bluuebunny/crossref_metadata_2025_split huggingface dataset:
Directing Oncogenic Fusion Genes into Stem Cells Via an Scl Enhancer.
Authors: Eguchi Mariko , Eguchi-Ishimae Minenori , Green Anthony R. , Enver Tariq , Greaves Mel 
Published: October 2019

Abstract
Chimeric fusion genes generated by chromosomal translocation are a consistent feature of leukemias and some other cancer types, including sarcomas, and usually specific to particular subtypes of leukemia or tumors. One favoured explanation for this selective transformation is that it may reflect context-dependent oncogenic functions in particular stem cells and their progeny rather than highly restricted origins of fusion gene recombination itself. We have assessed this proposition by directing the expression of fusion oncogenes in stem cells in vivo.
TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it associates with both rare solid tumors (congenital fibrosarcoma, congenital mesoblastic nephroma and secretory breast carcinoma) and acute leukemia, but a single exon difference (in TEL) between the two phenotypes. We expressed the two TEL-TRKC variants in mice using the 3′ regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (- exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia in transgenic mice. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype around day 12.5 (E12.5) with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. These data indicate that oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type specific developmental impacts dependent upon their intrinsic molecular properties.
The Roles of Stat3 and ERK in G-CSF Signaling.
Authors: Kamezaki Kenjirou , Shimoda Kazuya , Numata Akihiko , Yoshie Masumi , Yamamoto Masahiro , Takeda Kiyoshi , Matsuda Tadashi , Akira Shizuo , Ogawa Katsuhiro , Harada Mine 
Published: October 2019

Abstract
G-CSF specifically stimulates the proliferation and differentiation of cells that are committed to the neutrophil-granulocyte lineage. We examined the role of stat3 in G-CSF signaling using the Cre-loxP recombination system. Although Stat3 was thought to be essential for the transduction of G-CSF-induced cell proliferation and differentiation signals, mice deficient for Stat3 in hematopoietic cells show neutrocytosis and infiltration of cells into the digestive tract. The number of progenitor cells in the neutrophil lineage is not changed, and G-CSF-induced proliferation of progenitor cells and prolonged neutrophil survival were observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3 null bone marrow cells displayed a significant activation of ERK1/2 under basal conditions, and the activation of ERK was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. These results indicate that Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression, and ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.
Prevalence of Microbially Contaminated Hematopoietic Stem Cell Products.
Authors: Champlin Richard E. , Loberiza Fausto R. , Eapen Mary , Rizzo J. Douglas , Bredeson Christopher N. , Wagner John E. , Horowitz Mary M. ,   on behalf of the Histocompatibility Alternative Stem Cell Sources Working Committee of the Center for International Blood Marrow Transplant Research (CIBMTR)
Published: October 2019

In 2001, the Docket Report from the Food and Drug Administration expressed concerns regarding the potential of microbially contaminated hematopoietic stem cell products to produce morbidity and mortality in transplant recipients. This concern was the basis for development of regulatory standards for hematopoietic stem cell products.
We surveyed a total of 2972 patients at 121 U.S. transplant centers that registered patients with the CIBMTR in the years 2000 and 2001. Information regarding microbial contamination of infused grafts was obtained from 94 transplant centers (80% response rate) for 2312 patients. 52 (2%) of 2286 infused grafts tested were culture positive for bacterial or fungal organisms. The microbial isolates included: coagulase negative staphylococcus (56%), gram negative organisms (15%), coagulase positive staphylococcus (10%), gram positive rods (10%), streptococcus (8%), and fungus (1%). Prophylactic antibiotics targeted at the contaminant were given to 17 of the 52 recipients of contaminated grafts. Antibiotic regimens included vancomycin alone (76%), aminoglycosides and vancomycin (12%), or cephalosporin and vancomycin (12%). 47 (50%) of the centers that participated have existing policies regarding contaminated products. Patients with non-malignant disorders or who received bone marrow were more likely to have a contaminated graft. No differences in age distribution, sex, race, type of transplant (allogeneic vs autologous) and year of transplant were noted between recipients of contaminated and non-contaminated grafts. The unadjusted 100-day survival of persons receiving contaminated grafts was 86% (95% Confidence Interval [CI] 72–93%) versus 81% (95% CI 80–83%) among those receiving non-contaminated grafts, p=0.35.
In summary, about 2% of hematopoietic stem cell products infused for allogeneic or autologous transplantations in U.S. centers will test positive for microbial contamination, but such contamination does not increase posttransplant mortality. The absence of significant 100-day mortality among patients infused with contaminated grafts suggests that stringent regulatory policies regarding the use of contaminated hematopoietic cell products may not be indicated.
Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials.
Authors: Silver Richard T. , Talpaz Moshe , Sawyers Charles L. , Druker Brian J. , Hochhaus Andreas , Schiffer Charles A. , Guilhot Francois , Goldman John M. , Smith B. Douglas , Mone Manisha , Kranhnke Tillmann , Kantarjian Hagop M. 
Published: October 2019

Abstract
Background
This report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003).
Methods
Between August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts.
Results
As of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment.
At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001).
Conclusion
In large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).
Avascular Necrosis of Bone after Therapy for Multiple Myeloma: A Study of 561 Consecutive Patients.
Authors: Anaissie Elias J. , Talamo Giampaolo , Angtuaco Edgardo , Walker Ronald C. , Dong Li , Zangari Maurizio , Tricot Guido , Barlogie Bart 
Published: October 2019

Abstract
Purpose: To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy.
Patients And Methods: We reviewed the medical records of 561 myeloma patients (553 evaluable) enrolled in a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem cell transplantation (ASCT), consolidation chemotherapy and maintenance with alfa-interferon. Patients were randomized at enrollment to receive thalidomide (269 pts) or no thalidomide (284 pts) throughout the study period.
Results: At a median follow-up of 33 months (range, 5–114 months), AVN of the femoral head (s) developed in 49 of 553 patients (9%). Median time to onset of AVN was 12 months (range, 2–41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (p=0.0006; O.R. 1.028; 95% C.I. 1.012–1.044 per 40 mg dexamethasone), male gender (p=0.009; O.R. 0.390; 95% C.I. 0.192–0.790) and younger age (p=0.0122; 95% O.R. 0.961, C.I. 0.934–0991/year). AVN-related pain and limited range of motion of the affected joint were present in only 9 and 4 patients, respectively. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) failed to detect abnormal uptake in the AVN-affected bones. Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8 % vs.10%, respectively; p=0.58).
Conclusion: AVN is a rare and usually asymptomatic complication in myeloma patients undergoing antineoplastic treatment with dexamethasone-containing regimens and ASCT. Cumulative dexamethasone dose, male gender and younger age, but not thalidomide, increase the risk of AVN. FDG-PET does not contribute to the diagnosis of this complication
Serum Transferrin Receptor Value as a Universal Indicator of Erythropoietic Activity.
Authors: Lee Young Soo , Kim Chul Soo , Choi Jong Weon 
Published: October 2019

Abstract
The serum transferrin receptor (sTfR) is thought a sensitive and quantitative parameter of tissue iron deficiency as well as an indicator of erythropoietic activity. This study was aimed at the verification of a hypothesis that sTfR is a general indicator of erythropoiesis regardless whatever the cause is. A total of 173 patients in heterogeneous diseases who underwent bone marrow study as a workup for anemia were measured for sTfR, reticulocyte maturity index (RMI), erythroid element proportion of bone marrow cells, and other hematologic parameters (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width, absolute reticulocyte count). By immunoenzymometric method sTfR was measured using IDeATMcTfR kids (Orion Diagnostica, Orion, Finland). Reticulocyte count and proportion was measured manually by one expert examiner after standard blood smear and stain. Reticulocyte subpopulation was automatically analyzed by flow cytometry using R-3000 TM (Sysmex, TOA, Japan). RMI was calculated from the equation of (medium fluorescent reticulocyte fraction + high fluorescent reticulocyte fraction) X 100 / low fluorescent reticulocyte fraction. Correlation analysis was done among the variables including sTfR, RMI, erythroid element proportion of bone marrow cells, and other hematologic parameters using SAS 6.12 soft ware. The analysis was carried out for the whole 173 patients to see the general trends and repeated for 4 groups of disease category, arbitrarily divided to group 1 (n=33, iron deficiency or or disease with no predisposition to anemia of chronic disease), group 2 (n=53, hematologic malignancies), group 3 (n=44, solid tumors), and group 4 (n=43, chronic or infectious disease) to see if the trends may be affected by specific diseases. The results showed a solid correlation of sTfR with RMI as well as erythroid precursors in bone marrow, not only in the whole patient population (e.g. sTfR vs RMI, R=0.587, p=0.0001) but also in individual groups (e.g. sTfR vs RMI, R=0.48, p=0.005 in group 1, R=0.69, p=0.0001 in group 2, R=0.58, p=0.0001 in group 3, R=0.81, p=0.0001 in group 4). These findings indicated the significance of sTfR is valid under any clinical setting as a universal indicator of hematopoietic activity. The sTfR can be used as a useful parameter for monitoring of erythropoiesis in a variety disease.
An Extra Ordinary Respone of Castleman’s Disease to Rituximab.
Authors: Abdou Sherif , Salib Hayman 
Published: October 2019

Abstract
Castleman’s disease is a very rare non-neoplastic lymphoproliferative disorder of unknown cause that is diagnosed on a pathological basis. It is often associated with autoimmune diseases, and diagnosed in the context of human immunodeficiency virus (HIV) positive patients. No standard treatment has been developed for this rare disease.
CASE REPORT: This 54-year-old male presented with nausea and vomiting. He has a past medical history of hypertension and chronic glomerulonephritis. His laboratory results showed acute renal failure. Hemodialysis was started prior to further work up. A chest x-ray showed bilateral hilar lymphadenopathy that was later confirmed by computerized tomography (CT) of the chest. A mediastinoscopy and mediastinotomy were performed. Mediastinal lymph node biopsy showed findings consistent with Castleman’s disease including atrophic follicles with hyalinized vessels. Remission was obtained for one year by prednisone and cyclophosphamide, but the patient relapsed with multiple lymphadenopathy. Biopsy confirmed the recurrence of Castleman’s disease. Rituximab was added to cyclophosphamide as a treatment regimen and for more than two years the patient has done extremely well. His kidney function returned to his baseline, hemodialysis was stopped, and the patient has long-term remission on CT scan and postron emission tomography (PET).
DISCUSSION: Castleman’s disease is lymphadenopathy of unknown cause. About 400 patients have been reported to date. It is diagnosed microscopically by lymphadenopathy with angiofollicular hyperplasia and plasma cell infiltration. It has a rapid progressive and often fatal course. Traditional treatment is chemotherapy. A new trend in the treatment of Castleman’s disease is Rituximab which is a monoclonal antibody that showed success in HIV positive patients with Castleman’s disease. We believe that this is the first reported case of long-term remission of Castleman’s disease in an HIV-negative patient treated with Rituximab and chemotherapy.
Injury of Endothelium during the Cytostatic Therapy of AML Patients.
Authors: Chervontseva Alevtina , Savchenko Valeri , Romanov Yuri 
Published: October 2019

Abstract
Background: At present, program chemotherapy represents the main approach to the treatment of patients with acute myeloid leukemia (AML). Chemotherapy is directed to the eradication of tumor clones and restoration of normal hematopoiesis. Using “7 + 3” protocol, including standard doses of cytosine arabinoside (ara-C) and daunorubicin (DNR) it is possible to obtain complete remission in 60–70% of patients. However, several vascular complications may take place during chemotherapy that could be related to vascular endothelium injury.
Aims: To investigate the effects of ara-C and DNR on cultured human vascular endothelial cells (ECs) and to confirm endothelial injury by the detection of circulating ECs.
Methods: Experiments were performed on cultured human umbilical vein ECs; cytostatic drugs were studied at therapeutical concentrations ranging from 1 ng/ml to 1 mg/ml. Effects were screened using phase-contrast microscopy, cell viability test, BRDU incorporation, immunocytochemistry, and flow cytometry.
Results: At various concentrations, ara-C and DNR induced EC monolayer changes associated with either cytostatic or cytotoxic action. DNR provoked irreversible cell changes and monolayer damage; the action of ara-C leaded to elimination of mitotic ECs from self-renewing monolayer and to significant decrease of its density. Simultaneously, remaining ECs increased the expression of the cell adhesion molecules (P- and E-selectins, VCAM-1, ICAM-1, and PECAM-1) and enhanced their adhesiveness to blood mononuclear cells. Comparing the level of ECs circulating in peripheral blood of healthy donors and AML patients undergoing chemotherapy, we have find remarkable differences. In the studied group, the concentration of circulating ECs could be as high as 250–750 cells per 1 ml of blood.
Conclusions: Obtained results allow to conclude that cytostatic therapy may cause systemic injury of the vascular endothelium related to functional cell alterations and/or massive EC loss.
ALFA-9000 Trial - An Analysis of Cytogenetic Subsets: Significant Long-Term Benefit of Early Induction Reinforcement Is Observed in CBF-AML Only.
Authors: Gardin Claude , Chevret Sylvie , Charrin Christiane , Thomas Xavier , Bastard Christian , Lai Jean-Luc , Maarek Odile , de Botton Stephane , Bordessoule Dominique , Tilly Herve , de Revel Thierry , Terre Christine , Preudhomme Claude , Bauters Francis , Michallet Mauricette , Fiere Denis , Castaigne Sylvie , Fenaux Pierre , Dombret Herve 
Published: October 2019

Abstract
We have recently reported the results of the ALFA-9000 randomized trial in which younger adults with AML had a significant better long-term relapse-free interval when receiving a timed-sequentially reinforced induction (arm C) as compared to either standard 3+7 (arm A) or double (arm B) induction (Castaigne et al, Blood 2004). Both arms B and C included the same induction reinforcement with mitoxantrone and intermediate-dose cytarabine (ID-AraC) systematically administered at day 20 in arm B or at day 8 in arm C. Although patients aged between 15 and 65 years were included in this study, the gain in relapse incidence associated with arm C was observed in those less than 50 years of age only. We report here the outcomes of cytogenetic subsets, according to the arm C versus arm A/B stratification. Overall, 405 karyotypes were available (68%) and classified according to the SWOG classification as 56 favorable (CBF-AML, 46/56 under the age of 50 years), 215 intermediate (including 194 normal), 91 unfavorable, and 43 of unknown significance. Outcome of unfavorable and unknown subsets did not differ significantly in C versus A/B. Patients with complex karyotype or chromosome 7, 5q, or 3q abnormalities, as well as those with 11q23 abnormalities, had a similar outcome whatever their induction arm. Similarly, no benefit of early reinforcement was observed in the intermediate group, nor in patients with a normal karyotype even after adjustment on WBC or when considering only those aged less than 50 years. In the favorable subset, patients with either t(8;21) (N=30) or inv(16) (N=26) had identical long-term outcome. Contrary to other subsets, this outcome differed strikingly among induction arms with better disease-free survival in arm C (64% versus 28% at 5 years, P=.05 after adjustment on WBC) with a similar trend observed for event-free survival. The value of higher than standard doses of cytarabine in CBF-AML patients, either during induction or as post-remission therapy, has been demonstrated by several cooperative groups. Our results do suggest that early introduction of ID-AraC is also associated with long-term benefit in this favorable subgroup of patients, even greater when made at day 8 instead of day 20. We will evaluate prospectively this induction approach in the next French Intergroup CBF-AML study, in which all patients will then receive high-dose cytarabine during post-remission therapy.
Effects of Single-Dose BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor - in Subjects with Extreme Body Weight.
Authors: Kubitza Dagmar , Becka Michael , Zuehlsdorf Michael , Mueck Wolfgang 
Published: October 2019

Abstract
Currently, agents used for the prevention of venous thromboembolism, such as low molecular weight heparins and pentasaccharides, require dose adjustments for patients in extreme weight categories. BAY 59-7939 is a novel, oral, direct Factor Xa (FXa) inhibitor currently undergoing clinical development for the prevention and treatment of thromboembolic disorders. In this single-center, randomized, single-blind, placebo-controlled, parallel-group study, the influence of extremely low and high body weight on the safety, tolerability, pharmacodynamics and pharmacokinetics of a single 10 mg dose of BAY 59-7939 administered with food was investigated. In total, 48 healthy male and female subjects aged 20–54 years and in three different weight groups (≤ 50, 70–80, and >120 kg) were evaluated; 12 received placebo and 36 received BAY 59-7939. The 70–80 kg and >120 kg groups were gender-balanced (six men and six women in each group); the ≤ 50 kg group comprised of 12 women. Overall, BAY 59-7939 was well tolerated. No serious adverse events were reported; all events were of mild to moderate intensity and resolved 7 days after drug administration. The occurrence of adverse events was similar among the weight groups. No adverse events were reported in the placebo group. FXa was inhibited by BAY 59-7939 in all three weight groups, with a maximum inhibition (Emax) of 46.8%, 45.8%, and 41.7% in the ≤ 50, 70–80, and >120 kg groups, respectively; maximum inhibition was observed about 2–3 hours after BAY 59-7939 administration in all three weight groups. AUC for inhibition of Factor Xa activity was comparable for all volunteer groups regardless of the body weight. BAY 59-7939 prolonged prothrombin time (PT), which was less pronounced in the higher weight groups: 1.7 times baseline (tb), 1.6 tb, and 1.5 tb in subjects ≤ 50, 70–80, and >120 kg, respectively. The pharmacodynamic parameters have returned to baseline within 24 hours in all weight groups. Placebo treatment had no effect on PT. The clotting tests activated partial thromboplastin time and HepTest were also distinctly prolonged after drug administration in all weight groups; the prolongation was slightly more pronounced in subjects in the ≤ 50 kg group than in the other weight groups. The bioavailability of BAY 59-7939 as a 10 mg single dose, in terms of AUC of plasma concentrations, was similar in all three weight groups (P=0.205). However, peak plasma concentrations (Cmax) were 24% higher in subjects with ≤ 50 kg body weight compared with normal-weight subjects. For subjects >120 kg, Cmax was similar to normal-weight subjects. No pharmacokinetic differences between men and women were detected in the normal-weight and >120 kg groups. In conclusion, these data demonstrate that only small influences of body weight on pharmacodynamic or pharmacokinetic parameters are observed which require no dose adjustment of BAY 59-7936 in subjects with extreme body weight.