bluuebunny/crossref_metadata_2025_split huggingface dataset:
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Authors: Emanuel Peter Dean , Wang Zhuo , Cai Danying , Stofega Mary R. , Keck James G. , Estrov Zeev , Brown Gail L. , Ochoa-Bayona Jose L. , Callander Natalie 
Published: October 2019

Abstract
TLK199 is a novel glutathione analog that is a selective inhibitor of the enzyme glutathione S-transferase (GST) P1-1. TLK199 treatment induces hematopoietic cell proliferation and differentiation through activation of the MAP kinase signaling pathway leading to activation of JNK and ERK2. In rodent models of chemotherapy induced neutropenia, treatment with TLK199 accelerated recovery of white cell counts at rates comparable to treatment with G-CSF. We now report TLK199 treatment of myeloid progenitor cells isolated from normal human blood resulted in the increased formation of CFU-GM (46%) CFU-MK (47%) and BFU-E (142%) lineages over baseline. A corresponding increase in the percentage of cells expressing CD11b, a granulocyte and monocyte marker, was observed in the CFU-GM cells. Since TLK199 is currently being evaluated in a Phase 2a trial in patients with refractory MDS, we examined the effect of treatment on formation of BFU-E, CFU-GM and CFU-GEMM before and after TLK199 treatment at doses of 50 to 400 mg/m2. A significant increase in the number of hematopoietic progenitor cell colonies measured from patient peripheral blood and bone marrow was observed as early as Day 4 of Cycle 1 as compared to pretreatment baseline. Ten of 12 patients showed an increase in at least one colony forming type (BFU-E, CFU-GM and CFU-GEMM) and 7 of 12 had an increase in all three colony forming types following TLK199 administration. These results correlate with clinical improvement in hematological parameters in peripheral blood and bone marrow observed in MDS patients treated with TLK199. Studies are underway to define the mechanism of bone marrow and peripheral blood count recovery observed following treatment of MDS patients with TLK199 and the role of GST P1-1 as a regulatory element in myeloid proliferation and differentiation.
Evaluation of Cytokines Mobilizing Hematopoietic Progenitor Cells in Patients with Myelofibrosis with Myeloid Metaplasia (MMM).
Authors: Campanelli Rita , Massa Margherita , Meli Valentina , Rosti Vittorio , Ramajoli Isabella , Pecci Alessandro , Viarengo Gian Luca , Marchetti Monia 
Published: October 2019

Abstract
We have previously shown that in patients with MMM the number of circulating hematopoietic and endothelial progenitor cells is increased compared to other Ph-negative myeloproliferative disorders (Ph-CMPD). The aim of this study was to investigate the relevance of cytokines involved in the mobilization of progenitor cells from bone marrow to peripheral blood. We studied 120 patients with MMM, 22 patients with other Ph-CMPDs, and 30 healthy subjects. We evaluated by ELISA the plasma levels of stem cell factor (SCF), vascular endothelial growth factor (VEGF), and stromal derived factor-1alpha (SDF-1a). Moreover, the percentage of circulating CD34+ cells co-expressing the cytokine receptors CD117, VEGFR-2, or CXCR4 (for SCF, VEGF and SDF-1a, respectively) were assayed by flow cytometry. In all patients and controls, the percentage of circulating hematopoietic CD45+CD34+ cells and CD34+CD133+VEGFR-2+ endothelial progenitor cells were evaluated. SCF (median 872 pg/ml, range 281–2000), VEGF (median 38.9 pg/ml, range <15.6–2000), and SDF-1a (median, 3879 pg/ml, range <1560–18118) plasma levels were significantly higher (p<0.05, p<0.002, p<0.001, respectively) in patients with MMM than in normal controls (SCF, median 742 pg/ml, range 461–1167; VEGF, median <15.6 pg/ml, range <15.6–605; SDF-1a, median 1880 pg/ml, range <1560–8919). SDF-1a plasma levels of patients with MMM were also significantly higher (p<0.001) than those in other Ph-CMPDs (median 2896 pg/ml; range <1560–14144). In patients with MMM, cytokine plasma levels correlate with neither the percentage of CD34+ cells expressing their receptors, nor the percentage of circulating hemopoietic or endothelial progenitor cells. When clinical parameters were tested, we found a significant correlation between SDF-1a plasma levels and both the spleen size (n=113, R=0.20, p<0.05), and the number of immature myeloid cells (n=87, R=0.23, p<0.03). These data show increased plasma levels of SCF, VEGF, and SDF-1a in patients with MMM compared to normal controls; however, only SDF-1a characterizes patients with MMM with respect to those with other Ph-CMPDs. Neither the plasma levels of SDF-1a nor those of the other measured cytokines correlated with the extent of progenitor cells mobilization.
A Clinically Relevant SCID-hu in Vivo Model of Human Multiple Myeloma.
Authors: Tassone Pierfrancesco , Neri Paola , Carrasco Daniel R. , Burger Renate , Catley Laurence , Venuta Salvatore , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Human multiple myeloma (MM) xenografts in immunodeficient mice have limitations as a model for the human disease since they lack the human bone marrow (huBM) microenvironment. In contrast, murine models harboring a huBM microenvironment with implantation of patient MM cells in the huBM recapitulate the in vivo pathophysiology of MM and have significant advantages over conventional murine models for pre-clinical evaluation of investigational drugs. However, there are significant limitations in using patient MM cells in such models since i) not all patient MM samples engraft in the huBM; ii) only a fraction of engrafted specimens produce measurable paraprotein and/or osteolytic lesions; and iii) a limited number of MM cells can be harvested from an individual patient, thus limiting the number of mice that can be injected with cells from the same patient. To overcome these limitations, we have developed a novel murine model of MM by engrafting INA-6, a cytokine-dependent human MM cell line into SCID mice previously implanted with a human fetal bone chip (SCID-hu mice). INA-6 cells require either exogenous IL-6 or interaction with the bone marrow stromal cells (BMSCs) to proliferate in vitro. In this model, we monitored the in vivo growth of INA-6 cells stably transfected with a green fluorescent protein (GFP) expression vector (INA-6GFP+). Serum soluble human IL-6 receptor (shuIL-6R) and fluorescence imaging of host animals were sensitive indicators of tumor burden with time dependent increase. Fluorescence imaging was able to detect the myeloma cell growth earlier than measurement of sIL-6R levels. INA-6 MM cells grew in SCID-hu mice, but not in SCID mice injected subcutaneously or intravenously without the human fetal bone. We have further confirmed the feasibility of this model in monitoring the response to therapeutic agents such as dexamethasone by detecting reduction in the intensity of the fluorescent lesions as well as shuIL-6R in SCID-hu mice following anti-MM treatment. This highly reproducible model therefore allows for evaluation of investigational drugs targeting MM cells in the huBM milieu.
AHOD00P1, a Pilot Study of Re-Induction Chemotherapy with Ifosfamide, and Vinorelbine (IV) in Children with Refractory/Relapsed Hodgkin Disease.
Authors: Trippett Tanya , De Alarcon Pedro , London Wendy , Sposto Richard , Chen Allen , Gardner Sharon , Schwartz Cindy 
Published: October 2019

Abstract
A COG Phase II pilot study was conducted to assess the efficacy of the novel re-induction regimen of ifosfamide/vinorelbine (IV) in pediatric patients with heavily pre-treated relapsed/refractory Hodgkin disease. The treatment regimen consisted of : Ifosfamide 3 gm/m2/d continuous 24-hr IV infusion on Days 1–4; MESNA 3 gm/m2/d continuous 24-hr IV infusion on Days 1–5; and vinorelbine 25 mg/m2/dose IV bolus on Days 1, 5. Filgrastim was administered on Day 6 of Cycle 1 at a dose of 5 μg/kg until ANC ≥ 1000/μl for 3 consecutive days or ≥ 10,000/μl for 1 day and on Day 6 of Cycle 2 at a dose of 10 μg/kg to continue daily until completion of peripheral stem cell mobilization. We report the results of the first phase of the study, that evaluated the re-induction regimen IV which was substantiated as an effective re-induction regimen based on acceptable toxicity profile, capacity to mobilize hematopoietic stem cells (CD34+), and response sufficient to allow subsequent stem-cell transplantation in a large fraction of patients. Twenty-nine patients were accrued on study; 12 male (41%), 17 female (59%); median age at time of enrollment was 16 (range 5–20 yrs). The protocol mandated two cycles of therapy, although some patients received an optional third cycle. This report is based on data from the first 2 cycles only. Twenty-five patients had complete toxicity data. The predominant toxicity was hematologic, specifically leukopenia/neutropenia. The frequencies of grade 3–4 hematologic toxicities included: anemia (62%), leukopenia (100%), neutropenia (95%), and thrombocytopenia (50%). Hypophosphatemia (3%), febrile neutropenia (34.9%) and infection with grade 3 or 4 neutropenia (21.6%), and neurotoxicity (3%), each occurred in a minority of patients. There were no toxic deaths. Harvest was attempted in 25 patients. At least 2.5 x 106 CD34+ cells/kg were collected in 19 (76%), and at least 5.0 x 106 were collected in 16 (64%). Complete response data were available for twenty-five patients. Seven patients attained a complete response (CR) and eleven a partial response (PR) (CR/PR rate 72%). IV was substantiated as an acceptable re-induction regimen for children with Hodgkin disease. It was effective, well tolerated, and allowed for collection of sufficient CD34+ cells to support peripheral stem cell transplantation. Based upon these findings, 35 additional patients will be accrued to more precisely establish the definitive response rate in pediatric patients. In addition, minimally pretreated patients will now be included, allowing assessment of response, toxicity and hematopoietic stem cells (CD34+) mobilization in minimally pre-treated patients as well as in the heavily pre-treated population.
p53 Silencing by Lentiviral Vector Mediated RNA Interference in Murine Hematopoietic Cells and the Development of a Myelogenous Proliferative Disease.
Authors: Woods Niels-Bjarne R. , Tergaonkar Vinay , Singer Oded , Bottero Virginie , Verma Inder M. 
Published: October 2019

Abstract
The ability for siRNA containing lentiviral vectors to specifically downregulate gene expression in the hematopoietic system following hematopoietic stem cell transplantation provides a new tool for developing disease models of leukemia and other hematological disorders. The tumor suppressor gene, p53, has been implicated in the genesis or progression of hematological malignancies, such as AML, MDS, and CML, and disorders such as myeloproliferative disease (MPD). Following transduction of Ly5.1 hematopoietic stem cells using a lentiviral vector expressing small interfering RNAs specific for mouse p53, cells were transplanted into lethally irradiated syngeneic recipient mice. Peripheral blood analyses by FACS at 7 weeks posttransplant showed significantly increased numbers of Gr1 Mac1 double positive progenitor like cells in 4 of 4 mice (73±14% compared to control siGFP transplanted mice 5±0.5%). Interestingly, 3 of 4 transplanted mice showed signs of morbidity by 16 weeks posttransplant due to a myelogenous proliferative disease (MPD) phenotype characterized by high peripheral blood neutrophil counts (>70% of white blood cells) and anemia (<106 RBC/μL), and extensive neutrophil infiltration into spleen and liver. Furthermore, peripheral blood smears show an expansion of megakaryocytes. Bone marrow mononuclear cells from transplanted mice were analyzed for p53 protein expression following p53 stabilization by irradiation and significantly lower levels of p53 were detected in sip53-transduced mice compared to siGFP lentiviral vector control mice. No altering of normal hematopoietic cell differentiation was observed in control mice from nonspecific RNAi interactions, as determined by FACS or blood cell count analyses. These results demonstrate that downregulated expression of p53 in mice hematopoietic cells yields a myelogenous proliferative disease and creates a model for the study of p53 involvement in the genesis and progression of hematological disorders. Furthermore, these results demonstrate the ability of lentiviral vector mediated siRNA to efficiently downregulate endogenous gene expression in vivo and model human disease.
Atherosclerosis as a Risk Factor for Venous Thromboembolism (VTE): A Population-Based Cohort Study.
Authors: Petterson Tanya M. , Agmon Yoram , Meissner Irene , Khandheria Bijoy K. , Heit John A. 
Published: October 2019

Abstract
While atherosclerosis has been suggested as a risk factor for VTE, previously identified mechanisms for atherosclerosis and VTE differ dramatically.
Objectives: To compare (a) VTE-free survival and (b) observed vs. expected number of VTE events, among adult patients with and without aortic atherosclerosis.
Design/Setting: Population-based prospective cohort study in Olmsted County, MN.
Patients: Age- and sex-stratified random sample of the adult (≥45 years old) Olmsted County population identified over the three-year period, 1993–1995 (n=573), performed as part of the Stroke Prevention: Assessment of Risk in the Community (SPARC) study.
Measurements: The SPARC study included a baseline clinical evaluation (interviews, review of medical records), blood pressure measurements, blood sampling, and transesophageal echocardiography (TEE). The Risk Factors for VTE in the Community study identified all incident VTE among Olmsted County residents over the 32-year period, 1966–1997, from which expected VTE events by age and sex were calculated.
Results: Over 2830 person-years of follow-up, 12 SPARC patients developed VTE (7 idiopathic). The 4-year VTE-free survival was 99% and 98% for those with and those without any TEE-detected aortic atherosclerosis. Adjusting for age in a Cox proportional hazards model, lack of aortic atherosclerosis was significantly associated with subsequent VTE (p=0.01). Among the 276 patients without atherosclerosis observed for 1423 person-years, 7 VTE were observed compared to 2.6 expected (RR=2.7, 95%CI: 1.1, 5.6). Among the 291 patients with atherosclerosis (plaque ≥2mm), 4 VTE were observed compared to 5.8 expected (RR=0.7, 95%CI: 0.2, 1.8).
Conclusions: Atherosclerosis is not a risk factor for incident VTE.
Risk Factors Associated with Venous Thromboembolic Events in Patients with Malignancy.
Authors: Lin Jules , Li Hang , Wakefield Thomas W. , Henke Peter K. 
Published: October 2019

Abstract
Malignancy is a major risk factor for venous thromboembolic events (VTE), but not all patients with malignancy develop this complication. Who best to aggressively prophylax is thus not well defined. In the current study, 960 consecutive patients, 523 men and 437 women, admitted to the University of Michigan with malignancy between 1992–2000 were identified using ICD-9CM codes. Factors including cancer stage, type, therapy, and patient vital status were obtained from a database maintained prospectively by the University of Michigan Cancer Registry as well as a review of the medical record. Acute VTE, confirmed on radiological or ultrasound studies, occurred in 408 patients and were compared to 552 patients who did not experience any VTE using logistic regression analysis. Factors associated with VTE include solid tumors (Odds Ratio 5.0; 95% confidence interval 1.65–14.9, P =.004), infection (4.9; 1.2–19.8, P =.025), and advanced age (1.05; 1.03–1.08, P <.001). Interestingly, while leukopenia (4.2; 1.23–14.6, P =.023) was associated with an increased incidence of VTE, neutropenia was not, suggesting that a deficiency of a different class of leukocytes is more important in predisposing to primary VTE. Neutropenia was associated with recurrent, but not primary VTE (P =.034). Type of therapy, gender, and stage were not associated with VTE. Kaplan Meier estimated survival was decreased in patients with VTE as compared to those without (3.3 vs. 3.7 years, P=.18). Factors associated with a decreased survival include solid tumors (3.9; 1.8–8.4, P <.01), infection (3.3; 1.1–9.9, P =.03), advanced stage (1.6; 1.2–2.1, P <.01), and increased age (1.02; 1.0–1.04, P =.01). Patients with solid tumors, advanced age, and leukopenia have a significantly increased risk of VTE and might benefit from aggressive VTE prophylaxis, whereas other patients with malignancy can probably be carefully observed.
Oligosaccharide Expression and Modification Defines Novel Targets within the Vascular Tree: Selective Chondroitin Sulfate C Expression in the Tumor Microenvironment Generates a Novel Target of Otherwise Constitutive Receptors.
Authors: El-Sheikh Amr , Bhattacharjee Gourab , Borgstrom Per , Belting Mattias , Edgington Thomas 
Published: October 2019

Abstract
The expression of certain proteoglycans or modification of proteins within the vascular tree, dependent on the microenvironment, is critical for elucidating the biology of endothelium specificity and development. It also facilitates the targeting of physiologic and therapeutic agents to different addresses within the vascular map. Using in vivo panning, we have identified a truncated heparin-binding domain (HBDt) that recognizes its target selectively in tumor vasculature. Here we show that it localizes selectively to the endothelial cells of intra-tumoral blood vessels of various murine tumor models, such as CT26, LLC, N202, and Tramp-L1. The HBDt, as a part of the VEGF heparin-binding domain, is conserved throughout evolution and is known to bind the VEGFR-2/Npn-1 complex. Although the VEGFR-2/Npn-1 complex is expressed elsewhere in the vascular tree, this domain only localizes to a target in tumor vasculature. We have analyzed the basis of this selectivity in vitro and in vivo. In vitro analysis has shown that chondroitin sulfates are the most potent inhibitors of HBDt binding to heparin. We also show, using Western blot and confocal microscopy analyses, that VEGFR-2 and Npn-1, although expressed in different organs, are only recognized by HBDt when coexpressed with chondroitin sulfate C (C6S) in the tumor vasculature. The HBDt colocalized with VEGFR-2, Npn-1, and C6S but with not bFGFR or heparan sulfates in the intravasculature of different tumor models. Furthermore, the selective expression of C6S oligosaccaharide, in conjunction with VEGFR-2 and Npn-1, during the angiogenesis of tumor endothelium defines the target for the HBDt but not during aortic angiogensis. Therefore, our data demonstrate that the expression of C6S, as part of the HBDt receptor, is an example of the tumor microenvironment conditioning, which imparts association of a novel target on endothelium surfaces of tumors.
APRIL Promotes Survival and Proliferation of T Cells: Implications for T-Cell Lymphoma.
Authors: Yang Zhi-Zhang , Ansell Stephen M. , Witzig Thomas E. , Novak Anne J. 
Published: October 2019

Abstract
Background: Cutaneous T-cell lymphoma (CTCL) is an incurable lymphoproliferative disorder characterized by the clonal expansion of malignant CD4+ T cells. Currently there is a poor understanding of the underlying mechanisms in the development and progression of this disease. Members of the TNF superfamily have been shown to be important mediators in the formation and regulation of normal T cell responses. A proliferation-inducing ligand (APRIL), a newly identified member of the TNF superfamily, has been shown to stimulate tumor cell growth as well as proliferation of primary B and T lymphocytes. APRIL transcript levels are reported to be low in normal tissues with the highest levels found in peripheral blood leucocytes. In contrast, higher mRNA levels have been detected in tumor cell lines and primary tumor tissues and various tumor cell lines have been shown to respond to APRIL with increased tumor cell proliferation and decreased apoptosis. The striking effects of APRIL on tumor cell growth and survival raise the possibility that the APRIL and its receptors-TACI and BCMA may be involved in the pathogenesis and maintenance of T cell malignancies.
Goal: To explore the involvement of APRIL on normal and malignant T cell growth and survival.
Results: Under resting conditions, there was minimal APRIL binding to normal T-cells and no TACI or BCMA expression. However, stimulation of resting T cells with OKT3 (anti-CD3) or a combination of PMA and ionomycin resulted in an increase in APRIL binding and TACI expression on a subset of activated T-cells. When CD3+ resting human T cells were cultured in the presence of APRIL, IL-2, or OKT3 alone or a combination, normal T cells had greater viability compared to the nil control and APRIL mediated-T cell survival was similar level to that seen with IL-2 or OKT3 alone. CSFE labeled T cells were activated with suboptimal dose of OKT3 and incubated in the presence of APRIL and /or IL-2. Both APRIL and IL-2 alone induced cell proliferation, while treatment with the combination of APRIL and IL-2 had a synergistic effect on T cell proliferation. Malignant T cells isolated from the blood of patients with Sezary Syndrome exhibited a similar pattern of APRIL binding and APRIL also enhanced their survival. Gene array experiments were performed to identify genes involved in APRIL-mediated survival. In normal and primary malignant T cells the anti-apoptotic genes BCL2A1, BIRC6, CHK1, MCL-1, and MDM2 were upregulated and the pro-apoptotic genes CASP5, DR5, and TNFR2 were downregulated in response to APRIL.
Conclusion: APRIL promotes the survival of normal and malignant T cells and co-stimulates CD3-mediated T cell proliferation. The gene array experiments suggest that APRIL regulates the expression of anti-apoptotic and pro-apoptotic genes in both normal and malignant T cells. Taken together, these data indicate an important role for APRIL in the biology of normal T cells and in the pathophysiology of T cell lymphoma.