bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peculiar Hepatocellular Carcinoma Clinical Findings in patients with Thalassemia Syndromes.
Authors: Restivo Gaetano , Valenza Franco , D'Amato Fabio , Vitrano Angela , Rigano Paolo , Renda Disma , Cassarà Filippo , Maggio Aurelio 
Published: October 2019

Abstract
Abstract 5108

Background
Hepatocellular carcinoma (HCC) is the most common primary hepatic cancer, and the fifth and eighth most common malignancy worldwide in men and women, respectively. Hepatitis B and C, primary and secondary hemochromatosis and cirrhosis have been identified as major risk factors. Hepatitis C or B virus infection and secondary hemochromatosis are the major cause of morbidity and mortality. In the last years, HCC on cirrhosis is a common reported complication in patients with thalassemia syndromes1,2,3. In non thalassemia patients HCC is a late complication of cirrhosis and prognosis depends on suitability for treatment. In this group, the last is low (40%) considering that cirrhosis severe stage C, according to Child-Pugh score is generally observed (personal communication).

Aim of the study
describing, in a homogeneous cohort of thalassemia patients, the main clinical findings of HCC.

Patients and Methods
All subjects with risk factors for HCC as iron overloading, HCV or HBV chronic infection, histological evidence of cirrhosis were undergone every six months to an ultrasound evaluation associated with alphaphetoprotein determination. Nine new cases, since January 2000 until July 2009, were detected. Table I shows the main clinical findings. Mean value of serum ferritin levels, in the last 2 years before diagnosis, was 1049±721. All patients except one were anti-HCV positive (Table I). Seven of them were HCV-RNA positive (Table I). None of them had previous HBV infection.

Results
Only one patient had severe stage C, according to Child-Pugh score. None of the patients had significant high levels of alphaphetoprotein (AFP) at diagnosis. However, a slightly increase of AFP levels was shown, during the 6 months before diagnosis, in 50% of cases. Three patients had a delayed diagnosis because of atypical imaging for HCC at TC scan or a negative previous histology for HCC after liver biopsy. Five patients had multifocal HCC at the diagnosis (Table I). Four showed an unifocal HCC, developing two of them multifocal HCC during the follow-up (Table I). Four patients died during the follow-up for decompensated cirrhosis. Five patients are alive after treatment. Main used treatments are shown on Table I. The overall mean survival was 28±25 months (range 3-64).

Conclusions
1) almost all talassemia patients with HCC are suitable for treatment ; 2) baseline liver function is the most main factor conditioning survival and suitability for treatment ; 3) periodical serum AFP determnations can reveal a slight increase; 3) iron overloading alone can be related to the development of HCC in a liver with still good functional reserve, giving more opportunity for treatment 4) monitoring for HCC by liver ultrasound evaluation, every six months, in at risk patients with thalassemia syndromes should be mandatory.

Disclosures
No relevant conflicts of interest to declare.
Roles of Thromboxane A2 On High Salt Induced-Fetal Defect.
Authors: Pai Chen-Hsueh , Lin Shu-Wha , Yu I-Shing , Yen Ching-Tzu , Yang Yung-Li , Jou Shiann-Tarng , Lin Dong-Tsamn , Chen Jiann-Shiuh , Lin Shu-Rung 
Published: October 2019

Abstract
Abstract 5129

Introduction
Preeclampsia is a pregnancy-induced disorder. If a pregnant woman suffered from preeclampsia, her worse developed-placenta might result in growth retardation of the fetus, and in the most severe cases, it would cause fetal and maternal death. Several previous studies showed that circulating thromboxane A2 in preeclampsic women was higher than that of normal pregnant women, and higher thromboxane A2 level might induce thrombosis and hypertension in these patients. Thus, thromboxane A2 was thought to be an important metabolite relevant to the development of preeclampsia.

Materials and Methods
In order to clearly clarify the roles of thromboxane A2 on preeclampsia, wild type and thromboxane A2 synthase knockout pregnant mice were fed with drinking water containing high concentration of sodium chloride. The effect of thromboxane A2 on preeclampsia was observed by measuring blood pressure, urinary protein, systemic edema in pregnant mice, and placenta weight, fetal weight, fetal size and fetal sections were also measured and stained.

Results
In the groups of pregnant mice fed with high salt, maternal body weight, fetal size and fetal weight were severely decreased in wild type mice as compared to thromboxane A2 synthase knockout mice. Furthermore, abnormal cell degeneration was observed in fetus of wild type pregnant mice, but less in thromboxane A2 synthase knockout fetus.

Conclusions
These results demonstrate that knockout pregnant mice were more resistant to high salt treatment, implying the roles of thromboxane A2 on the development of maternal and fetal defects during high salt treatment.

Disclosures
No relevant conflicts of interest to declare.
Quality of Life in Adolescents and Adults with Thalassemia: A Report of the Thalassemia Longitudinal Cohort.
Authors: Sobota Amy , Yamashita Robert , Xu Yan , Trachtenberg Felicia , Kleinert Dorothy A. , Giardina Patricia J , Kwiatkowski Janet L , Foote Dru , Thayalasuthan Vivekanandan , Porter John B , Thompson Alexis A. , Schilling Leann , Quinn Charles T. , Neufeld Ellis J 
Published: October 2019

Abstract
Abstract 556

Background:
Advances in the treatment of thalassemia have led to increased life expectancy, making outcomes such as health related quality of life (HRQOL) especially important in assessing interventions. However little has been published about the HRQOL of patients living with thalassemia. We report the baseline data from the Thalassemia Clinical Research Network's (TCRNs) Thalassemia Longitudinal Cohort (TLC) study.

Patients and Methods:
The TCRN is an NIH sponsored network of 16 major thalassemia centers in the US, Canada and London. This study is part of the TCRN's longitudinal cohort (TLC) study. HRQOL was measured by self-report with the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF36v2), a generic measure of functional health status and well being with results reported as 8 subscale and two summary measures. It has been validated in numerous populations and diseases, and is considered the gold standard for measuring HRQOL. We report here the results from 245 patients over the age of 14 who completed baseline assessments. Comparisons within the study population and with US norms using t-test and linear regression were performed.

Results:
There were 245 patients [47% male; mean age 29 years (range 14-58)]. When compared to US norms, TLC patients had statistically significant (p<0.05) worse HRQOL on 5 of the 8 SF36v2 subscales (physical functioning, role-physical, general health, social functioning and role-emotional) and on both summary scales (physical component summary and mental component summary). As is also seen in the US population, women had worse HRQOL than men on all subscales except vitality, and on both component summary scores. HRQOL decreased with age in all scales, more so than expected compared to US norms.

Conclusions:
In general, adolescents and adults with thalassemia have worse HRQOL than the US population, despite contemporary therapy. Further investigation is needed to determine predictors of low HRQOL so that these may be better addressed by a multidisciplinary team.

Disclosures:
No relevant conflicts of interest to declare.
Signal Transducer and Activator of Transcription (Stat)-3 Activates the Receptor Tyrosine Kinase-Like Orphan (ROR)-1 Gene in Chronic Lymphocytic Leukemia (CLL).
Authors: Ping Li , Harris David , Liu Zhiming , Keating Michael , Estrov Zeev 
Published: October 2019

Abstract
Abstract 57
ROR1, an embryonic protein involved in organogenesis and Wnt signaling, is expressed in B-cell CLL. Because Stat3 is constitutively activated in CLL and sequence analysis revealed that the ROR1 promoter harbors ψ-interferon activation sequence (GAS)-like elements typically activated by Stat3, we sought to determine whether Stat3 activates ROR1. In MM1 cells interleukin (IL)-6 induced Stat3 phosphorylation and upregulated ROR1 whereas STAT3-siRNA downregulated both Stat3 and ROR1 protein levels, suggesting that Stat3 transcribes ROR1. Therefore, we cloned the human ROR1 promoter, generated a series of truncated promoter constructs and assessed their activity by using the luciferase assay. We found that IL-6 augmented the luciferase activity of ROR1 -195, ROR1 -666, ROR1 -834, and co-transfection with Stat3-siRNA significantly attenuated it, suggesting that IL-6 enhanced ROR1 expression by activating Stat3. Furthermore, we established that a region, located between bp -122 and -134, harbors a GAS-like element and activates the ROR1 promoter upon exposure to IL-6. Binding of Stat3 to that region in IL-6-stimulated MM1 cells was confirmed by the electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). To test whether Stat3 transcribes ROR1 in CLL, we obtained fresh CLL cells and by using the same GAS-like element-containing probe we performed EMSA. CLL cell nuclear protein bound this probe and anti-Stat3 and -phsophoserine Stat3 antibodies induced a super-shift. CLL cell ChIP confirmed that Stat3 binds to the promoter of ROR1 as well as the promoters of the Stat3-regulated genes STAT3, c-Myc and P21, but not that of the control gene RPL30. Finally, using qRT-PCR and western immunoblotting we determined that STAT3-shRNA downregulated ROR1, STAT3 and STAT3-regulated gene mRNA by 4-6 fold, and Stat3 and ROR1 protein levels by 50%. Taken together, these data suggest that constitutively activated Stat3 binds to the ROR1 promoter, activates transcription, and induces production of ROR1 protein in CLL cells.

Disclosures:
No relevant conflicts of interest to declare.
Hemolysis-Associated Elevation in Tricuspid Regurgitation Velocity Predicts Reduction in Six-Minute Walk Distance After Two Years of Follow up in Children and Adolescents with Sickle Cell Disease.
Authors: Gordeuk Victor R. , Luchtman-Jones Lori , Campbell Andrew D. , Rana Sohail R , Nouraie Mehdi , Sable Craig , Dham Niti , Ensing Gregory , Minniti Caterina , Kato Gregory J , Gladwin Mark , Castro Oswaldo L 
Published: October 2019

Abstract
Abstract 574

Background.
Elevated tricuspid regurgitation velocity (TRV) as determined by echocardiography correlates with elevated systolic pulmonary artery pressure and is associated with increased morbidity and mortality in adults with sickle cell disease. The importance of elevated TRV in children and adolescents with sickle cell disease is not known. The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study is an ongoing, longitudinal and observational multicenter study of children with sickle cell disease.

Methods.
Baseline echocardiography and six-minute walk test were performed prospectively in 361 children and adolescents with sickle cell disease at steady state and then repeat studies were performed in 209 after a median of 22 months of follow up (range 10 months to 36 months), also at steady state. A hemolytic component was derived by principal component analysis of baseline values for reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and total bilirubin.

Results.
TRV or six-minute walk test were measured at both baseline and follow-up in 193 patients. Twenty-one of these 193 patients had elevated TRV of 2.60 m/sec or higher at baseline. Elevated baseline TRV was associated with high hemolytic rate in 15 patients, defined as hemolytic component above the median for the population studied, and with lower hemolytic rate in six patients. Elevated baseline TRV with high hemolytic rate predicted elevated TRV at follow up (odds ratio 7.7; 95% confidence interval [CI] 2.5 to 24.2; P <0.001) but elevated baseline TRV with lower hemolytic rate did not (odds ratio 1.6; 95% CI 0.2 to 14.1; P = 0.7). Elevated baseline TRV with high hemolytic rate also predicted a decline in the six-minute walk distance by 10% or more at follow-up (hazard ratio 3.9; 95% CI 1.4 to 10.7; P = 0.009). In contrast, higher cardiac output as measured by the left ventricular end diastolic dimension z-score was associated with reduced risk for a decline in the walk distance (hazard ratio 0.7; 95%CI 0.6 to 0.9; P = 0.006).

Conclusion.
Steady-state TRV elevation in association with a high hemolytic rate occurs on screening in about 8% of children and adolescents with sickle cell disease and is predictive of elevated TRV and reduced six-minute walk distance after approximately two years of follow. Such children may be at risk for adverse clinical consequences of pulmonary hypertension as young adults. Further studies are indicated to identify the molecular mechanisms and to develop appropriate medical management for children and adolescents with this complication.

Disclosures:
No relevant conflicts of interest to declare.
Chronic Phosphodiesterase Type 5 Inhibitor Therapy Reduces Priapic Activity in Transgenic Sickle Cell Mice: Restoring Nitric Oxide/Redox Balance in the Penis.
Authors: Burnett Arthur L. , Musicki Biljana , Champion Hunter C. , Bivalacqua Trinity J. 
Published: October 2019

Abstract
Abstract 576

Introduction:
Sickle cell disease (SCD)-associated priapism is characterized by aberrant nitric oxide (NO) regulatory pathway signaling and reduced endothelial NO bioavailability resulting in phosphodiesterase type 5 (PDE5) dysregulation in the penis. Our objective was to determine the effect of chronic PDE5 inhibitor therapy on in vivo erectile responses as well as on NO signaling and redox actions in the penis in an animal model of SCD in order to identify mechanisms associated with this therapeutic effect. Our animal model comprised transgenic sickle cell (SS) mice, expressing human sickle hemoglobin.

Methods:
Five groups of mice were used: 1) wild type (WT), 2) sickle cell heterozygotes (Hemi), 3) sickle cell homozygotes (Sickle), 4) WT + sildenafil (100 mg/kg per day), and 5) Sickle + sildenafil (100 mg/kg per day). All experimental groups underwent cavernous nerve electrical stimulation (CNS; 0.5 - 6 V) to assess erectile function (intracavernous pressure; ICP), and their responses were compared to WT. The frequency of erectile responses (erections/hr) pre- and post-stimulation was also determined. Analyses of penes were: total endothelial NOS (eNOS) and its phosphorylated/activated form (p-eNOS, Ser-1177), and PDE5 expressions; eNOS uncoupling (ratio of active eNOS dimer vs. inactive monomer); reactive oxygen species (ROS) generation; cGMP, NOS and PDE5 activities; and electron microscopy.

Results:
Erectile responses to CNS were significantly enhanced (P<0.05) in the Sickle when compared to Hemi and WT at all voltage settings. Sickle mice treated with sildenafil had a reduction (P<0.05) in spontaneous erections and reduced erectile responses to CNS, while sildenafil therapy had no effect on erectile responses in WT. EM showed endothelial cell interruption with loss of normal endothelial architecture and increased smooth muscle cell hyperplasia in Sickle mice penes. Sickle mice penes had reduced eNOS activity, p-eNOS expression, cGMP level, and PDE5 activity and increased eNOS uncoupling and ROS generation. Sildenafil therapy restored cGMP, NOS and PDE5 activities, improved p-eNOS expression, prevented eNOS uncoupling, and reduced ROS generation in Sickle mice penes compared to WT.

Conclusions:
The priapic activity in the Sickle mouse is associated with a reduction in the functions of NOS and PDE5 and an NO/redox imbalance in the penis, and chronic PDE5 inhibitor therapy reverses this phenotype by restoring normal NO-mediated penile vascular homeostasis. These data support the use of PDE5 inhibitors for the treatment of priapism associated with hematologic dyscrasias.

Disclosures:
Burnett: Pfizer Inc: Research Funding; Lilly LLC: Research Funding. Off Label Use: Sildenafil and tadalafil are FDA approved for treating erectile dysfunction.
Tyrosine Phosphorylation of Runx1 In Megakaryocytes by Src Family Kinases
Authors: Huang Hui , Waldon Zachary , Chan Gordon , Zhu Helen , Steen Hanno , Feng Gen-Sheng , Neel Benjamin , Cantor Alan 
Published: October 2019

Abstract
Abstract 742
Runx1 and its cofactor, CBF-beta, are the most frequent targets of chromosomal translocations in human leukemias. Point mutations in Runx-1 also occur in some cases of myelodysplastic syndrome and undifferentiated leukemia. During normal hematopoiesis, Runx1 is required for the ontogeny of all definitive hematopoietic stem cells and for the proper maturation of megakaryocytes (Mks) and lymphocytes. Despite these critical roles, the regulation of Runx1 activity via cell signaling pathways remains incompletely understood. Here, we report that Runx-1 is tyrosine phosphorylated in Mks. This occurs on multiple residues and is mediated by src-family tyrosine kinases (SFKs). Loss of Runx1 tyrosine phosphorylation correlates with phorbol ester induced differentiation of L8057 megakaryoblastic cells, suggesting a negative regulatory function. Consistent with this model, retroviral expression of a tyrosine non-phosphorylatable mutant Runx1 molecule increases primary murine fetal liver Mk maturation and Runx1 target gene expression to a greater extent than wild type Runx1. Moreover, treatment of wild type primary Mks with SFK inhibitors markedly enhances Mk maturation, as previously reported (Lannutti BJ, et al 2005 Blood;105:3875-3878). Treatment of L8057 cells with the pan-tyrosine phosphatase inhibitor Na3VO4, significantly increases Runx1 tyrosine phosphorylation levels, suggesting that tyrosine phosphorylation of Runx1 is dynamically regulated under steady-state conditions. Using a proteomic approach, we found that Runx1 physically interacts with the non-receptor tyrosine phosphatase SHP-2 (Ptpn11). We validated this interaction and showed that it occurs via direct interactions involving the Runx1 runt domain. ShRNA mediated knock down of SHP-2 in L8057 cells increases Runx1 tyrosine phosphorylation levels. Conditional knockout of SHP-2 in Mks using SHP-2fl/fl, PF4-Cre mice leads to reduced peripheral blood platelet counts and delayed platelet recovery following transient anti-GPIb antibody induced immune thrombocytopenia. Lastly, we show that treatment of TPA-induced L8057 cells with Na3VO4 markedly diminishes binding between Runx1 and the key Mk transcription factor GATA-1. Taken together, our data suggest that tyrosine phosphorylation of Runx1 via SFKs inhibits Runx1 function. Dephosphorylation, at least in part via SHP-2, relieves this inhibition and promotes Mk maturation. These effects are likely mediated through altered protein-protein interactions.

Disclosures:
No relevant conflicts of interest to declare.
Patterns of Use of FDG-PET for the Initial Staging of Follicular Lymphoma (FL) and Its Impact on Initial Treatment Strategy and Outcomes In the National Comprehensive Cancer Network (NCCN) Lymphoma Database
Authors: Abou-Nassar Karim E , Vanderplas Ann , Friedberg Jonathan W. , Abel Gregory , Niland Joyce , Rodriguez Maria A. , Czuczman Myron S. , Millenson Michael , Crosby Allison , Gordon Leo I , Zelenetz Andrew D , LaCasce Ann 
Published: October 2019

Abstract
Abstract 81

Background:
The management of follicular lymphoma (FL) can vary according to stage at presentation. The use of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for initial staging of FL may result in upstaging and/or changes in treatment strategy. In this study, we describe the patterns of use of FDG-PET for the initial staging of patients with newly diagnosed FL and its potential impact on treatment.

Methods:
Data were obtained from the NCCN Non-Hodgkin's Lymphoma Outcomes Database, a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients treated at 7 participating NCCN centers. Patients who presented between January 1, 2001 and September 30, 2009 with newly diagnosed low grade FL (grade 1, 2), received staging imaging within 6 weeks of diagnosis, and with at least 6 months of follow-up were included. We compared baseline and clinical characteristics as well as treatment among patients by receipt of FDG-PET for initial staging.

Results:
We identified 953 eligible FL patients with a mean age of 56 years; 532 (56%) underwent FDG-PET as part of initial staging. Use of FDG-PET varied significantly across NCCN centers (p<0.0001). Among patients who underwent FDG-PET for initial staging, 438 (82%) received early treatment (defined as treatment within 180 days of diagnosis) compared to 259 (61.5%) who were staged with conventional CT scanning only (p<0.0001).
Among 189 patients with early stage FL (ESFL), 120 (63.5%) underwent FDG-PET for initial staging. Significant differences in use were observed across NCCN centers (p<0.0001). Of all ESFL, 55 (29.1%) were treated with radiotherapy (RT) alone, 68 (36%) with chemotherapy/immunotherapy (CIT) alone, 28 (14.8%) with combined RT and CIT and 38 (20.1%) were observed. Initial treatment strategy for ESFL varied significantly according to NCCN centers (p<0.001). Choice of initial treatment strategy for ESFL did not vary significantly by use of FDG-PET (p=0.09).

Conclusions:
The use of FDG-PET for staging of FL varies by center and is widespread despite a paucity of evidence supporting its use in this disease. Patients who undergo FDG-PET scan for initial staging appear more likely to receive early therapy although this may not be directly attributed to FDG-PET results. The management of ESFL is surprisingly heterogeneous and varies across NCCN centers but is not influenced by the use of FDG-PET scan at staging. Given the widespread use and high cost of FDG-PET, its clinical utility in ESFL should be further evaluated.

Disclosures:
No relevant conflicts of interest to declare.