bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparanase Promotes the Spontaneous Metastasis of Myeloma Cells to Bone.
Authors: Yang Yang , MacLeod Veronica , Bendre Manali , Huang Yan , Theus Allison M. , Miao Hua-Quan , Kussie Paul , Yaccoby Shmuel , Epstein Joshua , Suva Larry J. , Kelly Thomas , Sanderson Ralph D. 
Published: October 2019

Abstract
Although widespread skeletal dissemination is a critical step in the progression of myeloma, little is known regarding mechanisms that control this process. High levels of the syndecan-1 heparan sulfate proteoglycan are present in the myeloma microenvironment where they bind numerous growth factors (e.g., HGF, FGF-2) that control myeloma growth, angiogenesis and dissemination. Heparanase-1 (HPSE1) is an enzyme that cleaves heparan sulfate chains of proteoglycans and thus may regulate heparan-binding growth factor activity. We have previously demonstrated that human myeloma cells express heparanase and that active enzyme is present in the plasma harvested from the marrow of myeloma patients (Cancer Res. 63: 8749–56). In the present study, experiments were performed to determine the effects of enhanced expression of heparanase on myeloma tumor growth and dissemination in vivo. The human myeloma cell line, CAG, was transfected with human HPSE1 cDNA (CAGHPSE1) or with corresponding vector only (CAGNeo). The transfected cells were injected either directly into the tibia or subcutaneously into the flank of severe combined immune deficient (SCID) mice and tumor growth rate, microvessel density and metastasis to bone were analyzed. We discovered that expression of heparanase: (i) accelerates the initial growth of the primary tumor, (ii) increases whole body tumor burden as compared to controls, and (iii) enhances both the number and size of microvessels within the primary tumor. In addition, enhanced expression of heparanase dramatically upregulates spontaneous metastasis of subcutaneously-injected myeloma cells to bone (95% in mice bearing CAGHPSE1 tumors, n = 21; as compared to 6% in mice bearing CAGNeo tumors, n=16). When tumor was injected directly into the tibia, 100% of the mice bearing CAGHPSE1 tumor cells had metastases within the contralateral femur (n=10) while only 29% of the mice bearing CAGNeo tumor had metastases (n=7). These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo. Thus, therapeutic modulation of heparanase expression or function may be of value in the treatment of myeloma and other cancers that metastasize to bone.
NK4, an Antagonist of Hepatocyte Growth Factor (HGF), Inhibits Growth of Multiple Myeloma Cells In Vitro and In Vivo: A Mouse Model for Molecular Targeting of Angiogenic Growth Factor.
Authors: Hattori Yutaka , Du Wenlin , Yamada Taketo , Matsumoto Kunio , Nakamura Toshikazu , Otsuki Takemi , Niikura Takako , Nukiwa Toshihiro , Ikeda Yasuo 
Published: October 2019

Abstract
Background and rationale: Recent study showed that bone marrow angiogenesis and angiogenic growth factors including hepatocyte growth factor (HGF) are associated with pathogenesis and disease activity of multiple myeloma. In our experience, plasma concentration of HGF significantly elevated in 30 % of patients with clinically active myeloma and declined along with response to therapy. Thus, HGF signaling is considered to play a role in progression of myeloma and is a potential therapeutic target. The aim of this study is to establish a novel therapy targeting HGF and the receptor, c-MET, using NK4 molecule which is an HGF-antagonist consisting of N-terminal kringle domain of HGF.
Results: 1) Among eleven myeloma cell lines established from Japanese patients, two lines, KMS11 and 34, secreted HGF while c-MET is expressed in all eleven cells. 2) 10nM of NK4 protein significantly inhibited growth of the two HGF-producing cells in vitro. NK4 protein showed additive anti-myeloma effect to dexamethasone (Dex) in Dex-sensitive KMS11 cells, and is also effective for growth suppression of Dex-resistant KMS 34 cells. 3) NK4 significantly reduced phosphorylation of ERK1/2 while no significant effect on STAT3 activation. 4) Adenoviral vector carrying NK4 cDNA (Ad-NK4) was injected in femoral muscle of lcr/scid mice. Pharmacokinetic study showed that NK4 proteins were detected in plasma, liver, lung and kidney up to three weeks and attained a maximum level at day 10–14. 5) Ad-NK4 injection to tumor-bearing lcr-SCID mice significantly inhibited growth of subcutaneous tumor derived from KMS11 and 34 cells compared with empty vector injection (n=10, p<. 05). Co-injection of Ad-NK4 and Dex revealed synergistic or additive anti-tumor effect in mice bearing KMS11 tumor. Anti-myeloma effect of Ad-NK4 is also confirmed by histopathological examination.
Conclusion: Above results directly showed that HGF/c-MET signal plays an important role in progression of myeloma cells producing HGF. Molecular targeting of HGF by NK4 is considered as a novel approach for the treatment of myeloma via independent mechanism of glucocorticoid therapy.
Inhibition of Human Plasmacytoma Cell Growth by a Novel JAK Kinase Inhibitor.
Authors: Burger Renate , Legouill Steven , Tai Yu-Tzu , Shringarpure Reshma , Podar Klaus , Catley Laurence , Tassone Pierfrancesco , Neri Paola , Hideshima Teru , Chauhan Dharminder , Fridman Jordan S. , Anderson Kenneth C. 
Published: October 2019

Abstract
Novel strategies in cancer therapy aim at inhibiting distinct signal transduction pathways that are aberrantly activated in malignant cells. Protein tyrosine kinases of the JAK family are associated with a number of cytokine and cytokine-like hormone receptors and regulate important cellular functions such as proliferation, survival, and differentiation. Constitutive or enhanced JAK activation has been implicated in neoplastic transformation and abnormal cell proliferation in various hematological malignancies. In multiple myeloma (MM), JAK kinases play a critical role because of their association with cytokine receptors of the IL-6/gp130 family. A novel small-molecule inhibitor was developed that shows a 100 to 1,000-fold selectivity for JAK1, JAK2, JAK3, and TYK2 relative to other kinases including Abl, Aurora, c-Raf, FGFR3, GSK3b, IGF-1R, Lck, PDGFRa, PKBb, and Zap-70. Growth of MM cell lines and primary patient cells was inhibited by this compound in a dose-dependent manner. The IL-6 dependent cell line INA-6 and derived sublines were sensitive to the drug, with IC50’s of less than 1 mM, in [3H]-thymidine uptake and a colorimetric, tetrazolium compound (MTS) based assay (CellTiter 96® Aqueous One Solution Cell Proliferation Assay, Promega, Madison, WI). Importantly, INA-6 and patient tumor cell growth was also inhibited in the presence of bone marrow stromal cells, which by themselves remained largely unaffected. Growth suppression of INA-6 correlated with a significant and dose-dependent increase in the percentage of apoptotic cells, as evaluated by Apo2.7 staining after 48 hours of drug treatment. In addition, the compound blocked IL-6 induced phosphorylation of STAT3, a direct downstream target of JAK kinases and important transcription factor triggering anti-apoptotic pathways. In other myeloma cell lines, the drug overcame the protective effect of gp130 cytokines on dexamethasone induced apoptosis. In MM1.S cells, it completely blocked IL-6 induced phosphorylation of SHP-2 and AKT, both known to mediate the protective effects of IL-6. In contrast, AKT phosphorylation induced by IGF-1 remained unchanged, demonstrating selectivity of the compound. These studies show that disruption of JAK kinase activity and downstream signaling pathways inhibits myeloma cell growth and survival as well as circumvents drug resistance, thereby providing the conceptual basis for the use of JAK kinase inhibitors as a novel therapeutic approach in MM.
Low-Dose Irradiation Promotes Tissue Revascularization through Matrix Metalloproteinase-9 Mediated VEGF Release from Mast Cells.
Authors: Hattori Koichi , Ohki Yuichi , Sato Yayoi , Rafii Shahin , Werb Zena , Heissig Beate 
Published: October 2019

Abstract
Irradiation is one of the pillars in the treatment of malignancies. The combination of radiotherapy and anti-angiogenic strategies has been shown to increase the tumor response in various tumor models. The more than additive effect of irradiation and anti-angiogenic treatment suggested that irradiation might have a pro-angiogenic effect. However, the mechanism remained unclear.
Bone marrow(BM)-derived progenitor cells contribute to tissue regeneration by promoting angiogenesis/vasculogenesis. We demonstrated that chemokine/cytokine mediated progenitor mobilization is dependent on the activation of matrix metalloproteinase-9 (MMP-9). Here, we show that following irradiation hematopoietic and endothelial progenitors are released into circulation in MMP-9 wild-type, but not MMP-9 deficient (−/−) mice. We have observed that low-dose irradiation fosters vascular regeneration in a limb ischemia model. Vascular regeneration was driven by the upregulation of MMP-9 mediating the release of soluble Kit-ligand (KitL) and increasing plasma vascular endothelial growth factor (VEGF), followed by mobilization of BM-derived hematopoietic and endothelial progenitor cells. Release of sKitL and production of VEGF were impaired in MMP-9-/- mice resulting in failure of mobilization of hematopoietic and endothelial progenitors, and delayed vessel formation in the ischemic limb. The blood vessels forming in the ischemic tissue of MMP-9−/− mice lacked smooth muscle cell coverage, whereas stable vessels were formed in MMP-9 wild-type animals. But which cell type might be responsible for the observed VEGF increase following irradiation? Mast cells are known to harbor a variety of growth factors and angiogenic factors, including VEGF and have been shown to have pro-angiogenic effects. We analyzed various tissues of irradiated and non-irradiated controls. The number of mast cells was increased in the irradiated muscle tissue in MMP-9 wild-type, but not MMP-9−/− mice. VEGF was mainly produced by mast cells in a MMP-9 dependent manner as determined by in situ hybridization. Likewise, the number of mast cells was increased in the ischemic tissue of MMP-9 wild-type, but not in MMP-9 deficient mice. We could show that both VEGF and KitL can promote mast cell migration and that irradiation-induced soluble KitL in collaboration with VEGF promoted migration of mast cells in vitro.
Taken together, low-dose irradiation promoted hematopoietic and endothelial progenitor cell mobilization and activation of mast cells thereby promoting vasculogenesis/angiogenesis in a hind limb model. These data not only show a novel mechanism of neovascularization and tissue regeneration but suggest that low-dose irradiation can be used for therapeutic angiogenesis augmenting collateral vessel growth in ischemic tissues.
P-Selectin Activates Leukocyte Integrin alphaMbeta2 by Recruiting Phosphatidylinositol-3 Kinase to P-Selectin Glycoprotein Ligand-1 Cytoplasmic Domain through Adaptor Protein Naf1.
Authors: Geng Jian-Guo , Wang Hai-Bo , Chen Ming , Xu Tao , Zhang Lei , Zhu Xueliang , Plow Edward F. 
Published: October 2019

Abstract
The interaction of endothelial P-selectin (CD62P) with neutrophil PSGL-1 (P-selectin glycoprotein ligand-1, CD162) mediates neutrophil rolling, which acts in concert with cytokines and chemoattractants for integrin-mediated firm adhesion of neutrophils to vascular endothelial cells. Numerous studies have established that this sequence of events is critical to the extravasation of neutrophils during an inflammatory response. We have recently shown that cross-linking of PSGL-1 with P-selectin acts cooperatively with extracellular stimuli, such as cytokines and chemoattractants released from and displayed on the activated endothelial lining of the vessel walls, for optimal activation of beta2-integrins, an increase in their apparent affinity/avidity for cognate ligands, which in turn supports firm adhesion and transendothelial migration. To identify cellular proteins which interact with human PSGL-1 and trigger this cascade of events, we used the cytoplasmic domain of human PSGL-1 as the bait for screening of human leukocyte yeast two-hybrid library. During this genetic screening, we identified Naf-1 (Nef-associated factor 1; also called ABIN, A20 binding inhibitor of NF-kB, or VAN, virion-associated nuclear shuttle protein) as a binding partner to the cytoplasmic domain of PSGL-1. The specific interaction of Naf1 with PSGL-1 was confirmed by GST-fusion protein pull-down and co-immunoprecipitation experiments. As YPPM at 552–555 of Naf1a amino acid sequence is a known binding motif for p85 subunit of phosphatidylinositol-3 kinase (PI3K; YXXM in which phosphorylated Y is required for p85 binding), we performed co-immunoprecipitation experiments to show that Naf1a actually acted as an adaptor protein for PSGL-1 and p85 subunit of PI3K. In addition, we found that P-selectin activated the enzyme activity of PI3K in human neutrophils and PI3K specific inhibitors, wortmannin and LY294002, inhibited alphaMbeta2 activation and clustering induced by P-selectin. Our data thus delineate a novel PSGL-1 signal transduction pathway essential for transactivation of beta2-integrins.
Gender Counts: Defining the Core Genetic Profile of Polycythemia Vera.
Authors: Spivak Jerry L. , Jie Chunfa , Williams Donna M. , Moliterno Alison R. 
Published: October 2019

Abstract
Intra-abdominal venous thrombosis and exuberant extramedullary hematopoiesis leading to painful splenomegaly and hepatomegaly are two of the most serious consequences of polycythemia vera. Although polycythemia vera is slightly more common in men, both of these complications appear to be more common in women, in whom the disease also presents at an earlier age. We previously reported that polycythemia vera peripheral blood (pb) CD34+ cells could be distinguished from their immunophenotypically similar normal counterparts by gene expression profiling. We, therefore, hypothesized that phenotypic differences in disease behavior between men and women with polycythemia vera were a consequence of gender-based genotypic differences and have employed gene expression profiling to examine this issue. For this purpose, cRNA was prepared from the total RNA of pb CD34+ cells of eleven polycythemia vera patients and six normal controls purified by immunomagnetic bead chromatography. The cRNA was hybridized to an Affymetrix HU133 high-density oligonucleotide microarray chip representing 22,000 genes. Approximately 30–45 % of chip genes were recorded as present in the RNA samples. GC-RMA (Robust Multiarray Analysis) was used for normalization, to adjust for probe effects and for signal estimation. A parametric empirical Bayes statistical modeling method was used for differential gene expression analysis between the patients and controls. A posterior probability of >0.5 was taken to indicate significant differential gene expression. As previously reported, all polycythemia vera patients could be unequivocally distinguished from the controls, indicating that gene expression profiling can be employed as diagnostic test for polycythemia vera. With respect to gender, comparing male patients with male controls, 1106 genes were differentially expressed in the patient group; comparing female patients with female controls, 461 genes were differentially expressed in the patient group. Using unsupervised hierarchical clustering, the control patients segregated as a single group while the polycythemia vera patients segregated into two groups based on exuberant extramedullary hematopoiesis but this segregation was not gender-based despite the marked differences in gender-specific gene expression. Importantly, however, after eliminating gender-specific genes, only 93 genes were concordantly expressed in the male and female patients (59 up regulated and 34 down regulated). This small group appears to represent core genes in polycythemia vera whose behavior may be modified by gender-specific genes but the specific up regulation or repression of which is essential for disease expression. These data indicate that gender-specific effects on gene expression must be addressed in order to determine the basic genetic signature of a hematologic malignancy and they also define a core genetic profile in polycythemia vera.
Efficacy and Safety of Cladribine in Adult Systemic Mastocytosis : A French Multicenter Study of 33 Patients.
Authors: Lortholary Olivier , Vargaftig Jacques , Feger Frederic , Palmerini Fabienne , Delarue Richard , Ferriole Valerie , Launay Jean Marie , Bonte Isabelle , Barete Stephane , Bodemer Christine , Freytag Sylvie , Casassus Philippe , Arock Michel , Dubreuil Patrice , Hermine Olivier 
Published: October 2019

Abstract
Systemic mastocytosis (SM) is a myeloproliferative disabling disorder for which no consensual curative therapy is currently available. Recent preliminary experiences in small groups of patients using cladribine (2-CdA) were encouraging. We thus studied the efficacy and safety of 2-CdA in 33 patients enrolled in a compassionate program in France. Characteristics of patients were as follows: 19 male, 14 female, mean age 55y (17–76y), mean duration of disease 10 y (1m–71y). Treatment consisted in intravenous 2-CdA (1 to 6 cycles of 0.15 mg/kg/d administered in a 2-hour infusion or subcutaneously for 5 d, repeated at 4–12 weeks) for severe SM-related infiltration or symptoms. Patients were classified as having indolent SM (n=6), aggressive SM (n=22) or SM with an associated clonal hematologic non-MC-lineage (AHNMD) (n=4), mast cell leukemia (n=1). C-kit mutation analysis was performed in skin and/or bone marrow in 27 cases (D816V =24; WT=3). All failed previous symptomatic therapy and/or recombinant interferon-a (n=5). Evaluation was based according to consensus criteria (Valent et al. Leuk Research 2003). Major response, partial response and no response were observed in 24, 2, 7 patients, respectively. Mean time to best response was 4 months (1–12m), and mean duration of response was 16m (2–36). In responding patients skin lesions, hepatomegaly/ascitis, splenomegaly, bone involvement, peripheral blood cytopenia, major asthenia, flush, syncope/anaphylaxis, GI tract and pulmonary symptoms improved or disappeared. Treatment was overall well tolerated. Adverse events consisted mainly in peripheral blood cytopenia (n=10) with resolutive opportunistic infections in 2 patients. Although mast cell infiltration persisted in bone marrow, the patient with mast cell leukemia, responded to treatment with disappearance of circulating abnormal mast cells, and resolution of thrombocytopenia. Death was observed in 4 cases related to two disease progression and two acute myeloid leukemia.
Therefore, as a single agent, cladribine is an effective and safe treatment in symptomatic and agressive SM. In contrast with interferon, cladribine may induce regression of mast cell tumoral burden. However, cladribine is ineffective to improve AHNMD. Further work is warranted to define the optimal regimen with respect to dose and schedule, and the usefulness of maintenance cladribine therapy.
Specialized Bone Marrow Endothelium Defines Microdomains for Tumor and Stem Cell Engraftment.
Authors: Sipkins Dorothy A. , Wei Xunbin , Wu Juwell W. , Means Terry K. , Luster Andrew D. , Lin Charles P. , Scadden David T. 
Published: October 2019

Abstract
The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation and regeneration, yet relatively little is known about the architecture of microenvironments that support malignant proliferation. Using dynamic in vivo confocal and multi-photon imaging, we show that the bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant SDF-1 in discrete, discontinuous areas that localize the homing and early engraftment of both leukemic and normal primitive hematopoietic cells. Real-time imaging of cell-cell interactions in SCID mice bone marrow was performed after injection of fluorescently-labeled leukemic and other malignant cell lines. Progressive scanning and optical sectioning through the marrow revealed the existence of unique, spatially-restricted vascular domains to which the majority of marrow-homing tumor cells rolled and arrested. Serial imaging of mice on days 3 – 14 demonstrated that leukemic (Nalm-6 pre-B ALL) extravasation and early proliferation were restricted to these vascular beds. To define the molecular basis of these homing interactions, in vivo labeling of key vascular cell adhesion molecules and chemokines using fluorescent antibodies was performed. We observed that while ICAM-1, VCAM-1, PECAM-1 and P-selectin were expressed diffusely throughout the marrow vasculature, the expression of E-selectin and the chemokine receptor CXCR4 ligand SDF-1 was distinctly limited to vessels that supported leukemic cell engraftment. In vivo co-localization experiments confirmed Nalm-6 binding was restricted to vascular beds expressing both E-selectin and SDF-1. In functional studies, disruption of E-selection had a modest effect on leukemic homing (<20% diminution), while pharmacologic blockade of CXCR4 decreased Nalm-6 binding to vessels by approximately 80%. To explore the normal function of this vascular niche, we next examined whether benign primitive hematopoietic cells might preferentially home to these same vascular microdomains. Fluorescently-labeled stem and progenitor cells (HSPC) isolated from donor balb/c mice were injected into recipient mice and imaging was performed at multiple time points. HSPC were found to adhere to the BM microvasculature in the same restricted domains. At 70 days post-injection, HSPC had extravasated, were persistent in these perivascular areas and had undergone cell division as assessed by dye dilution. Our findings show that these microdomains serve as vascular portals around which leukemic and hematopoietic stem cells engraft, suggesting that this molecularly distinct vasculature provides both a cancer and normal stem cell niche. Specialized vascular structures therefore appear to delineate a stem cell microenvironment that is exploited by malignancy.