynamic capabilities for managing change processes to meet with new external demands (Piening, 2013), led by managerial efforts (Felin & Powell, 2016). Our finding suggest implementing a reflective management cycle, where sustainability goals are formulated, operationalized, implemented and continuously re-evaluated in light of new knowledge and diverse understandings of value

Mielisairaalamuistot nykykulttuurissa

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Muistot mielisairaalasta kulkevat ihmisten mukana

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