bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate
Authors: Phillips Andrew C. , Boghaert Erwin R. , Vaidya Kedar S. , Falls Hugh D. , Mitten Michael J. , DeVries Peter J. , Benatuil Lorenzo , Hsieh Chung-Ming , Meulbroek Jonathan A. , Panchal Sanjay C. , Buchanan Fritz G. , Durbin Kenneth R. , Voorbach Martin J. , Reuter David R. , Mudd Sarah R. , Loberg Lise I. , Ralston Sherry L. , Cao Diana , Gan Hui K. , Scott Andrew M. , Reilly Edward B.
Published: February 2018

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795–805. ©2018 AACR.
The Combined Association of Modifiable Risk Factors with Breast Cancer Risk in the Women's Health Initiative
Authors: Arthur Rhonda , Wassertheil-Smoller Sylvia , Manson JoAnn E. , Luo Juhua , Snetselaar Linda , Hastert Theresa , Caan Bette , Qi Lihong , Rohan Thomas
Published: February 2018

Although several modifiable risk factors have been independently associated with risk of breast cancer, few studies have investigated their joint association with breast cancer risk. Using a healthy lifestyle index (HLI) score, we assessed the association of a combination of selected modifiable risk factors (diet, alcohol, physical activity, BMI, and smoking) with risk of invasive breast cancer in the Women's Health Initiative (WHI). This study comprised 131,833 postmenopausal women, of whom 8,168 had breast cancer, who were enrolled in the WHI Observational Study or the WHI clinical trials. Cox proportional hazards regression was used to estimate the HRs and 95% confidence intervals (CI) for the association of the score with the risk of developing breast cancer overall and according to specific breast cancer clinicopathologic characteristics. There was a 4% reduction in the risk of breast cancer per unit increase in the HLI score. Compared with those with an HLI score in the lowest quintile level, those in the highest quintile level had 30%, 37%, and 30% lower risk for overall, ER+/PR+, and HER2+ breast cancer, respectively (HR = 0.70; 95% CI, 0.64–0.76; 0.63, 0.57–0.69; and 0.70; 0.55–0.90, respectively). We also observed inverse associations between the score and risk of breast cancer irrespective of nodal status, tumor grade, and stage of the disease. Most individual lifestyle factors were independently associated with the risk of breast cancer. Our findings support the view that promoting healthy lifestyle practices may be beneficial with respect to lowering risk of breast cancer among postmenopausal women. Cancer Prev Res; 11(6); 317–26. ©2018 AACR.

See related editorial by Friedenreich and McTiernan, p. 313
Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts
Authors: Drapkin Benjamin J. , George Julie , Christensen Camilla L. , Mino-Kenudson Mari , Dries Ruben , Sundaresan Tilak , Phat Sarah , Myers David T. , Zhong Jun , Igo Peter , Hazar-Rethinam Mehlika H. , Licausi Joseph A. , Gomez-Caraballo Maria , Kem Marina , Jani Kandarp N. , Azimi Roxana , Abedpour Nima , Menon Roopika , Lakis Sotirios , Heist Rebecca S. , Büttner Reinhard , Haas Stefan , Sequist Lecia V. , Shaw Alice T. , Wong Kwok-Kin , Hata Aaron N. , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A. , Peifer Martin , Dyson Nicholas , Thomas Roman K. , Farago Anna F.
Published: February 2018

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical–translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.

Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600–15. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517
Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties
Authors: Gao Yijun , Chang Matthew T. , McKay Daniel , Na Na , Zhou Bing , Yaeger Rona , Torres Neilawattie M. , Muniz Keven , Drosten Matthias , Barbacid Mariano , Caponigro Giordano , Stuart Darrin , Moebitz Henrik , Solit David B. , Abdel-Wahab Omar , Taylor Barry S. , Yao Zhan , Rosen Neal
Published: February 2018

Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.

Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648–61. ©2018 AACR.

See related commentary by Maust et al., p. 534.

This article is highlighted in the In This Issue feature, p. 517
Response of Retinoic Acid in Patients with Radioactive Iodine-Refractory Thyroid Cancer: A Meta-Analysis
Authors: Pak Kyoungjune , Shin Seunghyeon , Kim Seong-Jang , Kim In-Joo , Chang Samuel , Koo Phillip , Kwak Jennifer , Kim Jae-Ho
Published: February 2018

Purpose: The purpose of this study was to evaluate the response of retinoic acid (RA) in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). Methods: Systematic searches of MEDLINE (from inception to December 2016) and of EMBASE (from inception to December 2016) were performed for English-language publications on thyroid cancer treated with RA. Studies were classified according to the response criteria used: (1) 123I or 131I whole body scintigraphy (WBS), (2) serum thyroglobulin (Tg) level, (3) the response evaluation criteria in solid tumors (RECIST) version 1.0, and (4) World Health Organization (WHO) criteria. Results: Disease response rates as determined by WBS ranged widely between 6.2% and 46.1% with a pooled disease response rate of 27.6% (95% confidence interval: 21.7-34.0%). Response rates as determined by Tg level ranged from 56.6% to 83.3% (pooled response rate 61.3% (51.0-70.9%)), RECIST response rates from 0% to 45.5% (pooled response rate 17.0% (1.4-44.5%)), and according to WHO criteria, the pooled response rate was 30.8% (12.7-52.7%). Conclusions: A minority of patients with RAI-refractory DTC respond to RA treatment.
Use of Vitamin K Antagonists and Brain Morphological Changes in Older Adults: An Exposed/Unexposed Voxel-Based Morphometric Study
Authors: Brangier Antoine , Celle Sébastien , Roche Frédéric , Beauchet Olivier , Ferland Guylaine , Annweiler Cédric
Published: February 2018

Background: Vitamin K antagonists (VKAs) are commonly used for their role in haemostasis by interfering with the vitamin K cycle. Since vitamin K also participates in brain physiology, this voxel-based morphometric study aimed to determine whether the duration of exposure to VKAs correlated with focal brain volume reduction in older adults. Methods: In this exposed/unexposed (1: 2) study nested within the GAIT (Gait and Alzheimer Interactions Tracking) cohort, 18 participants exposed to VKA (mean age 75 ± 5 years; 33.3% female; mean exposure 2,122 ± 1,799 days) and 36 matched participants using no VKA (mean age 75 ± 5 years; 33.3% female) underwent MRI scanning of the brain. Cortical grey and white matter volumes were automatically segmented using statistical parametric mapping. Age, gender, educational level, history of atrial fibrillation, type of MRI, and total intracranial volume were included as covariables. Results: The duration of exposure to VKA correlated inversely across the whole brain with the subvolumes of two clusters in the grey matter (right frontal inferior operculum and right precuneus) and one cluster in the white matter (left middle frontal gyrus). In contrast, the grade of white matter hyperintensities did not differ according to the use of VKA. Conclusion: We found focal atrophies in older adults exposed to VKA. These findings provide new insights elucidating the effects of VKAs on brain health and function in older adults.
Activation of the ERK1/2-MAPK Signaling Pathway by Complement Serum in UV-POS-Pretreated ARPE-19 Cells
Authors: Busch Martin , Wasmuth Susanne , Spital Georg , Lommatzsch Albrecht , Pauleikhoff Daniel
Published: February 2018

Background: Retinal pigment epithelial (RPE) cells undergo functional changes upon complement stimulation, which play a role in the pathogenesis of age-related macular degeneration (AMD). These effects are in part enhanced by pretreating ARPE-19 cells with UV-irradiated photoreceptor outer segments (UV-POS) in vitro. The aim of this study was to investigate the effects of human complement serum (HCS) treatment on p44/42 mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 [ERK1/2]) activation in ARPE-19 cells pretreated with UV-POS. Methods: UV-POS-pretreated ARPE-19 cells were stimulated with 5% HCS or heat-inactivated HCS (HI-HCS) as a control. Pro tein expression of phosphorylated (activated) ERK1/2, total ERK1/2, Bax, and Bcl-2 was analyzed by Western blotting. Cell culture supernatants were analyzed for IL-6, IL-8, MCP-1, and VEGF by enzyme-linked immunosorbent assay (ELISA). Furthermore, extra- and intracellular reactive oxygen species (ROS) were determined. Results: The amount of phosphorylated ERK1/2 was increased in UV-POS-pretreated ARPE-19 cells, especially in combination with HCS stimulation, compared to non-pretreated ARPE-19 cells incubated with HCS alone or HI-HCS. The same observation was made for Bax and Bcl-2 expression. Furthermore, an increase in extra- and intracellular ROS was detected in UV-POS-pretreated ARPE-19 cells. The ELISA data showed that the production of IL-6, IL-8, and MCP-1 tended to increase in response to HCS in both UV-POS-pretreated and non-pretreated ARPE-19 cells. Conclusions: Our data imply that ERK1/2 activation in ARPE-19 cells may represent a response mechanism to cellular and oxidative stress, associated with apoptosis-regulating factors such as Bax and Bcl-2, which might play a role in AMD, while ERK1/2 seems not to represent the crucial signaling pathway mediating the functional changes in RPE cells in response to complement stimulation.
Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells
Authors: Gupta Pranav , Zhang Yun-Kai , Zhang Xiao-Yu , Wang Yi-Jun , Lu Kimberly W. , Hall Timothy , Peng Richard , Yang Dong-Hua , Xie Ni , Chen Zhe-Sheng
Published: February 2018

Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.
ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways
Authors: Ji Jia-Fu , Jiao Wan-Zhen , Cheng Yan , Yan Hua , Su Fan , Chi Li-Li
Published: February 2018

Background/Aims: Nonalcoholic steatohepatitis includes steatosis along with liver inflammation, hepatocyte injury and fibrosis. In this study, we investigated the protective role and the potential mechanisms of a traditional Chinese medicine ShenFu (SF) preparation in an in vitro hepatic steatosis model. Methods: In palmitic acid (PA)-induced murine hepatic AML12 cell injury, effects of SF preparation on cellular apoptosis and intracellular triglyceride (iTG) level were assessed using TUNEL and TG Colorimetric Assay. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were measured using DCF and JC-1 assay. Cytokine levels were evaluated using ELISA assay. Immunoblot was used to compare the activation level of c-Jun N terminal kinase (JNK), NADPH oxidase (Nox4), and NFκB pathways. Results: Addition of SF preparation prevented PA-mediated increase of apoptosis and iTG as well as IL-8 and IL-6. In PA-treated cell, SF preparation reduced the level of Nox4 and ROS, while increasing the level of MMP and the expression of manganese superoxide dismutase (MnSOD) and catalase, indicating emendation of mitochondrial dysfunction. Nox4 inhibitor GKT137381 prevented PA-induced increase of ROS and apoptosis, while decreasing iTG slightly and not influencing the level of IL-8 and IL-6. SF preparation prevented PA-induced upregulation of phospho-JNK. JNK inhibitor SP600125 prevented PA-mediated increase of Nox4, IL-8, IL-6 and iTG. Nuclear translocation of NFκB/p65 was detected in PA-treated cells, which was prevented by SF preparation. An IκB degradation inhibitor, BAY11-7082, prevented PA-induced increase of IL-8 and IL-6 as well as iTG, whereas it only decreased ROS levels slightly and showed no influence on cellular apoptosis. Conclusion: SF preparation shows a beneficial role in prevention of hepatocyte injury by attenuating oxidative stress and cytokines production at least partially through inhibition of JNK/Nox4 and JNK/NFκB pathway, respectively.
MicroRNA-214 Suppresses Ovarian Cancer by Targeting β-Catenin
Authors: Liu Yang , Lin Jie , Zhai Shujuan , Sun Chunyi , Xu Changjun , Zhou Honglin , Liu Huijin
Published: February 2018

Background/Aims: Ovarian cancer is one of the most common malignancies with a high rate of mortality in women. However, current therapies for ovarian cancer treatment are ineffective. Therefore, novel target identification is an urgent requisite. The present study aimed to investigate the role of microRNA-214 (miR-214) in ovarian cancer. Methods: The expression of miR-214, β-catenin, cyclin D1, c-myc, and TCF-1 at the transcriptional level was measured by real-time PCR, while that of β-catenin, Cyclin D1, and c-Myc at the protein level were detected by western blot. Colony formation assay and transwell assay were used to explore the invasion ability of the cancer cells. Cell cycle was measured by flow cytometry. Results: Real-time PCR showed that miR-214 expression in ovarian cancer cell lines was lower than that in the human normal ovarian epithelial cells, IOSE80. Furthermore, the low expression of miR-214 was correlated with high pathological grade. The rate of colony formation and invasion of miR-214 overexpression in SKOV-3 cells were weaker than that in control cells. Moreover, miR-214 overexpression led to the G0/G1 phase arrest. The expression of β-catenin, Cyclin D1, and c-Myc was suppressed by the overexpression of miR-214. Conclusion: These results suggested that miR-214 may serve as a tumor suppressor of ovarian cancer by targeting the β-catenin pathway.
The role of university extension in support of family farming in São Pedro/SP town
Authors: Marques Paulo Eduardo Moruzzi , Lucas Ademir De , Trivellato Gabriela Maria Leme
Published: February 2018

O presente artigo foi concebido para discorrer sobre as atividades do GESP (Grupo de Extensão de São Pedro) junto aos agricultores familiares do Alto da Serra de São Pedro. A noção de agricultura multifuncional é mobilizada para esta análise, que é fundada na experiência de quase trinta anos de ações do GESP. Este trabalho da extensão universitária contribuiu com a sólida organização do grupo de agricultores, o que levou a uma grande participação de suas famílias nas dinâmicas sociais, econômicas e políticas locais.
Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement
Authors: Ljungberg Johan , Janiec Mikael , Bergdahl Ingvar A. , Holmgren Anders , Hultdin Johan , Johansson Bengt , Näslund Ulf , Siegbahn Agneta , Fall Tove , Söderberg Stefan
Published: February 2018

Background:

Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights.

Methods:

Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study.

Results:

Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease.

Conclusions:

We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.
Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure
Authors: Morine Kevin J. , Qiao Xiaoying , York Sam , Natov Peter S. , Paruchuri Vikram , Zhang Yali , Aronovitz Mark J. , Karas Richard H. , Kapur Navin K.
Published: February 2018

Background:

Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity.

Methods:

We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling.

Results:

BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9
–/–
mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction–induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3.

Conclusions:

Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.
Characterisation of biological and biocontrol traits of entomopathogenic nematodes promising for control of striped flea beetle (Phyllotreta striolata)
Authors: Yan Xun , Lin Yinying , Huang Zhenmao , Han Richou
Published: February 2018

The biological and biocontrol traits of two entomopathogenic nematode isolates,Steinernema pakistanense94-1 (Sp94-1) andHeterorhabditis indica212-2 (Hi212-2), were evaluated. The highest yield of infective juveniles (IJ) in monoxenic sponge culture system for Sp94-1 and Hi212-2 was 3.52 (± 0.45) × 105and 7.08 (± 0.11) × 105 IJ g−1, respectively. The optimum storage temperature was 25°C for Sp94-1 and 14°C for Hi212-2. Sp94-1 showed greater tolerance to heat exposure and UV radiation, whileS. carpocapsaeAll, a commercial strain, was more resistant to osmotic pressure, desiccation, cold treatment and hypoxia than the other tested isolates. Hi212-2 suppressed thePhyllotreta striolatalarvae when applied at 1.5 × 109 IJ ha−1or higher concentrations, while Sp94-1 suppressed theP. striolatalarvae only when applied at 4.5 × 109 IJ ha−1. Our study indicates the possibility of commercialisation of the EPN isolates, and further confirms their efficacy against theP. striolatalarvae in the field.
Sign Levels Synopsis
Authors: Clarke D.S.
Published: February 2018

This Tractatus-style sequence of propositions describes logical features of natural language discourse, pre-linguistic levels of signs interpreted in associative learning and animal communication, and the specialized discourses of the institutions of science, religion, law, politics, and the arts. Its comprehensive scope is designed to help overcome the compartmentalization of philosophy into its branches of epistemology, ethics, political philosophy, and aesthetics. The general perspective is that of pragmatic naturalism as developed by the classical pragmatists Peirce, James, Schiller, and Dewey. Central to pragmatism is its emphasis on the use of practical inferences combining descriptive and expressive premisses with prescriptive “ought” conclusions guiding conduct. I argue that by making such inferences its focus, pragmatism enables contemporary philosophy to offset the effects of social specialization.
Genus-level taxonomical changes in the Lepanthes affinity (Orchidaceae, Pleurothallidinae)
Authors: BOGARÍN DIEGO , KARREMANS ADAM P. , FERNÁNDEZ MELANIA
Published: February 2018

We propose a new classification of the Lepanthes affinity based on previous studies and our ongoing phylogenetic re-evaluation of the Pleurothallidinae. Fourteen genera are recognized as belonging to the affinity. They are found highly supported in a DNA-based phylogenetic inference of combined plastid (matK) and nuclear (nrITS) datasets. The necessary changes, including four novel generic concepts, needed to reorganize the Lepanthes affinity, are proposed here to insure monophyly. The integral discussion on the phylogenetics and biogeography of the group, together with morphological characterization of each clade will be presented in a follow up study.
A taxonomic revision of Iris section Psammiris (Iridaceae) in Russia
Authors: ALEXEEVA NINA B.
Published: February 2018

Until now, as few as 2–4 species of the genus Iris sect. Psammiris (Iris bloudowii, I. humilis, I. mandshurica, and I. potaninii) have been reported in Russia in botanical publications. We have analysed the diagnostic value of morphological characters. At the series level, features of the root system, the shape of basal leaves, the height of flowering scape, and the length of perianth tube are most significant. The shape and size of spathes are also usable for species identification. In the present contribution, a synopsis of I. sect. Psammiris in Russia is presented, including the description of a new series, Vorobievia. In that country, the section comprises 7 species belonging to 3 series and occurring mainly in Siberia and the Far East, one species extending to the Eastern Europe. A key for species determination is compiled, and the distribution areas of the accepted species are specified. Types are indicated for all involved names, two of which (lectotypes) are designated here. Furthermore, previous results of molecular studies including taxa in this section are analysed and discussed, which demonstrate that I. sect. Psammiris is indeed monophyletic according to the morphological and molecular data available so far.
On the Border of the Syrian Refugee Crisis: Views From Two Different Cultural Perspectives
Authors: Dimitrova Daniela V. , Ozdora-Aksak Emel , Connolly-Ahern Colleen
Published: February 2018

Since the Syrian refugee crisis represents the worst humanitarian crisis in modern history, it is critical to examine how global media covered this issue. Focusing on two nations significantly affected by the refugee crisis—Bulgaria and Turkey, this study employs a content analysis to examine differences in refugee portrayals in national media. The results show that Turkish media coverage was more personalized and more likely to emphasize the victim frame. In contrast, Bulgarian coverage was less personalized and more likely to emphasize the administrative frame. The findings are placed within national context and their implications for media framing of refugees are discussed.
Low Levels of High-Density Lipoprotein Cholesterol Are Linked to Impaired Clopidogrel-Mediated Platelet Inhibition
Authors: Wadowski Patricia P. , Lee Silvia , Kopp Christoph W. , Koppensteiner Renate , Panzer Simon , Gremmel Thomas
Published: February 2018

Low high-density lipoprotein cholesterol (HDL-C) levels are an independent predictor of ischemic events in patients with atherosclerotic cardiovascular disease. This may in part be due to decreased clopidogrel-mediated platelet inhibition in patients with low HDL-C. We investigated the association of HDL-C with on-treatment platelet reactivity to adenosine diphosphate (ADP) in 314 patients on dual antiplatelet therapy with clopidogrel and aspirin undergoing angioplasty and stenting. Platelet P-selectin expression was assessed by flow cytometry, and platelet aggregation was determined by the VerifyNow P2Y12 assay and the Impact-R. High-density lipoprotein cholesterol levels were inversely associated with P-selectin expression and the VerifyNow P2Y12 assay (both P ≤ .01). Moreover, we found a positive correlation of HDL-C with surface coverage by the Impact-R ( P = .003). Patients with low HDL-C (≤35 mg/dL) exhibited a significantly higher P-selectin expression in response to ADP and higher platelet aggregation by the VerifyNow P2Y12 assay and the Impact-R than patients with normal HDL-C (>35 mg/dL; all P < .05). High on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay occurred significantly more frequently in patients with low HDL-C levels than in those with normal HDL-C (47.4% vs 30.1%, P = .01). In conclusion, low HDL-C is linked to impaired clopidogrel-mediated platelet inhibition after angioplasty and stenting.
Measuring occupational balance and its relationship to perceived stress and health
Authors: Yu Yu , Manku Mandeep , Backman Catherine L.
Published: February 2018

Background.

There is an assumption that occupational balance is integrally related to health and well-being.

Purpose.

This study aimed to investigate test-retest reliability of the English-translated Occupational Balance Questionnaire (OBQ), its relationship to measures of health (Short Form Health Survey–36 Version 2.0 [SF-36v2]) and stress (Perceived Stress Scale–10; PSS-10), and demographic differences in OBQ scores in Canadian adults.

Method.

Test-retest reliability (2 weeks) was assessed using intraclass correlation (ICC) coefficients. Online surveys from 86 adults were analyzed using descriptive, correlational, and t test statistics.

Findings.

OBQ test-retest reliability was ICC = 0.74 (95% CI [0.34, 0.90]; p = .003) when excluding an influential case ( n = 20). OBQ correlations with PSS-10 were r = –.72; with SF-36v2 Mental Component Score, r = .65; and with Physical Component Score, r = .31; all p < .001. Age and gender had no impact on OBQ scores.

Implications.

Findings help elucidate relationships among health, stress, and occupational balance; however, further psychometric testing is warranted before using OBQ for clinical purposes.
Una trincea fatta di libri: La Nuova Biblioteca editrice di Carlo Bernari
Authors: Acocella Silvia
Published: February 2018

Nei canali sommersi della clandestinità, la Resistenza passò anche attraverso una cultura che si conservava ostinatamente di respiro europeo, attraverso i vasti orizzonti dei progetti editoriali: come quello de La Nuova Biblioteca editrice, di Carlo Bernari, che portò avanti lo sperimentalismo degli anni Trenta (e di una Napoli in contatto con la Parigi di Breton e con il secondo surrealismo al servizio della rivoluzione), aprendosi alle nuove correnti artistiche d'Europa, non solo anticipando la visione del mondo del dopoguerra e le domande su una nuova definizione di uomo, ma anche mantenendo ampi i confini di una stagione che fu definita neorealistica quando ormai il termine, almeno in letteratura, aveva perso molto del suo significato originario. Si dovrebbe parlare, piuttosto, per gli anni dell’immediato dopoguerra, di neo-espressionismo, come le scelte editoriali de La Nuova Biblioteca confermano, orientate verso quella “seconda ondata dell'espressionismo” che Contini individua nella Germania Weimar. Solo dopo il ritrovamento dell'intero catalogo delle edizioni de La Nuova Biblioteca, pubblicato il 7 giugno 1944 nella Roma appena liberata, si è potuta ricostruire la portata di questo progetto e il vasto orizzonte che ne orientava il disegno. A rendere prezioso il catalogo de La Nuova Biblioteca non è solo la preparazione di testi che sarebbero stati fondamentali per la nuova cultura del dopoguerra (come, per la prima volta in Italia, l’ opera omnia di Antonio Gramsci, in un'edizione priva di tagli e perciò anticipatrice dell'edizione critica di Gerratana del 1975) o la presenza di nomi come Delio Cantimori, Umberto Barbaro, Franco Calamandrei, Ettore Lo Gatto, Lombardo Radice, Alicata e Sapegno, ma è anche la particolare fase cronologica in cui questo progetto prende forma: si tratta di un lasso di tempo breve, apertosi a ridosso della guerra e destinato a chiudersi rapidamente: è come uno squarcio, in cui il magma di materiali diversi accumulatosi nei canali della clandestinità affiora per un’ultima volta prima che intorno si irrigidiscano gli schemi di nuove culture sempre più dominanti. Torneranno a inabissarsi, queste narrazioni aperte alla deformazione, alla menzogna romanzesca e alla commistione tra le arti; tuttavia come un fiume carsico continueranno a scorrere, andando a unirsi a tutte quelle correnti che procedendo parallele, tra inversioni, stalli e rivolgimenti, attraverseranno l'intero secolo.
3D visual simulation of individual and crowd behavior in earthquake evacuation
Authors: Liu Tingting , Liu Zhen , Ma Minhua , Chen Tian , Liu Cuijuan , Chai Yanjie
Published: February 2018

Simulation of behaviors in emergencies is an interesting subject that helps to understand evacuation processes and to give out warnings for contingency plans. Individual and crowd behaviors in the earthquake are different from those under normal circumstances. Panic will spread in the crowd and cause chaos. Without considering emotion, most existing behavioral simulation methods analyze the movement of people from the point of view of mechanics. After summarizing existing studies, a new simulation method is discussed in this paper. First, 3D virtual scenes are constructed with the proposed platform. Second, an individual cognitive architecture, which integrates perception, motivation, behavior, emotion, and personality, is proposed. Typical behaviors are analyzed and individual evacuation animations are realized with data captured by motion capture devices. Quantitative descriptions are presented to describe emotional changes in individual evacuation. Facial expression animation is used to represent individuals’ emotions. Finally, a crowd behavior model is designed on the basis of a social force model. Experiments are carried out to validate the proposed method. Results showed that individuals’ behavior, emotional changes, and crowd aggregation can be well simulated. Users can learn evacuation processes from many angles. The method can be an intuitional approach to safety education and crowd management.
Falling Behind: Lingering Costs of the High School Transition for Youth Friendships and Grades
Authors: Felmlee Diane , McMillan Cassie , Inara Rodis Paulina , Osgood D. Wayne
Published: February 2018

This study investigates the influence of structural transitions to high school on adolescents’ friendship networks and academic grades from 6th through 12th grade, in a direct comparison of students who do and do not transition. We utilize data from 14,462 youth in 51 networks from 26 districts (Promoting School–Community Partnerships to Enhance Resilience). Results underscore the challenging nature of compulsory school changes. Students that structurally transition to high school between eighth and ninth grade, as compared with those who do not, receive fewer friendship nominations following the move and are more likely to become isolates, according to a three-level Poisson model. Students who transition also report significantly lower odds of obtaining high grades after the shift, and these penalties persist throughout high school. Our findings highlight the social and academic difficulties associated with this particular normative adolescent life transition and point to a disruption in social network ties as part of the problem.
The financialisation of urban infrastructure: A framework of analysis
Authors: O’Neill Phillip
Published: February 2018

The literature on the financialisation of urban infrastructure typically traces how an infrastructure asset’s balance sheet is (re)engineered to create a financial asset. What the literature neglects are the processes by which an asset generates urban flows. Attention to these processes, we argue, not only gives better insight into the processes of financialisation of infrastructure but also exposes how the act of financing affects the operations of cities through its influence on the performance of infrastructure assets. The argument presented in the article is informed by case studies of infrastructure investments revealed in interviews conducted in New York, London and Sydney. This material is drawn on to generate a framework for understanding the relationships between infrastructure investing and the infrastructure-enabled flows of a city. This framework has three dimensions through which the financialisation process is seen to be mediated. These are capital structure, organisational structure and regulatory structure. The article argues that these mezzanine-level conceptualisations enable us to explore the to-and-fro between financing and operating cities. A key proposition is that the physical flows of a city are basic not only to the design and enactment of an investment instrument but also to its financial viability. The realisation of this relationship has changed the way investors approach infrastructure assets as investment products. Implications for urban management are drawn.
A Triangulated Qualitative Study of Veteran Decision-Making to Seek Care During Heart Failure Exacerbation: Implications of Dual Health System Use
Authors: Pope Charlene A. , Davis Boyd H. , Wine Leticia , Nemeth Lynne S. , Axon Robert N.
Published: February 2018

Among Veterans, heart failure (HF) contributes to frequent emergency department visits and hospitalization. Dual health care system use (dual use) occurs when Veterans Health Administration (VA) enrollees also receive care from non-VA sources. Mounting evidence suggests that dual use decreases efficiency and patient safety. This qualitative study used constructivist grounded theory and content analysis to examine decision making among 25 Veterans with HF, for similarities and differences between all-VA users and dual users. In general, all-VA users praised specific VA providers, called services helpful, and expressed positive capacity for managing HF. In addition, several Veterans who described inadvertent one-time non-VA health care utilization in emergent situations more closely mirrored all-VA users. By contrast, committed dual users more often reported unmet needs, nonresponse to VA requests, and faster services in non-VA facilities. However, a primary trigger for dual use was VA telephone referral for escalating symptoms, instead of care coordination or primary/specialty care problem-solving.
Assessing the Predictive Value of Parasocial Relationship Intensity in a Political Context
Authors: Cohen Jonathan , Holbert R. Lance
Published: February 2018

This study explores the ability of parasocial relationships to predict support for political candidates and elected officials. A May 2017 survey of U.S. adults ( N = 2,055) included items that reflect traditional approaches to the study of candidate support (e.g., political party identification, policy agreement) along with several batteries of a newly developed political parasocial relationship (PPSR) measure. This study gives primary attention to predicting support for U.S. President Donald J. Trump, but also focuses on Secretary Hillary Clinton and U.S. Speaker of the House Paul Ryan. Parasocial relations prove to be a powerful predictor of Trump-Support, outperforming all other predictors (including past voting behavior). This study also explores what predicts citizen-politician PPSR. Citizens’ parasocial relationships with Trump are predicted by general political knowledge (–), 2016 Trump voting (+), support for Trump’s policies (+), along with news media exposure (+), and social media following of Trump (+).
Treatment of Severe Cyclical Mastalgia
Authors: Montgomery A C V , Biswas S , Palmer B V , Monteiro J C M P
Published: February 2018

In a sequential study to compare the efficacy of bromocryptine and danazol in the treatment of severe cyclical mastalgia, 70% of patients in both groups were relieved of their symptoms. Patients tended to prefer bromocryptine because of its limited side effects. There was a significant fall in prolactin levels with bromocryptine, but not with danazol.
Timing of Tourniquet Removal after Knee Replacement
Authors: Newman J H , Jackson J P , Waugh W
Published: February 2018

This paper describes a prospective trial which was set up in order to decide whether after knee replacement it is better to remove the tourniquet (pneumatic cuff) before closure of the wound or to leave it on until compressive dressings have been applied. In 80 operations studied, there was less blood loss when the tourniquet was removed after closure and bandaging, but there was no difference in wound complications. The only statistically significant difference was attributed to the timing of tourniquet removal in those patients (about half) who were receiving low-dose heparin.
Percutaneous Cholangiography in Prolonged Jaundice of Childhood
Authors: Howard Edward R , Nunnerley Heather B
Published: February 2018

Fine-needle percutaneous cholangiography has been carried out on a selected group of 22 infants and children who were jaundiced from a variety of causes. The technique has aided both the diagnosis and surgical management of the patients and has been free from complications.
Fertility and Sex Ratio of Offspring of Female HBsAg Carriers
Authors: Livadas D , Economidou J , Hesser J E , Koutras D A , Hadziyannis S
Published: February 2018

The relation of the HBsAg carrier state with fertility parameters and the sex ratio of offspring was studied in 1129 married women in 12 villages from different areas in Greece, in whom blood samples were tested for HBsAg. The results were compared between the group of HBsAg asymptomatic carriers and the HBsAg-negative group. An increase of the sex ratio was found in the group of HBsAg carriers. Furthermore, a decrease in the live births and a reduction in the number of female children were observed. It is concluded that a fertility disturbance in the HBsAg-positive group is probably responsible for the alteration of the sex ratio. An immunological mechanism may be the cause of the fertility disturbance found in the HBsAg carriers.