bluuebunny/crossref_metadata_2025 huggingface dataset:
The mechanisms of α-H and proton transfers of glycine induced by Mg2+
Authors: Zhang Qing , Meng Xiang-Jun
Published: January 2015

A MP2/6-31++G(d,p)//B3LYP/6-31++G(d,p) method was used to investigate the mechanisms of α- H and proton transfers of glycine induced by Mg 2+. Eight complexes were obtained, six of which were neutral and the other two were zwitterionic. Among them, the zwitterion with a binding energy of 159.4 kcal/mol was the most stable structure. Conformation transformations of the complexes caused by the rotation of single bond and the transfers of α- H and proton were completed via seven transition states. The inductive effect of Mg 2+ made the electron cloud of glycine deviate to Mg 2+, which activated the covalent bond involving the transferred proton. The neutral complex can be turned into the zwitterionic one by the transfers of both carboxyl hydrogen and α- H , and the energy barrier of each reaction was less than 9.2 kcal/mol. After the transfer of α- H , a delocalized π bond was formed in glycine skeleton and the α- C atom took 0.19 positive charges. So the chemical activity of the glycine enhanced, and glycine was readily available for addition and nucleophilic substitution reactions. The path from the most stable glycine conformer G1 to the zwitterionic conformation I is G1 → G1–G3 → G3 → G3–G4 → G4 → G2–G4 → G2 → VI → I–VI → I, and the highest energy barrier of this path is 9.2 kcal/mol.
On correlated reaction sets and coupled reaction sets in metabolic networks
Authors: Marashi Sayed-Amir , Hosseini Zhaleh
Published: January 2015

Two reactions are in the same "correlated reaction set" (or "Co-Set") if their fluxes are linearly correlated. On the other hand, two reactions are "coupled" if nonzero flux through one reaction implies nonzero flux through the other reaction. Flux correlation analysis has been previously used in the analysis of enzyme dysregulation and enzymopathy, while flux coupling analysis has been used to predict co-expression of genes and to model network evolution. The goal of this paper is to emphasize, through a few examples, that these two concepts are inherently different. In other words, except for the case of full coupling, which implies perfect correlation between two fluxes (R2 = 1), there are no constraints on Pearson correlation coefficients (CC) in case of any other type of (un)coupling relations. In other words, Pearson CC can take any value between 0 and 1 in other cases. Furthermore, by analyzing genome-scale metabolic networks, we confirm that there are some examples in real networks of bacteria, yeast and human, which approve that flux coupling and flux correlation cannot be used interchangeably.
Hopf analysis of a differential-algebraic predator–prey model with Allee effect and time delay
Authors: Zhang Xue , Zhang Qingling
Published: January 2015

A differential-algebraic prey–predator model with time delay and Allee effect on the growth of the prey population is investigated. Using differential-algebraic system theory, we transform the prey–predator model into its normal form and study its dynamics in terms of local analysis and Hopf bifurcation. By analyzing the associated characteristic equation, it is observed that the model undergoes a Hopf bifurcation at some critical value of time delay. In particular, we study the direction of Hopf bifurcation and the stability of bifurcated periodic solutions, and an explicit algorithm is given by applying the normal form theory and the center manifold reduction for functional differential equations. Finally, numerical simulations supporting the theoretical analysis are also included.
Study of two-nutrient and two-micro-organism chemostat model with pulsed input in a polluted environment
Authors: Jia Jianwen , Lv Tingting
Published: January 2015

In this paper, a model of Beddington–DeAngelies chemostat involving two species of micro-organism competing for two perfectly complementary growth-limiting nutrients and pulsed input of toxicant in the polluted environment was studied. Using Floquet theory and small amplitude perturbation method, a conclusion was that there exists two-micro-organism eradication periodic solution and which is global asymptotical stability. At the same time, the condition of the permanence for system was obtained. From the biological point of view, the method for protecting species is to improve the amount of impulsive period, and control the amount of toxicant input to the chemostat. Finally, our results are illustrated by numerical simulations.
Effects of skeletal unloading on the vasomotor properties of the rat femur principal nutrient artery
Authors: Prisby Rhonda D. , Behnke Bradley J. , Allen Matthew R. , Delp Michael D.
Published: January 2015

Spaceflight and prolonged bed rest induce deconditioning of the cardiovascular system and bone loss. Previous research has shown declines in femoral bone and marrow perfusion during unloading and with subsequent reloading in hindlimb-unloaded (HU) rats, an animal model of chronic disuse. We hypothesized that the attenuated bone and marrow perfusion may result from altered vasomotor properties of the bone resistance vasculature. Therefore, the purpose of this study was to determine the effects of unloading on the vasoconstrictor and vasodilator properties of the femoral principal nutrient artery (PNA), the main conduit for blood flow to the femur, in 2 wk HU and control (CON) rats. Vasoconstriction of the femoral PNA was assessed in vitro using norepinephrine, phenylephrine, clonidine, KCl, endothelin-1, arginine vasopressin, and myogenic responsiveness. Vasodilation through endothelium-dependent [acetylcholine, bradykinin, and flow-mediated dilation (FMD)] and endothelium-independent mechanisms [sodium nitroprusside (SNP) and adenosine] were also determined. Vasoconstrictor responsiveness of the PNA from HU rats was not enhanced through any of the mechanisms tested. Endothelium-dependent vasodilation to acetylcholine (CON, 86 ± 3%; HU, 48 ± 7% vasodilation) and FMD (CON, 61 ± 9%; HU, 11 ± 11% vasodilation) were attenuated in PNAs from HU rats, while responses to bradykinin were not different between groups. Endothelium-independent vasodilation to SNP and adenosine were not different between groups. These data indicate that unloading-induced decrements in bone and marrow perfusion and increases in vascular resistance are not the result of enhanced vasoconstrictor responsiveness of the bone resistance arteries but are associated with reductions in endothelium-dependent vasodilation.
Chemotherapy-Induced miRNA-29c/Catenin-δ Signaling Suppresses Metastasis in Gastric Cancer
Authors: Wang Yuxuan , Liu Changzheng , Luo Min , Zhang Zhengyi , Gong Jianan , Li Jingjing , You Lei , Dong Lei , Su Rui , Lin Haishuang , Ma Yanni , Wang Fang , Wang Yi , Chen Jie , Zhang Junwu , Jia Hongyan , Kong Yan , Yu Jia
Published: January 2015

Chemotherapy has improved the survival of patients with gastric cancer by unknown mechanisms. In this study, we showed that cisplatin and docetaxel used in gastric cancer treatment increase the expression of miRNA-29 (miR-29) family members and decrease the expression of their oncogenic targets, mediating a significant part of the efficacious benefits of these chemotherapeutic agents. In particular, patients with gastric cancer who experienced recurrences after chemotherapy tended to exhibit low levels of miR-29c expression in their tumors, suggesting that miR-29c activation may contribute to the chemotherapeutic efficacy. Enforced expression of miR-29s in gastric cancer cells inhibited cell invasion in vitro and in vivo by directly targeting catenin-δ (CTNND1). Drug treatment suppressed gastric cancer cell invasion by restoring miR-29c–mediated suppression of catenin-δ and RhoA signaling. In parallel, drug treatment also activated several tumor-suppressive miRNAs, thereby decreasing expression of their oncogenic effector targets. Overall, our findings defined a global mechanism for understanding the efficacious effects of cytotoxic chemotherapy in gastric cancer. Cancer Res; 75(7); 1332–44. ©2015 AACR.
Prostaglandin E2 Inhibits p53 in Human Breast Adipose Stromal Cells: A Novel Mechanism for the Regulation of Aromatase in Obesity and Breast Cancer
Authors: Wang Xuyi , Docanto Maria M. , Sasano Hironobu ,   Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Lo Camden , Simpson Evan R. , Brown Kristy A.
Published: January 2015

Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor–positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E2 (PGE2), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE2 and involved in the PGE2-mediated regulation of aromatase. Results demonstrate that PGE2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE2-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE2. Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li–Fraumeni patients (germline TP53 mutations) compared with non-Li–Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE2 provides a novel mechanism for aromatase regulation in obesity and breast cancer. Cancer Res; 75(4); 645–55. ©2015 AACR.
Emerging Links between E2F Control and Mitochondrial Function
Authors: Benevolenskaya Elizaveta V. , Frolov Maxim V.
Published: January 2015

The family of E2F transcription factors is the key downstream target of the retinoblastoma tumor suppressor protein (pRB), which is frequently inactivated in human cancer. E2F is best known for its role in cell-cycle regulation and triggering apoptosis. However, E2F binds to thousands of genes and, thus, could directly influence a number of biologic processes. Given the plethora of potential E2F targets, the major challenge in the field is to identify specific processes in which E2F plays a functional role and the contexts in which a particular subset of E2F targets dictates a biologic outcome. Recent studies implicated E2F in regulation of expression of mitochondria-associated genes. The loss of such regulation results in severe mitochondrial defects. The consequences become evident during irradiation-induced apoptosis, where E2F-deficient cells are insensitive to cell death despite induction of canonical apoptotic genes. Thus, this novel function of E2F may have a major impact on cell viability, and it is independent of induction of apoptotic genes. Here, we discuss the implications of these findings in cancer biology. Cancer Res; 75(4); 619–23. ©2015 AACR.
Evolutionary Action Score ofTP53Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer
Authors: Neskey David M. , Osman Abdullah A. , Ow Thomas J. , Katsonis Panagiotis , McDonald Thomas , Hicks Stephanie C. , Hsu Teng-Kuei , Pickering Curtis R. , Ward Alexandra , Patel Ameeta , Yordy John S. , Skinner Heath D. , Giri Uma , Sano Daisuke , Story Michael D. , Beadle Beth M. , El-Naggar Adel K. , Kies Merrill S. , William William N. , Caulin Carlos , Frederick Mitchell , Kimmel Marek , Myers Jeffrey N. , Lichtarge Olivier
Published: January 2015

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations. Cancer Res; 75(7); 1527–36. ©2015 AACR.
GOLPH3 Links the Golgi, DNA Damage, and Cancer
Authors: Buschman Matthew D. , Rahajeng Juliati , Field Seth J.
Published: January 2015

GOLPH3 is the first example of an oncogene that functions in secretory trafficking at the Golgi. The discovery of GOLPH3′s roles in both cancer and Golgi trafficking raises questions about how GOLPH3 and the Golgi contribute to cancer. Our recent investigation of the regulation of GOLPH3 revealed a surprising response by the Golgi upon DNA damage that is mediated by DNA-PK and GOLPH3. These results provide new insight into the DNA damage response with important implications for understanding the cellular response to standard cancer therapeutic agents. Cancer Res; 75(4); 624–7. ©2015 AACR.
Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma
Authors: O'Leary Brianne R. , Fath Melissa A. , Bellizzi Andrew M. , Hrabe Jennifer E. , Button Anna M. , Allen Bryan G. , Case Adam J. , Altekruse Sean , Wagner Brett A. , Buettner Garry R. , Lynch Charles F. , Hernandez Brenda Y. , Cozen Wendy , Beardsley Robert A. , Keene Jeffery , Henry Michael D. , Domann Frederick E. , Spitz Douglas R. , Mezhir James J.
Published: January 2015

Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA.

Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA.

Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity.

Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. Clin Cancer Res; 21(7); 1741–51. ©2015 AACR.
Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features
Authors: Rettig Eleni M. , Chung Christine H. , Bishop Justin A. , Howard Jason D. , Sharma Rajni , Li Ryan J. , Douville Christopher , Karchin Rachel , Izumchenko Evgeny , Sidransky David , Koch Wayne , Califano Joseph , Agrawal Nishant , Fakhry Carole
Published: January 2015

The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P < 0.001). Most NOTCH1–wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92–133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90–30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53–399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001–1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1–wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31–276.15; P = 0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein. Cancer Prev Res; 8(4); 287–95. ©2015 AACR.
Resiquimod as an Immunologic Adjuvant for NY-ESO-1 Protein Vaccination in Patients with High-Risk Melanoma
Authors: Sabado Rachel Lubong , Pavlick Anna , Gnjatic Sacha , Cruz Crystal M. , Vengco Isabelita , Hasan Farah , Spadaccia Meredith , Darvishian Farbod , Chiriboga Luis , Holman Rose Marie , Escalon Juliet , Muren Caroline , Escano Crystal , Yepes Ethel , Sharpe Dunbar , Vasilakos John P. , Rolnitzsky Linda , Goldberg Judith D. , Mandeli John , Adams Sylvia , Jungbluth Achim , Pan Linda , Venhaus Ralph , Ott Patrick A. , Bhardwaj Nina
Published: January 2015

The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1–specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1–specific CD4+ T-cell responses. CD8+ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1–specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4+ T-cell responses in the majority of patients; the small proportion of CD8+ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1–specific CD8+ T-cell responses. Cancer Immunol Res; 3(3); 278–87. ©2015 AACR.
Long-Term Outcomes of Organ Preservation in Patients with Small Cell Carcinoma of the Bladder
Authors: Eswara Jairam R. , Heney Niall M. , Wu Chin-Lee , McDougal W. Scott
Published: January 2015

Background: Small cell carcinoma of the bladder is an uncommon but clinically aggressive disease. There is no standard surgical or medical management for the disease. Methods: Between 1995 and 2009, 28 patients underwent transurethral resection (TUR) and/or cystectomy, chemotherapy, and/or radiation for small cell carcinoma of the bladder at our institution. Results: The median follow-up for survivors was 34 months. Patients presented most often with muscle-invasive disease (T2-4 - 89%), and 21% had lymph node/distant metastases. Tobacco use and chemical exposure were noted in 64 and 4% of patients, respectively. Patients with T1-2N0M0 had a median survival of 22 months compared to 8 months for those with more advanced disease (p = 0.03). Patients with T3-4 or nodal/metastatic disease who were given chemotherapy had an improved survival compared to those with T3-4 or nodal/metastatic disease who did not undergo chemotherapy (13 vs. 4 months, p = 0.005). The median time to recurrence of the entire cohort was 8 months, overall and cancer-specific survival was 14 months, and 5-year survival was 11%. Conclusions: Small cell carcinoma of the bladder is an aggressive disease with poor outcomes. Patients with T1-2N0M0 disease survived longer than those with advanced disease. Patients with T3-4 or nodal/metastatic disease had improved survival with chemotherapy.
Trends in Serial Measurements of Ultrasound Markers in Second and Third Trimester Down Syndrome Fetuses
Authors: Vos F.I. , De Jong-Pleij E.A.P. , Bakker M. , Tromp E. , Bilardo C.M.
Published: January 2015

Objectives: To evaluate trends of nasal bone length (NBL), prenasal thickness (PT), nuchal fold (NF), prenasal thickness to nasal bone length (PT-NBL) ratio, and prefrontal space ratio (PFSR), measured serially in second- and third-trimester Down syndrome (DS) fetuses. Methods: Prenatal databases were searched for cases of continuing DS pregnancies with serial measurements, taken at least two weeks apart. Trends were plotted on previously reported normal ranges. Results: Serial measurements were available in 25 Down syndrome fetuses. Median gestational age (GA) was 25 weeks; average number of visits per case was 2.44, with a median interval of 39 days between investigations. In DS fetuses, NBL and PT showed fairly stable trends with gestation. PFSR, but especially NF, had a more unpredictable trend. The PT-NBL ratio was the most stable marker, remaining unchanged in 95% of cases. NBL, PT, and NF showed more deviance from the normal range with advancing gestation, but MoM values remained stable. All but two fetuses had ultrasound markers or structural anomalies, especially heart defects. Conclusions: The PT-NBL ratio is the most constant DS marker throughout gestation, following a predictable trend.
Intestinal Vascular Endothelial Growth Factor Is Decreased in Necrotizing Enterocolitis
Authors: Sabnis Animesh , Carrasco Rosa , Liu Shirley X.L. , Yan Xiaocai , Managlia Elizabeth , Chou Pauline M. , Tan Xiao-Di , De Plaen Isabelle G.
Published: January 2015

Background: Decreased intestinal perfusion may contribute to the development of necrotizing enterocolitis (NEC). Vascular endothelial growth factor (VEGF) is an angiogenic protein necessary for the development and maintenance of capillary networks. Whether VEGF is dysregulated in NEC remains unknown. Objectives: The objective of this study was to determine whether intestinal VEGF expression is altered in a neonatal mouse model of NEC and in human NEC patients. Methods: We first assessed changes of intestinal VEGF mRNA and protein in a neonatal mouse NEC model before significant injury occurs. We then examined whether exposure to formula feeding, bacterial inoculation, cold stress and/or intermittent hypoxia affected intestinal VEGF expression. Last, we visualized VEGF protein in intestinal tissues of murine and human NEC and control cases by immunohistochemistry. Results: Intestinal VEGF protein and mRNA were significantly decreased in pups exposed to the NEC protocol compared to controls. Hypoxia, cold stress and commensal bacteria, when administered together, significantly downregulated intestinal VEGF expression, while they had no significant effect when given alone. VEGF was localized to a few single intestinal epithelial cells and some cells of the lamina propria and myenteric plexus. VEGF staining was decreased in murine and human NEC intestines when compared to control tissues. Conclusion: Intestinal VEGF protein is reduced in human and experimental NEC. Decreased VEGF production might contribute to NEC pathogenesis.
β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor
Authors: Propping Stefan , Newe Manja , Lorenz Kristina , Wirth Manfred P. , Ravens Ursula
Published: January 2015

Aims: To study the β-adrenoceptor subtypes involved in the relaxation responses to (-)-isoprenaline in carbachol-pre-contracted (CCh) mouse detrusor muscle with intact and denuded mucosa. Methods: Isolated muscle strips from the urinary bladder of male C57BL6 mice or β2-adrenoceptor knockout mice were pre-contracted with CCh, 1 µM and relaxed with increasing concentrations of the β-adrenoceptor (β-AR) agonist (-)-isoprenaline and forskolin. For estimating the β-AR subtypes involved, subtype-selective receptor blockers were used, that is, CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Results: Unlike in KCl-pre-contracted muscle, the mucosa did not affect the sensitivity of the relaxation response to (-)-isoprenaline in CCh-pre-contracted murine detrusor strips. Increasing concentrations of (-)-isoprenaline produced a biphasic concentration-relaxation response without any difference both during the presence and absence of mucosa. The relaxation fraction produced by low (-)-isoprenaline concentrations was mediated by β2-AR as evidenced by a shift of the concentration-response curve to higher concentrations with ICI 118,551, but not with CGP 20712A and L748,337, and by the absence of this fraction in β2-AR-KO mice. The relaxation response with low sensitivity to (-)-isoprenaline was not affected by any of the β-AR subtype-selective blockers and was the only response detected in detrusor strips from β2-AR-KO mice. Conclusions: In CCh-pre-contracted mouse detrusor, β2-ARs are responsible for the relaxation component with high sensitivity to (-)-isoprenaline as indicated by the conversion of a biphasic into a monophasic CRC with ICI 118,551 or by its absence in β2-AR KO mice. The mucosa does not impair relaxation under these conditions.
Mesenchymal Stem Cells Recruit Macrophages to Alleviate Experimental Colitis Through TGFβ1
Authors: Liu Weixin , Zhang Shen , Gu Shouzhi , Sang Lixuan , Dai Cong
Published: January 2015

Background/Aims: Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate dextran sulfate sodium (DSS) -induced colitis through modulation of transforming growth factor β (TGFβ) receptor signaling. However, the exact molecular mechanisms are not known. Methods: Here, we transplanted primary mouse MSCs or injected TGFβ1 into mice with DSS-induced colitis. Cells were purified by flow cytometry. Gene expression was analyzed by RT-qPCR. Results: We found that MSCs significantly alleviated the DSS-induced colitis, and the major sources for TGFβ1 were macrophages that were recruited by MSCs. Specific ablation of macrophages completely abolished the anti-inflammatory effects of MSCs. On the other hand, TGFβ1 administration, without the presence of MSCs, was sufficient to reduce the severity of DSS-induced colitis. Conclusions: Taken together, our data suggest that MSCs transplantation may recruit macrophages to produce TGFβ1, which mitigates the pathology of colitis. Thus, MSCs transplantation appears to be a promising therapy for severe enteritis.
SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression
Authors: Song Hongyuan , Pan Dongyan , Sun Weifeng , Gu Cao , Zhang Yuelu , Zhao Ping , Qi Zhongtian , Zhao Shihong
Published: January 2015

Background/Aims: Annexin II receptor (AXIIR) is able to mediate Annexin II signal and induce apoptosis, but its role in angiogenesis remains unclear. This study tries to investigate the role of AXIIR in angiogenesis and the plausible molecular mechanism. Methods/Results: RNA interference technology was used to silence AXIIR, and the subsequent effects in vitro and in vivo were evaluated thereafter. Our data indicated that human umbilical vein endothelial cells (HUVECs) expressed AXIIR and knockdown of AXIIR significantly inhibited HUVECs proliferation, adhesion, migration, and tube formation in vitro and suppressed angiogenesis in vivo. Furthermore, AXIIR siRNA induced cell arrest in the S/G2 phase while had no effect on cell apoptosis. We found that these subsequent effects might be via suppressing the expression of matrix metalloproteinase 2and matrix metalloproteinase 9. Conclusion: AXIIR participates in angiogenesis, and may be a potential therapeutic target for angiogenesis related diseases.
DNA Damage-Induced NF-κB Activation in Human Glioblastoma Cells Promotes miR-181b Expression and Cell Proliferation
Authors: Xu Rui-Xue , Liu Rong-Yao , Wu Chun-Ming , Zhao Yong-Shun , Li Yang , Yao Yi-Qun , Xu Ying-Hui
Published: January 2015

Background: Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. After surgery, radiotherapy is the mainstay of treatment for GBM patients. Unfortunately, the vast majority of GBM patients fail responding to radiotherapy because GBM cells remain highly resistant to radiation. Radiotherapy-induced DNA damage response may correlate with therapeutic resistance. Methods: Ionizing radiation (IR) was used to induce DNA damage. Cell proliferation and migration were detected by wound-healing, MTT and apoptosis assays. Dual-luciferase assays and Western blot analysis were performed to evaluate NF-κB activation and validate microRNA targets. Real-time PCR was used to study mRNA and microRNA levels. Results: IR-induced DNA damage activated NF-κB in GBM cells which promoted expression of IL-6, IL-8 and Bcl-xL, thereby contributing to cell survival and invasion. Knockdown SENP2 expression enhanced NF-κB essential modulator (NEMO) SUMOylation and NF-κB activity following IR exposure. miR-181b targets SENP2 and positively regulated NF-κB activity. Conclusion: NF-κB activation by DNA damage in GBM cells confers resistance to radiation-induced death.
Future Directions in the Study of Health Behavior among Older Adults
Authors: Ziegelmann Jochen P. , Knoll Nina
Published: January 2015

The study of health behaviors and fostering health-behavior change is an important endeavor even in old age. The aim of this viewpoint article is threefold. First, we use a broad perspective for the definition of health behaviors to capture all relevant aspects of health-behavior change in older adults. Particularly, we suggest a distinction between proximal (e.g., physical activity) and distal health behaviors (e.g., social participation). Second, we recommend a stronger orientation towards processes in order to study health behaviors and the design of health-behavior change interventions. Third, we review the advantages of a developmental perspective in health psychology. Future directions in the study of health behavior among older adults are discussed.
A Prospective Open-Label Study to Assess the Efficacy and Safety of a Herbal Medicinal Product (Sinupret) in Patients with Acute Rhinosinusitis
Authors: Passali Desiderio , Loglisci Michele , Passali Giulio Cesare , Cassano Pasquale , Rodriguez Hugo Anibal , Bellussi Luisa Maria
Published: January 2015

Aims: We present a multicenter, prospective, open-label study to assess the efficacy and safety of a phytomedicine. The aim of the research was to evaluate the efficacy and safety of 14 days of treatment with Sinupret for acute rhinosinusitis. Sinupret is a herbal preparation used to restore and maintain the physiological function of the membranes in the sinus cavity. Methods: Sixty patients with acute rhinosinusitis based on the EPOS guidelines were enrolled in the study. Thirty patients were treated with Sinupret Forte, while 30 patients were treated with intranasal fluticasone furoate. The criteria for the evaluation of efficacy were the major symptom scores according to the investigator and the Health-Related Quality of Life score. The criteria used to evaluate safety were the number of patients with adverse events, the patients' vital signs, and laboratory safety. Results: All patients considered showed significant improvements in symptoms. Among the patients treated with Sinupret, none had an adverse event, while 3 patients treated with fluticasone furoate had minor adverse events. The patients' vital signs and laboratory values were normal. Conclusions: The results of this study suggest that this phytomedicinal preparation has a significant level of efficacy in acute rhinosinusitis and that treatment is safe.
Active Bone Conduction System: Outcomes with the Bonebridge Transcutaneous Device
Authors: Bianchin Giovanni , Bonali Marco , Russo Melania , Tribi Lorenzo
Published: January 2015

Objective: To describe our experience with positioning the Bonebridge (BB) device, a semi-implantable transcutaneous bone conduction implant for patients with conductive and mixed hearing loss as well as for those suffering from single-sided deafness. Methods: The following is a retrospective case review of 4 adults suffering from conductive or mixed hearing loss and single-sided deafness. The BB device was implanted unilaterally via 2 different approaches selected case by case: the presigmoid transmastoid and the retrosigmoid approach. An audiological evaluation in the free field was conducted to observe the functional benefit with this device. The Glasgow Health Status Inventory (GHSI) and the Glasgow Benefit Inventory (GBI) questionnaires were filled out to evaluate patients' quality of life in relationship to the intervention. Results: No intra- or postoperative complications were observed. The performance in the speech test in all 4 cases reached 100% in the aided condition at 65 dB, while in the unaided condition at 65 dB, it was less than 10%. The GHSI and GBI questionnaires showed an improvement in quality of life after implantation. Conclusions: The BB device is a safe and effective solution for individuals with pathologies such as chronic otitis media, atresia auris and otosclerosis with inadequate benefit from conventional surgery or bone conduction hearing aids.
Renal C3 Complement Component: Feed Forward to Diabetic Kidney Disease
Authors: Kelly Katherine J. , Liu Yunlong , Zhang Jizhong , Dominguez Jesus H.
Published: January 2015

Background: Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions. Methods: Comprehensive genomic profiling (RNAseq) was employed in the ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates. Results: Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by the activation of the renal complement system in DI, and to a lesser extent in sham-operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8, and C9 over sham-operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibit the membrane attack complex. C3, C4, and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3-generating renal tubular cells and other immune competent migratory cells. Conclusions: We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy.
Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression
Authors: Jiang Hong , Huang Shuhong , Li Xinyun , Li Xian , Zhang Yun , Chen Zhe-Yu
Published: January 2015

Objective—

Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor. In addition to its nervous system functions, TrkB is also expressed in the cardiovascular system. However, the association of TrkB and coronary artery disease (CAD) remains unknown. We investigated the role of TrkB in the development of CAD and its mechanism.

Approach and Results—

We performed a case–control study in 2 independent cohort of Chinese subjects and found –69C>G polymorphisms of TrkB gene significantly associated with CAD. TrkB –69C homozygotes, which corresponded to decreased TrkB expression by luciferase reporter assay, showed increased risk for CAD. Immunofluorescence analysis revealed that TrkB was expressed in the aortic endothelium in atherosclerotic lesions in humans and ApoE
–/–
mice. TrkB knockdown in the aortic endothelium resulted in vascular leakage in ApoE
–/–
mice. Mechanistic studies showed that TrkB regulated vascular endothelial cadherin (VE-cadherin) expression through induction and activation of Ets1 transcriptional factor. Importantly, TrkB activation attenuated proatherosclerotic factors induced-endothelial hyperpermeability in human vascular endothelial cells.

Conclusions—

Our data demonstrate that TrkB protects endothelial integrity during atherogenesis by promoting Ets1-mediated VE-cadherin expression and plays a previously unknown protective role in the development of CAD.
Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Patients With Abdominal Aortic Aneurysms
Authors: Kristensen Karl Emil , Torp-Pedersen Christian , Gislason Gunnar Hilmar , Egfjord Martin , Rasmussen Henrik Berg , Hansen Peter Riis
Published: January 2015

Objective—

The renin–angiotensin system is thought to play a pivotal role in the pathogenesis of abdominal aortic aneurysms (AAAs). However, effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) on human AAAs remain unclear. We therefore examined whether treatment with ACEIs or ARBs influenced hard clinical end points in a nation-wide cohort of patients with AAA.

Approach and Results—

All patients diagnosed with AAA during the period 1995 to 2011 were identified from the Danish nation-wide registries. Subjects were divided according to ACEI and ARB treatment status and followed up for an average of 5 years. Study outcomes were evaluated by time-dependent Cox proportional hazard models. Of 9441 patients with AAA, 12.6% were treated with ACEIs and 5.0% received ARBs. Incidence rates of death from AAA per 100 patient-years were 3.7, 3.6, 4.0, and 4.7 for treatment with ACEIs or ARBs, ACEIs, ARBs, and no ACEI/ARB, respectively. Hazard ratios of death from AAA were 0.64 (95% confidence interval, 0.51–0.80;
P
<0.001) for patients receiving ACEIs and 0.65 (95% confidence interval, 0.48–0.88;
P
=0.006) for those receiving ARBs, respectively (
P
for difference=0.944). The risk of surgery for AAA was significantly reduced in patients receiving ACEIs (hazard ratio, 0.86 [95% confidence interval, 0.74–0.99];
P
=0.040) but not in patients receiving ARBs (hazard ratio, 1.02 [95% confidence interval, 0.84–1.23];
P
=0.867;
P
for difference=0.119).

Conclusions—

In this observational study, treatment with ACEIs or ARBs was associated with a comparable reduction in mortality but not in surgery for AAA among patients with AAA. Randomized controlled trials are warranted to confirm these findings.
SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification
Authors: Sánchez-Duffhues Gonzalo , de Vinuesa Amaya García , Lindeman Jan H. , Mulder-Stapel Adri , DeRuiter Marco C. , Van Munsteren Conny , Goumans Marie-José , Hierck Beerend P. , ten Dijke Peter
Published: January 2015

Objective—

Arterial calcification is considered a major cause of death and disabilities worldwide because the associated vascular remodeling leads to myocardial infarction, stroke, aneurysm, and pulmonary embolism. This process occurs via poorly understood mechanisms involving a variety of cell types, intracellular mediators, and extracellular cues within the vascular wall. An inverse correlation between endothelial primary cilia and vascular calcified areas has been described although the signaling mechanisms involved remain unknown. We aim to investigate the signaling pathways regulated by the primary cilium that modulate the contribution of endothelial cells to vascular calcification.

Approach and Results—

We found that human and murine endothelial cells lacking primary cilia are prone to undergo mineralization in response to bone morphogenetic proteins stimulation in vitro. Using the Tg737
orpk/orpk
cillium-defective mouse model, we show that nonciliated aortic endothelial cells acquire the ability to transdifferentiate into mineralizing osteogenic cells, in a bone morphogenetic protein–dependent manner. We identify β-CATENIN–induced SLUG as a key transcription factor controlling this process. Moreover, we show that the endothelial expression of SLUG is restricted to atheroprone areas in the aorta of LDLR
−/−
mice. Finally, we demonstrate that SLUG and phospho-homolog of the Drosophila protein, mothers against decapentaplegic (MAD) and the
Caenorhabditis elegans
protein SMA (from gene sma for small body size)-1/5/8 expression increases in endothelial cells constituting the vasa vasorum in the human aorta during the progression toward atherosclerosis.

Conclusions—

We demonstrated that the lack of primary cilia sensitizes the endothelium to undergo bone morphogenetic protein–dependent-osteogenic differentiation. These data emphasize the role of the endothelial cells on the vascular calcification and uncovers SLUG as a key target in atherosclerosis.
Robocygne: Dancing Life into an Animal-Human-Machine
Authors: Unander-Scharin Åsa , Unander-Scharin Carl
Published: January 2015

Robocygne is an artistic project that revolves around the development of a custom-built robotic bird, dancing to a remix of Tchaikovsky’s Swan Lake. The artists created the choreography through a process in which movements were danced into the robot by the choreographer’s manipulation of the bird’s limbs, by hand, to the music. To enable this multitracking procedure, the artists, in collaboration with the engineers, developed novel software that allowed overlying recording of motions in synchronization with an audio track. From an artistic perspective, the authors discuss the search for choreographic and musical qualities and emphasize how material aspects of body and technology interrelate with emotional expression in Robocygne.
From Persepolis to Jerusalem: A Reevaluation of Old Persian-Hebrew Contact in the Achaemenid Period
Authors: Wilson-Wright Aren
Published: January 2015

This paper examines the effects and mechanisms of Old Persian contact on Biblical Hebrew. I first reevaluate the number and distribution of Old Persian loanwords in the Hebrew Bible. Then I demonstrate that there was direct contact between speakers of Old Persian and speakers of Hebrew in the Achaemenid period beginning under Artaxerxes i, before proposing the existence of two Old Persian calques in Biblical Hebrew. The distribution of these Old Persian loanwords and calques strengthens the case for distinguishing between Late Biblical Hebrew and Classical Biblical Hebrew on linguistic grounds. With one exception, these features cluster in well-known Late Biblical Hebrew texts.
Debt and the Decalogue: The Tenth Commandment
Authors: Kessler Rainer
Published: January 2015

This article seeks to demonstrate that the question of debt is present in the Decalogue. It is included in the last (or the last two) commandments: “You shall not covet your neighbour’s house; you shall not covet your neighbour’s wife etc.” (Exod 20:17). Obviously, this commandment must have a meaning that differs from the commandments not to commit adultery and not to steal. The main means for taking over possession of the goods of others, besides stealing them, was debt. The loan of goods or money involved the handing over of a pledge. If the debtor was unable to repay the debt he lost fields and houses. Mic 2:1-2, where the same word “to covet” is used as in the Decalogue, is best explained by such mechanisms of the old Israelite debt system: the rich and powerful who “covet fields” do “seize” fields and houses because their current owners are not able to refund their debt. What is true for mobile and immobile goods is also true for persons. Neh 5:1-5 demonstrates that daughters and sons had to be given away as slaves because parents were “having to borrow money”. In dire straights, it was also possible that a wife could become the slave of another. In Elephantine a case is documented in which the wife of one man at the same time is the slave of another. So the commandment of the Decalogue not to “covet your neighbor’s wife” has nothing to do with sexual relations. It forbids the desire to take one’s neighbour’s wife as a slave in one’s own household.
Future Projection of Ocean Wave Climate: Analysis of SST Impacts on Wave Climate Changes in the Western North Pacific
Authors: Shimura Tomoya , Mori Nobuhito , Mase Hajime
Published: January 2015

Changes in ocean surface waves elicit a variety of impacts on coastal environments. To assess the future changes in the ocean surface wave climate, several future projections of global wave climate have been simulated in previous studies. However, previously there has been little discussion about the causes behind changes in the future wave climate and the differences between projections. The objective of this study is to estimate the future changes in mean wave climate and the sensitivity of the wave climate to sea surface temperature (SST) conditions in an effort to understand the mechanism behind the wave climate changes by specifically looking at spatial SST variation. A series of wave climate projections forced by surface winds from the MRI-AGCM3.2 were conducted based on SST ensemble experiments. The results yield future changes in annual mean wave height that are within about ±0.3 m. The future changes in summertime wave height in the western North Pacific (WNP), which are influenced by tropical cyclone changes, are highly sensitive to SST conditions. To generalize the result, the wave climate change and SST relation found by this study was compared with multimodel wave ensemble products from the Coordinated Ocean Wave Climate Project (COWCLIP). The spatial variation of SST in the tropical Pacific Ocean is a major factor in the wave climate changes for the WNP during summer.