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  • American Society of Hematology  (8)
  • 1
    In: Blood, American Society of Hematology, Vol. 121, No. 8 ( 2013-02-21), p. 1357-1366
    Abstract: Anti–IFN-γ autoantibodies are associated with HLA-DRB1*16:02 and DQB1*05:02.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3650-3650
    Abstract: Background: Transfusion is a standard therapy for acute and chronic complications of sickle cell disease (SCD). They are complicated by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patients. Reasons for this increased prevalence are unclear. Some studies have suggested genetic predisposition to alloimmunization in all transfused patient populations. Others suggested that mismatched red cell antigens occurring commonly between blood donors of European ancestry and patients with SCD who are of African ancestry is a primary cause in SCD. Accordingly, phenotypic antigen matching and transfusion from African American donors are proposed strategies to minimize alloimmunization risk. We hypothesized that if these population differences are the etiologic basis that analysis of ancestry at the genetic level could identify significant genetic susceptibility contributions and localize susceptibility loci. Methods: The Bethesda Sickle Cell Cohort Study consisting of adults evaluated at NIH from 2001-2015 (n=721) was reviewed for transfusion history and the presence of allo-antibodies confirmed with a blood bank. Genomic DNA was genotyped with an admixture panel consisting of 2251 ancestry informative SNPs in 359 patients and in HapMap controls. A final panel of 1622 SNPs was used to infer ancestry proportions using Structure assuming 3 ancestral populations. Ancestry was analyzed in regression models along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where the ancestry proportions differed significantly between cases and controls. We used AncestryMap for a log-additive case control study assuming various risk models. Results: Five hundred fifty four subjects (77% of cohort) had a transfusion history with 153 (27.6 %) with allo-antibodies, 336 (60.6 %) with a history of transfusions and no antibodies and 65 (11.7 %) with no prior transfusions. Sixty five percent had a history of more than 1 antibody. The RH, Kell, MNS and Duffy systems were most commonly associated with antibodies (Fig 1A and B). Clinical factors associated with cases in univariate analysis included transfusion burden (P 〈 0.0001), pain hospitalizations (P=0.0007), hemoglobin (P=0.02), ferritin (P=0.002), alkaline phosphatase (P=0.02) and ESR (P=0.05). Only transfusion history remained significant in multivariable models, both when using logistic (antibody status, β=0.56, P=6.31 x 10-6) or linear (number of antibodies, β=0.35, P=0.0004) regressions. Given the univariate associations with pain hospitalizations and ferritin which are known mortality risk factors, it was not surprising that allo-immunization was associated with mortality when compared to the no antibody and non-transfusion groups (Fig 1C; median follow-up 3.8 years, range 0-14.4). The absence of allo-immunization showed decreased risk of death when limited to only those with prior transfusions (Fig 1D; Hazard Ratio 0.53, P=0.006). When considering genotype data, Asian/Amerindian ancestry was associated with antibody status (logistic, β=4.60, P=0.03) and number of antibodies (linear, β=4.92, P=0.006) by regression, while African and European ancestry were not. The relative ancestry contribution remained unchanged when the number of prior transfusions was also included in both models, P=0.09 and P=0.06, respectively (Fig 1E). Genetic data also indicated that 21% (n=77) of genotyped subjects were not admixed (100% African ancestry) which violates AncestryMap's assumption that all subjects are admixed. These subjects were removed from the admixture scan: an analysis of 81 cases and 159 controls with prior transfusions is underway to identify specific susceptibility loci. Conclusions: In a large cohort of adults with SCD, the prevalence of red cell alloimmunization is 27.6%, with approximately 60% of antibodies attributable to RH and Kell. Asian/Amerindian ancestry is a risk factor, as is the number of prior transfusions. This study demonstrates genetic susceptibility to this complication which is associated with an ancestral population not typically considered in SCD. Identification of additional Amerindian ancestry SNPs will help to fine map susceptibility loci. Long term studies will be necessary to determine the relative contribution of alloimmunization to mortality in adults with SCD. Figure Figure. Disclosures Kato: Mast Therapeutics: Consultancy; Bayer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4059-4059
    Abstract: Homozygous hemoglobin (Hb) SS is the most common form of sickle cell disease (SCD), while HbSC represents a third of patients and has been less studied. Despite similarities in pathogenesis, there are significant clinical differences between genotypes. To elucidate any molecular differences, we compared gene expression profiles for HbSS and HbSC using microarrays. The Paxgene (PAX) blood RNA system was used to extract RNA from whole blood, which was then globin reduced. We also isolated peripheral blood mononuclear cell (PBMC) RNA to assess transcript patterns in cell populations lacking erythrocytes and granulocytes. To demonstrate clinical differences, we compared HbSS and HbSC subjects from the Bethesda Sickle Cell Cohort Study (ClinicalTrials.gov identifier: NCT00011648). Hematologic parameters were significantly different, with HbSS having higher leukocytes, lower hematocrit, and higher platelets, reticulocytes and fetal hemoglobin. Significant differences were also observed for transaminases, LDH, bilirubin, creatinine kinase, ESR and ferritin. On the other hand, HbSC patients had higher diastolic blood pressure (P=0.0009), higher SpO2 (P 〈 0.0001), less frequent leg ulcers (Odds Ratio 2.90, 95% CI 1.15-7.35, P=0.008) and more prevalent tricuspid jet velocity above 2.9 m/s (Odds Ratio 5.07, 95% CI 1.75-14.71, P=0.0006). These associations led us to hypothesize that these are distinct forms of SCD whose biological differences might be identified with gene expression profiling. RNA was isolated from ten subjects each with HbSS, HbSC or normal volunteers (NVs) using whole blood, PBMCs and Ficoll purified PBMCs (devoid of platelets). Microarray profiling showed that SCD subjects, regardless of genotype, have significant enrichment in glucose metabolism, cellular respiration, and mitochondrial energy generation pathways compared to NVs. Next, we used hierarchical clustering to distinguish SCD expression profiles from NVs, but we were unable to further distinguish HbSS from HbSC samples using this method. We attribute the above differences between SCD and NV samples to the erythroid cell RNA expression in whole blood. There is significant overlap between the 100 most abundantly expressed transcripts and a published signature in purified reticulocytes. However, no significant differences were observed when comparing SCD and NV samples using PBMCs and Ficoll purified PBMCs. We only observed expression differences comparing HbSS and HbSC at the gene level for ATP1B1 (1.3 fold change, P=1.04E-4), WSB1 (1.3 FC, P=3.64E-3) and IL6ST (1.3 FC, P=1.13E-4), despite the evident hematological and clinical differences. ATP1B1 encodes a small ATPase for Na+/K+ transport and has hardly been explored in hemoglobinopathies. Furthermore, ATP1B1 was highly up-regulated in HbSS patients (against controls) but showed less change in HbSC patients. Our results provide an important first step towards elucidating the molecular pathophysiology that might explain the differences in clinical symptoms and survival between these 2 common forms of SCD. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2171-2171
    Abstract: Sickle cell anemia (SCA) is characterized by end organ damage, especially in the kidney and heart, resulting in a high prevalence of chronic kidney disease (CKD), tricuspid regurgitation and left ventricular hypertrophy (LVH). In the general population, dysregulation of calcium/phosphate homeostasis by elevated plasma fibroblast growth factor 23 (FGF23) directly promotes LVH in end stage CKD without SCA. Accordingly, the high mortality associated with end stage renal disease is primarily cardiac, and is associated with ventricular remodeling and elevated plasma FGF23. However, FGF23 has not been investigated as a biomarker for CKD, LVH and mortality in SCA. Here, we assessed the relationships between CKD, LVH, plasma FGF23 and mortality in adults with SCA. First, we determined that LVH is a common entity in SCA-CKD using a nested case control study of all SS subjects with stage 3-5 CKD (eGFR 〈 60) enrolled in the Bethesda Sickle Cell Cohort Study (ClinicalTrials.gov identifier: NCT00011648) and age and sex-matched SCA subjects with normal renal function. Of those with SCA-CKD (n=42), LVH defined by echocardiogram was present in 74% compared to 41% in those with normal kidney function (odds ratio 3.79; 95%CI 1.57 - 10.06; p=0.0039). We next measured plasma FGF23 levels in normal volunteers (n=37) and age and sex-matched SCA subjects with and without CKD (n=37), using ELISA. We observed a 3.5-fold increase in plasma FGF23 levels among subjects with SCA (p 〈 0.0001) and a 22-fold increase in those with SCA-CKD (p 〈 0.0001). FGF23 levels are elevated at baseline in adults with SCA which has not previously been reported. The much higher fold increase in SCA-CKD was not unexpected, based upon previously reported high plasma FGF23 associated with CKD in the absence of SCA. Spearman correlations between plasma FGF23 levels in adults with SCA were correlated with creatinine (r=0.52, p=0.0011), eGFR (r=-0.57, p=0.0003), left ventricular mass index (LVMI, r=0.48, p=0.0029), and tricuspid regurgitant velocity (TRV; r=0.44, p=0.01). These data suggest that as in CKD without SCA, plasma FGF23 is a biomarker associated with both a decline in renal function and an increase in the prevalence of LVH and tricuspid regurgitation. We next sought to determine if plasma FGF23 levels are a biomarker associated with mortality in the overall SCA patient population. Univariate Kaplan-Meier analyses showed that categorical FGF23 levels (above versus below log mean; hazard ratio=1.74, 95% confidence interval 1.09-2.85, p=0.02] and elevated TRV (≥2.5 m/s versus all others, hazard ratio=4.42, 95% confidence interval 2.60-7.52, p 〈 0.0001) are significantly associated with increased mortality in 478 adults with SCA. LVH defined by sex adjusted echocardiographic thresholds for LVMI was not associated with an increased risk of death (p=0.71). Multivariable Cox proportional hazard analysis indicated that log FGF23 is an independent risk factor for death (hazard ratio=1.46, 95% confidence interval 1.01-2.10, p=0.04), in addition, to the known mortality association with elevated TRV (hazard ratio=4.90, 95% confidence interval 2.86-8.39, p 〈 0.0001). The Cox analysis suggests that plasma FGF23 is a biomarker for mortality in SCA, although the echocardiographic abnormality associated with death in this model is TRV and not LVMI. In conclusion, we observed a high prevalence of LVH in adults with SCA-CKD (70.3%), and SCA-CKD is associated with a 22 fold increase in plasma FGF23 levels. One limitation of our study was the inability to assess associations between plasma FGF23, LVMI, TRV and mortality risk in SCA-CKD due to a limited number of CKD subjects. When FGF23 was investigated in all adults with SCA, plasma FGF23 was a significant risk factor for death, independent of TRV and other known risk factors. Larger SCA-CKD studies will be necessary in the future to better understand the relationships between TRV, LVH, FGF23 and mortality. Overall, plasma FGF23 is a potentially helpful biomarker to further elucidate the pathobiology of SCA-CKD end organ complications. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 5
    Online Resource
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    American Society of Hematology ; 2017
    In:  Blood Vol. 130, No. Suppl_1 ( 2017-12-07), p. 956-956
    In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 956-956
    Abstract: Background: Transfusion is a standard treatment for acute and chronic complications of sickle cell disease (SCD). This therapy is limited by a high prevalence of red cell antigen alloimmunization, which is not seen in other frequently transfused patient populations. Reasons for this increased prevalence have not been elucidated. One model based study suggested a genetic predisposition in all patient populations. Other studies have provided evidence that antigen mismatches occur commonly between blood donors of European ancestry and SCD patients and that this is a primary cause for alloimmunization. Accordingly, limited phenotypic antigen matching is a standard practice used to minimize alloimmunization risk. We hypothesized that if these population differences are the biologic basis for this phenomenon that admixture mapping could identify significant susceptibility loci. Methods: A cohort study consisting of adults evaluated at NIH and Howard University between 2001-2015 (n=721) had allo-antibody status confirmed with the blood bank at the hospital where the most recent transfusion was performed. Genomic DNA was genotyped for a panel of 1622 ancestry informative SNPs in 359 patients. Genotypes were used to infer ancestry proportions using Structure software assuming a 3 population model. Ancestry was analyzed by regression along with clinical variables. Genome wide admixture mapping was performed to identify regions of the genome where ancestry differences between cases and controls suggested an association. We used AncestryMap for a log-additive case control study assuming various risk models. Results: Five hundred fifty four subjects (77% of cohort) had a transfusion history with 153 (27.6 %) with allo-antibodies and 65 (11.7 %) with no prior transfusions. Antibodies directed against RH, Kell, MNS and Duffy antigens were the most prevalent. Clinical factors associated with alloimmunization in regression models were only significant for lifetime transfusion history by both logistic (antibody status, β=0.56, P=6.31 x 10-6) and linear (number of antibodies, β=0.35, P=0.0004) regressions. When considering genotype data, Amerindian ancestry was associated with antibody status (logistic, β=4.60, P=0.03) and number of antibodies (linear, β=4.92, P=0.006), while African and European ancestry were not. The association between ancestry and alloimmunization risk remained unchanged when the number of prior transfusions was also included in both multivariable models for alloimmunization status and number of antibodies, P=0.09 and P=0.06, respectively. Genome wide mapping by admixture linkage disequilibrium compared 91 allo-Ab cases to 210 controls with prior transfusions under 10 different risk models (range 0.25-9.0). The most significant result was the 0.25 risk model which was highly suggestive for association (genome log factor 10.96, P & lt;0.001; Figure 1A). This scan identified region of chromosome 5 (5q21.3-5q31.1) defined by 14 snps spanning 21.685 Mb and a highly significant peak LOD score of 13.5 (Figure 1B). While this region contains & gt;540 genes, the linkage region is noteworthy for a cytokine gene cluster implicated in hematopoiesis and immune responses. Conclusions: In a large cohort of adults with SCD, the prevalence of red cell alloimmunization is 27.6%. Amerindian ancestry is a risk factor and suggests a genetic component to this phenotype. The number of prior transfusions is also a significant risk factor. Genome wide admixture mapping identified a strong association at chromosome 5q21.3-5q31.1 using a 0.25 risk model. This chromosome 5 association is particularly interesting given the presence a cytokine gene cluster within a portion of the associated region. Analysis of larger, admixed populations will help to fine map allo-immunization susceptibility variants within specific genes that underlie these loci. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
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  • 6
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3861-3861
    Abstract: Background Acute myeloid leukemia (AML) is a common hematologic neoplasm in the elderly. The high mortality in elderly AML patients is reported to be associated with old age, poor performance status, and several disease characteristics. Several risk stratification models have been reported. Our aims were to explore risk factors for early mortality in older AML patients and compare the discrimination ability of existing prognostic models. Methods We enrolled newly diagnosed AML patients age 60 and above at Taipei Veterans General Hospital, a national medical center in Taiwan, between July 1, 2008 and May 31, 2017. Our primary endpoint was early mortality, defined as death within two months after initial AML diagnosis. Performance of several existing scoring systems were compared by using the Akaike information criteria (AIC) and Bayesian information criterion (BIC) calculations. Model discrimination ability was also estimated by Harrell's C statistics. Results A total of 478 AML patients were diagnosed during the eight-year follow-up period. After excluding young patients (age 〈 60) and those without a histopathologic diagnosis, the final cohort included 277 patients. The median age was 74 (range 60-96), and 171 (61.7%) of them were male. One hundred sixteen patients (41.9%) had Eastern Cooperative Oncology Group performance (ECOG) ≥ 2 and 33.9% patients had poor/adverse cytogenetics or molecular abnormalities. The two-month mortality rate was 29.9% (95% confidence interval [CI] 24.8%-35.9%). Age ≥ 80 (adjusted HR 1.95, 95% CI 1.12-3.42), having an antecedent hematologic disorder (adjusted HR 1.86, 95% CI 1.01-3.43), ECOG ≥ 2 (adjusted HR 2.06, 95% CI 1.20-3.54), complex karyotype (adjusted HR 3.13, 95% CI 1.76-5.55), BM blasts ≥ 70% (adjusted HR 1.79, 95% CI 1.02-3.13), WBC ≥ 100 ×109/L (adjusted HR 3.27, 95% CI 1.58-6.75), and creatinine 〉 1.3 mg/dL (adjusted HR 2.04, 95% CI 1.23-3.39) were identified as independent predictors for early mortality in the multivariate analysis. Furthermore, we systematically reviewed existing prognostic models for elderly AML. We found five scoring models that don't require additional specific examinations beyond clinical practice and later applied them to our elderly AML cohort. The performance of the five models is shown in Table. Kantarjian's prognostic model (Kantarjian H, et. al. Blood 2010) had the highest Harrell's C statistic and the ALMA score (Ramos F, et. al.Leukemia Research 2015) had the lowest AIC and BIC compared with the other prognostic models. Conclusion We identified seven risk factors for early mortality and compared the performance of five prognostic models for elderly AML patients. The finding may help clinicians to stratify patients and initiate appropriate management. Table Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 7
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4608-4608
    Abstract: Background: For patients with acute myeloid leukemia (AML) who were classified as high risks, failed to achieve complete remission, or relapsed disease after remissions, allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers the chance of durable remission and the potential to cure. In the absence of 8/8 matched donors, an HLA 1-allele mismatched (7/8 1-MM) unrelated donor is an alternative source of hematopoietic stem cell. However, the impact of HLA homozygosity at 1-MM on the outcome and the consensus at desirable donor screening in 7/8 HLA mismatched is not yet clear. A 1-MM in the host-versus-graft (HVG) direction is a 7/8 unidirectional mismatch for a homozygous recipient receiving a graft from a heterozygous donor. A 1-MM in the graft-versus-host (GVH) is for a heterozygous recipient receiving a graft from a homozygous donor. 7/8 bidirectional mismatch is a heterozygous recipient receiving a graft from heterozygous donor. From the biological perceptions, the impact of different histocompatibility transplantations may differ on the prognosis. This study evaluated the outcome of unidirectional and bidirectional 7/8 mismatches in recipients receiving either bone marrow or peripheral blood hematopoietic stem cell for AML patients. Methods: Patients who were at least 12 years of age with AML receiving first hematopoietic stem cell transplantation from a serologically HLA-A, -B, -C, and -DR allele data were included in our study between 2009 and 2014. Data were obtained from Taiwan Society of Blood and Marrow Transplantation (TBMT) Research Database. We excluded those who received HLA-matched sibling grafts, HLA-haploidentical grafts, or unrelated donors who had more than 1-allele mismatch. Those who lacked the clinical information on survival status or survival date were also eliminated. Patients were divided into four histocompatibility groups based on typing at HLA-A, -B, -C, and -DR as unidirectional 7/8 HVG, unidirectional 7/8 GVH, bidirectional 7/8, and 8/8 matched group. Descriptive statistics were used to describe the patients' characteristics, disease status on the time receiving HSCT, intensity of conditioning regimen and treatment features. Associations between four groups and outcomes of overall survival, relapse-free survival, acute GVHD, chronic GVHD, treatment-related mortality (TRM), relapse rate, neutrophil engraftment, engraftment syndrome, and engraftment failures were reviewed. Results: A total of 222 recipients of all-HSCT were included in the analysis. The four comparison groups included nine patients designated as 1-MM HVG, nine as 1-MM GVH, 71 as 1-MM bidirectional, and 133 as 8/8 matched group. Table 1 shows patient and transplant characteristics. Superior overall survival was significantly associated with the higher intensity of induction regimen (myeloablative conditioning, MAC and reduced intensity conditioning, RIC, p 〈 0.05) and the disease status on the time receiving allo-HSCT (p=0.1). Relapse-free survival was significantly decreased with RIC regimen (p 〈 0.05, figure 1). The cumulative 5-year overall survival rate was 75% in the 1-MM HVG group, 50% in the 1-MM GVH group, 50% in the 1-MM bidirectional group, and 44% in the 8/8 matched group. Median survival of 1-MM HVG and 8/8 matched group didn't reach under analysis, and which is 62.2 months in 1-MM GVH, 30.9 months in 1-MM bidirectional group. The outcome of overall survival was more favorable in the 1-MM HVG group (Figure 2 and Figure 3), especially comparing with 1-MM bidirectional group (p=0.07), where there was no significant difference between 8/8-matched group and 1-MM GVH group or the 1-MM bidirectional group. Superior overall survival and relapse free survival was observed in 1-MM HVG group, although the differences were not statistically significant. Hyper-acute GVHD was slightly higher in 7/8 bidirectional group, while no significant difference was observed in acute and chronic GVHD among four groups. The primary causes of death were reviewed. 8/8 matched group had higher deaths attributed to disease relapse (26.3%), while 1-MM GVH group had more deaths attributed to GVHD (22.2%). Conclusion: Myeloabltive conditioning regimen is associated with more favorable outcomes of overall survival and relapse free survival. 1-MM HVG also tends to have superior overall survival and relapse free survival, although there is no statistical significance due to limited cases. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 132, No. 11 ( 2018-09-13), p. 1146-1158
    Abstract: Alterations in JAK/STAT signaling pathway are highly prevalent in PTCL and NKTL, where STAT3 and TP53 are the most frequently mutated genes. STAT3 activation drives PD-L1 expression in NKTL, providing a rationale to combine STAT3 inhibitors with immune checkpoint inhibitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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