bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment
Authors: Patten Piers E. M. , Buggins Andrea G. S. , Richards Julie , Wotherspoon Andrew , Salisbury Jon , Mufti Ghulam J. , Hamblin Terry J. , Devereux Stephen 
Published: March 2008

AbstractChronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with a highly variable outcome. The prognosis of patients with CLL may be predicted using a number of biomarkers, including the level of CD38 expression at the leukemic cell surface. This study investigates the hypothesis that CD38 expression by CLL cells reflects interactions with nonmalignant cells within pseudofollicles in secondary lymphoid tissue where tumor cell proliferation is thought to occur. CD38 expression is higher in tissues that contain pseudofollicles compared with those that do not. In addition, we show that CD38 expression in CLL is dynamic, changes in response to contact with activated CD4+ T cells, and identifies cells that are primed to proliferate. Finally, we demonstrate close contact between activated CD4+ T cells and proliferating tumor in primary patient tissue. Proliferating tumor cells in lymph nodes express CD38, which is in turn associated with an increased number of CD31+ vascular endothelial cells. Although the factors resulting in colocalization of tumor, T cells, and endothelium remain unclear, the existence of these cellular clusters may provide an explanation for the association between CD38 expression and adverse outcome in CLL and suggests novel therapeutic targets.
α4β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells
Authors: Redondo-Muñoz Javier , Ugarte-Berzal Estefanía , García-Marco José A. , del Cerro Mercedes Hernández , Van den Steen Philippe E. , Opdenakker Ghislain , Terol María José , García-Pardo Angeles 
Published: March 2008

AbstractAs B-cell chronic lymphocytic leukemia (B-CLL) progresses, malignant cells extravasate and infiltrate lymphoid tissues. Several molecules, including gelatinase B/MMP-9, contribute to these processes. Although mainly a secreted protease, some MMP-9 is present at the B-CLL cell surface and the function, mode of anchoring, and interactions of this MMP-9 are unknown. Here we show that anti–MMP-9 antibodies immunoprecipitated a 190-kDa CD44v isoform and α4β1 integrin from B-CLL cells, but not from normal B cells. Function-blocking antibodies to α4β1 or CD44, or transfection with specific siRNAs, decreased cell-associated proMMP-9 and increased the secreted form. B-CLL cells attached to and bound proMMP-9 and active MMP-9, and this was inhibited by blocking the expression or function of α4β1 or CD44. The MMP-9 hemopexin domain was critical in these interactions. α4β1 and 190-kDa CD44v (but not CD44H) formed a complex at the cell surface, since they both coimmunoprecipitated with anti-α4, anti-β1, or anti-CD44 antibodies. Immunofluorescence analyses confirmed that α4β1 and CD44v colocalized with MMP-9. Binding of proMMP-9 inhibited B-CLL cell migration, and this required MMP-9 proteolytic activity. Thus, we have identified α4β1 and CD44v as a novel proMMP-9 cell surface docking complex and show that cell-associated MMP-9 may regulate B-CLL cell migration and arrest.
Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin
Authors: Xia Yin , Babitt Jodie L. , Sidis Yisrael , Chung Raymond T. , Lin Herbert Y. 
Published: March 2008

AbstractHemojuvelin (HJV) is a coreceptor for bone morphogenetic protein (BMP) signaling that regulates hepcidin expression and iron metabolism. However, the precise combinations of BMP ligands and receptors used by HJV remain unknown. HJV has also been demonstrated to bind to neogenin, but it is not known whether this interaction has a role in regulating hepcidin expression. In the present study, we show that BMP-2, BMP-4, and BMP-6 are endogenous ligands for HJV in hepatoma-derived cell lines, and that all 3 of these ligands are expressed in human liver. We demonstrate in vitro that HJV selectively uses the BMP type II receptors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-2 and BMP-4. Interestingly, ActRIIA is the predominant BMP type II receptor expressed in human liver. While HJV can use all 3 BMP type I receptors (ALK2, ALK3, and ALK6) in vitro, only ALK2 and ALK3 are detected in human liver. Finally, we show that HJV-induced BMP signaling and hepcidin expression are not altered by neogenin overexpression or by inhibition of endogenous neogenin expression. Thus, HJV-mediated BMP signaling and hepcidin regulation occur via a distinct subset of BMP ligands and BMP receptors, independently of neogenin.
The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate
Authors: Schüler Andrea , Schwieger Maike , Engelmann Afra , Weber Kristoffer , Horn Stefan , Müller Ursula , Arnold Michael A. , Olson Eric N. , Stocking Carol 
Published: March 2008

AbstractMef2c is a MADS (MCM1-agamous–deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2cΔ/− mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBPα, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity—and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.
Calcitonin receptor-like receptor guides arterial differentiation in zebrafish
Authors: Nicoli Stefania , Tobia Chiara , Gualandi Laura , De Sena Giulia , Presta Marco 
Published: March 2008

AbstractThe calcitonin receptor-like receptor (crlr) is a major endothelial cell receptor for adrenomedullin, a peptide vasodilator involved in cardiovascular development, homeostasis, and disease. Here, we used the zebrafish (Danio rerio) model to characterize the role of crlr in vascular development. Crlr is expressed within somites from the 4- to the 13-somite stage and by arterial progenitors and axial vessels during zebrafish development. Loss of crlr results in profound alterations in vascular development and angiogenesis, including atrophic trunk dorsal aorta and interruption of anterior aortic bifurcation, delay in intersomitic vessel development, and lack of blood circulation. Remarkably, crlr morphants are characterized by the loss of arterial endothelial cell identity in dorsal aorta, as shown by the lack of expression of the arterial markers ephrin-B2a, DeltaC, and notch5. Down-regulation of crlr affects vascular endothelial growth factor (vegf) expression, whereas vegf overexpression is sufficient to rescue arterial differentiation in crlr morphants. Finally, genetic and biochemical evidences indicate that somitic crlr expression is under the control of sonic hedgehog. These data demonstrate that crlr plays a nonredundant role in arterial differentiation, representing a novel element of the sonic hedgehog–vegf-notch signaling cascade that controls arterial/venous fate.
Dysregulation of TGF-β signaling and regulatory and effector T-cell function in virus-induced neuroinflammatory disease
Authors: Grant Christian , Oh Unsong , Yao Karen , Yamano Yoshihisa , Jacobson Steven 
Published: March 2008

Abstract
We previously demonstrated that CD4+CD25+ T regulatory cells (Tregs), important for the maintenance of immune tolerance and prevention of autoimmune disease, from patients with human T lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) exhibit reduced Foxp3 expression and Treg suppressor function compared with healthy donors. Since TGF-β signaling has been previously reported to be critical for both Foxp3 expression and Treg function, we examined whether this signaling pathway was dysregulated in patients with HAM/TSP. Levels of TGF-β receptor II (TGF-βRII) as well as Smad7 (a TGF-β–inducible gene) were significantly reduced in CD4+ T cells in patients with HAM/TSP compared with healthy donors, and the expression of TGF-βRII inversely correlated with the HTLV-I tax proviral load. Importantly, both CD4+CD25+ and CD4+CD25− T cells from HAM/TSP patients exhibited reduced TGF-βRII expression compared with healthy donors, which was associated with functional deficits in vitro, including a block in TGF-β–inducible Foxp3 expression that inversely correlated with the HTLV-I tax proviral load, loss of Treg suppressor function, and escape of effector T cells from Treg-mediated control. This evidence suggests that a virus-induced breakdown of immune tolerance affecting both regulatory and effector T cells contributes to the pathogenesis of HAM/TSP.
Development and dynamics of robust T-cell responses to CML under imatinib treatment
Authors: Chen Christiane I-U. , Maecker Holden T. , Lee Peter P. 
Published: March 2008

Abstract
Novel molecular targeted therapies, such as imatinib for chronic myelogenous leukemia (CML), represent the first agents that inhibit cancer cells more than other dividing cells, such as immune cells. We hypothesize that imatinib may create a window in which the immune response is partially restored while apoptotic leukemic cells are present, thus rendering leukemic cells immunogenic as patients enter remission. To detect and quantify antileukemia immune responses in an antigen-unbiased way, we used cryopreserved autologous pretreatment blood samples (representing predominantly leukemic cells) as stimulators to detect antileukemia T-cell responses in CML patients in remission on imatinib. We studied patients over time to address the dynamics of such responses. Our data show that antileukemia T-cell responses develop in the majority of CML patients (9 of 14) in remission and that CD4+ T cells producing tumor necrosis factor-α (median 17.6%) represent the major response over interferon-γ. This confirms the immune system's ability to respond to leukemia under certain conditions. Such responses may be further amplified as a potential therapy that synergizes with imatinib for improved control of CML.
Use of IGHV3–21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post–germinal center leukemogenic selection
Authors: Ghia Emanuela M. , Jain Sonia , Widhopf George F. , Rassenti Laura Z. , Keating Michael J. , Wierda William G. , Gribben John G. , Brown Jennifer R. , Rai Kanti R. , Byrd John C. , Kay Neil E. , Greaves Andrew W. , Kipps Thomas J. 
Published: March 2008

AbstractWe examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.
Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts
Authors: Walter Roland B. , Boyle Kelli M. , Appelbaum Frederick R. , Bernstein Irwin D. , Pagel John M. 
Published: March 2008

AbstractTargeting CD33 or CD45 is currently exploited for immunotherapy of acute myeloid leukemia (AML). Gemtuzumab ozogamicin (GO), an immunoconjugate of an anti-CD33 antibody that facilitates cellular uptake of a toxic calicheamicin-γ1 derivative, induces complete remissions in a subset of patients with AML. We herein tested whether simultaneous targeting of CD45 could improve GO cytotoxicity against AML cell lines and primary AML cells. We found that the anti-CD45 antibody, BC8, dose-dependently increased cytotoxicity induced by GO, and, to a lesser degree, free calicheamicin-γ1. BC8 promoted CD33 endocytosis, suggesting that its effect on GO cytotoxicity may be, at least partly, due to increased uptake and intracellular GO availability. Finally, compared with either agent alone, BC8 combined with GO resulted in marked tumor growth inhibition and superior survival rates of mice bearing human AML xenografts. These data suggest that further study of this antibody combination for clinical use in AML is warranted.
Different effects of femoral and tibial rotation on the different measurements of patella tilting: An axial computed tomography study
Authors: Lin Yeong-Fwu , Jan Mei-Hwa , Lin Da-Hon , Cheng Cheng-Kung 
Published: March 2008

Abstract

Background
The various measurements of patellar tilting failed to isolate patellar tilting from the confounding effect of its neighboring bone rotation (femoral and tibial rotation) in people sustaining patellofemoral pain (PFPS). Abnormal motions of the tibia and the femur are believed to have an effect on patellofemoral mechanics and therefore PFPS. The current work is to explore the various effects of neighboring bone rotation on the various measurements of patellar tilting, through an axial computed tomography study, to help selecting a better parameter for patella tilting and implement a rationale for the necessary intervention at controlling the limb alignment in the therapeutic regime of PFPS.

Methods
Forty seven patients (90 knees), comprising of 34 females and 11 males, participated in this study. Forty five knees, from randomly selected sides of bilaterally painful knees and the painful knees of unilaterally painful knees, were enrolled into the study. From the axial CT images in the subject knees in extension with quadriceps relaxed, the measurements of femoral rotation, tibial rotation, femoral rotation relative to tibia, and 3 parameters for patella tilting were obtained and analyzed to explore the relationship between the different measurements of patella tilt angle and the measurements of its neighboring bone rotation (femoral, tibial rotation, and femoral rotation relative to tibia).

Results
The effect of femoral, tibial rotation, and femoral rotation relative to tibia on patella tilting varied with the difference in the way of measuring the patella tilt angle. Patella tilt angle of Grelsamer increased with increase in femoral rotation, and tibial rotation. Patella tilt angle of Sasaki was stationary with change in femoral rotation, tibial rotation, or femoral rotation relative to tibia. While, modified patella tilt angle of Fulkerson decreased with increase in femoral rotation, tibial rotation, or femoral rotation relative to tibia.

Conclusion
The current study has demonstrated various effects of regional bony alignment on the different measurements of the patellar tilt. And the influence of bony malalignment on the patellar tilt might draw a clinical implication that patellar malalignment can not be treated, separately, independent of the related limb alignment. This clinical implication has to be verified by further works, with a comprehensive evaluation of the various treatments of patellar malalignment.
Effects of two different anaesthetics on serum concentrations of cortisol and luteinizing hormone in barrows and gilts
Authors: Clapper Jeffrey A 
Published: March 2008

Summary To determine if administration of the anaesthetic cocktail, telazol–ketamine–xylazine (TKX) and pentothal (PEN) decreases serum concentrations of luteinizing hormone (LH) in pigs, the following experiment was performed. On day 1, eight gilts and six barrows of similar weight (75 kg) were anaesthetized with TKX (1 mL/22.5 kg body weight [BW] intramuscularly) and indwelling jugular catheters were inserted. On days 2, 6 and 8 blood samples were taken every 20 min, for 4 h before pigs were administered saline (day 2) or anaesthetized with TKX (day 6) and PEN (8.9 mg/kg BW intravenously, day 8). Blood samples were taken every 20 min for 4 h following administration of saline and anaesthetics. Mean serum concentrations of LH and cortisol did not differ ( P > 0.05) within barrows or gilts from before administration of saline (day 2) to following saline administration. Mean serum concentrations of LH and cortisol were not different ( P > 0.05) within barrows and gilts before administration of TKX (pre-TKX) or PEN compared with day 2 samples. Following administration of TKX (post-TKX), mean serum concentrations of LH decreased ( P < 0.05) and remained decreased for 140 min, while mean serum concentrations of cortisol increased ( P < 0.05) post-TKX and remained elevated for 140 min. In gilts, mean serum concentrations of LH did not differ ( P > 0.05) from pre- to post-TKX. However, mean serum concentrations of cortisol increased ( P < 0.05) post-TKX in gilts and remained elevated for 240 min. Following administration of PEN, mean serum concentrations of LH and cortisol within barrows and gilts were not different ( P > 0.05) from concentrations before administration of PEN. Administration of TKX to barrows and gilts increased serum concentrations of Cortisol, but transient decreases in serum concentrations of LH were observed only in barrows, indicating gonadal status and/or sex may influence the ability of TKX to alter circulating concentrations of LH in pigs.
Prevalence of herpes B virus genome in the trigeminal ganglia of seropositive cynomolgus macaques
Authors: Oya C , Ochiai Y , Taniuchi Y , Takano T , Fujima A , Ueda F , Hondo R , Yoshikawa Y 
Published: March 2008

Summary Herpes B virus infection is almost asymptomatic in macaques ( Macaca spp.), which are the natural hosts of this pathogen, but is the cause of high mortality in humans. Reactivation of the latent virus in the trigeminal ganglia (TG) results in the shedding of infectious particles into the oral mucosal membrane. Saliva contaminated with the reactivated virus from the ganglia of the natural host is considered to be important for viral transmission to humans and other monkeys. In the present study, we investigated the prevalence of the herpes B virus genome in the left and right TG of seropositive asymptomatic cynomolgus macaques. The latent virus genome was detected using a polymerase chain reaction and microplate hybridization assay. We found that the virus DNA was present in one or both TG of 12 of the 30 macaques (40%) tested, with the virus being detected from both TG in five of the 12 macaques and from a single TG in the remaining seven.
Changes in minimal alveolar concentration of isoflurane following treatment with medetomidine and tiletamine/zolazepam, epidural morphine or systemic buprenorphine in pigs
Authors: Malavasi L M , Jensen-Waern M , Augustsson H , Nyman G 
Published: March 2008

Summary The aim of this study was to determine the changes in minimal alveolar concentration (MAC) of isoflurane after treatment with medetomidine and tiletamine/zolazepam (MTZ), epidural morphine or systemic buprenorphine in 11 healthy crossbred pigs. The first part of this study was to measure the baseline values in pigs induced with isoflurane (5%) by face mask and maintained with isoflurane in air and oxygen for 2 h (ISO). Baseline isoflurane MAC was determined using mechanical stimulation. Thereafter, each pig was randomly chosen for a crossover test in which the same animal received three different treatments with at least one week in between treatments. The three treatments were as follows: induction of anaesthesia with medetomidine (0.05 mg kg–1) and tiletamine/zolazepam (2.5 mg kg–1 each) given intramuscularly (MTZ); MTZ followed by epidural morphine (0.1 mg kg–1; MTZ/M); and MTZ followed by intramuscular buprenorphine (0.1 mg kg–1; MTZ/B). All pigs were maintained with isoflurane in oxygen and air for 2 h and their lungs were mechanically ventilated. The end-tidal isoflurane concentration, respiratory rate, inspiratory and expiratory O2 and CO2 concentrations, heart rate (HR) and arterial blood pressure were recorded every 10 min. Arterial blood gases were analysed every 20 min. Among the treatment groups, differences in isoflurane MAC were tested using GLM and Tukey's method for further comparison; P < 0.05 was adopted as significant. Isoflurane MAC was 1.9 ± 0.3%. MTZ reduced isoflurane MAC to 0.6 ± 0.1%. Additional morphine or buprenorphine reduced the MTZ isoflurane MAC further to 0.4 ± 0.2 and 0.3 ± 0.1%, respectively. During MTZ, MTZ/M and MTZ/B mean arterial blood pressure was higher and the alveolar-arterial oxygen tension difference was lower compared with ISO. In conclusion, induction of anaesthesia with MTZ reduced the isoflurane MAC in pigs by 68%. Additional epidural morphine or systemic buprenorphine decreased MTZ isoflurane MAC by 33 and 50%, respectively.
Aggression in cataract-bearing α-1,3-galactosyltransferase knockout mice
Authors: SØRensen Dorte Bratbo , Dahl Kirsten , Ersbøll Annette Kjær , Kirkeby Svend , D'apice Anthony J F , Hansen Axel Kornerup 
Published: March 2008

Summary The Galα1-3Galβ1-4GlcNAc epitope is the key antigen in the hyperacute rejection of pig-toman xenotransplantation. In the α-1,3-galactosyltransferase knockout (α-1,3GT-KO) mouse – a model for xenograft donor pigs – a targeted mutation of the α-1,3 galactosyltransferase gene (Ggta1) has been constructed. These mice are depleted of the carbohydrate antigen and besides the mice are also known to develop cortical cataracts. The present study aimed at evaluating the morphology and the degree of the cataract in a population of α-GT KO mice, its age of onset, its progression and the impact the cataract may have on aggression, anxiety and perception of light. The α-gal epitope could be shown in the lenses with lectin GS1 B4 in all wild-type and none of the α-GT KO mice. Histology showed apparent cataract in all α-GT KO mice from six weeks of age. Apart from a single wild-type mouse with a small degree of microscopically visible cataract without epithelial involvement at the age of 30 weeks none of the wild-type mice showed signs of cataract. Behavioural testing demonstrated significantly more mounting behaviour and a longer duration of attacking in the α-GT KO mice. Apart from this, the agonistic behaviour was not influenced by genotype. Neither did the genotype affect anxiety or perception of light.