bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue Transglutaminase Inhibits Autophagy in Pancreatic Cancer Cells
Authors: Akar Ugur , Ozpolat Bulent , Mehta Kapil , Fok Jansina , Kondo Yasuko , Lopez-Berestein Gabriel 
Published: March 2007

AbstractElevated expression of tissue transglutaminase (TG2) in cancer cells has been implicated in the development of drug resistance and metastatic phenotypes. However, the role and the mechanisms that regulate TG2 expression remain elusive. Here, we provide evidence that protein kinase Cδ (PKCδ) regulates TG2 expression, which in turn inhibits autophagy, a type II programmed cell death, in pancreatic cancer cells that are frequently insensitive to standard chemotherapeutic agents. Rottlerin, a PKCδ-specific inhibitor, and PKCδ small interfering RNA (siRNA) down-regulated the expression of TG2 mRNA and protein and induced growth inhibition without inducing apoptosis in pancreatic cancer cells. Inhibition of PKCδ by rottlerin or knockdown of TG2 protein by a TG2-specific siRNA resulted in a marked increase in autophagy shown by presence of autophagic vacuoles in the cytoplasm, formation of the acidic vesicular organelles, membrane association of microtubule-associated protein 1 light chain 3 (LC3) with autophagosomes, and a marked induction of LC3-II protein, important hallmarks of autophagy, and by electron microscopy. Furthermore, inhibition of TG2 by rottlerin or by the siRNA led to accumulation of green fluorescent protein (GFP)-LC3-II in autophagosomes in pancreatic cancer cells transfected with GFP-LC3 (GFP-ATG8) expression vector. Knockdown of Beclin-1, a specific autophagy-promoting protein and the product of Becn1 (ATG6), inhibited rottlerin-induced and TG2 siRNA–induced autophagy, indicating that Beclin-1 is required for this process. These results revealed that PKCδ plays a critical role in the expression of TG2, which in turn regulates autophagy. In conclusion, these results suggest a novel mechanism of regulation of TG2 and TG2-mediated autophagy in pancreatic cancer cells. (Mol Cancer Res 2007;5(3):241–9)
BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs
Authors: Buckley Niamh E. , Hosey Alison M. , Gorski Julia J. , Purcell James W. , Mulligan Jude M. , Harkin D. Paul , Mullan Paul B. 
Published: March 2007

AbstractBRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-γ, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-γ. We also show that the induction of IRF-7 by BRCA1 and IFN-γ is dependent on the type I IFNs, IFN-α and IFN-β. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-γ. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-α and IFN-β in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-γ regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261–70)
Constitutive Suppressor of Cytokine Signaling 3 Expression Confers a Growth Advantage to a Human Melanoma Cell Line
Authors: Komyod Waraporn , Böhm Markus , Metze Dieter , Heinrich Peter C. , Behrmann Iris 
Published: March 2007

Abstract
The growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, whereas late stage melanoma cells have often been reported to be “multi-cytokine–resistant.” Here, we analyzed the melanoma cell line 1286, resistant towards the growth-inhibitory effects of interleukin 6 (IL-6), and oncostatin M (OSM), to better understand the mechanisms underlying cytokine resistance. Although the relevant receptors gp130 and OSMR are expressed at the cell surface of these cells, cytokine stimulation hardly led to the activation of Janus kinase 1 and signal transducer and activator of transcription (STAT)3 and STAT1. We found a high-level constitutive expression of suppressors of cytokine signaling 3 (SOCS3) that did not further increase after cytokine treatment. Importantly, upon suppression of SOCS3 by short interfering RNA, cells became susceptible towards OSM and IL-6: they showed an enhanced STAT3 phosphorylation and a dramatically increased STAT1 phosphorylation. Moreover, suppression of SOCS3 rendered 1286 cells sensitive to the antiproliferative action of IL-6 and OSM, but not of IFN-α. Interestingly, SOCS3–short interfering RNA treatment also increased the growth-inhibitory effect in cytokine-sensitive WM239 cells expressing SOCS3 in an inducible way. Thus, SOCS3 expression confers a growth advantage to these cell lines. Constitutive SOCS3 mRNA expression, although at lower levels than in 1286 cells, was found in nine additional human melanoma cell lines and in normal human melanocytes, although at the protein level, SOCS3 expression was marginal at best. However, in situ analysis of human melanoma specimens revealed SOCS3 immunoreactivity in 3 out of 10 samples, suggesting that in vivo SOCS3 may possibly play a role in IL-6 resistance in at least a fraction of tumors. (Mol Cancer Res 2007;5(2):271–81)
Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility
Authors: Larsen Alice Bjerregaard , Pedersen Mikkel Wandahl , Stockhausen Marie-Thérése , Grandal Michael Vibo , Deurs Bo van , Poulsen Hans Skovgaard 
Published: March 2007

AbstractEphA2 overexpression has been reported in many cancers and is believed to play an important role in tumor metastasis and angiogenesis. We show that the activated epidermal growth factor receptor (EGFR) and the cancer-specific constitutively active EGFR type III deletion mutant (EGFRvIII) induce the expression of EphA2 in mammalian cell lines, including the human cancer cell lines A431 and HN5. The regulation is partially dependent on downstream activation of mitogen-activated protein kinase/extracellular signal–regulated kinase kinase and is a direct effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to the plasma membrane and EphA2 coimmunoprecipitates with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a functional role of EphA2 in EGFR-expressing cancer cells. (Mol Cancer Res 2007;5(3):283–93)
The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents
Authors: Tabernero Josep 
Published: March 2007

AbstractMultiple cellular pathways influence the growth and metastatic potential of tumors. This creates heterogeneity, redundancy, and the potential for tumors to bypass signaling pathway blockade, resulting in primary or acquired resistance. Combining therapies that inhibit different signaling pathways has the potential to be more effective than inhibition of a single pathway and to overcome tumor resistance. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors have become key therapies in several tumor types. Close relationships between these factors exist: VEGF signaling is up-regulated by EGFR expression and, conversely, VEGF up-regulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor–resistant cell lines. Clinical trials have also produced promising data: combining the anti-VEGF monoclonal antibody bevacizumab with the anti-EGFR antibody cetuximab or the EGFR tyrosine kinase inhibitor erlotinib increases benefit compared with either of these anti-EGFR agents alone or combined with chemotherapy. The potential of this novel approach to anticancer therapy will be elucidated by large, ongoing clinical trials. (Mol Cancer Res 2007;5(3):203–20)
Elastin Stabilization for Treatment of Abdominal Aortic Aneurysms
Authors: Isenburg Jason C. , Simionescu Dan T. , Starcher Barry C. , Vyavahare Narendra R. 
Published: March 2007

Background—Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development.Methods and Results—Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl2-mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells.Conclusions—Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.
"Great Command O'Ersways the Order": Purgatory, Revenge, and Maimed Rites in Hamlet
Authors: Beauregard David 
Published: March 2007

AbstractCertain elements in Hamlet, together with historical and biographical events, suggest that Shakespeare's play can be better understood from a Catholic perspective. The representation of the Ghost from Purgatory contains obviously Catholic imagery and allusions. The notion of revenge or vengeance, understood in terms of a proper intention in appropriate circumstances, is considered a virtue in Thomistic theology rather than a vice, a notion applicable to the play particularly when the opposing vices of being excessive and being remiss in punishing (cruelty and negligence) are taken into account. And, finally, the Erastian measures taken by Claudius, whose "great command o'ersways the order" of Ophelia's funeral, deforms a traditional Catholic liturgy in producing "maimed rites."
The Siyar — An Islamic Law Of Nations?
Authors: Bouzenita Anke Iman 
Published: March 2007

AbstractThis article deals with an essential part of Islamic law usually referred to as siyar. It discusses the development of siyar in an Islamic context and in comparison to the development of the modern law of nations. It further follows up the evaluation of siyar in the Western literature and analyses recurring paradigms of categorisation used in this literature. The author discusses Kruse's (1979) approach to differentiate between an "Islamic" and a "Muslim" law of nations. As case studies of argumentative weaknesses and loopholes, the author scrutinizes the attempts to attribute siyar to a particular type of law of nations and to render it as a legal order of either personal or territorial validity. The article focuses on methodological aspects involved in presenting two independent legal systems as commensurable. The author concludes that a terminological transfer, be it with the intention of explaining Islamic legal concepts to a non-specialized reader, be it with the intention to reconcile between both systems, cannot do justice to either one of the legal systems.
Expressions of Religiosity and Blasphemy in Modern Societies
Authors: Hassan Riaz 
Published: March 2007

AbstractIn Abrahamic religions blasphemy exists to prevent challenge to the notions of the sacred. Its existence is a litmus test of the standards a society feels it must enforce to preserve its religious beliefs and morality in order to prevent mockery of the Divine. Its commission has invariably evoked severe punishment. This paper examines the debates around these issues in Christianity and Islam. It examines the struggle against blasphemy laws in Christian and Muslim countries. It concludes by arguing that modernity plays a significant role in shaping attitudes towards blasphemy in modern societies. Using empirical evidence it explores the relationship between modernity, religiosity and blasphemy in seven contemporary Muslim countries.
Institutional Transformations in the Regime of Knowledge Production: The University as a catalyst for the Science-Based Knowledge Economy
Authors: Dzisah James 
Published: March 2007

AbstractAlthough, the process of the capitalization of academic scientific knowledge is not benign across university campuses, recent acceleration of the process have sparked debates in many circles. This debate mirrors two sets of issues-public versus private interests. While the discourse has shed some light on the socio-economic and political forces at work, it is not devoid of problems. The paper argues that the understanding of the university as a catalyst for the science-based knowledge economy should be built around the framework that the university like industry and government is responding to a wide range of socio-economic and political demands that cannot be delinked from each other. It contends that, in a period of an ever-increasing demand for science and technology, universities' as citadels of knowledge have through the capitalization of academic scientific knowledge become a catalyst for the science-based knowledge economy.
Septic Arthrt anitis after Arthroscopic Anterior Cruciate Ligament Reconstruction
Authors: Van Tongel Alexander , Stuyck Jos , Bellemans Johan , Vandenneucker Hilde 
Published: March 2007

Background Septic arthritis after arthroscopic anterior cruciate ligament reconstruction is a rare complication. In the literature, several different managements are proposed. Hypothesis The graft can be retained during treatment of a septic arthritis after anterior cruciate ligament reconstruction. Study Design Case series; Level of evidence, 4. Methods A retrospective analysis of knee joint infections occurring after arthroscopically assisted anterior cruciate ligament reconstructions was conducted. Fifteen patients were treated for postoperative septic arthritis of the knee after anterior cruciate ligament reconstruction between 1996 and 2005. All patients underwent an urgent extensive arthroscopic debridement (washout and synovectomy) and parenteral antibiotics and oral antibiotics subsequently. Repetitive wash-outs were performed if necessary. The average time at follow-up for our series was 58 months (range, 9-99 months). Results Only 1 graft was removed during debridement because it was nonfunctional. All other patients retained their anterior cruciate ligament reconstruction. There was no reinfection. There were 2 traumatic reruptures. We evaluated 11 patients: in 6 patients the Lachman test showed a translation of more than 3 mm, but all patients had a firm endpoint and there was no subjective instability. Early signs of radiological degeneration were seen in 3 patients. The value for the Lysholm knee scoring scale was 83, on average, ranging from 57 to 100. Regarding the International Knee Documentation Committee score, 2 patients had a final evaluation of normal, 7 patients nearly normal, and 2 patients abnormal. Conclusion The graft can be retained during treatment of septic arthritis after anterior cruciate ligament reconstruction.
The Relationship between Neurocognitive Function and Noncontact Anterior Cruciate Ligament Injuries
Authors: Swanik Charles Buz , Covassin Tracey , Stearne David J. , Schatz Philip 
Published: March 2007

Background Biomechanical analyses suggest that the loss of neuromuscular control is associated with noncontact anterior cruciate ligament sprains; however, previous research has not explored the link between neurocognitive function and unintentional knee injuries. Purpose To determine if athletes who suffer a noncontact anterior cruciate ligament injury demonstrate decreased baseline neurocognitive performance when compared with matched controls. Study Design Case control study; Level of evidence, 3. Methods The baseline scores from a computerized neurocognitive test battery (ImPACT) were analyzed to compare verbal memory, visual memory, processing speed, and reaction time. Eighty intercollegiate athletes who, subsequent to testing, experienced noncontact anterior cruciate ligament injuries, were matched with 80 controls based on height, weight, age, gender, sport, position, and years of experience at the collegiate level. Results Statistical differences were found between the noncontact anterior cruciate ligament injury group and the matched controls on all 4 neurocognitive subtests. Noncontact anterior cruciate ligament—injured athletes demonstrated significantly slower reaction time (F1,158 = 9.66, P = .002) and processing speed (F1,158 = 12.04, P = .001) and performed worse on visual (F1,158 = 19.16, P = .000) and verbal memory (F 1,158 = 4.08, P = .045) composite scores when compared with controls. Conclusion Neurocognitive differences may be associated with the loss of neuromuscular control and coordination errors, predisposing certain intercollegiate athletes to noncontact anterior cruciate ligament injuries.
Physical Examination for Partial Tears of the Biceps Tendon
Authors: Gill Harpreet S. , El Rassi George , Bahk Michael S. , Castillo Renan C. , McFarland Edward G. 
Published: March 2007

Background The accuracy of the physical examination for tears of the long head of the biceps remains controversial. Purpose The goals were 1) to characterize the occurrence of partial tears of the long head of the biceps tendon in a group of consecutive patients, and 2) to analyze the diagnostic value of various clinical tests for pathologic lesions of the proximal biceps tendon. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods Of 847 consecutive patients who underwent arthroscopic procedures for a variety of shoulder conditions, 40 were found at the time of arthroscopy to have partial biceps tendon tears. The average age of these 24 men and 16 women was 59 years (range, 18-83). Preoperative physical examinations had included 9 commonly used tests for shoulder examination. Statistical analysis included sensitivity, specificity, negative predictive value, positive predictive value, and likelihood ratios for these tests. Results The prevalence rate of partial tears was 5% (40/847) of all arthroscopic procedures. The most commonly associated conditions included rotator cuff tears (85% [34/40]) and anterior instability (7.5% [3/40]). Tenderness on palpation of the long head of the biceps tendon had a sensitivity of 53%, a specificity of 54%, and a likelihood ratio of 1.13. The sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios for Speed's test were 50%, 67%, 8%, 96%, and 1.51, respectively. Conclusion In patients with rotator cuff abnormality, the diagnosis of partial biceps tears cannot be made reliably with existing physical examination tests. Diagnostic arthroscopy is recommended, if clinically indicated, for potential partial tears of the long head of the biceps tendon. The treating physician should be prepared to treat unsuspected tears of the long head of the biceps tendon at the time of surgery.
Screening for depression among patients with multiple sclerosis: two questions may be enough
Authors: Mohr Dc , Hart Sl , Julian L , Tasch Es 
Published: March 2007

Background Depression among patients with multiple sclerosis (MS) is common and has a significant impact on quality of life. As many as two-thirds of depressed MS patients receive no treatment for their depression. While guidelines for depression management suggest screening, the only validated screening tools are questionnaires, which have not been widely implemented in practice. This is the first study on the effectiveness of using two questions assessing mood and anhedonia (loss of interest or pleasure) in screening for major depressive disorder (MDD) in MS. Methods MS patients under the care of neurologists were recruited from a large health maintenance organization (HMO). The MDD module of the Structured Clinical Interview for the DSM-IV and screening questions was administered. Results Of the 260 participants, 26% met the criteria for MDD. Among patients with MDD, 67% received no anti-depressant medication. The MDD screen identified 99% (95% CI: 91–100%) of cases. Discussion A brief, two question screen is reliable in identifying MS patients with MDD. This suggests that asking these two brief questions could identify almost all MS patients meeting MDD criteria, with minimal numbers of false positives. Multiple Sclerosis 2007; 13: 215–219. http://msj.sagepub.com
Mechanisms of induction of endothelial cell E-selectin expression by smooth muscle cells and its inhibition by shear stress
Authors: Chiu Jeng-Jiann , Chen Li-Jing , Lee Chih-I , Lee Pei-Ling , Lee Ding-Yu , Tsai Min-Chien , Lin Chia-Wen , Usami Shunichi , Chien Shu 
Published: March 2007

Abstract
E-selectin is a major adhesion molecule expressed by endothelial cells (ECs), which are exposed to shear stress and neighboring smooth muscle cells (SMCs). We investigated the mechanisms underlying the modulation of EC E-selectin expression by SMCs and shear stress. SMC coculture induced rapid and sustained increases in expression of E-selectin and phosphorylation of interleukin-1 (IL-1) receptor-associated kinase glycoprotein-130, as well as the downstream mitogen-activated protein kinases (MAPKs) and Akt. By using specific inhibitors, dominant-negative mutants, and small interfering RNA, we demonstrated that activations of c-Jun-NH2-terminal kinase (JNK) and p38 of the MAPK pathways are critical for the coculture-induced E-selectin expression. Gel shifting and chromatin immunoprecipitation assays showed that SMC coculture increased the nuclear factor-κB (NF-κB)–promoter binding activity in ECs; inhibition of NF-κB activation by p65-antisense, lactacystin, and N-acetyl-cysteine blocked the coculture-induced E-selectin promoter activity. Protein arrays and blocking assays using neutralizing antibodies demonstrated that IL-1β and IL-6 produced by EC/SMC cocultures are major contributors to the coculture induction of EC signaling and E-selectin expression. Preshearing of ECs at 12 dynes/cm2 inhibited the coculture-induced EC signaling and E-selectin expression. Our findings have elucidated the molecular mechanisms underlying the SMC induction of EC E-selectin expression and the shear stress protection against this SMC induction.