bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoimmunity in Patients (pts) with Chronic Myelomonocytic Leukemia (CMML): A Frequent Finding
Authors: Swedeh Amer , Patnaik Mrinal , Alfakara Dima , Ashrani Aneel A , Pruthi Rajiv , Elliott Michelle , Litzow Mark , Al-Kali Aref 
Published: October 2019

Abstract
Abstract 4930

Background:
Autoimmune disorders have been observed in pts with myeloid neoplasms but their frequency and impact on the natural history of the myeloid neoplasms remains to be defined.

Aim:
To describe the frequency and prognostic impact of autoimmunity in pts with CMML.

Methods:
After IRB approval, a retrospective chart review of all pts diagnosed with CMML at Mayo Clinic between 1994 – 2011. Autoimmunity (AI) was defined as positive serologic tests (Anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti –cyclic citrullinate peptide (CCP), and antineutrophil cytoplasmic antibodies (ANCA)), diagnosis of connective tissue disease (Rheumatoid arthritis, RA), vasculitis, or auto-immune thrombocytopenia (ITP). Survival estimates were calculated using Kaplan-Meier estimates and Cox regression model for multivariate analysis for via JMP software v. 9.

Results:
During the study period, 288 pts with CMML were evaluated at Mayo Clinic, 35% (n=100) were female. Median age at diagnosis was 71yr (20–95). Median hemoglobin was 11 g/dL(6–16), median white blood cell (WBC) 12 x109/L (1–302), and median platelet count 86 x109/L (1–1110). Median peripheral blood (PB) and bone marrow (BM) blasts were 0 and 5 respectively, while median PB and BM monocytes were 20% and 8% respectively. Eight-nine percent of pts had CMML1, while 10% had CMML2 and only 2 pts had CMML transforming into acute myeloid leukemia (-t). Karyotype analysis performed in demonstrated normal (diploid) karyotype in 180 (63%) pts and complex karyotype in 31 pts (11%). JAK2 mutation analysis was performed in 76 pts, 13% (10/76) of which were positive for JAK2V617F mutation.
Autoimmunity was found in 46 (16%) of 288 pts. When tested, positive ANA, RF, CCP, and ANCA were found in 28/89 (31%), 8/61 (13%), 1/20 (5%), and 7/25 (28%), respectively. However, RA was reported positive in 6/288 (2%), and vasculitis was reported in only 4 pts. Median overall survival of the 288 patients was 496 days. Pts with evidence of autoimmunity had a median survival of 400 days compared to 527 days to the rest of the group (p 0. 73). On multivariate analysis, autoimmunity was not an independent risk factor for survival (p 0. 15), but age, platelets, WBC and body mass index (BMI) were independent factors.

Conclusion:
Autoimmunity is a frequent finding in pts with CMML. When tested, autoimmune antibodies were very frequent up to 31% of pts with CMML, but this did not confer into higher frequency of autoimmune diseases. Presence of positive autoimmune antibodies did not affect overall survival adversely.

Disclosures:
No relevant conflicts of interest to declare.
Outcome of 5-Azacitidine and Decitabine Treatment in Elderly Patients with Myelodysplastic Syndrome
Authors: Nam Seung-Hyun , Lim Taekyu , Kim Bong-Seog 
Published: October 2019

Abstract
Abstract 4959

Background:
Myelodysplastic syndrome (MDS) are heterogenous group of hematologic disorders broadly characterized by cytopenias associated with a dysmorphic and usually cellular bone marrow, and by consequent ineffective blood cell production. For patients with MDS an epigenetic therapy with hypomethylating agents is considered standard of care. We evaluated the outcome of 5-Azacitidine and Decitabine treatment in elderly patients with myelodysplastic syndrome in our veterans hospital.

Method:
For analysis, patients were included if they were > 60 years, had morphological evidence of MDS per bone marrow examination at the time of diagnosis and were treated with either hypomethylating agent, 5-azacitidine and decitabine. The patients received 5-azacitidine 75mg/m2, d1–7 or decitabine 20mg/m2, d1–5 at four weeks interval. The primary end point was overall response rate.

Results:
A total of 25 patients were analyzed. Median age was 68 years (range 61–81 years). 9(36%) patients had received 5-azacitidine and 16(64%) patients had received decitabine. The International Prognostic Scoring System risk category was Intermediate-2/High in 44%. A median of 5 courses (range 1–16) were delivered and 60%(15/25) patients were treated 4 cycles over. The overall response rate was 59%. Patients who showed response (CR+PR+HI) had significantly longer overall survival than those who did not (30 months vs 5months, p=0. 01). With a median follow-up duration of 12 months, median overall survival was 14. 7 months. The difference in overall survival was evident in the Intermediate-2/High risk group but not in the Intermediate-1 risk group. However, the difference between 5-azacitidine and decitabine group was not stastically significant.

Conclusion:
In our study, both 5-azacitidine and decitabine were feasible and effective in elderly patients with myelodysplastic syndrome. The overall survival was significantly longer in patients showing response. There were needed additional large-scale prospective studies.

Disclosures:
No relevant conflicts of interest to declare.
Adenosine Regulates Bone Metabolism Via A1, A2A and A2B Receptors in Bone Marrow Cells From Normal and Patients with Multiple Myeloma
Authors: He Wenjie , Park Jeesun , Mazumder Amitabha , Cronstein Bruce 
Published: October 2019

Abstract
Abstract 4977

Background:
Multiple myeloma is characterized by osteolytic bone lesions, wherein coupled bone remodeling is disrupted with increased osteoclast activation and decreased osteoblast differentiation. We have previously demonstrated that adenosine, acting via A2A receptors, diminishes human and murine osteoclast formation and others have reported that adenosine, acting at A2Breceptors, promotes osteoblast differentiation in murine osteoblast precursors and cell lines. In this study, we examined the effect of adenosine on osteoblast and osteoclast differentiation derived from multiple myeloma (MM) patients.

Methods:
Human bone marrow was collected from multiple myeloma patients. Bone marrow stromal cells (BMSCs) and bone marrow derived mononuclear (BMMs) cells were isolated and osteoblasts and osteoclastswere cultured, respectively. Adenosine A1 receptor agonist CHA and antagonist Rolofylline, A2A receptor agonist CGS and antagonist ZM, and A2b receptor agonist BAY and antagonist MRS 1754, A3receptor agonist IB-MECA and antagonist MRS 1191; and dipyridamole, a nucleoside transport inhibitor, were added to the culture media. Alkaline phosphatase (ALP) activity assay was used to quantitate the osteoblast differentiation. In vitro osteoblast calcification was determined by alizarin red staining. TRAP+ staining was used to examine the osteoclast differentiation and bone resorption assay was used to study the osteoclast activity.

Results:
We found that A1R blockade by rolofyllineand A2aR ligation by CGS21680 inhibited differentiation of both normal and MM BMMs into TRAP+ multinucleated cells (IC50= 1nM for A1R, IC50= 10μM for A2AR;p<0. 001, n=3 for both). The inhibition of osteoclast differentiation by Rolofylline was also seen in bone resorption assay (Pit formation assay). The A2A receptor antagonist completely reversed the effects of CGS21680 on osteoclast differentiation. Moreover, enhanced adenosine accumulation in the presence of dipyridamole (0. 5μM) and A2BR activation promoted the differentiation of BMSCs from myeloma patients into osteoblasts shown byArlizarin red staining and ALP activity assay (by 1. 8 ± 0. 41 and 1. 57 ± 0. 26 fold, respectively, p<0. 05, compared with osteogenic media only, n=3 for both).

Conclusions:
These results indicate that adenosine A2 receptors may be useful targets for the treatment and prevention of MM-induced bone disease.

Disclosures:
No relevant conflicts of interest to declare.
Hypophosphorylated Retinoic Acid Receptor Alpha Inhibits the Proliferation of Multiple Myeloma Cells
Authors: Zheng Dong , Li Juan , Xiaojuan Guo , Chaoxu Zheng , Longjuan Zhang 
Published: October 2019

Abstract
Abstract 4990

Background:
Previous studies have shown that the effects of all-trans retinoic acid (ATRA) are mediated mainly through retinoic acid receptor alpha (RARα) and that the phosphorylation of a serine residue at amino acid 77 in the AF-1 domain of RARα was required for the basal activation function of RARα. In the present study, the effect of hypophosphorylated RARα(RARαS77A) in the proliferation of multiple myeloma(MM) was investigated.

Methods:
To determine whether RARαS77A would inhibit the proliferation of MM cells, RPMI8226 cells were transfected with constructing lentivirus-RARαS77A. The proliferation inhibition of ATRA and RARαS77A on MM cells were detectd by CCK-8. The molecular mechanisms of ATRA and RARαS77A on MM cells were explored by flow cytometer and western blotting.

Results:
The proliferation of RPMI8226 cells was inhibited by ATRA in a dose- and time-dependent manner. Compared with the control group, ATRA significantly arrested the cell cycle at the G1 phase (P<0. 05). The proliferation of MM cells transfected with lentivirus-RARαS77A was significantly inhibited compared with cells transfected with the control vector (p<0. 05). In addition, G1 arrest was significantly observed in MM cells transfected with lentivirus-RARαS77A (p<0. 05). The expression levels of retinoblastoma protein (Rb) and caspase-3 in the ATRA-treated and lentivirus-RARαS77A-transfected groups were increased compared with the control group.

Conclusion:
RARαS77A could mimic the proliferation inhibition and apoptosis promotion effects of ATRA on human RPMI8226 myeloma cells. Similar to ATRA, RARαS77A could induce G1 arrest by increasing the expression levels of Rb and caspase-3 in the anti-proliferation of MM cells.

Disclosures:
No relevant conflicts of interest to declare.
Identification and Characterization of Inhibitors That Specifically Target TORC2 in Multiple Myeloma
Authors: Hoang Bao , Gera Joseph , Lichtenstein Alan 
Published: October 2019

Abstract
Abstract 5026
Recent data indicate that TORC2 is necessary for survival of multiple myeloma (MM) cells. Currently, drugs targeting mTOR either inhibit TORC1 alone or both TORC1 and TORC2. To identify drugs that specifically target TORC2, we performed a drug screen in a yeast-two hybrid system to identify compounds that prevented an interaction between rictor and mTOR. We identified several potential compounds and have begun to characterize their molecular activity. These compounds induced significant MM cell apoptosis when used at concentrations below 4 uM. This cytotoxic effect was accomplished by a down regulation of TOR activity which was specific for TORC2 (ie., decreased S473 AKT phosphorylation and NDRG T346 phosphorylation). Co-immunoprecipitation experiments confirmed that at least some of the compounds prevented binding of rictor to mTOR within MM cells while having no effect on binding of raptor to mTOR. In addition, myeloma cells expressing TORC2 phosphomimetic protein substrates (AKTS473D or SGKS422D) were significantly less sensitive to apoptosis as compared to the empty vector control when treated with these compounds. These data suggest that the drug-induced cytotoxicity was mediated specifically through the inhibition of TORC2 kinase activity. These results are the initial characterization of TORC2-specific drugs and support a rationale for targeting TORC2 in multiple myeloma.

Disclosures:
No relevant conflicts of interest to declare.
Heparin Does Not Increase Live Births in Pregnant Women with Previous Unexplained Recurrent Miscarriages: A Systematic Review and Meta-Analysis
Authors: Al-Khabori Murtadha K. , Al-Hosni Zainab S. , Ghaithi Hajer M. Al , Maamari Altaf M. Al , Bessiso Wafa S. , Farsi Khalil Al , Al-Huneini Mohammed , Al-Riyami Arwa Z. , Daar Shahina 
Published: October 2019

Abstract
Abstract 504

Background:
The impact of heparin in pregnant women with previous unexplained recurrent miscarriages remains uncertain. The use of heparin in this patient population has been increasing with the hope of improving the rate of live births. We performed a systematic review of the randomized clinical trials addressing this question.

Methods:
We searched MEDLINE (searched July 1st 2012), CENTRAL (Issue 7 of 12, July 2012), American Society of Hematology (searched July 1st 2012), clinical trials registries (http://clinicaltrials.gov/, searched July 1st 2012), and bibliographies of relevant studies for randomized clinical trials comparing heparin (unfractionated or low molecular weight) to other best care approaches. Use of aspirin was allowed in either study arms. Included patients were pregnant women over 18 years of age with previous recurrent unexplained miscarriages (at least two at any trimester). We performed a meta-analysis using random effects models to estimate the pooled odds ratio. Statistical heterogeneity was calculated by using the I2 statistic.

Results:
Eight trials proved eligible, five of which provided data from 1141 patients that could be included in the meta-analysis and three of which remain unpublished. Only the subgroup of patients with no antiphospholipid antibodies or inherited thrombophilia was included. There was a total of 839 live births observed. Enoxaparin was used in four trials and nadroparin was used in one trial. All trials randomized patients before the 8th week of gestation. There were 430 live births (among a total of 561 pregnancies) and 409 live births (among a total of 580 pregnancies) in the heparin and other best care treatment arms respectively. The difference between the two treatment arms was not statistically significant with a pooled odds ratio of 1.49 (95% confidence interval: 0.84, 2.66; P = 0.17). There was a substantial heterogeneity among the results of different trials (Chi2 = 14.91, P = 0.005; I2 = 73%).

Conclusions:
Available evidence suggests that heparin does not increase live births in pregnant women with previous unexplained recurrent miscarriages with no evidence of antiphospholipid antibodies or inherited thrombophilia. Future trials should explore new treatment strategies.

Disclosures:
No relevant conflicts of interest to declare.
The Significance of CD44ICD in Difuse Large B- Cell Lymphoma Cell Line SUDHL2 and the Preliminary Study On the Mechanism
Authors: Feng Ru , Duan Wenbing , Chen Dayan , Wei Xiaolei , Wei Yongqiang , Huang Fen , Yu J. Jessica , Ye B. Hilda 
Published: October 2019

Abstract
Abstract 5087

Objective:
Diffuse large B cell lymphoma (the diffuse large B-cell lymphoma, DLBCL), is one of the most common type of non-Hodhkin's lymphomawith high heterogeneity. γ-secretase can induce the hydrolysis of CD44, which play a key important in DLBCL, producing the CD44 intracellular domain. According to our research, the inhibition of CD44ICD can decrease the expression of NF-„KB and Stat-3 in SUDHL2 cell line from ABC-DLBCL cell line. Therefore the aim of this study was put important on the change of proliferation, apoptosis and main surface markers, ERK1/2 and phosphor-ERK1/2 in CD44 positive cell line from ABC-DLBCL after inhibiting the production of CD44ICD.

Method:
The surface expression of CD44 in SUDHL2 and OCI-ly3 cell lines was tested by flow cytometry, and then chose the CD44 positive cell line. Using 0. 1, 1. 0, 5. 0, 10, 25, 50, 75 and 100μM DAPT inhibited the production of CD44ICD in CD44 positive cell line respectively, and then tested the cell proliferation, apoptosis and main surface markers(CD44, CD19, CD20) by MTT analysis, Annexin V-FITC/PI and flow cytomety separately after 24h. mean while western blot was used to detected whether ERK1/2 and phosphor-ERK1/2 expressed in the chosen cell line, if they expressed in it, tested their change after blocking the release of CD44ICD for 1h.

Results

Conclusion
The ERK1/2 signal path participated in the regulation of SUDHL2 cell line, moreover after inhibited the release of CD44ICD, both the ERK1/2 and phosphor-ERK1/2 could be regulated up, however further study must go on.

Disclosures:
No relevant conflicts of interest to declare.
A Modified Glasgow Prognostic Score (mGPS) Based On Systemic Inflammatory Response Is a Useful Indicator to Predict Response and Survival in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Jung Sung-Hoon , Yang Deok-Hwan , Ahn Jae-Sook , Kim Yeo-Kyeoung , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Abstract 5089
Systemic inflammatory responses as evidenced by CRP and albumin have reported as a useful indicator of prognosis in patients with advanced cancers. We retrospectively evaluated the relationship between the systemic inflammation score and survival in 213 patients with DLBCL receiving the first-line R-CHOP chemotherapy between October 2003 and December 2011 at Chonnam National University Hwasun Hospital. Patients were assorted into three groups based on initial serum CRP, albumin and LDH level at diagnosis, as named by ¡°modified Glasgow prognostic score (mGPS)¡±. Patients with elevated CRP (> 1. 0 mg/dL), hypoalbuminemia (< 3. 5 g/dL) and elevated LDH (> 1¢¥ upper normal value) were assigned a score of 2. Patients in whom one or two of these biochemical abnormalities was present were assigned of 1. Patients in whom neither of these abnormalities was present were assigned a score of 0. In Cox multivariate analysis, the independent poor prognostic factors for progression free survival (PFS) were mGPS 2 (HR 5. 415, 95% CI 2. 028–14. 454, P = 0. 001), ECOG PS ¡Ã 2 (HR 3. 504, 95% CI 1. 655–7. 419, P = 0. 001), and bulky lesion ¡Ã 10cm (HR 2. 030, 95% CI 1. 037–3. 972, P = 0. 039). In addition, the independent poor prognostic factors for overall survival (OS) were mGPS 2 (HR 5. 898, 95% CI 2. 028–14. 454, P = 0. 001) and ECOG PS ¡Ã 2 (HR 3. 525, 95% CI 1. 642–7. 567, P = 0. 001). The overall response rate, including complete response and partial response, for the R-CHOP chemotherapy was decreased according to the mGPS; 96. 7% at mGPS 0, 87% at mGPS 1, and 75% at mGPS 2 (P = 0. 009). This study suggest that the modified Glasgow prognostic score (mGPS) based on systemic inflammatory responses (CRP, albumin and LDH) was a useful prognostic indicator for OS and PFS and also a reliable method to predict the response for R-CHOP chemotherapy in patients with newly diagnosed DLBCL.

Disclosures:
No relevant conflicts of interest to declare.
Significance of Clinical Factors As Prognostic Indicators for Mature T-Cell Non-Hodgkin Lymphoma Patients: A Retrospective Analysis of Chinese Cases
Authors: Xie Wanzhuo , Hu Keyue , Xu Fan , Zhou De , Huang Weijia , Li Li , He Jingsong , Shi Jimin , Luo Yi , Zhu Jingjing , Wei Guoqing , Zhang Jie , Lin Maofang , Ye Xiujin , Cai Zhen , Huang He 
Published: October 2019

Abstract
Abstract 5093

Objectives:
To retrospectively analyze the significance of different clinical factors for predicting the prognosis of mature T-cell non-Hodgkin lymphoma (MTCL) patients.

Methods:
Two hundred and fifty-two MTCL patients admitted from 2005 to 2011 into the First Affiliated Hospital of the Zhejiang University were retrospectively reviewed. All diagnoses were confirmed by histopathological hematoxylin and eosin (HE) staining and prognostic values of β2-microglobulin (β2-MG) levels, lactate dehydrogenase (LDH) levels, B symptoms, Ann Arbor stages, international prognostic index (IPI), Eastern Cooperative Oncology Group (ECOG) performance status, bone marrow involvement (BMI) and extra nodal involvement (ENI) for the overall survival (OS) were evaluated. Additionally, we compared the OS of patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and patients treated with an alternative intensive chemotherapy.

Results:
At a median follow-up of 23 months, the OS rate was 23. 8%. Our results revealed that the presence of B symptoms (P <0. 001), ECOG score≥2 (P <0. 001), BMI (P <0. 001), elevated LDH levels (P <0. 001), elevated β2-MG levels (P<0. 001), Ann Arbor stages III/IV (P=0. 007) and IPI ≥3 (P=0. 001) were factors for a poor OS prognosis and intensive chemotherapy showed a better OS outcome than CHOP treatment.

Conclusion:
Elevated LDH and β2-MG levels, B symptoms, Ann Arbor stage III/IV, BMI, high IPI indexes and ECOG scores predict an unfavorable prognosis of MTCL patients. When compared with the classical CHOP regimen, the intensive chemotherapy treatment can improve the prognosis of patients with MTCL.

Disclosures:
No relevant conflicts of interest to declare.
The Potential Role of STAT's in Anti-Leukemic Therapy with Different Drugs
Authors: Kiper Hatice Demet , Kaymaz Burcin Tezcanli , Purclutepe Ozlem , Dalgic Ceyda Tunakan , Selvi Nur , Dalmizrak Aysegul , Avci Cigir Biray , Kosova Buket , Sahin Fahri , Aktan Cagdas , Saydam Guray 
Published: October 2019

Abstract
Abstract 5120
STAT pathways play a pivotal role in oncogenesis and leukemogenesis, thus targeting STAT signalling appears to be an effective anticancer treatment strategy. It has been described that constitutive activation of STAT3 and STAT5 plays a pro-oncogenic role both in acute and chronic myeloid neoplasms. In this study, we aimed to clarify the potential relationship between drug-induced apoptosis with different agents and STAT pathway. A third-generation bisphosphonate; zoledronate, an angiotensin-converting enzyme inhibitor (ACE-I); enalapril, a proteasome inhibitor which is used for treatment of multiple myeloma; bortezomib and a second-generation tyrosine kinase inhibitor; dasatinib were examined in this goal.
Cell viability and cytotoxicity tests were conducted by using Trypan blue dye exclusion and XTT assays, respectively. Apoptotic analyses were performed by AnnexinV-EGFP staining method and fluorescence microscopy. Expression levels of STAT3, −5A and −5B genes were analysed in myeloid cell lines by qRT-PCR.
The results showed that zoledronate; bortezomib and dasatinib decreased viability and proliferation and induced apoptosis in CML cell line K562 in a dose- and time-dependent manner which is associated by prominent decrease of STAT3, STAT5A and STAT5B mRNA expressions. Enalapril was also found to be cytotoxic and induced apoptosis in APL cell line HL60 in a dose- and time-dependent manner and the expression levels of STAT5A gene have significantly reduced in enalapril-treated HL60 cells as compared to untreated controls. Treatments of cell lines with other drugs were also associated with significant apoptosis in certain time points. The results and changes in expression of STAT's in mRNA level at 72nd hours are summarized in table.
Taken together all these data showed that targeting STAT pathways by different drugs may be an appropriate approach in anti-leukemic therapy. This finding is important to propose that discovery or identification of novel agents targeted STATs may open new windows to the other hematological and solid malignancies which are associated with aberrant STAT expression.
Table: The changes in STAT expressions after drug exposure in time-dependent manner with the dose of IC50. DRUGS CELL LINE IC50 APOPTOSIS (%) STAT3 mRNA Down Regulation (%) STAT5A mRNA Down Regulation (%) STAT5B mRNA Down Regulation (%) ENALAPRIL HL-60 7 μM 20 20* 76 5* ZOLEDRONATE K562 60 μM 34 63 31 57 BORTEZOMIB K562 177 μM 37 98 100 99 DASATINIB K562 3,314 nM 75 NA 33 78 * : Not significant NA: not applied

Disclosures:
No relevant conflicts of interest to declare.