bluuebunny/crossref_metadata_2025_split huggingface dataset:
U.S. Inhibitor Pilot Project: Participant Characteristics and Infusion Log Adherence.
Authors: Creary Melissa S. , Soucie John M. , Miller Connie H. , Hooper W.C. , Abshire Thomas C. , Brettler Doreen B. , Pockenstedt Paula L. , DiPaola Jorge , Massey Gita , Neff Anne T. , Shapiro Amy D. , Tarantino Michael D. , Wicklund Brian M. , DiMichele Donna ,   Hemophilia Treatment Centers
Published: October 2019

Abstract
Inhibitors are now considered to be the most important complication of clotting factor replacement therapy in hemophilia. In January 2005, the Universal Data Collection (UDC) project, which includes data on over 14,000 patients with hemophilia A or B, was amended to include prospective data collection on inhibitors. We report interim results of a pilot project involving 9 selected Hemophilia Treatment Centers in the U.S. Dedicated data managers collected risk factor and product exposure data from enrolled patients on a monthly basis. Tracked infusion log submissions were used to estimate patient adherence to infusion log completion. A blood specimen is collected at baseline, annually, at product switch, or for clinical indication and is tested centrally for inhibitor using the Nijmegen modification method. Results are reported and any above a threshold value are followed up with repeat testing and clinical correlation. As of August 2007, 514 male patients with hemophilia, ages 2–84 years (mean 23 yrs SD 17) had been enrolled. Of these, 415 (81%) had FVIII deficiency (64% severe, 20% moderate, 16% mild) and 99 (19%) had FIX deficiency (35%, 43%, and 22%, respectively). 85% of the patients were caucasian, 8% black, and 4% Hispanic. A previous history of inhibitor was present at enrollment in 71 (14%). Prophylactic treatment was used by 37% and 80% received product by home infusion. Historical exposure to product collected at enrollment was as follows: 14% had 0–20 exposure days (ED), 12% had 21–100 ED, 7% had 101–150 ED, and 64% > 150 ED. During follow-up, 6 patients have had inhibitor titer measurements over 0.4 BU. One of these was known to have an active inhibitor at enrollment. Confirmatory testing of remaining cases is underway. Mean adherence rate for patient infusion log completion in the 9 HTC’s was 45% (range 7% to 74%). Overall adherence increased with time on study from about 40% at one month to nearly 60% for those enrolled at least 10 months. In summary, enrolled participants represent a wide range of characteristics including age, race, disease severity and number of factor exposures. Interim findings indicate that prospective collection of factor infusion data from hemophilia patients necessary to appropriately monitor inhibitor formation, is feasible but labor intensive and requires patient adherence to completion and submission of accurate infusion logs. Because inhibitor formation is rare and the potential risk factors are many, large scale studies with long-term follow-up will be needed to fully assess risk factors for inhibitors.
Preliminary Results of CNTO 328, an Anti-Interleukin (IL)-6 Monoclonal Antibody (mAb), in Combination with Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma.
Authors: Manges Robert F. , Sutherland Heather J. , Jagannath Sundar , Orlowski Robert Z. , La Police David , DeWitte Mark , Lang Zhihui , Corringham Robert E. , Rossi Jean Francois 
Published: October 2019

Abstract
Background: Bortezomib represents a significant advance in the treatment of relapsed/refractory myeloma, but its efficacy is limited by a number of resistance mechanisms including activation of the anti-apoptotic heat shock protein (HSP) and stress response pathways. CNTO 328 is an anti-IL-6 chimeric monoclonal antibody shown to have anti - myeloma activities in vitro. Because IL-6 signaling augments the HSP response, downregulation of IL-6 signaling may enhance bortezomib’s clinical anti-myeloma activity. Pre-clinical studies demonstrated that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines (Voorhees et al., 2007, in press).
Methods: In this safety lead-in cohort of a pivotal trial (clinicaltrials.gov), CNTO 328, 6 mg/kg, was administered by IV every 2 weeks in combination with bortezomib, 1.3 mg/m2, given by IV on days 1, 4, 8, and 11 every 3 weeks. Pateints received a maximum of four, 6-week treatment cycles, after which the bortezomib schedule was reduced to four, once weekly doses in a 5-week maintenance cycle. When disease progression was documented, oral dexamethasone was added at 20 mg and given on the day of, and day after each bortezomib infusion, for a maximum of two cycles. All later cycles included 20 mg dexamethasone given only on the day of bortezomib administration.
Results: Preliminary results from the first 6 patients are available. Pateint characteristics included median age of 68 years; B2M > 3.0 mg/L, (n = 4 pateints); CRP > 3.0 mg/L (3); a median of 2 prior regimens (range 1 – 3), and prior bone marrow or peripheral blood stem cell transplantation in three patients. Using the EBMT response criteria, three patients achieved confirmed partial responses (PRs). Additionally, two patients had unconfirmed PRs. One patient discontinued prior to confirmation, while a follow up assessment for the other patient is pending. The median number of cycles administered was 3. Two of the patients ended treatment prematurely, 1 due to disease progression and 1 due to adverse events. The remaining 4 patients continue on study. Grade 3/4 adverse events (AEs) considered possibly related to CNTO 328 and bortezomib include neutropenia (2 patients), leukopenia (1), lymphopenia (1), and bloody diarrhea (1).
Conclusion: Treatment with anti-IL-6 CNTO 328 in combination with bortezomib has been evaluated for safety and efficacy in the first 6 patients of an ongoing pivotal trial for the treatment of relapsed or refractory multiple myeloma. Initial activity observed with this combination is encouraging, and enrollment is continuing to explore its full potential.
c-Myb Regulates CD9 Gene Expression during Megakaryopoiesis.
Authors: Mukai Harumi Y. , Kono Tomoko , Motohashi Hozumi , Yamamoto Masayuki , Kojima Hiroshi 
Published: October 2019

Abstract
The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We previously generated through insertion mutagenesis a c-myb gene knockdown (KD) line of mice. In the mice transgene was inserted 77-kb upstream of the c-myb gene and c-Myb expression was markedly decreased in megakaryocyte-erythrocyte lineage-restricted progenitors (MEPs) of the homozygous knockdown mutant mice (c-myb KD mice). The c-myb KD mice exhibited anemia, thrombocythemia, and splenomegaly and these abnormalities were reproducible in a co-culture assay of MEPs with OP9 cells, but abrogated by the retroviral expression of c-Myb in MEPs. To understand the transcriptional program that accompanies the decline of c-myb gene expression, we performed DNA microarray analysis with MEPs and identified 74 genes that are upregulated and 36 genes that are downregulated in the c-myb KD mice. Of these genes, expression levels 15 genes are actually changed significantly in bone marrow cells of the c-myb KD mice. These genes harbor c-Myb recognition elements in their regulatory regions. Especially, we found that the CD9 expression was upregulated in the c-myb KD mice. Reverse correlation of c-Myb expression with the CD9 gene expression was verified using a luciferase reporter assay and chromatin immunoprecipitation assay. Agonistic antibody of CD9 stimulated megakaryocytic colony formation. On the contrary, upon the bone marrow suppression with 5-fluorouracil recovery of platelet number was delayed in the CD9-null mice. Furthermore, proplatelet formation was impaired when we used CD9-null mouse megakaryocytes, and the size of proplatelets was smaller than those generated by wild-type megakaryocytes. These results thus demonstrate that c-Myb suppresses the CD9 expression in a steady-state condition, while in the stress megakaryopoiesis CD9 is derepressed and acts to induce the megakaryopoiesis. Elucidation of c-myb-based transcription network seems to be of important to understand the megakaryocytic differentiation.
Durable Responses with Bortezomib in Patients with Relapsed or Refractory Mantle Cell Lymphoma (MCL): Updated Time-to-Event Analyses of the Multicenter PINNACLE Study.
Authors: Goy Andre , Bernstein Steven , Kahl Brad , Djulbegovic Benjamin , Robertson Michael , de Vos Sven , Epner Elliot , Krishnan Amrita , Leonard John , Lonial Sagar , Stadtmauer Edward , O’Connor Owen , Shi Hongliang , Boral Anthony , Fisher Richard 
Published: October 2019

Abstract
Background: We previously reported substantial activity with single-agent bortezomib (VELCADE®; Vc) in patients (pts) with relapsed or refractory MCL in the PINNACLE study (JCO2006;24:4867–74), which resulted in approval of Vc for MCL pts following ≥1 prior therapy. All pts have now completed treatment. Here we report updated time-to-event data in all pts, and by response category, with extended follow-up.
Methods: 155 pts (median age 65 yrs; 55%/41%/4% with 1/2/≥3 prior therapies; 77% Stage IV MCL; 55% positive bone marrow) received Vc 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles; of these, 141 were response-evaluable. Response and progression were determined by modified International Workshop Response Criteria using independent radiology review.
Results: After a median follow-up of 26.4 mo, 55 pts (35%) remained in follow-up; 93 (60%) had died, 2 (1%) had withdrawn consent, and 5 (3%) were lost to follow-up. Pts received a median of 4 treatment cycles (range 1–21; 8 in responding pts). Median time to first response was 1.3 months. Median duration of response (DOR) was 9.2 mo in all responders and has not been reached in pts achieving CR/CRu. Median time to progression (TTP), time to next therapy (TTNT; first Vc dose to start of next therapy), and overall survival (OS) are shown in the table for all pts and by response.
Survival rate at 12-mo was 69% overall and 91% in responding pts. In pts refractory to their last therapy (no response or response with TTP <6 mo; n=58), median DOR was 5.9 mo, median TTP was 3.9 mo, median TTNT was 4.6 mo, and median survival was 17.3 mo. Safety profile was similar to previously reported; most common grade ≥3 AEs were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). The most common AE resulting in Vc discontinuation was peripheral neuropathy (10%). Twelve (8%) pts died on-study, including 5 (3%) considered related to Vc.
Conclusions: Vc provides durable responses plus prolonged time off-therapy and survival in responding pts, suggesting substantial clinical benefit in relapsed/refractory MCL.
Median TTP, TTNT, and OS (months) in all pts and by response All pts (N=155) Responders (N=45) CR/CRu (N=11) PR (N=34) SD (N=52) PD (N=34) NE, not estimable TTP 6.7 12.4 NE 9.1 6.9 1.2 TTNT 7.4 14.3 23.9 13.3 7.0 2.3 OS 23.5 35.4 36.0 35.1 27.8 13.7
Differential Role of the Transcription Factor ZBP-89 in Hemangioblast Fate Determination: ZBP-89 Is a Direct Regulator of SCL.
Authors: Li Xiangen , Shelley Carl Simon , Arnaout M. Amin 
Published: October 2019

Abstract
Several molecular pathways have been identified that regulate distinct stages in the developmental progression from mesoderm to the formation of the hematopoietic and vascular lineages. Our previous work indicated that ectopic expression of the zinc finger transcription factor ZBP-89 promotes hematopoietic lineage development and represses endothelial cell lineage differentiation from hemangioblasts in murine embryonic stem cells. Here we evaluated the functional consequences of stable knockdown of ZBP-89 in embryonic stem cells (ESC) on hematopoietic and vascular development. Stable knock down of ZBP-89 in ESC significantly decreased the number of Blast Colony Forming Cells (BL-CFC) hemangioblasts, as well as primitive and definitive hematopoietic progenitor colonies BFU-E, GM-CFU, G-CFU, M-CFU and GEMM-CFU in vitro. In contrast, sprouting angiogenesis was markedly increased in EB cultures. Flow cytometric analysis of the lineages derived from ZBP-89 deficient EB cultures showed that the early (C-kit+Sca-1+) and definitive (CD45+) hematopoietic stem cells populations were reduced, but the endothelial cell population (CD31+ VE-Cadherin+) was increased. RT-PCR analysis of EB cultures revealed a direct correlation between the expression levels of ZBP-89 and hematopoietic markers (including SCL and Runx1) but an inverse correlation with the vascular marker CD31, with no change in Oct4 expression level. To investigate the mechanism underlying the role of ZBP-89 in hematopoiesis, the effect of ZBP-89 on expression of SCL, a master regulator of hematopoiesis, was examined. The murine SCL promoter transduced into the ZBP-89-expressing MEL cell line drove luciferase gene expression. ZBP-89 knockdown in MEL cells markedly reduced SCL expression. ChIP analysis showed that endogenous ZBP-89 protein bound directly to the murine SCL promoter in MEL cells. Thus ZBP-89 plays a central role in fate determination of hemangioblasts; its induction suppresses angiogenesis but enhances differentiation of hemangioblasts along the hematopoietic pathway, an effect mediated through the regulated expression of SCL.
Generation of Megakaryocytes from Human Embryonic Stem Cells.
Authors: French Deborah L. , Jirouskova Marketa , Kennedy Marion , Coller Barry S. , Keller Gordon 
Published: October 2019

Abstract
The ability to generate multiple cell types from human embryonic stem cells (hESC) in culture offers an unprecedented opportunity to produce an unlimited supply of cells for research and clinical purposes. Megakaryocytes comprise only 0.02–0.05% of the nucleated cell population in the bone marrow, thus making them a difficult cell to isolate and study. The ES cell technology provides a resource for generating megakaryocyte progenitors for in vitro and in vivo analyses. For this approach to be successful, reproducible differentiation schemes that generate sufficient numbers of cells are necessary. With an embryoid body (EB)-based protocol, in serum-free media we are able to generate hematopoietic populations with megakaryocyte potential from two different hESC lines; H1 and HES2. Using CD41 as an early marker of definitive hematopoiesis, we found that 4 to 12% of the day 11–12 EB population expressed high levels of the marker (CD41Hi) whereas 10 to 20% expressed low levels of the marker (CD41Lo). Cells from the CD41Hi but not the CD41Lo population expressed the megakaryocyte marker GPIb. To further analyze these populations, both were isolated from day 12 EBs by cell sorting and cultured in media containing TPO and SCF. Following several days in culture, the CD41Hi population expressed increasing levels of GPIb, as determined by flow cytometry and real time PCR. PF4 was detected in the sorted CD41Hi population and levels increased 10-fold following culture. These cells also adhered to fibrinogen and collagen and stained positive for von Willebrand factor (vWF) and P-selectin. Following activation by PAR1, the cells bound soluble fibrinogen and expressed P-selectin on their surface. Few to no progenitors were detected in the CD41Hi fraction by colony assays suggesting that this population contained cells that were already committed to the megakaryocyte lineage. Incubation of the CD41Lo population of cells in the presence of TPO resulted in 70–80% of the cells expressing increased levels of CD41 and GPIb. Immunostaining revealed vWF and P-selectin expression following adhesion of the cells to fibrinogen and collagen. Both fibrinogen binding and P-selectin surface expression were detected following activation with PAR1. Quantitative PCR analysis demonstrated low levels of PF4 message in the sorted population with an increase of 3-fold following incubation in the presence of TPO. Progenitor cells were detected in colony assays suggesting that this population of cells contained megakaryocyte-like progenitors. Taken together, these finding demonstrate the efficient and reproducible generation of megakaryocytes from hESC using a serum-free EB protocol.
HoxA2 Regulates Proliferation of an Embryonic Megakaryocyte Progenitor, Which Can Effectively Produce Platelets In Vitro.
Authors: Iacovino Michelina , Osawa Mitsujiro , Xu Zhaohui , Prather Melissa G. , Kyba Michael 
Published: October 2019

Abstract
Megakaryocytes are rare cells in the bone marrow, and are solely responsible for thrombopoiesis throughout the life of the organism. Various transcription factors regulating megakaryopoiesis have been identified, including GATA1, Fli1 and NF-E2, which are important for the maturation and differentiation of megakaryocytes and SCL and FOG1, which play important roles in the specification and proliferation of the early megakaryocyte progenitor but no single factor capable of sustaining long-term proliferation of the megakaryocyte progenitor has been identified. The rarity of this progenitor, and the difficulty of proliferating megakaryocytes in vitro have seriously hampered the effort to produce large quantities platelets in vitro, and to date the only source of platelets for transplantation remains human donors. In this study, through a gain of function screen of Hox genes in which each paralog group was tested, we identified HoxA2 as an important transcription factor for the proliferation of early embryonic megakaryocytic progenitors. HoxA2 promoted the outgrowth of undifferentiated megakaryocyte progenitors when transduced into precirculation yolk sac stem and progenitor cells, however it had no effect on megakaryocytic progenitors derived from definitive HSCs of adult bone marrow. To study this unique embryonic regulatory circuit further, we generated an inducible mouse embryonic stem cell line, in which the expression of murine HoxA2 is regulated by doxycycline. Embryoid body differentiation of these cells, followed by sorting and reculture of the Kit+/CD41+ hematopoietic progenitor fraction at day 6 in the presence of continual HoxA2 expression allowed undifferentiated c-Kit+/CD41+/CD45+ megakaryocyte progenitors to proliferate for upwards of 2 months. When doxycycline is removed, numerous gene expression changes take plase, and these progenitors differentiate into mature c-Kitneg/CD41high/CD45neg megakaryocytes, which undergo proplatelet formation, releasing large quantities of platelets (∼107/ml) into the medium. As this rate of production can be sustained for weeks, a highly efficient platelet bioreactor is enabled. The platelets express the integrin αIIb-β3 (GPIIb-IIIa complex), and upon stimulation they bind fibrinogen, demonstrating functionality. We are currently investigating the transplantation potential of these cells.Our data suggest that adult and embryonic megakaryopoiesis have distinct regulatory circuits, and demonstrate a novel and uniquely embryonic role for HoxA2, which opens up the possibility of producing industrial quantities of platelets in vitro for therapeutic purposes.
Coagulation Factors, Postmenopausal Hormone Replacement Therapy and the Risk of Venous Thrombosis: The WHI Clinical Trials of Postmenopausal Hormone Therapy.
Authors: Cushman Mary , Larson Joseph , Rosendaal Frits R. , Phillips Lawrence S. , Howard Barbara V. , Curb J. David , Hays-Grudo Jennifer , Baird Alison , Eaton Charles B. , Heckbert Susan R. , Stafford Randall S. 
Published: October 2019

Abstract
Background. Postmenopausal estrogen (E) therapy, especially in combination with progestin (P) doubles the relative risk of venous thrombosis (VTE). Risk with hormones is higher with increasing age, obesity and with factor V Leiden. We studied coagulation markers as susceptibility factors for postmenopausal hormone-related VTE.
Methods. The Women’s Health Initiative program included two placebo-controlled double-blind randomized trials of two E regimens, E (conjugated equine estrogens) or E+P (E + medroxyprogesterone acetate), in 16,608 postmenopausal women aged 50–79. We performed a nested case control study that measured baseline levels of coagulation markers in 215 women who developed VTE during follow up and 867 age-matched controls. The joint effects of treatment assignment to either E regimen vs placebo and prespecified abnormal levels of each coagulation factor on relative risk of VTE were estimated by logistic regression adjusting for age, race, body-mass index and type of E regimen.
Results. Low levels of protein C and free protein S (<5th percentile), high D-dimer (top quartile), and high plasmin antiplasmin complex (PAP) and prothrombin fragment 1–2 (top decile) were all associated with risk of VTE with adjusted odds ratios (95% CI) of 2.0 (1.0–4.1), 2.9 (1.5–5.6), 2.8 (2.0–4.0), 2.5 (1.6–4.0) and 1.9 (1.2–3.1), respectively. Elevated factors II, VIII, IX and fibrinogen were not VTE risk factors. Compared to women with normal coagulation marker levels assigned to placebo, the joint odds of VTE with either E regimen plus an abnormal coagulation marker were more than additive compared to the separate effects of hormones and coagulation abnormalities for low protein C, low free protein S, and elevated D-dimer, PAP and F1–2. The odds ratios of VTE with the combination of an abnormal coagulation factor and assignment to hormones were (in order listed in prior sentence), 4.5 (95% CI 2.0–10.2), 6.7 (3.0–14.5), 6.1 (3.7–10), 5.8 (3.2–10.5) and 4.4 (2.4–7.7).
Conclusions. We report new findings of elevated F1-2 and PAP as VTE risk factors in women in this prospective study nested in trials of E or E+P versus placebo. Protein C or S values below the 5th percentile were also clinically relevant even though they do not represent inherited deficiency. Lower protein C and free protein S, and higher D-dimer, F1-2 and PAP all identified women at increased risk of VTE with hormones. If our findings are confirmed in management studies, measurement of these factors might assist women with decision-making on safety of E or E+P.