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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2016-01-21)
    Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2553671-0
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  • 2
    In: Clinical Nutrition, Elsevier BV, Vol. 38, No. 2 ( 2019-04), p. 738-744
    Type of Medium: Online Resource
    ISSN: 0261-5614
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2009052-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3515-3515
    Abstract: Abstract 3515 With the advent of tyrosine kinase inhibitors (TKI), allogeneic stem cell transplantation (allo-SCT) is largely reserved for patients with CML who do not achieve durable cytogenetic responses to TKIs or patients with advanced phase (Adv) disease. Data relating to the outcome of transplant in Adv-CML is limited. We have allografted 43 patients (median age 40.8 yrs) for Adv phase disease who had received prior treatment with one or more TKI. The indications for allo-SCT included progression from CP to accelerated phase (AP) (n=16) or blast crisis (BC) (n=11) on TKI and presentation in accelerated phase (AP) (n=9) or blast crisis (BC) (n=7). The median duration of TKI therapy prior to transplantation was 5.5 months (range 1–51 months); 42 patients received imatinib, 9 received dasatinib (8 following imatinib failure), 2 received nilotinib (following imatinib and dasatinib failure). 35 patients were transplanted from HLA-identical siblings and 36 patients received myeloablative conditioning. The status at transplant was CP 〉 1 in 17 patients, AP in 24, and BC in 2. In patients in whom CP was restored prior to transplant (n=17), this had been achieved using a TKI only in 6 and with combination chemotherapy in 11. There was no difference in disease-free survival (DFS) or overall survival (OS) between the TKI only group and the group that received chemotherapy in addition. Among the 43 patients in the TKI-treated cohort, 13 died without relapse, 3 from graft versus host disease (GVHD), 8 from sepsis, pneumonitis and multiorgan failure, and one each from graft failure and VOD. The estimated probabilities of non-relapse mortality (NRM) at 100 days and 1 year were 17.3% and 43.3%, Grade 2–4 acute GVHD was seen in 24% and extensive cGVHD in 54%. The estimated 1- and 3-year DFS rates were 23% and 16%. The 1 year and 3 year estimates of overall survival according to disease stage at allo-SCT were as follows: AP (54.2% and 50%), CP 〉 1 (49.4% and 29.6%) and BC disease 0% and 0%. The impact of maximal disease stage was examined, documented as either AP (23/43 patients) or BP (20/43 patients) at any time prior to allo-SCT. The probability of 3 year OS for patients who were in AP at maximal disease stage was 61% compared to 33% of patients who had at one time been in BC (p=0.04). Post allo-SCT, patients were monitored for relapse by RQ-PCR. Eleven patients received TKIs, 5 for molecular relapse, 1 for cytogenetic relapse, 4 for hematological relapse and 1 for GvHD. Three of the 11 remain alive, 2 of whom received a TKI for molecular relapse.We compared the outcome of these 43 patients with that of 158 patients who were transplanted for Adv-CML but who had been treated before TKI became available. The disease status at time of transplant was AP (n=90), CP 〉 1 (n=41) and BC (n=27). The two groups were matched for type of donor, conditioning regimens and time from diagnosis to transplant but the historical group were younger at allo-SCT with a median age of 33.3 yrs (p=0.001). There were no significant differences in the incidences of acute and chronic GvHD, NRM, DFS or OS between the two groups. The 1 year and 3 year estimates of OS for the historical cohort were 46.4% and 38.5% in AP, 53.7% and 24.3% for CP 〉 1 and 7% and 0% in BC. For the total group of 201 patients the outcome of transplant defined as 3yr OS was 40.9% for AP 25.7% for CP 〉 1 and 0% for BC. In conclusion, we found that patients receiving transplant for advanced phase disease after prior treatment with a TKI have similar outcomes to a historical group of advanced phase patients transplanted prior to the advent of TKI therapy. Our data strongly support the influence of disease stage in prediction of allo-SCT survival. Allo-SCT may be valuable for CML patients who have never progressed to BC. Overt BC is a predictor of poor allo-SCT outcome, so attempts should be made to restore CP prior to allo-SCT. Close monitoring of patients still classifiable as AP who are responding poorly to TKI should permit identification of those who may do well if offered allo-SCT before their disease has progressed further. Disclosures: Marin: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4403-4403
    Abstract: Introduction: The EBMT Lymphoma Working Party has previously reported on the long-term outcome of allogeneic HCT for patients with advanced MF/SS [J Clin Oncol 2014; 32: 3347-8 ]. Among a number of disease and transplant factors influencing patient outcome, the use of UD showed to be the strongest independent factor influencing overall survival (OS). The main shortcoming of the original reports was a limited number of 60 cases in the series, of which only 15 received allogeneic HCT from UD. As UD have been increasingly used during recent years, we sought to extend our previous analysis (1997-2007) to include patients with MF/SS allografted between 2008-2011. Patient and Methods: Endpoints were OS, progression-free survival (PFS), non-relapse mortality (NRM) and incidence of disease relapse/progression (DRP). Eligible were patients 〉 = 18 years who were registered with the EBMT and had received an allogeneic HCT for MF/SS between 1997-2011. Centers with eligible patients were contacted to provide additional treatment and follow-up information including a written diagnostic report. Data were collected from the EBMT Registry (closed in July 2014), and endpoints were defined and analyses performed according to EBMT statistical guidelines (www.ebmt.org). Results: Eligible for final analysis were a total of 113 patients, including our original 60 cases (1997-2007) and 53 new cases (2008-2011): 71 men and 42 women, median age at HCT 48 years (21-72), 77 MF (68%) and 36 SS (32%), with 7 EORTC/ISCL stage IIB, 17 stage III, 46 stage IV-A and 26 stage IV-B (17 missing). Demographics of both time periods were comparable, except for a marked increase in the use of UD (15/60, 25% vs 29/53, 55%; p=0.001) and a reduction in the use of TBI for conditioning (30/60, 50% vs 15/53, 28%; p=0.031) in recent years. At HCT, 52 patients (46%) were refractory or in relapse/progression and 61 (54%) in complete or partial remission. Eighty-six patients (76%) received reduced-intensity (RIC) and 27 (24%) myeloablative (MAC) conditioning regimens, including TBI in 45 cases (40%). With a median follow up in survivors of 72 months (IQR: 39-97), allogeneic HCT for MF/SS offers an estimated OS of 56% at 1 year, 44% at 3 years and 38% at 5 years, and PFS of 34% at 1 year, 28% at 3 years and 25% at 5 years. NRM was 26% at 1 year and 28% at 3 years and thereafter. DRP was the main cause of treatment failure, with a probability of 40% at 1 year, 44% at 3 years and 47% at 5 years, and a mortality rate after DRP of 70% (35/50). It is worth noting that 15 patients (30%) remain alive at last follow up despite DRP, suggesting that some of these patients can be successfully rescued with donor lymphocyte infusions and other therapeutic interventions. The cumulative incidence of acute GVHD was 47% at day 100, and chronic GVHD 35% at 1 year, 45% at 3 years and 48% at 5 years. Interestingly, the univariate analysis showed a statistical trend towards a poorer OS in the cohort of new cases registered from 2008 (p=0.106). However, transplant period had no significant impact when included as a covariate in multivariate analysis, and appears to associate with the higher percentage of UD transplants in the new cohort. The use UD remained the main negative independent factor for OS (HR: 0.490; 95CI: 0.283-0.848; p=0.011) and PFS (HR: 0.468; 95CI: 0.259-0.843; p=0.011) in the multivariate models unstratified and stratified by inclusion period. The use of TBI in conditioning appears to have an independent effect to reduce the risk of DRP in the multivariate analysis (HR: 0.427; 95CI: 0.199-0.917; p=0.029), but does not translate into OS or PFS. Conclusions: This extended series confirms the existence of a clinically relevant graft-versus-lymphoma effect in MF/SS, permitting long-term disease control in a substantial proportion of high-risk patients. Follow-up studies need to address the still significant adverse effect of UD and the role of TBI conditioning in order to improve HCT results in these otherwise fatal disorders. Disclosures Mufti: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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  • 6
    In: mBio, American Society for Microbiology, Vol. 11, No. 4 ( 2020-08-25)
    Abstract: To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TRS) and eliminating ORF8 transcription. The earliest 382-nt deletion variant was detected in Singapore on 29 January 2020, with the deletion viruses circulating in the country and accounting for 23.6% (45/191) of SARS-CoV-2 samples screened in this study. SARS-CoV-2 with the same deletion has since been detected in Taiwan, and other ORF7b/8 deletions of various lengths, ranging from 62 nt to 345 nt, have been observed in other geographic locations, including Australia, Bangladesh, and Spain. Mutations or deletions in ORF8 of SARS-CoV have been associated with reduced replicative fitness and virus attenuation. In contrast, the SARS-CoV-2 382-nt deletion viruses showed significantly higher replicative fitness in vitro than the wild type, while no difference was observed in patient viral load, indicating that the deletion variant viruses retained their replicative fitness. A robust antibody response to ORF8 has been observed in SARS-CoV-2 infection, suggesting that the emergence of ORF8 deletions may be due to immune-driven selection and that further deletion variants may emerge during the sustained transmission of SARS-CoV-2 in humans. IMPORTANCE During the SARS epidemic in 2003/2004, a number of deletions were observed in ORF8 of SARS-CoV, and eventually deletion variants became predominant, leading to the hypothesis that ORF8 was an evolutionary hot spot for adaptation of SARS-CoV to humans. However, due to the successful control of the SARS epidemic, the importance of these deletions for the epidemiological fitness of SARS-CoV in humans could not be established. The emergence of multiple SARS-CoV-2 strains with ORF8 deletions, combined with evidence of a robust immune response to ORF8, suggests that the lack of ORF8 may assist with host immune evasion. In addition to providing a key insight into the evolutionary behavior of SARS-CoV-2 as the virus adapts to its new human hosts, the emergence of ORF8 deletion variants may also impact vaccination strategies.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2557172-2
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  • 7
    Online Resource
    Online Resource
    Informa UK Limited ; 2007
    In:  Leukemia & Lymphoma Vol. 48, No. 2 ( 2007-01), p. 403-405
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 48, No. 2 ( 2007-01), p. 403-405
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2007
    detail.hit.zdb_id: 2030637-4
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 29 ( 2010-10-10), p. 4492-4499
    Abstract: To analyze the outcome of allogeneic transplantation for mycosis fungoides and Sézary syndrome (MF/SS) in terms of nonrelapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) and to identify factors associated with the outcome. Patient and Methods Sixty patients with MF (n = 36) and SS (n = 24) who received a first allogeneic hematopoietic cell transplantation (HCT) from a matched related (mRD; n = 45) or unrelated donor (mUD; n = 15) between 1997 and 2007 and who were registered in the European Group for Blood and Marrow Transplantation database were analyzed: 37 men and 23 women, median age 46.5 years (range, 22 to 66 years). Forty-four patients had TNM stage IV, and 40 patients were at advanced phase at transplantation. Forty-four patients received reduced-intensity conditioning (RIC) regimens, and 25 underwent T-cell depletion (TCD). Results Allogeneic transplantation in MF/SS offers an estimated OS of 66% at 1 year and 54% at 3 years, primarily driven by donor type, disease phase, and type of conditioning. RIC decreased NRM (relative risk [RR] = 4.7; P = .008) without increasing REL, leading to a higher OS (RR = 2.8; P = .03). Advanced-phase disease increases REL (RR = 3.0; P = .03) and reduces PFS (RR = 4.4; P = .002) and OS (RR = 3.5; P = .023). Recipients of mRD allogeneic HCT had better PFS (RR = 2.7; P = .006) and OS (RR = 4.0; P = .001) than their mUD counterparts. The risk of REL increases with TCD (RR = 3.2; P = .005). Some patients who experience relapse can successfully undergo rescue treatment with donor lymphocyte infusions. Conclusion Allogeneic transplantation is a valid therapeutic alternative for high-risk patients with advanced-stage MF/SS. Our data also suggest the existence of a clinically relevant graft-versus-lymphoma effect in MF/SS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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  • 9
    Online Resource
    Online Resource
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 4225-4225
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 4225-4225
    Abstract: Introduction. Chronic myeloid leukaemia (CML) is a malignant clonal myeloproliferative disorder characterised by the presence of the Philadelphia chromosome (Ph) and expression of the BCR-ABL fusion protein with constitutive tyrosine kinase activity and multi-target dysregulation. Standard therapy employs the use of tyrosine kinase inhibitors, such as Imatinib mesylate, with a high level of success. However, in a proportion of patients this approach is sub-optimal necessitating the use other treatment modalities. Allogeneic stem cell transplantation (allo-SCT) is established and potentially curative via the immunologically mediated graft-versus-leukaemia (GvL) effect, but it is associated with significant morbidity, long term effects and high mortality rate (30%). An alternative approach is to employ peptide vaccines directed against leukaemia associated antigens (LAA) in order to evoke a curative anti-leukaemia immune response without the risk of graft versus host disease. Prevalent among these LAAs are WT1 (Wilms Tumour 1) and PRAME (preferentially expressed antigen in melanoma). WT1 encodes a transcription factor of the zinc-finger family, and is known to be over-expressed in many types of leukaemia. PRAME (PRA) is a cancer testis antigens over-expressed in haematological malignancies including CML, making it an attractive target for immunotherapy. HLA-A2 and A-24 restricted epitopes derived from PRA have been shown to be immunogenic by a number of groups. Here, we studied the value of PRA and WT1 measurement in assessing minimal residual disease (MRD) in CML compared to BCR-ABL. Materials & Methods. cDNA from PB samples from 76 diagnostic samples and 127 follow-up samples from 114 patients were tested. The follow-up samples were subdivided into 3 groups according to BCR-ABL expression: MRD1 & gt;10%, MRD2: 1%-10%, MRD3 & lt;1%. All samples were analysed for WT1 and PRA, except for the diagnostic samples, where only 6 were available for PRA analysis due to a lack of material. All expression data was obtained by quantitative real-time PCR (Q-PCR) on the ABI 7500 platform. The BCR-ABL was expressed as a percentage ratio against ABL, using absolute quantification. WT1 and PRA expression was derived using the relative expression dCt method, normalised against a house keeping gene (GUS), after ensuring equivalent Q-PCR efficiencies. Results. WT1 and PRA expression was detectable in all samples analysed. A non-parametric correlation, performed on all data points, found a positive correlation between expression of BCR-ABL and expression of WT1 (r= 0.6710, P & lt;0.0001) and PRA (r= 0.4194, P & lt;0.0001) (Figure 1). The median WT1 and PRA expression of the remission samples was calculated and used as a cut-off to define over-expression (2.89E-05 and 7.04E-05, respectively). This was then used to assess the proportion of samples from the diagnostic and follow-up groups that over-expressed WT1 (Diag= 96.1%, MRD1= 90.0%, MRD2= 66.7%, MRD3= 33.3%) and PRA (Diag= 100%, MRD1= 82.5%, MRD2= 41.7%, MRD3= 60.0%). The differences in over-expression between the groups were found to be highly significant by 2×4 contingency Chi square test (P & lt;0.0001 for both WT1 and PRA). Discussion. This analysis shows that both WT1 and PRA expression positively correlate with BCR-ABL level in CML patients, and can be reliably quantitated using Q-PCR. This technique can therefore provide useful information for treatment monitoring of immunotherapy directed against such antigens. The median expression of the remission samples can be used as a useful cut-off for assessing over-expression for WT1, but maybe of less value in respect to PRA, due to a lack of discrimination at low BCR-ABL levels shown by the discordantly high value of positivity in the MRD3 group. Figure 1. Expression of A: WT1 and B: PRAME in CML, subdivided by BCR-AEL expression (vertical lines) and over-expression thresold (horizontal line). Figure 1. Expression of A: WT1 and B: PRAME in CML, subdivided by BCR-AEL expression (vertical lines) and over-expression thresold (horizontal line).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1932-1932
    Abstract: Abstract 1932 High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). At present, G-CSF-mobilized peripheral blood stem cells (PBSCs) are the preferred stem cell source for autologous HSCT. Fludarabine and lenalidomide are essential drugs in the front line treatment of NHL and MM respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. Prior to the drug approval in Europe, a plerixafor compassionate use program (CUP) was available from July 2008 to August 2010 to provide access to the drug for patients with MM or lymphoma who had previously failed a mobilization attempt, and who were not eligible for another specific plerixafor trial. In the European CUP, 48 patients (median age 57 years; range, 36–69), previously treated with fludarabine (median 5 cycles; range, 1–7 cycles) were given plerixafor plus G-CSF for remobilization following a primary mobilisation attempt. All 48 patients had a diagnosis of NHL. The overall median number of CD34+ cells collected was 2.3×106 /Kg (range, 0.3–13.4). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 58% of patients, while only 3 patients (6%) collected ≥5.0×106 CD34+ cells. The collection target of 2.0×106/Kg was reached in a median of 2 apheresis sessions (range, 1–3). Thirty-five patients (median age 57 years; range, 34–66), previously treated with lenalidomide (median 5 cycles; range, 1–10 cycles) were given plerixafor plus G-CSF for remobilization. All patients the 35 patients had MM. The overall median number of CD34+ cells collected was 3.4×106/Kg (range, 1.1–14.8). The minimum required number of CD34+ cells (≥2.0×106 per kg) was collected from 69% of patients, including 12 patients (34%) who were able to collect ≥5.0×106 cells/Kg. In the Len group, 7 patients (20%) had received a prior autologous HSCT before salvage mobilization with plerixafor. Both targets were reached with a median of 2 apheresis sessions (range, 1–4). In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for large prospective studies evaluating the efficacy of plerixafor for frontline mobilization in this subgroup of patients.Table 1.Study population characteristicsCharacteristic (%)Fludarabine (N=48)Lenalidomide (N=35)Patient age, median (range)57 (36–69)57 (34–66)Patient gender    Male26 (54)18 (51)    Female22 (46)17 (42)Fludarabine or Lenalidomide cycles, median (range)5 (1–7)5 (1–10)Diagnosis and disease statusIndolent NHL48 (100)0 (0)Multiple myeloma0 (0)35 (100)Previous chemotherapy: number of lines, median (range)3 (1–6)4 (1–9)Previous autograft    Yes07 (20)    No43 (90)20 (57)    Data missing5 (10)8 (23)Radiotherapy    Yes5 (10)3 (9)    No36 (75)24 (68)    Data missing7 (15)8 (23)Mobilization strategy with plerixafor    Steady-state GCSF mobilization38 (79)27 (77)    Chemotherapy+GCSF mobilization10 (21)8 (23)No. of patients collected44 (92)34 (97)CD34+ cells collected per Kg, median (range)2.3 (0.3–13.4)3.4 (1.1–14.8)No. of patients who reached ≥ 2.106 CD34+28 (58)24 (69)No. of apheresis days to reach ≥ 2.106 CD34+2 (1–3)2 (1–4)No. of patients who reached ≥ 5.106 CD34+3 (6)12 (34)No. of apheresis days to reach ≥ 5.106 CD34+2 (1–3)2 (1–3)NHL, non-Hodgkin lymphoma Disclosures: Mohty: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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