bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait
Authors: Rodríguez-Arias M. , Roger-Sánchez C. , Vilanova I. , Revert N. , Manzanedo C. , Miñarro J. , Aguilar M. A.
Published: December 2015

Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.
An Identification Method for the Unbalance Parameters of a Rotor-Bearing System
Authors: Mao Wengui , Liu Guiping , Li Jianhua , Liu Jie
Published: December 2015

This paper is to be submitting an identification method for the unbalance parameters of a rotor-bearing system. In the method, the unbalance parameters identification problem is formulated as the unbalance force reconstruction which belongs to solving deconvolution problem, in which the unbalance force is expressed in the time domain. The unbalance response is expressed by the convolution integral of Green’s function and the unbalance force. In order to avoid the unstable solution arising from the noisy responses and the deconvolution, a regularization method is adopted to stabilize the solution. Meanwhile, a searching of the sensitive measured point has also been carried out to confirm the robustness of the method. Numerical example and a test rig have been used to illustrate the proposed method.
Gastrointestinal Symptoms of Patients with Fabry Disease
Authors: Pensabene Licia , Sestito Simona , Nicoletti Angela , Graziano Francesca , Strisciuglio Pietro , Concolino Daniela
Published: December 2015

In order to characterize gastrointestinal (GI) symptoms of 50 patients with Fabry disease (FD) (22 M; age range: 4–70 y; 35 adults and 15 children), validated questionnaires of GI symptoms were used to diagnose the functional gastrointestinal disorders (FGIDs) of the patients with GI symptoms (33/50 (66%); 25/35 adults and 8/15 children) according to Rome III criteria. In 16/25 of these adults and 2/8 of these children, the symptoms mimicked FGID. The adult subgroup included patients with unspecified functional bowel disorder (n=9), functional bloating (n=7), and IBS (n=5), and the child subgroup included patients with abdominal migraine (n=1) and IBS (n=1). Among the 25 adults, 14 reported feeling full after a regular-size meal, and 12 complained of abdominal bloating/distension. All of the children with GI symptoms complained of low abdominal pain associated with changes in the form of the stool/improvements with defecation. In conclusion, according to Rome III criteria, the most frequent diagnoses of FGID among the adults with FD were unspecified functional bowel disorder, followed by functional bloating and IBS. The most frequent GI symptom in the children in our population was IBS-like abdominal pain, while the adults exhibited a full feeling following a regular-size meal and abdominal bloating/distension.
Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer
Authors: Farren Matthew R. , Mace Thomas A. , Geyer Susan , Mikhail Sameh , Wu Christina , Ciombor Kristen , Tahiri Sanaa , Ahn Daniel , Noonan Anne M. , Villalona-Calero Miguel , Bekaii-Saab Tanios , Lesinski Gregory B.
Published: December 2015

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients.

Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry.

Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62).

Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565–74. ©2015 AACR.
Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy
Authors: Kohlhapp Frederick J. , Kaufman Howard L.
Published: December 2015

Oncolytic viruses are native or engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more efficient viral replication, and with selected deletion of specific viral genes, replication in normal cells with activated PKR may not be possible. Direct tumor cell lysis, release of soluble tumor antigens, and danger-associated molecular factors are all thought to help prime and promote tumor-specific immunity. Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type I and is the first oncolytic virus to demonstrate a clinical benefit in patients with melanoma. T-VEC has also been evaluated for the treatment of head and neck cancer, pancreatic cancer, and likely other types of cancer will be targeted in the near future. T-VEC has been modified for improved safety, tumor-selective replication, and induction of host immunity by deletion of several viral genes and expression of human granulocyte-macrophage colony stimulating factor. Although the mechanism of action for T-VEC is incompletely understood, the safety profile of T-VEC and ability to promote immune responses suggest future combination studies with other immunotherapy approaches including checkpoint blockade through PD-1, PD-L1, and CTLA-4 to be a high priority for clinical development. Oncolytic viruses also represent unique regulatory and biosafety challenges but offer a potential new class of agents for the treatment of cancer. Clin Cancer Res; 22(5); 1048–54. ©2015 AACR.
Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia
Authors: Nemoto Atsushi , Saida Satoshi , Kato Itaru , Kikuchi Jiro , Furukawa Yusuke , Maeda Yasuhiro , Akahane Koshi , Honna-Oshiro Hiroko , Goi Kumiko , Kagami Keiko , Kimura Shinya , Sato Yuko , Okabe Seiichi , Niwa Akira , Watanabe Kenichiro , Nakahata Tatsutoshi , Heike Toshio , Sugita Kanji , Inukai Takeshi
Published: December 2015

S-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph+ ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph+ ALL cell lines in the nanomolar range by the induction of G0–G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph+ lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph+ lymphoid leukemia cells was significantly higher than that in Ph− lymphoid leukemia cells. Of note, three Ph+ ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph+ ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph+ ALL patients after treatment with tyrosine kinase inhibitors. Mol Cancer Ther; 15(1); 94–105. ©2015 AACR.
Activation of EGFR Bypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells
Authors: Tani Tetsuo , Yasuda Hiroyuki , Hamamoto Junko , Kuroda Aoi , Arai Daisuke , Ishioka Kota , Ohgino Keiko , Miyawaki Masayoshi , Kawada Ichiro , Naoki Katsuhiko , Hayashi Yuichiro , Betsuyaku Tomoko , Soejima Kenzo
Published: December 2015

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non–small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling. Mol Cancer Ther; 15(1); 162–71. ©2015 AACR.
Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues
Authors: Zhu Charles , Bandekar Amey , Sempkowski Michelle , Banerjee Sangeeta Ray , Pomper Martin G. , Bruchertseifer Frank , Morgenstern Alfred , Sofou Stavroula
Published: December 2015

This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of α-particle emitters by using different radionuclide carriers in the setting of targeted antivascular α-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the α-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four α-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of α-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of α-particle emitters. Mol Cancer Ther; 15(1); 106–13. ©2015 AACR.
AT2R Gene Delivered by Condensed Polylysine Complexes Attenuates Lewis Lung Carcinoma after Intravenous Injection or Intratracheal Spray
Authors: Alhakamy Nabil A. , Ishiguro Susumu , Uppalapati Deepthi , Berkland Cory J. , Tamura Masaaki
Published: December 2015

Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Cell-penetrating peptides (CPP) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Here, a synthetic CPP (polylysine, K9 peptide) was complexed with angiotensin II type 2 receptor (AT2R) plasmid DNA (pAT2R) and complexes were condensed using calcium chloride. The resulting complexes were small (∼150 nm) and showed high levels of gene expression in vitro and in vivo. This simple nonviral formulation approach showed negligible cytotoxicity in four different human cell lines (cervix, breast, kidney, and lung cell lines) and one mouse cell line (a lung cancer cell line). In addition, this K9-pDNA-Ca2+ complex demonstrated cancer-targeted gene delivery when administered via intravenous injection or intratracheal spray. The transfection efficiency was evaluated in Lewis lung carcinoma (LLC) cell lines cultured in vitro and in orthotopic cancer grafts in syngeneic mice. Immunohistochemical analysis confirmed that the complex effectively delivered pAT2R to the cancer cells, where it was expressed mainly in cancer cells along with bronchial epithelial cells. A single administration of these complexes markedly attenuated lung cancer growth, offering preclinical proof-of-concept for a novel nonviral gene delivery method exhibiting effective lung tumor gene therapy via either intravenous or intratracheal administration. Mol Cancer Ther; 15(1); 209–18. ©2015 AACR.
A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non–Small Cell Lung Cancer Cell Lines
Authors: Zubovych Iryna O. , Sethi Anirudh , Kulkarni Aditya , Tagal Vural , Roth Michael G.
Published: December 2015

SW044248, identified through a screen for chemicals that are selectively toxic for non–small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A. Mol Cancer Ther; 15(1); 23–36. ©2015 AACR.
Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor
Authors: Rosebeck Shaun , Alonge Mattina M. , Kandarpa Malathi , Mayampurath Anoop , Volchenboum Samuel L. , Jasielec Jagoda , Dytfeld Dominik , Maxwell Sean P. , Kraftson Stephanie J. , McCauley Dilara , Shacham Sharon , Kauffman Michael , Jakubowiak Andrzej J.
Published: December 2015

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.
Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity
Authors: Yan Haoheng , Endo Yukinori , Shen Yi , Rotstein David , Dokmanovic Milos , Mohan Nishant , Mukhopadhyay Partha , Gao Bin , Pacher Pal , Wu Wen Jin
Published: December 2015

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1–induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1–induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1–induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1–induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1–induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. Mol Cancer Ther; 15(3); 480–90. ©2015 AACR.
Mutated Pathways as a Guide to Adjuvant Therapy Treatments for Breast Cancer
Authors: Liu Yang , Hu Zhenjun , DeLisi Charles
Published: December 2015

Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy, if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here, we report a correlation between adjuvant strategy and mutated pathway patterns. In particular, we find that for breast cancer patients, pathways enriched in nonsynonymous mutations in the chemotherapy group are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same—generally large—number of samples. In particular, we find the following: (i) a chemotherapy group consisting of three pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive; (ii) each group is highly enriched in breast cancer drivers; and (iii) the pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available. Mol Cancer Ther; 15(1); 184–9. ©2015 AACR.
A Fast Hydrogen Sulfide–Releasing Donor Increases the Tumor Response to Radiotherapy
Authors: De Preter Géraldine , Deriemaeker Caroline , Danhier Pierre , Brisson Lucie , Cao Pham Thanh Trang , Grégoire Vincent , Jordan Bénédicte F. , Sonveaux Pierre , Gallez Bernard
Published: December 2015

Hydrogen sulfide (H2S) is the last gaseous transmitter identified in mammals, and previous studies have reported disparate conclusions regarding the implication of H2S in cancer progression. In the present study, we hypothesized that sodium hydrosulfide (NaHS), a fast H2S-releasing donor, might interfere with the mitochondrial respiratory chain of tumor cells, increase tumor oxygenation, and potentiate the response to irradiation. Using electron paramagnetic resonance (EPR) oximetry, we found a rapid increase in tumor pO2 after NaHS administration (0.1 mmol/kg) in two human tumor models (breast MDA-MB-231 and cervix SiHa), an effect that was due to a decreased oxygen consumption and an increased tumor perfusion. Tumors irradiated 15 minutes after a single NaHS administration were more sensitive to irradiation compared with those that received irradiation alone (increase in growth delay by 50%). This radiosensitization was due to the oxygen effect, as the increased growth delay was abolished when temporarily clamped tumors were irradiated. In contrast, daily NaHS injection (0.1 mmol/kg/day for 14 days) did not provide any effect on tumor growth in vivo. To understand these paradoxical data, we analyzed the impact of external factors on the cellular response to NaHS. We found that extracellular pH had a dramatic effect on the cell response to NaHS, as the proliferation rate (measured in vitro by BrdU incorporation) was increased at pH = 7.4, but decreased at pH = 6.5. Overall, our study highlights the complex role of environmental components in the response of cancer cells to H2S and suggests a new approach for the use of H2S donors in combination with radiotherapy. Mol Cancer Ther; 15(1); 154–61. ©2015 AACR.
An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors
Authors: Szablowski Jerzy O. , Raskatov Jevgenij A. , Dervan Peter B.
Published: December 2015

Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration, and cancer. Hypoxia-inducible factor-1 (HIF1), a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis, and cell survival. Pyrrole-imidazole polyamide 1 has been shown to inhibit HIF1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels, and suppresses tumor growth. Tumors treated with 1 show no increase in HIF1α and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF1α-positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF1 has potent antitumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response. Mol Cancer Ther; 15(4); 608–17. ©2015 AACR.
Alai! Alai! – a new species of the Gloydius halys (Pallas, 1776) complex (Viperidae, Crotalinae), including a brief review of the complex
Authors: Wagner Philipp , Tiutenko Arthur , Mazepa Glib , Borkin Leo J. , Simonov Evgeniy
Published: December 2015

During a scientific field expedition to the Alai-Pamir range five specimens of the genus Gloydius have been collected in the larger Alai. A morphological and genetical examination of the specimens has shown that they are part of the G. halys complex, but represent a new taxon which is characterized by the following unique character combination: It is a slender and moderately stout small snake, up to 479 mm total length. The head has nine symmetrical plates on the upper head, 7 supralabial and 8-9 infralabial scales. Body scales in 20-22 rows around midbody, 143-156 ventral and 35-45 usually paired subcaudal scales. The cloacal plate not divided. The general coloration consists of various different tones of olive, tan and brown, having a distinct head, but an indistinct body pattern with, excluding the tail, 26-29 transverse crossbands, which are not extending to the sides of the body. The haplotype network shows the new species within the G. halys complex and close related to both, G. h. halys and G. h. caraganus. So far the new described species is only known from the Alai range. However, various Gloydius specimens are found in Kyrgyzstan and because of the complicated taxonomy those specimens have to re-identified to clarify their status and the status of the new species.
The South American Water Balance: The Influence of Low-Level Jets
Authors: Guedes do Nascimento Marília , Herdies Dirceu Luis , Oliveira de Souza Diego
Published: December 2015

To study the climatology of the water balance over South America and analyze the influence of low-level jets (LLJs), a climate study of the water balance and its main components was performed, specifically in the Amazon and La Plata basin (LPB) region, from 1979 to 2008. The results showed that on average for the analysis period, the Amazon basin and LPB performed as a sink of moisture (ET < P) and as a moisture convergence for the regions, which accounted for approximately 62% and 43% of the precipitation, respectively. During the study period, 884 days with an occurrence of LLJs were observed, occurring most frequently during the winter and around 0000 and 0600 UTC. When considering the water balance for the days with LLJs, it was observed that the Amazon acts as a source of moisture, especially in the dry season, and that the LPB behaves as a sink during all months. The influence of the LLJ as a modulator for precipitation on the LPB is clear, as the precipitation is 32% higher during the LLJ events compared with days without LLJs. This main pattern shows that the moisture convergence trough of the LLJs is crucial for the water balance on the LPB, whereas evapotranspiration is a more important variable of the water balance on the Amazon basin with or without the LLJs.
Diversity, Nonlinearity, Seasonality, and Memory Effect in ENSO Simulation and Prediction Using Empirical Model Reduction
Authors: Chen Chen , Cane Mark A. , Henderson Naomi , Lee Dong Eun , Chapman David , Kondrashov Dmitri , Chekroun Mickaël D.
Published: December 2015

A suite of empirical model experiments under the empirical model reduction framework are conducted to advance the understanding of ENSO diversity, nonlinearity, seasonality, and the memory effect in the simulation and prediction of tropical Pacific sea surface temperature (SST) anomalies. The model training and evaluation are carried out using 4000-yr preindustrial control simulation data from the coupled model GFDL CM2.1. The results show that multivariate models with tropical Pacific subsurface information and multilevel models with SST history information both improve the prediction skill dramatically. These two types of models represent the ENSO memory effect based on either the recharge oscillator or the time-delayed oscillator viewpoint. Multilevel SST models are a bit more efficient, requiring fewer model coefficients. Nonlinearity is found necessary to reproduce the ENSO diversity feature for extreme events. The nonlinear models reconstruct the skewed probability density function of SST anomalies and improve the prediction of the skewed amplitude, though the role of nonlinearity may be slightly overestimated given the strong nonlinear ENSO in GFDL CM2.1. The models with periodic terms reproduce the SST seasonal phase locking but do not improve the prediction appreciably. The models with multiple ingredients capture several ENSO characteristics simultaneously and exhibit overall better prediction skill for more diverse target patterns. In particular, they alleviate the spring/autumn prediction barrier and reduce the tendency for predicted values to lag the target month value.
A Temporal Kernel Method to Compute Effective Radiative Forcing in CMIP5 Transient Simulations*
Authors: Larson Erik J. L. , Portmann Robert W.
Published: December 2015

Effective radiative forcing (ERF) is calculated as the flux change at the top of the atmosphere after allowing rapid adjustments resulting from a forcing agent, such as greenhouse gases. Rapid adjustments include changes to atmospheric temperature, water vapor, and clouds. Accurate estimates of ERF are necessary in order to understand the drivers of climate change. This work presents a new method of calculating ERF using a kernel derived from the time series of a model variable (e.g., global mean surface temperature) in a model-step change experiment. The top-of-atmosphere (TOA) radiative imbalance has the best noise tolerance for retrieving the ERF of the model variables tested. This temporal kernel method is compared with an energy balance method, which equates ERF to the TOA radiative imbalance plus the scaled surface temperature change. Sensitivities and biases of these methods are quantified using output from phase 5 of the the Coupled Model Intercomparison Project (CMIP5). The temporal kernel method is likely more accurate for models in which a linear fit is a poor approximation for the relationship between temperature change and TOA imbalance. The difference between these methods is most apparent in forcing estimates for the representative concentration pathway 8.5 (RCP8.5) scenario. The CMIP5 multimodel mean ERF calculated for large volcanic eruptions is 80% of the adjusted forcing reported by the IPCC Fifth Assessment Report (AR5). This suggests that about 5% more energy has come into the earth system since 1870 than suggested by the IPCC AR5.
A Climatology of Southern Appalachian Cold-Air Damming*
Authors: Rackley Jared A. , Knox John A.
Published: December 2015

A 30-yr climatology (1981–2010) of cold-air damming (CAD) events in the southern Appalachians was conducted using hourly surface observations and North American Regional Reanalysis (NARR) data. Analysis of the spatial distribution and frequency of these events reveals that some part of the Southeast is affected by CAD on 50 days out of each year, and even the northern Florida panhandle and much of Alabama experience CAD conditions on about 30 days annually. Spatially, different CAD types tend to exhibit one of two patterns in the southernmost extent of the cold-air dome: a more southerly dome with a ridge axis oriented from north-northeast to south-southwest or a more westerly dome with a ridge axis in a northeast to west-southwest orientation. These patterns may be the result of both splitting around the region of higher terrain in east-central Alabama and Coriolis forcing in stronger CAD types with higher wind speeds. Analysis of the frequency of CAD by type on a month-by-month and year-by-year basis confirms previous work that CAD is much more frequent during the cold season versus the warm season, with CAD occurring on 6.8 days month−1 during December and only 1.3 days month−1 during July. Analysis was also stratified by CAD type, revealing that weak/dry events were the most common. Classical type events with stronger and more favorably positioned parent highs exhibited the longest average duration, nearly 45 h, while other CAD types averaged approximately half as long.
Regionalism, Ethnic Diversity, and Variation in Public Good Provision by National States
Authors: Soifer Hillel David
Published: December 2015

This article argues that variation in public good provision is determined by the salience of demographic and economic regionalism, conceptualized as the presence of multiple large population centers and distinct economic units within a single country’s borders. Two mechanisms—divergent public good preferences and regional self-sufficiency—underpin this relationship. Evidence of these mechanisms as central to low public good provision is found in case studies of Ecuador and Colombia, two countries that score high on standard measures of ethnic diversity and that saw little public good provision during the first century after independence. A region-wide examination of post-independence South America and an investigation of change over time in Venezuela provide further support for the claim that regionalism affects public good provision. A plausible case for this aspect of geography as a cause of low public good provision poses a challenge to the scholarship attributing it to ethnic diversity.
Analysis of Food Hub Commerce and Participation Using Agent-Based Modeling
Authors: Krejci Caroline C. , Stone Richard T. , Dorneich Michael C. , Gilbert Stephen B.
Published: December 2015

Objective:

Factors influencing long-term viability of an intermediated regional food supply network (food hub) were modeled using agent-based modeling techniques informed by interview data gathered from food hub participants.

Background:

Previous analyses of food hub dynamics focused primarily on financial drivers rather than social factors and have not used mathematical models.

Method:

Based on qualitative and quantitative data gathered from 22 customers and 11 vendors at a midwestern food hub, an agent-based model (ABM) was created with distinct consumer personas characterizing the range of consumer priorities. A comparison study determined if the ABM behaved differently than a model based on traditional economic assumptions. Further simulation studies assessed the effect of changes in parameters, such as producer reliability and the consumer profiles, on long-term food hub sustainability.

Results:

The persona-based ABM model produced different and more resilient results than the more traditional way of modeling consumers. Reduced producer reliability significantly reduced trade; in some instances, a modest reduction in reliability threatened the sustainability of the system. Finally, a modest increase in price-driven consumers at the outset of the simulation quickly resulted in those consumers becoming a majority of the overall customer base.

Conclusion:

Results suggest that social factors, such as desire to support the community, can be more important than financial factors.

Application:

An ABM of food hub dynamics, based on human factors data gathered from the field, can be a useful tool for policy decisions. Similar approaches can be used for modeling customer dynamics with other sustainable organizations.
Fracture modeling in dual-phase steel grades based on the random cellular automata finite element approach
Authors: Perzynski Konrad , Madej Lukasz
Published: December 2015

The development of a parallel version of the fracture model dedicated for multi-phase materials based on a combination of the finite element model and random cellular automata approach is the overall goal of this study. Dual-phase (DP) steel, commonly used in the automotive industry, is selected as a case study for the present investigation. Firstly, various fracture modes that can occur during deformation in DP steel grade microstructures are presented from an experimental point of view. To consider explicitly microstructure features that play a significant role during initiation and subsequent failure propagation, the digital material representation concept is used. Then, details of the developed random cellular automata model, fully embedded within the finite element framework, are discussed. The cellular automata space definition, internal variables, state variables and transition rules replicating investigated fracture modes are presented in detail and discussed. The concept of data transfer and parallelization based on the Message Passing Interface methodology in such an innovative hybrid numerical model is also clearly presented. The final section of the paper is devoted to examples of obtained results highlighting model predictive capabilities.
The Trinity and the canonical process
Authors: Sumpter Philip
Published: December 2015

This article brings Brevard Childs’s thesis concerning the nature of Scripture into dialogue with Karl Barth’s doctrine of revelation. It does so by reducing Childs’s thesis to its constituent building blocks in order to understand its logical structure and then comparing this structure to Barth’s understanding of the trinitarian pattern of God’s self-manifestation. The purpose is two-fold. On the one hand, it hopes to further understanding of Childs’s canonical approach by highlighting the centrality of the concept of “reality” to his understanding of the “canonical process.” On the other hand it hopes to contribute to the ongoing task of Christian hermeneutical reflection by illustrating the manner in which a doctrine of God and historical-critical speculation can be mutually illuminating.
Institutional Agents at a Hispanic Serving Institution: Using Social Capital to Empower Students
Authors: Garcia Gina A. , Ramirez Jenesis J.
Published: December 2015

As enrollment-driven postsecondary institutions, Hispanic Serving Institutions (HSIs) must actively find ways to better “serve” their students. Guided by Stanton-Salazar’s social capital framework, this study sought to understand how institutional agents use various forms of capital to develop structures that support and empower minoritized students. Using data from a study of one 4-year, master’s granting HSI, we highlight how four institutional leaders serve as empowerment agents for students, seeking ways to challenge the status quo while developing the structures and policies necessary for serving minoritized students.
Assessing the Psychoeducational Approach to Transcendence and Health Program
Authors: McCarthy Valerie Lander , Bowland Sharon , Hall Lynne A. , Connelly Jennifer
Published: December 2015

The late-life developmental process of self-transcendence shapes elders’ perspectives on self, others, the nature of this world, and of a dimension beyond the here and now. This qualitative pilot study evaluated the Psychoeducational Approach to Transcendence and Health (PATH) Program, a psychoeducational intervention to promote self-transcendence and well-being in community-dwelling women at a senior center. The intervention involved eight weekly group sessions using group processes, mindfulness practices, creative experiences, and independent at-home practice. The findings supported the underlying theory-based structure and content of the intervention and indicated the intervention may empower elders to attend to self-care, develop acceptance, and learn new skills associated with health and well-being, thus merits further study. Based on insights gained from facilitators’ and participants’ experiences and perceptions, the intervention will be revised and strengthened.
Ecuador’s Buen vivir
Authors: Caria Sara , Domínguez Rafael
Published: December 2015

The concept of buen vivir (good living) has attracted interest far beyond its source in the Andean ethnic tradition. It is being debated internationally as a contribution to development theory and has become the fundamental purpose of Ecuador’s policy since the adoption of the new constitution in 2008. There are, however, deep contradictions between the constitutional prescriptions and spirit of buen vivir and recently formulated policies that reveal a pragmatic approach on the part of the government. These contradictions suggest that, far from being a strategic orientation for effective policy making, buen vivir serves as a new ideology and is being used to support a reform plan based on a quite traditional understanding of the concept of development.

El concepto de “buen vivir” ha despertado interés más allá de su origen en la tradición étnica andina. Su contribución a la teoría del desarrollo es parte del debate internacional y también se ha convertido en el objetivo fundamental de la política pública del Ecuador desde que se adoptó la nueva constitución en 2008. Hay, sin embargo, profundas contradicciones entre las prescripciones constitucionales y el espíritu del buen vivir y algunas políticas formuladas recientemente que revelan un enfoque pragmático de parte del gobierno. Estas contradicciones sugieren que, lejos de ser una orientación estratégica para la formulación de políticas más eficaces, el buen vivir sirve como una nueva ideología y está siendo usado para apoyar un plan de reforma basado en una interpretación bastante tradicional del concepto de desarrollo.
Fostering a sense of belonging at school––five orientations to practice that assist vulnerable youth to create a positive student identity
Authors: Sanders Jackie , Munford Robyn
Published: December 2015

Drawing on data from a mixed-method longitudinal study of marginalized youth from New Zealand, most of whom did not complete high school, we explore the concept of a sense of belonging as it relates to the way these youth explain their experiences of school. We identify the centrality of this sense of belonging at school to an understanding of resilience for vulnerable youth. Based on youth accounts we identify five orientations to practice that made the most difference to youth capacity to stay at school. These orientations are able to be used by a wide range of school professionals, including school psychologists, to enable youth to successfully stay in mainstream educational settings and achieve to their abilities.
The everyday ways that school ecologies facilitate resilience: Implications for school psychologists
Authors: Theron Linda C.
Published: December 2015

From a socio-ecological perspective of resilience, social ecologies are crucial to children’s functional outcomes in the face of adversity. Schools, in particular, are integral to the multiple social systems that children are embedded in. Consequently schools have a special responsibility towards meaningfully and routinely supporting children’s resilience. Drawing on a synthesis of 33 publications, I document the everyday ways that school ecologies enact this responsibility. I caution that although much of this everyday routine is potentially protective, it neglects important leverage points for supporting resilience. These include championing resilience in contextually-sensitive ways, pre-empting risk and advocating for systemic change, and being mindful of the costs of resilience. To optimize these leverage points, school psychologists need child-informed understandings of how school ecologies facilitate resilience differentially. They also need to adopt an activist stance that animates social change. The resilience-themed edition of School Psychology International, which this article introduces, develops this agenda.
Activating the sociological imagination to explore the boundaries of resilience research and practice
Authors: VanderPlaat Madine
Published: December 2015

Traditionally, the field of resilience research, especially as it relates to children and youth, has been well ensconced in the discipline of psychology. Sociologists, when they do engage with the concept, tend to do so at the level of the community. In recent years, an increasing number of scholars have called for a construction of resilience and resilience-promoting interventions that recognizes the importance of context and culture for the positive development of youth living in stressful circumstances. As such, the social ecologies surrounding a youth and the responsiveness of interventions within these ecologies are argued to be as important, if not more so, than the risk and protective factors characterizing the individual. This shift in gaze from the individual to systemic structures creates important challenges for practitioners such as school psychologists and opens up an interesting discursive space for sociologists to participate in the exploration and explication of what the concept of resilience is all about. In this article I explore how a sociological perspective can enrich the discourse and how the activation of the sociological imagination can serve to expand the boundaries of resilience research and school psychology practice.
Illiberal or simply unorthodox? Public Administration education in Hungary
Authors: Hajnal Gyorgy
Published: December 2015

Over the past decades, Public Administration (PA) education programmes in Europe shifted their focus from a predominantly law-oriented approach to a more multidisciplinary, social science and managerial one. This paper deals with the tenacity of traditional, law-oriented PA education programmes that can be found in a limited, but not insignificant, range of countries throughout Europe. The paper has two aims. Firstly, it attempts to test hypotheses which seek to explain this tenacity. Secondly, it wishes to examine the extent to which this tenacity is related to new forms and paradigms of government emerging in certain Central and Eastern European countries, sometimes referred to as “illiberal democracy”. The method is a two-case comparative study of Germany and Hungary.