bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency
Authors: Hickstein Dennis D. , Shah Nirali N , Freeman Alexandra F , Zerbe Christa , Holland Steven M. , Parta Mark 
Published: October 2019

Abstract

Background: Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) represents the only definitive therapy for GATA2 deficiency.
Methods: Eleven patients with GATA2 deficiency received a myeloablative-conditioning regimen (2 matched related donors or MRD, 4 matched unrelated donors or URD, and 5 haploidentical related donors. MRD and URD received busulfan 3.2 mg/kg/day and fludarabine 40 mg/m2/day on days -6, -5, -4, and -3. Haploidentical related donors received cyclophosphamide 14.5 mg/kg on day's -6 and -5, fludarabine 30 mg/m2/day on day's -6 to -2, busulfan 3.2 mg/kg/day on day's -4 and -3, and 200 cGy TBI on day -1. MRD and URD recipients received tacrolimus and short course methotrexate post-transplant, while haploidentical related donor recipients received cyclophosphamide 50 mg/kg/day on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil as post-transplant immunosuppression for graft-versus-host disease.
Results: Ten of the 11 (91%) of patients are alive and disease-free at a mean follow-up of 12 months (range 1 mo to 24 mo). One URD recipient died from persistent acute myelogenous leukemia. Four patients developed graft-versus-host disease, one case Grade 4. All 10 patients who survived had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant. All 10 patients had reversal of the infection susceptibility phenotype. In particular, there were no recurrences of NTM infections. Importantly, all 10 patients had correction of the cytogenetic abnormalities present pre-transplant (5 patients with trisomy 8 and 1 patient with monosomy 7).
Conclusions: Myeloablative HSCT in GATA2 deficiency results in uniform engraftment and reversal of the hematologic, cytogenetic, and clinical manifestations of GATA2 deficiency. There was a low regimen-related toxicity, even in this cohort of patients with considerable co-morbidities. We anticipate that with HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML or CMML occurs, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Haploidentical related donor transplant appears to be particularly well suited for this disease, especially when the disease presents as a hypocellular myelodysplastic syndrome.

Disclosures
No relevant conflicts of interest to declare.
Microrna-9 Promotes Proliferation of Leukemia Cells in Adult CD34 Positive Acute Myeloid Leukemia with Normal Karyotype By Down-Regulation of Hes1
Authors: Tian Chen , Zheng Guoguang , You M. James , Zhang Yizhuo 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies sustained by a small population of leukemic stem cells (LSCs) that can resist treatment and act as barriers to cure. Previously, we observed that Hes1 and p21 expression was down-regulated in AML cell lines compared to that of normal bone marrow mononuclear cells. However, the activation status of Hes1-p21 pathway and its regulation in LSCs as well as normal hematopoietic stem cells (HSCs) in AML has not been elucidated. In this study, the Hes1-p21 pathway in LSCs and leukemic progenitors (LPs) was studied in adult CD34+ AML with normal karyotype and no genetic mutations and the upstream miRNA regulators were screened. Our results showed that the level of either Hes1 or p21 was lower in LSCs or LPs than that of HSCs whereas the level of miR-9 was higher in LSCs or LPs than HSCs. An inverse correlation was observed in the expression of Hes1 and miR-9. Furthermore, we validated miR-9 as one of the regulators of Hes1 by reporter gene analysis. Knockdown of miR-9 by lentivirus infection suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro. Moreover, knockdown of miR-9 resulted in decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model. Our results indicate that the miR-9-Hes1-p21 pathway plays an important role in supporting AML cell growth and survival, and that miR-9 has a potential to be a therapeutic target for suppressing AML.

Disclosures
No relevant conflicts of interest to declare.
ROS-Mediated Jab1-Thioredoxin Interaction in Acute Monocytic Leukemia
Authors: Zhou Fuling 
Published: October 2019

Abstract
SUMMARY
Increased production of reactive oxygen species (ROS) or an inefficient antioxidant system leads to oxidative stress, which influences hematopoietic cell function in acute myeloid leukemia (AML); however, the mechanisms of this stress remain poorly understood. Investigations were carried out on matched samples from the same 58 patients with AML-M5 (33 males and 25 females) who experienced a relapse after treatment. They had a median age of 43.90 ± 17.39 years (range, 14-77 years) at diagnosis and 44.86 ± 16.28 years at relapse. The mean white blood cell (WBC) counts were 16.58 x 109/L at diagnosis and 24.41 x 109/L at relapse (P < 0.05). Here, our studies showed that abnormally high ROS levels and low antioxidant enzyme capacity were characteristic of AML-M5 at both diagnosis and relapse. It is worth mentioning Jab1 and Trx protein levels were higher in all leukemia cell lines tested (THP-1, U937, and MOLM-13 cells), as well as in leukemic cells derived from AML-M5 patients, than in CD34+ cells from healthy donors (Figure 1A-D). A chi-square test revealed that patients with high Jab1 levels were less sensitive to Ara-c-based chemotherapy (Figure 1E). Consistently, high gene expression levels of thioredoxin (Trx) and Jab1 were associated with poor survival rates in AML-M5 patients(Figure 1F-H). Moreover, stimulating AML-M5 cells with a low concentration of hydrogen peroxide increased Jab1 and Trx expression. Additionally, depletion of Jab1 inhibited cellular proliferation and invasion, which was accompanied by a decrease in Trx expression.
Mechanistically, we demonstrate that Jab1 controls a major antioxidative cellular molecule Trx by interacting with and enhancing its transcriptional levels through AP-1 binding sites. To assess whether Jab1 and Trx interact we performed co-immunoprecipitation assays and demonstrated that Jab1 and Trx proteins interacted specifically with each other using endogenous proteins or ectopically expressed tagged-proteins, in U937 and THP-1 cells (Figure 2A and B). Furthermore, our results demonstrate that Jab1 knockdown remarkably reduced Trx levels (Figure 2C). Inversely, Jab1 overexpression induced higher endogenous Trx levels (Figure 2D). However, neither Trx silencing nor Trx overexpression affected Jab1 levels. Thus, our findings indicate that Jab1 is an upstream regulator and positively controls Trx expression in AML-M5 cells. To further delineate whether Jab1 regulates transcriptionally Trx, we performed a luciferase reporter assays with the human Trx promoter. Our data demonstrated that transactivation of Trx expression is driven by Jab1 through the AP-1 binding site (Figure 2E-H). In conclusion, these results elucidate a novel Jab1 and Trx axis, which is a critical cellular process in the pathobiology of AML-M5 and could promotes AML-M5 relapse.

Disclosures
No relevant conflicts of interest to declare.
Wild-Type Kras Inhibits NrasQ61R/+-Induced Leukemias
Authors: Wen Zhi , Zhang Jing 
Published: October 2019

Ras proteins belong to the super family of small GTPases. Although RAS mutations are oncogenic, it remains highly controversial whether wild-type (WT) RAS facilitates or inhibits tumorigenesis in the presence of oncogenic RAS. Previous studies suggest that this might depend on cell type, specific RAS isoforms, and/or stage of tumorigenesis (e.g. tumor initiation versus tumor progression). Recently, we found that deletion of WT Kras in oncogenic Kras mice promotes myeloidproliferative neoplasm (MPN) in a cell-autonomous manner. This is through promoting activation of all Ras isoforms and thus enhancing cytokine signaling in vivo. However, it remains unknown whether WT Kras plays a similar role in oncogenic Nras-induced leukemogenesis.
To address this issue, we conditionally down-regulated WT Kras expression in a novel leukemia model induced by endogenous NrasQ61R/+. Detailed characterization of NrasQ61R allele reveals that NrasQ61R/+ displays an intermediate leukemogenic activity between NrasG12D/+ and NrasG12D/G12D. NrasQ61R/+ mice developed MPN (100%) and acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) (~10%) at the moribund stage with a median survival of 197 days. Therefore, NrasQ61R/+ mice provide an excellent experimental system to test genetic lesions promoting or inhibiting oncogenic Nras-induced leukemogenesis. We observed that 3-weeks after activation of NrasQ61R/+ and deletion of WT Kras, the double mutant mice displayed more severe MPN phenotypes than NrasQ61R/+ mice, as demonstrated by more prominent hepatosplenomegaly and further expanded myeloid compartment in bone marrow and spleen. Consistent with these MPN phenotypes, NrasQ61R/+; Kras-/- myeloid progenitor and precursor cells showed prolonged and hyperactivated GM-CSF signaling compared to NrasQ61R/+ cells. In addition, NrasQ61R/+; Kras-/- mice displayed further expanded common lymphoid progenitor compartment and a less differentiated phenotype in thymic T-cells than NrasQ61R/+ mice. In NrasQ61R/+; Kras-/- mice, early thymic T cell progenitors demonstrated enhanced cell proliferation and stronger ERK1/2 signaling compared to NrasQ61R/+ cells. Consequently, NrasQ61R/+; Kras-/- mice survived significantly shorter than NrasQ61R/+ mice (median survival: 97 days; P < 0.001) and 100% of them developed both MPN and T-ALL at the moribund stage. Preliminary results from bone marrow transplantation assay indicate that loss of WT Kras expression promoted NrasQ61R/+-induced MPN and T-ALL in a cell-autonomous manner. Taken together, our results suggest that loss of WT Kras promotes leukemogenesis in NrasQ61R/+ mice. We are currently studying on the underlying mechanisms.

Disclosures
No relevant conflicts of interest to declare.
Towards a Targeted Therapy:Phosphoproteomics Reveals Signaling Pathways That Are Normalized in AML Cells Following Treatment with Anti-CD44 Antibodies
Authors: Jalal El-Din Heba M. , Merzaban Jasmeen S. 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a clonal malignant disease characterized by a blockage in the differentiation of myeloid cells resulting in the accumulation of highly proliferating immature blast cells. With the success of All Trans Retinoic acid (ATRA) in acute promyelocytic leukemia (AML3), differentiation therapy has become a very attractive treatment option. Ligation of CD44 (a cell surface antigen) with anti-CD44 monoclonal antibodies (mAbs) is reported to reverse the blockage of differentiation and suppress the proliferation of blasts derived from most AML subtypes. However, the molecular mechanisms underlying this apparent 'normalization' (reversal) of AML cells induced by CD44 have not been fully elucidated. To expand our understanding of the cellular regulation and circuitry involved, we aimed to apply a quantitative phosphoproteomic approach using Stable Isotope Labeling with Amino acids in Cell culture (SILAC) to monitor dynamic changes of phosphorylation states in HL60 cells following treatment with CD44 mAbs. Phosphoproteomic analysis identified differentially phosphorylated proteins among CD44 mAb treated and control HL60 cells that are involved in a number of major signaling pathways as determined by the Ingenuity Pathway analysis (IPA) platform. Among others, Rho signaling emerged as a major pathway significantly changed by CD44 mAb treatment. Rho GTPases are well-recognized regulators of the actin cytoskeleton but have also been implicated in diverse cellular events such as cell polarity, microtubule dynamics, membrane trafficking, transcriptional regulation, cell growth control and development. An interesting Rho family member, PAK-2 was identified in our search. PAK-2 is a ubiquitously expressed serine/threonine protein kinase, which is a direct target for small GTPases and has been identified as a switch between cell survival and cell death signaling depending on its mode of activation. Western-blot analysis of cell lysates of CD44 mAb treated and control HL60 cells confirmed that the phosphorylation of Pak-2 was altered as early as 5 minutes following treatment. Further validation and characterization of the activation mode, phosphorylation dynamics and protein-protein interactions of PAK-2 are essential in understanding its role in AML.

Disclosures
No relevant conflicts of interest to declare.
Effect of Melphalan 140 Mg/m2 Versus 200 Mg/m2 on Toxicities and Outcomes in Multiple Myeloma Patients Undergoing Single Autologous Stem Cell Transplantation
Authors: Katragadda Lakshmikanth , McCullough Lindsay , Dai Yunfeng , Hsu Jack W , Hiemenz John W , May W. Stratford , Cogle Christopher R. , Norkin Maxim , Brown Randy A , Wingard John R. , Chang Myron , Moreb Jan S 
Published: October 2019

Abstract
Introduction: Although melphalan at a dose of 140 mg/m2 (MEL-140) is known to be an effective preparative regimen for autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma (MM) patients, there are very few studies comparing it to the most commonly used dose of 200 mg/m2 ( MEL-200).
Methods: We retrospectively reviewed the records of all myeloma patients who underwent an ASCT between 2001 and 2010 at our institution. We then identified patients who received melphalan as their preparative regimen at doses of 140 mg/m2 or 200 mg/m2. Patients who received any other drug as conditioning regimen or had more than one ASCT or had documented amyloidosis were excluded. Data were collected for variables known to possibly affect prognosis of MM patients. We assessed effect of melphalan dose on toxicities and outcomes.
Results: A total of 129 eligible patients were identified, with 33 receiving MEL-140 and 96 receiving MEL-200. As was expected significantly higher percentage of patients in the MEL-140 arm were older than 65 years (P=<0.001) or had cardiac ejection fraction < 50 (P=0.0001) or had Karnofsky score < 80 (P=0.01) or had creatinine > 2 either at diagnosis (P=0.004) or the time of ASCT (P=0.001). Rest of the patient and disease characteristics including Durie-Salmon stage, myeloma subtype and disease status at ASCT were not significantly different between the 2 arms. Patients in MEL-140 needed significantly longer time to ANC engraftment (P=0.037) and also had significantly higher frequency of neutropenic fever (P=0.003). There were no significant differences in mucositis (including grade), nausea, vomiting, diarrhea, bacteremia, or length of hospital stay and frequency of repeat hospitalizations among both groups. There was no treatment related mortality in either group. At a median follow up of 74 months (range, 52-140) from ASCT, there were no significant differences in relapse free survival (RFS) (P=0.4988) and overall survival (OS) (P=0.6936) between the two groups. Five year OS for MEL-140 and MEL-200 is 71.6% and 78.9%, while RFS is 23.9% and 34%, respectively. Proportion of patients whose myeloma status improved to ≥ VGPR at 3 months post ASCT was also not different (P=0.385). Importantly, similar proportions of patients received various post ASCT maintenance therapy (P=0.605). In multivariate cox proportional hazards model only disease status of ≥VGPR at the time of ASCT significantly affected RFS (P=0.024) but did not impact OS (P=0.104).
Conclusion: MM patients who received MEL-140 had similar long term outcomes as those who received MEL-200 despite their older age, lower performance status and renal insufficiency.

Disclosures
No relevant conflicts of interest to declare.
A Comparison of Lamivudine and Entecavir for the Prophylaxis of Hepatitis B Virus Reactivation in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Single Institutional Experience
Authors: Shang Jin , Sun Jing , Fan Zhiping , Huang Fen , Zhang Yu , Jiang Qianli , Zhou Hongsheng , Liu Qifa 
Published: October 2019

Abstract
Backgroud:
To compare the efficacy of lamivudine and entecavir in the prevention of hepatitis B virus (HBV) reactivation in HBsAg-positive patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Method:
A total of 216 consecutive HBV surface antigen (HBsAg) positive patients undergoing allo-HSCT at our institute between March 2008 and March 2014 were enrolled in this retrospective investigation.
Results:
Of the 216 patients, 119 received lamivudine and 97 received entecavir to prevent HBV reactivation. The cumulative rate of HBV reactivation at 24 th, 48 th, and 96 th post-transplantation were 7.0% and 0.0%, 15.0% and 1.0%, and 24.0% and 2.0% in lamivudine and entecavir groups, respectively. The cumulative rate of severe hepatitis attributable to HBV reactivation were 5.9% and 0.0% (p = 0.01) in lamivudine and entecavir groups at week 96 post-transplantation, respectively. On the 12th, 24th, and 48th weeks of anti-viral therapythe average serum HBV-DNA levels reduction in entecavir group were greater than in the lamivudine Drug-resistant mutation sites were detected in 25 (21.0%) patients in the lamivudine group and in one patient (1.0%) in the entecavir group.
Conclusion:
Our data indicates that entecavir might reduce the incidence of HBV reactivation and severe HBV reactivation hepatitis in HBsAg-positive allo-HSCT recipients compared to lamivudine.

Disclosures
No relevant conflicts of interest to declare.
Design and Development of a Novel Orally-Active, PI3K-p110Beta/Delta Inhibitor with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity
Authors: Shuttleworth Stephen Joseph 
Published: October 2019

Abstract
The phosphatidylinositide 3-kinases (PI3Ks) have emerged as important therapeutic targets for the treatment of hematological malignancies and solid tumors. In hematological cancer therapy, the majority of clinical activity has centered on the inhibition of the class IA isoform p110δ and the class IB enzyme p110γ, whereas for solid tumor treatment the landscape has been dominated by inhibitors of all four class I PI3Ks (p110α, β, δ and γ) or dual class I/mTOR inhibitors of limited selectivity. Our research has focused on the emerging role of p110β and p110δ in both cancer types, in which overexpression, mutation and PTEN-defectiveness have been shown to be key features in disease pathogenesis and progression. We have designed and developed a uniquely selective series of small molecules that inhibit the p110β/δ isoforms, and which display extremely high specificity in the human kinome. The design of such molecules has enabled us to interrogate the function of p110δ in tumor immunotherapy and p110β in primary tumor growth and metastasis; our lead compounds show promising oral activity in syngeneic models, in which they inhibit tumor growth and metastatic spread whilst also impacting on downstream biomarker responses. Additionally, through our ability to tune selectivity over p110α and p110γ, elimination of the mechanism-related toxicities associated with those isoforms can be realized, making selective dual p110β/δ inhibition potentially more conducive to combination therapy than for pan-PI3K inhibitors. Described herein is data for our clinical development candidate, KA2237, which is an orally-active, potent and selective p110β/δ inhibitor. This molecule displays potent in vitro growth inhibition and PD responses in a spectrum of hematological tumor lines, including in MCL and PTEN-null GCB-DLBCL, and has potential to treat BTK inhibitor-resistant malignancies of the hematopoietic system. KA2237 will enter Phase I studies in hematological cancer at the end of 2015.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of Pulmonary Embolism Among Patients with Acute Exacerbations of Chronic Obstructive Pulmonary: Data from Nationwide Inpatient Sample
Authors: Pathak Ranjan , Giri Smith , Karmacharya Paras , Donato Anthony 
Published: October 2019

Abstract
Background
Patients suffering from acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are thought to be at a higher risk of developing venous thromboembolism due to various reasons such as smoking, immobilization and a transient procoagulant state. However, clinical diagnosis of acute pulmonary embolism (PE) in patients with AECOPD is often difficult due to the similarity in the presenting symptoms of the two conditions. Literature regarding the true prevalence of PE among patients with AECOPD and the role of routine screening for PE in these patients with imaging is controversial. Although some studies have suggested prevalence rates to be as high as 20-25%, thus justifying a routine CT pulmonary angiography (CTPA) to evaluate for PE in these patients, other studies have refuted such findings.
Methods
We used the 2011 Nationwide Inpatient Sample database to identify patients aged ≥18 years admitted with AECOPD (International Classification of Diseases, 9th Revision, Clinical-Modification [ICD-9-CM] code 491.21). Patients with AECOPD with co-existing PE were identified using the ICD-9-CM codes 415.1x and 673.2x. Prevalence of PE in patients with AECOPD was calculated. Similarly, in-hospital mortality, length of stay and mean hospital charge was derived for patient with AECOPD, with and without PE. Statistical analysis was performed using Stata 13.1 (STATA Corp, College Station, TX), which accounted for the complex survey design and clustering of the database.
Results
A total of 1,187,808 admissions with AECOPD were identified, of which 1.18% (n=13,988) patients were found to have co-existent PE. On Univariate analyses, no differences were seen in the demographic characteristics (mean age, sex, race, primary payer, region, bed-size, teaching status) of AECOPD patients with and without PE. However, diagnosis of concurrent PE in patients with AECOPD was associated with higher in-hospital mortality (10.6% vs. 3.81%, p<0.001), mean length of stay (9.38 vs. 5.92 days, p<0.001) and mean total hospital charges ($74,234 vs. 40,424, p<0.001).
Conclusion
In this study of large national database, we found the prevalence of PE in patients admitted for AECOPD to be much lower than reported in literature, suggesting that routine imaging to rule out PE is unlikely to be cost effective. Furthermore, routine screening of AECOPD patients for PE with CTPA might actually result in more untoward effects such as incidental pulmonary nodules and PEs with further unnecessary testing and treatment.

Disclosures
No relevant conflicts of interest to declare.