bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Deptor Inhibitor Induces Its Degradation with Resulting Anti-Myeloma Cytotoxicity in Vitro and In Vivo
Authors: Vega Mario I , Shi Yijiang , Frost Patrick , Huerta-Yepez Sara , Lichtenstein Alan 
Published: November 2019

Multiple myeloma (MM) is a hematological disorder characterized by a proliferation of malignant monoclonal plasma cells in the bone marrow (BM) and / or in extramedullary sites. Despite recent progress in OS rates, MM remains an incurable disease and most patients will relapse and require treatment. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. It is known that the inhibition of Deptor results in the inhibition of the proliferation and induction of apoptosis in MM cells. In addition, high levels of Deptor are predictive of a poor response to conventional therapies, indicating that Deptor expression are important as a prognostic marker for patients with myeloma and is a possible therapeutic target. Our group previously identified a drug which prevents mTOR-Deptor binding (NSC126405) and induces cellular cytotoxicity in MM (Shi Y, et al 2016). In this study, we developed a new related chemical inhibitor (43 M) capable of inducing the inhibition of the mTOR / Deptor interaction and results in the negative regulation of Deptor that leads to the inhibition of proliferation and induces apoptosis in several MM cell lines. The cytotoxic effect of 43 M is not dependent of caspase activation and induces the activation of p70 and AKT (T308). This leads to the induction of apoptosis in MM cell lines and tumor cells derived from MM patients. The degradation of Deptor induced by 43 M is dependent on the proteasome complex since it was prevented in the presence of MG132. In vivo, 43 M prevents the expression of Deptor in a xenograft tumor, and delayed tumor growth and interestingly, induces the eradication of tumors in 40% of mice in a murine model of MM, without significant toxic implications. Recent studies show that Deptor expression protects MM cells against Bortezomib treatment, suggesting that anti-Deptor drugs can synergize with proteasome inhibitors (PIs). However, the combination of 43 M + Bortezomib was not synergistic, and was antagonistic in vitro. These results are probably due to the prevention of the proteasomal degradation of Deptor, suggesting a possible use of the 43 M inhibitor in MM in the absence of the current PIs. This study describes for the first time the possible role of Deptor as a therapeutic target using a chemical inhibitor capable of degrading and inducing a cytotoxic effect in MM cell lines. In addition, Deptor is reported as an important therapeutic target in an in vivo MM model.
Shi Y, Daniels-Wells TR, Frost P, Lee J, Finn RS, Bardeleben C, Penichet ML, Jung ME, Gera J, Lichtenstein A. Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells. Cancer Res. 2016 Oct 1;76(19):5822-5831

Disclosures
No relevant conflicts of interest to declare.
A Distinct Metabolic Signature in DNMT3A-Mutated Leukemia
Authors: Dai Yu-Jun , Hu Fang , He Si-Yuan , Tian Xiao-Peng , Li Hong-Hong , Qin Ze-Yuan , Chen Siliang , Liang Yang 
Published: November 2019

Background: Acute myeloid leukemia (AML) is a type of cancer that consists of a group of hematological malignancies with high heterogeneity. AML patients with DNMT3A mutations often have a poor prognosis. Metabolic alterations have long been recognized in cancer cells. Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change the cellular metabolism, priming cells for malignancy. It is well known that 2-hydroxyglutarate (2-HG) is an oncometabolite resulting from mutations of the isocitrate dehydrogenase 1 and 2 (IDH1and IDH2) genes and isa strong prognostic predictor independent of other clinical and molecular features. Alpha-ketoglutarate-dependent dioxygenase encodedby the TET2 gene could catalyze 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), thereby regulating DNA methylation and inducing hematopoietic malignancies.
Methods: Metabolomic profiles of all serum samples were achieved using the GC-TOF MS platform. CCK-8 assays were used to examine cell viability and cytotoxic activity of 2-ketoisocaproic acid (2-KA) to leukemia cells. Methyl-Cellulose colony-forming cell assays and flow cytometry were performed to assess cell proliferation and cell differentiation. The pIpC was administrated in the Dnmt3aR878H/WTMx1Cre+mice at the time of weaning (4 weeks old) to activate transgene expression in vivo. The expressions of genes/proteins were detected by RNA sequencing, quantitative RT-PCR and western blot.
Results: We report a metabolomics study with a total of 171 newly diagnosed AML patients and identified a distinct leucine metabolic signature in AML patients with DNMT3A mutations. The prognostic value of 2-KA was demonstrated in cytogenetically normal AML patients, and a low 2-KA level predicted a poor overall patient survival. We further compared the gene expression patterns of the blast cells in bone marrow (BM) between AML groups with and without a DNMT3A mutation; these patterns correlated well with those of the leucine metabolic pathways and exhibited enhanced ACAA1 and decreased ALDH7A1 gene expression in DNMT3A-mutated leukemic cells. In vitro results demonstrated that a high 2-KA level could inhibit the proliferation of DNMT3A-mutated cells but did not affect the differentiation of these leukemic cells.
Conclusions:Our data suggest that 2-KA isa unique feature of AML with a DNMT3A mutation and might be a metabolic marker of early-stage hematopoietic malignances.This study also suggests that ACAA1 and ALDH7A1 were aberrantly expressed in DNMT3A mutant leukemic cells and may be potential targetsfor AML therapy. We also hypothesized that a combination of the metabolic inhibitor and chemotherapeutic agent may be a possible treatment strategy for DNMT3A-mutated AML.

Disclosures
No relevant conflicts of interest to declare.
ST2 and Rg3a As a Biomarker for Predicting of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Goker Hakan , Aladag Elifcan , Buyukasik Yahya , Chao Nelson J. , Akman Umit , Demiroglu Haluk 
Published: November 2019

Background:Graft-versus-Host Disease (GvHD) is a crucial complication after leading to significant morbidity and mortality allogeneic hematopoietic stem cell transplantation (AHSCT) which occurs in approximately half the transplant recipients. Although there are some studies conducted, a biomarker which can be shown to accurately predict acute GVHD has not been well established, yet. Suppression of tumorigenicity 2 (ST2) and Regenerating islet-derived 3-alphamight be important biomarkers to predict acute GVHD or GVHD with acute exacerbations.
Material and Methods: In the present study, blood samples were collected from 17 patients with acute GVHD and 12 control patients after allogeneic stem cell transplantation. All patients save informed consent in accordance with declaration of Helsinki. ST2 and Reg3a were measured in plasma samples and we compared the ST2 and Reg3a levels of patients with acute GVHD patients and controls.
Results:The median age of the study population was 42 (range,19-49). As compared with the patients with acute GVHD and controls, the ST2 levels had the significant association with Acute GVHD (mean 9794 ng/dl vs 2646 ng/dl, p:0.008 )
Conclusion:The ST2 level could be used as a significant biomarker for predicting acute GVHD. However, further studies with larger patient populations are needed.

Disclosures
No relevant conflicts of interest to declare.
Population-Level Trends in Early Mortality and Overall Survival of Patients with Multiple Myeloma. Are We Facing Stagnation?
Authors: Costa Luciano J. , Bal Susan , Chhabra Saurabh 
Published: November 2019

Background: Therapeutic advances in multiple myeloma (MM) in the last two decades resulted in population-level reduction in early mortality (EM) and improvements in overall and relative survival when consecutive cohorts are compared. We utilized updated information from the Surveillance Epidemiology and End Result (SEER-18) program to test whether prior improvement trends have persisted in more recent years.
Methods: Patients diagnosed with MM as first malignant neoplasm between the years of 2001 and 2015 were included in the analysis. Survival data are available up to the end of 2016. We analyzed year-by-year EM, herein defined as death from any cause within the first year of diagnosis of MM. Updated 5-year OS was available for patients diagnosed 2001-2011 and analyzed year-by-year. We also analyzed outcomes using age brackets (<65, 65-74 and 75+ years) and race/ethnicity subgroups [non-Hispanic White (NHW), non-Hispanic Black (NHB) and Hispanic].
Results: There were 54,475 patients included in the EM analysis and 37,452 in the 5-year OS analysis. For the EM analysis, 42.7% of patients were <65, 29.0% were 65-74 and 28.4% were 75+. NHW were 62.0%, NHB 19.7%, Hispanic 11.4% , and 54.6% of patients were male. We observe a year-by-year decline in EM between 2001 (31.0%) and 2012 (20.5%), however no significant reduction in EM was noted between 2013 (19.5%) and 2015 (18.5%) (P= 0.24). Such plateau in EM was also noted in each of the age brackets (Figure 1) and race/ethnicity subsets, with no significant difference seen in the last 3 years of data. For patients diagnosed in 2015, EM remained high at 11.6% for patients <65, 17.1% for patients 65-74, 31.5% for patients 75+, 19.5% for NHW, 18.8% for NHB and 16.8% for Hispanics. Five-year OS improved between cohorts of patients diagnosed in 2001 (29.3%) and patients diagnosed in 2008 (43.3%) (P<0.001), but remained stable for patients diagnosed between 2009 (44.4%) and 2011 (44.2%) (P=0.86). Similar pattern was seen for all age (Figure 2) and race/ethnicity subsets.
Conclusions: These data indicate possible stagnation in risk of EM and 5-year survival for patients diagnosed with MM in the US beyond the introduction of proteasome inhibitors and immunomodulatory agents. The absolute risk of EM remains unacceptably high for all ages pointing to an unmet need in MM care. Future data will indicate whether the introduction of monoclonal antibodies and other new classes of drugs will have sufficient impact to change population-level outcomes in MM.

Disclosures
Costa: Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Janssen: Research Funding, Speakers Bureau; Abbvie: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau.
Dasatinib and Nilotinib As Upfront Therapy for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) in Qatar: A Cost Effectiveness Analysis (CEA)
Authors: Adel Ahmad M , Abushanab Dina , Hamad Anas , Abdulla Mohammad Abdul-Jaber , Yassin Mohamed A 
Published: November 2019

Objectives: Many tyrosine kinase inhibitors (TKIs) are approved for treating the chronic phase of chronic myeloid leukemia (CML-CP). This study aims at identifying the optimal upfront TKI treatment strategy; considering cost-effectiveness for CML patients from Qatar healthcare system perspective. Evaluated strategies included the newer generation TKIs; dasatinib 100 mg once daily and nilotinib 300mg twice daily. We evaluated both treatments considering their molecular and cytogenetic response outcomes at 12 months follow up as well their respective acquisition costs.
Methods: A decision tree model was developed linking clinical effectiveness (defined as major molecular response MMR and/or complete cytogenetic response CCyR), utility, and cost data over a 12-months period. The choice of 12 months period is due to the evidence that the degree of short-term molecular and cytogenetic responses at certain follow- up times is correlated with CML prognosis. Patients who achieve a CCyR are shown to have high remission rates as well overall survival (OS) rates. Patients with newly diagnosed CML are adopted from Qatar Cancer Registry.The probability of primary clinical outcome is calculated from DASISON (dasatinib) and ENESTnd (nilotinib) trials. Direct healthcare costs were derived from the national healthcare payer system, whereas ADR data were derived from local incident reporting system.
Results: In the first-line treatments of CML patients, with greater MMR (39% nilotinib vs 12% dasatinib) and CCyR (24% nilotinib vs 16% dastinib) response outcomes, and more adverse drug reactions (ADR) than dasatinib (13.3% vs 4%), nilotinib use is more cost effective with annual costs (QAR 232,102) and after 12 months follow up. Despite the lower acquisition annual cost of dasatinib (QAR 217,125), the incremental cost effectiveness ratio (ICER) of nilotinib versus dasatinib per MMR/CCyR achieved was 56,506 QAR per year. There were no cases in both arms that progressed to accelerated or blast phase. At a threshold of 3 times GDP per capita of Qatar and according to WHO recommendation, the nilotinib use is still cost-effective.
Limitations: For the surrogate outcome, we only consider the percentage of patients with or without MMR / CCyR response at 12 months. Nevertheless, we do not consider the depth and the duration of the MMR or CCyR.
Conclusions: Upfront therapy of CML-CP patients by nilotinib plan appears to be more cost-effective than dasatinib. Although local real-life data for the effectiveness of these drugs are still warranted. The results of this study implying that nilotinib would be advantageous as first-line treatment for CML-CP patients from Qatar healthcare system perspective.

Disclosures
No relevant conflicts of interest to declare.
Evaluation of Ogata, Red and Combined Score of Flow Cytometry in the Study of Myelodysplastic Syndrome
Authors: Serrano Juan Carlos Carlos , Velez Graciela , Varon Carlos Roberto 
Published: November 2019

Background
Flow cytometry (CF) is an important diagnostic tool for myelodysplastic syndrome (MDS). Different analysis systems have been developed, the "Ogata score" is a simple two-color protocol based on surface expression SSC, CD45 and CD34, which has been validated in a multicentric study showing sensitivity of 69% and specificity of 92% in low risk MDS. Scoring based on erythroid markers by CF (Red) uses the coefficient of variation of CD36 and CD71 in combination with the fluorescence intensity of CD71 and the percentage of CD117 + in erythroid progenitors.
Goals.
To analyze the usefulness of the "Ogata, Red score and combined system" in the diagnosis of MDS of a patient population in Cucuta, the north of Santander, Colombia.
Methods
Case-control study, conducted at the "Unidad Hematológica Especializada" of Cucuta, a total of 32 patients with MDS and 28 control patients were included estimating the "Ogata and Red score", we followed protocols of Euroflow that includes processes of dyeing, analysis and washing using as a Lysis / fixation solution, but it deferred from Leukemia-Net standards. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and prevalence were established in our cohort, in addition we estimated a combined scoring system that integrated "Ogata and Red score"
Results
In "Ogata score" the sensitivity was 47% (95% CI 0.30-0.64) the specificity 90% (95% IC 0.77-1.03), PPV 88% (95% IC 0, 73-1.03), NPV 51% (95% IC 0.35-0.68), prevalence 62%. Red score showed sensitivity of 38% (95% IC 0.21- 0.54), specificity of 85% (95% IC 0.69-1.01), PPV 80% (95% CI 0.60-1.00), NPV 46% (95% IC 0.30-0.62) and prevalence of 62% Combined score of "Ogata plus Red", obtained sensitivity of 62.50% (95%CI 43.69 -78.90), specificity 90.62% (95%CI, 74.98 -98.02), PPV 86.96 (95% CI 68.72-95.29), NPV 70.73% (95%CI 60.38 -79.30) with a prevalence of 50% (95% CI 37.23 -62.77).
Conclusions
In our study, low sensitivity was found in the "Ogata and Red" score, but "Ogata" score showed lower sensibility than the published studies. Both scores had a high specificity and negative predictive value, in accordance with literature. Lysis method could interfere in this results. The Combined Score in FC helped increase the sensitivity of the test for MDS. It is necessary to implement strategies for the harmonization of FC techniques in different laboratories, in order to become a coadjutant tool that contributes to the diagnosis of MDS along with morphology, cytogenetics and molecular biology.

Disclosures
No relevant conflicts of interest to declare.
A State Level Retrospective Analysis of Newborn Screening for Hemoglobinopathies
Authors: Gbadamosi-Akindele Maryam , Aurit Sarah , Johnson Amissabah , Nester Alex 
Published: November 2019

Introduction: Screening for variant hemoglobin is essential in identifying newborns born with hemoglobinopathies, including sickle cell trait (SCT). Screening allows families the opportunity for patient education as well as genetic counseling. This study aimed to better understand the trends in newborn screening of variant hemoglobin in the state of Nebraska over a period of eight years.
Methods: Using the Department of Health and Human Services state-level screening information,the crude incidence rate of SCT was calculated as the screened positives divided by the total number of screened newborns within the state of Nebraska from 2011 to 2018. Rates were further delineated by variant. A Daniel's test was utilized to determine if the crude incidence rates exhibited characteristics of a trend. Rates were also examined with joinpoint regression to determine annual percent change (APC). Excel v 1808 and Joinpoint Trend Analysis v 4.5 software packages were used for all analyses; p < 0.05 was considered significant.
Results: We identified 3,416 newborns with SCT among a total of 211,697 live births, which is an incidence rate of 161.4 cases per 10,000 screened newborns. There was no evidence of a trend in the overall incidence rate from 2011 to 2018 (p = 0.493). However, the incidence of FA Barts significantly increased over the examined interval (p = 0.015) with a 4.4% APC (95% CI: 0.7% to 8.3%; p =0.026)
Conclusion: The data obtained from this study showed no significant change in the incidence of SCT in the state of Nebraska from 2011 to 2018. However, there was a significant increase in the incidence of Hemoglobin FA Barts. Hemoglobin FA Barts is associated primarily with alpha thalassemia, which is most prevalent in southeast Asia, but is also common in the Mediterranean, Africa, Middle east, Central Asia and India. This finding is of interest and likely related to the changing migration patterns in the state of Nebraska. For the healthcare system to continue to provide appropriate care, future studies should aim to further elucidate this trend and patient demographics of this increasing patient population in the state of Nebraska.

Disclosures
No relevant conflicts of interest to declare.
The Frequency of Cytogenetic and FISH Abnormalities Is Higher in Female Than in Male Multiple Myeloma (MM) Patients
Authors: Cantu Eduardo S , Szymanska Jadwiga , Watson Alan R , Trevizo Sandy L , Rostami Sassan 
Published: November 2019

Sex determination in Homo sapiens is generally dependent on the inheritance of sex chromosome combination of XX (♀) or XY (♂). One could surmise that clinical manifestations may also be sex-dependent and detectable by genetic testing. Therefore, this laboratory examined whether different cytogenetic and FISH results occur that are sex-dependent in multiple myeloma (MM) patients.
De-identified cytogenetic and FISH records of 146 MM patients (03/03/17 to 04/19/19) were retrospectively reviewed. There were 58 females (age range 40 to 88 years) and 88 males (age range of 38 to 90 years) in this survey. Data was collected from these cases and formatted into an Excel spreadsheet in order to use the TTest for statistical analyses.
Cytogenetic studies showed an abnormal-to-normal (A:N) ratio of 20:38 (0.53) in females and an A:N ratio of 10:78 (0.13) in males. This ratio for females was significantly higher than for males (P=0.003244). By FISH studies the A:N ratio was 43:15 (2.87) in females, while in males it was 50:38 (1.32) and again significantly higher in females (P=0.023312). The number of females tested was considerably less than for males (58:88=0.66), however the detection rate of abnormalities was much higher in females by both these testing methods. Specific numerical (+1 & -13) and structural abnormalities (1p & 17p modifications) detected by cytogenetics showed over-representation in females than in males. Also, FISH studies indicated that +1q and +7 were noticeably higher in females. With the exception of +7, these are genetic markers associated with poor clinical outcomes. These results are different than expected for equal distribution of abnormalities between the two genders.
The data collected showed that: 1) there are fewer females tested than males (either a true prevalence or underdiagnosed MM females), 2) the frequency of abnormalities detected by cytogenetics and FISH is higher in females than in males especially for certain markers, and 3) the 1p and -13/13q- (cytogenetics) and +1q abnormalities (FISH) found in females (but not as high in males) is not only different but may be more consequential clinically. These data suggest that there are fewer "XX" MM females (or perhaps underdiagnosed) with a higher risk of a more serious clinical outcome. By contrast, there are a greater number of "XY" MM males with a less frequent severe phenotype. MM is a multifactorial clinical entity that presently eludes a complete understanding. However, the genetic basis for MM includes sex chromosome influences that manifest chromosome abnormalities differently in females than in males.

Disclosures
No relevant conflicts of interest to declare.