bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of Clostridium Difficile Infection in Leukemia and Lymphoma Patients
Authors: Abdelfatah Mohamed , Mohamed Amr , Rabih Nayfe , Kathleen Enriquez , Ala Nijim , Richard Watkins 
Published: October 2019

Abstract
Background: Clostridium difficile is the most important cause of nosocomial infectious diarrhea. The prevelance of C. difficile infection (CDI) has been poorly investigated in patients with hematologic malignancies such as leukemia and lymphoma.
Purpose: To evaluate the clostridium difficile infection (CDI) incidence, severity, recurrence, developing sepsis and 30-days mortality among hospitalized patients with Leukemia and lymphoma.
Methods: IRB approved retrospective case control study. 2020 patients were admitted for >48 hours in our institution between July 2007 and December 2013 with CDI, and had adequate follow up. CDI was defined as more than 3 episodes of loose stools in less than 24 hrs with a positive CD stool toxin assay. Recurrent CDI (RCDI) defined as readmission for recurrent diarrhea with 2nd positive stool test 15 days following complete resolution of previous diarrheal episode and cessation of CDI treatment.
Computerized medical records to investigate demographics, laboratory blood work, Carlson Co-morbidity index, and medication used. Patients were divided into leukemia lymphoma group and control group. Group-1 included all patients with Leukemia lymphoma; AML, CML, ALL CML.
Univariate predictors of CDI and multiple logistic regressions were used to assess whether patients with leukemia lymphoma had higher incidence of severity, recurrence and mortality. Controlling for Age, Serum Albumin, modified Carlson Co-morbidity index (CCI), PPI, antibiotics, and CDI treatment.
Results: 2020 patients had been identified; in group-1 19 out of 95 patients (25%) had RCDI. In the control group, 364 out of 1655 patients (18%) had RCDI (p=0.614). 30-days mortality 7 out of 95 patients died within group-1 versus 157 out of 1924 in control group (p=0.799). Criteria for sepsis was fulfilled in 37 out of 95 in group-1 versus 482 out of 1924 in control group (p=0.003)
Conclusion: We conclude that hospitalized patient with Leukemia and lymphoma had higher incidence of developing sepsis from CDI. There was no difference in the incidence of recurrence and 30-days mortality between patients with Leukemia lymphoma than control group. Physicians should have high suspicious for CDI in Leukemia lymphoma patients. Depend on this study we suggest early diagnosis and starting second line stronger treatment may help in decrease the incidence of CDI related sepsis.

Disclosures
No relevant conflicts of interest to declare.
Parental, in Utero, and Early-Life exposure to Benzene and Risk of Childhood Leukemia: A Meta-Analysis
Authors: Smith Martyn T. , Carlos-Wallace Frolayne M , Zhang Luoping , Rader Gabriella , Steinmaus Craig 
Published: October 2019

Abstract
Benzene is an established cause of adult leukemia but its association with childhood leukemia remains unclear. We performed a systematic review of the epidemiologic literature on benzene and childhood leukemia, and used meta-analysis to explore causal inference, evaluate bias, and identify sources of heterogeneity. The summary relative risk estimate (RR) for childhood leukemia for all studies combined was 1.84 (95% confidence interval [CI]: 1.43, 2.37; n=23). In studies of acute myeloid leukemia (AML), the RR was 2.22 (95%CI: 1.65, 2.99; n=8). For studies of acute lymphocytic leukemia (ALL), the RR was lower (RR=1.62; 95%CI: 1.28, 2.04; n=16). Summary relative risks were higher for studies examining maternal (RR=1.96; 95%CI: 1.39, 2.78; n=13) versus paternal exposure (RR=1.23; 95%CI: 1.07, 1.41; n=14), and in studies assessing benzene exposure based on maternal occupation (RR=1.71; 95%CI: 0.91, 3.24; n=6) compared to paternal occupation (RR=1.18; 95%CI: 0.94, 1.50; n=6) or traffic density (RR=0.97; 95%CI: 0.75, 1.25; n=6). Summary relative risks were also higher for exposure during gestation (RR=1.91; 95%CI: 1.32, 2.75; n=12) compared to other periods, and remained elevated in studies adjusted for smoking or socioeconomic status. Overall, these findings suggest that benzene is associated with increased risk of childhood leukemia.

Disclosures
Smith: University of California: Consultancy.
Complement Activation May Trigger the Onset of Thrombotic Thrombocytopenic Purpura in Patients with Severe ADAMTS13 Deficiency
Authors: Hu Xiao-Hui , Bao Jialing , Ueda Yoshiyasu , Miwa Takashi , Song Wenchao , Zheng X. Long 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP), a potential fatal syndrome, is often associated with severe deficiency of plasma ADAMTS13 activity, either resulting from ADAMTS13 mutations or acquired anti-ADAMTS13 autoantibodies that inhibit plasma ADAMTS13 activity. Patients with severe ADAMTS13 do not always have TTP signs and symptoms, which often occur following infections or inflammatory responses. The mechanism of TTP flare is not fully understood. In the present study, complement activation markers (iC3b, C5b, Bb, and C4b) were determined by enzyme-linked absorbent assays (ELISA) in the initial plasmas (prior to plasma exchange) of 20 patients with acquired TTP with severe ADAMTS13 deficiency (less than 20% of normal) and plasmas from 20 healthy controls. Of 20 TTP patients, 19 exhibited positive inhibitor in the 50:50 mixing study. Plasma levels of iC3b (1,000 ± 1,062 ng/ml), sC5b-9 (1,342±867 ng/ml), and Bb (38.2±47.7 ng/ml), as well as C4b (74.3±49.5 ng/ml) in acquired TTP patients were significantly higher than those in healthy controls (p value less than 0.01) These results indicate that complement activation in both classic and alternative pathways is a common phenomenon in patients with acquired autoimmune TTP. To demonstrate the causative effect of complement activation in TTP, we turned to our Adamts13 null mice. C57BL/6 (Adamts13-/-) mice are resistant to the development of spontaneous and Shigatoxin-induced TTP syndrome. When injected with a murine specific monoclonal antibody against complement factor H (CFH) (800 micro grams/mouse), which inhibits binding of circulating CFH to endothelial cells and C3b, Adamts13-/- mice (C57BL/6) developed more severe thrombocytopenia and anemia than wild type mice did within 6 days without additional challenge. However, renal insufficiency manifested by the increase of plasma BUN concentration was similar in both groups (Fig. 1). These results indicate that complement activation through an alternative pathway, following antibody-mediated inhibition of CFH or other complement regulatory components, may trigger the onset of TTP in light of severe ADAMTS13 deficiency.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Granulocyte-Colony Stimulating Factor (G-CSF) in Secondary Prophylaxis for Advanced-Stage Hodgkin Lymphoma Treated with ABVD Chemotherapy: A Cost-Effectiveness Analysis
Authors: Cheung Matthew C , Prica Anca , Graczyk Joanna , Buckstein Rena , Chan Kelvin KW 
Published: October 2019

Abstract
Background: G-CSF is commonly administered to patients with advanced-stage Hodgkin Lymphoma (HL) with severe neutropenia during therapy, although such an approach does not appear to provide a survival benefit. Although the therapy may reduce episodes of febrile neutropenia, any benefit might be offset by increased costs and the potential for increased bleomycin lung toxicity with G-CSF exposure, suggested in prior studies (Martin et al., JCO 2005). As an alternative to secondary prophylaxis, single institution studies have suggested that ABVD chemotherapy can be administered without G-CSF support, treatment delays, or dose reductions. The relative costs and benefits of such an approach compared to routine use of G-CSF is unknown.
Methods: We constructed a Markov decision-analytic model to compare the strategy of secondary prophylaxis with G-CSF to a strategy of "no G-CSF" in response to therapy-related severe neutropenia for a cohort of 40 year-old patients with clinical stage IIB to IV HL treated with 8 cycles of ABVD. A 2-year time horizon was simulated. Baseline probability estimates and utilities were derived from a systematic review of relevant published studies. Direct medical costs were obtained from publicly available administrative databases or from the literature and applied to the health states. All costs and benefits were discounted by 3%. A Canadian public health payer's perspective was considered and costs were presented in 2013 Canadian dollars. Key variables were subjected to sensitivity analyses.
Results: The quality-adjusted life years (QALYs) attained with the G-CSF and "no G-CSF" strategies were 1.403 and 1.416, respectively, for a net expected benefit of 0.013 QALYs associated with omitting G-CSF. Costs for the strategies with and without G-CSF were $38,971 and $33,982, respectively, with a cost savings of $4,989 when G-CSF is omitted. In the base case analysis, the "no G-CSF" strategy was associated with both cost savings and improved quality-adjusted outcomes compared to secondary prophylaxis; therefore, the "no G-CSF" approach was dominant. This analysis was robust to one-way sensitivity analyses involving all key variables; the "no-GCSF" strategy remained dominant even when the cost of G-CSF was zero (Figure 1). In probabilistic sensitivity analysis (1000 simulations), the "no-G-CSF" strategy remained dominant in all pairwise simulations compared to an approach with G-CSF for secondary prophylaxis (Figure 2).
Conclusions: For patients with severe neutropenia during ABVD chemotherapy for advanced-stage HL, a strategy without G-CSF support, treatment delay or dose reduction is associated with improved quality-adjusted outcomes and cost savings and is the preferred approach.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Profilin2 Is Controlled By the Iron Regulatory Proteins and Modulates Iron Homeostasis
Authors: Luscieti Sara , Pilo Boyl Pietro , Galy Bruno , Gutierrez Lucia , Shvartsman Maya , Morales M. Puertos , Hentze Matthias W. , Witke Walter , Sanchez Mayka 
Published: October 2019

Abstract
Objective: The IRPs/IRE regulatory network plays a central role in the control of cellular iron homeostasis. Using a high throughput approach, we have previously identified novel IRP1 and IRP2 interacting mRNAs. Among the identified mRNAs, we studied more in depth Profilin2 (Pfn2), a protein involved in endocytosis and neurotransmitters release. The aim of this work is to characterize Pfn2 as a novel IRPs target mRNA and study its role in iron homeostasis.
Materials and Methods: Mouse and human Pfn2 mRNAs were tested by non-radioactive competitive electrophoretic mobility shift assays (EMSA) for the binding to IRP1 and IRP2. To test the responsiveness of Pfn2 to IRP activity, Pfn2 mRNA levels were analyzed in mice with intestinal IRP1 and IRP2 deficiency. The labile iron pool (LIP) was measured in HeLa and Hepa1-6 cell lines with transient or stable overexpression of Pfn2. Tissues derived from Pfn2 knock-out mice were analyzed for iron content, measured by atomic absorption or colorimetric assay, and for mRNA and protein levels of iron-related genes.
Results: Combination of EMSA experiments and bioinformatic analyses allowed the identification of a novel and conserved 3’UTR iron responsive element in Pfn2 mRNA with an atypical hexanucleotide apical loop (AAGUGG). Pfn2 mRNA levels were significantly reduced (~20-25%) in duodenal samples from mice with IRP1 and IRP2 intestinal specific ablation, suggesting that IRPs exert a positive effect on Pfn2 mRNA expression in vivo. Overexpression of Pfn2 cDNA in HeLa and Hepa1-6 cells reduces LIP levels compared to control cells. Finally, analysis of Pfn2 KO mice showed iron accumulation in discrete areas of the brain (olfactory bulb, hippocampus and midbrain) together with an hepatic iron deficiency with ferritin reduction.
Conclusion: Our results indicate that Pfn2 is controlled by the IRP regulatory system in vivo and that Pfn2 modulates iron homeostasis in cell lines and mice.
Funding: Work supported by grant SAF2012-40106 from Spanish Secretary of Research, Development and Innovation (MINECO) and grant CIVP16A1857 “Ayudas a proyectos de Investigación en Ciéncias de la Vida - Fundación Ramón Areces” to M.S. M.S. held a research contract under the Ramón y Cajal program from the Spanish Ministry of Science and Innovation (RYC-2008-02352).

Disclosures
No relevant conflicts of interest to declare.
Targeting Meningeoma-1 Driven AML through Epigenetic Modulation of the Cell of Origin
Authors: Riedel Simone , Bernt Kathrin M , Haladyna Jessica , Bezzant Matthew , Stevens Brett , Pollyea Daniel A. , Sinha Amit U. , Armstrong Scott A. , Wei Qi , Jordan Craig T. , Neff Tobias 
Published: October 2019

Abstract
Meningeoma-1 (MN1) overexpression in AML is common and predicts a poor prognosis. Forced expression of MN1 in early murine hematopoietic progenitors (CMP and LSK) but not hematopoietic stem cells (HSC) or committed progenitors (GMP) induces an aggressive myeloid leukemia as a single hit. This leukemia is strictly dependent on the high-level expression of a defined gene expression program in the cell of origin, which includes the key component HoxA9. This “susceptibility program” has been proposed as a therapeutic target in MN1high AML, but means to modulate this program have so far remained elusive.
We previously showed that the pharmacologically targetable histone methyltransferase Dot1l is critically required for HoxA9 expression in MLL-rearranged leukemias. We now report dependence on Dot1l of the MN1 “susceptibility-program” in murine MN1-driven leukemia using a genetic loss of function model. Key genes including HoxA9 depend on Dot1l in normal LSK-cells, and in MN1 transduced leukemogenic early progenitors. Inactivation of Dot1l prevents leukemia establishment and abrogates leukemia maintenance in vivo. Phenotypically, deletion of Dot1l in MN1-driven leukemias induces differentiation, cell cycle arrest and apoptosis. RNA-Seq data document that deletion of Dot1l antagonizes the cell of origin-derived susceptibility program in MN1 leukemias, including HoxA9 expression. We also confirm previous reports that MN1-transduced HSC can expand ex vivo but fail to cause leukemia in vivo. This has been linked to a lower expression level of HoxA9 in normal and MN1-transformed HSCs compared to early progenitors. We confirm that HoxA9 expression levels in MN1-transduced HSCs are lower than in MN1 transduced progenitors. Importantly, in contrast to MN1-transduced progenitors, this lower, “HSC-level” expression of HoxA9 is independent of Dot1l. This suggests a developmental switch at the HSC-to-progenitor transition that involves increased expression of HoxA9 and a change from Dot1l-independent to Dot1l-dependent regulation. The high HoxA9 expression necessary to cooperate with MN1 to cause AML is strictly Dot1l-dependent.
HOXA9 is co-expressed with MN1 in a subset of clinical MN1high AML. Exposure of MN1highHOXA9high AML primary patient samples to a pharmacologic inhibitor of DOT1L (EPZ4777) demonstrated sensitivity to DOT1L inhibition as expected from the murine model. Taken together, these data point to DOT1L as a potential therapeutic target in MN1high AML. The targeted epigenetic modulation of the interplay between an oncogenic lesion and its cooperating normal developmental program could represent a new paradigm for the treatment of AML.

Disclosures
Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees. Armstrong:Epizyme : Consultancy.
The Mir-17-92 Cluster Contributes to MLL Leukemia through the Repression of PKNOX1, a MEIS1 Competitor
Authors: Mian Yousaf A , Zeleznik-Le Nancy J. 
Published: October 2019

Abstract
Leukemias which arise as a result of translocations between the MLL gene and one of more than 80 different partner genes have a relatively poor prognosis. As a result of chromosome translocation, the carboxy-terminal portion of MLL containing the H3K4 methyltransferase domain is replaced by partner protein domains. In most cases this causes constitutive recruitment of transcriptional elongation machinery to MLL target genes. Downstream targets of MLL are aberrantly upregulated and include developmentally important HOX genes and MEIS1, as well as multiple microRNAs. Here we examine the contribution of specific miRNAs in the miR-17-92 cluster to MLL leukemia through the use of custom antagomiR oligonucleotides. Combinatorial treatment with antagomiRs against miR-17 and miR-19a dramatically reduce colony forming ability of MLL-fusion containing cells, but not non-MLL AML controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17 and miR-19a. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX proteins. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of Pknox1 to leukemia in a murine MLL-AF9 model. Collectively, these data implicate the miR-17-92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia. This approach represents a paradigm where targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen.

Disclosures
No relevant conflicts of interest to declare.
PAX5-PML Induces Pro B Acute Lymphoblastic Leukemia in Mice
Authors: Imoto Naoto , Kurahashi Shingo , Hayakawa Fumihiko , Yasuda Takahiko , Sugimoto Keiki , Kojima Yuki , Morishita Takanobu , Inagaki Yuichiro , Tsuzuki Shinobu , Naoe Tomoki , Kiyoi Hitoshi 
Published: October 2019

Abstract
PAX5 is a transcription factor required for B-cell development and maintenance. We previously showed that PAX5-PML, a fusion gene found in acute lymphoblastic leukemia (ALL), dominant negatively inhibited PAX5 transcriptional activity. Reported data including ours revealed that PAX5 fusion proteins had possible oncogenic ability; however, leukemogenicity of PAX5 fusion genes and other PAX5 mutations in mice model has not been clarified, yet. Here we demonstrated leukemia development in mice by introducing PAX5-PML. Pro B cells derived from mouse fetal liver were transfected with PAX5-PML expression vector and transplanted into mice. All 8 transplanted mice died with pro B ALL from day 63 to 158. Leukemic cells could be serially transplanted and mice died more rapidly with repetition (Figure A). Among the target genes transcriptionally activated by PAX5, expressions of BLNK, Fcer2a, and CD72 were significantly repressed in leukemia cells but repression of CD19 and CD79a were mild, suggesting the importance of down regulation of these genes for differentiation block. We compared mRNA expression profile between leukemia cells and normal pro B cells and gene set enrichement analysis (GSEA) identified candidates for second hits for development of leukemia. We analyzed the mechanism of the selective repression of CD19, Fcer2a, and BLNK and the significance of the second hit candidates, using a cell line established from leukemia cells of the third transplanted mouse. The results will show the meeting.
Figure 1 Figure 1.

Disclosures
Sugimoto: Otsuka Pharmaceutical Co., Ltd: Employment. Naoe:Zenyaku Kogyo: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Kyowa Hakko Kirin Co. LTD: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Novartis Pharma,: Research Funding; Bristol-Myers Squibb: Research Funding; Otsuka Pharmaceutical Co. LTD: Research Funding; FUJIFILM Corporation: Research Funding. Kiyoi:Zenyaku Kogyo: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Kyowa Hakko Kirin Co. LTD.: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Bristol-Myers Squibb: Research Funding; FUJIFILM Corporation: Research Funding.
Loss of Wild-Type Kras is Associated with Enhanced Fitness and Increased Mitogen-Activated Protein Kinase Pathway Addiction in K-RasG12D Acute Myeloid Leukemia
Authors: Burgess Michael R. , Hwang Eugene , Wandler Anica M. , Asthana Saurabh , Davis Elizabeth M. , Le Beau Michelle M. , Taylor Barry , Shannon Kevin 
Published: October 2019

Abstract
Functional analysis of therapeutic outlier responses in cancer therapy can identify unexpected synthetic lethal interactions and uncover biomarkers that predict enhanced sensitivity to targeted agents. We performed preclinical trials of the MEK inhibitor PD0325901 (PD901) in primary murine acute myeloid leukemias (AMLs) generated using retroviral insertional mutagenesis in KrasG12D “knock-in” mice. Similar to previous observations Nf1 and Nras mutant leukemias, treatment with PD901 prolonged survival in six independent leukemias harboring diverse retroviral integrations. Intriguingly, one outlier leukemia, clone Kras.101, demonstrated a greater than 4-fold improvement in median overall survival when treated with the MEK inhibitor. Importantly, this AML demonstrated a novel retroviral integration at relapse, indicating clonal evolution during treatment. The relapsed clone displayed phenotypic resistance upon transplantation into secondary recipients and retreatment with PD901. We performed a detailed analysis of the paired PD901-sensitive/resistant Kras.101 clones to identify the mediators of mitogen-activated protein kinase pathway (MAPK) addiction. Functional studies demonstrated that the novel dominant retroviral integration in the PD901 resistant clone did not directly alter drug response. However, genome-wide analysis of copy number alterations revealed a gain of chromosome 6 involving the Kras locus in the resistant clone, which was confirmed by spectral karyotyping and fluorescence in situ hybridization. Surprisingly, the PD901-sensitive leukemia harbored two copies of oncogenic KrasG12D due to somatic uniparental disomy, while the resistant clone harbored two mutant and one wild-type Kras alleles. This observation and paired single nucleotide polymorphism analysis indicated that the PD901-resistant leukemia was evolutionarily ancestral to the drug sensitive clone. Consistent with this hypothesis, competitive repopulation experiments with fluorescently labeled leukemia cells demonstrated increased fitness of the drug sensitive leukemia in the absence of the MEK inhibitor and over-expression of wild type K-Ras in the drug-sensitive leukemia reduced fitness in vivo. Finally, utilizing a tetracycline-inducible system, we found that wild-type Kras expression enhances the fitness of the Kras.101 clone only in the presence of the MEK inhibitor. Together, these data suggest that loss of wild-type Kras imparts a fitness advantage at the expense of increased MAPK pathway addiction, which results in enhanced sensitivity to MEK inhibition in leukemias driven by oncogenic K-Ras.

Disclosures
No relevant conflicts of interest to declare.