bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Integrin Expression and Activation by VEGF in Human Brain Microvascular Endothelial Cells: Implication of α6 Integrin in Angiogenesis.
Authors: Lee Tae-Hee , Avraham Hava Karsenty , Li Huchun , Kennel Stephen J. , Avraham Shalom 
Published: October 2019

Abstract
The precise role of vascular endothelial growth factor (VEGF) in the regulation of integrins is not well elucidated due to their high redundancy. Here, we examined the effects of VEGF on the expression and activation of integrins in human brain microvascular endothelial cells (HBMECs). Using human cDNA arrays and Ribonuclease (RNase) protection assays which cover most of the known integrins, we observed that VEGF significantly upregulated the mRNA expression of α1, α2, and α6 integrins in HBMECs. While VEGF was reported to induce α1 and α2 integrins, the observation of α6 integrin induction by VEGF is novel. Using small interfering RNA (siRNA) oligonucleotides for α6 integrin, we observed downregulation of the cell surface expression of α6 integrin in HBMECs. This downregulation resulted in inhibition of both HBMEC capillary morphogenesis and of the VEGF-induced adhesion and migration of the cells. VEGF also induced the activation of α6 integrin in the HBMECs. Functional blocking of α6 integrin by its specific antibody led to inhibition of VEGF-induced adhesion and migration as well as of in vivo angiogenesis, and significantly suppressed tumor angiogenesis and breast carcinoma cell growth in vivo. These results indicate that VEGF can modulate the in vitro angiogenesis of HBMECs via increased expression and activation of the α6 integrin, and that this integrin participates in VEGF-driven angiogenesis in vivo.
Vascular Endothelial Cadherin-Expressing Cells Involved in Both Developmental and Adult Neovascularization.
Authors: Kogata Naoko , Arai Yuji , Hashimoto Kazuaki , Ogawa Minetaro , Mochizuki Naoki 
Published: October 2019

Abstract
Vessel formation, including vasculogenesis and angiogenesis, is thought to be directly mediated by adhesive molecules between vascular endothelial cells and adjacent cells. Vascular endothelial cadherin (VE-cadherin, CD144) is a adhesive molecule exclusively expressed in adherens junctions of cultured endothelial cells. VE-cadherin transcripts have been detected at first in mesodermal cells. However, no work has focused on which cell type expresses VE-cadherin during vessel formation and after vessel stabilization. To monitor VE-cadherin in vivo, we generated transgenic mice expressing a VE-cadherin promoter-driven Cre (VE-cad-Cre). By crossing VE-cad-Cre with loxP-based EGFP reporter mice (CAG-CAT-EGFP) and LacZ reporter mice (cAct-XstopX-LacZ), we obtained two double transgenic mice; one expressing EGFP (VE/EG) another expressing LacZ (VE/Z) dependently upon Cre driven by VE-cadherin promoter. Both reporter expression was increased in developing vasculature during embryogenesis, while it was decreased in postnatal vessel maturation. Intriguingly, LacZ reporter was found in the budding cells and lining cells of the dorsal aorta in the aorta-gonad-mesonephros region, suggesting that VE-cadherin-expressing cells belongs to hemangioblasts. Consistently, although VE-cadherin and its mRNA was detected in vasculature by immunohistochemistry and in situ hybridization, respectively, during embryogenesis, it was not detected in maturated vessels. These results indicated that VE-cadherin promoter activity reflects the endogeneous VE-cadherin expression and that VE-cadherin promoter is activated during developmental vasculogenesis and angiogenesis. To test whether the VE-cadherin promoter is re-activated in postnatal neovascularization, we used two models; a VEGF-induced cornea angiogenesis model and a myocardial ischemia model. VEGF implanted in the VE/EG eyes promoted the neovascularization visualized by EGFP expression. Myocardial ischemia in which the coronary artery was banded triggered the VE-cadherin promoter, thereby inducing reporter expression in vascular cells (endothelial cells and mural cells) of undamaged region and in infiltrated cells of damaged region. Furthermore, by flow cytometric analyses, we confirmed that myocardial ischemia re-activated the VE-cadherin promoter of both bone marrow cells and peripheral blood cells, as indicated by the remarkable increase of EGFP-positive cells. These data show that the VE-cadherin promoter is re-activated in pre-existing vascular cells and infiltrated cells during adult neovascularization. Collectively, VE-cadherin-expressing cells participates in both developmental and postnatal vasulogenesis and angiogenesis.
Interferon Alpha-2B (IFN-a) Is an Effective Agent for the Treatment of Primary Cutaneous T- and B-Cell Lymphoma.
Authors: Siakantaris Marina P. , Kyrtsonis Marie-Christine , Tzenou Tatiana , Dimitriadou Evangelia M. , Dimopoulou Maria N. , Angelopoulou Maria K. , Kokoris Styliani I. , Vassilakopoulos Theodoros P. , Korkolopoulou Penelope , Giannakakis Antonia , Plata Eleni , Patsouris Eustratios , Katsambas Andreas , Pangalis Gerassimos A. 
Published: October 2019

Abstract
Primary cutaneous lymphoma comprise a wide range of rare diseases of which the commonest T- cell subtypes include mycosis fungoides (MF), Sezary syndrome (SS) and peripheral T-cell lymphoma (PTCL) while follicle center cell lymphoma (FCL), diffuse large B-cell lymphoma (DLBL) and extranodal marginal zone B-cell lymphoma (MZL) represent the B-cell subtypes. The behavior of these diseases is different from nodal NHL and it has been shown that IFN-a can produce long-lasting remissions in early stages MF. On the contrary, there are no reports on the efficacy of IFN- a for primary cutaneous B-cell lymphomas (CBCL). The purpose of this study was to present our experience on IFN -a treatment for patients with both primary T-cell and B-cell cutaneous NHL. Forty-one patients, 25 with primary cutaneous T-cell NHL (CTCL) (16 MF, 4 SS, 5 PTCL) and 16 with CBCL (4 MZL, 3 FCL, 8 DLBL, 1 lymphoblastic NHL) were included in this study. Of the 25 CTCL patients, 20 were males (median age 48y); 16 received IFN-a as first line treatment, 5 after PUVA and 4 after failure of other treatment modalities. Of the 16 CBCL patients, 8 were males (median age 57y); 14 received IFN-a frontline and 2 after treatment failure. Three to 5 MU IFN-a were administered subcutaneously daily with paracetamol prophylactically 1 hour before injection and two hours after. 17 out of 24 CTCL patients responded (overall response rate 71%, 42% CR and 29% PR) (12/16 MF, 1/4 SS and 3/5 PTCL). Median time to response was 4 months (1–17). Median duration of response was 15 months (8–38). 11 patients relapsed, 1 responder rapidly discontinued treatment because of side effects (cataract), the others are still under treatment with IFN-a. Among patients with CBCL 12/14 responded (overall response rate 86%, 64% CR and 22% PR). Median time to response was 2 months (1–4) and median response duration 23 months (13–30); 4 patients relapsed, 1 discontinued treatment because of side effects (depression), another continued with Peg- IFN because of chronic fatigue and the others are still under IFN-a treatment. With respect to histologic subtype, all 4 MZL patients responded; 2/3 FCL and 4/8 DLBL also responded. Flu-like syndrome was observed in the majority of patients at treatment initiation and 60% of patients presented mild leukopenia. In conclusion IFN-a is an effective treatment in primary cutaneous NHL and is usually well tolerated. As already reported response rate is satisfactory in MF. The high response rate observed in CBCL, especially in low-grade subtypes, but also in half of DLBL patients has not been reported previously.
Intravenous Forodesine (BCX-1777), a Novel Purine Nucleoside Phosphorylase (PNP) Inhibitor, Demonstrates Clinical Activity in Phase I/II Studies in Patients with B-Cell Acute Lymphoblastic Leukemia.
Authors: Furman Richard R. , Gandhi Varsha V. , Bennett J. Claude , Bantia Shanta , Kilpatrick J. Michael 
Published: October 2019

Abstract
Forodesine is a potent, specific transition-state analog inhibitor of PNP with clinical activity in T-cell malignancies. Pharmacodynamic studies support that this anti-leukemic effect is mediated through the accumulation of plasma 2′-deoxyguanosine (dGuo) and intracellular Dgtp. In vitro studies indicated that B-cell acute lymphoblastic leukemia (B-ALL) cells can also accumulate Dgtp. These preclinical data led to a phase I/II multicenter dose-escalation study to evaluate forodesine in pts with various hematologic malignancies. 15 pts were treated with forodesine, including 6 with B-ALL. Forodesine was given via a 30-min IV infusion followed 24 hrs later by doses every 12 hrs for a total of 9 doses. A second course could be repeated after a 2-week break. Doses were escalated by 50% to pts grouped in cohorts of 3 (starting dose: 40 mg/m2). There was a rapid rise in plasma dGuo and a maximum PNP inhibition was achieved at 40 mg/m2 (Fig 1). 7/15 treated pts (2 T-cell malignancies and 5 B-ALL), including 5/6 treated B-ALL pts, demonstrated a hematologic benefit, defined as a decrease in tumor burden. 3 of the responding B-ALL pts were further treated with 6 courses of forodesine on a compassionate use protocol. One pt treated at 135 mg/m2 demonstrated a complete response with a decrease in bone marrow blast cells from 22% to 5% at the end of therapy. The other 2 pts, treated with 90 mg/m2 and 135 mg/m2 forodesine respectively, showed dramatic improvement in their CBC despite the persistence of bone marrow blasts. The dramatic fall in WBC count was accompanied in each pt by a rise in plasma dGuo (Cmax: 1.9–7.1 μM) and intracellular Dgtp (380–800 pmoles/107 cells vs 25–40 pmoles/107 cells pre-treatment), The response of the pt treated with 90 mg/m2 forodesine is shown in Fig 2. The absolute neutrophil count (ANC) improved from ~0 at pre-treatment to 1800 cells/mm3 at Day 18.

To-date forodesine has been safe and well-tolerated at all dose levels tested with no dose-limiting toxicities. Clinical activity has been seen in T- and B-ALL. It is interesting to note the restoration of normal hematopoiesis, indicating the specificity of forodesine for leukemic cell populations and supporting that forodesine represents an important breakthrough in the development of less toxic ALL therapy. This encouraging clinical activity has led to the initiation of a phase II trial in pts with B-ALL. Additional clinical and pharmacodynamic results will be presented.
Long-Term Follow-Up of 5,930 Unrelated Volunteers Donating Bone Marrow or Peripheral Blood Stem Cells.
Authors: Ehninger Gerhard , Rall Gabi , Kroschinsky Frank , Schuler Ulrich S. , Schmidt Alexander , Hoelig Kristina , Bornhaeuser Martin , Rutt Claudia 
Published: October 2019

Abstract
More than 1,1 million donors are registered in the DKMS Deutsche Knochenmarkspenderdatei donor center. Since the start of the program, 5,930 have donated bone marrow or peripheral blood stem cells. These donors were included in a follow up program with questionnaires and blood cell counts 1, 6, and 12 months, and thereafter annually. Non responding donors were interviewed via a telephone call which enables us to have a follow-up of all donors. The age range at harvest was 18 to 60 years (median 32.4 years). The cumulative observation years were 13,350 years for 2,644 bone marrow donors and 7,980 years for 3,286 peripheral blood stem cell donors. No severe immediate complications occurred during the harvests. Seven out of 2,644 bone marrow donors (0.3%) suffered from long lasting severe local pain. Three of them were hospitalized within 6 weeks after donation with hematoma, local infection or severe local pain. One donor of the peripheral blood stem cell group suffered from severe hyperthyroidism 14 days after donation. In this donor, euthyroidism was documented at the day of leukapheresis. Antibodies to thyroid peroxidase were already detectable in retrospectively analyzed cryopreserved samples from these time points. TSH receptor stimulating immunoglobulin appeared only after harvest accompanied by symptoms of hyperthyroidism. Rheumatoid arthritis was diagnosed in 2 peripheral blood stem cell donors (interval from harvest: 0 days and 1 year) and joint complaints were addressed by additional 4 donors. Vascular events were seen in 4 peripheral blood stem cell donors (cerebral ischemia in 3 donors 3 months, 1 year and 2.5 years after donation; myocardial infarction in a 58 years old male donor 2 years after donation) and in one bone marrow donor (Brown-Séquard-syndrome 4 years after harvest). Four donors of the bone marrow group and 5 donors of the peripheral blood stem cell group developed malignancies during the follow-up observation. Four donors of the bone marrow group died 1 year to 8 years after donation (sudden death, car accident, suicide, and unknown). In unrelated donors, bone marrow harvests and peripheral blood stem cell donations are safe procedures in specialized collection centers. Even in a large donor center as DKMS, the numbers of adverse events in the follow up period are small. The documentation of diseases early after harvest (autoimmune diseases, thromboembolic events etc.) needs a careful follow-up. A case-controlled study with sex-, age- and HLA-matched volunteers within the donor pool will therefore be initiated by DKMS.
Is a Younger 10-Allele-Matched Unrelated Donor (MUD) Better Than an Older 6-Antigen-Matched Sibling Donor (MSD) for Allogeneic HSCT?.
Authors: Mehta Jayesh , Gordon L. , Tallman M. , Winter J. , Williams S. , Evens A. , Grinblatt D. , Kaminer L. , Singhal S. 
Published: October 2019

Abstract
56 adults with hematologic malignancies underwent blood cell allografts from A/B-DR-identical MSDs or A/B/C/DRB1/DQB1-allele-identical MUDs after 100 mg/m2 melphalan with (n=39; no prior autograft) or without (n=17; prior autograft) 50 mg/kg cyclophosphamide. GVHD prophylaxis comprised mycophenolate with cyclosporine (MSD) or tacrolimus (MUD). No growth factors were used. Supportive care was uniform. There were significant differences between groups (Table 1); most strikingly with respect to donor age.
MSD (n=37) MUD (n=19) P Pt age 53 (38–66) 47 (27–62) 0.085 Pt age >55 32% 32% 0.95 Donor age 51 (31–69) 33 (24–50) <0.0001 Donor age >45 76% 16% <0.0001 Refractory disease 49% 68% 0.16 PS 2–3 22% 32% 0.42 LDH 172 (83–1298) 237 (105–1919) 0.082 Abnormal LDH 43% 63% 0.16 CD34+ cell dose 5.0 (3.0–7.6) 6.0 (1.4–11.8) 0.12 CD34+ cell dose >6 11% 47% 0.002
10 patients experienced transplant-related mortality (TRM), and 29 relapsed (23 dead). The following factors were analyzed in a Cox model for effect on outcome: chemosensitive (n=25) vs refractory disease (n=31), patient age ≤55 (n=38) vs >55 (n=18), performance status (PS) 0–1 (n=42) vs 2–3 (n=14), normal (n=28) vs abnormal (n=28) LDH, prior autograft or not, CD34+ cell dose ≤6 (n=43) vs 6 (n=13) x 106/kg, MSD vs MUD, male (n=38) vs female (n=18) donor, and donor age ≤45 (n=25) vs >45 (n=31). Donor age was also analyzed as a continuous variable. Patient age >55 and PS 2–3 resulted in higher TRM. Refractory disease and abnormal LDH resulted in higher relapse, and lower disease-free (DFS) and overall (OS) survival. PS 2–3 resulted in lower DFS and OS. Patient age >55 and MSD resulted in lower OS. OS was reanalyzed after excluding donor type as a variable (*) because of its correlation with donor age. Table 2 shows the favorable effect of donor age ≤45 on relapse, DFS and OS.
Outcome RR (95% CI) P Relapse 0.28 (0.12–0.64) 0.003 DFS 0.27 (0.13–0.57) 0.001 OS* 0.42 (0.19–0.94) 0.035
When analyzed as a continuous variable, lower age resulted in lower relapse and higher OS with donor type in the model, and with higher DFS when donor type was excluded. Figures 1 and 2 show the effect of donor age on relapse and DFS in plots generated from the Cox model at the means of the covariates.
Figure Figure
These data appear to suggest that a young MUD may be preferable to an older MSD. However, small numbers preclude obtaining an answer to the question of the age at which a sibling donor should be considered too old. Additionally, logistic issues involved in obtaining a MUD may reduce any benefit from having a young donor. We conclude that a younger donor should be chosen whenever possible. Further work is required to address the intrguing possibility of superiority of MUD over MSD based on age.
Clinical and Biological Relevance of NF-κB Activation in B-CLL.
Authors: Rodriguez Antonia , Martinez Nerea , Camacho Francisca I. , Ruiz-Ballesteros Elena , Algara Patrocinio , Artiga Maria J. , Garcia Juan-Fernando , Piris Miguel A. 
Published: October 2019

Abstract
Based on previous observations, we postulate that the molecular and clinical variability of Chronic Lymphocytic Leukemia (CLL) could reflect differences in the degree of NF-κB activation. To test this hypothesis, the expression profile (mRNA and protein expression) of a series of 41 B-CLL cases with lymph node involvement was analyzed at the same time, with a cDNA microarray (OncoChip, 7K clones) and an oligo microarray (Human 1A Agilent, 22K sequences). Results were correlated with the IgVH mutational status, ZAP-70 expression, clinical outcome and NF-κB activation status, as determined by EMSA and phosphorylated IκBα (p-IκBα) detection by Western Blotting. The study showed a correlation between the presence of a surrogate marker of NF-κB activation, p-IκBα, and changes in the degree of NF-κB activation, as determined by EMSA. NF-κB activation was associated with the expression of 2200 and 894 genes using the oligo and cDNA microarray platforms respectively. These sets of genes comprise key genes involved in the control of B-cell receptor signaling, signal transduction and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, BAFF. Cases with higher levels of NF-κB activation showed longer overall survival than cases with lower activation. A Cox regression model was derived to analyze variables of potential prognostic interest in this series: IgVH mutational status, ZAP-70 and p-IκBα expression. The multivariate analysis disclosed p-IκBα and ZAP-70 expression as independent prognostic factors related with overall survival. In conclusion, a variable degree of activation of NF-κB, as determined by the expression of p-IκBα and EMSA, is a relevant event in CLL, associated with changes in the survival probability, and correlated with the expression of a large set of genes identified by two different microarray platforms.
Treatment with AMD3100 in Multiple Myeloma or Non-Hodgkin’s Lymphoma Patients to Increase the Number of Peripheral Blood Stem Cells When Given with a Mobilizing Regimen of Chemotherapy and G-CSF.
Authors: Dugan Michael J. , Akard Luke P. , Thompson James M. , Nademanee Auayporn , Maziarz Richard T. , Bensinger William I. , Liesveld Jane , Badel Karin , Dehner Christine , Gibney Colleen , Calandra Gary , Jansen Jan 
Published: October 2019

Abstract
AMD3100 is a reversible inhibitor of the binding of SDF-1α to its cognate receptor CXCR4. Patients with MM and NHL given AMD3100 alone have increased circulating C D34+ cells. The purpose of the present study is to determine if AMD3100 added to a chemotherapy and G-CSF mobilization regimen can increase the circulating levels of PBSC, and the removal of such cells by leukapheresis. The only change to the standard care is the addition of AMD3100 to a cyclophosphamide (2.5 g/m2) mobilization for MM and either (R)ESHAP or (R)ICE in the case of NHL. In both arms G-CSF is given at 10 mcg/kg/d. AMD3100 is given after the first apheresis collection. To date, 10 patients (8 MM, 2 NHL) have completed the mobilization phase of the protocol. During recovery the mean number of PB CD34+ cells/μL was 191. This rose to 304 [2.0 fold increase, p=0.008] following the administration of AMD3100. The baseline collection resulted in a mean of 16.7 x 106 CD34+ cells/kg. This rose to 24.0 [1.8 fold increase, p=0.007] following the administration of AMD3100. Historic controls with MM receiving cyclophosphamide (4 g/m2), etoposide (400 mg/m2) and G-CSF had an inferior collection on day 2 [37.9 x 106 CD34+ cells/kg day 1 vs. 29.5 day 2, p=0.009]. Untoward events related to the combination of chemotherapy, G-CSF, and AMD3100 have not been noted. The 9 patients transplanted following this mobilization strategy have achieved an ANC > 500 at a median of 10 days, and platelet independence (>20k) at a median of 11 days. Validation of this strategy continues in additional patient cohorts to assess alternative AMD3100 administration schedules and to define CD34+ cell recruitment/release during recovery from mobilizing chemotherapy.
Activation of Classical and Alternative Nuclear Factor-kappaB (NF-kB) Pathways in Diffuse Large B-Cell Lymphomas.
Authors: Timar Botond , Chadburn Amy , Knowles Daniel , Cesarman Ethel 
Published: October 2019

Abstract
Activation of the NF-kB pathway is involved in many human neoplasms. In this study we examined the status of the NF-kB canonical (IkB, p50/p65) and non-canonical (p52, RelB) pathways in diffuse large B-cell lymphomas (DLBCL), which are a common and heterogeneous group of lymphoid malignancies. DLBCL have been divided into activated B-cell (ABC) like, and germinal center B-cell (GCB) like subgroups, which have been reported to have high and low NF-kB activity, respectively. However, the nature of the NF-kB complexes in this lymphoma entity has not been previously evaluated. Therefore we performed Western blotting, electrophoretic mobility shift assays (EMSA) and real time quantitative RT-PCRs on nuclear and cytoplasmic protein and total RNA extracts in 20 primary tumor samples and 9 different DLBCL cell lines. In the cell lines, presence of NF-kB proteins in nuclear extracts correlated with expression of NF-kB target genes (CCR7, IkBa, CCND2, BCL-2, IRF4) as determined by RT-PCR. Therefore, these could be assigned into GCB and ABC-like categories. In primary DLBCLs, EMSA showed NF-kB binding in all but one case. The same cases (19/20) had high p52 in the nucleus indicating activation of the alternative pathway. TNF family ligand BAFF was also found to be expressed in all primary samples and most cell lines. The classical pathway, as determined by nuclear p50, was also present in these cases. Levels of p65 and RelB expression were variable, but did not correlate with the mRNA expression of NF-kB target genes. In conclusion, while DLBCL cell lines may be divided into two distinct categories, the primary samples represented a spectrum of NF-kB target gene activity, while levels of NF-kB expression were high. BAFF expression and activation of the alternative pathway may be important in the pathogenesis of DLBCL.