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Uhlin, Michael
Publications (10 of 17) Show all publications
Törlén, J., Gaballa, A., Remberger, M., Mörk, L.-M. -., Sundberg, B., Mattsson, J. & Uhlin, M. (2019). Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of blood and marrow transplantation, 25(6), 1260-1268
Open this publication in new window or tab >>Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation
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2019 (English)In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 25, no 6, p. 1260-1268Article in journal (Refereed) Published
Abstract [en]

Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P <.05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343). 

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Allogeneic hematopoietic stem cell transplantation, Clinical trial, GVHD prophylaxis, Immune reconstitution, Lymphocyte excision circles
National Category
Hematology
Identifiers
urn:nbn:se:kth:diva-252244 (URN)10.1016/j.bbmt.2019.01.029 (DOI)000472986900027 ()30710687 (PubMedID)2-s2.0-85062075801 (Scopus ID)
Note

QC 20190610

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-07-31Bibliographically approved
Arruda, L. C. M., Gaballa, A. & Uhlin, M. (2019). Graft gamma delta T-cell receptor sequencing identifies public clonotypes associated to HSCT efficacy in AML patients and unravels CMV impact on repertoire distribution. Paper presented at 45th Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), MAR 24-27, 2019, Frankfurt, GERMANY. Bone Marrow Transplantation, 54, 134-135
Open this publication in new window or tab >>Graft gamma delta T-cell receptor sequencing identifies public clonotypes associated to HSCT efficacy in AML patients and unravels CMV impact on repertoire distribution
2019 (English)In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 54, p. 134-135Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-261982 (URN)000487707800137 ()
Conference
45th Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation (EBMT), MAR 24-27, 2019, Frankfurt, GERMANY
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2019-10-11Bibliographically approved
Arruda, L. C., Gaballa, A. & Uhlin, M. (2019). Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution. Journal of Immunology, 202(6), 1859-1870
Open this publication in new window or tab >>Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution
2019 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 6, p. 1859-1870Article in journal (Refereed) Published
Abstract [en]

Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/- The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.

Place, publisher, year, edition, pages
NLM (Medline), 2019
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:kth:diva-246475 (URN)10.4049/jimmunol.1801448 (DOI)000461015600023 ()30710048 (PubMedID)2-s2.0-85062416847 (Scopus ID)
Note

QC 20190402

Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-03Bibliographically approved
Berglund, S., Watz, E., Remberger, M., Legert, K. G., Axdorph-Nygell, U., Sundin, M., . . . Mattsson, J. (2019). Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation. Vox Sanguinis, 114(7), 769-777
Open this publication in new window or tab >>Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation
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2019 (English)In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 114, no 7, p. 769-777Article in journal (Refereed) Published
Abstract [en]

Background and objectives Mucositis is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), and is caused by a combination of conditioning-induced mucosal damage and severe neutropenia. The symptoms include oral and abdominal pain, inability to swallow food and fluids, and severe diarrhoea. Severe mucositis is associated with increased risk of Graft-versus-Host disease and infection. Granulocyte transfusions (GCX) could be a treatment option, and our objective was to study its feasibility and potential benefits. Material and methods This retrospective, single-centre study included 30 patients receiving GCX because of severe oral mucositis after HSCT during 2005-2017. Clinical outcome, response to GCX, change in opiate administration and adverse events were studied. Results Twenty-seven patients received GCX from donors pre-treated with steroids and G-CSF, and three from donors pre-treated with steroids only. Overall response was 83% (24/29 evaluable patients). Fifteen patients reached a complete response. In 14 of 24 responders, a reduction of the administration of opiate pain relief was seen. In eight patients this reduction was >= 50% of the dose. Adverse events (AEs) were reported in 14 cases, and were mild to moderate, and well manageable with symptomatic treatment. No life-threatening or fatal AEs were recorded. Conclusions These results indicate that GCX could be a safe and effective treatment for oral mucositis after HSCT with the potential to reduce the necessity of opiate analgesic treatment in this disorder. No severe AEs were seen in this study, but the risk for severe pulmonary AEs after GCX needs to be considered.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
stem cell transplantation, cellular therapy, transfusion therapy, granulocyte transfusion, oral mucositis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:kth:diva-257445 (URN)10.1111/vox.12835 (DOI)000481199700001 ()31402469 (PubMedID)2-s2.0-85070710946 (Scopus ID)
Note

QC 20190902

Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-10-31Bibliographically approved
Radestad, E., Klynning, C., Stikvoort, A., Mogensen, O., Nava, S., Magalhaes, I. & Uhlin, M. (2019). Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer. Oncoimmunology, 8(2), Article ID e1535730.
Open this publication in new window or tab >>Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer
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2019 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 2, article id e1535730Article in journal (Refereed) Published
Abstract [en]

Suppression of immune reactivity by increased expression of co-inhibitory receptors has been discussed as a major reason as to why the immune system fails to control tumor development. Elucidating the co-inhibitory expression pattern of tumor-infiltrating lymphocytes in different cancer types will help to develop future treatment strategies. We characterized markers reflecting and affecting T-cell functionality by flow cytometry on lymphocytes isolated from blood, ascites and tumor from advanced ovarian cancer patients (n = 35). Significantly higher proportions of CD4+ and CD8+ T-cells expressed coinhibitory receptors LAG-3, PD-1 and TIM-3 in tumor and ascites compared to blood. Co-expression was predominantly observed among intratumoral CD8+ T-cells and the most common combination was PD-1 and TIM-3. Analysis of 26 soluble factors revealed highest concentrations of IP-10 and MCP-1 in both ascites and tumor. Correlating these results with clinical outcome revealed the proportion of CD8+ T-cells without expression of LAG-3, PD-1 and TIM-3 to be beneficial for overall survival. In total we identified eight immune-related risk factors associated with reduced survival. Ex vivo activation showed tumor-derived CD4+ and CD8+ T-cells to be functionally active, assessed by the production of IFN-gamma, IL-2, TNF-alpha, IL-17 and CD107a. Blocking the PD-1 receptor resulted in significantly increased release of IFN-. suggesting potential reinvigoration. The ovarian tumor environment exhibits an inflammatory milieu with abundant presence of infiltrating immune cells expressing inhibitory checkpoints. Importantly, we found subsets of CD8+ T-cells with double and triple expression of co-inhibitory receptors, supporting the need for multiple checkpoint-targeting agents to overcome T-cell dysfunction in ovarian cancer.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
Ovarian cancer, tumor-infiltrating lymphocytes, tumor-associated lymphocytes, ascites, checkpoint blockade, PD-1 blockade, co-inhibition, PD-1, TIM-3, LAG-3
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-244138 (URN)10.1080/2162402X.2018.1535730 (DOI)000457343600012 ()30713791 (PubMedID)2-s2.0-85057524933 (Scopus ID)
Note

QC 20190218

Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-18Bibliographically approved
Radestad, E., Sundin, M., Torlen, J., Thunberg, S., Önfelt, B., Ljungman, P., . . . Uhlin, M. (2019). Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion. Frontiers in Immunology, 10, Article ID 189.
Open this publication in new window or tab >>Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 189Article in journal (Refereed) Published
Abstract [en]

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of alpha beta T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The alpha beta T-cell depleted cell products were characterized by flow cytometry. The median log depletion of alpha beta T-cells was -4.3 and the median yield of gamma delta T-cells was 73.5%. The median CD34+ cell dose was 4.4 x 10(6)/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of alpha beta T-cell depleted products as stem cell boosters with encouraging results.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
alpha beta T-cell depletion, gamma delta T-cells, allogeneic hematopoietic stem cell transplantation, stem cell booster, donor lymphocyte infusion, graft manipulation, CliniMACS
National Category
Hematology
Identifiers
urn:nbn:se:kth:diva-244508 (URN)10.3389/fimmu.2019.00189 (DOI)000458248300001 ()2-s2.0-85062186448 (Scopus ID)
Note

QC 20190402

Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-08-27Bibliographically approved
Gaballa, A., Stikvoort, A., Önfelt, B., Mattsson, J., Sundin, M., Watz, E. & Uhlin, M. (2019). T-cell frequencies of CD8(+) gamma delta and CD27(+) gamma delta cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation, 54(10), 1562-1574
Open this publication in new window or tab >>T-cell frequencies of CD8(+) gamma delta and CD27(+) gamma delta cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation
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2019 (English)In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 54, no 10, p. 1562-1574Article in journal (Refereed) Published
Abstract [en]

The impact of intra-graft T cells on the clinical outcome after allogeneic hematopoietic cell transplantation has been investigated. Most previous studies have focused on the role of alpha beta cells while gamma delta cells have received less attention. It has been an open question whether gamma delta cells are beneficial or not for patient outcome, especially with regards to graft versus host disease. In this study, graft composition of.d cell subsets was analyzed and correlated to clinical outcome in 105 recipients who underwent allogeneic hematopoietic cell transplantation between 2013 and 2016. We demonstrate for the first time that grafts containing higher T-cell proportions of CD8(+) gamma delta cells were associated with increased cumulative incidence of acute graft versus host disease grade II-III (50% vs 22.6%; P = 0.008). Additionally, graft T-cell frequency of CD27(+) gamma delta cells was inversely correlated with relapse (P = 0.006) and CMV reactivation (P = 0.05). We conclude that clinical outcome after allogeneic hematopoietic cell transplantation is influenced by the proportions of distinct gamma delta cell subsets in the stem cell graft. We also provide evidence that CD8(+) gamma delta cells are potentially alloreactive and may play a role in acute graft versus host disease. This study illustrates the importance of better understanding of the role of distinct subsets of.d cells in allogeneic hematopoietic cell transplantation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-262782 (URN)10.1038/s41409-019-0462-z (DOI)000488520400005 ()30723262 (PubMedID)2-s2.0-85061175298 (Scopus ID)
Note

QC 20191022

Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Wang, T., Remberger, M., Nygell, U. A., Sundin, M., Björklund, A., Mattsson, J., . . . Watz, E. (2018). Change of apheresis device decreased the incidence of severe acute graft-versus-host disease among patients after allogeneic stem cell transplantation with sibling donors. Transfusion, 58(6), 1442-1451
Open this publication in new window or tab >>Change of apheresis device decreased the incidence of severe acute graft-versus-host disease among patients after allogeneic stem cell transplantation with sibling donors
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2018 (English)In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 58, no 6, p. 1442-1451Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The composition of the graft used for allogeneic hematopoietic stem cell transplantation (HSCT) is important for the treatment outcome. Different apheresis devices may yield significant differences in peripheral blood stem cell graft cellular composition. We compared stem cell grafts produced by Cobe Spectra (Cobe) and Spectra Optia (Optia) with use of the mononuclear cell (MNC) protocol, and evaluated clinical outcome parameters such as graft-versus-host disease (GvHD), transplant-related mortality (TRM), relapse, and overall survival.

STUDY DESIGN AND METHODS: During 5 years, 31 Cobe Spectra and 40 Spectra Optia grafts were analyzed for CD34, CD3, CD4, CD8, CD19, and CD56 cell content. Clinical outcome parameters were correlated and compared between the two patient groups using different apheresis devices.

RESULTS: Optia grafts contained fewer lymphocytes compared to Cobe (p<0.001). Optia grafts had a significantly lower incidence of acute GvHD Grades II through IV (Cobe 45% vs. Optia 23%; p=0.039) and TRM (16% vs. 2.5%; p<0.05) but higher chronic GvHD (32% vs. 67%; p=0.005) compared to Cobe grafts. Finally, the multivariate analysis showed a significant correlation among the different apheresis devices and both acute GvHD II through IV and severe chronic GvHD. The multivariate analysis also showed a significant correlation between the CD3+ cell dose and the incidence of severe acute GvHD.

CONCLUSION: Optia-obtained grafts yielded a lower acute GvHD Grades II-IV and TRM risk, but had no impact on relapse or overall survival in this study. Understanding and further improvement of peripheral blood stem cell (PBSC) apheresis techniques may be used in the future to personalize HSCT by, for example, fine-tuning the GvHD incidence.

Place, publisher, year, edition, pages
WILEY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:kth:diva-232270 (URN)10.1111/trf.14579 (DOI)000436409400018 ()29536557 (PubMedID)2-s2.0-85043601140 (Scopus ID)
Note

QC 20180719

Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved
Berglund, S., Gaballa, A., Sawaisorn, P., Sundberg, B. & Uhlin, M. (2018). Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility. STEM CELLS INTERNATIONAL, Article ID 8529104.
Open this publication in new window or tab >>Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility
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2018 (English)In: STEM CELLS INTERNATIONAL, ISSN 1687-966X, article id 8529104Article in journal (Refereed) Published
Abstract [en]

Gammadelta (gamma delta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gamma delta T cells in umbilical cord blood (UCB) is low, and the majority express delta 1, in contrast to blood, whereas the main subset is delta 2 gamma 9 T cells. UCB gamma delta T cells are functionally immature, which together with their scarcity complicates the development of UCB gamma delta T cell therapies. We aimed to develop an effective expansion protocol for UCB gamma delta T cells based on zoledronate and IL-2. We found that culture with 5 mu M zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma 9 delta 2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal gamma delta T cell repertoire and the main memory subset was central memory (CD45RO(+) CD27(+)). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB gamma delta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.

Place, publisher, year, edition, pages
HINDAWI LTD, 2018
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-225760 (URN)10.1155/2018/8529104 (DOI)000427843100001 ()
Note

QC 20180410

Available from: 2018-04-10 Created: 2018-04-10 Last updated: 2018-04-10Bibliographically approved
Nair, D., Radestad, E., Khalkar, P., Diaz-Argelich, N., Schroder, A., Klynning, C., . . . Fernandes, A. P. (2018). Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels. Frontiers in Oncology, 8, Article ID 407.
Open this publication in new window or tab >>Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels
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2018 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 8, article id 407Article in journal (Refereed) Published
Abstract [en]

Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1 alpha, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
selenium, methylseleninic acid, PDL1, VEGF, HIF-1 alpha
National Category
Cell Biology
Identifiers
urn:nbn:se:kth:diva-236007 (URN)10.3389/fonc.2018.00407 (DOI)000445882100001 ()
Funder
Swedish Cancer Society, CAN 2016/606Marianne and Marcus Wallenberg FoundationThe Cancer Society in Stockholm
Note

QC 20181015

Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15Bibliographically approved
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