bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Analysis of VWF Multimerization Patterns In a well-defined TTP Cohort
Authors: Yang Shangbin , Haven Sara , Jin Ming , Geyer Susan , Cataland Spero R , Wu Haifeng 
Published: October 2019

Abstract
Abstract 4308
VWF function has long been implicated in TTP's pathogenesis. Initial study reported unusually large (UL)VWF multimers in patients with relapsing TTP. Later, ULVWF were demonstrated in TTP patients during remission that are acutely consumed at the onset of disease. However, many detailed steps concerning the timely relationship between VWF multimerization and clinical courses such as disease onset, mortality, disease refractoriness, and treatment response are still missing. In this study, we performed VWF multimeric analyses in over 400 serial samples longitudinally collected from more than 20 TTP patients at various clinical stages, including initial presentation, acute treatment, clinical remission, and clinical visits prior to TTP relapses. At the time of acute presentation, approximately 50% of cases show presence of ULVWF multimer patterns, while around 35% demonstrate acute consumption of UL and high molecular weight VWF multimers. The other 15% of cases however reveal normal VWF multimer patterns at the time of disease presentation. For the TTP patients who normally respond to plasma exchange (PE) therapy, a mild ULVWF multimer pattern may be present after discontinuation of daily PE therapy. Upon restoration of ADAMTS13 activity and achievement of sustained remission, VWF multimer patterns are normalized. During the period of daily plasma exchange for acute episodes of TTP, a persistent presence of ULVWF multimer patterns appears indicative of disease refractoriness and is associated with disease mortality. In the course of this study, ADAMTS13 activity levels (reportable range of 0.5 % –100%) in these longitudinal samples were also precisely determined using SELDI-TOF mass spectrometry to establish the correlation between ADAMTS13 activity measured in vitro and VWF multimeric patterns formed in vivo. Our study for the first time defines the dynamic changes of VWF multimeric patterns in relation to the evolution and natural history of TTP in a large well-defined clinical cohort. These novel observations provide new implications into the pathobiology of TTP and may help to develop new biomarkers for monitoring therapeutic responses and for screening for TTP relapses.

Disclosures:
No relevant conflicts of interest to declare.
Kruppel-Like Factor 10 (KLF10)-Deficient Mice Have Marked Defects In EPC Differentiation, Function, and Angiogenesis
Authors: Wara Akm Khyrul , Croce Kevin , Foo ShiYin , Sun Xinghui , Icli Basak , Tesmenitsky Yevgenia , Cao Zhuoxiao , Esen Fehim , Subramaniam Malayannan , Kutok Jeffery , Rodig Scott J. , Spelsberg Thomas , Rosenzweig Anthony , Feinberg Mark 
Published: October 2019

Abstract
Abstract 4314

Background:
Emerging evidence demonstrates that endothelial progenitor cells (EPCs) may originate from the bone marrow and are capable of being recruited to sites of ischemic injury and contribute to neovascularization. However, the identities of these bone marrow cells and the signaling pathways that regulate their differentiation into functional EPCs remain poorly understood.

Methods and Results:
We previously identified that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) can preferentially differentiate into EPCs and possess high angiogenic activity under ischemic conditions compared to megakaryocyte-erythrocyte progenitors (MEPs), hematopoietic stem cells (HSCs), and common lymphoid progenitors (CLPs). Herein, we identify that a TGF-β1-responsive Kruppel-like Factor, KLF10, is robustly expressed in EPCs derived from CMPs and GMPs, compared to progenitors lacking EPC markers. KLF10–/– mice have marked defects in circulating EPCs (–23.6% vs. WT, P&lt;0.004). In addition, EPC differentiation and TGF-β induced KDR responsiveness is markedly impaired (CMPs: WT 22.3% vs. KO 8.64%, P&lt;0.0001; GMPs: WT 32.8% vs. KO 8.97%, P&lt;0.00001). Functionally, KLF10–/– EPCs derived from CMPs and GMPs adhered less to fibronectin-coated plates (CMPs: WT 285 vs. KO 144.25, P&lt; 0.0004; GMPs: WT 275.25 vs. KO 108.75, P &lt;0.0003) and had decreased rates of migration in transwell Boyden chambers (CMPs: WT 692 vs. KO 298.66, P&lt;0.00004; GMPs: WT 635.66 vs. KO 263.66, P&lt;0.00001). KLF10–/– mice displayed impaired blood flow recovery after hindlimb ischemia (day 14, WT 0.827 vs. KO 0.640, P &lt;0.009), an effect completely rescued by WT EPCs, but not KLF10–/– EPCs. Matrigel plug implantation studies demonstrated impaired angiogenesis in KLF10–/– mice compared to WT mice (WT 158 vs. KO 39.83, P&lt;0.00000004). Overexpression studies revealed that KLF10 rescued EPC formation from TGF-β1+/– CMPs and GMPs. Mechanistically, TGF-β1 and KLF10 target the VEGFR2 promoter in EPCs which may underlie these effects.

Background:
Collectively, these observations identify that TGF-β1 signaling and KLF10 are part of a key signaling pathway that regulates EPC differentiation from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.

Disclosures:
No relevant conflicts of interest to declare.
Cell Adhesion Molecule 1 (CADM1), a Novel Venous Thrombosis Risk Factor, Is Ubiquitously Present In Vascular Endothelium and Smooth Muscle Cells
Authors: Tatsumi Kanayo , Taatjes Douglas J , Bouchard Beth A , Trotman Winifred , Bovill Edwin G 
Published: October 2019

Abstract
Abstract 4316
We recently demonstrated that CADM1, interacting with protein C deficiency, is a novel risk factor for venous thrombosis (VT) Blood 114:3084-3091, 2009. CADM1 likely plays a role in maintaining endothelial barrier function. Prior to this study CADM1 had not been identified in endothelial cells. In this study we have determined the distribution of CADM1 in human vasculature.

Methods:
Human tissue samples representing all organs as well as large vessels were accessioned from archived paraffin blocks from the surgical pathology division of FAHC. Tissue sections were processed for immunoflourescence using as primary antibodies a chicken monoclonal anti-CADM1 IgY antibody (anti-SynCAM/TSLC1 clone 3E1, MBL Inc, Woburn, MA) and anti-smooth muscle actin (SMA) clone 1A4 (Sigma, St. Louis, MO), anti-von Willebrand factor (vWF) rabbit polyclonal antibody (DAKO Inc., Glostrup, DK). vWF staining was used to identify endothelial cells. The secondary antibodies for CADM1, SMA, and vWF were donkey anti chicken alexa 488, donkey anti mouse alexa 647, and donkey anti rabbit alexa 647, respectively. Appropriate negative and positive controls were run. Intensity of staining was rated as absent, trace or present by three observers (TK, DJT, and EGB). Immunoelectron microscopy (IEM) was performed on cultured human umbilical vein endothelial cells (Allcells LLC, Emeryville, CA) using a post embedding procedure with protein-A gold. Peripheral blood leukocytes were evaluated for the presence of CADM1 using the same antibody following cytospin preparation.

Results
CADM1 was found ubiquitously in the macro- and micro-vasculature of all organs as well as the aorta and saphenous vein with intensity of staining showing modest variability from organ to organ. CADM1 staining of SMA was observed in both arterial and venous vessels but was considerably stronger on the arterial side. IEM demonstrated cytoplasmic immunogold staining associated with elements of rough endoplasmic reticulum and actin filaments as well as at the membranes of filopodia. In contrast, peripheral blood monocytes, lymphocytes and granulocytes were negative for CADM1expression.

Conclusions:
CADM1 is expressed ubiquitously in endothelial and smooth muscle cells of the macro-and micro-vasculature with IEM evidence for its presence in filopodial cytoplasm and membranes. Peripheral blood leukocytes did not show evidence of CADM1 expression. This is the first report of CADM1 positivity in vascular smooth muscle cells. The biological role of CADM1 remains to be determined but its ubiquitous expression in the endothelium of the macro- and micro-circulation, together with an apparent role in endothelial cell motility, suggests an important role in endothelial homeostasis.

Disclosures:
Bovill: Haemotologic Technologies, Essex Jct., VT: Equity Ownership.
Circulating Plasma Levels of Connective Tissue Growth Factor (CTGF) Are Elevated In Patients Afflicted with Rheumatoid Arthritis
Authors: Del Carpio-Cano Fabiola , Rico Mario C , Kunapuli Satya P. , Safadi Fayez , De La Cadena Raul A. 
Published: October 2019

Abstract
Abstract 4320
Biologic therapy for rheumatoid arthritis (RA) targets specific molecules that mediate and sustain the clinical manifestations of this complex illness. Compared with the general population, patients with RA are at an increased risk to develop cardiovascular diseases and the precise mechanism(s) of action remain obscure. This laboratory has proposed the existence of a pro-inflammatory axis in RA comprised by thrombospondin-1 (TSP1), transforming growth factor-beta (TGF-b) and CTGF. The present study evaluated plasma levels of TSP1, TGFb and CTGF in patients with RA by ELISA as well as specific cytokines and chemokines. CTGF plasma levels in RA patients (9.2 pg/ml mean, range 3.44–17.08) were found significantly increased (P<0.047) when compared to control subjects (mean 4.43 pg/ml, range 1.62–7.35). This is the first report in the medical literature documenting an augmented human plasma circulating levels of CTGF in RA. TSP1 circulating levels were found elevated in RA patients when compared to control subjects (mean 315 ng/ml vs. 25.4 ng/ml respectively, P<0.039). TGFb showed a trend for higher levels in patients with RA (10.1 ng/ml vs. 4.5 ng/m, P<0.095). The source CTGF in plasma could not be determined precisely but there is evidence of platelet activation in RA (Platelets 19:146, 2008), and TSP1 is the major content of the platelet a-granule (25%). CTGF can attract monocytes and both have been found co-localized in atherosclerotic plaques (Circulation 95, 831, 1997). IL-6 (P< 0.05), IL-12p70 (P<0.04), IP-10 (P<0.03) and MIP1b (P<0.016) were increased in the RA patients when compared to controls. Recent findings have placed platelet microparticles (Science 327; 580, 2010) as playing a major role (arsonists) in RA via monocytes and neutrophils. In summary, our results provide evidence that a pro-inflammatory axis is active in RA potentially contributing to cytokine changes as well as the cardiovascular disease associated with RA since TSP1 can induced IL-6 generation from monocytes and can activate inert TGFb on cell surfaces (fibroblasts and synoviocytes) with the subsequent up-regulation of CTGF. Disruption of the axis in experimental models of RA may prove to be an emerging therapeutic target in RA. Elucidation of the source of CTGF should provide as well key information for cell-targeting to prevent CTGF secretion into the blood milieu.

Disclosures:
No relevant conflicts of interest to declare.
Irradiation-Induced Growth Hormone Neurosecretory Disfunction In ALL Patients
Authors: Biceroglu Gulay , Akcay Teoman , Aydogan Gonul , Akcay Arzu , Akici Ferhan , Tugcu Deniz , Salcioglu Zafer , Sayilan Hulya , Ayaz Nuray 
Published: October 2019

Abstract
Abstract 4329
With the recent developments in the treatment of ALL life expectancy is prolonged and complications due to therapy are increased. Combined chemotherapy may be applied in combination with distinct doses and schema of cranial radiotherapy according to the risk groups of patients. CRT damages the hypothalamus-hypophysis axis and affects the secretion of growth hormone (GH) at first and the other anterior hypophysis hormones also. At high doses of CRT, GH deficiency might occur in the long term follow-up, at lower doses the secretion pattern of GH may change. In this study, GH axis of the ALL patients treated with prophylactic CRT were evaluated.
Thirty-two children (14 girls and 18 boys), diagnosed as ALL and applied prophylactic cranial therapy were enrolled to the study. Physical findings, weight and height measurements, Tanner stagings and bone age evaluations were performed to all patients. In order to interpret the functions of anterior and posterior hypophysis morning basal IGF-1, IGFBP-3, thyroid hormones, cortisol, prolactin and dansity of urine were measured. Gonodotrophins were not tested because none of our patients had the signs of early or late puberty. In order to evaluate the growth rate, weights and heights of the patients were measured after the first year. Even though the growth rate of some patients were normal, GH stimulation tests with clonidine were done to all cases, due to the fact that GH deficiency and neurosecretory dysfunction might be present pharmacologically. Second GH stimulation test with L-dopa were applied to patients with peak GH levels of <10 ng/ml. If the level was low in the second test, patients were accepted as GH deficient. For patients with low growth rate, low IGF-1/IGFBP-3 according to age and sex, but normal GH levels, night GH secretion pattern were tested. Patients with inadequate response to night secretion test were accepted as neurosecretory dysfunction.
In our study, 25% of the patients were found to have complete and 21,7% incomplete GH deficiency. In 9.3% of cases there was GH-neurosecretory dysfunction (GH_NSD). There was no statistically significant relationship between the time passed after radiotherapy and GH axis dysfunction degree. IGF-BP3 was found to be more reliable than IGF-1 in estimating GH deficiency/GH-NSD.
As a result, it is clear that prophylactic CRT affects the GH axis negatively in ALL patients, so their close follow-up is precious and mandatory.

Disclosures:
No relevant conflicts of interest to declare.
Hypercvad+Bortezomib Is a Well Tolerated Salvage Regimen for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia
Authors: Raychaudhuri Jyotishankar , Ahmad Mudhasir , Kalra Manas , Dua Harsh , Chopra Rakesh , Rawat Sangeeta , Thakur Rashmi 
Published: October 2019

Abstract
Abstract 4345
We report the excellent tolerability of a regimen of HyperCVAD+Bortezomib for relapsed/refractory ALL in adults. The regimen consisted of addition of two doses of Bortezomib 2 mg(1mg/m2) on day 1 and day 4 of the HyperCVAD regimen(arm A). The doses of bortezomib were given an hour after the second dose of cyclophosphamide on day 1 and on day 4. GCSF 10 mcg/kg was used from nadir to recovery of ANC > 500. Two patients, one with relapsed ALL and the second with primary induction failure were treated with this regimen after informed consent. The first patient was a 38 year male who was diagnosed with Ph+ ALL four years ago and had relapsed three years later on maintenance treatment. He was subsequently treated with Adriamycin, Etoposide and Cyclophosphamide with minimal response. Last bone marrow showed 35–40% blasts. The second patient was 40 year female with CALLA + Pre-B cell ALL with primary induction failure with a BFM regimen. Both patient reached nadir counts by day 10–11 and recovered the absolute neutrophil counts > 500 by day 16. There was minimal blood product requirement and minimal episodes of neutropenic fever which were treated as per institutional protocol. All cultures were negative. Isolation was not required. Strict aseptic precautions were maintained. Minimal grade I mucositis occurred in the first patient. Minimal diarrhea with nausea and vomiting occurred in the second patient on day 15. No neuropathy was noted. On day +21, the first patient, who was resistant to multiple chemo agents still has 40% blasts in the marrow but also shows recovery of the normal marrow elements. The second patient, who had primary induction failure is in complete remission in the marrow. One report of a phase I trial by Messinger et al from Minnesota showed the feasibility and tolerability of Bortezomib added to VXLD in pediatric ALL. Horton et al from a COG phase I study did not find any objective responses to single agent Bortezomib in resistant leukemia even though it suppressed NfKB activity. This is the first report to our knowledge on the use of salvage bortezomib based regimen in relapsed/refractory adult ALL. We used low dose bortezomib(1 mg/m2) after the administration of chemotherapy on day 1 and day 4. The timing of bortezomib just after chemotherapy is probably important. One ASH abstract #949(2007) by Lonial et al suggested that Bortezomib following high dose melphalan in multiple myeloma results in increased apoptosis of MM cells than if Bortezomib precedes melphalan. We plan to proceed to a phase II trial to test this regimen in relapsed/refractory ALL.

Disclosures:
Off Label Use: Bortezomib as chemosensitizer with Hyper CVAD in ALL.
Protein Degradation and Resultant Hsp90 Dephosphorylation as An Alternative C-KIT Kinase Inhibition Strategy
Authors: Zhang Bo , Fang Haitong , Pan Xiaofen , Xie Jun , Chen Yonglong , Chen Sai-Juan , Zhou Guangbiao 
Published: October 2019

Abstract
Abstract 4361
Occupying the ATP binding pocket represents a common strategy for tyrosine kinase inhibition, exemplified by imatinib mesylate in BCR-ABL positive leukemia and gefitinib in EGFR mutated lung cancer. Here we report that the natural compound triptolide and proteasome inhibitor Bortezomib induce C-KIT turnover in cancer cells. Bortezomib triggers a clathrin-mediated endocytosis and lysosomal degradation of KIT in t(8;21) leukemia. While phosphorylation of heat shock protein 90 (Hsp90) by KIT is required for Hsp90-caused suppression of apoptosis, Bortezomib causes dephosphorylation of Hsp90 and lease of Apaf-1/cytochrome C, leading to reactivation of caspase-3 which cleaves the t(8;21)-generated AML1-ETO/AML1-ETO9a oncoproteins with production of cleavage fragments. The cleavage fragments antagonize the parental proteins in vitro and in vivo. Intriguingly, Bortezomib shows potent anti-leukemia efficacy in two murine models. These data indicate that degradation of C-KIT/dephosphorylation of Hsp90 represents a novel strategy for kinase inhibition, and drugs inhibiting both transcription factor and kinase could be a powerful therapeutic regimen for human leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Comparing Induction and Consolidation with or without Cytarabine In the Treatment of Acute Promyelocytic Leukaemia In Hong Kong Chinese
Authors: Law Man Fai , Yip Sze-Fai , Chan Hay Nun , Yeung Yiu Ming , Choi Wai 
Published: October 2019

Abstract
Abstract 4366
Previous studies suggested that cytarabine was not required in the treatment of newly diagnosed acute promyelocytic leukaemia (APL). They suggested that omitting cytarabine in the treatment of APL could reduce treatment toxicity without increasing relapses and affecting survival. No previous study assessed the effect of cytarabine in the treatment of Chinese APL patients.
We compared the outcome of APL patients with or without cytarabine in induction and consolidation therapy in Hong Kong Chinese in a local hospital.

Method
It was a retrospective study of newly diagnosed APL patients from Jan 1996 to Dec 2009. They were divided into two groups. One group was given ATRA (All-trans-retinoic acid) 45mg/m2/day combined with daunorubicin 60mg/m2/day for 3 days plus cytarabine 200mg/m2/day for 7 days as induction therapy. It was followed by two courses of consolidation with daunorubicin and cytarabine and then 2-year maintenance with low dose chemotherapy and intermittent ATRA. Another group was given the same treatment without cytarabine. The remission rate, relapse rate, overall survival and event-free survival were compared in the two groups of patients.

Results
Eighteen patients with median age of 41 (range 24–62) received cytarabine. 22% of them had initial WBC count >10,000/uL. Eight patients with median age of 42 (range 16–57) received no cytarabine. 25% of them had WBC count >10,000/uL. The complete remission rates were 100% in both groups. The two-year relapse rate was 5.5% (1/18) for cytarabine group and 62% (5/8) for no cytarabine group (p=0.004, Fisher's exact test).
The two-year event-free survival was 82% for cytarabine group and 37% for no cytarabine group (p=0.0017). The two-year overall survival was 89% for cytarabine group and 75% for no cytarabine group (p=0.18). The adverse effects profile was similar in both groups.

Conclusion
The results support a role of cytarabine in addition to ATRA and daunorubicin in the treatment of newly diagnosed APL. The relapse rate was much lower in patients receiving cytarabine. The two-year event-free survival and two-year overall survival were also significantly better in the cytarabine group.

Disclosures:
No relevant conflicts of interest to declare.
Incidence and Clinical Features of Acute Promyelocytic Leukemia In a Population-Based Canadian Cohort
Authors: Paulson Kristjan , Szwajcer David , Ahsanuddin Arshad , Lambert Pascal , Turner Donna , Rubinger Morel , Kumar Rajat , Seftel Matthew D. 
Published: October 2019

Abstract
Abstract 4374

Introduction:
Acute promyelocytic leukemia (APL) is a rare malignancy whose causes and epidemiology are not well known. The incidence of APL in the United States was estimated to be 0.22 cases per 100,000 population, and a higher incidence has been suggested in specific geographic or ethnic sub-groups. However, clinical and epidemiological data on APL arise primarily from clinical trials and single centre experiences rather than population-based data, which may lead to selection bias. We studied a cohort of APL cases in a well defined population using the diagnostic gold standard of polymerase chain reaction (PCR) testing.

Methods:
The Canadian province of Manitoba, with a population of 1.2 million, has a single referral centre for the definitive diagnosis and clinical care of all acute leukemia patients. Only one laboratory is capable of performing PCR based testing for the PML-RARA fusion gene product. We examined consecutively diagnosed patients with APL based on PCR testing from January 1999 until July 31 2010 in order to determine the incidence, clinical characteristics, and outcomes of patients with APL.

Results:
Over the 11.5 year period of observation, 24 patients were diagnosed with APL. Based on the 2006 Canadian census, the annual incidence of APL in Manitoba is thus 0.18/100,000 population. These cases did not appear to be distributed evenly, with an average of 1.1 cases diagnosed annually between 2002 and 2008 compared to six cases diagnosed in the most recent period between 2009 and 2010 (relative to 2002–2008, incident rate ratio (IRR) 2.61, p = 0.075) and ten cases diagnosed between 1999 and 2001 (IRR 2.94, p = 0.023). Symptomatic CNS disease at diagnosis was present in 3 (12.5%) patients. Thirteen patients developed differentiation syndrome during the course of their therapy (54.1%). In all but one patient, ATRA was able to be successfully resumed. Ten patients presented with DIC (41.7%).

Conclusions:
In this population-based study, we noted episodic clustering of new cases and a relatively high proportion of CNS disease at diagnosis. While these observations may be due to normal fluctuations in the patterns a rare disease, this could also suggest an underlying environmental trigger. Additional investigation is required to confirm or refute this hypothesis, due to the relatively small numbers in this cohort. The high rate of CNS disease suggests that this finding maybe more common than previously thought. As the pathogenesis of APL remains unclear, these observations deserve additional epidemiological investigation in larger cohorts.

Disclosures:
Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees.