bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the Molecular Action of Bortezomib Treatment In Multiple Myeloma
Authors: Ballabio Erica , Chen Xiao-He , Tramonti Daniela , Wainscoat James S. , Boultwood Jacqueline , Hatton Chris S.R , Lawrie Charles H. 
Published: October 2019

Abstract
Abstract 5038
Bortezomib (Velcade®) is a 26S proteasome inhibitor currently used for the treatment of relapsed multiple myeloma (MM) and more recently mantle cell lymphoma patients. Clinical trials are under way to evaluate its efficacy in other hematological malignancies diseases including diffuse large B cell lymphoma (DLBCL). Although it was widely accepted that bortezomib acts as a NF-κB inhibitor, this view has recently been challenged by work by Hideshima et al. (Blood 2009) who found that treated myeloma cells actually displayed down-regulation of NF-κB inhibitors (IκBα), increased activity of pro-NF-κB molecules (RIP2 and IKKβ) as well as increasing levels of NF-κB DNA binding. Additionally, although bortezomib has a potent anti-tumor activity, not all MM patients are responsive. The identification and understanding of the molecular mechanisms leading to bortezomib-resistance will help with the development of new approaches and will improve the treatment of these patients. In order to investigate the direct effect of bortezomib on lymphomas, we treated different cell lines with this drug and levels of cell proliferation and apoptosis were measured. Bortezomib was shown to significantly inhibit proliferation and promote apoptosis in MM cell lines (RPMI-8226, NCI-H929, JJN-3 and Thiel) and DLBCL cell lines (SU-DHL-4 and SU-DHL-10, HLY-1, HLB-1 and RIVA). Since MM cell lines were shown to be the most sensitive to the bortezomib, we selected them to carry out further studies. We next employed whole genome expression arrays (Affymetrix U113plus2.0) and microRNA arrays to identify molecules associated with treatment in these cell lines. Using unsupervised cluster analysis, we observed that the cells treated with bortezomib have a distinct microRNA and gene expression profile from their counterpart controls. Additionally, we used a shRNA whole-genome library to carry out a loss-of-function screen for cells resistant to bortezomib-induced apoptosis. The RPMI-8226 cell line was transduced with the shRNA library. One half of the cells was then treated with bortezomib. Relative gene expression levels were measured by hybridizing samples to custom-made arrays. Unsupervised cluster analysis identified a number of shRNAs which might be involved in mechanisms of resistance to bortezomib. Further functional studies will be necessary to investigate the role of these microRNAs in the mechanism of action of bortezomib.

Disclosures:
No relevant conflicts of interest to declare.
New Cases of Acute Promyelocytic Leukemia Treatment by Arsenic Trioxide Alone and Their Long Term Follow up
Authors: Ghavamzadeh Ardeshir , Alimoghaddam Kamran , Rostami Shahrbano , Ghaffari Seyed Hamidolah , Jahani Mohamad , Jalili Mahdi , Mousavi Seyed Asadollah , Iravani Masood , Baybordi Eisa , Bahar Babak , Alizadeh Nassrin 
Published: October 2019

Abstract
Abstract 506
Long term follow-up of APL patients treated by ATRA and chemotherapy is available and shows promising results of DFS and OS. Although several studies show acceptable efficacy of Arsenic Trioxide in new cases of APL, its long term result needs better clarification.

Materials and methods:
one hundred ninety seven, new cases of APL treated by Arsenic trioxide (0.15 mg/kg daily i.v infusion till complete remission). After achieving to CR patients received 4 more courses of Arsenic trioxide as consolidation. Then patients followed by CBC and RT-PCR on peripheral blood for detection of MRD every three months or till relapse or death.

Results:
Morphologic complete remission rate was 85.8% and most common cause of remission failure was early death due to hemorrhage of APL differentiation syndrome.(14.7%) Most important prognostic factor for early mortality is high WBC count at presentation. Disease free survival was 90%+/−2%, 72.7%+/−3% and 66.7%+/−4% for 2, 3 and 5 years respectively. Relapse for patients who remained in CR after 5 years was very uncommon. Overall survival for patients after diagnosis by intention to treat analysis was 80.2%+/−3%, 75.9%+/−3% and 64.4%+/− 4% for 2, 3 and 5 years. Also OS and DFS were the same between patients with high and low WBC count.

Conclusion:
Long term follow up of newly diagnosed cases of APL, treated with single agent Arsenic Trioxide shows promising result. Arsenic trioxide potentially eliminates the adverse effect of prognostic factors of APL treatment such as high WBC count. We suggest that it is time to integrate Arsenic trioxide in treatment of new cases of APL.

Disclosures:
No relevant conflicts of interest to declare.
Decitabine and Gemtuzumab Ozogamicin In Patients with Advanced Myelofibrosis
Authors: Al-Ameri Ali Al-Ameri , Kantarjian Hagop , Malik Asifa , Badoux Xavier , Andreeff Michael , Quintas-Cardama Alfonso , Borthakur Gautam 
Published: October 2019

Abstract
Abstract 5061

Background:
While hypomethylating agents, azacitidine and decitabine, are approved for use in treatment of myelodysplastic syndromes (MDS), their role in treatment of myeloproliferative disorders is evolving. The modified dosing schedule of decitabine (20 mg/m2 IV for 5 days) in MDS has shown overall response rates of approximately 40%. A clinical study of azacitidine in myelofibrosis (MF) has shown a response rate of 32%. We investigated the activity of the combination of decitabine and gemtuzumab ozogamicin (GO) (anti-CD33 antibody), a combination with activity in patients with MDS and acute myelogenous leukemia (AML), in patients with advanced myelofibrosis.

Patients and Method:
We reviewed the records of patients with MF treated with the combination of decitabine and GO.

Result:
Seven patients were treated till the decisions by FDA to withdraw GO from the market. Age ranged from 60–69 years (median 65 years), 5 patients were male and no of prior therapies ranged 0–4 (median2). Three patients had MF progressed to acute myeloid leukemia. Prior treatments included, hydroxyura, thalidomide, prednisone, pomolidamide etc. All patients were positive for JAK 2 V617F mutation. Cytogenetic abnormalities were seen in 4 patients (hyperdiploid, complex or -5/-7) and 3 were with diploid cytogenetics. Five patients received 3 cycles of Decitabine plus myelotarg while 2 patients had only one cycle. Four patients had stable disease, one had clearance of marrow blasts (40%>0%), two had no response. Three patients showed decreases in splenic size. Clinically significant infectious complications were encountered in 4 patients.

Conclusions:
The combination of decitabine and GO showed early signs of activity in patients with MF but future investigation of this combination will be limited due to lack of access to GO.

Disclosures:
Borthakur: eisai: Research Funding.
Statins and Venous Thromboembolism In Lung Cancer
Authors: Khushman Moh'd , Abu-samra Abdel-ghanie , Farhan Shatha , Jacobsen Gordon , Hanbali Amr , Wang Ding 
Published: October 2019

Abstract
Abstract 5122

Background:
Dyslipidemia plays a major role in the pathophysiology of atherosclerosis which may also contributed to an increased risk of and thromboembolism from the injury of the vascular endothelium and its activation of platelets, thereafter, the coagulation cascade. It has been well-established that the use of statins in patients with dyslipidemia reduces cardiovascular events and mortality, therefore, improves survival. In addition to a cholesterol-lowering effect, statins exhibit antithrombotic and anti-inflammatory properties that may confer a protective benefit to an increased risk of thromboembolism in cancer patients. Several case-controlled studies reported that cancer patients receiving long-term statins, but not other non-statin lipid lowering treatment, had a lower incidence of venous thromboembolism.

Methods:
To investigate any protective benefit from statin use in lung cancer patients, we have conducted this retrospective, case-controlled study. Total of 1548 patients with lung cancer were included from the tumor registery at Henry Ford Health System, Detroit, Michigan, between January 1999 and December 2004. The data were extracted from available electronic medical records of these patients. Statistical analyses were performed and stratified for statin users versus non statin users.

Results:
Out of 1,548 patients, 315 patients (average age was 68, range 46–90) were statin users at the time of their lung cancer diagnosis. The remaining 1233 patients (average age was 65.9, range 29–94) were non- statin users. After stratifying for statin use, 25 of the 315 statin users developed DVT/PE (7.9%), while 100 of the 1233 non-statin users developed DVT/PE (8.1%). This potential benefit from statin use can also be better visualized from comparing the development of DVT/PE between the statin and non-statin groups in a Kaplan-Meier curve for the probability of freedom from DVT/PE across time. Though statistical significance was not reached (log-rank p-value = 0.377), a trend towards a slightly decreased incidence of DVT/PE onset in the patients who receiving statin as the lipid-lowering agent has been observed.

Conclusion:
Based on our preliminary data, statin use in patients with lung cancer has demonstrated a weak but favorable protective effect on the development of a venous thromboembolism. The nature as a retrospective study and not well-balanced two group of patients (e.g., the average age of statin users were 2 years older than the non-statin users) may limit our results from reaching statistical significance. In addition, some of the patients who had no clear documentation of their home medications had also been categorized as non-statin users in our study. The results from our final data analysis will be presented.

Disclosures:
No relevant conflicts of interest to declare.
A Biotin-Avidin-EL ISA for Studying on Platelet Membrane Surface P-Selectin and Its Clinical Application
Authors: Zhao Yiming , Zhang Youtao , Lu Shiqi , Zhu Mingqing , He Yang , Ruan Changgeng 
Published: October 2019

Abstract
Abstract 5132

Introduction
To define the abnormalities in surface GPs expression on circulating platelets and provide better biomarker of bleeding and thrombotic disorders, we develop a high-throughput assay using biotin-avidin enzyme-linked immunosorbent assay (BA-ELISA) to test platelet responses to key platelet agonists and antagonists.

Methods
SZ51(anti-P-selectin mAb) coated-plate was added into 100μ l PRP with 10μ l ADP (27μ mol/L ADP)or 10μ l PBS without ADP and incubated for 1 h. Activated platelets captured were reacted with biotin-SZ-2 for 1 h. Then, the plate was re-incubated with avidin-HRP coiugated for 1h. Binding avidin was detected with OPD. The levels of P-selectin were detected in AMI group, ICH group, DM group or control group using the BA-ELISA method. This BA-ELISA was compared with flow cytometer (FCM). Inhibition of platelet GPs function was evaluated with inhibitory mAb, SZ21 and aspirin respectively.

Results
The BA-ELISA can detect platelet count as low as 6.25 × 109/L in PRP. Both of the inter-assay and intra-assay coefficient variation (C V) were less than 10%. The OD492nm values of the ADP-induced P-selectin in 30 AMI, 30 ICH and 30 DM platelets in PRP were 1.76± 0.56, 1.95±0.53 and 1.51±0.14 which was significantly higher than that in controls (0.68±0.21, P<0.01). The OD 492nm values of non ADP-induced P-selectin in 30 AMI, 30 ICH or 30 DM platelets in PRP were 0.72±0.25, 1.53±0.61 and 0.61±0.16 significantly higher than that in 30 controls (0.18±0.09, P<0.01). The correlation between the BA-ELISA and FCM was concordant (R=0.86). SZ21 or aspirin could inhibit the expression of P-selectin induced by ADP.

Conclusion
BA-ELISA is suitable for measuring platelet GP function and is also useful for diagnostic tests and for screening of inhibitors/activators of platelet activation.

Disclosures:
No relevant conflicts of interest to declare.
Anaemia In Nonagenarians: Incidence, Severity and Aetiology
Authors: Brady Justine S , van Bilsen Nenna , Han Ping , Mulligan Stephen P 
Published: October 2019

Abstract
Abstract 5138

INTRODUCTION:
The population of Australians aged 90–99 years has increased by 204% (42,234 to 128,654) [0.25% to 0.59%] between 1990 and 2010 compared to a 30% increase in the general population (17.06 million to 21.99 million) highlighting the trend to aging of the population. At this age bracket the M:F ratio is ~1:3. One third of the Australian population lives in the state of New South Wales (NSW) (www.abs.gov.au). The Australian heathcare system of federally funded pathology has resulted in marked consolidation of pathology providers servicing all non-hospital healthcare settings. Symbion Pathology account for ~35% of all pathology services in NSW and hence closely reflects the community incidence for laboratory diagnosed disorders. Community-based pathology laboratories now see large numbers of patients in this 90–99 year old age range.

METHODS:
We assessed all individual patients aged between 90 and 99 years with anaemia over the 5 year period 2005–2009. Patients were included in the analysis if they had at least one full blood count (FBC/CBC) showing a hemoglobin below the laboratory reference range (RR) of 130g/L for males and 115g/L for females. All duplicate individuals and full blood counts (FBC) were excluded.

RESULTS:
There were 4,369 (33.8%) of 12,921 individuals with anaemia. Classification by red cell size showed the majority were normochromic (80.6%), while 5.8% were microcytic and 13.6% were macrocytic.
In microcytic anaemias, 136 (53%) had a ferritin level performed and 63 (46% of this 136 patients) were iron deficient. In macrocytic anaemias, only 149 (25%) had B12 assays and 13 were deficient. In normocytic anaemias, 2910 (82.7%) had urea performed with 1413 patients had urea >10 mmol/L (48%) and 976 patients had urea >12 mmol/L (33%) (RR 3.5–9.0 mmol/L). Pancytopenia was present in 44 (1%) patients. In most patients, anaemia was mild but 25% of females and 50% of males had Hb >15g/L below the lower limit of the RR.

CONCLUSION:
Anaemia is very common in individuals aged 90–99 years occurring in one-third of the population at this age. Half the males and a quarter of females have a Hb >15g/L below the RR making this a significant comorbidity in the very elderly. As might be expected the aetiology is heterogeneous but appears to be frequently under investigated. In particular, simple haematinic assays appear to be under-utilised to better define the aetiology despite being inexpensive and readily available. The study highlights the substantial social, economic and healthcare implications in this era of significant ageing of the population.

Disclosures:
No relevant conflicts of interest to declare.
Population Screening for Thalassemia In West Bengal with a Goal to Make Zero Thalassmia Growth
Authors: Basak Jayasri , Majumdar Deboshree , Mukhopadhyay Soma , Dasgupta Swati , Das Priyabrata , Pal Nabamita , Dey Subhasish , Mukhopadhyay Ashis 
Published: October 2019

Abstract
Abstract 5175

Background:
India is in the Thalassemia belt of the world. Presently prevalence of Thalassemia carrier in India is 3.7% of its total population. Annual increment of Thalassemia carrier is 50,000. Both Alpha and Beta Thalassemia are found in West Bengal, a state in Eastern part of India. Beta Thalassemia is most common in West Bengal. Annual Increment of beta carrier is 2000–2500. With a motivation to make zero Thalassemia growth in West Bengal we started this program in 2005 taking Cyprus as an example. We regularly arranged camps in different districts and rural areas of West Bengal. To aware the general people seminars on Thalassemia were organized. Usually we took help from Principals of colleges & schools, Presidents of club, Gram Pradhans, Priests, Fathers & Celebrities etc.

Materials & Methods:
Duration of this screening study is from January 2005 to July 2010. Interested people came for thalassemia screening irrespective of cast & creed. Screening procedure consisted of the following steps. NESTROF test for all individuals was done on the spot which was followed by CBC and HPLC, done in the Laboratory. Finally to reveal different mutations in b globin gene and deletions in alpha globin gene, ARMS-PCR and gap PCR were performed respectively with the DNA of the suspected individuals.

Result:
For thalassemia carrier screening we had organized 122 camps in different rural as well as urban areas of West Bengal from January 2005 to July 2010. Total number of individuals screened is 29,350 (Male: 18197, Female: 11153). 24% individuals were found positive from NESTROF test and 28% has doubtful CBC. NESTROF positive and doubtful CBC samples were undergone HPLC test. Finally, 13% individuals were found beta carrier. In two camps at north Bengal we have collected about 278 samples having positive NESTROFT value and having abnormal CBC values (MCV < 80 fl, MCH< 27 pg, MCHC > 30 g/dl, RDW > 13%) were tested for HPLC. HbA2 values were found in the normal range. DNA analysis by gap PCR revealed that approximately 47% of them are alpha Thalassemia carrier, 32% having 3.7 kb deletion, 11% having 4.2 kb deletion and 4% other deletions.

Conclusion:
As the percentage of thalassemia carrier in West Bengal is very high we have to take concrete steps to control the disease from the Government level. From our part we are screening the boys and girls at marriageable age and advising them not to marry between two carriers.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Scale Central Memory T Cell Enrichment for Adoptive T Cell Therapy
Authors: Casati Anna , Schmitz J\)rgen , Abken Hinrich , Chmielewski Markus , Nahvi Azam , Dudley Mark , Assenmacher Mario , Scheffold Alexander 
Published: October 2019

Abstract
Abstract 5180
The adoptive transfer of genetically engineered lymphocytes is a promising strategy to treat cancer. However, the efficacy of adoptive immunotherapy in humans is often limited and the critical parameters for the in vivo efficacy remain poorly defined. One aspect may be the limited survival time and self renewal capacity of transferred T cells in vivo.
Antigen-experienced memory T cells (TM) can be divided further into central memory (TCM) and effector memory (TEM) subsets. CD8+ TEM lack CCR7/CD62L, migrate preferentially to peripheral tissues, and exhibit immediate effector function, whereas CD8+ TCM express CD62L and CCR7, which promote migration into LNs. TCM proliferate rapidly if re-exposed to antigen and there is evidence that T cell lines derived from TCM have increased persistence and functionality in vivo. Thus TCM might be a superior starting population for T cell therapy using transduced T cells.
We have developed a GMP compatible sorting strategy for TCM allowing their selective transduction and large-scale expansion. TCM cell were isolated by a sequential depletion of CD45RA+ and CD4+ and subsequent enrichment of CD62L+ cells using the CliniMACS® Plus Instrument. CD8+ TCM from peripheral blood of cancer patients were obtained in large numbers from leukapheresis products and genetically engineered with tumor-specific TCRs. After expansion in vitro to numbers sufficient for patient treatment the TCM population retained high CD62L expression. This protocol can be the basis for clinical studies on the efficiency of TCM derived T cell lines in T cell therapy against tumors.

Disclosures:
Casati: Miltenyi Biotec: Employment. Schmitz:Miltenyi Biotec: Employment. Assenmacher:m: Employment. Scheffold:Miltenyi Biotec: Employment.
Upregulation of Inflammatory Mediators In End-Stage Renal Disease as Measured Via Biochip Array Technology
Authors: Bansal Vinod , Davis Rachael , Litinas Evangelos , Hoppensteadt Debra , Thethi Indermohan , Fareed Jawed 
Published: October 2019

Abstract
Abstract 5186
End-Stage Renal Disease (ESRD) is a complex syndrome in which systemic vascular pathophysiologic changes contribute to adverse cardiovascular and cerebrovascular manifestations. Cardiovascular disease alone is present in over 60% of patients with ESRD and contributes heavily to mortality among this population. Given that inflammatory and hemostatic aberrations contribute to the overall pathogenesis of the syndrome, the purpose of this study is to profile several inflammatory mediators in order to better understand their role in the underlying mechanism of vascular changes in ESRD. Plasma samples from 49 patients with ESRD were collected prior to maintenance hemodialysis sessions. A group of 56 normal individuals, both male and female, was included as control. Cerebral Array II chips were used in the Randox® system to simultaneously measure Neuron Specific Enolase (NSE), Neutrophil Gelatinase-associated Lipocalin (NGAL), Soluble Tumor Necrosis Factor Receptor I (TNFRI), D-Dimer (DD), Thrombomodulin (TM), and C-reactive protein (CRP). The Randox® Evidence Investigator™ is a new biochip array technology that utilizes multiple discrete test regions of immobilized antibody to simultaneously quantify multiple markers from a single patient plasma sample based on the light signal generated from each test region. The data was statistically analyzed using the Mann-Whitney U test (two-tailed with Gaussian approximation). As compared to the normal individual, all of the markers studied showed an upregulation in patients with ESRD. Most notably, TNFRI showed a 19.8 fold increase in patients with ESRD (mean 7.8 ± 2.8 ng/ml, range 0.8 to 13.7) compared to the control (mean 0.4 ± 0.2, range 0.1 to 1.0). TM was increased 5.2 fold (mean 6.5 ± 2.6, range 0.7 to 14.1) compared to control (mean 1.2 ± 0.4, range 0.6 to 2.3). Also, NGAL showed a 4.6 fold increase (mean 1390 ± 257, range 406 to 1729), compared to control (mean 299 ± 99, range 115 to 603), and CRP a 4.2 fold increase (mean 5.7 ± 4.2 ug/ml, range 0.6 to 13.2) compared to control (mean 1.4 ± 1.7, range 0.2 to 11.4). DD and NSE were also increased 3.0 and 1.8 fold respectively. These studies show that some newer markers such as TNFRI, NGAL and NSE are upregulated in ESRD. The marked increase in TM is highly suggestive of endothelial damage. Similarly, the increase in TNFRI supports a state of increased cellular damage. The elevations in NGAL and CRP imply a state of increased inflammation and indicate a polypathologic process, which may predispose ESRD patients to both cardiovascular and cerebrovascular thromboembolic events. Finally, this study further validates the role of endothelial damage and endogenous thrombotic processes in ESRD as evidenced by the increased levels of TM and DD. However, the clinical significance of these markers still needs to be further explored.

Disclosures:
No relevant conflicts of interest to declare.