bluuebunny/crossref_metadata_2025 huggingface dataset:
The Catholic Church and International Law
Authors: Boyle Elizabeth Heger , Golden Shannon , Liao Wenjie
Published: July 2017

Since the 1960s, the Catholic Church has been immensely influential in shaping international law. It provides a compelling example of how nonstate actors, relying on principled positions rather than resources, can alter the course of global policy making. The Church's authority rests on three distinct features: (a) independence from the nation-state system; (b) a centralized transnational bureaucracy; and (c) its enduring ideology. In this review, we elaborate on the Church's role in promoting peace, serving the poor, and blocking the institutionalization of access to contraception and abortion. Church ideology finds strong secular counterparts in the cases of promoting peace and support for the poor. It is on shakier ground when it ventures into gender issues, which it has done with zeal in recent years. Its primary allies on gender issues have been other religious organizations and Islamic states, reinforcing the religious rather than human rights basis for Church positions. The Church's role as the moral authority in the secular United Nations system is therefore less clear when it speaks about gender and sexuality.
The Role of Social Science Expertise in Same-Sex Marriage Litigation
Authors: Hull Kathleen E.
Published: July 2017

This article examines the role of social science in US same-sex marriage (SSM) court cases. The existing literature on the role of social science in courts is inconclusive, with studies suggesting social science exerts influence in some but not all areas of law. The literature on social science in SSM litigation is in its formative stage. This article reviews key SSM cases—including the three SSM trials and recent US Supreme Court cases—and describes how litigants and other interested parties invoked social science to address several key points related to legal recognition of SSM. A review of these cases suggests that social science may have exerted influence in SSM litigation because of the large volume of available evidence, the high level of scientific consensus on key issues, and contextual factors such as shifts in public opinion.
The Colorful World of Extracellular Electron Shuttles
Authors: Glasser Nathaniel R. , Saunders Scott H. , Newman Dianne K.
Published: July 2017

Descriptions of the changeable, striking colors associated with secreted natural products date back well over a century. These molecules can serve as extracellular electron shuttles (EESs) that permit microbes to access substrates at a distance. In this review, we argue that the colorful world of EESs has been too long neglected. Rather than simply serving as a diagnostic attribute of a particular microbial strain, redox-active natural products likely play fundamental, underappreciated roles in the biology of their producers, particularly those that inhabit biofilms. Here, we describe the chemical diversity and potential distribution of EES producers and users, discuss the costs associated with their biosynthesis, and critically evaluate strategies for their economical usage. We hope this review will inspire efforts to identify and explore the importance of EES cycling by a wide range of microorganisms so that their contributions to shaping microbial communities can be better assessed and exploited.
Pathophysiology of cardiorenal syndrome in patients with heart failure: potential therapeutic targets
Authors: Takahama Hiroyuki , Kitakaze Masafumi
Published: July 2017

Despite the development of pharmacological inventions and new nonpharmacological techniques to prevent and treat heart failure (HF), the mortality rate in patients with symptomatic HF remains high. To conquer these difficulties, the pathophysiology of HF should be considered within a wide range of views. Given the diverse mechanisms of HF pathophysiology, renal and cardiac functions have close and complementary interconnections. Recent studies have suggested that communication between the kidney and heart through bidirectional pathways causes significant pathological changes. This review summarizes the pathophysiology of cardiorenal syndrome (CRS) from three different viewpoints, namely, underlying chronic kidney disease, worsening renal function during hospitalization due to HF, and resistance to diuretics. We also summarize the presently available data on the pathophysiology of CRS, identify the challenges associated with some clinical approaches, and explore the potential therapeutic target for CRS.
Prolonged sitting leg vasculopathy: contributing factors and clinical implications
Authors: Padilla Jaume , Fadel Paul J.
Published: July 2017

Atherosclerotic peripheral artery disease primarily manifests in the medium- to large-sized conduit arteries of the lower extremities. However, the factors underlying this increased vulnerability of leg macrovasculature to disease are largely unidentified. On the basis of recent studies, we propose that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial cell dysfunction, a key predisposing factor to peripheral artery disease. In particular, this review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it.
FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice
Authors: Justet Aurélien , Joannes Audrey , Besnard Valérie , Marchal-Sommé Joëlle , Jaillet Madeleine , Bonniaud Philipe , Sallenave Jean Michel , Solhonne Brigitte , Castier Yves , Mordant Pierre , Mal Hervé , Cazes Aurélie , Borie Raphael , Mailleux Arnaud A. , Crestani Bruno
Published: July 2017

Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14. Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14. The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14. FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-β1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.
Multirapid Serial Visual Presentation Framework for EEG-Based Target Detection
Authors: Lin Zhimin , Zeng Ying , Gao Hui , Tong Li , Zhang Chi , Wang Xiaojuan , Wu Qunjian , Yan Bin
Published: July 2017

Target image detection based on a rapid serial visual presentation (RSVP) paradigm is a typical brain-computer interface system with various applications, such as image retrieval. In an RSVP paradigm, a P300 component is detected to determine target images. This strategy requires high-precision single-trial P300 detection methods. However, the performance of single-trial detection methods is relatively lower than that of multitrial P300 detection methods. Image retrieval based on multitrial P300 is a new research direction. In this paper, we propose a triple-RSVP paradigm with three images being presented simultaneously and a target image appearing three times. Thus, multitrial P300 classification methods can be used to improve detection accuracy. In this study, these mechanisms were extended and validated, and the characteristics of the multi-RSVP framework were further explored. Two different P300 detection algorithms were also utilized in multi-RSVP to demonstrate that the scheme is universally applicable. Results revealed that the detection accuracy of the multi-RSVP paradigm was higher than that of the standard RSVP paradigm. The results validate the effectiveness of the proposed method, and this method can provide a whole new idea in the field of EEG-based target detection.
A Review on Human Activity Recognition Using Vision-Based Method
Authors: Zhang Shugang , Wei Zhiqiang , Nie Jie , Huang Lei , Wang Shuang , Li Zhen
Published: July 2017

Human activity recognition (HAR) aims to recognize activities from a series of observations on the actions of subjects and the environmental conditions. The vision-based HAR research is the basis of many applications including video surveillance, health care, and human-computer interaction (HCI). This review highlights the advances of state-of-the-art activity recognition approaches, especially for the activity representation and classification methods. For the representation methods, we sort out a chronological research trajectory from global representations to local representations, and recent depth-based representations. For the classification methods, we conform to the categorization of template-based methods, discriminative models, and generative models and review several prevalent methods. Next, representative and available datasets are introduced. Aiming to provide an overview of those methods and a convenient way of comparing them, we classify existing literatures with a detailed taxonomy including representation and classification methods, as well as the datasets they used. Finally, we investigate the directions for future research.
The Role of Intereukin-31 in Pathogenesis of Itch and Its Intensity in a Course of Bullous Pemphigoid and Dermatitis Herpetiformis
Authors: Kulczycka-Siennicka Lilianna , Cynkier Anna , Waszczykowska Elżbieta , Woźniacka Anna , Żebrowska Agnieszka
Published: July 2017

Itch which is one of the major, subjective symptoms in a course of bullous pemphigoid and dermatitis herpetiformis makes those two diseases totally different than other autoimmune blistering diseases. Its pathogenesis is still not fully known. The aim of this research was to assess the role of IL-31 in development of itch as well as to measure its intensity. Obtained results, as well as literature data, show that lower concentration of IL-31 in patients’ serum may be correlated with its role in JAK/STAT signaling pathway which is involved in development of autoimmune blistering disease. Intensity of itch is surprisingly huge problem for the patients and the obtained results are comparable with results presented by atopic patients.
A Case of Fulminant Meningococcemia: It Is All in the Complement
Authors: Hawkins Kellie L. , Hoffman Mariah , Okuyama Sonia , Rowan Sarah E.
Published: July 2017

Eculizumab is a novel monoclonal antibody that inhibits complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Complement deficiency is a well-known risk factor for meningococcal infection. We describe a case of a young patient with PNH treated with eculizumab who presented with a life-threatening case of nongroupable meningococcemia. As this new biologic agent becomes more widely prescribed, providers should be aware of the increased risk of meningococcemia. In addition to vaccination, providers may consider the use of oral penicillin for antibiotic prophylaxis against Neisseria meningitidis in these cases of functional complement deficiency.
Solidified Floating Organic Drop Microextraction for the Detection of Trace Amount of Lead in Various Samples by Electrothermal Atomic Absorption Spectrometry
Authors: Aydın Urucu Oya , Dönmez Şeyda , Kök Yetimoğlu Ece
Published: July 2017

A novel method was developed for determination of trace amounts of lead in water and food samples. Solidified floating organic drop microextraction was used to preconcentrate the lead ion. After the analyte was complexed with 1-(2-pyridylazo)-2-naphthol, undecanol and acetonitrile were added as extraction and dispersive solvent, respectively. Variables such as pH, volumes of extraction and dispersive solvents, and concentration of chelating agent were optimized. Under the optimum conditions, the detection limit of Pb (II) was determined as 0.042 µg L−1 with an enrichment factor of 300. The relative standard deviation is <10%. Accuracy of the developed procedure was evaluated by the analysis of certified reference material of human hair (NCS DC 73347) and wastewater (SPS-WW2) with satisfactory results. The developed procedure was then successfully applied to biscuit and water samples for detection of Pb (II) ions.
Suppression of Ovarian Cancer Cell Tumorigenicity and Evasion of Cisplatin Resistance Using a Truncated Epidermal Growth Factor Receptor in a Rat Model
Authors: Chan John K. , Pham Huyen , You Xue Juan , Cloven Noelle G. , Burger Robert A. , Rose G. Scott , Van Nostrand Kristi , Korc Murray , DiSaia Philip J. , Fan Hung
Published: July 2017

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.
Mouse p10, an Alternative Spliced Form of p15INK4b, Inhibits Cell Cycle Progression and Malignant Transformation
Authors: Pérez de Castro Ignacio , Benet Marta , Jiménez María , Alzabin Saba , Malumbres Marcos , Pellicer Angel
Published: July 2017

The INK4 family of proteins negatively regulates cell cycle progression at the G1-S transition by inhibiting cyclin-dependent kinases. Two of these cell cycle inhibitors, p16INK4A and p15INK4B, have tumor suppressor activities and are inactivated in human cancer. Interestingly, both INK4 genes express alternative splicing variants. In addition to p16INK4A, the INK4A locus encodes a splice variant, termed p12—specifically expressed in human pancreas—and ARF, a protein encoded by an alternative reading frame that acts as a tumor suppressor through the p53 pathway. Similarly, the human INK4B locus encodes the p15INK4B tumor suppressor and one alternatively spliced form, termed as p10. We show here that p10, which arises from the use of an alternative splice donor site within intron 1, is conserved in the mouse genome and is widely expressed in mouse tissues. Similarly to mouse p15INK4B, p10 expression is also induced by oncogenic insults and transforming growth factor-β treatment and acts as a cell cycle inhibitor. Importantly, we show that mouse p10 is able to induce cell cycle arrest in a p53-dependent manner. We also show that mouse p10 is able to inhibit foci formation and anchorage-independent growth in wild-type mouse embryonic fibroblasts, and that these antitransforming properties of mouse p10 are also p53-dependent. These results indicate that the INK4B locus, similarly to INK4A-ARF, harbors two different splicing variants that can be involved in the regulation of both the p53 and retinoblastoma pathways, the two major molecular pathways in tumor suppression.
BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells
Authors: Andreu Enrique J. , Lledó Elisa , Poch Enric , Ivorra Carmen , Albero M. Pilar , Martínez-Climent José Angel , Montiel-Duarte Cristina , Rifón José , Pérez-Calvo Javier , Arbona Cristina , Prósper Felipe , Pérez-Roger Ignacio
Published: July 2017

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G1 cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27Kip1. We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
Cortactin Overexpression Inhibits Ligand-Induced Down-regulation of the Epidermal Growth Factor Receptor
Authors: Timpson Paul , Lynch Danielle K. , Schramek Daniel , Walker Francesca , Daly Roger J.
Published: July 2017

Ligand-induced receptor down-regulation by endocytosis is a critical process regulating the intensity and duration of receptor tyrosine kinase signaling. Ubiquitylation of specific receptor tyrosine kinases, for example, the epidermal growth factor receptor (EGFR) by the E3 ubiquitin ligase c-Cbl, provides a sorting signal for lysosomal degradation and leads to termination of receptor signaling. Cortactin, which couples the endocytic machinery to dynamic actin networks, is encoded by EMS1, a gene commonly amplified in breast and head and neck cancers. One mechanism whereby cortactin overexpression contributes to tumor progression is by enhancing tumor cell invasion and metastasis. However, in this study, we show that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the EGFR. This is independent of alterations in receptor autophosphorylation and correlates with impaired c-Cbl phosphorylation and association with the EGFR, reduced EGFR ubiquitylation, and sustained EGF-induced extracellular signal-regulated kinase activation. Furthermore, analysis of a panel of head and neck squamous cell carcinoma (HNSCC) cell lines revealed that cortactin overexpression is associated with attenuated ligand-induced EGFR down-regulation. Importantly, RNAi-mediated reduction of cortactin expression in an 11q13-amplified HNSCC cell line accelerates EGFR degradation. This represents the first demonstration of modulation of growth factor receptor signaling by cortactin. Moreover, enhanced EGFR signaling due to cortactin overexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.
Expression of the Brn-3b Transcription Factor Correlates with Expression of HSP-27 in Breast Cancer Biopsies and Is Required for Maximal Activation of the HSP-27 Promoter
Authors: Lee Sonia A. , Ndisang Daniel , Patel Chandrakant , Dennis Jonathan H. , Faulkes David J. , D'Arrigo Corrado , Samady Laila , Farooqui-Kabir Saleha , Heads Richard J. , Latchman David S. , Budhram-Mahadeo Vishwanie S.
Published: July 2017

In breast cancer, overexpression of the small heat shock protein, HSP-27, is associated with increased anchorage-independent growth, increased invasiveness, and resistance to chemotherapeutic drugs and is associated with poor prognosis and reduced disease-free survival. Therefore, factors that increase the expression of HSP-27 in breast cancer are likely to affect the prognosis and outcome of treatment. In this study, we show a strong correlation between elevated levels of the Brn-3b POU transcription factor and high levels of HSP-27 protein in manipulated MCF-7 breast cancer cells as well as in human breast biopsies. Conversely, HSP-27 is decreased on loss of Brn-3b. In cotransfection assays, Brn-3b can strongly transactivate the HSP-27 promoter, supporting a role for direct regulation of HSP-27 expression. Brn-3b also cooperates with the estrogen receptor (ER) to facilitate maximal stimulation of the HSP-27 promoter, with significantly enhanced activity of this promoter observed on coexpression of Brn-3b and ER compared with either alone. RNA interference and site-directed mutagenesis support the requirement for the Brn-3b binding site on the HSP-27 promoter, which facilitates maximal transactivation either alone or on interaction with the ER. Chromatin immunoprecipitation provides evidence for association of Brn-3b with the HSP-27 promoter in the intact cell. Thus, Brn-3b can, directly and indirectly (via interaction with the ER), activate HSP-27 expression, and this may represent one mechanism by which Brn-3b mediates its effects in breast cancer cells.
Proteomic-Based Prognosis of Brain Tumor Patients Using Direct-Tissue Matrix-Assisted Laser Desorption Ionization Mass Spectrometry
Authors: Schwartz Sarah A. , Weil Robert J. , Thompson Reid C. , Shyr Yu , Moore Jason H. , Toms Steven A. , Johnson Mahlon D. , Caprioli Richard M.
Published: July 2017

Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, nonsubjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.
A DNA Vaccine Targeting Fos-Related Antigen 1 Enhanced by IL-18 Induces Long-lived T-Cell Memory against Tumor Recurrence
Authors: Luo Yunping , Zhou He , Mizutani Masato , Mizutani Noriko , Liu Cheng , Xiang Rong , Reisfeld Ralph A.
Published: July 2017

A novel vaccination strategy induced specific CD8+ T cell–mediated immunity that eradicated spontaneous and experimental pulmonary cancer metastases in syngeneic mice and was also effective in a therapeutic setting of established breast cancer metastases. This was achieved by targeting transcription factor Fos-related antigen 1(Fra-1), overexpressed by many tumor cells, with an ubiquitinated DNA vaccine against Fra-1, coexpressing secretory IL-18. Insight into the immunologic mechanisms involved was provided by adoptive transfer of T lymphocytes from successfully immunized BALB/c mice to syngeneic severe combined immunodeficient (SCID) mice. Specifically, long-lived T memory cells were maintained dormant in nonlymphoid tissues by IL-18 in the absence of tumor antigen. Importantly, a second tumor cell challenge of these SCID mice restored both, robust tumor-specific cytotoxicity and long-lived T-cell memory, capable of eradicating established pulmonary cancer metastases, suggesting that this vaccine could be effective against tumor recurrence.
Toluidine Blue Staining Identifies High-Risk Primary Oral Premalignant Lesions with Poor Outcome
Authors: Zhang Lewei , Williams Michele , Poh Catherine F. , Laronde Denise , Epstein Joel B. , Durham Scott , Nakamura Hisae , Berean Ken , Hovan Alan , Le Nhu D. , Hislop Greg , Priddy Robert , Hay John , Lam Wan L. , Rosin Miriam P.
Published: July 2017

There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue–positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue–positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.
Selenium Disrupts Estrogen Signaling by Altering Estrogen Receptor Expression and Ligand Binding in Human Breast Cancer Cells
Authors: Lee Soo Ok , Nadiminty Nagalakshmi , Wu Xiu Xian , Lou Wei , Dong Yan , Ip Clement , Onate Sergio A. , Gao Allen C.
Published: July 2017

Cancer prevention studies suggest that selenium is effective in reducing the incidence of cancers including prostate, colon, and lung cancers. Previous reports showed that selenium inhibits premalignant human breast MCF-10AT1 and MCF10AT3B cell growth in vitro and reduces mammary tumor incidence after exposure to carcinogens in tumor models. Because estrogen is critical to the development and differentiation of estrogen target tissues, including the breast, the present study was designed to examine the effect of selenium on estrogen receptor (ER) expression and activation using methylseleninic acid (MSA), an active form of selenium in vitro. Selenium decreased the levels of expression of ERα mRNA and protein and reduced the binding of labeled estradiol to estrogen receptor in MCF-7 cells. Selenium inhibited the trans-activating activity of estrogen receptor in MCF-7 cells expressing functional estrogen receptor using a luciferase reporter construct linked to estrogen responsive element. Selenium decreased the binding of estrogen receptor to the estrogen responsive element site using an electrophoretic mobility gel shift assay. Selenium suppressed estrogen induction of the endogenous target gene c-myc. In contrast to the effect on ERα in MCF-7 cells, selenium increased ERβ mRNA expression in MDA-MB231 human breast cancer cells. Thus, differential regulation of ERα and ERβ in breast cancer cells may represent a novel mechanism of selenium action and provide a rationale for selenium breast cancer prevention trial.
Defective p38 Mitogen-Activated Protein Kinase Signaling Impairs Chemotaxic but not Proliferative Responses to Stromal-Derived Factor-1α in Acute Lymphoblastic Leukemia
Authors: Bendall Linda J. , Baraz Rana , Juarez Julius , Shen Wei , Bradstock Kenneth F.
Published: July 2017

The chemokine stromal-derived factor-1α (SDF-1α) regulates leukemic cell motility and proliferation; however, the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1α–mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1α, a subset of cases did not undergo chemotaxis in response to SDF-1α, while still demonstrating dependence on SDF-1α for proliferation in stroma-supported cultures. This chemotactic defect was associated with an absence of phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by SDF-1α, and of SDF-1α–induced augmentation of β1 integrin–mediated adhesion. Signaling through phosphoinositide 3-kinase and MEK was not affected. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This study suggests that signaling through p38 MAPK is required for ALL cell chemotaxis but not for proliferation, and that the loss of a chemotactic response to SDF-1α does not impede engraftment in NOD/SCID mice.
Fetal Stromal–Dependent Paracrine and Intracrine Vascular Endothelial Growth Factor-A/Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Proliferation and Motility of Human Primary Myeloma Cells
Authors: Vincent Loïc , Jin David K. , Karajannis Matthias A. , Shido Koji , Hooper Andrea T. , Rashbaum William K. , Pytowski Bronislaw , Wu Yan , Hicklin Daniel J. , Zhu Zhenping , Bohlen Peter , Niesvizky Ruben , Rafii Shahin
Published: July 2017

Induction of neoangiogenesis plays an important role in the pathogenesis of multiple myeloma. However, the mechanism by which expression of vascular endothelial growth factor (VEGF)-A and its receptors modulate the interaction of multiple myeloma cells with stromal cells is not known. Here, we describe a novel in vitro coculture system using fetal bone stromal cells as a feeder layer, which facilitates the survival and growth of human primary multiple myeloma cells. We show that stromal-dependent paracrine VEGF-A signaling promotes proliferation of human primary multiple myeloma cells. Primary multiple myeloma cells only expressed functional VEGF receptor (VEGFR)-1, but not VEGFR-2 or VEGFR-3. VEGFR-1 expression was detected in the cytoplasm and the nuclei of proliferating multiple myeloma cells. Inhibition of VEGFR-1 abrogated multiple myeloma cell proliferation and motility, suggesting that the functional interaction of VEGF-A with its cognate receptor is essential for the growth of primary multiple myeloma cells. Collectively, our results suggest that stromal-dependent paracrine and intracrine VEGF-A/VEGFR-1 signaling contributes to human primary multiple myeloma cell growth and therefore, VEGFR-1 blockade is a potential therapeutic strategy for the treatment of multiple myeloma.
Protein Kinase C Inhibition and X-Linked Inhibitor of Apoptosis Protein Degradation Contribute to the Sensitization Effect of Luteolin on Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Cancer Cells
Authors: Shi Ran-Xin , Ong Choon-Nam , Shen Han-Ming
Published: July 2017

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is an important member of the TNF superfamily with great potential in cancer therapy. Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we found that pretreatment with a noncytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29, and HepG2). Such sensitization is achieved through enhanced caspase-8 activation and caspase-3 maturation. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP protected against cell death induced by luteolin and TRAIL, showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation of XIAP. In search of the molecular mechanism responsible for XIAP down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination and proteasomal degradation. Next, we showed that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity, and bisindolylmaleimide I, a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis.
Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone
Authors: Gordon Andrew H. , O'Keefe Regis J. , Schwarz Edward M. , Rosier Randy N. , Puzas J. Edward
Published: July 2017

A central mediator of a wide host of target genes, the nuclear factor-κB (NF-κB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-κB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the bone-seeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IκB that prevents phosphorylation of IκBα and associated nuclear translocation of NF-κB. Blockade of NF-κB signaling in MDA-MB-231 cells by the mutant IκB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-κB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-κB at the bone-tumor interface. NF-κB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-κB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.
Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum
Authors: Wlodarski Pawel , Kasprzycka Monika , Liu Xiaobin , Marzec Michal , Robertson Erle S. , Slupianek Artur , Wasik Mariusz A.
Published: July 2017

The study examines the preponderance and mechanism of mammalian target of rapamycin (mTOR) activation in three distinct types of transformed B lymphocytes that differ in expression of the EBV genome. All three types [EBV-immortalized cells that express a broad spectrum of the virus-encoded genes (type III latency; EBV+/III), EBV-positive cells that express only a subset of the EBV-encoded genes (EBV+/I), and EBV-negative, germinal center–derived cells (EBV−)] universally displayed activation of the mTOR signaling pathway. However, only the EBV+/III transformed B cells displayed also activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that is considered to be the key activator of mTOR and of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway that coactivates one of the immediate targets of mTOR, p70 S6K1. Activation of the PI3K/Akt and MEK/ERK, but not of the mTOR pathway, was inhibited by serum withdrawal and restored by insulin growth factor-I. In contrast, activation of mTOR, but not PI3K/Akt and MEK/ERK, was sensitive to nutrient depletion. Both direct Akt (Akt inhibitors I-III) and a PI3K inhibitor (wortmannin at 1 nmol/L) suppressed Akt phosphorylation without significantly affecting mTOR activation. Furthermore, rapamycin, a potent and specific mTOR inhibitor, suppressed profoundly proliferation of cells from all three types of transformed B cells. U0126, a MEK inhibitor, had a moderate antiproliferative effect only on the EBV+/III cells. These results indicate that mTOR kinase activation is mediated in the transformed B cells by the mechanism(s) independent of the PI3K/Akt signaling pathway. They also suggest that inhibition of mTOR signaling might be effective in therapy of the large spectrum of B-cell lymphomas.
Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo
Authors: van der Pluijm Gabri , Que Ivo , Sijmons Bianca , Buijs Jeroen T. , Löwik Clemens W.G.M. , Wetterwald Antoinette , Thalmann George N. , Papapoulos Socrates E. , Cecchini Marco G.
Published: July 2017

Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc+) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis.
Induction of Polyploidy by Histone Deacetylase Inhibitor: A Pathway for Antitumor Effects
Authors: Xu Wei-Sheng , Perez Gisela , Ngo Lang , Gui Chang-Yun , Marks Paul A.
Published: July 2017

Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21WAF1−/− or HCT116 p53−/− cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21WAF1 or p53 genes.
Lysosomes as Targets for Cancer Therapy
Authors: Fehrenbacher Nicole , Jäättelä Marja
Published: July 2017

Tumor invasion and metastasis are associated with altered lysosomal trafficking and increased expression of the lysosomal proteases termed cathepsins. Emerging experimental evidence suggests that such alterations in lysosomes may form an “Achilles heel” for cancer cells by sensitizing them to death pathways involving lysosomal membrane permeabilization and the release of cathepsins into the cytosol. Here, we highlight recent results on cancer-related changes in the composition and function of lysosomes, focusing on possible implications for the development of novel cancer therapeutics that target tumor cell lysosomes.
Cancer Chemotherapy by Deoxynucleotide Depletion and E2F-1 Elevation
Authors: Wang Ajin , Li Chiang J. , Reddy Prem V. , Pardee Arthur B.
Published: July 2017

We propose that the lethality of commonly used anticancer drugs, e.g., methotrexate and cis-platinum are due, at least in part, to an increase of the E2F-1–mediated apoptotic cascade. The drugs directly or indirectly decrease deoxynucleoside triphosphates. The E2F family acts to provide control of S phase by transcribing genes required for deoxynucleoside triphosphate and DNA synthesis. Thus, a mechanism for control of E2F-1 is essential, a signal safeguarding against aberrant or uncontrolled cell proliferation. We have proposed a feedback control by NTPs that down-regulates E2F-1. Here, we provide evidence in support of this hypothesis.
HYAL1 Hyaluronidase in Prostate Cancer: A Tumor Promoter and Suppressor
Authors: Lokeshwar Vinata B. , Cerwinka Wolfgang H. , Isoyama Tadahiro , Lokeshwar Bal L.
Published: July 2017

Hyaluronidases degrade hyaluronic acid, which promotes metastasis. HYAL1 type hyaluronidase is an independent prognostic indicator of prostate cancer progression and a biomarker for bladder cancer. However, it is controversial whether hyaluronidase (e.g., HYAL1) functions as a tumor promoter or as a suppressor. We stably transfected prostate cancer cells, DU145 and PC-3 ML, with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector DNA. HYAL1-AS transfectants were not generated for PC-3 ML because it expresses little HYAL1. HYAL1-S transfectants produced ≤42 milliunits (moderate overproducers) or ≥80 milliunits hyaluronidase activity (high producers). HYAL1-AS transfectants produced <10% hyaluronidase activity when compared with vector transfectants (18-24 milliunits). Both blocking HYAL1 expression and high HYAL1 production resulted in a 4- to 5-fold decrease in prostate cancer cell proliferation. HYAL1-AS transfectants had a G2-M block due to decreased cyclin B1, cdc25c, and cdc2/p34 expression and cdc2/p34 kinase activity. High HYAL1 producers had a 3-fold increase in apoptotic activity and mitochondrial depolarization when compared with vector transfectants and expressed activated proapoptotic protein WOX1. Blocking HYAL1 expression inhibited tumor growth by 4- to 7-fold, whereas high HYAL1 producing transfectants either did not form tumors (DU145) or grew 3.5-fold slower (PC-3 ML). Whereas vector and moderate HYAL1 producers generated muscle and blood vessel infiltrating tumors, HYAL1-AS tumors were benign and contained smaller capillaries. Specimens of high HYAL1 producers were 99% free of tumor cells. This study shows that, depending on the concentration, HYAL1 functions as a tumor promoter and as a suppressor and provides a basis for anti-hyaluronidase and high-hyaluronidase treatments for cancer.
Identification of Novel p53 Target Genes in Ionizing Radiation Response
Authors: Jen Kuang-Yu , Cheung Vivian G.
Published: July 2017

The tumor suppressor p53 plays an essential role in cellular adaptation to stress. In response to ionizing radiation, p53 regulates the transcription of genes in a diverse set of pathways including DNA repair, cell cycle arrest, and apoptosis. Previously, we identified by microarray analysis a set of genes that are transcriptionally activated or repressed in response to radiation exposure. In this study, we use computational methods and molecular techniques, including location analysis (ChIP-on-chip assay), to identify ionizing radiation–responsive genes that are directly regulated by p53. Among the 489 ionizing radiation–responsive genes examined, 38 genes were found to be p53 targets. Some of these genes are previously known to be directly regulated by p53 whereas others are novel p53 targets. We further showed that the novel p53 target genes are transcriptionally regulated by p53. The binding of p53 to promoters of target genes correlated with increased transcript levels of these genes in cells with functional p53. However, p53 binding and subsequent transcriptional activation of these target genes were significantly diminished in cells with mutant p53 and in cells from patients with ataxia telangiectasia, which have impaired p53 activation following ionizing radiation exposure. Identification and characterization of ionizing radiation–responsive p53 target genes extend our knowledge of the diverse role that p53 plays in the DNA damage response.