44 results on '"Rožman, Primož"'
Search Results
2. Cytokine, Anti-SARS-CoV-2 Antibody, and Neutralizing Antibody Levels in Conventional Blood Donors Who Have Recovered from COVID-19.
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Maličev, Elvira, Žiberna, Klemen, Jazbec, Katerina, Kolenc, Ana, Mali, Polonca, Rahne Potokar, Urška, and Rožman, Primož
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Background: At the beginning of the pandemic, COVID-19 convalescent plasma (CCP) containing anti-SARS-CoV-2 antibodies was suggested as a source of therapy. In the last 3 years, many trials have demonstrated the limited usefulness of CCP therapy. This led us to the hypothesis that CCP could contain other elements, along with the desired neutralizing antibodies, which could potentially prevent it from having a therapeutic effect, among them cytokines, chemokines, growth factors, clotting factors, and autoantibodies. Methods: In total, 39 cytokines were analyzed in the plasma of 190 blood donors, and further research focused on the levels of 23 different cytokines in CCP (sCD40L, eotaxin, FGF-2, FLT-3L, ractalkine, GRO-α, IFNα2, IL-1β, IL-1RA, IL-5, IL-6, IL-8, IL-12, IL-13, IL-15, IL-17E, IP-10, MCP-1, MIP-1b, PDGF-AA, TGFα, TNFα, and TRAIL). Anti-SARS-CoV-2 antibodies and neutralizing antibodies were detected in CCP. Results: We found no significant differences between CCP taken within a maximum of 180 days from the onset of the first COVID-19 symptoms and the controls. We also made a comparison of the cytokine levels between the low neutralizing antibodies (<160) group and the high neutralizing antibodies (≥160) group and found there were no differences between the groups. Our research also showed no correlation either to levels of anti-SARS-CoV-2 IgG Ab or to the levels of neutralizing antibodies. There were also no significant changes in cytokine levels based on the period after the start of COVID-19 symptoms. Conclusions: No elements which could potentially be responsible for preventing CCP from having a therapeutic effect were found. [ABSTRACT FROM AUTHOR]
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- 2024
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3. The tolerogenic role of IFN-γ
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Rožman, Primož and Švajger, Urban
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- 2018
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4. The potential of non-myeloablative heterochronous autologous hematopoietic stem cell transplantation for extending a healthy life span
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Rožman, Primož
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- 2018
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5. The level of heparin-induced antibodies in correlation with the result of the flow cytometric functional assay in the patients with suspected HIT
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Maličev, Elvira, Maček Kvanka, Marjeta, Klemenc, Polona, and Rožman, Primož
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- 2017
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6. Morphological Characteristics of Young and Old Murine Hematopoietic Stem Cell Niches, as Modeled In Vitro.
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Justin, Mojca, Randl, Ema Rogač, Kononenko, Veno, Hočevar, Matej, Drobne, Damjana, and Rožman, Primož
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STEM cell niches ,CELL morphology ,CELL size ,HEMATOPOIETIC stem cells ,SCANNING electron microscopy ,CELL imaging - Abstract
The hematopoietic stem cell (HSC) niche undergoes detrimental changes with age. The molecular differences between young and old niches are well studied and understood; however, young and old niches have not yet been extensively characterized in terms of morphology. In the present work, a 2D stromal model of young and old HSC niches isolated from bone marrow was investigated using light and scanning electron microscopy (SEM) to characterize cell density after one, two, or three weeks of culturing, cell shape, and cell surface morphological features. Our work is aimed at identifying morphological differences between young and old niche cells that could be used to discriminate between their respective murine HSC niches. The results show several age-specific morphological characteristics. The old niches differ from the young ones in terms of lower cell proliferating capacity, increased cell size with a flattened appearance, increased number of adipocytes, and the presence of tunneling nanotubes. In addition, proliferating cell clusters are present in the young niches but not in the old niches. Together, these characteristics could be used as a relatively simple and reliable tool to discriminate between young and old murine HSC niches and as a complementary approach to imaging with specific cellular markers. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Amniotic membrane properties and current practice of amniotic membrane use in ophthalmology in Slovenia
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Cirman, Tina, Beltram, Matej, Schollmayer, Petra, Rožman, Primož, and Kreft, Mateja Erdani
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- 2014
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8. The hazards of DAPI photoconversion: effects of dye, mounting media and fixative, and how to minimize the problem
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Jež, Mojca, Bas, Tuba, Veber, Matija, Košir, Andrej, Dominko, Tanja, Page, Raymond, and Rožman, Primož
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- 2013
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9. The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients.
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Jazbec, Katerina, Jež, Mojca, Švajger, Urban, Smrekar, Boštjan, Miceska, Simona, Rajčevič, Uroš, Justin, Mojca, Završnik, Janja, Malovrh, Tadej, Švara, Tanja, Gombač, Mitja, Ramšak, Živa, and Rožman, Primož
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BONE marrow transplantation ,IMMUNE system ,FRAIL elderly ,AUTOPSY ,FRAILTY ,LONGEVITY - Abstract
The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7–13 weeks. At 21 months, donor chimerism was determined, and the immune system's innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded. The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects. [ABSTRACT FROM AUTHOR]
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- 2022
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10. ABO blood group does not influence the level of anti‐SARS‐CoV‐2 antibodies in convalescent plasma donors.
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Žiberna, Klemen, Jež, Mojca, Jazbec, Katerina, Mali, Polonca, Potokar, Urška Rahne, and Rožman, Primož
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CONVALESCENT plasma ,ABO blood group system ,BLOOD groups ,IMMUNOGLOBULINS ,COVID-19 - Abstract
Background: The association of the ABO blood group with COVID‐19 disease has been confirmed by several studies, with the blood group A patients being more susceptible and prone to a more severe clinical course of the disease. Additionally, several authors also addressed the association of ABO‐types and the levels of anti‐SARS‐CoV‐2 antibodies in convalescents, mostly supporting a theory that the non‐O blood group convalescents present with higher levels of anti‐SARS‐CoV‐2 antibodies. Study Design and Methods: Since previous findings were based on small convalescent cohorts, we quantified the anti‐SARS‐CoV‐2 antibody levels in a total of 3187 convalescent plasma donors with three commercial serological and one standard neutralizing antibody test. The majority of donors had undergone a mild form of the disease and the median time of sampling was 66 days after diagnosis. Results: None of the antibody quantitation results showed any significant association with the ABO blood group types. The same result was evident in the subgroup of vaccinated individuals (n = 370) and the subgroups when stratified according to post‐COVID‐19 periods (0–60, 60–120, and 120–180 days). Conclusion: In conclusion, we found no evidence to confirm that the ABO blood group types influence the level of SARS‐CoV‐2 antibody response in COVID‐19 convalescent plasma donors. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Matrix metalloproteinase-9 and cell kinetics during the collection of peripheral blood stem cells by leukapheresis
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Domanović, Dragoslav, Wozniak, Gordana, Černelč, Peter, Samardžija, Marina, Balen-Marunić, Sanja, and Rožman, Primož
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- 2005
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12. Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes
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Virant-Klun, Irma, Zech, Nicolas, Rožman, Primož, Vogler, Andrej, Cvjetičanin, Branko, Klemenc, Polona, Maličev, Elvira, and Meden-Vrtovec, Helena
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- 2008
13. Soluble tumor necrosis factor receptor I (sTNFRI) as a prognostic factor in melanoma patients in Slovene population
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Galvani, Vesna, Hartman, Katrina Pretnar, Rupreht, Ruth R., Novaković, Srdjan, Štabuc, Borut, Ocvirk, Janja, Menart, Viktor, Porekar, Vladimira Gaberc, Štalc, Anton, Rožman, Primož, and Šerbec, Vladka Čurin
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- 2000
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14. POSSIBLE IMPACT OF THE HPA-COMPATIBILITY ON THE OUTCOME OF THE BONE MARROW TRANSPLANTATION
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ROŽMAN, Primož, JERAS, Matjaž, DOVČ, Tadeja, URBAJS, Matjaž, BOHINJEC, Mateja, and PRETNAR, Jože
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- 1998
15. Platelet antigens. The role of human platelet alloantigens (HPA) in blood transfusion and transplantation
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Roz̆man, Primoz̆
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- 2002
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16. Mixed cultures of allogeneic dendritic cells are phenotypically and functionally stable – a potential for primary cell-based “off the shelf” product generation.
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ŠVAJGER, URBAN and ROŽMAN, PRIMOŽ J.
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DENDRITIC cells , *VACCINE manufacturing , *CANCER vaccines , *VACCINATION - Abstract
Vaccination against tumors using antigen-pulsed dendritic cell (DC) vaccines has greatly evolved over the last decade, with hundreds of active human clinical trials well on the way. The use of an autologous source for DC-based vaccine therapeutics remains the obvious choice in the majority of clinical studies; however, novel evidence suggests that an allogeneic source of DCs can yield success if administered in the right context. One of the challenges facing successful DC vaccination protocols is the generation of large enough numbers of DCs intended for vaccination and standardization of these procedures. In addition, variations in the quality of DC vaccines due to donor-to-donor variation represent an important therapeutic factor. To this day it has not been shown whether DCs from different donors can readily co-exist within the same co-culture for the extended periods required for vaccine manufacture. We demonstrate that generation of allogeneic DC co-cultures, generated from multiple unrelated donors, allows the preservation of their phenotypical and functional properties in vitro for up to 72 hours. Therefore, in the case of an allogeneic vaccination approach, one could ensure large numbers of DCs generated from a primary cell source intended for multiple vaccinations. By generating large amounts of ex vivo manufactured DCs from multiple donors, this would represent the possibility to ensure sufficient amounts of equipotent “off the shelf” product that could e.g. be used for an entire cohort of patients within a study. [ABSTRACT FROM AUTHOR]
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- 2021
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17. Application of the 3R principles: Vertebrae as an additional source of murine bone-marrow cells.
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Justin, Mojca, Jež, Mojca, Košir, Andrej, Miceska, Simona, Rožman, Primož, and Jazbec, Katerina
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CELL populations ,COLONY-forming units assay ,CELL separation ,BONE marrow ,VERTEBRAE ,FLOW cytometry ,STROMAL cells - Abstract
Copyright of Laboratory Animals is the property of Sage Publications, Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2021
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18. Heparin-induced thrombocytopenia: ELISA optical density value and 4T score in correlation with panel donor platelets activation in functional flow cytometric assay.
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Železnik, Klara, Rožman, Primož, Kocjan, Eva, and Maličev, Elvira
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- 2021
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19. How Could We Slow or Reverse the Human Aging Process and Extend the Healthy Life Span with Heterochronous Autologous Hematopoietic Stem Cell Transplantation.
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Rožman, Primož
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HEMATOPOIETIC stem cell transplantation , *LIFE spans , *BONE marrow cells , *ANIMAL longevity , *BONE marrow transplantation , *REJUVENATION , *AUTOGRAFTS , *HEMATOPOIETIC stem cells , *LONGEVITY , *ANIMALS - Abstract
The senescence of the immune system contributes considerably to the age-related diseases that are the main causes of death after the age of 65. In this study, we present an appealing option for the prevention of immune senescence and slowing or reversing the aging process, which can be achieved by heterochronous autologous hematopoietic stem cell transplantation (haHSCT), where healthy autologous bone marrow stem cells are collected from donors while young, cryopreserved and stored for a long period, and reinfused at a later time when indicated. After reinfusion and homing, these young HSCs could participate in normal hemato- and immunopoiesis and improve several immune functions by expanding the immune- as well as hematopoietic cell repertoire. Several animal studies have already confirmed the feasibility of this procedure, which extended the longevity of the treated animals. If translated to human medicine, haHSCT could prevent or mitigate age-related immune defects and extend the healthy life span. In this review, we describe the concept of haHSCT, recent studies that confirm its feasibility, and discuss the further research needed to translate this heterochronous methodology. [ABSTRACT FROM AUTHOR]
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- 2020
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20. Dendritic Cells Generated in the Presence of Platelet Lysate Have a Reduced Type 1 Polarization Capacity.
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Tešić, Nataša, Pekle Simonič, Iza, Roškar, Katja, Rožman, Primož, and Švajger, Urban
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DENDRITIC cells ,CHEMOKINE receptors ,PROSTAGLANDIN receptors ,BLOOD platelets ,TUMOR necrosis factors ,SERUM-free culture media ,POLYHYDRAMNIOS - Abstract
Previously, we have shown platelet lysate (PL) can be used as a non-xenogeneic serum supplement for generation of monocyte-derived dendritic cells (DCs). Since DC-based activation protocols are extremely sensitive to microenvironmental changes such as replacement of culture medium, we wanted to examine the behavior of DCs cultured in the presence of PL under various type-1 activation conditions and assess their type 1 polarization capacity. We compared the quality of DCs cultured in 10% PL-supplemented RPMI medium (plDCs) with clinical-grade DCs obtained using commercially available serum-free medium (sfDCs), frequently used in established DC vaccine protocols. The DC maturation protocols consisted of either monophosphoryl lipid A/IFN-γ, poly I:C/TNF-α/IFN-α or poly I:C/R848. In general, plDCs were inferior to sfDCs in most aspects of their functional type 1 polarization characteristics. After maturation, the expression of co-stimulatory, HLA class II and lymph node-homing molecules was strongly up-regulated, with some noticeable differences. The expression of CD80 and CD86 was more extensive on plDCs, which was particularly evident in case of CCR7. However, after observing their functional capacity, plDCs had significantly lower allo-stimulatory capacity both in terms of CD4
+ and CD8+ T cell stimulation. The high expression of CCR7 corresponded to higher CCL-19 directed DC migration of plDCs compared to sfDCs. Finally, their capacity to induce granzyme B and IFN-γ production in CD8+ T cells was significantly reduced in comparison to sfDCs. Based on these findings, the use of PL as an alternative serum supplement for generation of monocyte-derived DC anti-tumor vaccines is questionable. Abbreviations: Ag: antigen; CCL: chemokine ligand; CCR: chemokine receptor; DC: dendritic cells; DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; FBS: fetal bovine serum; GMP: good manufacturing practice; IFN: interferon; IL: interleukin; MPLA: monophosphoryl lipid A; PGE: prostaglandin E; pI:C: polyinosinic:polycytidylic acid; pl: platelet lysate; sf: serum free; TLR: toll-like receptor; TNF: tumor necrosis factor. [ABSTRACT FROM AUTHOR]- Published
- 2020
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21. Synergistic Effects of Interferon-γ and Vitamin D3 Signaling in Induction of ILT-3highPDL-1high Tolerogenic Dendritic Cells.
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Švajger, Urban and Rožman, Primož J.
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DENDRITIC cells ,T cell receptors ,IMMUNOREGULATION ,T cells ,ERGOCALCIFEROL ,VITAMINS ,MEMORY - Abstract
In the past, interferon (IFN)-γ and vitamin D
3 (vit D3 ) have both been associated with induction of tolerogenic characteristics in human dendritic cells (DCs). Although there are only a few reports on interdependency of their actions, the interplay between IFN-γ and vit D3 has been clearly demonstrated in certain aspects of immune reactivity. Since both agents have been associated with regulation of immune responses, we set out to examine their functional and mechanistic interactions in context of principal regulators of immunity, the DCs. Combined treatment with vit D3 and IFN-γ caused an extensive expression of immunoglobulin-like transcript (ILT)-3 and programmed death ligand (PDL)-1 on γ/D3 DCs, significantly greater than that caused by vit D3 alone. Such γ/D3 DCs retained all general DC characteristics. After CD40 ligand-induced activation, they produced increased amounts of IL-10 with almost absent production of IL-12p70. On the other hand, the co-stimulatory potential of γ/D3 DCs was weak, with cells possessing the capacity to inhibit CD4+ T cell, CD8+ T cell, as well as memory T cell responses. Naive CD4+ T cells stimulated with γ/D3 DCs produced increased amounts of IL-10 with concomitantly low IFN-γ production, upon T cell receptor activation. Additionally, γ/D3 DCs completely inhibited granzyme B expression by CD8+ T cells. The percentage of FoxP3-positive cells in co-cultures with naive CD4+ T cells was significantly higher where γ/D3 DCs were used as stimulators compared to DCs treated with vit D3 alone and it could be partially reversed by PDL-1 blockade. Interestingly, γ/D3 DCs were inefficient at suppressing mDC-induced CD4+ T cell proliferation, but were twice as effective as D3 DCs at suppressing mDC-induced CD8+ T cell proliferation. Blockade of indoleamine-2,3-dioxygenase did not reduce the tolerogenic phenotype induced by IFN-γ and vit D3 treatment. Examination of signaling pathways activation revealed a tendency toward increased ERK and Akt phosphorylation in γ/D3 DCs. Inhibition of MEK/ERK and PI3K/mTOR pathways significantly reduced the expression of ILT-3 and PDL-1 on γ/D3 DCs. In summary, we present the first evidence for existing synergy between IFN-γ and vit D3 in shaping a unique tolerogenic DC activation state. [ABSTRACT FROM AUTHOR]- Published
- 2019
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22. Rhd and C/cE/e genotyping in Slovenian population
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Rupreht, Ruth Rebeka, Faas, Brigitte Henrica Wilhelmina, Bojanič, Vesna, Wijk, Petra Anna Maaskant van, Glonar, Ljerka, Bricl, Irena, Rožman, Primož, and Šerbec, Vladka Čurin
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- 2000
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23. Weak D and partial D in Slovenian population through serology and genotyping
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Rupreht, Ruth Rebeka, Hartman, Katrina Pretnar, Galvani, Vesna, Rožman, Primož, and Šerbec, Vladka Čurin
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- 2000
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24. REGENERATION OF CHRONIC WOUNDS WITH ALLOGENEIC PLATELET GEL VERSUS HYDROGEL TREATMENT: A PROSPECTIVE STUDY.
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Semenič, Danijela, Cirman, Tina, Rožman, Primož, and Smrke, Dragica Maja
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- 2018
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25. Chimerism and gene therapy — Lessons learned from non‐conditioned murine bone marrow transplantation models.
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Jazbec, Katerina, Jež, Mojca, Smrekar, Boštjan, Miceska, Simona, Rožman, Jasmina‐Živa, Švajger, Urban, Završnik, Janja, Malovrh, Tadej, and Rožman, Primož
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CHIMERISM ,GENE therapy ,BONE marrow transplantation ,PROGENITOR cells ,HEMATOPOIETIC stem cells ,BONE marrow cells ,CELLULAR therapy ,THERAPEUTICS - Abstract
Abstract: Objective: Hematopoietic stem and progenitor cells (HSPCs) can be used as a vector for gene therapies. In order to predict the number of HSPCs cells necessary to achieve the target level of chimerism in an autologous setting, syngeneic male bone marrow (BM) cells were transplanted into 35 non‐conditioned female BALB/c mice. Method: The resulting chimerism was determined at 6‐53 weeks using qPCR, cell subpopulation sorting, and colony‐forming units (CFU) analysis. Results: After the transplantation of 125.8 ± 2.5 million nucleated BM cells, the BM of recipients contained 20.0 ± 2.8% donor cells, representing a chimerism of 0.16 ± 0.02% per one million transplanted nucleated BM cells. Chimerism levels in the BM, neutrophils, and B cells were comparable, whereas in T cells it was lower, and in CFU was approximately twice greater than in BM. Conclusion: By extrapolating our murine data, and data from some previous studies to a human non‐conditioned autologous CD34
+ HSPC transplantation setting, we conclude that approximately 44 million CD34+ HSPCs would be needed to achieve 20% donor chimerism in a 70‐kg human, which could serve as a starting point for the future use of HSCPs in gene and cell therapy. [ABSTRACT FROM AUTHOR]- Published
- 2018
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26. Concise Review: The Role of Oxygen in Hematopoietic Stem Cell Physiology.
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Jež, Mojca, Rožman, Primož, Ivanović, Zoran, and Bas, Tuba
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HEMATOPOIETIC stem cells , *CELL physiology , *CELL culture , *ELECTROPHILES , *CELL respiration , *OXIDATIVE phosphorylation , *CELL differentiation - Abstract
Molecular dioxygen, O2, is an important element in cellular microenvironment in vivo, and often overlooked in standard in vitro and ex vivo cell culture systems. Molecular oxygen is the ultimate electron acceptor in oxidative cellular respiration, and also a signal that regulates cell fate through concentration gradients. Recent advances in physiology of oxygen and adult stem cell research have shown that apart from being important for oxidative phosphorylation, thus energy metabolism, oxygen is also important as a signaling molecule and an integral part of the stem cell niche. This review article covers the influence of physiologically relevant oxygen levels on adult stem cells through highlighting the research on the effect of oxygen concentration on hematopoietic stem cell maintenance, proliferation and differentiation. This is important particularly to understand the embryonic and adult stem cell biology and physiology. The new discoveries in this field will help to further improve current tissue engineering and clinical applications. In addition, understanding the relationship between oxygen and stemness is invaluable for the advanced treatments of neoplastic diseases. Authors believe that in the future, active and programmed dynamic of oxygen levels will be routinely used for the programmed in vitro and ex vivo expansion of different adult stem cell types and tissue regeneration purposes. J. Cell. Physiol. 230: 1999-2005, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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27. Analysis of Glioblastoma Patients' Plasma Revealed the Presence of MicroRNAs with a Prognostic Impact on Survival and Those of Viral Origin.
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Herman, Ana, Gruden, Kristina, Blejec, Andrej, Podpečan, Vid, Motaln, Helena, Rožman, Primož, Hren, Matjaž, Zupančič, Klemen, Veber, Matija, Verbovšek, Urška, Lah Turnšek, Tamara, Porčnik, Andrej, Koršič, Marjan, Knežević, Miomir, and Jeras, Matjaž
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GLIOBLASTOMA multiforme ,MICRORNA genetics ,PLETHORA (Pathology) ,TUMOR markers ,GLIOBLASTOMA multiforme treatment ,GENE expression ,PROGNOSIS - Abstract
Background: Glioblastoma multiforme (GBM) is among the most aggressive cancers with a poor prognosis in spite of a plethora of established diagnostic and prognostic biomarkers and treatment modalities. Therefore, the current goal is the detection of novel biomarkers, possibly detectable in the blood of GBM patients that may enable an early diagnosis and are potential therapeutic targets, leading to more efficient interventions. Experimental Procedures: MicroRNA profiling of 734 human and human-associated viral miRNAs was performed on blood plasma samples from 16 healthy individuals and 16 patients with GBM, using the nCounter miRNA Expression Assay Kits. Results: We identified 19 miRNAs with significantly different plasma levels in GBM patients, compared to the healthy individuals group with the difference limited by a factor of 2. Additionally, 11 viral miRNAs were found differentially expressed in plasma of GBM patients and 24 miRNA levels significantly correlated with the patients’ survival. Moreover, the overlap between the group of candidate miRNAs for diagnostic biomarkers and the group of miRNAs associated with survival, consisted of ten miRNAs, showing both diagnostic and prognostic potential. Among them, hsa miR 592 and hsa miR 514a 3p have not been previously described in GBM and represent novel candidates for selective biomarkers. The possible signalling, induced by the revealed miRNAs is discussed, including those of viral origin, and in particular those related to the impaired immune response in the progression of GBM. Conclusion: The GBM burden is reflected in the alteration of the plasma miRNAs pattern, including viral miRNAs, representing the potential for future clinical application. Therefore proposed biomarker candidate miRNAs should be validated in a larger study of an independent cohort of patients. [ABSTRACT FROM AUTHOR]
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- 2015
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28. New antagonists of toll-like receptor 7 discovered through 3D ligand-based virtual screening.
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Švajger, Urban, Horvat, Žiga, Knez, Damijan, Rožman, Primož, Turk, Samo, and Gobec, Stanislav
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Toll-like receptor (TLR) 7 has an important role in immune activation processes and represents an emerging drug discovery target for the development of immunomodulators. Three-dimensional similarity-based virtual screening was performed using the Rapid Overlay of Chemical Structures software (vROCS version 3.1.1. OpenEye Scientific Software, Santa Fe, NM. ) to search for potential ligands of TLR7. Six new compounds with three new chemical scaffolds were discovered as initial hit antagonists of TLR7, with IC values in the micromolar range, as determined by reporter assays. With only the imidazoquinolines described as small-molecule TLR7 antagonists to date, the new chemotypes described in this report represent an important starting point for the development of drug candidates for treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]
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- 2015
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29. The Influence of Allogeneic Platelet Gel on the Morphology of Human Long Bones.
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Gubina, Borut, Rožman, Primož, Bišćević, Mirza, Domanović, Dragoslav, and Smrke, Dragica
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BONE grafting ,CANCELLOUS bone ,AUTOGRAFTS ,BLOOD platelets ,BONES ,PSEUDARTHROSIS ,MORPHOLOGY ,ANATOMY - Abstract
Copyright of Collegium Antropologicum is the property of Croatian Anthropological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2014
30. Reliable Determination of Fetal RhD Status by RHD Genotyping from Maternal Plasma.
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Dovč-Drnovšek, Tadeja, Klemenc, Polona, Toplak, Nataša, Blejec, Tanja, Bricl, Irena, and Rožman, Primož
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Background: Immunoprophylaxis with IgG anti-D is a standard prevention of hemolytic disease of the fetus and newborn. Fetal Rhesus D (RhD) blood group genotyping from maternal plasma of RhD-negative pregnant women allows targeted prophylaxis with IgG anti-D in RhD-positive pregnancies only. We set up a reliable protocol for prenatal RHD genotyping. Methods: 153 pregnant Caucasian RhD-negative women were tested in the 27th week (range 7-38th week) of pregnancy. 18 of them were alloimmunized to the RhD antigen. The fetal RHD genotype was determined based on an automated DNA extraction and real-time polymerase chain reaction method. Intron 4 and exons 5, 7 and 10 of the RHD gene and the SRY gene were targeted. Results: The fetal RhD status and gender was 100% correctly predicted in all 153 pregnancies (55 RhD-positive males, 45 RhD-positive females; 23 RhD-negative males, 30 RhD-negative females). Conclusion: The accuracy and applicability of our protocol for non-invasive fetal RhD determination allows the correct management of RhD-incompatible pregnancies. Our protocol could prevent unnecessary immunoprophylaxis in 53 of 153 cases. We therefore recommend that non-invasive fetal RHD genotyping is introduced as an obligatory part of prenatal screening. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. A "Crossomics" Study Analysing Variability of Different Components in Peripheral Blood of Healthy Caucasoid Individuals.
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Gruden, Kristina, Hren, Matjaž, Herman, Ana, Blejec, Andrej, Albrecht, Tanja, Selbig, Joachim, Bauer, Chris, Schuchardt, Johannes, Or-Guil, Michal, Zupančič, Klemen, Švajger, Urban, Štabuc, Borut, Ihan, Alojz, Kopitar, Andreja Nataša, Ravnikar, Maja, Kneževic, Miomir, Rožman, Primož, and Jeras, Matjaž
- Subjects
BLOOD ,IMMUNOTHERAPY ,CAUCASIAN race ,CANCER treatment ,T cells ,BODY mass index - Abstract
Background: Different immunotherapy approaches for the treatment of cancer and autoimmune diseases are being developed and tested in clinical studies worldwide. Their resulting complex experimental data should be properly evaluated, therefore reliable normal healthy control baseline values are indispensable. Methodology/Principal Findings: To assess intra- and inter-individual variability of various biomarkers, peripheral blood of 16 age and gender equilibrated healthy volunteers was sampled on 3 different days within a period of one month. Complex ''crossomics'' analyses of plasma metabolite profiles, antibody concentrations and lymphocyte subset counts as well as whole genome expression profiling in CD4
+ T and NK cells were performed. Some of the observed age, gender and BMI dependences are in agreement with the existing knowledge, like negative correlation between sex hormone levels and age or BMI related increase in lipids and soluble sugars. Thus we can assume that the distribution of all 39.743 analysed markers is well representing the normal Caucasoid population. All lymphocyte subsets, 20% of metabolites and less than 10% of genes, were identified as highly variable in our dataset. Conclusions/Significance: Our study shows that the intra-individual variability was at least two-fold lower compared to the inter-individual one at all investigated levels, showing the importance of personalised medicine approach from yet another perspective. [ABSTRACT FROM AUTHOR]- Published
- 2012
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32. Telemedicine in the blood transfusion laboratory – remote interpretation of pre-transfusion tests.
- Author
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Meža, Marko, Breskvar, Marko, Košir, Andrej, Bricl, Irena, Tasič, Jurij, and Rožman, Primož
- Subjects
TELEMEDICINE ,MEDICAL technology ,BLOOD transfusion ,AGGLUTINATION - Abstract
We have developed a telemedicine system for blood transfusion work, to supply the local hospital laboratory with an expert opinion from the central reference laboratory. The telemedicine system allows remote inspection and interpretation of pre-transfusion tests, which are performed by ID-cards (micro-tube gel technology). The system was installed at three blood transfusion laboratories in Slovenia, approximately 70 km apart. Validation of the telemedicine system was performed using 99 clinical cases selected randomly from routine work. Two groups of immunohaematology specialists participated. Group A (n = 8) performed the read-out of the pre-transfusion tests on ID-cards by using the telemedicine system. Group B (n = 2) then read the ID-cards independently using the standard visual method. All 98 final interpretations which were recorded using the telemedicine system were correct. We recorded 591 micro-tube read-outs of agglutination strength using the telemedicine system, of which 582 were correct. For comparison, we recorded 591 micro-tube read-outs using the standard visual method, of which 582 were correct. The validation proved that the telemedicine system was suitable for operational use. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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- View/download PDF
33. Allogeneic Platelet Gel with Autologous Cancellous Bone Graft for the Treatment of a Large Bone Defect.
- Author
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Smrke, Dragica, Gubina, Borut, Domanović, Dragoslav, and Rožman, Primož
- Subjects
BONE grafting ,HOMOGRAFTS ,TRANSPLANTATION of organs, tissues, etc. ,PLATELET activating factor ,BLOOD platelets ,POSTOPERATIVE care ,MEDICAL research - Abstract
Background/Aims: A 50-year-old type 2 diabetic male with a comminuted fracture of the tibia and delayed union after insufficient initial osteosynthesis with a resulting pseudoarthrosis was treated operatively by using a graft composed of platelet gel mixed with autologous cancellous bone. The essential idea of this therapy was to combine the healing capacities of platelet-derived growth factors and osteogenic stem cells and the modeling capacity of the gel. Due to a history of diabetes, allogeneic instead of autologous platelets were used. Methods: The allogeneic platelet concentrate was ABO- and RhD-matched, leukocyte-depleted, irradiated and activated by human thrombin. The defect of 45 ml was filled with the graft mixture and fixed with an external fixator. Results: Postoperative care was uneventful. After 6 months the graft was incorporated, the bone defect was fully bridged and full weight-bearing capacity was achieved. No side effects were observed and no platelet or HLA class I antibodies were detected. Conclusion: This case report shows that the clinical use of allogeneic platelet-derived growth factors is feasible and that a prospective study is necessary to prove the effectiveness and reproducibility of this therapeutic approach. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
34. Is the ABO incompatibility a risk factor in bone marrow transplantation?
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Rožman, Primož, Košir, Andrej, and Bohinjec, Mateja
- Subjects
- *
BONE marrow transplantation , *ABO blood group system , *BLOOD cells , *HEMATOPOIETIC stem cells , *ANTIGENS , *IMMUNOLOGY - Abstract
ABO histo-bloodgroups are strong transplantation antigens. In bone marrow transplantation, foreign ABO red cell antigens are not ignored by the immune system of the host, neither by the immunocompetent cells of the graft. Although ABO incompatibility is not considered a contraindication in bone marrow transplantation (BMT), its clinical consequences are still a matter of investigation. An overview of reports published by different groups is given and discussed. They present conflicting data regarding the role of the ABO match between patient and donor in the haematopoietic stem cell (HSC) transplantation. We report on the clinical outcome of bone marrow transplantation in 223 patients who received grafts from MHC identical siblings. Included are 139 ABO identical, 32 ABO minor mismatched, 34 major mismatched and 13 bi-directionally mismatched pairs. The statistical evaluation of standard parameters used to monitor the post-transplant period gave a proof that in neither group of patients with an ABO incompatible donor the recovery and success rate of transplantation, including the relapse incidence, risk of graft vs. host disease (GVHD) or overall survival, were significantly inferior. However, in all three cohorts of ABO mismatched patients, a delayed recovery of neutrophils was recorded as compared to the group receiving an ABO compatible graft. These finding leads us to the conclusion that the ABO compatibility is not a disadvantage in BMT, whereas the delayed recovery of neutrophils in patients having received an ABO mismatched graft is probably reflecting a transient humoral process leading to immune tolerance and graft accommodation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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- View/download PDF
35. Concerns About the Effects of Platelet Concentrate
- Author
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Vogrin, Matjaz, Rozman, Primoz, and Haspl, Miroslav
- Published
- 2009
- Full Text
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36. Recent discoveries in dendritic cell tolerance-inducing pharmacological molecules.
- Author
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Švajger, Urban and Rožman, Primož J.
- Subjects
- *
CHOLECALCIFEROL , *DENDRITIC cells , *SMALL molecules , *MOLECULES , *TRANSCRIPTION factors - Abstract
• Recent evidence points to increased diversity of Tol-DC characteristics. • Discovery of novel Tol-DC inducing agents will allow for advances in fine-tuning their immunosuppressive characteristics. • In the last 5 years, several pharmacological drugs have been found to be capable of inducing Tol-DCs. • Discovery of Tol-DC inducing protocols focusing on synergy between different agents can lead to enhancement of DC tolerogenic potential. Dendritic cells (DCs) represent one of the most important biological tools for cellular immunotherapy purposes. There are an increasing number of phase I and II studies, where regulatory or tolerogenic DCs (TolDCs) are utilized as negative vaccines, with the aim of inducing tolerogenic outcomes in patients with various autoimmune or chronic-inflammatory diseases, as well as in transplant settings. The induction of tolerogenic properties in DCs can be achieved by altering their activation state toward expression of immunosuppressive elements and/or by achieving resistance to maturation, which leads to insufficient co-stimulatory signal delivery and inability to efficiently present antigens. In the past, one of the most efficient ways to induce DC tolerance has been the application of selected pharmacological agents which actively induce a tolerogenic transcription program or inhibit major pro-inflammatory transcription factors such as Nf-κB. Important examples include immunosuppressants such as different corticosteroids, vitamin D 3 , rapamycin and others. The quality of TolDCs induced by different approaches is becoming a vital issue and recent evidence suggests substantial heterogeneity between variously-generated TolDCs as evidenced by their transcriptomic profile and function. The possibility of various "flavors" of TolDCs encourages future research in discovery of Tol-DC inducing agents to enrich various ways of DC manipulation. This would enable a broader range of tools to manipulate DC toward specific characteristics desirable in different disease settings. In recent years, several novel small molecules have been identified with the capacity to promote DC tolerogenic characteristics. In this review, we will present and discuss these novel findings and also highlight novel understandings of tolerogenic mechanisms by which DC tolerogenicity is induced by already established agents. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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37. An uncommon treatment of totally extruded and lost talus: a case report.
- Author
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Smrke, Dragica Maja, RoZman, PrimoZ, Gubina, Borut, FrangeZ, Igor, Smrke, Barbara Rejec, ArneZ, Zoran Marij, Rožman, Primož, Frangež, Igor, Rejec Smrke, Barbara, and Arnež, Zoran Marij
- Abstract
Introduction: Total extrusion and loss of the talus is a rare injury with a wide choice of appropriate treatment, but rarely resulting in a fully functional recovery. We report on an uncommon case, both for the severity of the injury and for the uncommon treatment due to the patient's rejection of secondary surgery.Case Presentation: We treated a 16-year-old Caucasian man with the most extreme variant of a totally extruded and lost talus, accompanied with complex injury of the soft tissues of the ankle and foot. The treatment included urgent microvascular foot reimplantation, microvascular muscle free flap transfer, and temporary fixation. This kind of injury should typically be treated by tibiocalcaneal arthrodesis. However, this was not performed, as after the successful early stages of the treatment he strongly objected to another surgery due to his fully functional status and the successful therapeutic results of our early treatment.Conclusions: The injury described in this case study would ordinarily be treated by amputation, but due to the well-executed treatment in the early stages after the injury, the outcome was satisfying. Surprisingly and against our expectations, the late results of the treatment were successful even without arthrodesis. He is now 37 years old and has a functional foot 21 years after the injury. [ABSTRACT FROM AUTHOR]- Published
- 2014
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38. Programmed death ligand 1 (PD-L1) plays a vital part in DC tolerogenicity induced by IFN-γ.
- Author
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Švajger, Urban, Tešić, Nataša, and Rožman, Primož
- Subjects
- *
PROGRAMMED death-ligand 1 , *T cells , *REGULATORY T cells , *MONOCYTES , *CELL populations , *PROGRAMMED cell death 1 receptors , *DENDRITIC cells - Abstract
• IFN-γ possesses the capacity to induce tolerogenic DC characteristics. • Dendritic cells treated with IFN-γ induce CD4+CD25+CD127−FoxP3+ T cell populations. • The induction of PD-L1 by IFN-γ is required for DCs' tolerogenic effect. Interferon-γ (IFN-γ) is the sole representative of type II IFNs, with well recognized role in numerous inflammatory processes. Lately, its significant pleiotropic nature has been recognized in many scenarios, where IFN-γ contributes to maintenance or induction of tolerogenic responses in context of various immune cell types. In this manuscript we demonstrate, that IFN-γ-mediated induction of programmed death ligand 1 (PD-L1) on human monocyte-derived dendritic cells (DCs) represents an important tolerogenic aspect in immunological network of type II IFNs. When fully differentiated, immature DCs were treated with increasing concentrations of IFN-γ there was no sign of maturation, as revealed by CD80, CD83 and CD86 expression. In terms of co-stimulatory receptor response, we did observe a dose-dependent increase in CD40 expression. Phenotypic analysis of inhibitory molecules revealed that PD-L1 expression is particularly sensitive to IFN-γ, as its expression can be induced almost 10-fold in comparison to non-treated DCs. Functional analysis of such PD-L1high DCs revealed significant immunosuppressive properties in a mixed lymphocyte reaction with whole or memory CD4+ T cells. When IFN-γ treated DCs were co-cultured with naive CD4+CD45RA+ T cells, they induced an increased percentage of CD4+CD25+CD127−FoxP3+ Tregs. Inhibition of PD-1/PD-L1 axis using neutralizing anti-PD-L1 mAbs, reversed the immunosuppressive effect of IFN-γ-treated DCs to suppress CD4+ T cell proliferation and to induce Tregs. In summary, our findings demonstrate the importance of IFN-γ-mediated tolerogenic effects, exerted on DCs by inducing increased expression of PD-L1, which enhances their regulatory function. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
39. MOLECULAR MECHANISMS OF STEM CELL AGING.
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Jazbec, Katerina, Jež, Mojca, Justin, Mojca, and Rožman, Primož
- Subjects
- *
CELLULAR aging , *STEM cells , *CELL polarity , *SOMATIC cells , *TELOMERES , *DNA damage - Abstract
The aging of multicellular organisms is a complex process, which is a result of various mutually complementary causes. One of these causes is the aging of stem cells. The biological function of stem cells is the replacement of cells that are lost due to illness, injury or normal fluctuations in the maintenance of tissue homeostasis. Molecular mechanisms involved in stem cell aging are similar to those involved in the aging of somatic cells. They include DNA damage and mutations, cell senescence, stem cell exhaustion, telomere shortening, epigenetic changes (alterations of histones and DNA and the consequent dysregulation of gene expression), changes in microRNAs, changes in metabolism, nutrient sensing, decline in mitochondrial integrity and biogenesis, alterations in microenvironment, accumulation of paracrine factors, and loss of cell polarity and proteostasis. Stem cells have developed special mechanisms that compensate for age-related accumulations of errors and they manage to maintain their stemness for a long time, however, they are able to keep cells in a good condition only for a limited period. This article describes the various mechanisms of stem cell aging and their consequences. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
40. Cytokine, Anti-SARS-CoV-2 Antibody, and Neutralizing Antibody Levels in Conventional Blood Donors Who Have Recovered from COVID-19.
- Author
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Maličev E, Žiberna K, Jazbec K, Kolenc A, Mali P, Potokar UR, and Rožman P
- Abstract
Background: At the beginning of the pandemic, COVID-19 convalescent plasma (CCP) containing anti-SARS-CoV-2 antibodies was suggested as a source of therapy. In the last 3 years, many trials have demonstrated the limited usefulness of CCP therapy. This led us to the hypothesis that CCP could contain other elements, along with the desired neutralizing antibodies, which could potentially prevent it from having a therapeutic effect, among them cytokines, chemokines, growth factors, clotting factors, and autoantibodies., Methods: In total, 39 cytokines were analyzed in the plasma of 190 blood donors, and further research focused on the levels of 23 different cytokines in CCP (sCD40L, eotaxin, FGF-2, FLT-3L, ractalkine, GRO-α, IFNα2, IL-1β, IL-1RA, IL-5, IL-6, IL-8, IL-12, IL-13, IL-15, IL-17E, IP-10, MCP-1, MIP-1b, PDGF-AA, TGFα, TNFα, and TRAIL). Anti-SARS-CoV-2 antibodies and neutralizing antibodies were detected in CCP., Results: We found no significant differences between CCP taken within a maximum of 180 days from the onset of the first COVID-19 symptoms and the controls. We also made a comparison of the cytokine levels between the low neutralizing antibodies (<160) group and the high neutralizing antibodies (≥160) group and found there were no differences between the groups. Our research also showed no correlation either to levels of anti-SARS-CoV-2 IgG Ab or to the levels of neutralizing antibodies. There were also no significant changes in cytokine levels based on the period after the start of COVID-19 symptoms., Conclusions: No elements which could potentially be responsible for preventing CCP from having a therapeutic effect were found., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2023
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- View/download PDF
41. Heparin-induced thrombocytopenia: ELISA optical density value and 4T score in correlation with panel donor platelets activation in functional flow cytometric assay.
- Author
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Železnik K, Rožman P, Kocjan E, and Maličev E
- Subjects
- Aged, Aged, 80 and over, Anticoagulants immunology, Blood Platelets drug effects, Blood Platelets immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Heparin immunology, Humans, Male, Thrombocytopenia blood, Thrombocytopenia immunology, Anticoagulants adverse effects, Heparin adverse effects, Platelet Activation drug effects, Thrombocytopenia chemically induced
- Abstract
Background: Serological assays for the diagnosis of heparin-induced thrombocytopenia (HIT) detect both platelet-activating and platelet non-activating anti-heparin/platelet factor 4 (PF4) antibodies and have therefore a limited positive predictive value. Functional assays confirm the presence of platelet-activating antibodies but require platelets from healthy donors, whose response to patient serum can differ. Our aim was to investigate the correlation between the level of anti-heparin/PF4 antibodies, 4T score, and the extent of panel donor platelet activation in the functional assay., Materials and Methods: In total, 38 sera from enzyme immunoassays (ELISA) positive patients were tested against panel platelets obtained from 10 healthy, randomly selected donors, using our routine flow cytometry functional test for CD62P expression. Levels of anti-heparin/PF4 antibodies from medical and surgical patients and 4T pretest probability scores (where available) were correlated with the number of activated panel platelets., Results: Sera with low ELISA optical density (OD) values (0.4-1) activated on average 5.6, sera with intermediate ELISA OD values (>1-2.5) activated on average 7.3, and sera with high ELISA OD values (>2.5) activated on average 8.6 out of 10 panel platelets. One serum with low 4T score did not activate donor platelets, 12 sera with intermediate 4T score activated on average 6.3 donors, 8 sera with high 4T score activated on average 8.5 panel platelets., Discussion: Sera with higher ELISA OD values activated platelets from a higher number of platelet donors, independently of patient type (medical or surgical). The average number of activated panel platelets increased with rising 4T score. Results indicate that both donor platelet reactivity and quantity of anti-heparin/PF4 antibodies affect the result of the functional assay, meaning special attention is needed in platelet donor selection when testing sera with low levels of antibodies.
- Published
- 2021
- Full Text
- View/download PDF
42. Effects of heterochronic, non-myeloablative bone marrow transplantation on age-related behavioural changes in mice.
- Author
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Lountzi D, Henzel K, Jazbec K, Bano D, Krauss S, Rožman P, and Ehninger D
- Subjects
- Allografts, Animals, Mice, Mice, Inbred BALB C, Aging, Behavior, Animal, Bone Marrow Transplantation
- Abstract
Experiments using heterochronic parabionts, i.e. young and old animals connected surgically and hence developing a shared circulation, have shown that blood-borne factors, transferred from young to old mice and vice versa, play a role in influencing a range of health outcomes associated with advanced age. Previous work has explored the contributory role of plasma-derived factors in mediating such parabiotic effects, including those on aging-associated neural and behavioural impairments. Here, we wanted to identify possible influences that blood-borne cellular factors may have on age-related behavioural phenotypes. Towards this end, we subjected old BALB/c H-2
d mice to repetitive non-myeloablative bone marrow transplants (BMT) from young donor animals and assessed effects on behaviour and cognition. We detected expected age-related alterations in our behavioural assays but did not discern any obvious differences between old BMT mice and old control animals. Our study represents the first to look at possible behavioural and cognitive effects of heterochronic, non-myeloablative BMT. Future work should extend this study by including additional behavioural tests in the analysis, addressing whether beneficial effects of BMT may be detectable on other genetic backgrounds and reconciling our findings with those achieved by myeloablative BMT., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
43. Synergistic Effects of Interferon-γ and Vitamin D 3 Signaling in Induction of ILT-3 high PDL-1 high Tolerogenic Dendritic Cells.
- Author
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Švajger U and Rožman PJ
- Subjects
- Dendritic Cells immunology, Humans, MAP Kinase Signaling System physiology, Phosphatidylinositol 3-Kinases physiology, Receptors, Calcitriol physiology, Signal Transduction physiology, TOR Serine-Threonine Kinases physiology, B7-H1 Antigen physiology, Cholecalciferol pharmacology, Dendritic Cells drug effects, Immune Tolerance immunology, Interferon-gamma pharmacology, Membrane Glycoproteins physiology, Receptors, Immunologic physiology
- Abstract
In the past, interferon (IFN)-γ and vitamin D
3 (vit D3 ) have both been associated with induction of tolerogenic characteristics in human dendritic cells (DCs). Although there are only a few reports on interdependency of their actions, the interplay between IFN-γ and vit D3 has been clearly demonstrated in certain aspects of immune reactivity. Since both agents have been associated with regulation of immune responses, we set out to examine their functional and mechanistic interactions in context of principal regulators of immunity, the DCs. Combined treatment with vit D3 and IFN-γ caused an extensive expression of immunoglobulin-like transcript (ILT)-3 and programmed death ligand (PDL)-1 on γ/D3 DCs, significantly greater than that caused by vit D3 alone. Such γ/D3 DCs retained all general DC characteristics. After CD40 ligand-induced activation, they produced increased amounts of IL-10 with almost absent production of IL-12p70. On the other hand, the co-stimulatory potential of γ/D3 DCs was weak, with cells possessing the capacity to inhibit CD4+ T cell, CD8+ T cell, as well as memory T cell responses. Naive CD4+ T cells stimulated with γ/D3 DCs produced increased amounts of IL-10 with concomitantly low IFN-γ production, upon T cell receptor activation. Additionally, γ/D3 DCs completely inhibited granzyme B expression by CD8+ T cells. The percentage of FoxP3-positive cells in co-cultures with naive CD4+ T cells was significantly higher where γ/D3 DCs were used as stimulators compared to DCs treated with vit D3 alone and it could be partially reversed by PDL-1 blockade. Interestingly, γ/D3 DCs were inefficient at suppressing mDC-induced CD4+ T cell proliferation, but were twice as effective as D3 DCs at suppressing mDC-induced CD8+ T cell proliferation. Blockade of indoleamine-2,3-dioxygenase did not reduce the tolerogenic phenotype induced by IFN-γ and vit D3 treatment. Examination of signaling pathways activation revealed a tendency toward increased ERK and Akt phosphorylation in γ/D3 DCs. Inhibition of MEK/ERK and PI3K/mTOR pathways significantly reduced the expression of ILT-3 and PDL-1 on γ/D3 DCs. In summary, we present the first evidence for existing synergy between IFN-γ and vit D3 in shaping a unique tolerogenic DC activation state., (Copyright © 2019 Švajger and Rožman.)- Published
- 2019
- Full Text
- View/download PDF
44. Induction of Tolerogenic Dendritic Cells by Endogenous Biomolecules: An Update.
- Author
-
Švajger U and Rožman P
- Subjects
- Animals, Cell Differentiation, Cellular Microenvironment, Humans, Immune Tolerance, Cytokines metabolism, Dendritic Cells immunology, Hormones metabolism, Intercellular Signaling Peptides and Proteins metabolism, T-Lymphocytes, Regulatory immunology
- Abstract
The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance-inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance-inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells.
- Published
- 2018
- Full Text
- View/download PDF
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