bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor XIII Associates with the Guanine Exchange Factors Cool-1 and Cool-2 in Human Platelets.
Authors: Morgan-Spencer Alex , Greenberg Daniel L. 
Published: October 2019

Abstract
Abstract 4015
Poster Board III-951
A major signaling pathway that regulates platelet shape change and reorganization of the cytoskeleton involves the Rho family of GTPases; CDC42, Rac1 and RhoA. These GTPases are converted from their inactive or GDP-loaded state to the active or GTP-loaded state by a class of enzymes called Guanine Exchange Factors (GEFs). GEFs are a family of multi-domain proteins that contain a GDP-GTP exchange domain (DH-PH) as well as other protein interacting domains that are regulated by the activation of receptors present on the platelet surface. We previously identified the presence of two homologous GEFs, Cool-1 and Cool-2, in human platelets. In nucleated cells, the activities and substrate specificities of the Cool GEFs are regulated by complex interactions with p21-activated kinases (PAK), Gb/g heterodimers, focal adhesion kinase, and the scaffolding proteins GIT-1 and GIT-2. The Cool GEFs are found at the sites of focal adhesions during spreading and migration in nucleated cells, however, little is known about the regulation or activity of Cool-1 or Cool-2 in platelets.
Co-immunoprecipitation experiments were performed with Cool-1 and Cool-2 antibodies using lysates from resting and thrombin stimulated human platelets. We analyzed the precipitated proteins by Mass Spectroscopy and found a number of structural and scaffold proteins bound to the Cool GEFs in the thrombin activated lysates. These cytoskeletal proteins include talin, multimerin, tubulin, filamin A, actin and fibrinogen. Interestingly, a large number of Factor XIII also co-immunoprecipitated with Cool-1 and Cool-2 in the thrombin activated platelet lysates. Western analysis of the co-immunoprecipated platelet proteins from thrombin, TRAP1 and TRAP4 demonstrated that the association of factor XIII with the Cool GEFs is calcium dependent. Inhibition of transglutaminase activity and presence of RGD peptide did not affect the association of Factor XIII with Cool-1 or Cool-2.
Factor XIII deficiency is commonly thought to result in bleeding due to the impaired crosslinking of fibrin. However, platelet factor XIII may also play an important role in cross linking platelet cytoskeleletal proteins such as actin and myosin. Consistent with that hypothesis is a recent report showing that platelet factor XIII deficiency results in decreased lamellapodia formation under static adhesive conditions. The association of Factor XIII with the Cool GEFs further supports investigating the potential for the transglutaminase to crosslink platelet cytoskeletal proteins.

Disclosures:
No relevant conflicts of interest to declare.
Silent Brain Abnormalities in Thalassemia Intermedia: A Combined MRI/PET Study.
Authors: Taher Ali , Musallam Khaled , Nasreddine Wassim , Beydoun Ahmad 
Published: October 2019

Abstract
Abstract 4077
Poster Board III-1012

Introduction
Patients with thalassemia intermedia (TI) have an increased risk of thrombosis compared with thalassemia major patients. Thromboembolic events are more frequently observed in older TI patients (>20 yrs) who are splenectomized and non-transfused. Brain involvement has not been widely studied; however, one study has documented silent strokes on brain MRI in 37% of patients, indicating that further investigation is warranted.

Patients and methods
This was a cross-sectional study on 30 TI patients >18 years of age, splenectomized, not receiving regular transfusion therapy, and receiving no antiplatelet or anticoagulant medication. Patients were initially screened to establish absence of neurological signs or symptoms and other stroke-related disease (diabetes, hypertension, carotid stenosis, cardiac disease or prothrombotic mutations). All patients underwent both MRI and 18F-FDG PET scan on the same day. The criterion for abnormality on PET was the decrease in neuronal function (glucose utilization). MRIs were performed using T1- and T2- weighted spin-echo techniques. Abnormality was defined as an area of abnormally increased signal intensity on the T2-weighted pulse sequences.

Results
The mean age was 31.9 yrs (range: 18–54 yrs) with a male to female ratio of 13:17. Among the group of 30 subjects, 18 (60%) had abnormal MRI findings, 19 (63.3%) had abnormal PET findings, and 26 (86.7%) had either an abnormal MRI or abnormal PET or both. Solitary findings were identified in 7 (26.9%) of patients while multiple lesions were observed in 19 (73.1%) of patients who had abnormality. Bilateral findings were documented in 14 (53.8%) of patients with abnormality. The most common regions of abnormality were the parietal (76.9%) and frontal (69.2%) lobes; followed by the temporal (53.8%) and occipital (15.4%) lobes.

Conclusions
MRI/PET evaluation has demonstrated that silent brain abnormality is a common finding in this population of adult, splenectomized, non-regularly-transfused TI patients.

Disclosures:
Taher: Novartis: Honoraria, Research Funding.
Phase I Trial of Nanomolecular Liposomal Annamycin in Adult Patients with Refractory Acute Lymphoblastic Leukemia.
Authors: Wetzler Meir , Wang Eunice S. , Shepard Robert , Thomas Deborah A. , Andreeff Michael , O'Brien Susan , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 4098
There continues to be no effective second line therapy for refractory acute lymphoblastic leukemia (ALL) in adult patients and the cure rate with current therapy has not significantly improved in decades. Annamycin is a highly lipophilic form of the anthracycline doxorubicin with the ability to bypass multi-drug resistance (MDR-1) mechanisms of cellular drug resistance. A novel nanomolecular liposomal entity of annamycin was recently specifically synthesized which overcomes MDR with little to no cardiac toxicity and improved anti-tumor activity when compared to the original annamycin formulation. We performed a phase I multi-center, open-label, study to determine the maximally tolerated dose (MTD) of nanomolecular liposomal annamycin in adult patients with refractory ALL. The secondary objective was to study the MDR-1 encoded (permeability glycoprotein) PgP-170 glycoprotein expression in correlation with CD34 expression and MDR-1 mRNA levels in refractory ALL patients prior to and after receiving liposomal annamycin treatment. Thirty patients were enrolled on the study. The MTD was determined to be 150 mg/m2/day for 3 days. Other than the tumor lysis syndrome, there was only 1 severe adverse event (SAE) definitely related to the study drug consisting of grade 3 mucositis. There were also 3 other SAEs of grade 3-4 mucositis probably related to the study drug which comprised the MTD determination. There was no reported cardiac toxicity in any patients. After determining the MTD, a 10-patient phase IIA was conducted. Eight of the patients completed 1 cycle of the 3 days of treatment at the MTD. Of these, 5 (62%) had an efficacy signal with complete clearing of circulating peripheral blasts. Three of these subjects also cleared bone marrow blasts with one subsequently proceeding onto successful stem cell transplantation. The other 2 developed tumor lysis syndrome and unfortunately expired prior to response assessment. Nanomolecular liposomal annamycin appears to be well-tolerated with no cardiotoxicity and evidence of clinical activity as a single agent in refractory adult ALL. Given that the likely mechanism of action is overcoming innate drug resistance via MDR, PgP-170 mRNA and protein expression will be presented. We are currently testing liposomal annamycin in a phase I study in children and young adults with refractory ALL or AML, and planning a phase 2 registration trial in adult ALL

Disclosures:
Wetzler: Callisto Reserach Funding: Research Funding. Off Label Use: Annamycin. Refractory relapse to ALL. Wang:Callisto : Research Funding. Shepard:Callisto: Research Funding. Thomas:Callisto: Research Funding. Andreeff:Callisto: Research Funding. Kantarjian:Callisto: Research Funding.
To Study the Proliferative Inhibition of Anticancer Drug in Two Kinds of Ph (+) Leukemia Cell Lines.
Authors: Gong Yuping , Yang Xi , Niu Ting 
Published: October 2019

Abstract
Abstract 4110

Objective
To study the proliferative inhibition of imatinib, daunorubicin and bortezomib in two kinds of Ph(+) leukemia cell lines: chronic myelogenous leukemia cell line K562 expressing P210 protein and acute lymphoblastic leukemia cell line SUP-B15 expressing P190 protein.

Methods
(1) Cell proliferation with imatinib, daunorubicin and bortezomib for 72 hours was analyzed by the MTT assay and displayed by growth curve and IC50 value. (2) The change of bcr-abl gene mRNA levels after the 48 hours' intervention of imatinib (final concentration at 0μM, 0.35μM, 1 μM) was detected by reverse transcription polymerase chain reaction (RT-PCR).

Results
(1) The IC50 values of K562 and SUP-B15 cells inhibited by imatinib, daunorubicin and bortezomib for 72 hours was respectively 0.286±0.06 (μmol/L), 0.303±0.009 (μmol/L), 22.127±3.592 (nmol/L) and 1.387±0.180(μmol/L), 0.117±0.017 (μmol/L), 12.350±0.740 (nmol/L), which indicated that the K562 cell line was the more sensitive to imatinib than SUP-B15 cell line, whereas the SUP-B15 cell line had the more sensitivity to daunorubicin and bortezomib. (2) There was no change of bcr-abl gene expression after the 48 hours' intervention of imatinib in both cell lines.

Conclusion
(1) Imatinib, daunorubicin and bortezomib had good anti-cancer effect to Ph+ leukemia cells in vitro. What's more, the K562 cell was the more sensitive to imatinib and only imatinib will have good effect on chronic myelogenous leukemia. Whereas the SUP-B15 cell had the more sensitivity to daunorubicin and bortezomib and combining imatinib with daunorubicin or bortezomib, the effect will be better on Ph(+) acute lymphoblastic leukemia. (2) The short time intervention of imatinib had no effect on the bcr-abl gene expression and imatinib could need long time to show curative effect for the Ph+ leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Multiprobe FISH Panels for Chromosome Rearrangements in Patients with Adult Acute Lymphoblastic Leukemia.
Authors: Du Qingfeng , Xiaoli Liu , Xu Na , Liu Zhi , Li Rong , Song Lanlin , Cao Rui , Yang Jun , Wang Yu , Xu Lulu 
Published: October 2019

Abstract
Abstract 4122
For acute Lymphoblastic Leukemia(ALL), several cytogenetic aberrations have been shown to play a crucial role in clinical Prognosis and also are being used as targets for response to therapy. This has led to Cytogenetics, and more recently Fluorescence In Situ ybridization(FISH), to be a tool for the detection of ALL treatment trials. Conventional cytogenetic(CC) analysis is a technically demanding and time-consuming process that is hindered by the limited availability of informative metaphase cells. Thus, interphase FISH is often used to complement CC,rule out submicroscopic rearrangements, and evaluate specimens with poor morphology or no growth in culture.
The Chromoprobe Multiprobe ALL panel (Cytocell Technologies,Cambridge, UK) has been designed to detect rearrangements that occur primarily in B-cell lineage ALL, and includ some T-lineage markers. This panel detect the rearrangements of MYC, E2A, MLL, IGH, and p16; fusions of BCR/ABL and TEL/AML1 simultaneously; enumeration of chromosomes 4, 10, and 17 Probes for the specific rearrangements can also be used to assess ploidy. In this study, we performed the multi-probe FISH assay on interphase cells to detect multiple abnormalities associated with adult ALL.At prensent, We analyzed 48 samples from ALL cases using a FISH panel,the results showed that 71% cases had 1 or more genetic abnormalities. The most frequent abnormality was BCR/ABL, followed by MLL, IGH abnormalities, MYC rearrangement, TEL/AML1 fusion, +10, p16, 8 cases had MLL with IGH abnormalities and TEL/AML1 fusion, 7 cases had BCR/ABL fusion with MYC rearrangement,3cases had MLL and p16, no fusion partner was detected in 14 cases. Meanwhile,detected this samples with CC,we found that 42% cases had chromosome abnormalities,and 16% samples without growth in culture. This reults preliminary demonstrated that ALL always with multiple karyotype abnormalities, Multiprobe FISH is an essential method to refine the cytogenetic analysis. This study is going on,further study including more samples was necessary.

Disclosures:
No relevant conflicts of interest to declare.
CD19 Expression in t(8;21)-Negative Acute Myeloid Leukemia Is Not Restricted to Cytogenetically Aberrant Populations.
Authors: Francis Jawad , Dharmadhikari Avinash , Sait Sheila N.J. , Deeb George , Wallace Paul K. , Thompson James E. , Wang Eunice S. , Wetzler Meir 
Published: October 2019

Abstract
Abstract 4128
Aberrant expression of the B lymphoid marker, CD19, in acute myeloid leukemia (AML) has frequently been associated with t(8;21)(q22;q22). However, AML cases lacking this translocation may occasionally express CD19. We identified eight such cases at Roswell Park Cancer Institute. Three of these cases had noticeable CD19-positive leukemic subsets with the following karyotypic abnormalities. The first case had monosomy X in 6 cells and normal karyotype in 14, the second case had trisomy 22 in 19 cells and normal karyotype in one, and the third case had monosomy 7 in 18 cells and trisomy 18 in two. We therefore asked if CD19 expression is restricted to the karyotypically abnormal leukemic cells. Bone marrow cells were sorted according to the specific immunophenotype. First, a generous mononuclear sorting region was drawn in the bivariate display of forward versus side scatter to exclude debris and aggregates. Next, the CD45-negative to CD45-dim, CD19-positive and CD34-positive leukemic cells were sorted. Fluorescent in situ hybridization (FISH) studies were carried out on the sorted samples using the following commercially available probes: the Centromere enumeration probe CEP X (SpectrumGreen) in the first case; the locus specific BCR (22q11) (SpectrumGreen)/ABL1 (9q34) (SpectrumOrange) dual color, dual fusion, translocation probe in the second, and the locus specific D7S486 (7q31) SpectrumOrange/CEP 7 SpectrumGreen probe in the third. A total of 200 nuclei were assessed in each case. The results are displayed in the Table below. There were no significant differences in the signal pattern between the CD19-positive and CD19-negative leukemic populations. These results indicate that aberrant CD19 expression in t(8;21)-negative AML is not restricted to leukemic cells that harbor specific karyotypic abnormalities.
Table FISH results based on CD19 expression Case # Probe Signal Pattern CD19-positive CD19-negative 1 CEP X 1 Green (-X) 20/200 30/200 2 BCR/ABL 3 Green/2 Orange (+22) 163/200 170/200 3 CEP 7 1 Green/1 Orange (-7) 200/200 200/200

Disclosures:
No relevant conflicts of interest to declare.
Association Between Genetic Polymorphism in DNA Repair Genes and Acute Myeloid Leukemia.
Authors: Kim Hee Nam , Kim Nan young , Yu Li , Tran Huong Thi Thanh , Kim Yeo-Kyeoung , Lee Il-Kwon , Yang Deok-Hwan , Lee Je-Jung , Kim Hee-Je , Min Woo-Sung , Park Moo-Rim , Jo Deog Yeon , Won Jong Ho , Kwak Jae-Yong , Kim Hyeoung-Joon 
Published: October 2019

Abstract
Abstract 4131
Genetic variants in DNA repair genes may affect DNA repair capacity and modulate cancer susceptibility. We analyzed genetic polymorphisms of 11 DNA repair genes: XRCC4, BRCA1, WRN, RAD51, XRCC3, ERCC1, ERCC2, XPC, OGG1, XRCC1 and MGMT to evaluate the association and risk of acute myeloid leukemia (AML). A large-scale population-based, case-control study of 1700 controls and 659 cases was conducted in Chonnam National University Hwasun Hospital, Korea.
Three single-nucleotide polymorphisms(SNPs), ERCC1 IVS5 +33 CC, WRN 787 GG and XRCC1 399 GA genotypes were associated with decreased risk for AML [odds ratio (OR) = 0.71; 95% confidence interval (CI) = 0.54-0.92, p=0.01 for IVS5 +33 CC, 0.67; 0.50–0.89, p=0.006 for 3149 GG and 0.81; 0.67–0.98, p=0.031 for 1316 GA]. We found no differences in the XRCC4 S307, BRCA1 P87L, RAD51 –G135C, XRCC3 T241M, ERCC2 K751Q, XPC K939Q, OGG1 S326C and MGMT L84F genotypes.
Our results suggest that these 3 SNPs in DNA repair genes may affect AML susceptibility by modulating activities to maintain the genome integrity of each individual.

Disclosures:
No relevant conflicts of interest to declare.
Expression and Clinical Significance of Antiapoptotic Gene Aven in De Novo acute Myeloid Leukemia Patients.
Authors: Geng SuXia , Du Xin , Weng Jianyu , Zhong Liye , Guo Rong , Lu Zesheng , Wu Suijing 
Published: October 2019

Abstract
Abstract 4132
The objective was to definite the expression level of aven mRNA of white blood cells from peripheral blood(PB)of de novo acute myeloid leukemia and preliminary analyze its clinical significance, providing a experimental basis for evaluating prognosis. Aven mRNA levels in PB samples from 69 AML patients were detected by using real-time quantitative PCR. The relation of aven mRNA level with clinical and hematological characteristics (age, sex, WBC, Hb, Plt, LDH, Blast% in PB and BM,FAB subtype) and treatment outcome (complete remission rate and relapse rate)were analyzed. Twenty-one normal individuals served as controls. The level of aven mRNA was between 11.72% and 178.93 %(median 37.2%) in de novo AML and between 10.81% and 50.98 %(median 28.81%) in normal individuals. Aven mRNA level was higher in the AML group than in the controls (p=0.006). When we compared aven mRNA with other clinical and hematological parameters, there were significant correlations between aven mRNA and age(r=0.25,p=0.039),aven mRNA and hemoglobin level (r=0.29,p=0.019),aven mRNA and FAB subtype(r=0.253,p=0.036). We found that median level of aven mRNA in group whose age older than median age was higher than group whose age younger than median level(p=0.018).The complete remission rate after two cycles chemotherapy in group with lower aven mRNA level(25/30,83.33%)was higher than group with higher aven mRNA level(21/30,70%). But the difference was not significant(p=0.22).The difference of aven mRNA expression level between AML patients with relapse and that without relapse was not significant (p=0.076). In conclusions, the level of aven mRNA in de novo AML is overexpression. The overexpression of aven mRNA is likely to play an important role in tumorigenesis of AML. Association of aven mRNA expression with treatment outcome and relapse was not observed.

Disclosures:
No relevant conflicts of interest to declare.
Phase I Study of Bendamustine in Refractory Leukemia.
Authors: Beth Rios Mary , Jabbour Elias , Ravandi Farhad , Kadia Tapan , Estrov Zeev , Borthakur Gautam , Burton Elizabeth , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 4156

Background
Alkylating agents are active in leukemia. Examples are cyclophosphamide, chlorambucil, melphalan, busulfan, and others. Bendamustine, a rationally designed drug that incorporates alkylating agent properties plus an adenosine-like ring structure, may be active in leukemia. Fractionated doses of alkylators may improve efficacy (e.g. fractioned cyclophosphamide in ALL).

Methods
We initiated a phase I-II study of bendamustine in patients with refractory leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes. Starting dose was 50mg/m2 IV BID over 1-2 hours for 4 days every 4 weeks (3 pts.) with escalation to 75mg (3 pts.), and 100mg (6 pts). Three additional patients were treated at 50mg/m2 once that dose was declared safe as allowed by study design. Diagnoses were AML 12, ALL 2, MDS 1. Median age was 48 (range 22 to 88). All patients were refractory or had relapsed after multiple courses of chemotherapy. The median number of prior therapies was 3 (range 1 to 9). Five patients had chromosome 5, 7, or 8 abnormalities, 6 patients had miscellaneous abnormalities, 4 patients were diploid.

Results
Toxicity – Grade 1-2 expected toxicities of nausea, vomiting, diarrhea, and transient transaminase elevations were seen at all dose levels. At the 75 mg/m2 dose level grade 3 transaminase elevation was seen in 1 pt. which occurred with rash and diarrhea, was thought to be related to GVHD and all subsided with dose increase of tacrolimus. One patient who began therapy with a creatinine of 1.8 had creatinine increase to 3.3 mg/DL. At the 100mg/m2 dose level 2/3 patients developed creatinine increase to 3.2 and 2.6 mg/DL. The creatinine increase occurred on day 7 and subsided by day 11 in both pts. An additional 3 pts. were treated at this dose level with no increase in creatinine to >2 mg/DL.

Results
Response – Antileukemic activity was encouraging: 8/15 patients with peripheral blasts had >90% reduction of the leukemic cells; 2 patients had >50% reduction of marrow blasts % (90 to 10, 86 to 40).

Bendamustine has shown activity in this heavily pretreated refractory leukemia group. While the creatinine elevations were not severe (grade 3-4 NCI CTC) they were consistent to consider a bendamustine dose schedule of 50-75 mg/m2 IV BID x 4 days as a reasonable phase II schedule to explore in better prognosis patients, particularly in adult ALL in phase II studies.

Disclosures:
Ravandi: Cephalon: Consultancy, Honoraria. Kantarjian:Cephalon: Research Funding.
Cytomegalovirus Infection in Patients with Acute Leukemia and MDS.
Authors: Yuasa Hiromi , Kyo Taiichi , Yoshida Noriaki , Katayama Yuta , Asaoku Hideki 
Published: October 2019

Abstract
Abstract 4167

[Background]
It is important for the progress of the support treatment for AML. It is possible for more than seventy years old patients to cure AML actively.

[Purpose]
We examined the CMV reactivation after chemotherapy of AML, MDS, and ALL.

[Methods]
The study design planned to enroll 195 patients. Diagnoses included AML (121), MDS (56), ALL (18). Patients received induction chemotherapy. Induction regimens consisted of IDA (12 mg/m2 per day, day 1, 3, 5 and 8) and BHAC (350 mg/ m2 per day, day 1-10)(= Ara-C 200 mg/ m2 per day, day 1-10). Patients received consolidation chemotherapy. Consolidation chemotherapy comprised of High-dose Ara-C Therapy-containing regimens. We examined the CMV reactivation when patients have fever but they were recovered from the leukocyte decrease term after chemotherapy.

[Results]
About 10% of patients experienced CMV reactivation. Thirteen of 121 AML patients experienced CMV reactivation. Three of 56 MDS patients experienced CMV reactivation. Four of 18 ALL patients experienced CMV reactivation.

[Conclusion]
It is important to be careful for CMV reactivation in patients receiving High-dose Ara-C Therapy.

Disclosures:
No relevant conflicts of interest to declare.