bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Synthetic Histone Deacetylase Inhibitor, SK-7041, Has Potent Anti-Proliferative Activity in Acute Myeloid Leukemia Cell Lines.
Authors: Yoon Sung-Soo , Bae Eunkyung , Park Juwon , Cha Yongjun , Lee Young Y. , Kim Byoung K. 
Published: October 2019

Abstract
Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities determine the acetylation status of histones, which regulates gene expression through chromatin remodeling. Aberrant histone acetylation is known to play a key role in leukemogenesis. Thus, histone deacetylase inhibitors (HDACIs) are emerging as a new class of anti-cancer agents for leukemia. In this study, we examined anti-proliferative effects of novel hybrid synthetic HDACI, SK-7041, in various acute myelogenous leukemia (AML) cell lines (KG-1, HL-60, HEL, U937, ML-1). SK-7041 induced the time-dependent hyperacetylation of histones H3 and H4 in AML cell lines. It preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, as compared with the other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041. All the cell lines tested showed similar patterns of growth inhibition by SK-7041. Their IC50 values were approximately 0.5 mM at 72 hours incubation. SK-7041 effectively induced the apoptosis via activation of caspase-3, -7, -9, and PARP, but not caspase-8. SK-7041 enhanced G1 arrest via decreasing Cyclin D1 expression and increasing p21 expression. Changes in gene expression profiles after treating KG-1 cells with various concentrations of SK-7041 were assessed using a cDNA microarray consisting of distinct cDNAs of cancer-related genes. 7 genes, namely RGL1, FYN, CARD9, ABCA7, TNFRSF6B, CASP9, and ENPP2 were induced substantially (Global M >2.0) and 8 genes, namely PTPN7, CD34, INSIG1, IL16, LHX6, TRIB3, BID, and PDCD4 were reduced substantially (Global M < 2.0). In conclusion, this study showed SK-7041 inhibited cancer cell growth and caused characteristic gene expression profile changes in AML cells. The alteration in levels of acetylated histones was closely associated with expression of specific cancer-related genes in AML cells.
Detection of Nucleophosmin Gene Mutations in Plasma from Patients with Acute Myeloid Leukemia: Clinical Significance and Implications.
Authors: Ma Wanlong , Zhang Xi , Jilani Iman , Ravandi Farhad , Estey Elihu , Kantarjian Hagop , Giles Francis , Sheikholeslami Mohammad , Keating Michael , Albitar Maher 
Published: October 2019

Abstract
Nucleotides insertion in the nucleophosphamin (NPM1) gene has been reported in about one third of patients with acute myeloid leukemia (AML). Multiple studies showed that the presence of NPM1 mutations associated with better outcome in patients with AML. Studies reported to date have analyzed leukemic cells obtained from bone marrow or peripheral blood. We tested for mutations in the NPM1 gene using peripheral blood plasma and compared results with clinical outcome from a single institution. Analyzing plasma from 98 newly diagnosed patient with AML showed NPM1 mutation in 24 (23%) of patient while only one (4%) of 28 previously untreated patients with myelodysplastic syndrome (MDS) showed NPM1 mutation. Compared with peripheral blood cells, 2 (8%) of the 24 positive patients were negative by cells; none were positive by cells and negative by plasma. Most of the mutations detected (45%) were in patients with FAB classification M2, M4 and M5. In addition to the reported 4 bp insertion, we also detected 4 bp deletion in one patient in cells and plasma. Patients with NPM1 mutation had a significantly higher white blood cell count (P = 0.0009) and a higher blast count in peripheral blood (P = 0.002) and in bone marrow (P = 0.002). Blasts in patients with NPM1 mutant expressed lower levels of HLA-DR (P = 0.005), CD13 (P = 0.02) and CD34 (P < 0.0001), but higher CD33 levels (P = 0.0004). Patients with NPM1 mutation appear to have better chance of responding to standard therapy (P = 0.06). Event free survival of patients with NPM1 mutation was longer (P = 0.056) than in patients with intermediate cytogenetic abnormalities. The most striking difference in survival was in patients who required >35 days to respond to therapy (Figure). Survival was significantly longer in patients with NPM1 mutation requiring >35 days to respond (P = 0.027). This data not only support that NPM1 plays a significant role in the biology and clinical behavior of AML, but also show that plasma DNA is enriched with leukemia-specific DNA and is a reliable source for testing.
Figure Figure
Survival Is Poorer in Patients with Secondary Core Binding Factor Acute Myelogenous Leukemia Compared with De Novo Core Binding Factor Leukemia.
Authors: Borthakur Gautam , Jain Nitin , Kantarjian Hagop , Lin E. , Ravandi Farhad , Pierce Sherry , Estey Elihu 
Published: October 2019

Abstract
Translocation (8;21)(q22;q22) and inversion of chromosome 16 [inv(16) (p13q22)] are considered good-risk cytogenetic abnormalities in acute myeloid leukemia (AML) accounting for 15% of primary AML cases (Blood. 2002 Dec 15;100(13):4325–36) and are characterized at the molecular level by disruption of genes encoding subunits of core binding factor (CBF). Increasing age, increasing peripheral blast percentage and complex cytogenetics are associated with poor overall survival in these patients (Br J Haematol. 2006 Oct;135(2):165–73). Here we assess differences in patient characteristics and outcomes between the primary and secondary core binding factor AML. One hundred eighty nine CBF AML patients treated at our institution were studied; 18 (9.5%) had secondary AML. Patients with secondary CBF AML were older (p= 0.02, median ages 57 vs. 44 years) and had lower WBC counts (p=0.03) (Table1). Overall survival (OS) was worse in the secondary AML patients (94 weeks versus 621 weeks, p=0.0016) (Figure 1). Age, hemoglobin, platelet count, and bilirubin were significantly associated with OS in the univariate analysis. In the multivariate analysis, after adjusting for age, hemoglobin, WBC, and bilirubin, secondary CBF AML was marginally significantly associated with worse OS (hazard ratio 1.884, CI95% 0.979–3.625, p=0.058) but not worse PFS (p= 0.15) (Table 2). These data suggest that the secondary CBF AML has much poorer prognosis than the primary CBF AML, further indicating that “CBF AML” is not a homogeneous entity with a uniformly good prognosis.
Table 1: Summary statistics of patients’ continuous characteristics by abnormality status Patient characteristics Total patients Primary AML (n=171, male=96) Secondary AML (n=18, male=8) p-value (primary vs secondary AML) Median (range) Median (range) Median (range) Age (years) 44 (16–88) 44 (16–88) 57 (31–75) 0.02 WBC (103/mm3) 14.7 (0.6–387) 16.4 (0.6–387) 6.6 (0.8–103.8) 0.03 Hemoglobin (g/dl) 8.1 (2.5–14.3) 8.2 (2.5–14.3) 7.8 (4.8–10.8) 0.33 Platelet count (103/mm3) 38 (5–350) 38 (5–350) 39 (9–139) 0.88 Bilirubin (mg/dl) 0.6 (0.0–15.3) 0.6 (0.0–5.0) 0.6 (0.1–15.3) 0.94 Creatinine (mg/dl) 0.9 (0.5–2.9) 0.9 (0.5–2.9) 0.9 (0.5–1.8) 0.66 Table 2: Multivariate Cox proportional hazards model in estimating the association between covariates and patients’ survival Variable Hazard ratio (95% CI) p-value Abnormality (secondary vs primary) 1.884 (0.979–3.625) 0.058 Age (1 year increase) 1.028 (1.012–1.044) 0.0004 Hemoglobin (1gm/dl increase) 0.864 (0.769–0.970) 0.014 WBC (103/mm3 increase) 1.003 (1.000–1.007) 0.061 Bilirubin (1 mg/dl increase) 1.179 (1.044–1.332) 0.008
Figure Figure
Prognostic Value of Serum Lactate Dehydrogenase (LDH) in Patients with Primary Systemic Amyloidosis Undergoing Stem Cell Transplantation.
Authors: Kumar Shaji , Lacy Martha Q. , Dispenzieri Angela , Hayman Suzanne , Buadi Francis K. , Dingli David , Litzow Mark R. , Gertz Morie A. 
Published: October 2019

Background: Primary amyloidosis (AL) is characterized by multi-organ deposition of light chain derived amyloid protein, resulting in organ dysfunction of varying severity. High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective treatment for AL, but is limited in applicability due to high transplant related mortality in patients with advanced organ dysfunction. Serum LDH, an enzyme that catalyzes the conversion of lactate to pyruvate, is present in large amounts in heart, kidney, liver, and muscle and is elevated with abnormalities in one or more of the organs. It is commonly elevated in a variety of hematologic malignancies. Given the multi-organ involvement in AL, we examined the prognostic value of LDH in AL.
Methods: We examined our transplant database to assess the prognostic value of LDH. Laboratory values from pre-ASCT evaluation were used for the analysis.
Results: Three hundred and thirteen pts who underwent ASCT between March 1997 and March 2007 were included in this analysis. The median age at ASCT was 57.5 years (range, 33–73); and 183 pts (58.3%) were male. The median duration from diagnosis to transplant was 4.1 months (range, 1–75) and the median follow up post transplant was 28.3 months (range, 1 m to 10 years) for the 229 pts (73%) alive at the time of analysis. The median LDH was 194 IU (range, 92-441) and 138 pts (44%) had an LDH > 200. The median overall survival post-ASCT for patients with an LDH > 200 was 59.4 mos (95% CI; 37.9, 80.8) compared to not reached for the rest (Figure). The prognostic value of LDH for post transplant OS was independent of cardiac troponin (cTnT). The median OS post ASCT for patients with cTnT > 0.035 (n=208) was 37.4 months (95% CI; 17, 57.9) compared to 97.5 months (95% CI; 64.8, 130.2) for the rest. In a Cox proportional hazards model, cTnT > 0.035 was associated with a 2.5 fold risk of death (p = 0.0013) and an LDH > 200 was associated with 1.7 fold risk (p = 0.04). We then examined if LDH added to the cTnT in a prognostic model for survival post ASCT. Pts with both cTnT < 0.035 and LDH < 200 (n=133) had a median OS that was not reached compared to 71 mos (95% CI; 48.3, 94) if one factor was abnormal (n=89) and 37.4 mos (95% CI; 16.1, 58.8) if both cTnT and LDH were abnormal as above (n=45); p < 0.001 (Figure 2).
Conclusions: In this study we have demonstrated the prognostic value of serum LDH in AL pts undergoing ASCT. Serum LDH appears to add to the value of troponin in prognostic staging of these patients. These results need to be examined in a larger cohort of patients undergoing different treatments. It is possible that LDH is able to globally assess abnormalities of multiple organs including heart, liver and lung. Prospective studies looking at the different LDH fractions are ongoing.
Figure Figure Figure Figure
Hepatic Response after High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis Associated Liver Disease.
Authors: Girnius Saulius , Seldin David C. , Skinner Martha , Finn Kathleen T. , Sanchorawala Vaishali 
Published: October 2019

Abstract
Immunoglobulin light chain (AL) amyloidosis is a plasma cell dyscrasia with extracellular protein deposition in various organ systems, including the liver. The natural history of AL amyloidosis with liver involvement has a poor prognosis, with median survival of only 8.5 to 9 months. High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. Patients were included who had hepatic involvement and received HDM/SCT from 1998 to 2006. Data was collected with the approval of the Institutional Review Board. Patients receiving HDM/SCT had to meet eligibility criteria to qualify for this aggressive treatment. Stem cells were mobilized using G-CSF alone. Intravenous melphalan was administered at 100–200 mg/m2 over 2 days in divided doses and stem cells were re-infused 24–72 hours after HDM. Liver response was determined by criteria set up by the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. Sixty-nine patients qualified for this study, including 47 males and 22 females. The median age was 56 years (range, 37–75), median bilirubin was 0.5 mg/dL (range, 0.1 to 5.7), median alkaline phosphatase was 193 U/L (range, 59 to 1243) and the median liver size was 3 cm (range, 0–20cm) below the costal margin. Nine patients (13%) died from treatment-related mortality. The hematologic CR one year after treatment was achieved by 53% (31/58) of evaluable patients. The overall survival was 84% at 1 year and 49% at 5 years, by Kaplan-Meier estimates. Hepatic response occurred in 21% (10/47) at 1 year after HDM/SCT and 40% (12/30) at 2 years after HDM/SCT. In summary, hepatic involvement with AL amyloidosis does not increase treatment-related mortality from HDM/SCT. Hepatic response follows a hematological response and can occur as far as 2 years from HDM/SCT. Forty % of surviving evaluable patients showed remission of their hepatic disease from AL amyloidosis by 2 years.
Reduction of Prion Infectivity in Packed Red Cells by Separation of Whole Blood and Washing of the Red Cell Fraction.
Authors: Morales Rodrigo , Buytaert-Hoefen Kimberley A. , Hansen Eric T. , Hlavinka Dennis , Goodrich Raymond , Soto Claudio 
Published: October 2019

Abstract
Although prion diseases are rare in humans, the established link between a new variant form of CJD (vCJD) and the consumption of cattle meat contaminated by BSE have raised concerns about a possible outbreak of a large epidemic in the human population. Over the past few years, BSE has become a significant health concern in several countries, and it now seems apparent that vCJD can also be iatrogenically transmitted from human to human by blood transfusion. Exacerbating this state of affairs is the lack of a reliable test to identify individuals incubating the disease during the long and silent period from the onset of infection to the appearance of clinical symptoms. The purpose of this research study was to evaluate the effectiveness of separation of whole blood and washing of the red cell fraction for the removal of infectious scrapie prion protein (PrPSc) from red blood cell (RBC) suspensions. Samples of human, whole blood were spiked with 5 × 106 LD50 263K PrPSc. Analysis of the treated sample supernatants by Western blot revealed that approximately >88% of the PrPSc was removed with the initial plasma expression and the equivalent of 6% was detected in a saline wash (300 mL; 0.9% saline). The final sample of RBCs revealed no detectable levels of PrPSc by Western blots. Further analysis of the treated RBCs using the PMCA assay indicated detectable amounts of PrPSc only after 2 consecutive amplification rounds. Semi-quantitative analysis of PMCA amplification enabled us to estimate that the treated RBCs contained less than 1 × 104 LD50 PrPSc. This corresponded to removal levels exceeding ≥99% of spiked material in whole blood. These in vitro estimations were confirmed by in vivo infectivity studies in a hamster model of disease transmission.
Results from in vivo studies displayed significant differences in the incubation periods of the spiked blood inoculated hamsters (100.1 ± 1.7) versus washed RBCs (135.8 ± 6.7). Moreover, a substantial difference in the attack rate (6/15: 40% in washed RBC, versus 13/13: 100% in spiked blood) further indicated a substantial removal of infectious prions. Comparison of this data with results of animals inoculated with different dilutions of infectious material, indicated a >99.94% reduction of infectivity. Washed, packed human red cells produced by this procedure were able to be stored in standard additive solutions (AS-3) for 42 days while still meeting all in vitro blood bank standards for acceptable red cell quality.
Conclusion This data suggests that separation of plasma coupled with a simple, low volume wash of red cells may represent an efficient method to remove prions from red blood cell fractions, thus reducing possible infectivity of these products.
Recovery of Donor Peripheral Blood Platelet Count Following Platelet Apheresis.
Authors: Dumont Larry J. , Lassahn L. , Tomasulo Peter A. , Harpool Dennis , Pinkard S. , Rugg Neeta , Cancelas Jose A. , Landry S. , Ambruso Daniel R. , Clementi Chris , Schuyler Robert 
Published: October 2019

Abstract
BACKGROUND: Apheresis platelet collection from healthy normal blood donors can reduce the donor peripheral blood platelet concentration by 50% or more. The kinetics of peripheral blood platelet count (PLT) recovery in the apheresis donors over the first 24 hours has not been described. The objective of this study was to determine the recovery kinetics of the donor peripheral blood platelet count following apheresis platelet donation.
METHODS: Healthy apheresis platelet donors were enrolled following informed consent. The apheresis platelet collection was performed using the Gambro Trima system (Gambro BCT, Lakewood, CO) following local SOP and manufacturer’s directions for use. The minimum predicted post-count was configured in the Trima to no less than 78K plt/μL. PLT was determined pre-procedure (Pre), immediately post procedure (Post), 4–11 h (FU1) and 11–41 h (FU2) post-donation using standard methods. The PLT recovery was evaluated as the increase in PLT following the donation (Delta). The effects of study site, time of sample, and the fraction of platelets collected (Fpc) at donation on Delta were evaluated using a random effects generalized linear regression model. A full regression model of Delta as a function of study site, follow-up period and Fpc with all main and interaction effects was used to test hypotheses.
RESULTS: 548 subjects were entered into the study at 3 study sites; Pre-PLT 276±59 × 103 plt/μL, Post-PLT 205±47 × 103 plt/μL, Fpc 25±10%. No adverse events were reported by any subjects. Recovery of platelet count following apheresis platelet donation is variable between subjects; and the independent variables of study site, follow-period and Fpc accounted for 25% of the total variation in Delta. PLT increased 12.4±0.9 × 103 plt/μL by the time of follow-up sampling (p=0.01), although there was no difference between PLT at FU1 (214±49 × 103 plt/μL) and FU2 (212±47 × 103 plt/μL; p=0.15). None of the donors reached their pre-donation platelet count during the follow-up period. There was no difference in Delta between centers (p=0.23). Fpc had a significant affect on Delta (p<0.0001); with estimated Delta of 5.2±0.9 × 103 plt/μL at Fpc=15% and 16.0±.8 × 103 plt/μL at Fpc=30%.
CONCLUSION: Platelet recovery following apheresis platelet donation was observed to be dependent on the fraction of platelets donated. Surprisingly, the recovery observed within the first 11 h was equivalent to that observed between 11–42 h, averaging 17.5% of the drop observed during apheresis. Recovery was not complete when observed for up to 41 h following donation in this study. Additional investigation of PLT recovery following apheresis donation is indicated to describe and differentiate the potential roles of de novo production, early pro-platelet release and platelet release from peripheral pools over the early post-donation period.
High Levels of Circulating HSP70 Levels in Patients with Chronic Myeloid Leukemia and Correlation with Resistance to Therapy with Imatinib.
Authors: Tseng Richard , Yeh Chen-Hsiung , Jilani Iman , Zhang Zhong , Kantarjian Hagop , Cortes Jorge , O’Brien Susan , Giles Francis , Hannah Alison , Estrov Zeev , Keating Michael , Albitar Maher 
Published: October 2019

Abstract
Cellular increase in the heat shock protein 70 (HSP70) inhibits death receptor and mitochondria-initiated signaling for apoptosis. In Vitro and in vivo data from patients with chronic myeloid leukemia (CML) indicates that overexpression of HSP70 in leukemic cells is associated with resistance to imatinib. The HSP70 protein is detectable in the plasma and has been reported to represent a marker for cardiovascular stress as well as prostate cancer. We measured HSP70 in the plasma of 139 patients with CML using a sandwich assay based on meso scale technology and correlated levels of HSP70 protein in plasma with clinical behavior. All samples were collected prior to initiating imatinib therapy. The levels of HSP70 in CML patients in chronic phase (N=93) were not significantly (P=0.08) different from those in patients with CML in accelerated/blast crisis (N=46) (median 33.24 ng/ml, range: 3.892–128.172 ng/ml Vs median 26.57 ng/ml, range: 4.498–114.746 ng/ml, respectively). However, CML patients had significantly (P<0.0001) higher levels of HSP70 than normal control (N=95, median=4.17 ng/ml, range:1.746–24.684 ng/ml). There was significant correlation between plasma levels of HSP70 and platelets (r=0.54), WBC (r=0.32), and basophils (r=0.31) in patients in chronic phase and with platelets (r=0.72), blasts (r=0.39), and basophils (r=0.50) in patients in Acc/Bl phase. Patients in chronic phase and high levels above the median had significantly (P=0.02) higher rate of progression to ACC/Bl phase while on therapy with imatinib (figure). In addition these patients appear to have a tendency toward shorter survival (P=0.07). There was no significant correlation between plasma HSP70 levels and survival in patients with ACC/Bl phase. This data support the reported role of HSP70 in the resistance to imatinib in patients with CML and potentially plasma HSP70 levels may represent a marker for resistance in patients with chronic phase CML.
Figure Figure
Gfi-1 Is Overexpressed on Chronic Myeloid Leukemic Cells.
Authors: Cheng Hui , Chang Wei , Huang Ming , Sun Ying , Zhang Yicheng 
Published: October 2019

Abstract
Gfi-1 oncogene was first discovered as an integration site for Moloney murine leukemia virus(MoMulv) in virally infected cells that were selected for interleukin-2 (IL-2) independence; In synergy with pim-1 and L-Myc genes, Gfi-1 was involved in the pathogenesis of lymphoid malignancies. Recent studies also indicated that Gfi-1 regulates self-renewal and engraftment of hematopoietic stem cells and the development of neutrophils. Normally, Gfi-1 zinc finger protein is expressed almost exclusively on thymocytes or stem cells. Chronic myeloid leukemia (CML) is a typical hematopoietic stem cell disease, we ask whether Gfi-1 is expressed on CML cells and the possible role in the leukemogenesis. By RT-PCR and flow cytometry, we analysed the expression of Gfi-1 in the transcription and the protein levels respectively on bone marrow mononuclear cells(MNC) from 53 CML patients. Control samples were taken from the ribs of 5 patients undergoing thoracic surgery for lung cancer. Results Gfi-1 mRNA was detected in K562 cell line and all the MNCs from CML patients but not or very weak in control MNCs; Flow cytometry study show that both the positive percentage (87.2±7.5% Vs 12.4±6.6%, p<0.01) and the relative fluorescence intensity (represented by mean fluorescence intensity, 58.94 ±22.09 Vs 18.67±7.88, p<0.01) were significantly increased in CML MNCs. Considering the complexity of the composition of bone marrow MNCs, we also sorted CD34+ cells from CML or control samples and examined by Rt-PCR and flow cytometry; The Gfi-1 was found to be overexpressed in CD34+ cells of CML; On confocal microscopy, Gfi-1 was mainly sublocalized in nucleus. Conclusion Gfi-1 was overexpressed in MNCs or CD34+ cells from CML patients; Gfi-1 may be implicated in the leukemogenesis of CML and potentially be targeted in the future for treatment of CML.