Magnus Björkholm

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (443)2253.39 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real-life studies have been published. This was a retrospective cohort study including consecutive AML/MDS patients treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008-2011 and 107 patients received posaconazole prophylaxis 2011-2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis. The two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, p < 0.01), invasive aspergillosis (0% vs. 5.7%, p = 0.02), and invasive candidiasis (0% vs. 4.0%, p < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow-up (78% vs. 7%). Posaconazole prophylaxis decreased the incidence of IFD but did not improve short-term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 04/2015; DOI:10.1111/ejh.12565 · 2.41 Impact Factor
  • Blood 03/2015; 125(13):2174-2175. DOI:10.1182/blood-2015-01-622068 · 9.78 Impact Factor
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    ABSTRACT: Patients with Hodgkin lymphoma (HL) have a well-characterized immune deficiency of T cell function, originally identified by increased susceptibility to certain infections. Epidemiological evidence has long pointed to infectious etiologies in younger HL patients. With the aim of expanding our knowledge on the potential role of pre-existing immune deficiency in HL and an infectious/inflammatory etiology, we conducted a comprehensive population-based case-control study in HL patients diagnosed in Sweden in the period 1965-2004, and their matched controls. In a large population-based study including 7,414 HL patients and 29,240 matched controls, we evaluated the subsequent risk of HL in relation to a broad range of infectious and inflammatory conditions, using unconditional logistic regression. A previous history of any reported infection was associated with an 11 % increased risk of HL (P < 0.05). More specifically, we found sinusitis (odds ratio = 1.81; 95 % confidence interval = 1.06-3.07), tuberculosis (1.76; 1.01-3.07), encephalitis (7.88; 1.97-31.5), and herpes zoster (2.20; 1.11-4.35) to be associated with excess HL risk. A personal prior history of chronic inflammatory condition was not associated with an increased risk of HL (0.94; 0.71-1.14). Our results suggest that underlying immune deficiency is a primary phenomenon in HL. Alternatively, certain infectious agents may be potential HL triggers.
    International Journal of Hematology 03/2015; DOI:10.1007/s12185-015-1772-6 · 1.68 Impact Factor
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    ABSTRACT: Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 03/2015; 169(5). DOI:10.1111/bjh.13346 · 4.96 Impact Factor
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    ABSTRACT: DNA methyltransferase inhibitors (DNMTIs) such as 5-azacytidine (5-AZA) have been used for treatment of acute myeloid leukemia (AML) and other malignancies. Although inhibiting global/gene-specific DNA methylation is widely accepted as a key mechanism behind DNMTI anti-tumor activity, other mechanisms are likely involved in DNMTI's action. Because telomerase reverse transcriptase (TERT) plays key roles in cancer through telomere elongation and telomere lengthening-independent activities, and TERT has been shown to confer chemo- or radio-resistance to cancer cells, we determine whether DNMTIs affect telomere function and whether TERT/telomerase interferes with their anti-cancer efficacy. We showed that 5-AZA induced DNA damage and telomere dysfunction in AML cell lines by demonstrating the presence of 53-BP1 foci and the co-localization of 53-BP1 foci with telomere signals, respectively. Telomere dysfunction was coupled with diminished TERT expression, shorter telomere and apoptosis in 5-AZA-treated cells. However, 5-AZA treatment did not lead to changes in the methylation status of subtelomere regions. Down-regulation of TERT expression similarly occurred in primary leukemic cells derived from AML patients exposed to 5-AZA. TERT over-expression significantly attenuated 5-AZA-mediated DNA damage, telomere dysfunction and apoptosis of AML cells. Collectively, 5-AZA mediates the down-regulation of TERT expression, and induces telomere dysfunction, which consequently exerts an anti-tumor activity.
    Oncotarget 01/2015; · 6.63 Impact Factor
  • 01/2015; DOI:10.1001/jamaoncol.2015.23
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    ABSTRACT: Larvae of the Northern pine processionary moth (Thaumetopoea pinivora, TP) carry microscopic needles (setae), which by penetrating skin and mucous membranes, may cause inflammatory/immune derived symptoms in man. In the present study the stimulatory effects of setae on human blood lymphocytes in vitro was investigated. Blood mononuclear cells were separated from venous blood or buffy coat of ten healthy individuals, six previously exposed to setae and four with no known exposure. Lymphoproliferation was measured as uptake of 3H-thymidine. Setae were prepared from TP larvae. Setae and saline setae extracts stimulated proliferation of T-lymphocytes in the presence of monocytic cells. Stimulation was pronounced in cells from persons who had been exposed to setae, and weak in cells from non-exposed donors. Chitin also induced lymphocyte proliferation in most donors, but to a lesser extent and independently of donor's previous exposure to setae. In conclusion, setae contain molecules that in the presence of monocytes activate human T-lymphocytes to proliferation. The antigenic nature of stimulatory molecules was supported by the significantly stronger lymphocyte response in persons previously exposed to setae than in non-exposed donors. The nature of such molecules remains to be defined.
    PLoS ONE 12/2014; 9(12):e113977. DOI:10.1371/journal.pone.0113977 · 3.53 Impact Factor
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    ABSTRACT: TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9 253) diagnosed from 1988 to 2004 with follow-up to 2007 and 34 931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (p<0.001). At one year of follow-up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed.
    Haematologica 10/2014; DOI:10.3324/haematol.2014.107714 · 5.87 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) develop in the bone marrow from haematopoietic progenitor cells. Two subsets, plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) have been identified. Little is known regarding DC levels in bone marrow of acute myeloid leukaemia (AML) patients before and after chemotherapy. We investigated relative pDC and mDC levels in bone marrow from 37 hospital controls and 60 AML patients (at diagnosis, complete remission [CR], and follow-up) using four-colour flow cytometry. The pDC immunophenotype was characterized as lin-⁄HLA-DR+ ⁄CD123+ and mDC as lin- ⁄HLA-DR+ ⁄ CD11c+. In 69% of AML patients, no DCs were detected at diagnosis. At CR, mDC levels were the same in AML patients and hospital controls while pDC levels were slightly lower. There was no association between minimal residual disease or survival rates and DC levels. Patients with low mDC levels at CR were more likely to suffer from complicated infections, though the difference was not statistically significant.Altogether, there was a profound decrease in DC levels in AML patients at diagnosis. DC levels increased at CR and were higher than in hospital controls after post-remission therapy, suggesting that DCs recover after repeated chemotherapy. There may be an association between mDC levels and infectious complications.This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 10/2014; 80(6). DOI:10.1111/sji.12223 · 1.88 Impact Factor
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    ABSTRACT: Background Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenstrom macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). Objectives To assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. Patients/methodsA total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsPatients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR=4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR=2.3, 95% CI 1.7-3.0) and 10years after diagnosis (HR=2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR=1.0, 95% CI 0.9-1.1). Conclusions Venous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients.
    Journal of Thrombosis and Haemostasis 09/2014; 12(11). DOI:10.1111/jth.12724 · 5.55 Impact Factor
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    ABSTRACT: Abstract Imatinib has revolutionized the treatment of chronic myeloid leukaemia (CML). We evaluated clinical outcome and cost-effectiveness, using Swedish registry data based on CML-patients diagnosed 1973-2008. Outcome from three time periods (I: 1973-1979; II: 1991-1997; III: 2002-2008) associated with symptomatic treatment, interferon-alpha/stem cell transplantation and implementation of imatinib, respectively, were compared and a lifetime cost-effectiveness model developed. Survival data from population registries, estimated resource use from clinical practice and QoL estimates were employed. Substantial health gains were noted over time, paralleled by increased treatment costs. Median survival was 1.9, 4.0 and 13 years during the respective time periods. The incremental cost-effectiveness ratios (ICER) between periods III and II was €52,700 per QALY gained. An estimated 80% price reduction of imatinib, related to patent expiry, would reduce this ICER to €22,300. Our data from four decades reveal dramatically improved survival in CML, paralleled by ICER levels generally accepted by health authorities.
    Leukemia and Lymphoma 08/2014; DOI:10.3109/10428194.2014.953141 · 2.61 Impact Factor
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    ABSTRACT: Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992–2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5–2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3–5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6–32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.
    Cancer Medicine 08/2014; 4(1). DOI:10.1002/cam4.316
  • Tiziano Barbui, Magnus Björkholm, Alois Gratwohl
    Haematologica 08/2014; 99(8):1273-6. DOI:10.3324/haematol.2014.104059 · 5.87 Impact Factor
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    ABSTRACT: Quantifying cancer patient survival from the perspective of cure is clinically relevant. However, most cure models estimate cure assuming no competing causes of death. We use a relative survival framework to demonstrate how flexible parametric cure models can be used in combination with competing-risks theory to incorporate noncancer deaths. Under a model that incorporates statistical cure, we present the probabilities that cancer patients (1) have died from their cancer, (2) have died from other causes, (3) will eventually die from their cancer, or (4) will eventually die from other causes, all as a function of time since diagnosis. We further demonstrate how conditional probabilities can be used to update the prognosis among survivors (eg, at 1 or 5 years after diagnosis) by summarizing the proportion of patients who will not die from their cancer. The proposed method is applied to Swedish population-based data for persons diagnosed with melanoma, colon cancer, or acute myeloid leukemia between 1973 and 2007.
    Epidemiology (Cambridge, Mass.) 07/2014; 25(5). DOI:10.1097/EDE.0000000000000130 · 6.18 Impact Factor
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    British Journal of Haematology 07/2014; 167(5). DOI:10.1111/bjh.13055 · 4.96 Impact Factor
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    ABSTRACT: Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS). The “true” rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P32 and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 06/2014; 27(2). DOI:10.1016/j.beha.2014.07.003 · 2.55 Impact Factor
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    ABSTRACT: In patients undergoing induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), posaconazole has been proven more effective in the prevention of invasive fungal infection (IFI) than fluconazole or itraconazole (standard azoles) The current analysis seeks to estimate the cost effectiveness of prophylactic posaconazole compared with standard azoles in AML or MDS patients with severe chemotherapy-induced neutropenia in Sweden. A decision-analytic model was used to estimate life expectancy, costs, and quality-adjusted life-years (QALYs). Efficacy data were derived from a phase III clinical trial. Life expectancy and quality of life data were collected from the literature. A modified Delphi method was used to gather expert opinion on resource use for an IFI. Unit costs were captured from hospital and pharmacy pricelists. A probabilistic sensitivity analysis (PSA) was used to investigate the impact of uncertainty in the model parameters on the cost-effectiveness results. The estimated mean direct cost per patient with posaconazole prophylaxis was 46,893 Swedish kronor (SEK) ( 5,387) and SEK50,017 ( 5,746) with standard azoles. Prophylaxis with posaconazole resulted in 0.075 QALYs gained compared with standard azoles. At a cost-effectiveness threshold of SEK500,000/QALY the PSA demonstrated a more than 95 % probability that posaconazole is cost effective versus standard azoles for the prevention of IFI in high-risk neutropenic patients in Sweden. Given the assumptions, methods, and data used, posaconazole is expected to be cost effective compared with standard azoles when used as antifungal prophylaxis in AML or MDS patients with chemotherapy-induced prolonged neutropenia in Sweden.
    Clinical Drug Investigation 05/2014; DOI:10.1007/s40261-014-0199-9 · 1.70 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973-2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported "a moderate" or "a lot" of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46-55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46-55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area.
    Annals of Hematology 04/2014; 93(9). DOI:10.1007/s00277-014-2088-y · 2.40 Impact Factor
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    ABSTRACT: The serotonin transporter gene (5-HTT)-linked polymorphic region (5-HTTLPR) plays an important role in modulating mood and behavior by regulating 5-HTT expression and thereby controlling the concentration of serotonin (5-HT) in brain synapses: The homozygous shorter allele (S/S) in 5-HTTLPR results in lower 5-HTT expression coupled with stronger psycho-pathological reactions to stressful experiences compared to the homozygous long (L/L) and heterozygous (S/L) alleles. Psychological insults and mood disorders have been shown to cause accelerated telomere shortening, a marker of biological aging, however, it is currently unclear whether the allelic variants of 5-HTTLPR affect telomere length (TL) in the healthy population without mood disorders. In the present study, we determined the relationship between TL and the 5-HTTLPR variants in healthy Han Chinese. The 5-HTTLPR genotyping and leukocyte TL analysis of 280 young female Han Chinese freshmen showed a significantly shorter TL in 149 of them carrying the 5-HTTLPR S/S version compared to those (131) with the L/S or L/S plus L/L genotypes (mean ± SD, 0.533±0.241 for S/S vs 0.607±0.312 for L/S, P = 0.034; or vs 0.604±0.313 for L/S plus L/L, P = 0.038). Similar results were achieved in the other cohort including 220 adult healthy individuals of different age, gender and profession (0.691±0.168 for S/S vs 0.729±0.211 for L/S, P = 0.046, or vs 0.725±0.213 for L/S plus L/L, P = 0.039). Taken together, shorter leukocyte TL is significantly associated with the 5-HTTLPR S/S allelic variant, which may be implicated in psychological stress-related health problems.
    PLoS ONE 04/2014; 9(4):e94442. DOI:10.1371/journal.pone.0094442 · 3.53 Impact Factor

Publication Stats

9k Citations
2,253.39 Total Impact Points

Institutions

  • 1977–2015
    • Karolinska Institutet
      • • Department of Hematology
      • • Institutionen för medicin, Huddinge
      Solna, Stockholm, Sweden
  • 1976–2015
    • Karolinska University Hospital
      • • Department of Hematology
      • • Department of Clinical Pharmacology
      • • Department of Hematology, Immunology, and HIV
      • • Department of Oncology
      Tukholma, Stockholm, Sweden
  • 2010
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2009
    • National Cancer Institute (USA)
      • Genetic Epidemiology
      Maryland, United States
  • 2002–2009
    • Uppsala University Hospital
      • Department of Hematology
      Uppsala, Uppsala, Sweden
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 2007
    • Shandong University
      • School of Nursing
      Jinan, Shandong Sheng, China
  • 2003–2007
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 2000–2005
    • Lund University
      • Department of Clinical Genetics
      Lund, Skåne, Sweden
  • 1994
    • Laboratory for Molecular Infection Medicine Sweden
      Umeå, Västerbotten, Sweden
  • 1981–1983
    • Danderyds Sjukhus AB
      Tukholma, Stockholm, Sweden
  • 1975–1983
    • Södersjukhuset
      Tukholma, Stockholm, Sweden