1,720,983 research outputs found
The role of animal models in the study of hematopoietic stem cell transplantation and GvHD: A historical overview.
No full textBone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review we retrace the history of bone marrow transplantation and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments
Karakterisering av NK-reseptorer og kjemokinreseptorer i αβ NKT-celler og γδ NKT-celler
No full textNKT (Natural Killer T) celler er en undergruppe av T-celler som har egenskaper til felles med både
NK (Natural Killer)-celler og konvensjonelle T-celler. De uttrykker både T-cellereseptor (TCR) og
NK-cellemarkører. T-cellereseptoren uttrykkes som en heterodimer med enten en α- og en β-kjede
eller en γ- og en δ-kjede. Konvensjonelle T-celler regnes til det adaptive immunforsvaret, mens NKTceller
fungerer som en celle i det medfødte immunforsvaret. Dette skyldes at de har en rask respons på
stimulering av T-cellereseptoren ved å produsere store mengder cytokiner. De er helt unike blant
lymfocytter ved at de nærmest eksplosivt frigjør IL-4. NKT-celler kan også ha cytotoksisk aktivitet
som vi ser hos NK-celler.
Mekanismene for NKT-celleaktivering og immunregulering er ikke klarlagt, men det ser ut til at NKTceller
er involvert i immunreguleringen av en rekke patologiske tilstander.
De fleste studiene av NKT-celler er gjort i mus. En rekke sykdomsassosierte humane gener har
homologer i rottegenomet. Det er derfor viktig å også ha kunnskap om rotte NKT-celler. Man vet i dag
svært lite om NKT-celler i rotte, og vi har derfor gjort en kartlegging av rotte NKT-cellers uttrykk av
NK-cellereseptorer og kjemokinreseptorer. I rotte defineres NKT-celler av NK-reseptoren NKR-P1A,
i kombinasjon med enten αβTCR eller γδTCR.
Vi har sortert ut αβNKT- og γδNKT-celler fra rottemilt og studert de to populasjonene med hensyn på
et repertoar av NK-reseptorer og kjemokinreseptorer. Utrykket av de ulike reseptorene er studert på
mRNA-nivå ved hjelp av RT-PCR og på proteinnivå ved bruk av flowcytometri. Vi fant
sammenfallende uttrykk av NK-reseptorer på de to gruppene av NKT-celler, mens det var enkelte
ulikheter i uttrykk av kjemokinreseptorer som kan ha betydning for in vivo distribusjon av cellene
Investigating functional effects of microRNAs contained in extracellular vesicles from Natural Killer cells
Full text linkNatural Killer (NK) cells are lymphocytes that secrete cytotoxic extracellular vesicles (EVs),
which are being investigated for their anti-cancer properties and therapeutic potential. Cancer
remains a significant global health concern, emphasizing the importance of continued
research in cancer therapy. Understanding how NK-EVs target and eliminate cancer cells is
crucial to exploit their anti-cancer properties. We hypothesize that microRNAs (miRNAs)
mediate some of the NK-EV-induced cell death, which is why this thesis focuses on
measuring the apoptotic-inducing effect of miRNAs previously shown by our group to be
enriched in cytotoxic NK-EVs.
Cell viability of the colon cancer cell line HCT 116 was evaluated following treatment with
miRNA mimics by using both a caspase-3/7 based flow cytometric assay and an adenosine
triphosphate (ATP)-based assay. Gene expression analysis of genes involved in cell cycle,
cellular proliferation, and apoptosis was conducted following treatment of HCT 116 cells with
miRNAs, measured using quantitative polymerase chain reaction (qPCR). Specific miRNAs
were inhibited in the NK cell line NK-92, and changes in the EVs’ cytotoxicity on HCT 116
cells were assessed using the caspase-3/7 based flow cytometric assay.
The main aim of the thesis was to investigate the functional effects of miRNAs contained in
NK-EVs. Apoptotic effects on HCT 116 cancer cells were observed in miR-15b-5p, miR-16-
5p, miR-19b-3p, miR-20a-5p, miR-22-3p, miR-29b-3p, miR-142-3p, and miR-181b-5p. MiR16-5p appeared to downregulate mRNA for the anti-apoptotic protein Bcl2, while miR-19b3p seemed to upregulate RICTOR mRNA, a regulator of cell growth. Inhibiting miR-29b-3p
in NK-92 cells appeared to enhance NK-EVs cytotoxicity against HCT 116 cells. However,
the observations lacked statistical significance, rendering them inconclusive.
In summary, this thesis indicates that miRNAs enriched in cytotoxic NK-EVs may indeed
have a functional effect on the cancer cell line HCT 116. These findings provide a foundation
for further research into these miRNAs to conclude their functional effects
Karakterisering av NK-reseptorer og kjemokinreseptorer i αβ NKT-celler og γδ NKT-celler
Full text linkMaster i biomedisinNKT (Natural Killer T) celler er en undergruppe av T-celler som har egenskaper til felles med både
NK (Natural Killer)-celler og konvensjonelle T-celler. De uttrykker både T-cellereseptor (TCR) og
NK-cellemarkører. T-cellereseptoren uttrykkes som en heterodimer med enten en α- og en β-kjede
eller en γ- og en δ-kjede. Konvensjonelle T-celler regnes til det adaptive immunforsvaret, mens NKTceller
fungerer som en celle i det medfødte immunforsvaret. Dette skyldes at de har en rask respons på
stimulering av T-cellereseptoren ved å produsere store mengder cytokiner. De er helt unike blant
lymfocytter ved at de nærmest eksplosivt frigjør IL-4. NKT-celler kan også ha cytotoksisk aktivitet
som vi ser hos NK-celler.
Mekanismene for NKT-celleaktivering og immunregulering er ikke klarlagt, men det ser ut til at NKTceller
er involvert i immunreguleringen av en rekke patologiske tilstander.
De fleste studiene av NKT-celler er gjort i mus. En rekke sykdomsassosierte humane gener har
homologer i rottegenomet. Det er derfor viktig å også ha kunnskap om rotte NKT-celler. Man vet i dag
svært lite om NKT-celler i rotte, og vi har derfor gjort en kartlegging av rotte NKT-cellers uttrykk av
NK-cellereseptorer og kjemokinreseptorer. I rotte defineres NKT-celler av NK-reseptoren NKR-P1A,
i kombinasjon med enten αβTCR eller γδTCR.
Vi har sortert ut αβNKT- og γδNKT-celler fra rottemilt og studert de to populasjonene med hensyn på
et repertoar av NK-reseptorer og kjemokinreseptorer. Utrykket av de ulike reseptorene er studert på
mRNA-nivå ved hjelp av RT-PCR og på proteinnivå ved bruk av flowcytometri. Vi fant
sammenfallende uttrykk av NK-reseptorer på de to gruppene av NKT-celler, mens det var enkelte
ulikheter i uttrykk av kjemokinreseptorer som kan ha betydning for in vivo distribusjon av cellene.NKT (Natural Killer T) cells is a subpopulation of T-cells that share some characteristics with both
NK (Natural Killer) -cells and conventional T-cells. They express both the T-cell receptors (TCR) and
NK-cell markers. The T-cell receptor is expressed as a heterodimer consisting of either an α- and a β-
chain or a γ- and a δ-chain. Conventional T cells are a part of the adaptive immune system, whereas
NKT cells function as cells in the non-adaptive immune system. They respond quickly to T-cell
receptor stimulation by producing high amounts of cytokines. NKT cells are quite unique among
lymphocytes due to their almost explosive release of IL-4. NKT cells do also show cytotoxic activity
similar to NK cells.
The mechanisms for NKT cell activation and immune regulation are not fully understood, but it seems
that NKT-cells are implicated in the regulation of several pathological conditions. Most studies of
NKT cells are done in mouse models. Many human genes associated to disease have homologues in
the rat genome. To have knowledge of rat NKT cells is therefore of great importance. Up till now, the
knowledge of rat NKT cells is quite limited. To take this knowledge a step further, we have done a
phenotypic survey of rat NKT cells with regard to NK receptors and chemokine receptors. In the rat,
NKT cells are defined by the NK receptor NKR-P1A in combination with αβTCR or γδTCR.
We have sorted out αβNKT cells and γδNKT cells from rat spleen, and studied a repertoire of NK
receptors and chemokine receptors on both subsets. The receptor expression was studied at the mRNA
level with RT-PCR, and at the protein level by flowcytometri. We found that the expression of NK
receptors where quite similar for the two subsets, whereas there were some differences in chemokine
receptor expression that may indicate differential localization in vivo
Rat acute GvHD is Th1 driven and characterized by predominant donor CD4+ T-cell infiltration of skin and gut
No full textAcute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of alloactivated donor T cells primarily into the gastrointestinal tract and skin. Although cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete inununoregulatory cytokines. aGvHD is thought to be initiated primarily by Thl cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. The aim of this study was to determine the contribution of distinct T-cell subsets to aGvHD in the rat. aGvHD was induced by transplanting irradiated rats with T-cell depleted major histocompatibility complex-mismatched bone marrow, followed 2 weeks later by donor lymphocyte infusion. Near complete donor T-cell chimerism was achieved in the blood and lymphatic tissues, in contrast to mixed chimerism in the skin and gut. Skin and gut donor T cells were predominantly CD4(+), in contrast to T cells in the blood and lymphatic tissues. Genes associated with Th1 cells were upregulated in gut, liver, lung, and skin tissues affected by aGvHD. Increased serum levels of CXCL10 and IL-18 preceded symptoms of aGvHD, accompanied by increased responsiveness to CXCL10 by blood CD4(+) T cells. No changes in the expression of Th2- or Th17-associated genes were observed, indicating that aGvHD in this rat model is mainly Thl driven. The rat model of aGvHD could be instrumental for further investigations of donor T-cell subsets in the skin and gut and for exploring therapeutic options to ameliorate symptoms of aGvHD. Copyright (C) 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.European Union [FP7-PEOPLE-2012-ITN-315963
New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions
No full textChronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
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