bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Risk of Residual Molecular and Hematological Relapse in Patients with Cml after KIRir-Ligand Mismatched Hematpoietic Stem Cell Transplantation.
Authors: Elmaagacli Ahmet H. , Ottinger Hellmut , Michael Koldehoff , Rudolf Peceny , Steckel Nina K. , Trenschel Rudolf , Biersack Harald , Grosse-Wilde Hans , Flasshove Michael , Beelen Dietrich W. 
Published: October 2019

Abstract
We compared the incidence of molecular and hematological relapse in 236 CML patients (pts) after HLA-identical (n=158) [group 1], HLA class I antigen mismatched and KIR-ligand compatible (n=49) [group 2], and HLA class I antigen mismatched and KIR-ligand incompatible (n=29) [group 3] hematopoietic stem cell transplantation. In group 1 133/158 (84%) pts were in first chronic phase of CML, the corresponding figures were 33/49 (67%) pts in group 2, and 19/29 (64%) in group 3 (p<0.05). Accordingly, 25/158 (16%) pts in group 1, 16/49 (33%) pts in group 2, and 10/29 (34%) pts in group 3 were in advanced disease phases of CML (accelerated phase, 2nd chronic phase, or blastic phase).
Stem cell grafts were from sibling donors in 97% of pts in group 1, 37% of pts in group 2, and in 59% of pts in group 3 (p<0.01 group 1 versus groups 2+3). Median age and gender constellations were not different between the three groups (age medians between 37–41 years, range 16–63).
Acute GVHD grade 2–4 occurred in 62/158 (39%) pts in group 1, in 24/49 (49%) pts in group 2, and in 15/29 (52%) pts in group 3 (NS). Estimates of chronic GVHD did not differ significantly between the study groups with 94% + 2% in group 1, 95% + 4% in group 2, and 91% ± 6% in group 3.
Molecular relapse as detected by real-time RT-PCR occurred in 1/29 (3%) pts of group 3 compared to 62/158 (39%) of pts in group 1, and in 11/49 (22%) pts in group 2 (p<0.001). A hematological relapse developed in 20/158 (13%) pts in group 1, in 2/49 (4%) pts in group 2 and in 0/29 (0%) pts in group 3 (p<0.05). Multivariate analysis on the risk molecular relapse included possible influencial covariates like disease stage, age (> 40 years or < 40 years), gender matching of donor and recipient, occurrence of acute and chronic GVHD, HLA matching between donor and recipient, donor source [sibling or unrelated], and graft type [bone marrow or PBSCs]. This analysis confirmed that KIR-mismatches are a strong independent predictor for the occurrence of bcr-abl transcripts after transplantation (p<0.02). The 8-year overall survival estimates were not different between the three groups (67% group 1, 52% group 2 66% group 3). In conclusion, KIR-ligand incompatibility is an important prognostic factor for the occurrence of molecular and hematological relapse after allogeneic transplantation for CML.
High-Dose Imatinib Mesylate Treatment in Patients (Pts) with Previously Untreated Early Chronic Phase (CP) Chronic Myeloid Leukemia (CML).
Authors: Cortes Jorge , Talpaz Moshe , O’Brien Susan , Giles Francis , Beth Rios Mary , Levtak Laurie , Kantarjian Hagop 
Published: October 2019

Abstract
Imatinib has become the treatment of choice for most with CML. The standard dose (SD) for CP CML is 400 mg daily, but pre-clinical and clinical observations suggest that higher doses (HD) may be more effective. We have treated 222 with previously untreated CML in early CP with imatinib in 3 consecutive trials: one using SD imatinib (400 mg/day) (n=50; all entered in April 2001) and 2 subsequent trials using 400 mg twice daily (total dose 800 mg/day) (n= 172; from June 2001 until present). The 2 HD trials had identical inclusion criteria and will be considered together for this analysis. Pts followed for at least 3 months (mo) are evaluable (n=210) for this report (n=49 at 400mg, 161 at 800 mg). The median age was 48 years (range, 15 to 84); platelets were >450 x109/L in 71 pts (34%), 78 (37%) had peripheral blood (PB) blasts, and 11 (5%) had clonal evolution. Sokal risk group classification was good in 128 (61%) pts, intermediate in 61 (29%) pts, and poor in 21 (10%) pts. There was no difference in pre-treatment characteristics between the standard SD and HD groups. The results at 18 months are as follows:
Response % Response p value* 400 mg/day 800 mg/day CR=Complete remission, Molecular Major=BCR-ABL/ABL <0.05%, Molecular CR=BCR-ABL undetectable (confirmed by nested PCR), *p value by log-rank Median follow-up (months) 36 19 Cytogenetic CR 81 96 0.0002 Cytogenetic Major 99 93 0.15 Molecular Major 47 67 0.0007 Molecular CR 8 24 0.02
Four pts treated with SD have transformed (3 to BP, 1 to AP) and 3 (2 to BP, 1 to AP) in the HD groups (p=0.05) (median time to transformation 11 mo, range 3 to 27). Estimated progression-free survival at 12 mo is 92% in the SD group and 99% in the HD group (p=0.42) (p=0.12 for the estimated transformation-free-survival, 94% and 99% for SD and HD at 12 mo). 4 have died (1 in SD and 3 in HD). Extramedullary toxicity was similar in the 2 groups, but myelosuppression was more common with HD, with grade ≥3 anemia, neutropenia and thrombocytopenia occurring in 7%, 39%, and 27% of pts receiving HD, respectively, and 4%, 20% and 12% of pts receiving SD. At 12 mo, the median actual dose for the HD group is still 800mg, with 40/112 (36%) evaluable having required dose reduction. This compares with 7/43 (14%) of those treated with SD. We conclude that high-dose imatinib results in higher rates of complete cytogenetic and molecular remissions, with some increase in myelosuppression.
Mechanisms of Plasmin-Catalyzed Inactivation of the Factor VIII.
Authors: Nogami Keiji , Shima Midori , Matsumoto Tomoko , Nishiya Katsumi , Takeyama Masahiro , Tatsumi Kohei , Tanaka Ichiro , Yoshioka Akira 
Published: October 2019

Abstract
Factor VIII (FVIII) functions as a cofactor for factor IXa in the intrinsic tenase complex. This tenase activity is down-regulated by activated protein C (APC) or factor Xa (FXa). Plasmin, the most potent fibrinolytic protease, inactivates FVIII as well as other clotting factors. However, the mechanism of FVIII inactivation by plasmin is poorly understood. FVIII activity reached to the peak value of ~2-fold increase at 3 min after the addition of plasmin in a one-stage clotting assay. Then, the activity was decreased rapidly and was undetectable within 30 min. This time-dependent reaction was not affected in the presence of von Willebrand factor and phospholipid. The activation of FVIII by plasmin was an ~50% level of that by FXa. The rate constant (min-1) of inactivation of FVIIIa by plasmin possessed ~11.3- and ~2.5-folds greater than those by FXa and APC in the presence of protein S, respectively. SDS-PAGE analysis showed that plasmin cleaved the 90~210-kDa heavy chain of FVIII to 50, 48,45, 40, and 38-kDa fragments via 90-kDa fragment. Using western blot and N-terminal sequence analyses, these fragments derived from the heavy chain were identified as A11-372, A1337-372-A2, A11-336, A2, and A137-336, respectively, by cleavages at Arg372, Arg740, Lys36 and Arg336 in the A1 domain. On the other hand, the 80-kDa light chain was cleaved to 67-kDa fragment via 70-kDa fragment by cleavages at Arg1721 and Arg1689, respectively, consistent with the pattern of cleavage by FXa. However, the cleavage at Arg336 by plasmin was much quicker than that at Arg372, contrast with that by FXa. Furthermore, this cleavage was faster than that by APC, consistent with rapid inactivation of FVIII. In addition, the cleavage at Arg336 of FVIIIa by plasmin was faster than that of isolated A1 or A1/A3-C1–C2 dimer, different with that by FXa. These results demonstrate the importance of cleavage at Arg336 for the mechanism of plasmin-catalyzed FVIII inactivation. Furthermore, this cleavage appears to be selectively modulated by the A2 domain that may interact with plasmin.
Diamond Blackfan Anemia: An RPS19 Transcript Variant Specifically Interacts with Nuclear Proteins.
Authors: Frojmark Anne-Sophie , Badhai Jitendra , Davey Edward J. , Dahl Niklas 
Published: October 2019

Abstract
Diamond Blackfan Anemia (DBA) is a rare congenic anemia characterized by reduced erythrocyte precursors. Mutations in the ribosomal protein S19 (RPS19) gene are found in about 20% of patients, although it is unclear how this relates to the pathophysiology of the disease. Two transcripts have been reported for human RPS19 in the NCBI database (BC000023 and BC018616), which only differ in the length of the 5′UTR. Both transcripts predict translation to the same protein product and we therefore speculate that the extended 5′UTR may be of importance. While the short (569bp) transcript is well studied, the long (873bp) transcript has not been investigated. We determined the size and tissue distribution as a basic characterization of the long RPS19 transcript. Furthermore, we examined proteins interacting with the different RPS19 transcript variants. Two methods were used determine the size of long RPS19 transcript. Ribonuclease protection assays and 5′-RACE indicate a transcript length consistent with the reported sequence with a 5′UTR of 372bp. Interestingly the 5′UTR predicted in the long transcript contains sequence for a previously reported promoter, suggesting a second novel promoter. Tissue distribution was determined using reverse transcriptase PCR on isolated RNA from a panel of tissues including heart, bone marrow, fetal liver, liver, brain, fetal brain, muscle, kidney, uterus, adrenal gland, lungs, placenta, prostate testes, ovary, thymus, colon, lymphocytes and from K562 and HeLa cell lines. Analysis indicated a ubiquitously expression of the long RPS19 transcript. In order to investigate interactions between the RPS19 transcripts and regulatory proteins, a UV cross-linking assay was performed using in vitro transcribed RNA representing both short and long transcripts. A protein of 55 kDa from nuclear fractions prepared from the erythroid cell lines K562, UT-7 and Cos-1 cells was found to bind to the long RPS19 transcript but not to the short RPS19 transcript. Our results provide evidence for an additional long, RPS19 transcript containing an extended 5′UTR that is ubiquitously transcribed and indicates the existence of a second promoter for RPS19. We further show that a nuclear protein, present in two different erythroid cell lines, interacts with the long RPS19 transcript indicating a function for the extended 5′UTR. This data suggests additional regulatory pathways involving RPS19 mRNA which may be of relevance to the understanding of the molecular mechanisms behind DBA.
Induction, Selection and Expansion of Acute Myeloid Leukemia Reactive Autologous T Cells for Adoptive Immunotherapy.
Authors: Zhong Rui-kun , Ball Edward D. 
Published: October 2019

Abstract
To generate highly AML reactive autologous CTL, the optimal protocol of growth factor combination and sequence of administration were screened and compared in an AML-DC culture system aimed to induce AML cell DC differentiation, activate and expand naïve T cells against AML; and simultaneously activate and expand possible rare existing AML reactive memory T cells. Primary AML peripheral blood or marrow cells containing more than 90% AML blasts were cultured in 96 well plates. Every single well was regarded and treated as an independent culture. Various growth factor combinations of GM-CSF, IL2, IL-3, IL-4, IL7, IL12, CD40L, TNF-α, anti-CTLA-4 mAb were compared for efficiency of AML cell DC differentiation induction and autologous T cell activation in 7 day culture. Significantly enhanced CD80/CD86 expression and total cell number (include both AML-DC and T cells, see attached figure) in the culture was observed when GM-CSF/IL-4 combined with IL-12. The T cells in each well were than expanded with high dose IL-2 (6000 u/ml) and CTL activity against autologous AML were examined by both 51Cr release assay and culture supernatant IFN-γ concentration assay. Multiple wells of AML cell culture from the same patient with the same cell number and culture condition exhibited substantial functional variation demonstrated by MHC-restricted autologous AML cell killing (3 - 70% specific lysis) and IFN-γ secretion (25 - 2994 pg/ml), indicating that the T cells randomly put in the independent wells vary greatly in efficiency of AML antigen recognition and activation. IL-12 alone exerted significant enhanced IFN-γ secretion in 4 of 5 patients. IL-12 combined with GM-CSF/IL-2/IL-4/IL-7 enhanced IFN-γ secretion compared with IL-12 alone in 3 of 5 patients. CTLA-4 blockade further significantly enhanced T cell activity in 5 of 5 patients. Highly active CTL lines were selected from high IFN-γ secretion wells and rapidly expanded using OKT-3/CD28 coated, mitomycin-c treated autologous AML cells. After expansion, the highly active lines still maintained high autologous AML cell killing compared to the low active lines. A therapeutic quantity of AML reactive autologous T cells (20.2±30.1)x109, (n=5) can be obtained after 6 weeks of culture from (6.4±2.9)x107 AML PBMC. This study demonstrated AML cells cultured in IL-12 or IL-12 combined with GM-CSF/IL-2/IL-4/IL-7/anti-CTLA4 mAb activated the potential of the patient immune system and may maximize the possibility of AML reactive CTL generation for adoptive immunotherapy.
Figure Figure
Prolonged Remissions with Autologous and Allogeneic Stem Cell Transplantation for Burkitt’s Lymphoma: Long Term Follow-Up at a Single Institution.
Authors: Gada Purvi , Defor Todd , Weisdorf Daniel J. , Miller Jeffrey S. , Orchard Paul J. , MacMillan Margaret L. , Arora Mukta , Tomblyn Marcie , Burns Linda J. 
Published: October 2019

Abstract
Burkitts Lymphoma (BL) is a highly aggressive form of non-Hodgkins lymphoma (NHL) that accounts for 50% of childhood cases of NHL, yet is rare in adults. B symptoms, advanced stage and extranodal disease are risk factors previously associated with poor survival. Hematopoietic stem cell transplantation (HCT) is often used because of either incomplete or short duration of remission with standard therapy yet little published data for HCT and BL exists. We evaluated the comparative safety and efficacy of a cyclophosphamide/total body irradiation-containing myeloablative conditioning regimen followed by either an autologous HCT (autoHCT) or allogeneic related donor HCT (alloHCT) in 38 patients who received transplants between October 1975 and June 2004. Twenty-five patients (median age 16 years [range, 4–65]) underwent an autoHCT; 13 patients (median age 13 [range, 4–62]) received an alloHCT. The median number of conventional chemotherapy regimens prior to transplant was 2 (range 1–4); the median duration of first complete remission (CR) was 0.4 years (range, 0–8.8). The majority of patients were in a complete remission (CR) at transplant (auto HCT - 16 [64%] [40% CR1]), alloHCT - 9 [69%] [23% CR1]). Patient demographics, disease characteristics at diagnosis, at relapse and at transplant were comparable between the two groups except for a greater incidence of high risk factors, including B symptoms, advanced stage at diagnosis, and extranodal (bone marrow and central nervous system) disease in the alloHCT group. The median follow up is 7 years (range 1–12) and 24 years (range 2–27) for the autoHCT and alloHCT groups, respectively. Post-transplant, 71% of auto-HCT and 75% of the alloHCT recipients obtained a CR. The 1-year treatment related mortality (TRM) was comparable in the two groups: 8% and 15% for the autoHCT and alloHCT groups, respectively (p=NS). Ten-year progression free survival (PFS) was 21% (95% CI, 4–38%) and overall survival (OS) 23% (95% CI, 5–41%) after autoHCT compared to 31% (95% CI, 6–66%) and 31% (95% CI, 6–66%) for alloHCT (p=NS). Six patients in autoHCT group and 3 in alloHCT survive disease free between 1 and 27 years; 5 survive beyond 10 years and 3 beyond 15 years from HCT. Donor choice did not significantly alter PFS. Two factors were predictive of superior PFS: fewer chemotherapy regimens prior to transplantation (1 vs ≥ 2) and CR (vs relapsed/persistent disease) at time of transplant. Patients with high risk factors more commonly underwent alloHCT, yet outcomes were comparable to autoHCT, suggesting that a powerful and durable graft versus lymphoma effect exists. These results demonstrate that prolonged remissions can be obtained with either auto or alloHCT, especially for high risk patients in CR. New approaches for patients in relapse are needed to improve these outcomes.
The Role of the Protein Kinase C (PKC) Family in Glucocorticoid-Induced Apoptosis of Human Leukemic Cells.
Authors: Komak Spogmai , Miller Aaron L. , Johnson Betty H. , Thompson E. Brad 
Published: October 2019

Abstract
Glucocorticoids (GC’s) are among the most important clinical agents for the treatment of human leukemias. Cells exist, however, that have a functional glucocorticoid (GC) receptor, but are resistance to GC-induced apoptosis—suggesting that major signal transduction pathways (ie PKC family) may influence cellular response to GC. In order to determine whether glucocorticoid-induced apoptosis is mediated by members of the PKC family, we first screened the CEM acute T-cell lymphoblastic leukemic cell line for the presence or absence of all known PKC isoforms. We used two clonal cell lines that were derived from the same parent, CEM-CCRF, but which subsequently developed a pronounced difference in their sensitivity to glucocorticoids. One of these cell lines, CEM C7-14 is sensitive to dexamethasone-induced apoptosis, while the second cell line, CEM C1-15, is resistant. Of the 12 known PKC isoforms, 5 were detected at the basal level, and furthermore that specific members (PKC iota) was up-regulated during resistance, while PKC theta was up-regulated during apoptosis. Selectively inhibiting the entire PKC family caused increased cellular susceptibility to GC-induced apoptosis. Selectively targeting specific isoforms (PKC iota) caused resistant cells to become sensitive to apoptosis. Using immunoflouresence imaging, we showed the selective translocation of PKC’s iota, theta, and alpha after treatment with glucocorticoids. In addition, we showed specific phosphorylation of the isoforms iota, theta, and alpha in cells undergoing DEX-induced apoptosis. Two-dimensional proteomic analysis indicated a large number of proteins in CEM cells that show significant change after DEX treatment. We successfully identified several proteins which were regulated both after treatment with DEX alone, and after treatment with DEX + the PKC specific inhibitor Safingol. These proteins may represent the potential cross talk between the glucocorticoid and PKC apoptosis pathways. Taken together, these studies show that the PKC family is directly involved in glucocorticoid-induced apoptosis.
Disseminated Intravascular Coagulation Associated with Acute Hemoglobinemia or Hemoglobinuria Following Rho(D) Immune Globulin Intravenous Administration for Immune Thrombocytopenic Purpura.
Authors: Gaines Ann R. 
Published: October 2019

Abstract
The Food and Drug Administration (FDA) licensed Rho(D) immune globulin intravenous (anti-D IGIV) in March 1995 for treatment of immune thrombocytopenic purpura (ITP). The presumed mechanism of action of anti-D IGIV is extravascular hemolysis of anti-D-sensitized RBCs by splenic macrophages. Although seemingly inconsistent with this mechanism of action, acute hemoglobinemia and hemoglobinuria have been reported and are listed in the professional package insert for anti-D IGIV as possible adverse events. Through November 30, 2004, FDA received 6 reports of disseminated intravascular coagulation (DIC) associated with “acute hemolysis” (or similar terms) following anti-D IGIV treatment for ITP (Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rho(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood.2005, 106(5):in press). All patients were clinically stable and were initially discharged home following anti-D IGIV administration. All were subsequently hospitalized for signs and symptoms of acute hemolysis or DIC. The mean decrease between pretreatment and nadir posttreatment hemoglobin levels was 5.8 g/dL (range: 3.0 to 9.6 g/dL); 4 patients received 2 to > 5 units of packed RBCs. Four patients whose baseline serum creatinine levels were within normal limits developed renal insufficiency; 2 of those patients underwent dialysis. The pediatric patient was subsequently discharged from the hospital without sequelae. However, all 5 adult patients remained hospitalized and died 3 to 10 days after anti-D IGIV administration. Attending or consulting physicians assessed that acute hemolysis and/or DIC caused or contributed to each death. Data from previously reported cases further suggested that previous uneventful administration of anti-D IGIV does not preclude the development of acute hemolysis upon subsequent administration of anti-D IGIV. These cases suggested that patients treated with anti-D IGIV for ITP who experience acute hemoglobinemia or hemoglobinuria be monitored for the development of DIC. To increase our knowledge about the seemingly rare but potentially serious complication of DIC following anti-D IGIV treatment for ITP, physicians and other health care professionals are encouraged to submit serious adverse event reports to the anti-D IGIV manufacturer or to FDA. Contact information for reporting adverse events to the manufacturer of any FDA-approved product is generally available in the professional package insert or on manufacturer- or distributor-sponsored web sites. Alternatively, adverse events can be reported directly to FDA through its adverse event reporting system, MedWatch, by Internet at http://www.fda.gov/medwatch, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; or by mail at MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787.
Stimulation of Platelet Production in Healthy Volunteers by a Novel Pegylated Peptide-Based Thrombopoietin (TPO) Receptor Agonist.
Authors: Cerneus Dirk , Brown K. , Harris R. , End D. , Molloy C. , Yurkow E. , Koblish H. , Franks C. , Moolenaar M. , Burggraaf K. 
Published: October 2019

Abstract
A novel, pegylated, peptide-based thrombopoietin receptor agonist (peg-TPOmp) was shown to possess in vitro and in vivo thrombopoietic activity. In cell-based assays, peg-TPOmp was active at picomolar concentrations. In vivo, peg-TPOmp increased platelet production dose-dependently in rats (ED50 single i.v. dose ~ 100 μg/kg), dogs and mice. A phase I study was conducted in healthy male volunteers to investigate the tolerability, PD and PK of peg-TPOmp. Forty volunteers were randomized to receive peg-TPOmp or placebo as a single i.v. bolus injection in a ratio of 6:2. The peg-TPOmp dose range explored was 0.375, 0.75, 1.5, 2.25 or 3 μg/kg. PK analysis indicated dose-related kinetics of peg-TPOmp, although at doses of 0.75 μg/kg or lower, plasma concentrations were generally below the LOQ of 6.25 ng/mL. Mean Cmax values ranged from 11 ng/mL for 0.75 μg/kg to 62 ng/mL at 3.0 μg/kg. The mean terminal half-life ranged from approx. 18 to 36 hours. Platelet counts increased dose-dependently reaching peak levels at Day 10–12, and counts returned to baseline within 3–4 weeks. Mean peak platelet levels ranged from 315 x109/L at 0.375 μg/kg to 685 x 109/L at 3 μg/kg. Mean increase of peak platelet counts from baseline ranged from 1.4-fold at 0.375 μg/kg to 3.2-fold at 3.0 μg/kg. Endogenous TPO levels dose-dependently increased, reaching peak levels at 3 days post-dose, possibly due to a reduced rate of clearance. No significant changes were observed in blood levels of IL-6, IL-11 and EPO levels. Platelet function, assessed as collagen-induced platelet aggregation in whole blood, was not different between the treatments. None of the subjects experienced serious adverse events or dose-limiting toxicities. The most frequently observed adverse events included mild headache and fatigue and occurred both after active treatment and placebo. No antibodies against peg-TPOmp were detected. Based on the safety, PK and PD data, peg-TPOmp shows promise as an agent to treat thrombocytopenic disorders.