bluuebunny/crossref_metadata_2025_split huggingface dataset:
z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response
Authors: Monticone Massimiliano , Biollo Emanuela , Fabiano Andrea , Fabbi Marina , Daga Antonio , Romeo Francesco , Maffei Massimo , Melotti Alice , Giaretti Walter , Corte Giorgio , Castagnola Patrizio 
Published: October 2009

Abstractγ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor–initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G2-M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models. (Mol Cancer Res 2009;7(11):1822–34)
Deguelin Inhibits Growth of Breast Cancer Cells by Modulating the Expression of Key Members of the Wnt Signaling Pathway
Authors: Murillo Genoveva , Peng Xinjian , Torres Karen E.O. , Mehta Rajendra G. 
Published: October 2009

Abstract
An emphasis in early detection and more effective treatments has decreased the mortality rate of breast cancer. Despite this decrease, breast cancer continues to be the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Hence, the aim of the present study was to assess the therapeutic efficacy of deguelin, a rotenoid isolated from several plant species, which has been reported to have chemopreventive and/or chemotherapeutic effects in skin, mammary, colon, and lung cancers. The effect of deguelin on cell proliferation was evaluated using four human breast carcinoma cell lines (MCF-7, BT474, T47D, and MDA-MB-231) by cell count and MTT. Moreover, apoptosis was evaluated by acridine/ethidium staining and DNA laddering. Gene expression changes following deguelin treatment in MDA-MB-231 cells was assessed through microarray analysis. Deguelin at 1 μmol/L was found to inhibit the growth of the breast cancer cell lines tested with a range of 37% to 87%. The highest inhibition was noted for the MDA-MB-231 cell line (MDA-MB-231&gt;BT474&gt;MCF7&gt;T47D&gt;MCF12F). An arrest at the S phase of the cell cycle and apoptosis were shown in the MDA-MB-231 cells treated with deguelin. The microarray profile indicated differential expression of two independent pathways, including clusters of apoptosis and Wnt/β-catenin signaling genes in cells as a result of deguelin treatment. These studies support the antiproliferative effects of deguelin in human breast cancer cells and, perhaps more importantly, illustrate novel actions by deguelin in the Wnt signaling pathway.
Dynamics of platelet mobilisation into lungs in response to 5-hydroxytryptamine (serotonin) in mice
Authors: Yu Zhiqian , Ohba Mami , Nakamura Masanori , Sasano Takashi , Ono Masao , Sugawara Shunji , Endo Yasuo 
Published: October 2009

SummaryIn experimental animals, the lung rapidly removes intravenously injected 5-hydroxytryptamine (5HT), but the mechanism underlying this pulmonary 5HT removal (P-5HT-R) and the responsible cells remains unclear. 5HT reportedly induces rapid pulmonary platelet accumulation (P-PLT-A). Here, we examined the relationship between P-5HT-R and P-PLT-A in mice by comparing the platelet count in the blood with the endogenous 5HT in the tissues (a marker for platelets because the 5HT is largely contained within platelets). 5HT levels in murine blood and tissues were also examined after intravenous injection of 5HT. The data revealed that: (i) 5HT injection (at ≥ 0.04 μmol/kg) induced a transient P-PLT-A (occurring within 6 seconds), (ii) platelets rapidly took up injected 5HT, (iii) the P-5HT-R was saturated following injection of 5HT at 1 μmol/kg, (iv) ketanserin (5HT2-receptor antagonist) strongly inhibited P-PLT-A, (v) under fluoxetine (5HT-uptake inhibitor), 5HT levels at 6 seconds after 5HT injection were markedly higher in blood, but significantly lower in lung (versus fluoxetine-untreated mice), (vi) P-5HT-R was barely detectable in mutant mice with platelets lacking dense bodies, and was much reduced in platelet-depleted mice, (vii) 5HT injected intravenously at 10 μmol/kg had a half-life in the lung of < 20 seconds, and (viii) unlike 5HT, injected histamine was largely excreted by the kidney. These results demonstrate that platelets rapidly translocate into the lung upon stimulation of 5HT2 receptors, take up 5HT (and possibly swiftly metabolise it), and then return to the circulation. Hence, pulmonary platelet accumulation plays an important role in pulmonary 5HT removal in mice.
Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections
Authors: Eitel Julia , Meixenberger Karolin , Suttorp Norbert , Opitz Bastian 
Published: October 2009

SummaryBacteraemia and viraemia are characterised by pathogens entering the bloodstream. Endothelial cells are among the first cells coming into contact with the microbes and also some endogenous molecules which are released by tissue damage. As part of the innate immune system, endothelial cells respond to these contacts by producing inflammatory mediators and expressing surface molecules. The initial sensing of microbial and endogenous danger-associated molecules is mediated by so-called pattern recognition receptors (PRRs). PRRs can be classified in different protein families such as the Toll-like receptors, the NODlike receptors and the RIG-I-like receptors. By activating inflammatory gene transcription and posttranslational processing, PRRs control the immediate innate immune reaction and also the subsequent adaptive immune response. Here we describe the current knowledge of extra-and intracellular PRRs in endothelial cells and their potential role in sepsis and vascular diseases.
A new oral antiplatelet agent with potent antithrombotic properties: Comparison of DZ-697b with clopidogrel in a randomised phase I study
Authors: Zafar Urooj , Ibáñez Borja , Choi Brian , Vorchheimer David , Piñero Antonio , Jin Xiaoping , Sharma Raman , Badimon Juan 
Published: October 2009

SummaryDZ-697b is a new orally active antiplatelet agent that inhibits collagen and ristocetin-mediated platelet activation. It does not require meta-bolisation to generate its active compound and has a safer profile than clopidogrel in pre-clinical studies. We compared the antithrombotic effects and bleeding time prolongations of three DZ-697b doses with clopidogrel 300 mg. In a four-treatment, three-period, crossover-design, 20 healthy subjects (31 ± 7 years, 85% males) were randomised to single oral doses of DZ-697b (60, 120 and 360 mg), and clopidogrel (300 mg) (n=15 in each treatment with crossing-over). Antithrombotic effects were assessed by measuring six-hour post-dose changes from baseline in thrombus size in the Badimon chamber and platelet adhesion using Diamed Impact-R platelet function assay. Bleeding times were also measured pre-dose and at six hours post-dose. DZ-697b caused dose-dependent reductions in thrombus size at both high- and low-shear rates (mean reductions at 60, 120 and 360 mg doses of: 13.0%, 18.7%, 26.4% and 11.4%, 12.7%, 22.1% respectively, p<0.05 for all). Effect of clopidogrel (reductions of 18.7% and 11.0% respectively, p<0.05 for both) was closest to DZ-697b 120 mg. Reductions in platelet adhesion were also dose-dependent. Bleeding time ratio from baseline were shorter with DZ-697b versus clopidogrel (1.3, 1.4 and 1.5 versus 1.9, p<0.05 for all). The oral agent DZ-697b shows potent, dose-dependent, antithrombotic effects that are comparable to 300 mg clopidogrel at the 120 mg dose. Despite having equal or greater anti-platelet potency than 300 mg clopidogrel, bleeding time prolongations are significantly shorter with DZ-697b.
Artificial Analog Neural Network: Conceptual and Technical Considerations
Authors: Stearns Phillip 
Published: October 2009

ABSTRACT
How is our notion of sound art shaped by the current technological landscape, and what is the role of science and technology in the pursuit of new multidisciplinary works? The author meditates on the topics of sound art, sonification, interactivity and network sciences in order to contextualize the Artificial Analog Neural Network (AANN) project.
Determinants of Mental Health Stigma Among Pharmacy Students in Australia, Belgium, Estonia, Finland, India and Latvia
Authors: Bell J.S. , Aaltonen S.E. , Airaksinen M.S. , Volmer D. , Gharat M.S. , Muceniece R. , Vitola A. , Foulon V. , Desplenter F.A. , Chen T.F. 
Published: October 2009

Background: Healthcare professionals commonly exhibit negative attitudes toward people with mental disorders. Few international studies have sought to investigate the determinants of stigma. Objective: To conduct an international comparison of pharmacy students’ stigma towards people with schizophrenia, and to determine whether stigma is consistently associated with stereotypical attributes of people with schizophrenia. Method: Students ( n = 649) at eight universities in Australia, Belgium, India, Finland, Estonia and Latvia completed a seven-item Social Distance Scale (SDS) and six items related to stereotypical attributes of people with schizophrenia. Results: Mean SDS scores were 19.65 (± 3.97) in Australia, 19.61 (± 2.92) in Belgium, 18.75 (± 3.57) in India, 18.05 (± 3.12) in Finland, and 20.90 (± 4.04) in Estonia and Latvia. Unpredictability was most strongly associated with having a high social distance in Australia (β = —1.285), the perception that people will never recover in India (β = — 0.881), dangerousness in Finland (β = —1.473) and the perception of being difficult to talk to in Estonia and Latvia (β = —2.076). Unpredictability was associated with lower social distance in Belgium (β = 0.839). Conclusion: The extent to which students held stigmatizing attitudes was similar in each country, however, the determinants of stigma were different. Pharmacy education may need to be tailored to address the determinants of stigma in each country.
Effect of Anterior Cruciate Ligament Reconstruction and Meniscectomy on Length of Career in National Football League Athletes
Authors: Brophy Robert H. , Gill Corey S. , Lyman Stephen , Barnes Ronnie P. , Rodeo Scott A. , Warren Russell F. 
Published: October 2009

Background Meniscal and anterior cruciate ligament (ACL) injuries are common in college football athletes. The effect of meniscectomy and/or ACL surgery on the length of an athlete’s career in the National Football League (NFL) has not been well examined. Hypothesis Athletes with a history of meniscectomy or ACL surgery before the NFL combine have a shorter career than matched controls. Study Design Case-control study; Level of evidence, 3. Methods A database containing the injury history and career NFL statistics of athletes from 1987–2000 was used to match athletes with a history of meniscectomy and/or ACL surgery, and no other surgery or major injury, to controls without previous surgeries. Athletes were matched by position, year drafted, round drafted, and additional injury history. Results Fifty-four athletes with a history of meniscectomy, 29 with a history of ACL reconstruction, and 11 with a history of both were identified and matched with controls. Isolated meniscectomy reduced the length of career in years (5.6 vs 7.0; P = .03) and games played (62 vs 85; P = .02). Isolated ACL surgery did not significantly reduce the length of career in years or games played. Comparing the athletes with meniscectomy or ACL reconstruction to athletes with combined ACL reconstruction and meniscectomy, a history of both surgeries, resulted in a shorter career in games started (7.9 vs 35.1; P <.01), games played (41 vs 63; P = .07), and years (4.0 vs 5.8; P = .08) than a history of either surgery alone. Conclusion A history of meniscectomy, but not ACL reconstruction, shortens the expected career of a professional football player. A combination of ACL reconstruction and meniscectomy may be more detrimental to an athlete’s durability than either surgery alone. Further research is warranted to better understand how these injuries and surgeries affect an athlete’s career and what can be done to improve the long-term outcome after treatment.
Recommendations and Treatment Outcomes for Patellofemoral Articular Cartilage Defects with Autologous Chondrocyte Implantation
Authors: Pascual-Garrido Cecilia , Slabaugh Mark A. , L'Heureux Daniel R. , Friel Nicole A. , Cole Brian J. 
Published: October 2009

Background Reported results of autologous chondrocyte implantation for chondral lesions in the patellofemoral joint have been encouraging when combined with realignment procedures. Purpose The objective of this study was to examine the clinical results of a patient cohort undergoing autologous chondrocyte implantation of the patellofemoral joint and elucidate characteristics associated with successful implantation. Study Design Case series; Level of evidence, 4. Methods The cohort included 62 patients who underwent autologous chondrocyte implantation of the PF joint. The mean defect size was 4.2 cm2 (61.6). The average age was 31.8 years (range, 15.8-49.4), and the average follow-up was 4 years (range, 2-7). Outcomes were assessed via clinical assessment and established outcome scales, including the Lysholm, International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome Scale (KOOS; includes the 5 categories of Pain, Symptoms, Activities of Daily Living, Sport, and Quality of Life), Tegner, Cincinnati, and Short Form-12. Results Mean improvement in the preoperative to postoperative scores was significant for the Lysholm (37-63, P<.001), International Knee Documentation Committee (31-57, P<.001), KOOS Pain (48-71, P<.001), KOOS Symptoms (51-70, P <.001), KOOS Activities of Daily Living (60-80, P <.001), KOOS Sport (25-42, P <.001), KOOS Quality of Life (24-49, P <.001), Short Form-12 Physical (38-41, P<.05), Cincinnati (43-63, P <.005), and Tegner (4-6, P <.05), but not for the Short Form-12 Mental. There was no statistical difference between outcomes in patients with a history of a previous failed cartilage procedure compared with those patients without a prior cartilage procedure (P > 05). Patients undergoing anteromedialization tended toward better outcomes than those without realignment. Forty-four percent of patients needed a subsequent procedure. There were 4 clinical failures (7.7%), which were defined as progression to arthroplasty or conversion to osteochondral allograft transplantation. Conclusion Autologous chondrocyte implantation is a viable treatment option for chondral defects of the patellofemoral joint. Combined autologous chondrocyte implantation with anteromedialization improves outcomes more than autologous chondrocyte implantation alone. Patients with failed prior cartilage procedures can also expect sustained and clinically meaningful improvement.
Treatment of Full-Thickness Chondral Defects with Hyalograft C in the Knee
Authors: Nehrer Stefan , Dorotka Ronald , Domayer Stephan , Stelzeneder David , Kotz Rainer 
Published: October 2009

Background Tissue engineering has become available for cartilage repair in clinical practice. Hypothesis The treatment of full-thickness chondral defects in the knee with a hyaluronan-based scaffold seeded with autolo-gous chondrocytes provides stable improvement of clinical outcome up to 7 years. Study Design Case series; Level of evidence, 4. Methods Fifty-three patients with deep osteochondral defects in the knee were treated with Hyalograft C. The mean age at implantation was 32 6 12 years, the mean defect size was 4.4 6 1.9 cm2, and the mean body mass index was 24.5 6 3.8 kg/m2. Implantations were performed with miniarthrotomy or arthroscopy. The primary indications for implantation with Hyalograft C included young patients with a stable joint, normal knee alignment, and isolated chondral defects with otherwise healthy adjacent cartilage. The secondary indications were patients who did not meet the primary indication criteria or were salvage procedures. Forty-two patients with primary indications and 11 patients with secondary indications were evaluated. Outcome was evaluated with the International Cartilage Repair Society and International Knee Documentation Committee scales, the Lysholm score, the modified Cincinnati score, and with Kaplan-Meier survival analysis. Statistical analysis consisted of bivariate correlation analysis and unpaired, 2-tailed t tests. Results A highly significant increase (P<001) in all knee scores was found in patients treated for the primary indications. Nine of 11 secondary indication cases underwent total knee arthroplasty due to persisting pain between 2 and 5 years after implantation. Graft failure occurred in 3 of 42 patients with primary indication between 6 months and 5 years after implantation. Kaplan-Meier survival demonstrated significantly different chances for survival between primary and secondary outcome and between simple, complex, and salvage cases, respectively (P <.001). Conclusion Hyalograft C autograft provides clinical improvement in healthy young patients with single cartilage defects. Less complicated surgery and lower morbidity are considered advantages of the technique. The results of treatment with Hyalograft C as a salvage procedure or in patients with osteoarthritis are poor.
Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate
Authors: Kivi Elina , Elima Kati , Aalto Kristiina , Nymalm Yvonne , Auvinen Kaisa , Koivunen Erkki , Otto Diana M. , Crocker Paul R. , Salminen Tiina A. , Salmi Marko , Jalkanen Sirpa 
Published: October 2009

AbstractLeukocytes migrate from the blood into areas of inflammation by interacting with various adhesion molecules on endothelial cells. Vascular adhesion protein-1 (VAP-1) is a glycoprotein expressed on inflamed endothelium where it plays a dual role: it is both an enzyme that oxidizes primary amines and an adhesin that is involved in leukocyte trafficking to sites of inflammation. Although VAP-1 was identified more than 15 years ago, the counterreceptor(s) for VAP-1 on leukocytes has remained unknown. Here we have identified Siglec-10 as a leukocyte ligand for VAP-1 using phage display screenings. The binding between Siglec-10 and VAP-1 was verified by different adhesion assays, and this interaction was also consistent with molecular modeling. Moreover, the interaction between Siglec-10 and VAP-1 led to increased hydrogen peroxide production, indicating that Siglec-10 serves as a substrate for VAP-1. Thus, the Siglec-10–VAP-1 interaction seems to mediate lymphocyte adhesion to endothelium and has the potential to modify the inflammatory microenvironment via the enzymatic end products.
Alpha-defensins secreted by dysplastic granulocytes inhibit the differentiation of monocytes in chronic myelomonocytic leukemia
Authors: Droin Nathalie , Jacquel Arnaud , Hendra Jean-Baptiste , Racoeur Cindy , Truntzer Caroline , Pecqueur Delphine , Benikhlef Naïma , Ciudad Marion , Guery Leslie , Jooste Valérie , Dufour Erick , Fenaux Pierre , Quesnel Bruno , Kosmider Olivier , Fontenay Michaëla , Ducoroy Patrick , Solary Eric 
Published: October 2009

Abstract
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that occurs in elderly patients. One of the main diagnostic criteria is the accumulation of heterogeneous monocytes in the peripheral blood. We further explored this cellular heterogeneity and observed that part of the leukemic clone in the peripheral blood was made of immature dysplastic granulocytes with a CD14−/CD24+ phenotype. The proteome profile of these cells is dramatically distinct from that of CD14+/CD24− monocytes from CMML patients or healthy donors. More specifically, CD14−/CD24+ CMML cells synthesize and secrete large amounts of alpha-defensin 1-3 (HNP1-3). Recombinant HNPs inhibit macrophage colony-stimulating factor (M-CSF)–driven differentiation of human peripheral blood monocytes into macrophages. Using transwell, antibody-mediated depletion, suramin inhibition of purinergic receptors, and competitive experiments with uridine diphosphate (UDP)/uridine triphosphate (UTP), we demonstrate that HNP1-3 secreted by CD14−/CD24+ cells inhibit M-CSF–induced differentiation of CD14+/CD24− cells at least in part through P2Y6, a receptor involved in macrophage differentiation. Altogether, these observations suggest that a population of immature dysplastic granulocytes contributes to the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the differentiation capabilities of monocytes.
How I treat multiple myeloma in younger patients
Authors: Stewart A. Keith , Richardson Paul G. , San-Miguel Jesus F. 
Published: October 2009

AbstractTherapeutic options for multiple myeloma (MM) patients have changed quickly in recent years and uncertainty has arisen about optimal approaches to therapy. A reasonable goal of MM treatment in younger “transplant eligible” patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control. To achieve this goal we recommend induction therapy with multi-agent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteriods) which when employed together elicit frequent, rapid, and deep responses. We recommend consolidation with high-dose melphalan and autologous stem cell transplantation in the majority of patients willing and able to undergo this procedure and subsequent maintenance therapy, especially in those failing to achieve a complete response or at high risk for early relapse based on prognostic, genetically defined risk factors. Defining genetic risk for early relapse is therefore an important aspect of early diagnostic testing and attention to minimizing expected toxicities once therapy begins is critical in ensuring the efficacy of modern combination therapy approaches. When access to newer drugs is restricted participation in clinical trials should be pursued.