bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Novel Role That Nrf2 Plays in Erythropoiesis during Aging
Authors: Mbiandjeu Serge Cedrick Toya , Mattè Alessandro , Federti Enrica , Perduca Massimiliano , Andolfo Immacolata , Iolascon Achille , Valenti Maria Teresa , Pisani Arianna , Dalle Carbonare Luca , Pucci Pietro , Amoresano Angela , Narla Mohandas , De Franceschi Lucia 
Published: November 2019

Erythropoiesis is a dynamic and multistep process, resulting in generation of red cells from hematopoietic stem cells. Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nrf2 is a key transcription factor that participates in acute response to oxidative stress and controls the expression of anti-oxidant and cytoprotective systems. We previously documented activation of Nrf2 during β-thalassemic erythropoiesis. In addition, a previous study reported a mild chronic hemolytic anemia as a result of increased erythrophagocytosis in mice genetically lacking Nrf2 (PNAS, 2004). Here, we show an age-dependent worsening of anemia in Nrf2-/- mice characterized by accelerated senescence of circulating erythrocytes in association with reticulocytopenia, suggesting a perturbation of erythroblast maturation. Indeed, we found ineffective erythropoiesis in 12 months-old Nrf2-/- mice with extramedullary erythropoiesis, increased ROS levels, reduction in the expression of Nrf2 related anti-oxidant proteins and apoptosis of erythroid precursor cells. In agreement, we observed an age dependent sensitivity of Nrf2-/- mice to stress erythropoiesis induced by either phenyhydrazine (PHZ) or doxorubicine. In 12-month-old mice we observed (i) activation of the unfoldeld protein response system (UPR) due to endosomal reticulum stress and (ii) impaired autophagy. The cytoprotective processes were unable to fully counteract oxidation re-directing cells towards apoptosis as supported by the increased activity of caspase-3. To understand the impact of oxidation in this model of accelerated senescence, we treated Nrf2-/- mice with astaxanthin, a powerful anti-oxidant but with low oral bioavailability, by administrating it in the form of PLGA loaded nanoparticles (ATS-NP). Treatment of Nrf2-/- mice with ATS-NP ameliorated the age-dependent anemia and decreased ineffective erythropoiesis through (i) inactivation of UPR system; (ii) improvement of autophagy and (iii) reduction in caspase-3 activity. In future studies, we plan to evaluate the impact of ATS-NP administration in other models of pathologic erythropoiesis. In summary, we propose that Nrf2, a key transcriptional factor plays a key protective role in regulating aged related oxidation and ensures normal erythroid maturation and growth.

Disclosures
No relevant conflicts of interest to declare.
Blockade of Lipid Receptor GPR31 Suppresses Platelet Reactivity and Thrombosis with Minimal Effect on Hemostasis
Authors: Van Doren Layla , Nguyen Nga , Garzia Chris , Fletcher Elizabeth , Stevenson Ryan , Jaramillo David , Kuliopulos Athan , Covic Lidija 
Published: November 2019

Objective: Platelet agonist-activated 12-lipoxygenase (12-LOX)/12-Hydroxyeicosatetraenoic acid (12-HETE)/G protein-coupled receptor 31 (GPR31) signaling has been proposed to regulate platelet reactivity. While inhibition or genetic ablation of 12-LOX supports an important role of 12-HETE in response to platelet agonists thrombin and collagen, the participation of GPR31 in platelet lipid signaling has not been examined. We developed a potent pepducin inhibitor, GPR-310, to test the downstream involvement of GPR31 in thrombin and collagen mediated platelet activation and thrombosis.
Approach and Results: Treatment of mice with GPR-310 reversibly inhibited ex vivo platelet aggregation in response to thrombin and the PAR4 agonist, AYPGKF. There was significant protection (P<0.002) against FeCl3-induced carotid artery injury in mice by extending occlusion time from 100% occlusion at 27 min in the vehicle cohort to 20% occluded at 45 min in the GPR-310 cohort. GPR-310 treatment did not affect tail bleeding time. In human platelets, GPR-310 significantly (P<0.001) inhibited PAR4 agonist and collagen-mediated platelet aggregation and PAR4 calcium release. GPR-310 inhibited 12(S)-HETE- and PAR4-mediated RAP1 activation, with no effect on the PAR1-RAP1 signal. Accordingly, PAR1-mediated aggregation of human platelets was not affected by either GPR-310 or the 12-LOX inhibitor, ML355. GPR-310 caused a 5-fold shift in thrombin-mediated human platelet aggregation, comparable to a direct P2Y12 inhibitor, AZD1283. Dual GPR31 and P2Y12 inhibition showed synergy and protected against thrombin-mediated human platelet aggregation with a 19-fold shift. Blockade of GPR31 was more effective than the P2Y12 inhibitor in a thrombin-mediated clot retraction assay. Co-immunoprecipitation studies revealed that GPR31 and PAR4 form a heterodimeric complex in recombinant systems.
Conclusions: GPR31 may serve as a new therapeutic target in platelet-dependent arterial thrombosis and aggregation in humans.

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Isolated Neutropenia Referred to Pediatric Hematology Oncology Clinic
Authors: Nagalapuram Vishnu , McCall David , Palabindela Prasannalaxmi , Bemrich Stolz Christina , Howard Thomas H. , Lebensburger Jeffrey D. , Hilliard Lee 
Published: November 2019

Introduction: Patients with absolute neutrophil count (ANC) <1500 x10^9/L are frequently referred to Pediatric Hematology Oncology. Scant literature exists on outcomes and interventions for isolated neutropenia. We hypothesize that most patients will have resolved neutropenia without the need for an intervention from Pediatric Hematology Oncology.
Methods: We performed a five-year IRB-approved, retrospective chart review of patients referred to a Pediatric Hematology-Oncology clinic for isolated neutropenia. Patients were excluded if they also had anemia or thrombocytopenia at the time of the referral. Degree of neutropenia was categorized: 1) at the time of referral, 2) at the lowest value, and 3) at the current ANC as Mild: 1.001-1.500 x109/L, Moderate: 0.501-1.000 x109/L, Severe: 0.201-0.5 x109/L, or Very Severe ≤0.2 x109/L. Descriptive statistics and odds ratios were performed.
Results: Among 154 patients referred with isolated neutropenia over five years, 45 (29%) had mild neutropenia, 65 (42%) had moderate neutropenia, 29 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia. Only 29 (19%) patients progressed to a lower ANC category than their referral ANC category. At a median follow-up of 12 months, 101 (66%) patients had resolved neutropenia, 40 (26%) patients had mild, ten (6%) patients had moderate, three patients had severe, and one patient had very severe neutropenia. Most patients (54%) were not identified with a specific diagnosis. The most common diagnoses included viral suppression (16%), autoimmune neutropenia (14%) and drug induced neutropenia (8%). The most common medications reported as responsible for neutropenia were either anti-epileptic medications or immunosuppressant medications. No patients were diagnosed with a malignancy. Black patients had a 3.5 times higher odds of having persistent, mild, undiagnosed neutropenia which, for some patients, may be benign ethnic neutropenia. Seven (4.5%) patients received G-CSF therapy. Five patients were either managed by a Rheumatologist or an Immunologist. Finally, there were 16 hospitalizations that occurred in 10 patients for a prevalence of one admission for every 21 patient years. The most common admission diagnosis was febrile neutropenia without subsequent bacteremia (n=13).
Conclusion: Most pediatric patients referred for isolated neutropenia do not progress, develop leukemia, or require sub-specialty interventions. Hospitalization of patients referred for isolated neutropenia is rare as is bacteremia. This study provides important outcome data that can improve our counseling of pediatric patients identified with isolated neutropenia.

Disclosures
Howard: Novartis: Consultancy. Lebensburger:Novartis: Consultancy; Pfizer: Research Funding.
Ruxolitinib Is an Effective Salvage Treatment for Multidrug-Resistant Graft-Versus-Host Disease after Allogeneic Hematopoietic Transplantation
Authors: Liu Sining , Zhao Jiaoyu , Xu Lanping , Zhang Xiaohui , Wang Yu , Chen Yuhong , Liu Kaiyan , Huang Xiaojun , Mo Xiaodong 
Published: November 2019

Aim:
Graft-versus-host disease (GVHD), particularly the multidrug-resistant (MDR) GVHD, is one of the most important complications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The purpose of our study is to identify the efficacy of ruxolitinib in allo-HSCT recipients with MDR-GVHD.
Methods:
A total of 44 patients who received ruxolitinib treatment for MDR-GVHD after allo-HSCT between 2017 and 2019 were enrolled in this study (HLA-identical sibling donors: n=10; HLA-haploidentical related donors: n=34). MDR-GVHD was defined as GVHD showing no improvement after at least 3 types of treatments. Patients were treated with ruxolitinib as an add-on immunosuppression therapy at a dose of 5 mg orally twice daily, and it could be increased to 10mg twice daily if hematologic parameters were stable and no treatment-related toxicities were observed after the first 7 days of treatment. This work was supported by the Capital's Funds for Health Improvement and Research (grant number 2018-4-4089).
Results:
The median number of previous GVHD-therapies was 4 for both MDR-aGVHD and MDR-cGVHD. For MDR-aGVHD (n=16), the median time to response was 10 days (range, 2 to 65), and the overall response rate (ORR) was 62.5% (10/16) in, including 37.5% (6/16) complete response (CR) and 25.0% (4/16) partial response (PR). Patients with 3 organs involvement had a lower ORR compared to that of those with 1-2 organs involvements (88.9% vs 28.6%, P=0.035). The 1-year probability of overall survival after ruxolitinib was 62.1%. The rates of hematologic and infectious toxicities were 75.0% and 50.0% after ruxolitinib treatment.
For MDR-cGVHD (n=28), the median time to response was 30 days (range, 6 to 270), and the ORR was 78.6% (22/28), including 28.6% (8/28) CR and 50% (14/28) PR. The 1-year probability of overall survival after ruxolitinib was 90.0%. The rates of hematologic and infectious toxicities were 46.4% and 42.9% after ruxolitinib treatment.
Conclusions:
Ruxolitinib is an effective and safe salvage treatment for both MDR-aGVHD and MDR-cGVHD in allo-HSCT recipients.

Disclosures
No relevant conflicts of interest to declare.
Safety Analysis of Two Randomized Controlled Studies of Venetoclax in Patients with Chronic Lymphocytic Leukemia
Authors: Al Hadidi Samer , Kamble Rammurti , Miller-Chism Courtney Nicole , Mims Martha P. 
Published: November 2019

ABSTRACT
BACKGROUND
Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to cell death of Chronic Lymphocytic Leukemia (CLL) cells. Multiple studies have demonstrated the efficacy and safety of venetoclax for treatment of relapsed/refractory or treatment naïve CLL.
METHODS
We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with venetoclax versus comparators. Data were pooled from 2 completed phase III randomized controlled studies that had included 406 venetoclax -treated and 402 comparator-treated patients with CLL as a first line in treatment naïve patients and for relapsed/refractory disease (Table.1). Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.
RESULTS
The median follow up duration is 25.95months (range: 23.8-28.1 months) for both venetoclax-treated and comparator-treated patients. Discontinuation because of AEs occurred at the same rate in both groups. When adjusted to exposure, hyperglycemia and diarrhea were the only common grade 3 AEs more often reported with venetoclax than with the comparators. The prevalence of common grade 3/4 AEs with venetoclax were <10% apart from neutropenia (55.2%) and infections/infestations (17.5%) though with adjustment to exposure time both of these side effects were more common in comparator arms (Table.2). Grade 3/4 venetoclax associated tumor lysis syndrome happened in 1.7%.
CONCLUSIONS
These results from an integrated analysis support a favorable benefit/risk profile of venetoclax in patients with CLL.

Disclosures
No relevant conflicts of interest to declare.
The Influence of FLT3-ITD Mutation on Baseline Levels of Selected Cytokines and Soluble Adhesion Molecules in Acute Myeloid Leukemia with Mutated NPM-1
Authors: Kupsa Tomas , Horacek Jan M , Jebavy Ladislav , Zak Pavel 
Published: November 2019

Introduction: Cytokines and adhesion molecules have been studied as markers of immune system activation in various diseases including AML/MDS. These factors form a dynamic network which affects AML cell susceptibility to chemotherapy. We analyzed whether these factors may be associated with mutations specific for AML. The aim of our study was to evaluate hypothesis that baseline serum levels of these factors may be associated with mutation profile on the model of AML with mutation in NPM-1 and FLT3-ITD.
Methods: A total of 42 de novo AML patients (age 55.9 ± 11.5, median 60 years; 16 males, 26 females; all Caucasian) were analyzed. All patients had normal karyotype and mutation in NPM-1, 25 patients had mutation in FLT3-ITD. The subgroups have not differed in age. We evaluated baseline circulating levels of the following factors: interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10), epidermal growth factor (EGF), interferon-gamma (IFN-γ), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), E-selectin (E-SEL), P-selectin (P-SEL), L-selectin (L-SEL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). All biomarkers were measured by biochip array technology on Evidence Investigator analyzer (Randox). Probability values (P) < 0.05 were considered statistically significant.
Results: The cases with FLT3-ITD mutation had higher levels of E-SEL (51.90 ± 19.90 mcg/L vs. 23.85 ± 14.07 mcg/L; p = 0.002), P-SEL (192.01 ± 77.29 mcg/L vs. 127.89 ± 48.47 mcg/L; p = 0.035) and lower levels of EGF (7.01 ± 7.08 ng/L vs. 20.64 ± 16.73 ng/L; p = 0.019) and TNF-α (3.55 ± 1.89 ng/L vs. 5.69 ± 3.55 ng/L; p = 0.049). The levels of L-SEL were higher in FLT3-ITD mutated AML, which was not statistically significant, possibly due to exceeding the upper limit or array sensitivity in majority of cases. The differences in baseline levels of other evaluated markers were not statistically significant.
Conclusions: Cytokines are an important part of cancer environment. In patients with normal karyotype and mutation in NPM-1, the presence of FLT3-ITD influenced levels of EGF, TNF-α, E-SEL, P-SEL and possibly L-SEL. Whether these findings are associated with adverse biology of FLT3-ITD positive leukemia is not known at the moment and requires further elucidation.

Disclosures
No relevant conflicts of interest to declare.
Value of Pre-Procedural Lymphocyte-to-Monocyte Ratio for Predicting New Cerebral Ischemic and Haemorrhagic Lesions Observed after Transcatheter Aortic Valve Implantation: A Pilot Study
Authors: Denimal Tom , Lassalle Fanny , Debry Nicolas , Rauch Antoine , Vincent Flavien , Staels Bart , Vincentelli André , Susen Sophie , Van Belle Eric , Dupont Annabelle 
Published: November 2019

Introduction: TAVI (Transcatheter Aortic Valve Implantation) represents the gold standard technique for the treatment of symptomatic severe aortic stenosis in patients at elevated surgical risk. This intervention is consistently associated with ischemic and haemorrhagic complications. In almost 60 % of the procedure, new cerebral ischemic lesions are observed on systematic magnetic resonance imaging (MRI) and it could speed up cognitive impairment. The lymphocyte-to-monocyte ratio (LMR), a new inflammatory marker, has been recently associated with ischemic burden in cardiovascular diseases.
Objective: To study LMR changes before and after TAVI and investigate if LMR could be a predictive factor of new ischemic and haemorrhagic cerebral lesions after TAVI.
Methods: Patients admitted for TAVI who accepted to be included in the METHYSTROKE study (NCT02972008) undergo cerebral MRI the day before the intervention and a second one 3 days after the procedure in order to observe the occurrence of ischemic and haemorrhagic cerebral lesions. LMR was gathered the day before (D0) and the day after TAVI (D1) from complete blood cell count.
Results: A total of 124 patients were included in the present study (mean age was 82 ± 5.2 (SEM) years and 46% were male). Between D0 and D1, we observed a decrease in lymphocytes rate (mean (SD) : 1.25 (0.58) vs 1.14 (0.52) G/L, p=0.02) whereas the rate of monocytes raises (0.51 (0.27) vs 0.85 (0.42) G/L, p&lt;0.0001). Between D0 and D1, the LMR significantly falls (3.1 (0.24) vs 1.51 (0.75), p&lt;0.0001). New ischemic lesions occurred in 80 patients among the 124 (64.5%); LMR is significantly lower at D0 in patients who developed new cerebral ischemic lesions (2.30 (0.8) versus 2.97 (1.2), p=0.03). Each raise of pre-procedure LMR of a range of 0.1 increases the risk of post-operative cerebral ischemic lesions of 5.5 % (OR= 0.46, IC 95% 0.22-0.97, p=0.04). On the other side, 31 patients developed new haemorrhagic lesions on post-operative cerebral MRI (25%). Pre-procedure LMR was not significantly different among patients with and without haemorrhagic post-procedural cerebral complications (2.38 (0.93) vs 2.42 (1.1)).
Conclusion: This study demonstrated that LMR decreases during TAVI and that pre-procedure LMR, a simple, readily available and low-cost biomarker, could be a predictive factor of post-TAVI new cerebral ischemic lesions.

Disclosures
No relevant conflicts of interest to declare.
Favorable Outcome of Allogenic Stem Cell Transplant in Patients with Acute Myeloid Leukemia Carrying t(6;9)(p22;q34) / DEK-NUP214 Rearrangement
Authors: Li Yan , Wang Jianxiang , Wei Hui , Mi Yingchang , Wang Ying 
Published: November 2019

Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is listed as a distinct entity in the 2016 WHO Classification of Tumors of Heamatopoetic and Lymphoid Tissues, but the clinical features and prognostic impact are still not well established. We retrospectively reviewed 1620 AML patients diagnosed from the year 2013 to 2019 and 15 patients with t(6;9)(p22;q34) were identified. Their morphology, immunophenotype, cytogenetics, molecular findings, treatment and prognosis were analyzed. The incidence of AML with t(6;9)(p22;q34) is 0.9% (15/1620). There was 10 women and 5 men (ratio, 2:1) with a median age of 39 years (range:16-64). The median WBC count at diagnosis was 9.72×109/L(range: 1.78-45.4). According to French-American- British classification, 10 (66.7%) were M5 and 5 were M4. At cytogenetic level, t(6;9)(p22;q34) was the sole cytogenetic abnormality in 12 patients (80%) while 2 had one additional aberration and 1 presented with a complex karyotype. Molecular studies using next generation sequencing showed a unique mutation profile characterized by a high frequency of FLT3 mutations (10/13, 77%) including 9 cases with ITD and 1 case with TKD. Other mutations included RAS (3 NRAS and 2 KRAS) (5/13), FAT1 (4/13), NOTCH1 and PRDM1 (2/13 respectively). However, the common mutations of AML, such DNMT3A and NPM1, were rare in this subtype. The median number of mutated genes was 3 (range:1-6). Among the 9 patients with FLT3-ITD, FLT3-ITD ratio was measured in 5 patients and all showed a high ratio (median: 0.62, range: 0.59-1.11). All patients received induction chemotherapy; 12 (80%) patients achieved complete remission (CR) after one or two cycles of induction. Among these 15 patients, 7 underwent allogenic stem cell transplant (SCT) and all were alive in CR status at the last follow-up (median OS: 32.9 mon). In contrast, among the 8 patients who did not receive SCT, 5 died of disease relapse and the remaining 3 patients were newly diagnosed with a relatively short follow-up time (median OS: 10.4mon). In conclusion, t(6;9)/DEK-NUP214 AML represents a unique subtype of AML, with unique gene expression profiling (a high frequency of FLT3-ITD). Most patients can achieve CR after chemotherapy, allo-SCT can improve long term survival.
Figure

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of Generic Imatinib in Chronic Phase of Chronic Myeloid Leukemia (CP-CML): Experience from a Multi-Center in China
Authors: Zhou Li , Liu Bingcheng , Hu Jianda , Qu Jianhua , Hou Ming , Sun Hui , Jin Jie , Shen Zhixiang 
Published: November 2019

Background: Imatinib is the first TKI that was officially approved by the Food and Drug Administration (FDA) for the treatment of patients (pts) with CP-CML and it is the most commonly used treatment in CML pts on the international scene. Generic imatinib was offered and accessible as frontline treatment of CML in china in June 2013, which predictably lowered the cost of CML therapy. However the statistics regarding their effectiveness and tolerability in greater proportion of the population of CML pts are not available. (ClinicalTrials. gov number, NCT02317159.)
Aim: To evaluate the efficacy and safety of generic imatinib in the treatment of pts that were newly diagnosed with CP-CML.
Methods: In this multi-center, prospective open-label study, 75 pts with CP-CML were enrolled to receive generic imatinib mesylate capsules at a dose of 400 mg once daily. The primary end point was major molecular response (MMR) by 12 months. Imatinib plasma level and adverse events (AEs) were assessed.
Results: The Median age at diagnosis was 46 years (range 19-75 years), and 50 pts (66.7%) were male. The median follow-up was 22.1 (range0.5-24) months. 35 pts (44%), 26 pts (34.7%) and 12 pts (16%) were in low, intermediate and high risk group, respectively, according to Sokal prognostic score (Not available in 2 pts). By 12 months, the cumulative rate of MMR (BCR-ABL1IS ≤0.1%) was 42.7% (32/75), and the cumulative rate of complete cytogenic response (CCyR) was74.7% (56/75). Complete hematologic response (CHR), CCyR, MMR rate at 3 months,6 months and 12 months were shown in Table 1. For pts who presented with BCR-ABL1 IS≤ 10% at 3 months, had better response as compared with those with BCR/ABL1IS> 10% (Table 2). The estimated progression-free survival at 12 months was 94.7%. Imatinib plasma levels at 29 days on imatinib were variable in individual, with 1522.9±775.3 ng/mL for median level (rang 394.4 to3891 ng/mL). Although those numerical values showed difference, no statistically significant correlations were found between imatinib plasma level and CCyR or MMR(P=0.902;P=0.349). The incidents and profile of AEs were similar to those reported previously.
Conclusion: This study confirmed that generic imatinib produced in China is effective and well-tolerated in Chinese CP-CML pts. The outcome of generic imatinib in the treatment of CP-CML is similar to brand imatinib reported in the literatures. The introduction of generic imatinib at a reduced and affordable cost may strikingly impact the cost of care for CML and improve the clinical outcomes of CML in China.

Disclosures
No relevant conflicts of interest to declare.