bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imatinib-induced apoptosis could be enhanced by Triptolide in Imatinib-resistant chronic myeloid leukemia cell line through down-regulation of HIF-1αand Nrf2
Authors: Xu Bing , Chen Feili , Liu Yuejian , Wang Shiyun , Li Rongwei , Dong Huijuan , Zha Jie 
Published: October 2019

Abstract

Background
The emergence of Imatinib has brought a new era for the treatment of chronic myeloid leukemia. However, resistant to Imatinib might lead to the treatment failure and death of patients. Thus, finding a drug which could enhance the Imatinib-induced apoptosis in vitro could provide the experimental base for the treatment of chronic myeloid leukemia. K562 cell line is a common cell line used in the study of chronic myeloid leukemia while K562/G cell line which is resistant to Imatinib is derived from K562 cell line.

Aim
This study aims to explore whether low-dose Triptolide(TPL) could enhance the Imatinib-induced apoptosis in K562/G cells and related mechanism.

Methods
K562/G cells were subjected to different treatments and thereafter MTT assay, flow cytometry and Western blot or RT-PCR were used to determine IC50, apoptotic status and expression of Nrf2, HIF-1α and their target genes.

Results
Triptolide is highly cytotoxic to K562/G cells in a concentration-dependent manner. To determine the combination effect of TPL and anticancer agents, K562/G cells were exposed to Imatinib(50μM) with or without TPL (25nM) for 24h. The apoptotic cells were determined by PI/Annexin V staining and flow cytometric analysis. Apoptotic ratio of cells treated by Imatinib together with TPL is significantly increased compared to cells treated by Imatinib alone (24.78±1.12 vs. 77.52±7.75, P<0.01). Next, the underlying mechanism was investigated. High expression of Hypoxia-inducible factor-1α (HIF-1α) has been shown to be related with bad clinical outcome in patients while Nrf2 is responsible for chemo-resistanct in cancer cells. Imatinib in combination with TPL could decrease Nrf2 and HIF-1α expression at protein and mRNA levels. Down-stream genes of Nrf2 e.g NQO1, GSR and HO-1 as well as target genes of HIF-1α e.g BNIP3, VEGF and CAIX are also down-regulated at mRNA level.

Conclusion
TPL could significantly increase the Imatinib-induced apoptotic ratio in K562/G cells through down-regulation of HIF-1α and Nrf2.

Disclosures:
No relevant conflicts of interest to declare.
New Gene Targets Detected By SNP Array Analysis In a Consecutive Series Of 215 Cases Of Adult Acute Lymphoblastic Leukemia
Authors: Safavi Setareh , Biloglav Andrea , Johansson Bertil , Paulsson Kajsa 
Published: October 2019

Abstract
Pediatric acute lymphoblastic leukemia (ALL) has a very favorable prognosis, effective treatment protocols and display a cure rate of more than 80%. However, adult ALL is associated with a much poorer prognosis; the long-term survival rate for adult cases is only a mere 30-40%, decreasing with higher age. For an improved prognosis and better treatment stratification in adult ALL, it is important to identify acquired genetic aberrations that could be linked to outcome. We present here the largest SNP array analysis to date, covering 5 million markers with a resolution of 10kb to investigate a consecutive series of 215 adult ALL cases, including samples obtained at diagnosis and relapse. We detected characteristic deletions, such as CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. In addition, the investigation uncovered several recurrent cryptic genetic events not previously implicated in adult ALL; the BCAT1, SERP2, RAB30, SRPR, ST3GAL4, ASS1, RASSF3, FUBP3, BCL11A, GAB1, LINGO2, TOX, and CXCR4 genes. Other frequent abnormalities included both partial and whole-chromosome uniparental isodisomies. Our findings provide insights into the leukemogenic process and may be clinically important in adult ALL.

Disclosures:
No relevant conflicts of interest to declare.
Minimal Residual Disease In Adult AML
Authors: Eldessouki Ihab A. , Khorshid Ola , Kandeel Eman , Lahloubi Nasr 
Published: October 2019

Abstract

Background
The achievement of complete hematologic remission (CR) is used as predictor for treatment response in patients with myeloid leukemia (AML).However <5% blasts in the bone marrow does not reflect the presence of tumor burden precisely. Minimal residual disease (MRD) in the first complete remission (CR1) may play a critical rule in assessment of treatment response and prediction of subsequent relapse.

Patients and Methods
Leukemia associated immunophenotyping (LAIP) for 73 patients with denovo AML monitored at diagnosis , day 14 and day28 post-induction by multiparametric flow cytometry (MFC).

Results
CR achieved in 60(82%) patients and 13(18%) patients did not. Among the 60(80%) patients who achieved CR 9 (15%) were MRD negative and 51(85%) were MRD positive at day14. Significant association between MRD detection and disease free survival (DFS) using 0.01% cut off value (P=.015). Day 28 post induction show highly significant association between MRD and DFS using 0.01% cut off value (P=0.001) as 38(63%) patients were MRD negative and (27%) were positive.
Significant association between MRD detection and overall survival (50 month) at day 14 and day 28 (P=0.02, P=0.001) respectively using cut off value 0.01%. MRD was positive in 63(86%) at day 14 and (37%) at day 28.

Conclusion
MRD detection at day28 and d14 at the end of induction in patients in CR may have a prognostic significance on clinical outcome and may thus be a useful marker for risk stratification.

Disclosures:
No relevant conflicts of interest to declare.
Stem Cell Programs Are Retained In Human Leukemic Lymphoblasts With Distinct Immunophenotypes
Authors: Hong Dengli 
Published: October 2019

Abstract
Leukemic lymphoblasts within different immunophenotypic populations possess stem cell Property. It remains largely unknown however whether self-renewal Program is retained from stem cells or endowed to Progenitors by leukemogenic molecules. We have addressed this issue in the context of TEL-AML1-associated acute lymphoblastic leukemia (ALL) by profiling a refined Program edited from genes essential for self-renewal of hematopoietic stem cells and B-cell development. Bioinformatic analysis shows that ALL populations are loosely clustered and all most close to the normal population that contains early lymphoid Progenitors, indicating that immunophenotypes do not reflect maturation stages in ALL and that self-renewal Program might be retained from stem cells. Results of assessing “first hit” function of TEL-AML1 in different populations of normal cells demonstrate the molecular model. Therefore, our studies reveal a leukemogenic scenario of human ALL that programs of stem cells are sustained in distinct fractions by leukemogenic mutations.

Disclosures:
No relevant conflicts of interest to declare.
EphA3 As a Target For Monoclonal Antibody Therapy For Acute Leukemia
Authors: Charmsaz Sara , Miller Kirrilee J , Day Bryan W , El-Ajeh Fares , Yarranton Geoff T , Bebbington Christopher R , Scott Andrew M , Lackmann Martin , Boyd Andrew W 
Published: October 2019

Abstract
Eph receptor tyrosine kinases interact with cell-surface ephrin ligands to direct cell growth, migration and cell positioning. High expression of EphA3 in a number of cancers has been linked to progression through facilitation of invasiveness and metastatic spread. EphA3 protein, which was originally described in leukemia, has also reported to be expressed in sarcomas, lung cancer, melanoma and glioblastoma. Using a Humaneered® derivative of the IIIA4 anti-EphA3 monoclonal antibody, KB004 (KaloBios Pharmaceuticals Inc), a clinical trial has commenced which targets the EphA3 protein in leukemia. The EphA3-specific monoclonal antibody, IIIA4, binds and activates human and mouse EphA3 with similar affinities, binding is followed by internalization of receptor-antibody complexes. We have shown high expression of EphA3 in the LK63 pre-B ALL and no expression of EphA3 in the Reh, a similar pre-B ALL cell line. We have examined the effect of the IIIA4 antibody in LK63 and Reh NOD/SCID xenograft models. In the LK63 xenograft model, administration of the IIIA4 antibody led to inhibition of tumour growth and decrease spread from bone marrow to the spleen and other organs and increased the latency of the disease, however no reduction in engraftment was observed in Reh xenograft model, suggesting that the effect was directed against the leukemic cells rather than the stromal and vascular elements. To further analyse the function of EphA3 expression, LK63 EphA3 knock down and EphA3-transfected Reh cells were tested in the xengraft model. Similar to LK63, antibody-treated Reh EphA3 xenografts showed reduction in the bone marrow engraftment and increased the latency of the disease. In contrast, LK63 EphA3 knock down xenografts showed minimal difference between treated and control group but notably showed a significant reduction in the splenic engraftment compared to the normal LK63 model. These results are consistent with IIIA4-mediated effects on the growth of EphA3-positive leukemic cells in the bone marrow and a secondary effect on the subsequent spread of the leukemic cells to extra-medullary sites and provides evidence that EphA3 is a functional therapeutic target in acute leukemias.

Disclosures:
No relevant conflicts of interest to declare.
Effects Of Metformin Addition To a Standard Chemotherapy Regimen For The Treatment Of Adult Acute Lymphoblastic Leukemia. An In Vitro and In Vivo study
Authors: Ramos Peñafiel Christian Omar , Carrillo Irma Olarte , Domínguez Jorge Zamora , Castellanos Sinco Humberto Baldemar , Fuller Etta Rozen , Peralta Enrique Miranda , Jaloma Juan Collazo , Tovar Adolfo Martínez 
Published: October 2019

Abstract
Antitumor effects of metformin are widely known. Unfortunately their use in the treatment of acute lymphoblastic leukemia is limited.

Study design
The study consisted of two stages
Phase 1: Cell assay adding metformin (40mM) assessing the viability and cell cycle in the cell line molt 4
Phase 2: Pilot study adding Metformin (850mg three time day) during the pre-treatment with steroids and the induction remission phase versus a control group (2:1 randomization)

Statistical analysis
Chi-square analysis was used to corroborate the hypothesis. The odds ratio was calculated for both, the absence of Good steroid response and refractory leukemia. Cox regression analysis and Kaplan-Meier curves were used for the survival analysis

Results
Celular assay. Metformin inhibited cell viability at 120hours reducing the percentage of cells in phase S.
Clinical assay. 151 patients were studied, 44 (29.1%) on Metformin arm, of these 59.1% ( n=26) archived a GSR compared with the control group (26.2%, n=28). A greater number of complete remission were presented in Metformin arm (81.8% versus 57.9%) shown to be a protective factor for GSR and complete remissions (odds ratio ; 0.2454 y 0.3062 respectively). In the Cox regression analysis, Metformin significantly impact in the global survival (p=0,012,95% IC) versus the other variables studied.

Conclusions
Metformin is useful both in vivo and in vitro treatment of adult acute lymphoblastic leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Hyperthermia Enhances The Effect Of Magnetic Fe3O4nanoparticle Loaded With Daunorubicin On Leukemia and Drug Accumulation In Tumor In Vivo
Authors: Liu Ran , Wu Weiwei , Chen Baoan , Cheng Jian , Wang Jun , Zhang Jia , Bao Wen , Zhang Xiaoping , Zhang Dongsheng , Wang Xuemei 
Published: October 2019

Abstract
Multidrug resistance in cancer and adverse effects of chemotherapy are the major obstacles for cancer therapeutics. This study was aimed to investigate the efficiency of novel multifunctional Fe3O4 magnetic nanoparticles combined with chemotherapeutic agents and hyperthermia in order to reverse multidrug resistance and reduce side effects by concentrating chemotherapeutics on the target site in vivo leukemia models. K562 and K562/A02 xenograft tumor-bearing nude mice were randomly divided into 4 groups, a control group and the treatment groups were allocated to receive daunorubicin (DNR), Fe3O4 magnetic nanoparticles (Fe3O4-MNP), and Fe3O4 magnetic nanoparticles loaded with daunorubicin (DNR-Fe3O4-MNP). All groups were subjected to hyperthermia in an alternating magnetic field. Tumor volume was measured with a vernier caliper. Daunorubicin concentrations in plasma, tumor and non-tumor tissues were determined by high performance liquid chromatography (HPLC). Tumor and non-tumor tissues were stained with Hematoxylin and Eosin for histopathological and microscopic examination. Locations of Fe3O4 magnetic nanoparticles in tumor tissues were stained with Prussian blue for microscope examination. In Fe3O4-MNP and DNR-Fe3O4-MNP treated groups of both K562 and K562/A02 xenograft models, tumor temperature obviously increased and tumor volume became significantly smaller. Apoptosis was observed in tumor cells treated with DNR-Fe3O4-MNP groups. In all DNR-Fe3O4-MNP groups of K562 and K562/A02 xenograft tumor models, the tumor inhibition rate, daunorubicin concentration were higher level and daunorubicin clearance in kidney also was delayed when compared with DNR alone treated group. Location of Fe3O4 magnetic nanoparticles with Prussian blue staining showed that Fe3O4 magnetic nanoparticles could be seen in tumor tissues. No obvious histopathological damage was observed in other non-tumor tissues. Fe3O4 magnetic nanoparticles played an important role in increasing tumor temperature during hyperthermia, and can be delivered successfully to tumor site in an alternating magnetic field. Fe3O4 magnetic nanoparticles loaded with daunorubicin with hyperthermia had the strongest inhibitory effect on tumor and would be potential approach for improving the efficacy of chemotherapeutics, reducing side effects and reversing multidrug resistance in the treatment of leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Impact Of Sex On Clinical Outcomes Of Mature B Cell Lymphoma In The Rituximab Era: A Multicenter, Retrospective Study
Authors: Nakamura Hiroyuki , Nagai Hirokazu , Watanabe Tomoyuki , Yano Takahiro , Uike Naokuni , Okamura Seiichi , Hanada Shuichi , Kawano Fumio , Sunami Kazutaka , Inoue Nobumasa , Yoshida Shin-ichiro , Shimomura Takeshi , Kitano Kiyoshi , Sawamura Morio , Horibe Keizo 
Published: October 2019

Abstract

Background
Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment.

Patients and Methods
Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test.

Results
A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen.

Conclusions
In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered.

Disclosures:
No relevant conflicts of interest to declare.
Clinical and Laboratory Fectures Of T-Cell Prolymphocytic Leukemia In China
Authors: Zhang Yanru , Qi Junyuan , Qiu Lugui 
Published: October 2019

Abstract

Objective
To investigate the clinical and laboratory characteristics and survival of Chinese patients with T-cell prolymphocytic leukemia (T-PLL).

Method
Eleven patients with T-PLL were retrospectively analysed.

Result
There were nine males and two females, with the median age of 56.0(19-69) years old. All the patients, except for three, presented with leukocytosis. Marked leukocytosis was less frequent than that in the British series (75%) (P = 0.00). It was easy to see PB lymphocytosis with the median ALC of 17.22(0.58-148.83) ×109/L. Lymphadenopathy and splenomegaly were the most common physical finding. It was common that serum lactate dehydrogenase (LDH) and beta 2 microglobulin (β2-MG) were higher than normal. All cases were positive for CD2/ CD3/ CD5/TCRαβand negative for CD1a /HLA-DR and TdT, as for surface markers, including strong expression of CD7. By chromosome analyses, most cases (9/10)have normal chromosome .This rate is significantly higher than that of the British and American series (3% and 25%) (P =0.000, P =0.001). And 14q11 abnormality and trisomy 8q, which are common among Western cases, were not observed in any cases. With a median follow-up of 23 months, three cases died. Two year progress free survival (PFS) and overall survival (OS) were 53.3% and 50% , respectively. However, whether three cases with normal cytogenetics and indolent clinical courses could regard as “T-CLL” is needs to be investigated in future studies.

Conclusion
It was common that the increased lymphocyte count and lymphadenopathy as well as splenomegaly with T-PLL. And most cases have high level of blood LDH and β2-MG and normal chromosome karyotype. Of great interest is similar features are observed in cases in other East Asian countries such as Japan. Genome-wide analyses such as high-throughput mutation profiling, previously performed in other T-cell malignancies, will clarify the differences between Western cases and East cases in the future.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Characteristics and Treatment Outcome Of CNS Involvement (Bing-Neel Syndrome) In Waldenstrom’s Macroglobulinemia
Authors: Kulkarni Tushar , Treon Steven Peter , Manning Robert , Xu Lian , Rinne Mikael , Lee Eudocia Quant , Ghobrial Irene M. , Norden Andrew , Kluk Michael J. , Nayak Lakshmi 
Published: October 2019

Abstract

Background
Waldenstrom’s Macroglobulinaemia (WM) is an IgM secreting lymphoplasmocytic lymphoma characterized by involvement mainly in the bone marrow, and occasionally in the lymph nodes and spleen. Central nervous system involvement of WM, known as Bing-Neel syndrome (BNS), is very uncommon and as such the clinical characteristics and treatment outcomes remain to be clarified.

Methods
We evaluated the incidence, clinical characteristics, and treatment outcome of BNS among patients with WM who were diagnosed at our Institution.

Results
We identified 13 patients with BNS from our database of 1,523 patients diagnosed with WM from 1999 -2013. The median age at diagnosis of BNS was 60 (range 51-75 years). The median time to development of BNS after WM diagnosis was 6.3 (range 0.3-11.9 years). Patients presented with a variety of neurological signs and symptoms including seizures, hearing loss, cognitive impairment, gait instability and lower extremity weakness. The diagnosis of BNS was confirmed by MRI in 11, and by examination of the CSF in 12 patients. CSF cytopathologic analysis demonstrated definitive evidence of malignant lymphoplasmacytic cells in 6 patients, and was suspicious for malignant cells in 2 patients. CSF flow cytometry was positive in 8, and a clonal immunoglobulin heavy chain gene rearrangement was identified in 6 patients. MYD88 L265P was identified in CSF sample of two patients in whom this examination was undertaken, and who demonstrated malignant disease by flow cytometry and cytological examination. Seven patients were treated with high-dose methotrexate (HD-MTX), 2 with intrathecal liposomal cytarabine, 1 with rituximab and intrathecal methotrexate, and 1 with rituximab and bendamustine. One patient was recommended treatment with HD-MTX and was lost to follow-up, 1 has been initiated on HD-MTX. Of 11 patients, 5 had a response in CSF and/or MRI, 4 had stable disease and 1 progressed following therapy. Of the responders, 2 patients had received HD-MTX, 2 intrathecal liposomal cytarabine and 1 rituximab-bendamustine. Four patients with stable disease had received HD-MTX. One patient who received intrathecal MTX developed treatment related “chemical meningitis”, and was subsequently treated with HD-MTX to which she had a CSF response. The median overall survival was not reached. Eleven patients are alive, 1 died and 1 was lost to follow-up.

Conclusions
BNS is an uncommon late complication of WM. MYD88 L265P may help in the diagnosis of BNS, and may represent a novel approach for targeted therapy of WM. HD-MTX is active in the treatment of BNS, though prospective studies are required to standardize treatment and improve outcomes.

Disclosures:
No relevant conflicts of interest to declare.