bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin E Isoforms Inhibit Cell Proliferation and Downregulate Homeobox Protein Expression in the Leukemic KG-1 Cells.
Authors: Saba Nakhle S. , Hammad Ahmad , Salman Huda , Campbell Sharon , Krishnan Koyamangalath 
Published: October 2019

Abstract
Vitamin E is a fat-soluble vitamin that exists in eight different isoforms: four tocopherols (alpha, beta-, gamma- and delta-), and four tocotrienols (also alpha-, beta-, gamma- and delta-). Studies are underway to determine whether vitamin E, through its ability to limit production of free radicals, might help prevent or delay the development of cancer. Other studies suggest that vitamin E may modulate signal transduction pathways to prevent or reverse the effects of cancer. In our study, we examined the effect of vitamin E isotypes on some gene products involved in acute leukemia such as HOXA9 (Homeobox A9), PBX1 (Pre-B cell leukemia transcription factor 1) and E2A-PBX1. HOXA9 is a transcription factor with a central role in both hemopoiesis and leukemia. A high level of HOXA9 is a characteristic feature of acute myeloid leukemia (AML) and may be sufficient to cause this disease. PBX1 is involved in a form of pre-B-cell acute lymphoblastic leukemia (B-ALL). E2A-PBX1 is a protein resulting from a chromosomal translocation t(1;19)(q23;p13.3) which involves PBX1 and E2A genes. E2A-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family. KG-1 cells were treated with 20 micromolar (μM) gamma tocotrienol (γT3) and delta tocotrienol (δT3) for 48 hours, and 50 μM gamma tocopherol (γT) and delta tocopherol (δT) for 72 hours. MTT Assays demonstrate 30% inhibition of cell proliferation using 50 μM γT after 72 hours, 60% inhibition of cell proliferation using 50 μM δT after 48 hours, 70% inhibition of cell proliferation using 25 μM γT3 after 48 hours, and 75% inhibition of cell proliferation using 25 μM δT3 after 48 hours. Western Blot analysis was performed on the cell lysates using HOXA9, PBX1 and E2A-PBX-1 antibodies. Our results showed that both δT and γT when used at a 50 μM concentration for 72 hours treatment, as well as δT3 and γT3 when used at a 20 μM concentration for 48 hours treatment, have a down regulatory effect on HOXA9, PBX1 and E2A-PBX-1 protein expression in the leukemic KG-1 cells. A down regulatory effect on cyclin D1 and cyclin D3 was also demonstrated.
Antitumor Activity of Bortezomib Alone and in Combination with TRAIL in Human Acute Myeloid Leukemia.
Authors: Conticello Concetta , Adamo Luana , Vicari Luisa , Giuffrida Raffaella , Iannolo Gioacchin , Anastasi Gabriele , Palumbo Giuseppe A. , Gulisano Massimo , De Maria Ruggero , Giustolisi Rosario , Di Raimondo Francesco 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60–70% of patients. Bortezomib has documented antitumor activity in multiple myeloma and other lymphoid malignancies. TRAIL is a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Here we examined the sensitivity to Bortezomib alone or in combination with TRAIL of bone marrow cells from AML patients (34 patients: 25 newly-diagnosed, 4 relapsed, 5 refractory). Immunofluorescence analysis showed that NF-κB was located in the nuclei of the AML blasts and it did not translocate after exposure to Bortezomib. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 μM for 24 and 48 hours) and was associated with down-regulation of Bcl-xL and Mcl-1, up-regulation of TRAIL-R1, TRAIL-R2, p21 and activation of executioner caspases. Moreover, low doses of Bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. Thus, the combination of proteasome inhibitors and TRAIL is effective for treating AML patients, even patients who are refractory to conventional chemotherapy.
The Production of Vascular Endothelial Growth Factor Is Decreased in Acute Myelogenous Leukemia Cases That Are Treated with Chemotherapeutic Agents and Show the Prolonged Bone Marrow Suppression.
Authors: Tashiro Haruko , Noguchi Mitsuho , Shirasaki Ryosuke , Kawasugi Kazuo , Shirafuji Naoki 
Published: October 2019

Abstract
Objective: There have been reported that the levels of serum vascular endothelial growth factor (VEGF) were decreased in aplastic anemia cases. We investigated VEGF system after chemotherapy to acute myelogenous leukemia (AML) cases, and determined whether VEGF system influenced the prolonged bone marrow suppression in these cases.
Materials and Methods: Sera and bone marrow cells were prepared from 30 AML cases including 10 cases of AML (M3) at the onset of the disease, after chemotherapy, and the recovery periods, and the concentration of VEGF in sera of the patients and in the conditioned media obtained from bone marrow-cell cultures was measured with ELISA kit (Quantikine; R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was analyzed with RT-PCR. The biological effect of VEGF on the bone marrow cells which showed the prolonged suppression after chemotherapy was assayed with colony-formation with or without any cytokines.
Result and Discussion: As was reported previously, VEGF levels were significantly increased in M3 cases. In other types of AML cases the levels of VEGF production varied. When patients were given chemotherapy and the bone marrow suppression was prolonged, the production levels of VEGF were significantly diminished less than that observed in AML cases with normal bone marrow recovery. In M3 cases that were treated with all-trans retinoic acid and the prolonged bone marrow-suppression was observed, VEGF production was also suppressed. The expression of VEGFR-1 and -2 was observed in bone marrow cells from prolonged bone marrow suppression cases. In these cases, when bone marrow cells were cultured with VEGF, synergistic effects with G-CSF and EPO were observed with colony-formation assay. These observations indicate that VEGF works on the important role for the hematopoietic recovery after chemotherapy in AML cases.
The Renin-Angiotensin Axis Regulates the Development of a Yolk Sac-Like Hemangioblastic Progenitor of Primitive and Definitive Hematopoiesis from Human Pluripotent Stem Cells.
Authors: Zambidis Elias T. , Park Tea Soon , Tam Ada , Levine Michal , Peault Bruno 
Published: October 2019

Abstract
We have defined serum-free (SF) culture conditions for efficiently generating clonogenic hemangioblasts from pluripotent human embryonic stem cells (hESC). We also report that angiotensin-converting enzyme (ACE), a critical physiologic regulator of blood pressure, angiogenesis, and inflammation, is a novel marker for identifying and purifying hemangioblastic stem-progenitors from differentiating hESC. Using in vitro clonal assays of primitive and definitive hematopoietic potential, we demonstrated that ACE+ human embryoid body (hEB) cell populations contain a common yolk sac (YS)-like progenitor for not only endothelium, but also both primitive and definitive hematopoieses. Thrombopoietin (TPO) and basic fibroblast growth factor (FGF2) were identified as critical growth factors for expanding ACE+ hemangioblasts. ACE+CD34-CD45- human embryoid body (hEB) cells contained the highest number of these progenitors. Further maturation of ACE+ hemangioblasts in a stromal environment produced definitive-type lympho-hematopoietic progenitors, albeit with a late YS, and not AGM phenotype. The developmental kinetics of YS-like hematopoiesis generated from hEB cells was remarkably in parallel to the actual timeline of human YS development, which occurs during weeks 2–6 of human gestation. We also showed that ACE and the renin-angiotensin system (RAS) axis plays a direct role in hESC-derived hemangioblastic differentiation, and is directly regulated via signaling through the two major angiotensin peptide receptors (AGTR1 and AGTR2). Moreover, directed differentiation of hemangioblasts toward either endothelium, or multipotent primitive hematopoietic progenitors was efficiently enhanced via modulation of either AGTR1 or AGTR2 signaling. RAS axis manipulation may therefore be exploited for directing the differentiation of transplantable hESC-derived hemangioblastic stem-progenitors, thus providing novel opportunities for human tissue engineering. The key molecular and cellular events of human hemato-endothelial genesis can now be delineated in a manner that was previously impossible due to inaccessibility of human embryonic tissue.
Figure Figure
Biologic Features and Treatment Outcome of Secondary Acute Lymphoblastic Leukemia - Review of 101 Cases.
Authors: Shivakumar Ranga , Tan Wei , Wilding Gregory , Wang Eunice S. , Wetzler Meir 
Published: October 2019

Abstract
Secondary acute lymphoblastic leukemia (sALL) is a rare disease and its biologic features are not well described. Data suggested that sALL occurs more frequently at older age. Since leukemia at older age in general is associated with worse outcome, we wanted to assess the biology and outcome of patients with sALL by age at time of primary diagnosis. We describe a cohort of 7 patients and found additional 94 cases in the literature on whom biological parameters were described. Patients were stratified (at least 5 patients per strata) according to their age at initial diagnosis (<18, 18–59, and ≥60 years of age), initial diagnosis [acute myeloid leukemia (AML), Hodgkin’s disease (HD), neuroblastoma, breast and prostate cancers], cytogenetic groups [diploid, t(9;22), 11q23 aberrations, complex karyotype], immunophenotypes (B vs. T), and Burkitt’s defined by either morphology and/or cytogenetic analysis demonstrating c-myc rearrangement. A total of 101 patients were evaluated; 29 were <18, 54 were 18–59 and 18 were ≥60 years old. The distribution of primary diagnoses was as expected: neuroblastoma was seen only in the <18 age group (P=0.003), HD was more common in the 18–59 age group (75% of all HD cases; P=0.084) while breast (P=0.003) and prostate (P=0.005) cancers were prevalent only in the >18 year old patients. The time interval to develop sALL was similar among the three age groups (3, 2.2 and 1.8 years, P=0.561). However, the time interval to develop sALL was longer for HD (5.5 years) and neuroblastoma (3.7 years) as compared to AML (1 year), breast (1.6 years) and prostate (1.98 years) cancers (overall P=0.0003). Further, the time interval to develop sALL was significantly longer for patients with complex karyotype (5.3 years) as compared to all other aberrations [11q23 − 1.78; t(9;22) − 1.9; diploid − 1.98 years; overall P=0.0497]. Disease characteristics at diagnosis were as follows: T cell immunophenotype was more common in the <18 age group (P=0.016) and the presence of 11q23, t(9;22), complex and normal karyotypes was equally distributed among the three age groups (P=0.2, 0.073, 0.635 and 0.271 individually). Complete remission was infrequent in the ≥60 age group (22.22%) compared to the other groups (73.9% for <18 and 67.7% for 18–59; P=0.025). Even though only patients <60 years old were transplanted (33.3% for <18 and 19.4% for 18–59; P=0.102), the overall survival was poor in all age groups [probability of survival at 1 year for <18=0.222, 18–59=0.226 and ≥60=0.3 (P=0.7941)]. Primary diagnoses, cytogenetic subgroups and immunophenotype did not affect outcome. In summary, the time interval to develop sALL is significantly longer for HD, neuroblastoma and complex karyotype. However, sALL is associated with very poor outcome regardless of age and any of the biologic features. Therefore, identification of prognostic factors to prevent the occurrence of sALL is needed.
Longitudinal Assessment of Nutritional Status in Adults with Acute Leukemia.
Authors: Serralde Aurora , Crespo-Solis Erick , Lopez-Karpovitch Xavier , Damasco Ericka , Rosas-Lopez Adriana , Aguayo Alvaro 
Published: October 2019

Abstract
RATIONALE: The nutritional status of patients with acute leukemia (AL) is frequently impaired during intensive induction chemotherapy. Previous studies have suggested that malnutrition may have an adverse effect on prognosis. The aim of the study was to determine the prevalence of malnutrition during induction chemotherapy treatment and its impact on the outcome.
METHODS: The study was performed over a period of 18 consecutive months. Acute leukemia patients were prospectively studied during first remission induction chemotherapy. The Subjective Global Assessment (SGA), anthropometric and laboratory data were determined at diagnosis and on day 30 of the treatment in order to evaluate nutritional status. Patients were prospectively followed until 60 days after diagnosis. An analysis was made including demographic data, nutritional assessment, albumin, complications, rate of complete remission (CR), rate of early mortality (EM) and length of hospital stay (LOS).
RESULTS: 32 patients (18 men, 14 women) were included; median age 31 years (range 15–62); 16 with myeloid leukemia, 13 with lymphocytic leukemia and 3 with hybrid leukemia. The median of body mass index (BMI) was 25 kg/m2 (18.3–41.7); triceps skinfold (TSF) 16.5 mm (7–42); albumin 3.24 g/dL (1.98–4.18). At diagnosis, the prevalence of malnutrition was 59% according to the SGA (moderately and severely malnourished) and increased to 90% on day 30, (p<0.05). We obtained initial CR in 22 patients (69%), the mortality rate due to post-chemotherapy aplasia (EM) in the prospective cohort was 9%. Patients with deterioration of the nutritional status had longer LOS in comparison with those patients well nourished (15.61 vs. 9.68 p<0.05). They also needed antibiotics for a longer time (16 vs. 10 days, p< 0.05). Nutritional status was not associated with CR rate or EM rate.
CONCLUSIONS: The high incidence of malnutrition at the time of diagnosis and during chemotherapy indicate the importance of nutritional status evaluation. Malnutrition in AL is caused by chemotherapy side effects and/or the disease itself, during this period intensive supportive care, including nutritional therapy is required.
The Clinical Features and the Efficient Therapy of 66 Acute Promyelocytic Leukemia Patients with High Initial White Blood Cell Count.
Authors: Qiu Hui-ying , Xue Meng-xing , Sun Ai-ning , Liu Yue-jun , Wu De Pei 
Published: October 2019

Abstract
Objective: To investigate the clinical features and the efficient therapy of acute promyelocytic leukemia(APL) with high initial white blood cell(WBC) count.
Methods: The clinical features of 66 newly diagnosed APL patients with high initial WBC and 152 patients without high initial WBC were retrospectively analyzed. Additionally, 66 patients with high WBC were divided into different groups and the therapeutic effects were compared according to the different induction therapy.
Results: The early death rate and the incidence of disseminated intravascular coagulation(DIC) and retinoic acid syndrome(RAS) were 30.3%,57.6% and 31.8% respectively for the group with initial high WBC, those were higher than the indexes of 7.2%,38.1% and 21.05% respectively for the group without initial high WBC (p <0.05),Whereas CR rate (63.6%) for the group with initial high WBC were lower than that (88.2%) for the group without initial high WBC (p <0.05). 61 of 66 patients with high WBC accepted induction therapy: 31 patients treated with all-trans retinoic acid(ATRA) alone ,21patients treated with the combination of ATRA and arsenic trioxide (ATO),9 treated with ATO alone, the early death rates were 27.3%,14.3%,55.6% respectively, CR rates were 67.7%,81.0%,44.4% respectively, the result showed there were the lowest rate of early death and the highest rate of CR in the combination group. Of 61 patients, 41 cases were given low-dose chemotherapy, the CR rate was 73.2%,total death rate was 19.5%, that of 20 patients without chemotherapy were 45.0%,55.0% respectively. The differences between two groups had statistical significance(p<0.05).
Conclusions: Compared with APL without high initial WBC, APL with high initial WBC has lower CR rate, higher early death rate, higher incidence of DIC and RAS .The combination of ATRA,ATO and chemotherapy is the most efficient therapeutic approach to APL patients with high initial WBC, which can significantly reduce the early death rate and improve the CR rate.
Addition of ATRA to the Maintenance Protocol Did Not Improve Disease-Free Survival: Results of the Russian APL Trial.
Authors: Parovichnikova Elena N. , Savchenko Valeri G. , Isaev Valentin G. , Shuravina Elena N. , Demidova Irina A. , Olshanskaya Julia V. , Misiurin Andrey V. , Kulikov Sergey M. 
Published: October 2019

Abstract
Russian Leukemia study group is presenting the final analysis of the APL-06.01. randomized clinical trial. The aim of the study was to identify the efficacy of ATRA substitution of each other chemotherapy course while the 2-yrs maintenance after three induction/ consolidation 7+3 with daunorubicin dose of 180 mg/m2 per course and ATRA for 30 days while the first induction. The patients were randomized for two types of maintenance - (I type) rotation of 5-days ARA-C (100 mg/m2 bid) combined with daunorubicin (45 mg/m2 for 2 days, till the total dose of 650 mg/m2) or 6-MP (50mg/m2 p.o.5 days) or CHP (800 mg/m2 i.v.1 day) or (II type) rotation of the same courses of chemotherapy with 5-days 45 mg/m2 ATRA course. The II type of maintenance treatment contained twice less chemotherapy. The intervals between courses were 4 weeks From July, 2001 till January, 2006 114 APL patients from 26 centers were enrolled in the study. In 95% of pts APL was confirmed by cytogenetics or PCR. 102 patients were included in the analysis. CR rate was 85%, ED rate -15%, 4-yrs OS -68,3%, DFS - 77,4%, CCR - 89,5%. Suvival analysis according to randomization did not demonstrate statistical differences, but showed a trend (p=0,06) towards better DFS and CCR in patients maintened with chemotherapy only: 85,2% and 94,3% (I type) and 77,7% and 85,6% (II type). In the multivariant analysis only one factor was defined as statistically significant - the number of the patients randomized by the participating centers. OS and DFS were much higher in the centers randomized 6 and more patients comparing with less than 6 patients: 82,9%and 90,7% vs 48,8% and 63%, respectively (0,003). 1. So we can suggest that maintenance with ATRA alternating with chemotherapy is less effective than chemotherapy only. Whether addition not substitution of ATRA to chemotherapy maintenance will change the results will be checked in the next study.2. The experince of the centers in APL treatment is a cruicial point for survival.
Salvage Therapy with Standard Dose Cytarabine Is Appropriate for Patients with Acute Myelogenous Leukemia Refractory to Front-Line Therapy with Hypomethylating Agents.
Authors: Borthakur Gautam , Kantarjian Hagop , Garcia-Manero Guillermo , Pierce Sherry , Estey Elihu 
Published: October 2019

Abstract
Treatment without cytarabine (ara-C) is increasingly being used as initial therapy for acute myelogenous leukemia (AML) particularly in patients (pts) deemed ineligible, usually on the basis of age, for standard ara-C-containing therapy; prime examples are the hypomethylating agents decitabine (DAC) and 5-azacitidine (Aza). This practice raises the question whether it is useful for patients whose disease fails to respond to hypomethylating agents to receive ara-C as salvage. Thirty-five pts treated from 2001 to 2006 failed to respond to initial therapy with decitabine/azacitidine. Twenty-five pts subsequently received ara-C as salvage and 10 received other salvage regimens. We compared their complete remission (CR) rates (Table 1). Although more pts who received non ara-C salvage had poor prognosis karyotype, CR rates in pts with standard-risk karyotype receiving ara-C and non ara-C salvage therapy were 7/20 (35%) vs. 0/6 (0%) respectively. Although this difference was not significant (p=.15) the 95% confidence limits for the true difference, computed so as to account for the small sample size, was [−.69, .11] indicating as much evidence for a true difference of 58% as for a true difference of 0% since zero and 58% are equidistant from the midpoint of the confidence interval (−0.29). Although future improvements in results with non ara-C containing salvage therapies will impact decision, the results suggest that it is worthwhile to give pts who fail initial therapy with decitabine or azacitidine, standard dose ara-C salvage provided the pts do not have −5/−7 (CR rate 0/5).
Table 1 Induction/salvage Patients Median age −5 / −7 CR DAC or Aza/ara-C 25 67 5 (20%) 7 (28%) DAC or Aza/no ara-C 10 71 4 (40%) 0
Feasibility Study of Temozolomide Maintenance Therapy in Elderly Patients with AML Following Induction Therapy with High Dose Mitoxantrone and High Dose Ara-C.
Authors: Ponce Doris , Katragadda Sreedhar , Liu Delong , Rasul Muhammad , Ahmed Nasir , Ahmed Tauseef , Seiter Karen 
Published: October 2019

Abstract
With intensive chemotherapy, approximately 50% of elderly patients with AML achieve a complete remission, however essentially all will relapse within 2 years. To date, there is no standard effective postremission therapy for these patients, and most elderly patients tolerate multiple courses of intensive chemotherapy poorly. We previously demonstrated that temozolomide has significant antileukemic activity in patients with relapsed/refractory acute leukemia (Seiter K, et al JCO 2002). In that study 9/20 patients treated had a significant reduction in bone marrow blasts, and 4 patients had a formal complete response. Currently we are evaluating the feasibility and efficacy of temozolomide maintenance therapy administered after one cycle of intensive induction chemotherapy in elderly patients with newly-diagnosed AML. Induction consists of ara-C, 3 gm/m2 daily for 5 days, and mitoxantrone, 80 mg/m2 times one on day 2. Patients achieving complete remission then receive temozolomide 200 mg/m2/d for 7 days every 5 weeks until progression. To date, 34 pts have been treated: median age 69.5 (range 61–84); M/F: 21/13; prior AHD: 47%; cytogenetics: good: 1, intermediate: 24, poor: 7, insufficient: 2. Response to high-dose ara-C/high-dose mitoxantrone induction: CR: 56%, failure: 32%, toxic death: 12%. Two pts expired in remission unrelated to temozolomide: pneumonia, 1 pt, C. difficile colitis: 1 pt. Of 19 patients in CR, 16 received temozolomide maintenance. The median number of temozolomide cycles was 2 (range 1–14). 3 pts stopped temozolomide after 1 cycle (1 refused further therapy, 1 had stem cell transplant, 1 died from C. difficile colitis). Treatment was well tolerated and was administered in the outpatient setting. The median duration of remission is 6.8 months (95% CI: 4.5–9.1 months), and median survival is 5.5 months (95% CI: 3.7–7.3 months) for all patients and 10.1 months (95% CI: 4.9–15.2 months) for patients achieving CR. Temozolomide maintenance is feasible in patients with AML in CR. Further accrual is continuing to assess if remission duration and survival will be improved compared to historical controls.