bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Performance of the Original and Simplified Wells Scores in Combination with Age-Adjusted D-Dimer Testing in the Diagnostic Management of Pulmonary Embolism
Authors: Kraaijpoel Noémie , van Es Nick , Büller Harry R , Klok Frederikus A , Huisman Menno V , den Exter Paul L , Galipienzo Javier , Middeldorp Saskia , Bossuyt Patrick M 
Published: October 2019

Abstract
Background: Among patients with suspected pulmonary embolism (PE), imaging can be safely withheld in those with a 'PE unlikely' Wells score and a negative D-dimer. A simplification of the Wells score has been proposed to improve clinical applicability (Table 1), but its performance is less clear, in particular in combination with age-adjusted D-dimer testing.
Objectives: To compare the performance of the original and simplified Wells scores alone and in combination with age-adjusted D-dimer testing.
Methods: Individual patient data from 7,268 patients with clinically suspected PE enrolled in 6 prospective diagnostic management studies were used. The discriminatory performance, calibration, and diagnostic accuracy of the original and simplified Wells scores were evaluated. The efficiency and failure rate of both dichotomized scores combined with age-adjusted D-dimer testing were compared using a one-stage random effects meta-analysis. Efficiency was defined as the proportion of patients in whom PE could be considered excluded based on a 'PE unlikely' Wells score and a D-dimer below the age-adjusted treshold, defined as ≤500 µg/L in patients of 50 years or younger and the patient's age times 10 µg/L in those older than 50 years. The failure rate was defined as the proportion of patients subsequently diagnosed with symptomatic venous thromboembolism during 3-month follow-up.
Results: The discriminatory performance of the original and simplified Wells scores was comparable (c-statistic 0.73 [95% CI 0.72-0.75] vs. 0.72 [95% CI 0.70-0.73]). When combined with age-adjusted D-dimer testing, the original and simplified Wells rules had comparable efficiency (33% [95% CI 25-42%] vs 30% [95% CI 21-40%]) and failure rates (0.9% [95% CI 0.6-1.5%] vs. 0.8% [95% CI 0.5-1.3%]).
Conclusion: Among patients with suspected PE, the original and simplified Wells rules in combination with age-adjusted D-dimer testing have similar performance in ruling out the disease. Given its ease of use in clinical practice, the simplified Wells rule may be preferred.

Disclosures
Huisman: Boehringer Ingelheim Pharma GmbH & Co.KG: Other: Grant support; GlaxoSmithKline: Other: Grant support; Bayer HealthCare: Other: Grant support; Pfizer: Other: Grant support; Actelion: Other: Grant support.
Dual Activation of NRF2 in Multiple Myeloma and Bone Marrow Mesenchymal Stromal Cells Regulates Chemotherapy Resistance
Authors: Sun Yu , Zaitseva Lyubov , Shafat Manar S , Bowles Kristian M , Rushworth Stuart A 
Published: October 2019

Abstract
Background
The cornerstone treatments of multiple myeloma (MM) are proteasome inhibitors bortezomib (BZ) and carfilzomib (CFZ). However, MM still remains incurable for that MM cells rapidly develop resistance to chemotherapy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathways have been shown to contribute to the malignant phenotypes of several cancers through effects on proliferation and drug sensitivity. NRF2 functions to rapidly change the sensitivity of the cells environment to oxidants and electrophiles by stimulating the transcriptional activation of drug metabolism and antioxidant genes. NRF2 is negatively regulated by proteasome degradation through its inhibitor KEAP1. The aim of this study was to determine if proteasome inhibitor induced NRF2 signalling orchestrates survival of MM in the bone marrow (BM) microenvironment.
Methods
To investigate the role of NRF2 in the MM microenvironment primary human MM and BM mesenchymal stromal cells (MSC) were obtained under UK ethical approval (LREC ref 07/H0310/146). NRF2 activity in MM and BM-MSC was measured by NRF2 protein expression, target genes expression and using promoter assays. Lentiviral mediated shRNA knockdown of NRF2 in the MM and BM-MSC. The NRF2 inhibitor, brusatol was used to verify the knockdown experiments.
Results
Results show that primary MM and MM cell lines have increased NRF2 activity in response to the proteasome inhibitors BZ and CFZ as measured by increased nuclear NRF2, increased NRF2 regulated genes and increased ARE activity in the promoter of heme oxygenase-1. Expression of basal NRF2 was high in the majority of primary MM cells and cell lines tested. Pharmacological inhibition and shRNA mediated knock-down of NRF2 showed a significant reduction in survival of MM cells, when treated alone and in combination with BZ or CFZ. Investigations also revealed that BM-MSC had increased NRF2 activity in response to BZ and CFZ. Moreover, knockdown of NRF2 in BM-MSC or pharmacological inhibition of NRF2 in BM-MSC/MM co-cultures reverses the protection conferred to MM by BM-MSC in response to BZ and CFZ.
Conclusion:
Here we show the first description of NRF2 driven cytoprotective responses in MM. We show that NRF2 in MM is activated by both BZ and CFZ which subsequently activates pro-survival mechanisms in response to proteasome inhibition. Furthermore, NRF2 is also activated in the BM microenvironment by BZ and CFZ, which also confers protection to MM. This highlights the importance of NRF2 in regulating MM drug resistance within the BM microenvironment through independent actions in both the tumour and the non-malignant BM-MSC which support it.

Disclosures
Rushworth: Infinity Pharmaceuticals: Research Funding.
Vitamin D Blocks CLL Cell-Mediated MDSC Induction
Authors: Mougiakakos Dimitrios , Bruns Heiko , Böttcher Martin , Qorraj Mirjeta , Fabri Mario , Dindorf Jochen , Busch Leonhard , Jitschin Regina , Mackensen Andreas 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence amongst adults. CLL-associated immune defects promote tumor immune escape and antagonize immune-based therapies. We and others have reported the accumulation of so-called myeloid-derived suppressor cells (MDSCs) in CLL. Accumulation of immunosuppressive CD14+HLA-DRlow monocytic MDSCs is associated with advanced disease and poor prognosis. The mechanisms re-polarizing CLL-monocytes remain unknown. Here, we describe that CLL-cell-derived exosomes elicit a phenotypical and functional skewing of regular monocytes towards MDSCs. However, pre-treating CLL-cells with vitamin D led to a loss of the exosomes' MDSC-promoting capability. In fact, higher vitamin 25D serum concentrations were linked to lower levels of circulating MDSCs in CLL. A plethora of bioactive molecules including microRNAs (miRs) is shuttled in exosomes. MiR-155 is found abundantly in CLL-exosomes and using antagomir against miR-155 prevented exosomal MDSC-induction. Furthermore, exosomes from patients with lower vitamin D levels contained more miR-155 copies. Accordingly, vitamin D application reduced miR-155 production in CLL-cells Overall, we identified that exosomal miR-155 transfer promotes MDSCs in CLL. Vitamin D interferes with this interplay and could thereby represent a mean for enhancing immune responses in CLL.

Disclosures
No relevant conflicts of interest to declare.
Transcriptional Repression of the LMO2 Oncogene By Ikaros in T-Cell Acute Lymphoblastic Leukemia
Authors: Ding Yali , Song Chunhua , Gowda Chandrika S. , Kapadia Malika , Payne Kimberly , Dovat Sinisa 
Published: October 2019

Abstract
LIM domain only protein 2 (LMO2) is a regulator of hematopoiesis and an oncogene that is overexpressed in a subset of T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of LMO2 in T-ALL is associated with a poor prognosis. The mechanisms that regulate LMO2 expression in T-ALL are still unknown. Here, we present evidence that expression of LMO2 in T-ALL is regulated at the transcriptional level by Ikaros, a tumor suppressor protein whose deletion is associated with the development T-ALL. Global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) studies in primary human acute lymphoblastic leukemia cells and in cell lines demonstrated Ikaros occupancy of the LMO2 promoter. Ikaros binding at the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary T-ALL and B-ALL cells. The role of Ikaros in the regulation of LMO2 transcription in T-ALL was tested using gain-of-function and loss-of-function experiments. Ikaros knock-down with siRNA resulted in increased transcription of LMO2 in T-ALL. Overexpression of Ikaros in human T-ALL was associated with strongly reduced transcription of LMO2. In mice, T-ALL cells that are derived from Ikaros-knockout mice express high levels of LMO2. Transduction of these cells with Ikaros-containing retrovirus, results in a sharp reduction of LMO2 expression. Since Ikaros function in T-ALL is negatively regulated by the pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition can enhance Ikaros-mediated transcriptional repression of LMO2. Molecular inhibition of CK2 using shRNA, as well as pharmacological inhibition with a specific CK2 inhibitor, resulted in reduced expression of LMO2 in primary human T-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the LMO2 promoter. Ikaros knock-down restored high expression of LMO2 in T-ALL cells that were treated with CK2 inhibitors. These data show that Ikaros is a major regulator of LMO2 transcription in T-ALL and that CK2 inhibition requires Ikaros activity to repress LMO2 transcription. Increased Ikaros binding was associated with reduced histone H3K9ac and H3K4me3 marks at the LMO2 promoter suggesting that Ikaros regulates LMO2 transcription via chromatin remodeling. In conclusion, these results provide evidence that expression of the LMO2 oncogene is regulated by Ikaros and CK2 in T-ALL. Targeting CK2 with specific inhibitors has been used as a therapeutic strategy in a preclinical model of T-ALL. The presented data reveal a novel mechanism of therapeutic action for CK2 inhibitors - repression of LMO2 expression via Ikaros. These results provide a rationale for the use of CK2 inhibitors in T-ALL with LMO2 overexpression.

Disclosures
No relevant conflicts of interest to declare.
FOXM1, CDK6 and Rb Dependent Drug Resistance and Senescence in Myeloma
Authors: Gu Chunyan , Chen Ruini , Jing Xuefang , Janz Siegfried , Yang Ye 
Published: October 2019

Abstract
We recently reported that FOXM1 is a promising therapeutic target in multiple myeloma (MM), particularly for the subset of patients with high-risk disease.Because high-risk myeloma exhibits a strong predilection to early drug-resistant relapse following first-line therapy, we here decided to evaluate the role of FOXM1 in the acquisition of drug resistance by myeloma cells.
We analyzed gene expression profiles of 88 paired myeloma samples at baseline and relapse from the UAMS Total Therapy 2 cohort and found that FOXM1 mRNA levels were significant upregulated in relapsed myeloma and that this was associated with poor event-free and overall survival. Laboratory studies showed that enforced expression of FOXM1 in human myeloma cell lines (HMCLs) results in decreased sensitivity of cells to widely used myeloma drugs, such as bortezomib and doxorubicin. This was observed in vitro, in both bulk cell and soft-agar culture, and in vivo using xenografting in mice. Biochemical analysis of HMCLs revealed physical interaction of FOXM1 with CDK6 and Rb, key regulators of cell cycle progression and cellular senescence, respectively.Treatment with small-compound CDK6 inhibitor, inhibited myeloma growth, decreased clonogenicity of myeloma, and ameliorated FOXM1-dependent senescence. Genetic and pharmacological targeting of FOXM1 in myeloma cells using shRNA and thiostreptone respectively, led to growth arrest and senescence, while elevated expression of FOXM1 reversed these phenotypes.
In sum, our findings implicating the FOXM1-CDK6-Rb network in drug resistance and senescence of high-risk myeloma point to new treatment opportunities for this difficult-to-cure neoplasm.

Disclosures
No relevant conflicts of interest to declare.
Bone Marrow Derived Mesenchymal Stromal Cells Reduce the Incidence of Chronic Graft-Versus-Host Disease after Allogenetic Hematopoietic Stem Cell Transplantation
Authors: Zhao Ke , Fan Zhiping , Huang Fen , Wang Shunqing , Xiang Peng , Zhang Qi , Liu Qifa 
Published: October 2019

Abstract
Background Chronic graft-versus-host disease (cGVHD) is the common long-term complication and the leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a significant impact on patient quality of life. Currently, mesenchymal stromal cells (MSCs) have been considered as a promising therapy for treating refractory acute/chronic GVHD and engraftment failure (EF) or poor graft function (PGF), but the efficacy of MSCs in the prophylaxis of cGVHD is rarely reported. Methods Eighty-two patients who received MSCs treatment after allo-HSCT were enrolled in our study, including 45 patients with refractory aGVHD, 33 patients with EF or PGF and 4 patients with virus infection. In order to evaluate the influence of bone marrow (BM) derived MSCs for the incidence and severity of cGVHD, 308 consecutive patients who underwent allo-HSCT in the same period but without MSCs treatment were considered as the control group. And no statistical significance was found between the two groups for the demographic and transplant characteristics. MSCs were given at a median dose of 1×106 cells/kg once weekly. Results All eighty-two patients in MSC group received a median of 5 (range:3-12) doses of MSCs per patient. In MSC group, seventeen patients (20.7%) had cGVHD, including 14 patients with limited cGVHD and 3 patients with extensive cGVHD. In the control group, 140 patients (45.5%) had cGVHD, including 95 patients with limited and 45 extensive cGVHD. The 2-year cumulative incidence of cGVHD was 26.7% (95%CI: 16.1%-37.5%) in MSC group and 50.4% (95%CI: 37%-63.8%) in the control group (P=0.037). Furthermore, the extensive cGVHD (3/82) in the MSC group were also significantly lower than those (45/308) in the control group (P=0.021). In addition, at a median follow-up time of 189 (range: 112-1035) days post-transplantation, 4 patients relapsed in MSC group and 13 patients relapsed in the control group. The incidence of tumor relapse was not different between the two groups (P=0.629). No short-term toxic side effects were observed and other secondary tumor occurred after MSCs treatment. Conclusion MSCs derived from BM reduce the incidence and severity of cGVHD after allo-HSCT, but not increase the risk of tumour relapse.

Disclosures
No relevant conflicts of interest to declare.
Feasibility of Allogeneic Hematopoietic Stem Cell Transplant for High Risk FLT3-ITD Mutant Patients with Acute Myeloid Leukemia in CR1- a Real Word Analysis
Authors: Kansagra Ankit J. , Alkhateeb Hassan B , Hefazi Mehrdad , Yalniz Fevzi , Hogan William J , Litzow Mark R , Patnaik Mrinal M 
Published: October 2019

Background:
Hematopoietic stem cell transplantation (HCT) remains the most effective postremission therapy for high-risk acute myeloid leukemia (AML). FMS-like tyrosine kinase3 (FLT3) mutations occur in about 30% of patients with cytogenetically normal AML. FLT3-ITD (internal tandem duplications) mutations are associated with short-lived remissions and poor outcomes. These adverse effects can be offset by allogeneic HCT in first complete remission (CR1). We carried out this study to get a real world perspective on feasibility of allogeneic HCT in CR1 for FLT3-ITD mutant AML patients.
Methods: The Mayo Clinic AML database was queried for all patients that had tested positive for the FLT3 ITD, from January 2003 to December 2014. 75 patients were identified, of which 28 (37%) underwent allogeneic HCT in CR1. 12 were excluded as they were transplant ineligible from an age standpoint, 6 patients actually had MDS and 2 were excluded for primary induction failure. Clinical and outcomes data were abstracted retrospectively.
Results:
29 patients were included in the final analysis, with a median age of 57 years (range 21-68), 38% males. Median time from diagnosis to last follow up was 339 days. 24(83%) had normal cytogenetics. 26(90%) received treatment with anthracycline + cytarabine based therapy, 3(10%) were enrolled on a clinical trial. 25(87%) patients went on to receive consolidation therapy. 22 (75%) of the patients relapsed after achieving a CR1, with a median time to relapse of 134 days (range 27-1710 days). Only 8 (26%) of the 22 patients were able to achieve a CR2 with salvage chemotherapy, of which 6 (75 %) successfully underwent allogeneic HCT.2 (25%) out of 8 patients received FLT3 inhibitor in 1st relapse. We then assessed the reasons why relapsed patients did not undergo HCT in CR1. The most common being; relapse during evaluation/work up for HCT in 8(27%) patients, 5 (17%) had comorbidities that precluded HCT, 3 (10%) were never referred for HCT due to personal preferences. At last follow up 19(65%) patients were dead.
Conclusion:
While allogeneic HCT is an effective consolidative strategy for FLT3 ITD mutant AML patients, in the real world, a large number are not transplanted in CR1 due to delays in donor search and transplant scheduling strategies resulting in disease relapse. Effective strategies to avoid delays in scheduling, rapid donor searches and the use of alternative donor sources are much needed for these patients.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Schistocytosis in B12 Deficiency (B12D) Reduces the MCV and Raises the RDW in the Absence of Iron Deficiency: a Cause of Unnecessary Plasmapheresis (PP)
Authors: Savjani Maushmi , Draksharam Padma , Braverman Albert S 
Published: October 2019

Abstract
Background:
RBC size variation and microcytes in B12D are often ascribed, but rarely shown, to be due to co-existing Fe deficiency. Schistocytes (aka poikilocytes) were included in early descriptions of pernicious anemia (PA). As it also causes thrombocytopenia, B12D may be confused with thrombotic thrombocytopenic purpura (TTP). Because of the urgency of PP for TTP, it has sometimes been initial therapy for B12D with schistocytes.
Purpose:
Here we describe 3 PA patients, and review reports of 15 other severely anemic B12D cases, with schistocytes. As they are smaller than mature RBC, they may normalize the MCV, while raising the RDW. We wished to determine whether primary lab studies help to distinguish B12D from TTP.
Case Reports:
These patients presented with symptoms of severe anemia:
Ferritins were normal or high, haptoglobins <30, anti-intrinsic factor and parietal cell antibodies present, and complete response to B12 therapy occurred. Significant numbers of schistocytes were present in all, as was a distinctive population of minute, hypochromic schistocytes (MHS).
Review:
We found 15 reports of individual B12D patients with schistocytes, published between 2003 and 2015. All but 2 vegans had PA, 6 being anti-IF Ab+. Median & median ages were 52 & 53, [Hb]'s 5.9 & 6.0, MCV's 120 & 117 (3 normal), platelets 97 & 85, WBC 3200 & 3120, LDH's 4050 & 5860; reticulocyte levels were all low for severe anemia. Iron deficiency anemia was not found; ferritin and/or Fe/TIBC were reported normal in 4. Six legible blood smear microphotographs were included, confirming schistocytosis. Five patients had one or more PP before B12 deficiency was discovered. All 15 responded completely to B12. MHS were also observed on 4 of the 6 legible microphotographs, and noted by authors. For comparison, our survey of 36 reported TTP legible blood smears failed to detect MHC.
Conclusions:
Schistocytes are observed in some severely anemic B12D, may account for as much as 6.7% of RBC, and alter their indices. Schistocytosis and thrombocytopenia suggest TTP, and may lead to unnecessary PP. But such patients' low reticulocyte counts and very high LDH levels are not typical of TTP.
Table Table. Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Correlation of Serum Ferritin Levels with Liver and Heart Mri T2 and Liver Iron Concentration in Beta Thalassemia Intermediate Patients: A Contemporary Issue
Authors: Karimi Mehran , Amirmoezi Fatemeh , Haghpanah Sezaneh , Ostad Seyed pouria , Lotfi Mehrzad , Sefidbakht Sepideh , Rezaian Shahed 
Published: October 2019

Abstract

Background: B-Thalassemia intermediate (B-TI) is a genetic disease that is milder than beta thalassemia major. The accumulation of iron in different organs causes tissue damage. The T2* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI for early detection of cardiac and hepatic iron overload in patients with beta thalassemia intermediate.
Methods: This cross-sectional study was conducted on 108 patients with B-TI who referred to tertiary Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Serum ferritin, hepatic and cardiac T2 MRI were assessed. The ROC curve was used to determine the sensitivity and specificity of cut-off value.
Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r= -0.290, P value=0.003) and positive correlation with LIC (r= 0.426, P value ˂ 0.001) in the patients with BTI. However, T2 cardiac MRI was not significantly correlated with serum ferritin levels (P value= 0.073).According to the analysis of ROC curves, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/ml. calculated sensitivities and specificities were 0.78 and 0.82 for T2 liver MRI and 0.76 and 0.86 for liver iron concentration (LIC) respectively.
Conclusion: Serum ferritin levels of 412 ng/ml might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin (around 500 ng/ml) could be considered for starting iron chelation therapy in patients with B-TI in areas where T2 MRI is not available.

Disclosures
No relevant conflicts of interest to declare.