bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-Invasive Hemoglobin Estimation in Patients with β-Thalassemia Major
Authors: Al-Khabori Murtadha K. , Al-Riyami Arwa Z. , Al-Huneini Mohammed , Farsi Khalil Al , Al-Hashim Abdulhakeem , Al-Kemyani Nasser , Mohsin Hussain M , Daar Shahina 
Published: October 2019

Abstract
Abstract 5179

Introduction:
Patients with β-thalassemia major receive regular blood transfusions. Non-invasive hemoglobin (Hb) estimation may simplify their care. Masimo Pronto-7 Pulse CO-oximetry device is used to non-invasively estimate the hemoglobin level but has not been previously validated in this group of patients. The primary objective of this study was to validate the pulse CO-oximetry based hemoglobin estimation in children and adults with thalassemia major.

Methods:
We conducted a prospective observational study on 108 children and adults with thalassemia major attending the daycare thalassemia center of a tertiary care hospital over 6 weeks. We estimated a spot Hemoglobin (Sp Hb) level using Masimo Pronto-7 Pulse CO-oximetry device (two measurements per patient) and compared it to a venous sample Hb (Reference Hemoglobin; Ref Hb) measured using Abbott CELL-DYN Sapphire hematology analyzer. We calculated Pearson correlation coefficient and coefficient of determination (R2). The multivariable linear regression model of predicting the estimation differences included age, gender, weight, height, blood pressure and reference hemoglobin.

Results:
We enrolled 108 patients (54 males, 54 females) with a mean age of 21. 6 years (SD 7. 3; 2. 5–38). There were 156 estimation episodes. The mean Ref Hb and SpHb were 9. 4 g/dL (SD 0. 9; 7. 1–12. 3) and 11. 1 g/dL (SD 1. 2; 7. 5–14. 7) respectively. The correlation coefficient between the Sp Hb and Ref Hb was 0. 49 (R2 = 24%) with a mean difference of 1. 7 g/dL (SD 1. 1; −1. 2 to 4. 3). In the multivariable model, Ref Hb level was the only statistically significant predictor of the difference in measurement (p =0. 002). There was a strong correlation between the two CO-oximetry Hb measurements (correlation coefficient 0. 70, R2 = 50%).

Conclusions:
Our results indicate that Masimo Pronto-7 Pulse CO-oximetry device overestimates the hemoglobin level and it cannot be recommended for patients with thalassemia major. Larger prospective studies are needed to confirm these results.

Disclosures:
No relevant conflicts of interest to declare.
Combination Therapy of Deferasirox and Deferoxamine As Paregoric Treatment of Severe Iron Overload in Patients with Thalassemia Major
Authors: Ladis Vassilis , Kyriacopoulou Dimitra , Stokidis Konstantinos , Moira Aggeliki , Kattamis Antonios 
Published: October 2019

Abstract
Abstract 5181

Background:
Despite the recent availability of multiple therapeutic options for chelation therapy, severe iron overload remains a significant cause of morbidity and mortality in a small group of patients with thalassemia major (TM). Every effort to induce negative iron balance for these patients is warranted. In this context, combination of deferasirox (DFX) and deferoxamine (DFO) may be of significant value. In this report, we present the paregoric use of DFX and DFO in severely iron overloaded thalassemic patients.

Patients and Methods:
Five patients (3 Males, 2 females) have been treated with DFX and DFO as a last rescue measure. In these patients previous combined treatment with DFO and DFP had failed. Informed consent and approval for the use of this schema as paregoric therapy was obtained by patients and hospital. The main inclusion criteria for this treatment were: LIC>30 mg/gr d. w. and T2* cardiac <10 msec. Treatment consisted of daily DFX at 30–40 mg/kg/day and DFO at 40–50 mg/kg/day for 3–6 days/week.

Results:
Patients' characteristics, results and toxicity are shown in table 1 and 2. Improvement in iron load status ranged widely during a follow-up from 1 to 3 yrs. LIC reduced in 4/5 patients, cardiac T2* increased in 3/5 patients, while LVEF showed no significant changes. Ferritin levels improved in 2/5 patients. Deterioration of safety parameters necessitated not to discontinue treatment.

Conclusions:
These data in the use of combination therapy of DFX and DFO suggest a potential modality of chelation therapy in severely iron overloaded patients. Response was variable and seemed not to be always related to compliance or the duration of treatment. Increase of serum creatinin and AST in all patients is a considerable problem in patients with persistent significant iron overload and already impaired hepatic and renal function, despite having been treated with different schema of iron chelation. Longer and cautious follow-up is needed to come to reliable conclusions.

Disclosures:
Ladis: Novartis: Consultancy, Honoraria, Research Funding; Apopharma: Consultancy, Honoraria, Research Funding. Kattamis:Apopharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.
Collagen Receptor-Mediated Mechanochemical Signaling Contributes to Human Pro-Angiogenic Mesenchymal Stem/Progenitor Cell-Induced Neo-Vasculogenesis
Authors: Gimona Mario , Rohban Rokhsareh , Lener Thomas , Peckl-Schmid Doris , Oeller Michaela , Schallmoser Katharina , Strunk Dirk , Rohde Eva 
Published: October 2019

Abstract
Abstract 5196

Background and rationale
Human mesenchymal stem/progenitor cells (MSPCs) are important tools for tissue repair and regenerative approaches. Co-application of autologous pairs of human MSPCs and endothelial colony forming progenitor cells (ECFCs) drives vessel formation in a mouse model. However, a more detailed mechanistic insight into the contribution of MSPCs to vasculogenesis is required prior to a potential application in clinical trials. The formation of perfused blood vessels following the co-injection of MSPC/ECFC pairs requires directed migration of these cell types through the extracellular matrix. For this, cells must interpret and respond to both biochemical cues and physical parameters of the matrix. Here we aimed at identifying changes in early signaling molecules that could potentially mediate these complex behaviors in ECFCs and MSPCs.

Results
By antibody array analysis of biopsies from vasculogenic regions we identified the levels of the discoidin domain receptor 2 (DDR2) to be upregulated about twofold in MSPCs in an MSPC/ECFC mixture compared to MSPC-only implants. Expression of DDR2 was confirmed by flow cytometry analysis. Employing immunofluorescence microscopy we showed components of the mechanotransduction and cytoskeleton machinery (Paxillin, ILK, Src, h1CaP, and cortactin) to be abundantly expressed and correctly localized in MSPCs. MSPCs also responded to manipulation of cytoskeletal integrity with phorbol dibutyrate or Y-27632, demonstrating the presence of a tissue transmigration machinery in MSPCs. Applying various three dimensional cell culture strategies we identified significant alterations in MSPC morphology, as well as in the mRNA levels for DDR1 and DDR2, and for miRNAs 29b, 199a, 331 in response to different matrix conditions.

Conclusions
Our data suggest a mechanosensitive regulation of MSPC function and we thus conclude that direct or indirect (miRNA-mediated) regulation of the collagen receptors DDR1/2 could have a role in modulating MSPC function during stem-cell induced neo-vascularization in vivo.

Disclosures:
No relevant conflicts of interest to declare.
IL-35 Is a Novel Responsive Anti-Inflammatory Cytokine - A New System of Categorizing Anti-Inflammatory Cytokines
Authors: Yang Xiao-Feng , Li Xinyuan , Mai Jietang , Virtue Anthony , Yin Ying , Sha Xiaojin , Wang Hong 
Published: October 2019

Abstract
Abstract 5197
It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies.

Disclosures:
No relevant conflicts of interest to declare.
Dasatinib (Sprycel®) and Low Intensity Chemotherapy for First-Line Treatment in Patients with De Novo Philadelphia Positive ALL Aged 55 and Over: Final Results of the EWALL-Ph-01 Study
Authors: Rousselot Philippe , Coudé Marie Magdeleine , Huguet Françoise , Lafage Marina , Leguay Thibaut , Salanoubat Celia , Witz Francis , Alexis Magda , Janvier Maud , Hunault Mathilde , Agape Philippe , Berthou Christian , Jourdan Eric , Fernandes José , Sutton Laurent , Banos Anne , Reman Oumedaly , Lioure Bruno , Cayuela Jean-Michel , Hayette Sandrine , Gokbuget Nicola , Hoelzer Dieter , Delannoy Andre , Gambacorti-Passerini Carlo , Bassan Renato , Ribera Josep-Maria , Giebel Sebastian , Dombret Herve , Ottmann Oliver G. 
Published: October 2019

Abstract
Abstract 666

Background.
Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. The EWALL group for adult ALL decided to run a study at the European level evaluating the combination of dasatinib and chemotherapy for Philadelphia positive (Ph+) ALL patients (pts) aged 55 and over.

Aim.
To analyse efficacy of Dasatinib combined to low intensity chemotherapy and to test factors associated with outcome. (EudraCT 2006–005694-21).

Methods.
After prephase, dasatinib was administered at 140 mg QD (100 mg over 70y) during the induction period in combination with weekly vincristine (VCR) 1 mg IV and dexamethasone (DEX) 40 mg for 2 days (20 mg over 70y) for 4 weeks. Consolidation

Disclosures:
Rousselot: BMS, Novartis: Research Funding. Gambacorti-Passerini:BMS, Novartis: Research Funding.
The Clinical Impact of Time to Response in De Novo Accelerated Phase Chronic Myeloid Leukemia (CML-AP)
Authors: Ohanian Maro , Kantarjian Hagop M. , Quintas-Cardama Alfonso , Jabbour Elias J. , Verstovsek Srdan , Borthakur Gautam , Ravandi Farhad , Garcia-Manero Guillermo , Ferrajoli Alessandra , Kadia Tapan M. , O'Brien Susan , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 72

Background:
Early (3-month) response is important in chronic phase chronic myeloid leukemia (CML-CP). Whether this applies also to CML in accelerated phase (CML-AP) has not been analyzed.

Aim:
To describe the impact of time to response on the outcome of patients (pts) with CML-AP.

Methods:
Frontline tyrosine kinase inhibitor (TKI) therapy was administered on consecutive or parallel clinical trials to 58 CML pts presenting with features of AP at the time of diagnosis, defined as blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=22), or more than 1 feature (n=3). 36 pts received imatinib. 22 pts received a 2nd generation TKI (2GTKI) (dasatinib, n = 5 or nilotinib, n= 17).We analyzed the impact of various degrees of molecular and cytogenetic responses at 3, 6, and 12-months on rates of major molecular response (MMR), MR4.5, overall survival (OS), event free survival (EFS), and transformation (to blast phase) free survival (TFS).

Results:
After a median follow-up of 73 months (range 3 to 142) the overall rate of CCyR was 81% (imatinib 75%, 2GTKI 91%), and MMR 69% (imatinib 64%, 2GTKI 77%). At 3 yrs, TFS was 92%, EFS 90% and OS 87%. At 3 months 43 (81%) out of 53 evaluable pts had achieved a major cytogenetic response (MCyR) (71% of pts treated with imatinib, 95% of pts treated with 2GTKI); BCR-ABL/ABL <10% was achieved in 27 (96%) out of 28 evaluable pts (100% with imatinib, 95% with 2GTKI). At 6 months, 44 (86%) out of 51 evaluable pts had achieved a MCyR (83% of pts treated with imatinib, 90% of pts treated with 2GTKI); BCR-ABL/ABL <10% was achieved in 26 (93%) out of 28 evaluable pts (100% with imatinib, 90% with 2GTKI). The probability of achieving various outcomes: MMR, MR4.5, OS, EFS, and TFS by response at 3 and 6 months are shown in Table 1 and 2. The number of pts evaluable for both cytogenetic and molecular responses at 3 and 6 months were 44 and 45 respectively.

Conclusion:
Pts with de novo CML-AP have an excellent outcome with TKIs, particularly 2GTKIs. As for chronic phase, pts with deep responses at 3 months (MCyR or BCR-ABL <10%) have the best probability of a favorable long-term outcome, although a few have not achieved MCyR at 3 months. TKIs should be standard for all pts with AP features at the time of diagnosis.

Disclosures:
Kantarjian: Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy. Ravandi:BMS: Honoraria, Research Funding; Novartis: Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
Novel Isoforms of Neutrophil Elastase Produced by Neutropenia-Associated Mutations of the Initiation Codon and an Internal Ribosomal Entry Site (IRES) of ELANE
Authors: Tidwell Timothy , Wechsler Jeremy , Horwitz Marshall S 
Published: October 2019

Abstract
Abstract 9
Severe congenital neutropenia is most commonly caused by mutations in the gene, ELANE, encoding neutrophil elastase, through a mechanism that is not fully understood. Two prevalent hypotheses point to mislocalization of neutrophil elastase or, alternatively, endoplasmic reticulum (ER) stress resulting from protein misfolding. We have recently identified disease-causing mutations in the “Kozak” ribosome-binding sequence and the initiation codon that do not easily fit with either theory. In cell culture models of neutrophil elastase expression, we found that when the ribosome binding site of ELANE is mutated, at least four polypeptides are expressed, all shorter than the wild type. All of the isoforms are reactive to a carboxyl-terminal antibody, indicating that they are likely produced from alternate start sites or represent amino-terminal truncations. ELANE contains three downstream in-frame initiation codons (ATG) that potentially could be utilized as alternate translation start sites, and mutations in the vicinity of these sequences predictably correlate with production of each of the shorter isoforms. Furthermore, a protein-coding region of ELANE mRNA is complementary to the 18s ribosomal RNA subunit and demonstrates internal ribosome entry site (IRES) activity, when tested using a bicistronic luciferase assay. Neutropenia-associated mutations within the identified IRES also affect expression of the shorter isoforms of neutrophil elastase. These findings suggest that some ELANE mutations could cause neutropenia, not through disturbing the primary sequence of full-length neutrophil elastase protein, but instead by altering mRNA-ribosome interactions, thus generating shorter isoforms of normal sequence that are initiated from internal translational start sites. We have therefore biochemically characterized the shorter isoforms. We found that they do not demonstrate proteolytic activity. Because they lack signal sequences and cannot be trafficked through the ER, it is also not surprising that they fail to induce the ER stress response. They do not trigger apoptosis, as measured in several assays. Nevertheless, they do reduce myeloid cell viability in a colony forming test. We propose that these shortened isoforms contribute to the pathogenesis of ELANE-associated neutropenia by impairing myeloid cell development. Because a diversity of ELANE mutations from different patients seem to have identical effects, these shorter neutrophil elastase polypeptides, common to multiple patients regardless of mutation, may offer promise as targets for drug development.

Disclosures:
No relevant conflicts of interest to declare.
Diamond Blackfan Anaemia Patients Have a Higher Rate of Hepatic Iron Accumulation Than Thalassaemia Major Patients Leading to Fibrosis
Authors: Evans Katharine , Goldin Robert , de la Fuente Josu 
Published: October 2019

Abstract
Abstract 997
Diamond Blackfan anaemia is an inherited bone marrow failure syndrome with haematological and systemic manifestations. The classical presentation of the condition is the development of anaemia in infancy, which occurs in approximately 85–90% of the patients. Long-term 40% require transfusions as they fail to maintain erythropoiesis at acceptable doses of steroids and only approximately 10% of the patients go into remission. To investigate the iron load caused by transfusions and its effect we studied the liver biopsies of 13 patients with DBA and compared them with 27 patients suffering from thalassaemia major (TM). The findings were correlated with the number of transfusions, chelation treatment, ferritin level and MR techniques. Image analysis of the degree of fibrosis was performed using NIS-elements software after staining liver biopsy slides with Sirius Red.
TM patients were significantly older [median age: TM 9 years (3–18), DBA 5 years (1–15); p=0.004], which was also reflected in the duration (months) of transfusion [TM 105 (12–198), DBA 52 (12–130); p=0.004]. However, there was no difference in the frequency of transfusions (p=0.51) and in the length of time (months) between starting transfusions and chelation (TM 19, DBA 27; p=0.08). DBA patients received proportionately more chelation per transfusion than TM patients at the time of biopsy (TM 1.24, DBA 1.58; p=0.015). Ferritin levels were higher in TM patients, though not significant [TM 2028 μg/L (1292–4901), DBA 1324 μg/L (535–2300); p=0.16).
Despite having significantly fewer transfusions, the grade of iron deposition was higher in the DBA group (TM 2, DBA 3; p=0.035). This was also reflected in MRI T2* quantitation, which demonstrated a higher hepatic iron load in DBA patients [TM 3 ms (1–12), DBA 2 ms (1–3); p=0.59]. The rate of biochemical iron accumulation (mg/g DW) for every month of transfusion was significantly higher in the DBA group (TM 0.05, DBA 0.11; p=0.005). The rate of fibrosis accumulation was 60% higher in the DBA group, although this was not statistically significant (TM 0.1, DBA 0.16; p=0.07) and could be due to a time lag between iron accumulation and fibrosis formation, particularly as the DBA patients were younger and had had shorter follow up. Biochemical iron, ferritin level and MRI T2* had low, significant correlations with fibrosis in TM patients (0.547, p=0.001; 0.357, p=0.033; −0.430, p=0.011, respectively) and FerriScan in DBA patients (0.75, p=0.05). In conclusion, DBA patients have a higher rate of iron accumulation with a trend to higher hepatic fibrosis.

Disclosures:
No relevant conflicts of interest to declare.
Fanconi Anemia: Emerging Therapeutic Opportunities
Authors: Grompe Markus , Postlethwait John , D'Andrea Alan D. , Olson Susan B. , Zhang Qingshuo , Bagby Grover C. 
Published: October 2019

Abstract
Abstract SCI-1
Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure, birth defects, and cancer susceptibility. At the cellular level, FA features hypersensitivity to DNA cross-linking agents, cell cycle abnormalities, and abnormal responses to cytokines. Therapy for the hematopoietic defects of FA has consisted of supportive care, stem cell transplantation, and administration of androgens such as oxymetholone. Unfortunately, even successfully transplanted FA patients have a very high risk of subsequent solid tumors, especially squamous cell carcinomas of the oropharyngeal and urogenital areas. The pharmacologic treatment of FA has been unchanged for several decades, and for this reason our group has embarked on a systematic search for small-molecule therapeutics that could benefit FA patients. This effort has been made possible by the cloning of 15 FA genes and biochemical insights into the function of FA proteins. Mouse models, zebra fish models, and FA patient cell lines, including induced pluripotent stem cells, are available for screening and validation. The specific goals of small-molecule interventions are to delay or prevent hematopoietic failure and also to delay or prevent carcinogenesis. To date, we have shown that the superoxide dismutase mimetic drug Tempol can significantly delay tumor formation in FA mice. Similarly, resveratrol clearly improved hematopoiesis in the same model. Medium-throughput screens have revealed numerous new molecules that ameliorate the FA phenotypes of cells, mice, and zebrafish. Using genetic approaches we also have identified the p53 pathway as a therapeutic target in FA. These therapeutic opportunities and progress in FA small-molecule screening will be discussed.

Disclosures:
No relevant conflicts of interest to declare.
Human Dendritic Cell Heterogeneity: Opportunities and Challenges for the Control of Immunity
Authors: Young James W. 
Published: October 2019

Abstract
Abstract SCI-21
Dendritic cells (DCs) comprise a heterogeneous population of potent antigen-presenting cells, which are master orchestrators of the immune response. DCs initiate immunity, and just as importantly, control its quality and outcome. DCs accomplish this by capitalizing on their defined subsets, which exert discrete functions in responding to different types of antigens and factors in the microenvironment. DCs, therefore, provide the immune system with an essential and robust flexibility to discriminate between enormous numbers of harmful and benign agents and to mount functionally distinct and appropriate responses in the contexts of innate and adaptive immunity. Our lab has focused on the contrasting functions of conventional human DC subsets, primarily monocyte-derived DCs (moDCs) versus CD34+ hematopoietic progenitor cell-derived Langerhans-type DCs (LCs). Recent findings that have defined the afferent sensitization of different types of immune responses by these distinct DC subtypes will be discussed. For example, LCs use an endogenous IL-15R-α/IL-15 mechanism to generate potent cytotoxic T lymphocytes and break tolerance against a self-differentiation tumor antigen like WT1. This contrasts with the potency of moDCs in maturing and stimulating NK cells by their production of IL-12p70, whereas LCs can only ensure NK-cell viability. The application of these findings to the holy grail of separating graft-versus-leukemia from the deleterious aspects of graft-versus-host disease in allotransplantation, at the level of afferent sensitization by these distinct DC subtypes, as well as the novel use of small-molecule inhibitors of JAK-STAT signaling in DC-stimulated T cells, will also be addressed.

Disclosures:
Off Label Use: JAK2 inhibitors (potentially several) for inhibition of dendritic cell stimulated alloreactivity - but all data will be in vitro, so perhaps this is not off-label drug use because it is not in vivo in humans.