bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relapsed Marginal Zone B-Cell Lymphoma: Clinical Features and Treatment Outcome.
Authors: Oh Sung Yong , Kim Won Seog , Kim Seok Jin , Kim Jin Seok , Kim Sung Hyun , Lee Dae Ho , Won Jong Ho , Hwang In Gyu , Kim Min Kyoung , Lee Soon Il , Kim Jong Gwang , Yang Deok-Hwan , Kang Hye Jin , Choi Chul Won , Park Jinny , Choi Young Jin , Kim Hyo Jung , Kwon Jung Hye , Suh Cheolwon , Kim Hyo-Jin 
Published: October 2019

Abstract
Abstract 5017

Background
Marginal zone B-cell lymphoma (MZL) has an indolent clinical course and long survival. During its long survival duration, MZL has tendency to relapse frequently. But the natural history and an optimal treatment modality for relapsed MZL has yet to be well established. So we performed a retrospective analysis of identifying the clinical features and outcomes of relapsed MZL.

Methods
From 1994 to 2008, a total of 92 patients with relapsed MZL were analyzed retrospectively.

Results
The median age of our subjects was 53.5 years (range: 23-82 years). This study involved 51 males (55.4%) and 41 females (44.6%). The most common primary sites of involvement were orbit and ocular adnexa (28.3%) followed by lymph node and lymphatic organs (23.9%), and multiple MALT sites (13.0%). The median time to relapse from initial diagnosis was 25.5 months (range: 1.6- 137 months). Of the 53 patients with stage I or II at diagnosis, 42 patients (79.2%) had been shown the loco-regional recurrence. Among these loco-regional relapsed patients, 27 patients were achieved CR (54.1%) or PR (18.9%). The other 11 patients (20.8%) had advanced stage at recurrence.
Adding to 39 patients initially advanced stage III or IV, totally 50 patients were advanced stage at relapse. Of these patients with advanced stage at relapse, 44 patients had been treated. The overall response rate was 54.5% (24 patients), with 18 CRs and 6 PRs.
The median time to progression (TTP) was 34.1 months (95% CI: 11.3-56.9 months) and the estimated 5-year OS was 84.3%.

Conclusion
Loco-regional recurrence was more dominant than distant metastases in stage I or II MZL regardless of treatment modality. Even though patients had relapsed MZL after initial treatment, most of them were well controlled with salvage treatment and could achieve prolong survival.

Disclosures
No relevant conflicts of interest to declare.
Increased Ratios of Internal Organ Volume to Body Mass in Chuvash Polycythemia and HIF-2α Repression of p21Cip Expression through C-MYC.
Authors: Yoon Donghoon , Okhotin David , Kim Bumjun , Okhotina Yulia , Okhotin Daniel J , Miasnikova Galina Y , Sergueeva Adelina I , Polyakova Lydia A , Maslow Alexei , Lee Yonggu , Semenza Gregg L , Prchal Josef T. , Gordeuk Victor R. 
Published: October 2019

Abstract
Abstract 5039
Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen sensing, is characterized by homozygous germ-line loss-of-function mutation of VHL (598C>T) resulting in elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased red cell mass and propensity to thrombosis. Organ size is determined by the size and number of cells, and its molecular mechanisms are not fully elucidated. Previous work from several groups demonstrated that cell proliferation is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing C-MYC from the promoter of the cyclin-dependent kinase inhibitor, p21Cip, and inducing its expression, while HIF-2α promotes MYC activity and cell proliferation. We determined the volumes of the liver, spleen, and kidneys and the diameter of the head of the pancreas by computerized tomography in 30 individuals with Chuvash polycythemia and 30 age- and sex-matched Chuvash controls and calculated the ratio of organ volume (or diameter) to body mass. The subjects with Chuvash polycythemia had larger ratios of the liver (P<0.01), spleen (P<0.01), kidneys (P<0.05) and head of the pancreas (P=0.05) than Chuvash controls. To test if HIF contributes to this phenotype, we examined Hif1a+/− mice and wild type littermates. We found that Hif1a+/− mice had larger median ratios of liver to body mass (factor of 1.5, P<0.005) and pancreas to body mass (factor of 1.3, P<0.05) than wild type mice. A hepatocyte size analysis revealed that there was no significant difference between Hif1a+/− and wild type mice. To identify how HIF contributes this phenotype, we performed gene expression profiles in the livers of Hif1a+/− and wild type littermates. The profiling results and subsequent individual confirmation showed that compared to wild type mice, Hif1a+/− mice had 2-fold higher HIF-2α mRNA levels (P<0.05) and 9.5-fold lower hepatic p21Cip mRNA levels (P<0.05). Our results showed that relative to body mass, liver, spleen, kidney and pancreas volumes are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21Cip1 levels, leading to increased hepatocyte proliferation.

Disclosures
No relevant conflicts of interest to declare.
EVI1 Is Activated During the Generation of Induced Pluripotent Stem (iPS) Cells.
Authors: Laricchia-Robbio Leopoldo , Montserrat Nuria , Giorgetti Alessandra , Belmonte Juan Carlos Izpisúa 
Published: October 2019

Abstract
Abstract 5048
EVI1 gene was first identified as a common site of retroviral integration in murine leukemia models. This gene is part of a complex genomic locus, MDS1-EVI1, that has been described as a target for retroviral integration that may lead to the emergence of a non-malignant dominant hematopoietic stem cell (HSC) clone in mice, in primates, and in humans. These studies suggested that one of the genes encoded by this locus could affect the self-renewal potential of HSC. Recent studies in mice revealed that indeed EVI1 plays an essential role in cell proliferation and it also enhances the self-renewal ability of HSC. The intense attention focused on the MDS1-EVI1 locus as retrovirus integration site prompted us to investigate whether EVI1 might have a role in somatic cell re-programming generated with retroviruses. Recent developments in stem cell research have enabled the re-programming of somatic cells to a pluripotent state using exogenous factors. Induced pluripotent stem (iPS) cells have the potential to differentiate into any cells types and that might be used in the future for clinical therapy. In order to elucidate the molecular events allowing the conversion of adult somatic into pluripotent stem cell, we evaluated EVI1 expression during this process. We found that EVI1 is activated in the early stages of re-programming and then it is silenced once the cells has been fully re-programmed. EVI1 seems to facilitate the initiation of cell re-programming by up-regulating a subset of genes previously described as potent stimulators of stem cells expansion.

Disclosures
No relevant conflicts of interest to declare.
The Effects of Site-Directed Mutation of SHIP Gene On the Regulating Mechanisms of PI3K/Akt Signal Pathway in Human Leukemia Cell Line K562.
Authors: Luo Jianmin , Yang Lin , Liu Xiaojun , Wen Shupeng , Zhang Jingyu 
Published: October 2019

Abstract
Abstract 5050

Introduction
SHIP is an SH2 domain containing inositol-5-phosphatasse that appears to be a negative regulator of hematopoiesis. Our previous researching works have first reported that SHIP gene was genetically altered in leukemia patients and proved that mutation of SHIP gene was closely correlated with the increased phosphorylation of Akt and poor prognosis of AML patients; SHIP gene is a key regulative gene in the PI3K/Akt pathway, and transfection with wild type SHIP gene into K562 cell line can inhibit the proliferation of K562. Up to now, however, there are no any reports about what changes of the PI3K/Akt signal transduction regulation will happened if SHIP has site mutation in leukemia cells. The objectives of our study is to investigate the effects of site-directed mutation of SHIP on the expression level of the protein related to the PI3K/Akt signal pathway in leukemia cells, and to study the effects of site-directed mutation of SHIP on the key PIP3 activity related to the PI3K/Akt signal pathway in leukemia cells.

Methods
Based on the results of our previous studies, the absence of endogenous SHIP in K562 cells provided a useful systerm to study the role of SHIP in growth and apoptosis. The recombined lentivirus plasmids wtSHIP or muSHIPP28L were transfected stably into human leukemia cells K562. The cell proliferation, cell life cycle and cell apoptosis of K562 transfected with wid-type SHIP or muSHIPP28L were determined by MTT, fluorescent staining and flow cytometry. The expression level and difference of total Akt□Ap-Akt473 and p-Akt308 were reconfirmed by SDS-PAGE western blot. PI(3,4,5)P3 and PI(3,4)P2 was assayed by High pressure liquid chromatography.

Results
The decreased ability of proliferation and DNA synthesis, cell colony fomation ability and enhanced apoptosis rate were observed in K562 cells transfected with wild-type SHIP (Group A), but the same changes had not been observed in K562 cells transfected with muSHIPP28L (Group B) or empty vector (Group C). Wild-type SHIP can down-regulate phosphorylations of Akt308 and Akt473, but muSHIPP28L can't. High pressure liquid chromatography results showed that the PI3,4,5-P3 level was obviously decreased in Group A,no changes above indicate in Group B and Group C. The PI3,4P2 level in Group A was significantly higher than Group B and Group C.

Conclusions
The results confirmed SHIP as a negative regulator for cell proliferation in leukemia cells, and implied that it may function through its normal structure.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of FACTOR IX-R338L (FACTOR IX PADUA) IN A COHORT of PATIENTS with Venous Thromboembolism and Mild Elevation of FACTOR IX LEVELS.
Authors: de Moraes Mazetto Bruna , Orsi Fernanda A. , Siqueira Lúcia Helena , de Paula Erich Vinicius , Mello Tayana B , Annichino-Bizzacchi Joyce Maria 
Published: October 2019

Abstract
Abstract 5057

Introduction
Elevated plasma levels of blood coagulation factor IX (FIX) have been associated with increased risk of venous thromboembolism (VTE) in humans. However, the molecular mechanisms underlying elevated FIX have not been elucidated. Recently, a mutation in the FIX gene resulting in a FIX molecule with Arginine Leucine substitution at position 338 (FIX-R338L or Factor IX Padua) has been associated with very high levels of FIX (776%) in a patient with spontaneous VTE. Recombinant expression of FIX-R338L confirmed the gain-of-function mutation.

Objective
Here we evaluated the levels of FIX and the prevalence of Factor IX Padua in a cohort of patients with VTE followed at our center. The prevalence of FIX Padua was evaluated by using a PCR-RFLP strategy by which PCR with specific primers was followed by digestion with the enzyme TaqI.

Results
The prevalence of FIX Padua was evaluated in a population of 192 patients with spontaneous VTE (69 males and 123 females; median age 36-yo). A population of 192 healthy individuals matched for age, sex and ethnicity was used as a control group for the determination of FIX levels. Median FIX levels was 128.0% (61.0-207.0%) in patients with VTE. Twenty-nine patients presented FIX levels above the 90th percentile (160.2%). Factor IX Padua was not identified in any patients or controls, even in those with elevated FIX levels.

Conclusion
in the present study FIX Padua was not identified in any of our patients, indicating that this mutation is not associated with mild elevations of FIX levels frequently observed in patients with VTE.

Disclosures
No relevant conflicts of interest to declare.
Heparin-Induced Thrombocytopenia: Comparison Between the Standard Gel-Particle Assay (PaGIA) and the Functional Flow Cytometric Assay.
Authors: Tomer Aaron 
Published: October 2019

Abstract 5060

Background
Heparin-induced thrombocytopenia and thrombosis (HIT) is an immune-mediated complication that may develop in patients sensitized to heparin. Approximately 5% of patients treated with full dose heparin develop clinical HIT, with about half develop thrombosis that may be associated with severe morbidity and death. However, antibodies may be detected in up to 30% of patients. Thus, current antibody-detection methods carry certain limitations, which pose a serious clinical dilemma in the diagnosis and treatment of HIT.

Objectives
To compare the gel-particle immuno-assay (PaGIA) for the detection of antibodies against heparin-PF4 complex, with the functional flow cytometric assay (FCA) which determines the capacity of the patient's serum to activate platelets in the presence of heparin, similar in concept to the gold-standard, the radioactive Serotonin-release assay.

Methods
Sequential samples from patients clinically suspected for HIT were tested by both PaGIA and the FCA (Tomer 1997, 1999).

Results
118 samples were tested. Positive: 9 (7.6%) patients tested positive by PaGIA, compared to 19 (16.1%) by the FCA. 7,out of the 9 (77.8%) PaGIA -positive samples were also positive by the FCA (relative sensitivity). Negative: 97 out of 109 gel-negative samples (89.0%) were also negative by the FCA (relative specificity). Thrombosis occurred in 3 of the 9 PaGIA-positive (33%) patients, and in 7 of the 19 FCA-positive (36.8%) patients. Of the 12 PaGIA -negative but FCA-positive patients, 4 (33%) had thrombosis. Death rate was also higher among FCA-positive (n=3) compared to PaGIA-positive (n=1) patients. Of the two PaGIA -positive but FCA-negative patients, one had APLA syndrome (APS) with chronic thrombocytopenia, and one had sepsis with cardiogenic shock and multiorgan failure.
ROC-Plot: Overall, the FCA showed significantly higher correlation with the clinical presentation of HIT (4Ts score), compared to the PaGIA (AUC 0.86 vs. 0.62, p<0.001)

Conclusion
The functional FCA demonstrates superior sensitivity and specificity compared to the antibody- detection PaGIA gel-particle assay. The feasible functional FCA (results in 1.5 hr) might be useful for initial diagnosis of HIT, and particularly for confirmation of HIT in patients with confounding presentation, including negative antibody-detection assay.

Disclosures
No relevant conflicts of interest to declare.
In Vivo Monitoring of Venous Thrombosis in Mice.
Authors: Aghourian Meghedi , Blostein Mark 
Published: October 2019

Abstract
Abstract 5061
Venous thromboembolism afflicts 117 people per 100,000 each year and is an important cause of morbidity and mortality. There has been extensive research dedicated to the clinical aspect of venous thrombosis, especially with regards to its diagnosis and treatment. However, animal models studying this phenomenon are scarce and, in most cases, very crude. Developing a murine model of venous thrombosis using techniques similar to the ones used to detect thrombosis in humans can be a constructive step in studying this phenomenon in more detail. The model developed in our lab uses ultrasound imaging to visualize venous clots in the Inferior Vena Cava (IVC) of mice, allowing for precise measurements of the formed clot. Ligation of the IVC is one of the well established models for studying thrombosis in mice. We ligated the IVC of wild type C57B6 mice, and allowed them to recover. We then followed clot formation at several time points after the operation using micro-ultrasonography, the Vevo 770®, a novel imaging ultrasound technology designed to monitor murine vasculature. To assess the precision of the clot measurements, we then sacrificed the mice, and dissected out the thrombi in order to precisely measure and weigh them. A thrombosis develops only after 5 hours of ligation post surgery when a clot is visualized in the IVC. The clot increases slightly over the next 24 hours. The measurements of the clot after dissection correlates favourably with the measurements done by ultrasonagraphy using the Vevo770®. These data suggest that the Vevo770® can be used as a reliable technique for non-invasive assessment of venous thromboembolism in mice. Developing a murine model for thrombosis using more accurate, and clinically more relevant techniques such as ultrasonography, is a step towards better understanding and treatment of venous thromboembolism.

Disclosures
No relevant conflicts of interest to declare.
Elevated Levels of Cytokines and Chemokines in Patients with Antiphospholipid (aPL) Antibodies.
Authors: Pierangeli Silvia S , Martinez-Martinez Laura Aline , Aguilar-Valenzuela Renan , Gwin Gerald Mc , Doan Ellis , Papalardo Elizabeth , Vega Jo Ann , Gonzalez Emilio B. , Murthy Vijaya , SEif Alan , Erkan Doruk 
Published: October 2019

Abstract
Abstract 5062

Purpose
Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) are two closely related diseases. APL antibodies are present in 30-40% of SLE patients. Studies have indicated that certain cytokines, chemokines, tissue factor (TF), vascular endothelial growth factor (VEGF), soluble (s) E-selectin (sE-sel), tumor necrosis (TNF)-a, may be associated with APS and/or SLE. However, whether those biomarkers are elevated in plasma of APS patients with or without SLE is uncertain. Here we examined whether the levels of cytokines/chemokines in aPL antibody-positive patients positive are different from controls.

Methods
Twenty-two sera/plasma of patients with significantly and persistently elevated levels aPL antibodies (IgG and/or IgM aCL, and/or IgG and/or IgM anti-β2glycoprotein I (β2GPI) and/or positive lupus anticoagulant (LAC), demographic and clinical data were obtained from an on-going pilot clinical study (clinical trials.gov#NCT00674297). Patients that were on more than 10 mg prednisone/day, or on other immunosuppressive therapy, or on hydroxychloroquine or on statins were excluded. Thirty-two healthy donors with no evidence of autoimmune, infectious or inflammatory diseases were used as controls. .Levels of IL1b, IL6, IL8, TNF-a, VEGF, IP-10, sCD40L were measured in serum using a Millipore Millliplex” Multiplex Assay; titers of sE-sel, and sTF were detected by ELISA. The Kruskal-Wallis test was used to compare levels of biomarkers in aPL positive subjects vs. controls and Spearman tests to correlate levels of the biomarkers in the different subgroups of patients.

Results
Significant number of aPL-positive samples had elevated levels of IL1b, IL6, TNF-a, VEGF, IP-10, sCD40L, sTF, sCD40L and sE-sel and their titers were significantly different when compared to controls. APS /SLE patients (n=8) showed significantly higher levels of TNF-a compared to APS without SLE (n=6), to “asymptomatic” aPL positive (n=4), to “asymptomatic” aPL positive with SLE (n=2) or with “catastrophic” APS (n=2) patients (p=0.00630).

Conclusions
This study underscores the importance of identifying biomarkers of disease that may help to better understand pathogenic mechanisms, predict disease activity and possibly to better address treatment of patients with aPL antibodies.

Disclosures
No relevant conflicts of interest to declare.
Characteristics and Outcomes of Pulmonary Embolism IN CANCER PATIENTS and IN PATIENTS without CANCER.
Authors: Karippot Asha , Maroules Michael , DeBari Vincent A 
Published: October 2019

Abstract
Abstract 5065

Background
Venous thromboembolism (VTE), a frequent complication in cancer and, occasionally, a harbinger of occult cancer, is one of the leading causes of death in cancer patients. VTE recurs with a three-fold greater frequency in cancer patients than in patients who do not have cancer, and requires long-term anticoagulation. There is a two-fold greater risk of bleeding complications in these patients compared to patients who do not have cancer. Because pulmonary embolism (PE) is a life-threatening sequel of VTE, we sought to evaluate the hypothesis that cancer patients suffer from extensive pulmonary embolism (involving central pulmonary artery or bilateral pulmonary arteries) and to determine if we could detect differences in two clinical outcomes, length of stay (LOS) and mortality.

Patients and Methods
This retrospective cohort of subjects with pulmonary embolism (PE) was developed using data beginning in January 2003 to December 2007 at a 680 bed, urban teaching hospital. The cohort of 118 patients with PE diagnosed with CT angiogram yielded 41 patients in cancer group (20 males and 21 females) and 47 (23 males and 24 females) patients in non cancer group. Other baseline characteristics gathered for the two groups included age, gender, race, co-morbidities, ambulatory status and therapeutic interventions. Criteria for being assigned to the “central PE” were a filling defect in the pulmonary arteries or the main stem. Patients who showed filling defects in both central and peripheral vessels were also assigned to the “central PE”. All other patients with filling defects in one or more peripheral vessels were assigned to the “peripheral PE” group.

Results
The baseline characteristics did not show significant differences between the groups. Our data demonstrated that central PE was strongly associated with the cancer group (26/41; 63.4%) compared with 15 of 47 (31.9%) in the non-cancer group (OR = 3.70; 95% CI: 1.53 to 8.95; p = 0.0051). The common cancers associated with VTE were genito–urinary (13) followed by gastro-intestinal (10), then lung and breast (6 in each group). LOS was significantly greater in the cancer group (median: 9d; IQR: 7-19d) compared to non-cancer group (median: 7d; IQR: 5-11d; p = 0.032. We detected no significant difference in overall mortality between the two groups (p = 0.11). Kaplan-Meier analysis of survival, similarly, demonstrated no significant difference (95% CI of HR: 0.62 to 3.18; p = 0.42)

Conclusion
Cancer patients appear to be at a higher risk for central PE and have longer stay in the hospital after diagnosis than patients without cancer. However, in this study we did not detect increased mortality over a twelve-month observation period.

Disclosures
No relevant conflicts of interest to declare.