bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro and In Vivo Anti Lymphoma Effect of GX15-070 in Mantle Cell Lymphoma.
Authors: Bebb Gwyn , Muzik Huong , Nguyen Sophia , Morris Don , Stewart Douglas A. 
Published: April 2020

Abstract
Introduction
Mantle cell lymphoma (MCL), an incurable B cell lymphoma, consistently over expresses bcl-2 despite not carrying the t(14;18). The attenuation of apoptosis by bcl-2 is thought to contribute to the malignant process and increase resistance to some cytotoxic agents. We recently demonstrated that GX15-070, a small molecular inhibitor of the BH3 binding groove of bcl-2, has activity against MCL cell lines in vitro. We set out to assess the effect of GX15-070 alone and in combination with Vincristine on the viability of MCL cells in vitro and in vivo.
Methods
3 previously characterized bcl-2 over expressing MCL cell lines (JVM-2, Hbl-2, granta) were used. Cells were grown in standard media and exposed to a range of concentrations of GX15-070 with and without Vincristine. Dose-response was assessed by measuring viability at 48 hours using the WST-1 assay. In vivo experiments were conducted on immune deficient mice in which 5×106 cells were injected in the flank then treated IV with GX15-070 (q 2days × 5 doses), Vincristine (q4 days × 3 doses) or both starting 5 days later. Tumours were measured three times weekly.
Results
All three MCL cell lines over-expressed bcl-2 by western blot. Each MCL cell line showed sensitivity to GX15-070 at a range of concentrations. The addition of GX15-070 to low dose Vincristine (10−6) caused significant growth inhibition of each MCL cell line (see table 1).
Discussion
Our results demonstrate that using GX15-070 to target bcl-2 is an effective anti neoplastic approach against MCL cell lines in vitro. In addition, our results suggest that combining Vincristine and GX15-070 is a promising strategy in treating MCL. In vivo experiments to confirm this additive activity are still ongoing and will be presented in full. Initial impressions suggest that there is a rationale for the addition of GX15-070 to current cytotoxic regimens used to treat MCL in the setting of clinical trials.
Table 1: Effect of Vincristine and GX15-070 on in vitro growth of 3 MCL cell lines Growth as % age of Control Cell Line JVM-2 HBL-2 Granta Vincristine alone (10-6 mg/ml) 92% 48% 89% GX15-070 alone (0.08 uM) 75% 76% 60% Vincristine 10-6 mg/ml and GX15-070 0.08 uM 52% 24% 52%
Treatment Outcomes for Imatinib Mesylate and Allogeneic Stem Cell Transplantation in Patients with CML Based on RQ-PCR, and the Efficacy of Dose Escalation of Imatinib Mesylate in Patients with Cytogenetic or Hematologic Resistance.
Authors: Sohn Sang Kyun , Cho Yoon Young , Ahn Byung Min , Chae Yee Soo , Kim Jong Gwang , Moon Joon Ho 
Published: April 2020

Abstract
This study examines the treatment outcome for imatinib mesylate (IM) and allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukemia (CML) based on quantitative PCR data and the efficacy of a dose increment of IM in patients with cytogenetic or hematologic resistance.
A total of 60 Ph+ CML patients that received IM and 17 patients that received allogeneic SCT were enrolled in the current study. The cumulative incidence of a complete hematologic response (CHR) was estimated as 71% after 1 month and 93% after 3 months, while the cumulative incidence of a major molecular response (MMR) was estimated as 53% after 6 months and 73% after 1 year. Five (22.7%) out of 22 evaluable patients achieved MMR after 3 months of IM treatment. At 24 months, 10 patients (45.5%) achieved MMR, while 7 patients (31.8%) remained as non-responders. Thrirteen patients that exhibited a cytogenetic or hematologic resistance to the standard dose of IM were treated with an increased dose of IM. Four (80%) out of 5 patients who had low levels (10–55%) of Ph+ cells in their bone marrow at the time of cytogenetic resistance achieved a complete cytogenetic response (CCR) or MMR again with the increased dose of IM, while all the patients (n=8) who failed to respond cytogenetically or hmatologically to the increased dose of IM had 100% Ph+ cells in their bone marrow at the time of cytogenetic resistance. The Philadelphia positivity in the bone marrow indicated a cytogenetic or molecular response to an increased dose of IM (P=0.009). The overall survival rate at 3 years was 88% for the IM group at the median follow-up duration of 851 days (range, 13–3346 days) and 47% for the SCT group at the median follow-up duration of 456 days (range, 34–2455 days), respectively (P&lt;0.001). Plus, the progression-free survival rate at 3 years was 61% for the IM and 47% for the SCT group, respectively (P=0.037). In conclusion, IM dose escalation can be regarded as an important treatment option in terms of reserving other treatment options, especially in patients with low levels (≤55%) of Ph+ cells in their marrow who are resistant cytogenetically or hematologically to the standard dose of IM.
Chronic Myeloid Leukemia in Two Patients with Gastrointestinal Stromal Tumor.
Authors: Sakamoto Erina , Nakamae Hirohisa , Koh Ki Ryang , Yamane Takahisa , Hino Masayuki 
Published: April 2020

Abstract
Imatinib competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. Most patients with chronic myeloid leukemia (CML) achieve clinically relevant hematologic and cytogenetic responses to imatinib. It is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, it was examined for therapeutic efficacy against malignant Gastrointestinal Stromal Tumor (GIST), which is a rare tumor of the gastrointestinal tract and is mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor. We report two rare cases of double cancer involving CML and GIST. The first case is a 66-year-old Japanese male patient who was presented to our hospital with leukothrombocytosis on February 27, 2006. The patient was diagnosed to be suffering from CML by the presence of Philadelphia chromosome. Several days later, he was admitted with acute peritonitis. A ruptured tumor on 80 cm oral side of ileum end was found by an emergency partial ilectomy. Microscopically, spindle-shaped and round epithelioid cells were growing externally from the intestinal muscular propia. Immunohistochemical analysis showed that the tumor cells were positive for c-kit and CD34 and negative for S-100 protein and desmin. The tumors were identified as GIST. Imatinib was administered to treat CML on the 8th postoperative day. The second case is a 57-year-old Japanese female patient who was presented to our hospital with marked thrombocytosis on March 6, 2006. The patient was diagnosed to be suffering from CML by the presence of Philadelphia chromosome. One year ago, she underwent distal gastrectomy for submucosal tumor. Pathological examination revealed proliferation of submucosal spindle-shaped cells with elongated cigar-shaped nuclei arranged in fascicles. Immunohistochemical stains confirmed the diagnosis of GIST.
These two cases provided a valuable opportunity for treating GIST with CML. We look forward to active effect of imatinib, not only in CML treatment but also in preventing recurrence of GIST. The occurrence mechanism of either CML or GIST at the biomolecular level has been established. However, we can show no relation between these malignancies. Therefore, it is natural for us to understand accidental coincidence. We should follow-up these patients carefully. Accumulation of such cases may contribute to clarify more precise mechanism of tumorgenesis.
The Recent Thymic Output Function Might Relate with BCR-ABL mRNA Level in Patients with CML.
Authors: Geng Suxia , Du Xin , Weng Jianyu , Yang Lijian , Chen Shaohua , Li Yangqiu 
Published: April 2020

Abstract
Objective In order to analyze the relationship between the content of T-cell receptor excision DNA circles (TRECs) and BCR-ABL mRNA levels, evaluating the prognostic significance of thymic recent output function monitoring in patients with chronic myelogenous leukemia (CML).
Methods Quantitative detection of TRECs and BCR-ABL fusion gene transcripts in peripheral blood from 15 CML patients were preformed using real-time PCR technique. And the TREC-number was related to the number of T-cells by determination of the number of CD3-positive cells. The change of BCR-ABL level in 6 CML patients was followed-up for two years.
Results There was no significant correlation between TRECs and BCR-ABL mRNA in peripheral blood from CML patients at the first diagnose. Patients who had higher TRECs at diagnosis had a larger reduction of BCR-ABL level after 2 years of follow-up. While in 2 patients who underwent haemopoietic stem cell transplantation(HSCT), BCR-ABL in one patient with higher pre-transplantation TRECs value became undetectable with three consecutive detections during the first year post transplantation, but low level of BCR-ABL could be identified in the other patient.
Conclusion High thymic output function in CML patients could be helpful for anti-residual CML cells.
Single and Multiple Oral Doses of AKR-501 (YM477) Increase the Platelet Count in Healthy Volunteers.
Authors: Desjardins Robert E. , Tempel Donna L. , Lucek Rudolph , Kuter David J. 
Published: April 2020

Abstract
AKR-501 is an orally active thrombopoietin (TPO) receptor agonist that increases platelet production through stimulation of megakaryocyte proliferation and differentiation. The effect of AKR-501 in in vitro and in vivo models is additive with that of rhTPO. AKR-501 is a potential new therapy for use in the prevention or treatment of thrombocytopenia of various etiologies. We evaluated the safety, pharmacokinetics and pharmacodynamic activity of AKR-501 when administered as single and multiple oral doses to healthy volunteers. In the single dose study, 7 dose cohorts of 9 subjects each were randomized in a ratio of 2:1 to receive increasing doses (1, 3, 10, 20, 50, 75 and 100 mg) of AKR-501 or placebo. In the multiple dose study, 5 dose cohorts of 9 subjects each were to be randomized in a ratio of 2:1 to receive increasing doses (3, 10, 20, 50 and 100 mg) of AKR-501 or placebo administered daily for 14 days. All subjects were evaluated for safety and pharmacodynamic activity as assessed by peripheral blood platelet counts (PBPC). Dose escalation was stopped on Day 10 of dosing in the 3rd dose cohort (20 mg/day) when 6 of the volunteers exhibited a platelet count above 500,000/mL. The protocol defined endpoint of &gt;50% increase over baseline platelet count was achieved in 5 of 6 volunteers given a single dose of 100 mg, and in all 6 volunteers given daily doses of 10 mg for 14 days and 20 mg for 10 days. The drug was well tolerated in both the single and multiple dose studies with no serious drug-related adverse experiences reported at any dose. AKR-501 was consistently well absorbed exhibiting dose linear pharmacokinetics following single and multiple dose administration, and a serum half-life of approximately 16 hours. The mean observed Cmax following administration of single doses increased from 5.67 ng/mL at 1 mg to 388 ng/mL at 100 mg. The mean observed AUC increased from 174 ng·hr/mL at 1 mg to 11052 ng·hr/mL at 100 mg. Accumulation to steady state with multiple dosing was consistent with predictions based on a linear model and the single dose PK parameter estimates. There was a linear correlation of individual observed peak activity with corresponding Cmax (single-dose r2=0.70 p&lt;.0001, multiple-dose r2=0.67 p&lt;0.0001). The mean change from baseline PBPC for each dose cohort in the single-dose (Figure 1) and multiple-dose (Figure 2) studies are shown in the following graphs.
Figure 1 Figure 1. Figure 2 Figure 2.
Study on the Mechanisms of CML Blast Crisis by Comparative Proteome Analysis.
Authors: Liu Xiaoli , Du Qingfeng , Zhang Song , Li Rong , Yao Feng , Fan Wei , Wang Yu 
Published: April 2020

Abstract
The clinical course of chronic myeloid leukemia(CML)is characteristically triphasic, comprising chronic and accelerated phases and blast crisis. Chronic phase(CP) is characterized by the Ph chromosome as the sole genetic abnormality and blast crisis(BC), which is the terminal phase of CML, often associated with additional chromosomal and molecular secondary changes. Although CML is probably the most extensively studied human malignancy, the mechanisms of CML blast crisis are still poorly understood. In current study, we analyzed the changes of protein expression between CML-CP(25 cases) and CML-BC(20 cases) by Two-dimensional polyacrylamide gel electrophoresis(2-D PAGE). Compared with that of CML-CP, 33 proteins’ intensities of CML-BC were found to have significant difference including 23 increasing and 13 decreasing. 15 proteins were identified by peptide mass fingerprint in combination with database searching including proteasome activator complex, hnRNP, annexin A4, serine proteinase inhibitor, annexin A1, GAPDH, RhoGDI, enolase, proteasome subunit 6a, GTP binding protein, leukotriene A4 hydrolase, Rac-RhoGDI, thioredoxin, proteasome subunit 4β and DJ-1 protein, and the functions of these proteins involve cell signal transduction, apoptosis, proliferation and transcription. In conclusion, our study provided a profile of protein expression difference between CML-CP and CML-BC and contributed to understand the mechanisms of CML blast crisis.
Imatinib (Glivec) and Nilotinib (AMN107), Two Selective Inhibitors of Bcr-Abl Tyrosine Kinase, Induce Hemoglobin Production in Human K-562 CML Erythroleukemia Cells in Addition To Promoting Apoptosis.
Authors: Tsiftsoglou Asterios S. , Manley Paul W. , Bonovolias Ioannis D. 
Published: April 2020

Abstract
Imatinib (Glivec) and Nilotinib (AMN107) have been developed as selective targeted inhibitors of Bcr-Abl chimaeric tyrosine kinase activated in CML and other malignancies characterized by the t(9;22) translocation (Manley P.W., et al. Biochim Biophys Acta 1754(1–2):3–13, 2005). Both agents are considered innovative targeted cell death promoting agents designed for treatment of human leukemias. During the course of their evaluation as apoptosis-promoting agents in human K-562 leukemia cells, we observed that both agents in addition to blocking Bcr-Abl tyrosine kinase, promoted production of hemoglobin but to different extent. Imatinib caused hemoglobin production in 6–7% of cells at concentration of 0.01 μM to 0.5 μM. This proportion reached 54% in the presence of 90 μM of Hemin. Nilotinib alone, on the other hand, caused hemoglobin production in 66% of cells at a concentration of 0.01 μM. This proportion increased to 75% in the presence of 30 μM of Hemin. These findings indicate that:
Imatinib and Nilotinib are weak and potent inducers of hemoglobin biosynthesis, respectively. Treatment of K-562 cells with either Imatinib (0.5 μM) and Nilotinib (0.01 μM) enhanced the ability of Hemin to promote erythroid differentiation. This ability of Nilotinib to induce hemoglobin accumulation at concentrations lower than those causing apoptosis, suggest that this agent may be clinically useful by promoting hemoglobin biosynthesis in diseases characterized by hemoglobin deficiency (hemoglobinopathies). We are currently investigating the mechanism whereby Nilotinib can selective activate the globin gene expression in K-562 leukemia cells.
Imatinib 400 mg in Early Chronic Phase CML: Results of a Multicentric, Prospective Non Academical Observational Study (by the GIMEMA CML Working Party).
Authors: Rosti Gianantonio , Castagnetti Fausto , Iacobucci Ilaria , Amabile Marilina , Palandri Francesca , Giannoulia Panagiota , Alimena Giuliana , Testoni Nicoletta , Luatti Simona , Martino Bruno , Specchia Giorgina , Rupoli Serena , Capucci Adele , Cavazzini F. , Radaelli Franca , Orlandi Ester , Cambrin Giovanna Rege , Usala Emilio , Testoni Nicoletta , Pane Fabrizio , Saglio Giuseppe , Martinelli Giovanni , Baccarani Michele 
Published: April 2020

Abstract
Imatinib 400 mg (SD) is the established first line treatment of chronic myeloid leukemia (CML) in chronic phase. The efficacy of imatinib in early chronic phase has been demonstrated by phase 2 and 3 controlled trials like the IRIS study (O’ Brien et al NEJM 348:11, 2004). Large multicentric studies aimed to evaluate the impact of imatinib 400 mg outside strictly monitored frameworks are not yet available. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML Working Party opened in January, 2004, an observational study (serial n. CML/023) to investigate the efficacy of imatinib SD in newly diagnosed CML pts. Clinical and anagraphical data were collected through a web-based system. Peripheral blood samples for quantitative molecular analysis (RT-Q-PCR, Bcr-Abl/Abl × 100 - Taqman) were centralized in Bologna. Overall, 55 italian centers enrolled 367 (359 evaluable) newly diagnosed CML pts in chronic phase between Jan 2004 and Jan 2006. Median age was 50 yrs (range 18–84), 220 male and 139 females. Sokal risk at diagnosis was low, intermediate and high in 221 (62%), 123 (34%), 15 (4%) pts, respectively. 359 pts are evaluable for response at 3 months, 310 at 6 months and 187 at 12 months. The median observation time is 12 months. At 3 months, 94% of the pts reached a stable CHR. At 6 months, 80% of evaluable cases obtained a complete cytogenetic response (100% Ph-neg, CCgR). A major molecular response (MMolR) defined as a Bcr-Abl/Abl × 100 ratio &lt; 0.1%, was shown in 52% of CCgR pts. At 12 months, the CCgR rate was 87% and the MMolR rate in CCgR pts was 63%. At 12 months, 3% of CCgR cases showed an undetectable level of transcript (ratio Bcr-Abl/Abl × 100 &lt; 0,0001). With this short observation period, only 4 pts (1,1%) progressed to accelerated/blastic phase. Limiting the observation to low Sokal risk, at 12 months 221 such pts got a CCgR and MMol rates of 88% and 62%, respectively; 201 low Sokal risk pts were enrolled in the IRIS trial: at 12 months CCgR and MMolR (reduction of Bcr-Abl/Bcr ratio level &gt; 3 logs) rates were 76% and 66%, respectively ( (T Hughes et al, NEJM 349:15, 2003). This study confirns that imatinib is efficacious and manageable, confirming and improving the results of the IRIS trial.
Additional Cytogenetic Abnormalities and/or Philadelphia Chromosome Metaphase Mosaicism Might Adversely Influence Survival and Imatinib Response in Chronic Myeloid Leukemia.
Authors: Landstrom Andrew P. , Ketterling Rhett P. , Knudson Ryan A. , Dewald Gordon W. , Tefferi Ayalew 
Published: April 2020

Abstract
Background: Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance of these two scenarios.
Methods: The study population consisted of 65 (47.7% female) consecutive, newly diagnosed CML patients seen at the Mayo Clinic with a median age of 59 years. 44.5 percent were initially treated with interferon alpha (IFN) resulting in complete cytogenetic remission in 10.7 percent for a median length of 5.83 years, partial cytogenetic remission in 3.57 percent for a median length of 2 years. 55.5 percent were treated with imatinib (Gleevec) resulting in complete cytogenetic remission in 54.1 percent for a median length of 3.08 years, partial cytogenetic remission in 13.5% for a median length of 1.08 years.
Results: Survival at five years through Kaplan-Meier analysis was approximately 92 percent in patients demonstrating only the Ph chromosome (n = 53), versus 60 percent in patients with additional chromosomal abnormalities (n = 12; p &lt; 0.0001 by both Logrank and Breslow-Gehan-Wilcox analysis). Furthermore, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, five year survival of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared to 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = 0.01 by Logrank and p = 0.001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = 0.05).
Conclusion: Although it is tempting to speculate the possibility that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study.
Figure Figure Figure Figure
Detection of BCR-ABL Transcript by Quantitative Real-Time PCR and Amp-CML (Transcript Mediated Amplification) during Imatinib Therapy for Chronic Myeloid Leukemia.
Authors: Miyamura Koichi , Yagasaki Fumiharu , Kyo Taiichi , Ohnishi Kazunori , Naoe Tomoki , Takeuchi Hitoshi , Nishimura Miki , Fujiwara Shin , Tauchi Tetsuzo , Ohno Ryuzo 
Published: April 2020

Abstract
Imatinib induces a complete cytogenetic response in the majority of patients and a reduction of BCR-ABL to 0.1% of the level at diagnosis is associated with longer progression free survival. However, the methods of BCR-ABL detection differ from study to study. Mostly, quantitative real-time PCR assay (RQ-PCR) has been used however, the control gene and expression of results have not been standardized to date. In Japan, only Amp-CML, a commercial kit composed of TMA (transcription mediated amplification) and HPA (hybridization protection assay) has been approved by the government. BCR-ABL was expressed by copy number per microgram RNA. The range of detection is between 50 to 2500 copies per assay. If 0.05 ug of RNA is used for the assay, the detection ranges between 1000 to 50000 copies per microgram RNA. However, the accuracy and sensitivity of Amp-CML in comparison with RQ-PCR are not well known. Thus we compared Amp-CML with RQ-PCR using a large number of patients enrolled in the Japan Adult Leukemia Study Group (JALSG).
In the JALSG clinical trial, imatinib was used as initial therapy for 171 patients with chronic myelogenous leukemia. We measured levels of BCR-ABL transcripts in the blood of all patients in this trial before and 1, 2, 3, 6 and 12 months after the treatment using RQ-PCR and Amp-CML. In both assays the results expressed the copy numbers of BCR-ABL per microgram of RNA. The median number of BCR-ABL transcripts detected by RQ-PCR was 98,964 at diagnosis and 63,442, 33182, 3342, 331 and 98 at 0, 1, 2, 3, 6, 12 months, respectively, after treatment. The median number of BCR-ABL transcripts detected by Amp-CML was &gt;50000 at diagnosis and &gt;50000, 20284, 2180, &lt;1000 and &lt;1000 at 0, 1, 2, 3, 6, 12 months, respectively, of treatment. These results suggested that results of Amp-CML and RQ-PCR were well correlated (R=0.67), although the range of Amp-CML was restricted. In the next step, we attempted to improve the sensitivity by increasing the amount of RNA used for Amp-CML. Using 0.5 ug of RNA, the range of detection by Amp-CML is between 100 and 5000 copies, and 50 additional samples were analyzed. In this range, BCR-ABL copy number was also well correlated. (R=0.968) Using 2ug of RNA, we are investigating more sensitive methods expecting range of detection by Amp-CML is between 25 and 1250 copies. Tentatively 13 samples which showed 10–100 copy/ug by RQ-PCR was reevaluated by both methods. Ratio of Amp-AML to RQ-PCR is 1.4 in median and range is 0.3-2.1. Thus Amp-CML may have accuracy even the very small range. Thus, Amp-CML can be used for the monitoring BCR-ABL transcripts during treatment with imatinib.