bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ''Gatekeeper'' Mutation T315I in BCR/ABL Confers Additional Oncogenic Activities to Philadelphia Chromosome Positive Leukemia
Authors: Zafar Usva , Yusuf Mohammed , Chakraborty Rikhia , Lalani El-Nasir M A , Mian Afsar Ali 
Published: November 2019

Chronic myeloid leukemia (CML) and 30% of adult acute lymphatic leukemia (ALL) are characterized by the Philadelphia chromosome (Ph+), having a (9;22) chromosomal translocation. The BCR/ABL fusion protein is the hallmark of Ph+ leukemia. BCR/ABL is characterized by deregulated and constitutively activated ABL tyrosine kinase activity that determines its transformation potential. Tyrosine kinase inhibitors (TKI) have greatly improved the overall prognosis of these diseases, particularly by altering the natural history of chronic phase (CP) CML and preventing the previously inexorable progression to terminal blast crisis (BC). However, unsatisfactory responses in advanced disease stages, resistance and long-term tolerability of BCR/ABL inhibitors represent major clinical problems. The most important mechanism of resistance against TKIs is the selection of leukemic clones driven by BCR/ABL harboring point mutations, such as the E255K, Y253F/H (P-loop), H396R (activation loop) or the T315I (gatekeeper). The "gatekeeper" mutation T315I confers resistance against all approved TKIs, with the only exception of Ponatinib, a multi-target kinase inhibitor. CML and Ph+ ALL, rarely present at diagnosis with a BCR/ABL harboring a resistance mutation to TKI. Resistant clones may be present and only detectable by highly sensitive methods. We have previously shown that the resistance mutations may influence the biology of BCR/ABL and its transformation potential.
We therefore hypothesized that the presence of mutations such as the T315I select for a "dormant cell population" which manifests following initial treatments with TKI inhibitors and treatment failure. The aim of this study was to determine whether the ''gatekeeper'' mutation T315I is able to confer biological features to BCR/ABL influencing its leukemogenic potential.
We investigated the influence of T315I on the biology of BCR/ABL in CML and Ph+ ALL. We used Ph+ ALL patient derived long term culture (PDLTCs), factor dependent Ba/F3 cells and syngeneic mouse model of BCR/ABL induced CML-like disease. These models allowed the direct comparison of BCR/ABL with BCR/ABL-T315I. We observed significantly slower proliferation of Ba/F3 cells and PDLTCs expressing BCR/ABL-T315I compared to the native BCR/ABL. This was further confirmed by undertaking mitotic index calculations and colony formation assays on both cell types. Furthermore, the induction of a CML-like disease in syngeneic mice was significantly delayed in the presence of T315I (median: BCR/ABL - 27 days; BCR/ABL-T315I - 61 days). We undertook functional studies to determine the putative signaling pathway and found that Ras/Erk1/2 pathway was activated inT315I positive cells.
This study may assist towards therapy decisions in patients with CML/Ph+ ALL with a T315I mutation.

Disclosures
No relevant conflicts of interest to declare.
Cost-Effectiveness of Avatrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease
Authors: Allen Lee F. , Aggarwal Kavita , Vredenburg Michael , Barnett Christine , Mladsi Deirdre , Kim Ray 
Published: November 2019

Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platelet counts &lt;50,000/mL) that can complicate the invasive diagnostic and therapeutic procedures these patients require as part of their clinical management, due to the increased bleeding risk. Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) that is approved for the treatment of thrombocytopenia in patients with CLD as an alternative to platelet transfusions for patients undergoing a procedure. The aim of this study was to evaluate the relative cost-effectiveness of avatrombopag compared with platelet transfusion or treatment with lusutrombopag, another TPO-RA also approved for the treatment of thrombocytopenia in adult patients with CLD.
Methods: A decision-tree model was developed from a US payer perspective to capture the clinical events observed in registration trials, and to project potential longer-term complications resulting from a major bleed or thromboembolic event in the scenario analyses. Treatment costs were taken from publicly available data sources; avatrombopag and lusutrombopag estimates were calculated from the US prescribing information and Phase 3 study data. The interventions were evaluated in the overall trial population, patients with platelet counts &lt;50,000/mL, and in subpopulations with higher (&gt;40,000/mL to &lt;50,000/mL) and lower (&lt;40,000/mL) Baseline platelet counts. The primary metric for this economic analysis was the per-person total cost, the cost of prophylactic platelet transfusions required, and the incremental cost per prophylactic platelet transfusion avoided.
Results: In the overall population, avatrombopag reduced the need for platelet transfusions and produced cost-savings per person compared to Intended Platelet Transfusion (80% fewer prophylactic platelet transfusions), resulting in a relative cost savings of $4,250. The cost for lusutrombopag (15% more platelet transfusions) relative to avatrombopag was $5,819 higher than the cost of avatrombopag. Similar results were seen in both the higher and lower platelet count subgroups. The one-way and probabilistic sensitivity analyses showed that the use of avatrombopag remained cost-saving over a wide range of changes in input variables, with the incremental cost-effectiveness ratio falling into quadrant IV (decreased costs while prophylactic platelet transfusions were avoided).
Conclusions: From the cost-effectiveness standpoint, the use of avatrombopag is a practical strategy compared with the cost of both platelet transfusion and lusutrombopag, as it saves costs and reduces the need for prophylactic platelet transfusions.
Table

Disclosures
Allen: Dova Pharmaceuticals: Equity Ownership, Other: Chief Medical Officer . Aggarwal:Dova Pharmaceuticals: Employment. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder.
Preemptive Therapy Based on the Load and Time of EBV-Emia for Preventing EBV Related PTLD after Haploidentical Hematopoietic Stem Cell Transplantation: A Prospective Multicenter Study
Authors: Liu Can , Lin Ren , Wang Yu , Huang Fen , Fan Zhiping , Zhang Shen , Xu Yajing , Yang Ting , Xuan Li , Xu Na , Ye Jieyu , Sun Jing , Huang Xiaojun , Liu Qifa 
Published: November 2019

Backgroud: To evaluate the efficacy of preemptive therapy for preventing EBV related PTLD based on the duration of EBV-emia and the viral loads in the patients undergoing haplo-HSCT, a prospective multicenter study was conducted.
Methods: Rituximab or rituximab followed by adoptive cellular therapy was applied for preemptive therapy if EBV-DNA in blood was positive twice consecutively with a rising trend over one log in virus loads or positive consecutively six times without a dropping trend over one log at least within three weeks or not turning negative consecutively eight times within four weeks.
Results : Of the 408 patients with acute leukemia enrolled in this study, 133 occurred EBV-emia, including 19 PTLD and 6 end-organ diseases. The patients with EBV-emia had inferior three-year overall survival (OS) and higher non-relapse mortality (NRM) to those without EBV-emia (OS: 58.0%±5.0% vs. 71.0%±3.0%, =0.042; NRM: 27.9%±3.9% vs. 18.9%±2.4%, =0.050, respectively). Compared with non-preemptive group, the negative conversion of EBV-emia was significantly higher (100% vs. 76.1%, =0.002) and the three-year incidence of PTLD was markedly lower in preemptive group (1.3% vs. 21.7%, =0.000). The median time from EBV-emia to EBV diseases onset was 15 days and the durative time of EBV-emia was positively correlated with PTLD occurrence (=0.419, =0.024).
Conclusion s: Rituximab preemptive therapy could reduce the incidence of PTLD. Earlier preemptive therapy should be advocated once the EBV-emia is positive persistently regardless of EBV-DNA levels (NCT01883180).

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Primary and Secondary Prophylaxis of Chemotherapy Induced and Febrile Neutropenia (CIN/FN) in Bendamustine Plus Rituximab (BR) Regimens in Patients with Lymphoma and Chronic Lymphocytic Leukemia (CLL): Real-World, Single-Center Experience
Authors: Moore Logan , Bartels Trace , Persky Daniel O. , Kumar Abhijeet , Abraham Ivo , Sanders Lauren , Ortega Alicia , Henglefelt Alyssa , McBride Ali 
Published: November 2019

Introduction:
Granulocyte stimulating growth factors (G-CSF) such as filgrastim or pegfilgrastim are indicated as prophylaxis of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). BR regimen is considered an intermediate FN risk (10-20%) per National Comprehensive Cancer Network guidelines. Therefore, patients receiving BR need to be assessed using patient specific risk factors to evaluate the need for primary prophylaxis. This study evaluates real-world patterns and outcomes associated with primary and secondary G-CSF prophylaxis in patients with B-cell lymphoma and CLL treated with BR.
Methods:
Retrospective chart review of all lymphoma or CLL patients treated with BR from 11/2013 through 6/2019 at the University of Arizona Cancer Center was conducted. Baseline demographic and chemotherapy cycle data was analyzed through Chi-Squared test and Unpaired t-test with a-priori p-value of 0.05 being considered statistically significant.
Results:
Eighty-five patients met inclusion criteria. Of these, 48 received G-CSF during all chemotherapy cycles for primary prophylaxis while 37 received G-CSF only for secondary prophylaxis. Same-day pegfilgrastim compared to next-day pegfilgrastim or filgrastim was the most common G-CSF dosing utilized with primary and secondary prophylaxis patients receiving it (87.5%, 94.6%) respectively. As shown in Table, primary and secondary prophylaxis groups were similar on baseline characteristics (p>0.05); the primary outcome of FN (p>0.05); all secondary outcomes (p>0.05) except for a higher frequency of dose delays in secondary (37.8%) vs primary prophylaxis patients (14.6%; p=0.01); and mean absolute neutrophil counts (ANC) in all cycles (p>0.05) except for cycles 3 and 5. Higher ANC levels were found in primary prophylaxis patients (4.06+0.43) vs secondary prophylaxis (3.03+0.30; p=0.03) for cycle 3 and (3.57+0.25) vs (2.88+0.26; p=0.03) for cycle 5.
Conclusion:
In this single-center retrospective study, BR-treated lymphoma and CLL patients receiving primary vs secondary with G-CSF showed similar outcomes except, notably, for chemotherapy dose delays that may put secondary patients at risk for poor treatment outcomes. Further research is needed to evaluate the impact of primary vs secondary prophylaxis on chemotherapy treatment outcomes.
Table

Disclosures
Persky: Sandoz: Consultancy; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. McBride:Sanofi Genzyme: Consultancy; Sandoz: Consultancy; teva: Consultancy.
Using Childhood International Prognostic Scoring in Pediatric Hodgkin Lymphoma Patients Treated with ABVD Can Mitigate Use of Interim PET in LMIC
Authors: Khedr Reham , Rashad Hanaa , Hamoda Asmaa Mohammed , Khorshed Eman , Elwakeel Madeha , Saad Mohamed , Mohamed Engy , Moussa Emad 
Published: November 2019

Background & aim:Although 'interim' positron emission tomography (PET) may inform therapeutic decisions, Risk stratification at diagnosis allows earlier and potentially better modification during treatment of HL. the prognosis of HL in our center.In this study, we aimed to identify the prognostic role of both the IPET and validate Childhood Hodgkin International Prognostic Score (CHIPS) in predicting the prognosis of HL at our hospital.
Patients and methods:This is a retrospective, single-center study where a total of 1140 patients with newly diagnosed Hodgkin lymphoma were enrolled. Only 737 patients were eligible for analysis of both IPET and CHIPS scoring. PET scan was performed at baseline and after two cycles of chemotherapy (ABVD). Treatment was not changed according to the results of the interim scan. Stage 4 disease, large mediastinal mass, albumin (&lt;3.5), and fever were each assigned one point in the CHIPS. Log-rank testing was used to compare EFS for each CHIPS (0-3) secondary analysis to detect EFS in relation to IPET was done.
Results : Only 737 patients were eligible for analysis of both IPET and CHIPS scoring. The 5-year EFS was 95% for patients with CHIPS=0, 94% for patients with CHIPS=1, 84.3% for patients with CHIPS=2, 82.4% for patients with CHIPS=3 and 70% for CHIPS=4 (P-value 0.001).The 5-year OS was 97.4% for patients with CHIPS=0, 97.9% for patients with CHIPS=1, 93.1% for patients with CHIPS=2, 94.7% for patients with CHIPS=3 and 85.6% for CHIPS=4 (P-value 0.039).
Slow early responders as detected by PET have 5-years EFS 73.8%, in comparison, those with evidence of response by PET had 5-year EFS of 91.3 %. Among this better risk patients, CHIPS can further classify patients; EFS 96.4% of patients with CHIPS 0 or 1 versus 85.8% for those with CHIPS 2, 3 or 4 who had an adverse outcome, even in the setting of response by PET (P&lt;0.001).
Conclusion:
CHIPS is a good tool for predicting risk in patients with HL that may help to tailor therapy to risk factors known early at diagnosis. The benefit of using CHIPS versus early response PET scan suggests the feasibility of eliminating the costly PET scans, especially in LMIC.
Figure

Disclosures
No relevant conflicts of interest to declare.
Application of Single Cell Technologies to the Study of Hematopoiesis
Authors: Gottgens Bertie 
Published: November 2019

The Gottgens group uses a combination of experimental and computational approaches to study how transcription factor networks control the function of blood stem cells and how mutations that perturb such networks cause diseases. The group's current research focuses on (i) single cell genomics of early blood development, (ii) computer models of the transcriptional landscape of blood stem cell differentiation, (iii) transcriptional consequences of leukaemogenic mutations, and (iv) molecular characterization of human blood stem cell populations used in cell and gene therapy protocols. As requested by the session chair, this year's presentation will first provide an overview of single cell technologies, and how they are advancing our understanding of multiple facets of haematology research. This will include single cell molecular profiling, as well as single cell functional assays, and in particular also how a combination of the two allows a more precise definition of haematopoietic stem and progenitor cell types. The rest of the presentation will focus on our multidisciplinary work combining single cell molecular profiling, bioinformatics analysis and experimental/functional validation to study the normal haematopoiesis, and contrast this with 6 mouse models of pre-leukaemic disease. Comprehensive bioinformatics analysis reveals not only qualitative changes in cellular abundance, but also pinpoints the underlying molecular changes that are most likely driving the early stages of malignant disease. An overarching theme will be how single cell landscapes allow us to move seamlessly between different scales of biological investigation, from the molecular to the cellular and whole tissue scale. Finally, extrapolation to human patient data demonstrates disease relevance of gene sets identified from comparative analysis of single cell transcriptional landscapes in mouse models.

Disclosures
Gottgens: Astra Zeneca: Research Funding; GSK: Research Funding; Novo Nordisk: Consultancy, Research Funding; Autolus: Consultancy, Research Funding.
Optimization of Ohmic Contacts to p-GaAs Nanowires
Authors: Rizzo Piton Marcelo , Hakkarainen Teemu , Hilska Joonas , Koivusalo Eero , Lupo Donald , Galeti Helder Vinicius Avanço , Galvão Gobato Yara , Guina Mircea 
Published: November 2019

AbstractThe performance of Ohmic contacts applied to semiconductor nanowires (NWs) is an important aspect for enabling their use in electronic or optoelectronic devices. Due to the small dimensions and specific surface orientation of NWs, the standard processing technology widely developed for planar heterostructures cannot be directly applied. Here, we report on the fabrication and optimization of Pt/Ti/Pt/Au Ohmic contacts for p-type GaAs nanowires grown by molecular beam epitaxy. The devices were characterized by current–voltage (IV) measurements. The linearity of the IV characteristics curves of individual nanowires was optimized by adjusting the layout of the contact metal layers, the surface treatment prior to metal evaporation, and post-processing thermal annealing. Our results reveal that the contact resistance is remarkably decreased when a Pt layer is deposited on the GaAs nanowire prior to the traditional Ti/Pt/Au multilayer layout used for p-type planar GaAs. These findings are explained by an improved quality of the metal-GaAs interface, which was evidenced by grazing incidence X-ray diffraction measurements in similar metallic thin films deposited on GaAs (110) substrates. In particular, we show that Ti exhibits low degree of crystallinity when deposited on GaAs (110) surface which directly affects the contact resistance of the NW devices. The deposition of a thin Pt layer on the NWs prior to Ti/Pt/Au results in a 95% decrease in the total electrical resistance of Be-doped GaAs NWs which is associated to the higher degree of crystallinity of Pt than Ti when deposited directly on GaAs (110).
Proteomic and transcriptomic analyses of early and late-chronic Toxoplasma gondii infection shows novel and stage specific transcripts
Authors: Garfoot Andrew L. , Wilson Gary M. , Coon Joshua J. , Knoll Laura J. 
Published: November 2019

Abstract
Background
The protozoan pathogen Toxoplasma gondii has the unique ability to develop a chronic infection in the brain of its host by transitioning from the fast growing tachyzoite morphology to latent bradyzoite morphology. A hallmark of the bradyzoite is the development of neuronal cysts that are resilient against host immune response and current therapeutics. The bradyzoite parasites within the cyst have a carbohydrate and protein-rich wall and a slow-replication cycle, allowing them to remain hidden from the host. The intracellular, encysted lifestyle of T. gondii has made them recalcitrant to molecular analysis in vivo.

Results
Here, we detail the results from transcriptional and proteomic analyses of bradyzoite-enriched fractions isolated from mouse brains infected with T. gondii over a time course of 21 to 150 days. The enrichment procedure afforded consistent identification of over 2000 parasitic peptides from the mixed-organism sample, representing 366 T. gondii proteins at 28, 90, and 120 day timepoints. Deep sequencing of transcripts expressed during these three timepoints revealed that a subpopulation of genes that are transcriptionally expressed at a high level. Approximately one-third of these transcripts are more enriched during bradyzoite conditions compared to tachyzoites and approximately half are expressed at similar levels during each phase. The T. gondii transcript which increased the most over the course of chronic infection, sporoAMA1, shows stage specific isoform expression of the gene.

Conclusions
We have expanded the transcriptional profile of in vivo bradyzoites to 120 days post-infection and provided the first in vivo proteomic profile of T. gondii bradyzoites. The RNA sequencing depth of in vivo bradyzoite T. gondii was over 250-fold greater than previous reports and allowed us to identify low level transcripts and a novel bradyzoite-specific isoform of sporoAMA1.
Transcriptome analysis of Aspergillus niger xlnR and xkiA mutants grown on corn Stover and soybean hulls reveals a highly complex regulatory network
Authors: Khosravi Claire , Kowalczyk Joanna E. , Chroumpi Tania , Battaglia Evy , Aguilar Pontes Maria-Victoria , Peng Mao , Wiebenga Ad , Ng Vivian , Lipzen Anna , He Guifen , Bauer Diane , Grigoriev Igor V. , de Vries Ronald P. 
Published: November 2019

Abstract
Background
Enzymatic plant biomass degradation by fungi is a highly complex process and one of the leading challenges in developing a biobased economy. Some industrial fungi (e.g. Aspergillus niger) have a long history of use with respect to plant biomass degradation and for that reason have become ‘model’ species for this topic. A. niger is a major industrial enzyme producer that has a broad ability to degrade plant based polysaccharides. A. niger wild-type, the (hemi-)cellulolytic regulator (xlnR) and xylulokinase (xkiA1) mutant strains were grown on a monocot (corn stover, CS) and dicot (soybean hulls, SBH) substrate. The xkiA1 mutant is unable to utilize the pentoses D-xylose and L-arabinose and the polysaccharide xylan, and was previously shown to accumulate inducers for the (hemi-)cellulolytic transcriptional activator XlnR and the arabinanolytic transcriptional activator AraR in the presence of pentoses, resulting in overexpression of their target genes. The xlnR mutant has reduced growth on xylan and down-regulation of its target genes. The mutants therefore have a similar phenotype on xylan, but an opposite transcriptional effect. D-xylose and L-arabinose are the most abundant monosaccharides after D-glucose in nearly all plant-derived biomass materials. In this study we evaluated the effect of the xlnR and xkiA1 mutation during growth on two pentose-rich substrates by transcriptome analysis.

Results
Particular attention was given to CAZymes, metabolic pathways and transcription factors related to the plant biomass degradation. Genes coding for the main enzymes involved in plant biomass degradation were down-regulated at the beginning of the growth on CS and SBH. However, at a later time point, significant differences were found in the expression profiles of both mutants on CS compared to SBH.

Conclusion
This study demonstrates the high complexity of the plant biomass degradation process by fungi, by showing that mutant strains with fairly straightforward phenotypes on pure mono- and polysaccharides, have much less clear-cut phenotypes and transcriptomes on crude plant biomass.