bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pegylated Liposomal Doxorubicin (PLD), Vincristine and Reduced-Dose Dexamethasone (DVd) in the Treatment of a Predominantly African American Population with Multiple Myeloma.
Authors: Jajeh Ahmad , Catchatourian Rosalind , Osafo David , Tamkus Deimante , Zalzaleh Ghassan , Bamrolia Anshul 
Published: October 2019

Abstract
Recently there has been an important recognition of potentially different responses to pharmaceuticals based on genetic predisposition, with the first FDA advisory panel recommending approval of a heart failure drug for African Americans alone. Liposomal doxorubicin (DOXIL; PLD) is a microscopic pegylated phospholipid vesicle with a core containing conventional doxorubicin. The pegylated coat protects the liposomes from detection by mononuclear phagocytes increasing blood circulation time (t½ = 55 hours). Due to its prolonged half-life, PLD provides a similar effect to using continuous infusion doxorubicin, but administered over 1-hour, transforming the regimen into an outpatient treatment. PLD has also been shown to have a significantly better cardiac safety profile than conventional doxorubicin. A phase II trial using DVd was started in October 2000 and is still enrolling (PLD 40 mg/m2, vincristine 2 mg IVP, and dexamethasone 40 mg PO 1–4 d every 4-weeks). Twenty-seven patients have been enrolled (11 males/16 females; mean age 56 years [range 41–75]). The majority of patients enrolled in this study are African American (74%), a patient population not commonly studied. Patients presented with relatively advanced disease (stages II – III). Baseline mean serum albumin level was 3.5 mg/dL (range 1.4 to 4.4), beta-2 microglobulin 3.38 (range 1.0 – 8.97), fourteen patients had IgG Kappa, three patients has IgG Lambda, six patients with IgA, and four patients with light chain disease. Eighteen patients completed six cycles of therapy, with two patients completing five cycles. Six patients underwent autologous bone marrow transplant following their response to DVd.
CR, and nCR was achieved in nine patients, partial responses were achieved in seven patients, minor response in two patients, and progressive disease in five patients, based on Blade Response Assessment. Median follow up is twenty-four months (range 3 months – 5 years). Overall medium time to progression is approximately 1 year. Twenty patients are still alive, one patient has been lost to follow up, and six deaths have occurred. Four early deaths were due to disease progression and sepsis. Two died after one year of therapy due to progressive refractory disease. One died after the second cycle because of sudden cardiac death with sepsis. Three of the early deaths had amyloidosis. No episodes of cardiac dysfunction were observed.
Conclusion: African Americans have a 3-fold higher risk of cardiac toxicity with conventional doxorubicin. The use of DVd in this predominantly African American patient population was cardiac safe and provided an easy administered outpatient option, with an overall response rate of ~66% in stage II–III patients.
Myc Targets Cks1 To Provoke Proliferation and Lymphomagenesis.
Authors: Keller Ulrich , Old Jennifer B. , Nilsson Jonas , Nilsson Lisa , Maclean Kirsteen , Yang Chunying , Spruck Charles , Boyd Kelli , Reed Steven I. , Cleveland John L. 
Published: October 2019

Abstract
Reduced levels of the cyclin dependent kinase inhibitor p27Kip1 connote poor prognosis in cancer. In human Burkitt lymphoma, and in pre-cancerous B cells and lymphomas arising in Eμ-Myc transgenic mice, p27Kip1 expression is markedly reduced. Furthermore, the Cks1 component of the SCFSkp2 complex that is necessary for p27Kip1 ubiquitylation and degradation, and to a lesser extent Skp2, are induced by Myc ex vivo and in Eμ-Myc B-cells and lymphomas, and up-regulation of CKS1 and SKP2 are hallmarks of Burkitt lymphoma. While loss of Skp2 has rather modest effects, the deletion of Cks1 in Eμ-Myc B-cells elevates p27Kip1 levels, reduces proliferation and delays lymphoma development. In contrast, Myc-induced apoptosis and transcriptional activity are not affected by Cks1 (or Skp2) loss. Therefore, Myc accelerates cell proliferation and promotes tumorigenesis through its ability to selectively induce Cks1.
Heparins Inhibit Tumor Angiogenesis by Sequestering Fibroblast Growth Factor (FGF) from Tumor Vascular Endothelial Cells.
Authors: Smiley Shannon L. , Henry Dale O. , Chen Shang-Chiung , Wong Michael K.K. 
Published: October 2019

Abstract
The association between cancer and thromboembolic disease is a well-known phenomenon and contributes to the morbidity and mortality of cancer patients. Clinical studies of thrombosis in these patients show that heparins may have beneficial effects on survival. Antithrombotic agents have been shown to exert an anti-tumor effect in various experimental models however the underlying mechanism remains unknown. We show that heparins inhibit in vivo tumor angiogenesis and offer molecular evidence that heparins exert an anti-angiogenic effect by directly sequestering fibroblast growth factor (FGF) from its receptor on tumor derived endothelial cells (TDECs). NIH-3T3 fibroblasts were stably transfected with an expression construct that results in the constitutive excretion of FGF-1 (Clone C). Clone C gives rise to aggressive and highly angiogenic xenograft tumors. Clone C was inoculated into nude mice and therapeutic doses of Low Molecular Weight (LMW) heparins were injected daily beginning on Day 2. Tumors in the control group were grossly angiogenic and highly vascularized. In contrast, the heparin treated tumors were pale and possessed only scant peri-tumoral vessels. In order to assess the biologic mechanism of this, murine TDECs were isolated and cultured as previously published. Unfractionated and LMW heparins inhibit FGF-induced TDEC mitogenesis in a concentration- and time-dependent manner. FGF overcame and rescued heparin-induced inhibition suggesting that an FGF-heparin interaction is responsible. In order to test the hypothesis that heparin strips and sequesters FGF off its receptor on TDECs, we used a FGF protein fused to a hemagglutinin peptide tag at the carboxyl-terminus end (FGF-HA). FGF-HA is biologically identical to wild type FGF, but its detection limit is 10X more sensitive. FGF-HA was allowed to bind to FGFR on TDECs. These cells were subsequently incubated with Heparin covalently linked to Sepharose beads (Heparin-Sepharose) or to Sepharose alone. These beads were removed, and TDEC growth analyzed prospectively. Heparin-Sepharose treatment results in significant TDEC growth inhibition as compared to incubation with Sepharose alone. Western blot analysis shows that FGF was sequestered only on the Heparin-Sepharose beads.
Conclusion: The anti-angiogenic mechanism of heparins resides, in part, in its ability to sequester angiogenic cytokines such as FGF from its receptor on tumor endothelium.
Secondary Malignancies after Hematopoietic Stem Cell Transplantation in Patients Treated with Total Body Irradiation.
Authors: de la Fuente Cristina , Berrocal Maria I. , Cabrera J. Rafael , Regueiro Carlos A. , Fores Rafael , Regidor Carmen , Millan Isabel , Nuñez Luis , Valcarcel Francisco , Fernandez Manuel N. , Sanjuan Isabel , de la Torre Alejandro 
Published: October 2019

Abstract
We have analyzed the incidence and risk factors of developing a secondary malignancy after total body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). From March 1986 to December 2002, 205 patients received TBI as a part of the HSCT conditioning regimen. TBI was administered in 6 fractions, twice a day, up to a total dose of 12 Gy, with a median dose rate of 11.44 cGy/min. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 119 patients and the other 86 patients received an autologous hematopoietic stem cell transplantation (AHSCT). Median age was 30 years (5–63). We have calculated the cumulative incidence of solid tumors and secondary hematologic malignancies among these patients. Death due to noncancerous causes and patients lost to follow-up were entered as a competitive risk. With a median follow-up of 32 months (0.2–229)- including patients deceased in the first three months- 13 (6.3%) developed a secondary malignancy, 7 of them (3.4%) developed a solid tumor and 6 (2.9%) developed a secondary hematologic malignancy. The 7 patients who developed a solid tumor-1 glioblastoma, 2 head and neck carcinoma, 2 basocelular carcinoma, 1 osteosarcoma and 1 cervical intraepithelial neoplasia- had received an allo-HSCT. The 6 patients that developed a secondary hematologic malignancy- 5 therapy-related leukemia/myelodisplasia (t-AML/MDS) and 1 B cell non Hodgkin’s lymphoma- had received an AHSCT. The overall probability of developing a secondary malignancy after HSCT is 2.5% at 3 years (95% confidence interval (CI) 1.1– 6); 5% at 10 years (95% CI 2.6–9.3), and 9% at 15 years (95% CI 5–16.5). The probability of developing a solid tumor after HSCT is 0.5% at 3 years (95% CI 0.1–3.6), 1.8 % at 10 years (95% CI 0.6–5.5), and 6 % at 15 years (95% CI 2.6–13.7) and the probability of developing a secondary hematologic malignancy is 2 % at 3 years (95% CI 0.8–5.3), and 3,1 % at 10 and 15 years (95% CI 1.4–6.9). Median time to develop a solid tumor was 134 months (29–229). Median time to develop a secondary hematologic malignancy was 31 (3–60) months. Multivariate analysis proved that allo-HSCT was the only risk factor of developing a solid tumor, and that AHSCT and advanced age were risk factors of developing secondary hematologic malignancy (mean age 30 vs. 50 years ). To conclude, the probability of developing a solid tumor after HSCT is higher if an allo-HSCT has been performed and increases with time. AHSCT and advanced age are risk factors for the development of a secondary hematologic malignancy, a risk that decreases 5 years after AHSCT.
Presence of a Flt-3 Internal Tandem Duplication in AML Blasts Predicts Inhibition of Differentiation towards Leukemic Dendritic Cells.
Authors: Houtenbos Ilse , Westers Theresia M. , Ossenkoppele Gert J. , van de Loosdrecht Arjan A. 
Published: October 2019

Abstract
In the search for new treatment modalities to eradicate minimal residual disease cells (MRD) in acute myeloid leukemia (AML), immunotherapy provides an attractive option. AML blasts show differentiation towards leukemic dendritic cells (DC), providing the unique opportunity to generate DC harbouring the full range of tumour antigens. In a large cohort of AML samples (n=154) AML-DC were generated by two culture methods, i.e. in presence of cytokines GM-CSF, TNF-α, SCF, Flt-3L, IL-3 and IL-4 (n=147) or calcium ionophore (CI) and IL-4 (n=108). Median AML-DC yield, defined by phenotypical DC characteristics, in the cytokine-based cultures was 12% (range:0–70%). Considering cultures yielding ≥10% AML-DC successful, 58% (85/147) of cytokine-based cultures were successful and 61% (66/108) of CI cultures. Overall, functional AML-DC generated with either method was possible in 66% (101/154) of patients. Identification of AML blast populations with DC differentiation capacity is important to select patients eligible for immunisation programs. Interestingly, presence of Flt-3 internal tandem duplication (ITD) was strongly correlated with decreased DC differentiation capacity in both culture methods (cytokine-based culture: p<0.001; CI-culture: p=0.03) suggesting that constitutive activation of tyrosine kinase receptors inhibits differentiation towards DC. In multiparameter regression analysis, powerful predictors for cytokine-based AML-DC culture outcomes were Flt-3 ITD (regression coefficient B:-3.41, p<0.001), CD14 (B:3.28, p<0.001) and TNFα-RI (B:2.82, p<0.001). This regression model predicts 88% of culture outcomes. ROC curves show high sensitivity (95%) and specificity (76%) with an AUC of 0.93 (p<0.001). In 25% of unsuccessful cytokine-based cultures, the CI-based culture method provides an alternative. This percentage increases to 56% if Flt-3 ITD+ AML samples are left out, emphasizing Flt-3 ITD+ blasts’ inability to differentiate towards leukemic DC. In conclusion, AML-DC cultures are successful in most patients. Selection of patients is well possible based upon the presence of Flt-3 ITD and the expression of CD14 and TNFα-RI. Based on these results, we are currently entering patients in a phase I/II clinical vaccination trial.
Studies on GM-CSF Induced Signaling and Cell Growth in JMML: An Experimental Model To Identify Mechanism Directed Targeted Therapeutics.
Authors: Ding Yu , Teja Bijan , Blackmore Chris , Dingwa Sumita , Ujack Eva , Brown Christopher , Narendran Aru 
Published: October 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is considered to be one of the most difficult to treat and deadliest diseases of early childhood. The pathogenesis of JMML involves deregulated cytokine signal transduction, especially a selective hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Current treatment modalities do not provide significant long-term disease control. We describe an experimental model system in which the effect of targeted agents can be studied in the context of GM-CSF mediated growth and survival of JMML cells.
Bone marrow and peripheral mononuclear cells from JMML patients were enriched by immunoaffinity chromatography and grown in the presence of GM-CSF. Purity of these cells was confirmed by FACS and their absolute dependence on GM-CSF for growth and survival was assessed. A direct role for GM-CSF was confirmed by the addition of neutralizing antibodies. Molecular techniques showed the lack of excess GM-CSF secretion by these cells that proved receptor hypersensitivity as the principal driving force behind the excessive proliferation. To understand the signaling pathways involved in this process, we constructed a capture antibody array with antibodies to critical signaling molecules. GM-CSF treated and control lysates were incubated with the arrays and the expression and phosphorylation of the signaling molecules were detected by anti p-tyr, p-Ser and p-Thr antibodies. Blots were then quantified by an automated image analysis program. Results showed consistent activation of a group of signaling molecules mediated by the addition of GM-CSF. These include IRS-1, FAK, IkappaB and LIFR. Using this assay system we then looked at the effects of a number of novel therapeutic agents to inhibit the growth and specifically interfere with the GM-CSF mediated signaling cascade. These novel therapeutic agents and targeted kinase inhibitors such as 17-AAG, DMAG, arsenic trioxide, rebeccamycin, AMN-107, and Prima-1. (IC50: 0.1, 0.01. 0.5, 0.1, 0 and 10, uM respectively). These agents were studied in combination to identify agents that exhibit synergistic and additive properties. Significant additive effects were seen with certain combinations, notably in combination with Hsp90 inhibitors.
We describe an effective experimental model to identify the players and pathways involved in the abnormal growth properties of JMML. We discuss in detail the implications of these findings in the development of potential anti JMML therapies in the future.
Platelet-Derived Microparticles Accelerate Engraftment of Peripheral Blood Stem Cells in Human Allogeneic Transplantation.
Authors: de Rop Christiane , Priesack Jan , Tiede Andreas , Trummer Arne 
Published: October 2019

Abstract
While the procoagulant activity of platelet derived microparticles (PMP) has been widely accepted, knowledge regarding their immunological and adhesive qualities is still limited. It has been shown that murine BM cells covered with PMP engrafted lethally irradiated mice significantly faster than those not covered, indicating that PMPs play an important role in the homing of peripheral blood stem cells (PBSC). Here we studied the impact of PMP on engraftment in human allogeneic PBSC transplants for patients with hematological malignancies. PBSC samples were collected in buffered citrate from transplantation bags after infusion of transplants into patients with hematological malignancies (AML = 5, ALL = 1). Conditioning regimens included busulfan/cyclophosphamide (Bu/Cy), anti-CD66b-radioimmunotherapy (RIT)/Bu/Cy, and reduced intensity regimens with fludarabin/busulfan (Flu/Bu) and FLAMSA. Platelet-poor plasma (PPP) was prepared (1500g for 20min), immediately shock-frozen in liquid nitrogen and stored at −80°C. For further analysis PPP’s were carefully thawed at room temperature (RT). 90μl of PPP was stained with 5μl of CD41-PE and CD62P-FITC each for 15min at RT in the dark (IgG1-FITC and -PE served as negative controls, TRAP-6 (10μM) stimulated whole blood processed in same way as samples as positive control). To stop staining 900μl PBS/BSA 2% was added and 500μl of this solution were transferred into BD Trucount tubes by reverse pipetting giving a final concentration of 100 beads/μl. Samples were analyzed immediately using Coulter FC500 flow cytometer with CXP software. As expected the CD34 cell count (mean=5.1x106/kg body weight, SD=2.0x106/kg) showed a significant correlation (p=0.0197, Pearson r=−0.83) with the time to engraftment (mean=15.7days, SD=2.0d). The amount of CD62P positive microparticles (mean=423/μl, SD=119/μl) and the conditioning regimen showed no significant correlation with CD34 cell count or time to engraftment with leucocytes >1000/μl. In contrast, CD41-PMP count (mean=1223/μl, SD=857μl) correlated significantly with the CD34 cell count (p=0.0086, Pearson r=0.92) and the time to engraftment (p=0.0039, Pearson r = −0.95). Therefore, PBSCT contain significant amounts of PMP which are most likely generated during apheresis. Preliminary results show a stronger correlation with time to engraftment than does CD34 cell count. We conclude that PMP may accelerate engraftment of PBSC in humans. However, this function seems unrelated to P-Selectin expression. Therefore, further studies aiming to identify other adhesion molecules involved in PMP-mediated engraftment of PBSCT are warranted.
Gene Correction in Human Cells Is Promoted by the Bacteriophage Protein Redβ.
Authors: Porter Andrew C. , Stewart Francis , Xu Ke 
Published: October 2019

Abstract
Correction of a disease gene mutation by homologous recombination (HR) with a transfected DNA repair template represents an ideal form of gene therapy for many inherited hematological disorders. Therapeutic gene correction via HR in hematopoietic stem cells is unlikely to succeed, however, without major improvements in its efficiency. One promising approach is to use an engineered zinc finger endonuclease to specifically cleave the target gene and so promote HR between a dsDNA template and its chromosomal target (Urnov et al (2005) Nature 435:646-51). We are exploring an alternative approach based on the expression of Redβ, a single stranded (ss) DNA annealing protein from bacteriophage λ. In bacteria, Redβ promotes HR-mediated gene modification using templates with short regions of homology (e.g. 30–100nt). Such HR is independent of RecA-mediated host cell HR. For double stranded (ds) DNA templates, co-expression of λ exonuclease (the red α gene product) is required, but ssDNA templated modifications are particularly efficient and require only Redβ expression. Such properties could be useful for therapeutic gene correction if reproduced in human cells. Preliminary experiments in mouse embryonic stem cells suggested that Redβ can function in mammalian cells (Zhang Y. et al, (2003) BMC Mol. Biol. 4). To explore this further, we have generated a human cell line in which large amounts of Redβ can be expressed inducibly in the nucleus. In contrast to the over-expression of endogenous HR proteins Rad51 (RecA homologue) or Rad52 (ssDNA annealing protein), sustained Redβ over-expression is well tolerated, with no impairment of cell proliferation or viability. We find that Redβ does indeed promote HR in human cells. Surprisingly, dsDNA and ssDNA templated gene modification are stimulated to similar extents by Redβ. Stimulations are modest, but similar to those achieved by human Rad51 over-expression. The effects of co-expressing Red α are under investigation. We have also shown that ssDNA-templated gene correction is stimulated by transient, RNAi-mediated, depletion of the mismatch repair protein MSH2, and that such stimulation is additive with Redβ-stimulated gene correction.
Systematic Review of Randomized Controlled Trials of Prophylactic Clotting Factor Concentrate in Hemophilia.
Authors: Stobart Kent , Iorio Alfonso 
Published: October 2019

Abstract
Introduction: One of the current approaches to managing persons with hemophilia entails the use of prophylactic treatment with clotting factor concentrates (CFC) to prevent bleeds and bleeding related complications. However, this process is not practiced in all countries, or is based on the synthesis of evidence from data of all trials.
Objective: To conduct a systematic review/meta-analysis (SR/MA) regarding the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B.
Methods: We conducted a SR of all randomized controlled trials (RCTs) that studied the effect of prophylactic CFCs in people with hemophilia A or B. We searched all major electronic databases (MEDLINE, LILACS, EMBASE, and the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Controlled Trials Register) as well as performing handsearches of journals and relevant meeting abstract books. We included RCTs that that compared the use of prophylactic CFCs to a control group.
Results: We identified 29 studies, of which four (including 37 participants) were eligible for inclusion. Three studies evaluated hemophilia A; one showed a decrease in frequency of joint bleeds with prophylaxis compared to placebo (non-physiological dose), with a rate difference (RD) −10.80 (95% confidence interval (CI) −16.33 to −5.27) bleeds per year. The remaining two studies evaluating hemophilia A compared two prophylaxis regimens, one study showed no difference in joint bleed frequency, RD −5.04 (95%CI −17.02 to 6.94) bleeds per year and another failed to demonstrate an advantage of factor VIII dosing based on individual pharmacokinetic data over the standard prophylaxis regimen with RD −0.14 (95% CI −1.34 to 1.05) bleeds per year. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, RD −3.30 (95% CI −5.50 to − 1.10) bleeds per year.
Conclusion: There is insufficient evidence to determine whether prophylactic clotting factor concentrates decrease bleeding and bleeding-related complications in hemophilia A or B, compared to placebo, on-demand treatment, or prophylaxis based on pharmacokinetic data from individuals. Well-designed RCTs are needed to assess the effectiveness of prophylactic clotting factor concentrates.