Ming-Qing Du

University of Cambridge, Cambridge, England, United Kingdom

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Publications (103)715.43 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: MALT1 is the only known paracaspase and is a critical mediator of B- and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.
    Nature Communications 01/2015; 6:5908. · 10.74 Impact Factor
  • Xuemin Xue, Naiyan Zeng, Zifen Gao, Ming-Qing Du
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Gene expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III subtypes, with ABC-DLBCL characterized by a poor prognosis and constitutive NF-κB activation. A major challenge for the application of this cell of origin (COO) classification in routine clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies. In this study, we investigated the possibility of COO-classification using FFPE tissue RNA samples by massive parallel quantitative reverse transcription PCR (qRT-PCR). We established a protocol for parallel qRT-PCR using FFPE RNA samples with the Fluidigm BioMark HD system, and quantified the expression of the COO classifier genes and the NF-κB targeted-genes that characterize ABC-DLBCL in 143 cases of DLBCL. We also trained and validated a series of basic machine-learning classifiers and their derived meta classifiers, and identified SimpleLogistic as the top classifier that gave excellent performance across various GEP data sets derived from fresh-frozen or FFPE tissues by different microarray platforms. Finally, we applied SimpleLogistic to our data set generated by qRT-PCR, and the ABC and GCB-DLBCL assigned showed the respective characteristics in their clinical outcome and NF-κB target gene expression. The methodology established in this study provides a robust approach for DLBCL sub-classification using routine FFPE diagnostic biopsies in a routine clinical setting.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.136.
    Laboratory Investigation 11/2014; 95(1). · 3.83 Impact Factor
  • Journal of clinical pathology 01/2014; · 2.55 Impact Factor
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    ABSTRACT: Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises 7-8% of B-cell lymphomas and commonly originates from a background of long-standing chronic inflammation. An association with distinct bacteria species has been confirmed for several anatomical sites of MALT lymphoma. For pulmonary MALT lymphoma, however, a clear link with an infectious agent or autoimmune disorder has not yet been reported. Using a 16S rRNA gene-based approach, we have recently identified Achromobacter (Alcaligenes) xylosoxidans in eight of nine cases of pulmonary MALT lymphoma. A. xylosoxidans is a gram-negative betaproteobacterium with low virulence, but high resistance to antibiotic treatment. To further examine a potential association with A. xylosoxidans, 124 cases of pulmonary MALT lymphoma and 82 control tissues from six European countries were analysed using a specific nested PCR. Although prevalence rates for A. xylosoxidans varied significantly from country to country, they were consistently higher for MALT lymphoma as compared to controls. Overall, 57/124 (46%) pulmonary MALT lymphomas and 15/82 (18%) control tissues were positive for A. xylosoxidans (P = 0·004). Whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma demonstrated in our study points to a potential causal role in the pathogenesis of this lymphoma will require further studies.
    British Journal of Haematology 12/2013; · 4.94 Impact Factor
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    ABSTRACT: AIMS: The aim of this study was to analyse the immunophenotypic and molecular features of a large series of follicular lymphomas, focusing in particular on atypical cases that fail to express CD10 and/or bcl-2. Such cases present diagnostic pitfalls, especially with regard to the differential diagnosis from follicular hyperplasia and marginal zone B-cell lymphoma. Therefore, we also included an immunohistochemical evaluation of stathmin, which is strongly expressed by germinal centre B cells, as a putative new marker for follicular lymphomas, particularly those with an atypical phenotype. METHODS AND RESULTS: Two hundred and five follicular lymphomas were investigated with immunohistochemistry and fluorescence in-situ hybridization (FISH). The use of three distinct anti-bcl-2 antibodies together with CD10 expression data and FISH analysis for bcl-2 and bcl-6 rearrangements allowed subclassification of follicular lymphoma into four distinct subgroups: (i) CD10-positive/bcl-2-positive, (ii) CD10-positive/bcl-2-negative, (iii) CD10-negative/bcl-2-positive, and (iv) CD10-negative/bcl-2-negative. All cases were bcl-6-positive. STMN1 (stathmin) was shown to be helpful in diagnosing bcl-2-negative and/or CD10-negative follicular lymphomas, and in their distinction from marginal zone B-cell lymphoma. CONCLUSIONS: Combined immunohistological and molecular analyses reveal that follicular lymphomas showing an atypical immunophenotypic and molecular profile exist, and we demonstrate that STMN1 represents a novel useful diagnostic marker for these.
    Histopathology 03/2013; · 3.30 Impact Factor
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    British Journal of Haematology 12/2012; · 4.94 Impact Factor
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    ABSTRACT: BACKGROUND: "Collision" tumours consist of different neoplasms coexisting within a single lesion. Whilst quite common in the skin, the gastrointestional tract, and the ovaries, intraocular collision tumours are exceedingly rare. We describe an exceptional case of a combined uveal melanoma and intraocular plasmacytoma. METHODS: Observational case report. A 61-year-old woman underwent enucleation for rubeotic glaucoma and cells in the anterior chamber after proton-beam radiotherapy of a cilio-choroidal melanoma of the right eye. Examination of the enucleated eye was performed with immunohistochemistry, multiplex ligation dependent probe amplification (MLPA), and polymerase chain reaction (PCR) for immunoglobulin heavy- and light-chain gene rearrangements. A review of the literature on ocular collision tumours and uveal involvement by plasma cell neoplasms was also performed. RESULTS: Morphological, immunophenotypical, and genotypical examination of the tumour revealed the co-existence of both a melanoma and a plasmacytoma within the choroid and ciliary body. The glaucoma was caused by extensive infiltration of the iris and trabecular meshwork by the plasmacytoma cells. Review of the literature revealed only four collision tumours involving the eyelid and three involving the choroid. All three intraocular collision tumours consisted of uveal melanoma and choroidal non-Hodgkin lymphoma. Uveal involvement by plasma cell neoplasms is also extremely rare, with only six reported cases. CONCLUSIONS: This is the first documented intraocular collision tumour consisting of a uveal melanoma and isolated plasmacytoma. If a patient presents with 'uveitis' after proton-beam radiotherapy of a cilio-choroidal melanoma, there may be scope for performing biopsies to determine whether the lymphoid infiltrate is reactive or neoplastic.
    Albrecht von Graæes Archiv für Ophthalmologie 12/2012; · 1.93 Impact Factor
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    ABSTRACT: Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion.
    PLoS ONE 09/2012; 7(9):e44997. · 3.53 Impact Factor
  • Journal of clinical pathology 07/2012; 65(11):1049-50. · 2.55 Impact Factor
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    ABSTRACT: Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.
    Proceedings of the National Academy of Sciences 06/2012; 109(26):10534-9. · 9.81 Impact Factor
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    ABSTRACT: Polymerase chain reaction (PCR) of the antigen receptor genes has clinical utility in establishing clonality in lymphoproliferations, which is an important correlate of lymphoid neoplasia. The most frequently used procedures for this purpose were developed by the BIOMED-2 consortium. One of the criteria for establishing monoclonality using PCR of the antigen receptor genes is the finding of an abundant amplicon within a size range determined by the positions of the PCR primers and the known variability in size inherent in the recombination events that assemble a functional antigen receptor gene. However, several cases have been reported in which an amplicon outside this size range has been shown to be a valid indicator of clonality after DNA sequence analysis. In this paper, we will report and discuss several additional cases in which an amplicon outside the accepted size range was consistent with a monoclonal lymphoproliferation. We conclude that oversized and undersized amplicons may indeed represent evidence for a monoclonal lymphoproliferation, but that this interpretation should preferably be confirmed by sequence analysis to avoid a false-positive result.
    Journal of Hematopathology. 06/2012; 5(1-2).
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    ABSTRACT:   A20 (TNFAIP3) is a nuclear factor-κB (NF-κB)-inducible component of tumour necrosis factor and Toll-like receptor intracellular signal transduction. It negatively regulates NF-κB, and has been identified as a tumour suppressor. Several studies have described A20 inactivation by deletion of the A20 locus at 6q23, inactivating mutations, and/or methylation of the A20 promoter in various lymphoma entities.   We generated a monoclonal antibody against the C-terminus of A20 (Ber-A20) and investigated full-length A20 expression of normal lymphoid tissue and lymphomas for the first time. We identified loss of A20 expression in tumour cells of 24% of classical Hodgkin lymphoma, 27% of diffuse large B-cell lymphoma, 20% of chronic lymphocytic leukaemia, 19% of follicular lymphoma, 13% of mantle cell lymphoma and 8% of primary mediastinal B-cell lymphoma cases by immunohistology. Loss of A20 expression rarely occurred in T-cell non-Hodgkin lymphoma.   Our data are in agreement with cytogenetic and molecular analyses. Among 21 cases of ocular adnexal marginal zone lymphomas with known A20 mutation status, we detected complete absence of A20 expression, whereas cases with wild-type A20 were weakly A20-positive. We demonstrate that A20 loss can be detected by immunohistology with a sensitivity similar to that of complex molecular and genetic methods.
    Histopathology 03/2012; 60(6B):E19-27. · 3.30 Impact Factor
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    ABSTRACT: More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis. Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200. We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio. Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection. Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.
    The Lancet Neurology 02/2012; 11(2):150-6. · 21.82 Impact Factor
  • Leukemia & lymphoma 01/2012; 53(9):1831-4. · 2.61 Impact Factor
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    ABSTRACT: To evaluate the status of the immune regulation and homeostasis mechanisms in Celiac Disease (CD), and its progression toward Refractory Celiac Disease (RCD) and transformation to EATL type 1 focusing on FOXP3+Tregs, ITGAX+DCs, BTLA+cell, PDCD1+TFH subpopulations. The series was comprised of 69 cases consisting on 50 samples of CD and 19 samples of EATL type 1. Protein expression was analyzed and quantified by digital image analysis. Histological compartmentalization included lamina propria, isolated lymphoid follicles and tumoral lymphoid area. In comparison to physiological conditions, CD was characterized by higher numbers of FOXP3+Tregs and ITGAX+DCs, but lower BTLA+cells and PDCD1+TFH cells. Progression from CD to RCD1, RCD2 and transformation to EATL was characterized by decreasing trends of FOXP3+Tregs and BTLA+cell. ITGAX+DCs showed a similar decreasing trend from CD to RCD stages but transformation to EATL was characterized with a striking increase. The RCD progression and EATL transformation stages show a defect in inhibitory pathways of FOXP3 and BTLA. Those results pinpoint the role of immune homeostasis and tolerance in CD and in the generation of cancer.
    Japanese Journal of Clinical Immunology 01/2012; 35(4):330b.
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    ABSTRACT: Recent studies showed A20 inactivation by deletion, mutation and promoter methylation in ocular adnexal mucosa-associated lymphoid tissue lymphoma. However, the incidences of A20 abnormalities and their clinical impact remain for the most part unknown. It is also unknown whether ABIN-1 and ABIN-2, the components of the A20 NF-κB inhibitor complex, are inactivated by genetic changes in ocular adnexal mucosa-associated lymphoid tissue lymphoma. A total of 105 cases were investigated for A20 mutation/deletion, ABIN-1/2 mutation, MALT1 and IGH involved translocation. Somatic mutation was seen frequently in A20 (28.6%) but rarely in ABIN-1 (1%) and ABIN-2 (1%). A20 mutations were significantly associated with A20 heterozygous deletion, and both were mutually exclusive from the MALT1 or IGH involved translocations. A20 mutation/deletion was also significantly associated with increased expression of the NF-κB target genes CCR2, TLR6 and BCL2. The cases with A20 mutation/deletion required significantly higher radiation dosages to achieve complete remission than those without these abnormalities.
    Haematologica 12/2011; 97(6):926-30. · 5.94 Impact Factor
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    ABSTRACT: The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-κB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-κB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-κB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.
    Haematologica 11/2011; 97(4):595-8. · 5.94 Impact Factor
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    British Journal of Haematology 11/2011; · 4.94 Impact Factor
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    ABSTRACT: B-cell clonality analysis is commonly performed by polymerase chain reaction (PCR) targeting the IGH genes although a high false-negative rate is recognized for germinal centre/post-germinal centre B-cell malignancies, especially follicular lymphoma. We assessed the diagnostic value of BIOMED-2 IGK assays and investigated the cause of IGH PCR failure in 77 patients with follicular lymphoma. Using the full set of BIOMED-2 reactions, clonal immunoglobulin gene rearrangements were detected in 74 (96%) cases. The clonality detection rate was 86% by two IGK reactions but only 68% by five IGH reactions (P < 0·001). Sequencing of the clonal PCR products showed significantly fewer somatic mutations in the rearranged IGKV (9/27 cases, 33%, mean mutation rate 0·5%) than IGHV (17/17 cases, 100%, rate 11·0%) (P < 0·01). All IGHV-IGHJ PCR failures occurred in cases with at least one mutation at the corresponding IGHV primer binding sites. t(14:18)(q32:q21)/IGH-BCL2 was detected in 50 of 71 (70%) cases and the presence of the translocation was not associated with the poor performance of IGH assays. Our results showed that BIOMED-2 IGK assays are significantly more sensitive than IGH assays in follicular lymphoma due to the fact that the rearranged IGKV is less frequently targeted by somatic hypermutation than IGHV, and therefore, are essential in routine clonality analysis of these lymphomas.
    British Journal of Haematology 07/2011; 155(1):84-92. · 4.94 Impact Factor
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    ABSTRACT: Diagnosis of T-cell lymphoproliferation is sometimes challenging, and in certain instances pathologists rely heavily on the clonality assessment results of T-cell receptor (TCR) gene rearrangement (TCR-GR). Many investigators have designed various in-house primer sets for PCR-based study targeting different loci of TCR genes. In recent years, the commercial BIOMED-2 protocols have become available. The in-house primers are very cheap while the BIOMED-2 primers are expensive. This parallel study aimed to compare the sensitivity of the in-house TCRG primers (two reactions) and the BIOMED-2 TCR primers (six reactions) in an attempt to develop a sensitive and cost-effective strategy for TCR-GR assessment. PCR-based analysis was performed on 69 samples of T-lineage neoplasms including 60 formalin-fixed paraffin-embedded (FFPE) tissues, 5 samples from peripheral blood (PB) and 4 samples from bone marrow (BM) aspirate. Forty-seven (78%) FFPE and all PB or BM aspirate samples yielded control DNA products suitable for clonality assessment including 4 precursor and 50 mature T-cell neoplasms. The detection rates of clonal TCR-GR were 63% (34/54) by the two in-house TCRG primers, 85% (46/54) by all six BIOMED-2 reactions, 91% (49/54) by combining the in-house and BIOMED-2 TCRG reactions and 94% (51/54) by combining the in-house and all BIOMED-2 reactions. By using the in-house and BIOMED-2 TCRG reactions with a total of four tubes, clonal TCR-GR was detected in 91% of the cases. The reagent cost for this combination was one-third of that for the six BIOMED-2 reactions and the detection rate was also higher than the latter alone (91% vs 85%). As the in-house primers were custom made and are much cheaper than the commercial kits, the authors concluded that this four-tube strategy was cost-effective and efficient for TCR-GR clonality assessment.
    Journal of clinical pathology 06/2011; 64(6):536-42. · 2.55 Impact Factor

Publication Stats

4k Citations
715.43 Total Impact Points


  • 2004–2013
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
    • University of Liège
      • Department of Pathology
      Liège, WAL, Belgium
  • 2000–2013
    • University College London
      • Department of Pathology
      Londinium, England, United Kingdom
  • 2012
    • Fourth Military Medical University
      Xi’an, Liaoning, China
  • 2003–2011
    • Chi-Mei Medical Center
      臺南市, Taiwan, Taiwan
  • 2009
    • University of Barcelona
      Barcino, Catalonia, Spain
  • 2007–2009
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 2008
    • University of Leeds
      • Faculty of Biological Sciences
      Leeds, England, United Kingdom
  • 2006
    • University of Hamburg
      • Center for Oncology
      Hamburg, Hamburg, Germany
  • 2002
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom