bluuebunny/crossref_metadata_2025 huggingface dataset:
Elaboration of the Method for Safety Assessment of Subsea Pipeline with Longitudinal Buckling
Authors: Muravyeva Liudmila , Vatin Nikolai
Published: May 2016

The issue of ensuring longitudinal stability of marine gas pipelines has been raised in view of construction of pipelines operating at significant temperature drops. Most commonly the pipelines deviation from the design conditions as well as equilibrium disturbance occurs due to longitudinal buckling. The task of designing the marine gas pipeline involves making the reliability analysis of the pipeline, taking into account the required conditions of structural reliability in all construction phases. As per the Russian standards, the vertical buckling is not considered in the stability analysis, whereas the standards of the USA, Norway (DNV-RP-F110), and the Great Britain emphasize the need for considering the lateral buckling caused by axial forces. This paper focuses on the operational reliability calculation for an underwater main gas pipeline, in which longitudinal buckling failure occurred. The calculation is based on the probabilistic and statistical method of assessing the pipeline state and operational reliability.
Consolidation Theory for a Stone Column Composite Foundation under Multistage Loading
Authors: Huang Shenggen , Feng Yingtao , Liu Hao , Wu Wenbing , Mei Guoxiong
Published: May 2016

The consolidation theories considering instant load cannot fully reveal the consolidation mechanism of a stone column composite foundation used in the expressway embankments due to the time effect of loading; that is, the expressway embankments are often constructed in several stages for a long time. Meanwhile, owing to the special property that the pile-soil stress ratio is larger than 1, the consolidation theory for sand drain well foundation cannot be used directly in the consolidation analysis of stone column composite foundation. Based on the principle that the vertical load applied on the composite foundation is shared by the stone column and the surrounding soil, the governing solutions for the stone column composite foundation under a multistage load are established. By virtue of the separation of variables, the corresponding solutions of degree of consolidation for loading stage and maintaining load stage are derived separately. According to the Carrillo theorem, the solution for the average total degree of consolidation of entire composite foundation is also obtained. Finally, the reasonableness of the present solution has been verified by comparing the consolidation curve calculated by the present solution with that measured by site test.
Prenatal Maternal Anxiety as a Risk Factor for Preterm Birth and the Effects of Heterogeneity on This Relationship: A Systematic Review and Meta-Analysis
Authors: Rose M. Sarah , Pana Gianella , Premji Shahirose
Published: May 2016

Background.Systematic reviews (SR) and meta-analyses (MA) that previously explored the relationship between prenatal maternal anxiety (PMA) and preterm birth (PTB) have not been comprehensive in study inclusion, failing to account for effects of heterogeneity and disagree in their conclusions.Objectives.This SRMA provides a summary of the published evidence of the relationship between PMA and PTB while examining methodological and statistical sources of heterogeneity.Methods.Published studies from MEDLINE, CINAHL, PsycINFO, and EMBASE, until June 2015, were extracted and reviewed.Results.Of the 37 eligible studies, 31 were used in this MA; six more were subsequently excluded due to statistical issues, substantially reducing the heterogeneity. The odds ratio for PMA was 1.70 (95% CI 1.33, 2.18) for PTB and 1.67 (95% CI 1.35, 2.07) for spontaneous PTB comparing higher levels of anxiety to lower levels.Conclusions.Consistent findings indicate a significant association between PMA and PTB. Due to the statistical problem of including collinear variables in a single regression model, it is hard to distinguish the effect of the various types of psychosocial distress on PTB. However, a prenatal program aimed at addressing mental health issues could be designed and evaluated using a randomised controlled trial to assess the causal nature of different aspects of mental health on PTB.
A New Transgenic Mouse Model of Heart Failure and Cardiac Cachexia Raised by Sustained Activation of Met Tyrosine Kinase in the Heart
Authors: Sala Valentina , Gatti Stefano , Gallo Simona , Medico Enzo , Cantarella Daniela , Cimino James , Ponzetto Antonio , Crepaldi Tiziana
Published: May 2016

Among other diseases characterized by the onset of cachexia, congestive heart failure takes a place of relevance, considering the high prevalence of this pathology in most European countries and in the United States, and is undergoing a rapid increase in developing countries. Actually, only few models of cardiac cachexia exist. Difficulties in the recruitment and follow-up of clinical trials implicate that new reproducible and well-characterized animal models are pivotal in developing therapeutic strategies for cachexia. We generated a new model of cardiac cachexia: a transgenic mouse expressing Tpr-Met receptor, the activated form of c-Met receptor of hepatocyte growth factor, specifically in the heart. We showed that the cardiac-specific induction of Tpr-Met raises a cardiac hypertrophic remodelling, which progresses into concentric hypertrophy with concomitant increase in Gdf15 mRNA levels. Hypertrophy progresses to congestive heart failure with preserved ejection fraction, characterized by reduced body weight gain and food intake and skeletal muscle wasting. Prevention trial by suppressing Tpr-Met showed that loss of body weight could be prevented. Skeletal muscle wasting was also associated with altered gene expression profiling. We propose transgenic Tpr-Met mice as a new model of cardiac cachexia, which will constitute a powerful tool to understand such complex pathology and test new drugs/approaches at the preclinical level.
Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis
Authors: Menard Julien A. , Christianson Helena C. , Kucharzewska Paulina , Bourseau-Guilmain Erika , Svensson Katrin J. , Lindqvist Eva , Chandran Vineesh Indira , Kjellén Lena , Welinder Charlotte , Bengzon Johan , Johansson Maria C. , Belting Mattias
Published: May 2016

Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential. Cancer Res; 76(16); 4828–40. ©2016 AACR.
Abstract B37: Selective tumor localization of CRLX101, a novel nanoparticle-drug conjugate
Authors: Peters Christian G. , Lazarus Douglas , Brown Donna , Zhang Ningning , Case Roy , Rohde Ellen , Eliasof Scott , Jayaraman Lata
Published: May 2016

CRLX101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin conjugated to a biocompatible copolymer of cyclodextrin and polyethylene glycol (PEG), is currently being evaluated clinically in multiple treatment-refractory solid tumors. CRLX101 is a dual inhibitor of topoisomerase 1 (TOPO 1) and hypoxia-inducible factor 1α (HIF-1α) and has been shown pre-clinically to be active in many different tumor types. It has a long circulation half-life and is believed to release camptothecin in a slow and prolonged fashion in the tumor. Camptothecin is an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of CRLX101, which has not demonstrated significant toxicity in over 250 patients dosed to date, offers a unique opportunity to improve cancer treatment in a meaningful way.

We have previously published that in gastric cancer patients treated with CRLX101, camptothecin fluorescence can be visualized in tumor tissue but not adjoining normal tissue. Based on these data we hypothesized that CRLX101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of CRLX101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we can detect camptothecin fluorescence in CRLX101- treated tumor cells in culture as well as in tumor tissue from mice treated with CRLX101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. We can also demonstrate that macropinocytosis plays a role in the manner by which tumor cells take up CRLX101. Using an anti-CD31 antibody, we can visualize the distance traversed by CRLX101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and CRLX101-conjugated camptothecin over time in CRLX101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with CRLX101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of CRLX101 into tumor tissue.

Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Selective tumor localization of CRLX101, a novel nanoparticle-drug conjugate. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B37.
Abstract C86: The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies
Authors: Attwell Sarah , Campeau Eric , Jahagirdar Ravi , Kharenko Olesya , Norek Karen , Tsujikawa Laura , Calosing Cyrus , Patel Reena , Gesner Emily , Lakhotia Sanjay , Hansen Henrik
Published: May 2016

ZEN-3694 is an orally bioavailable small molecule discovered and developed from a BET bromodomain inhibitor discovery platform. In vitro, ZEN-3694 selectively binds to both bromodomains of the BET proteins, inhibiting the interaction of acetylated histone peptide with IC50 values in low nM range. ZEN-3694 inhibits proliferation of MV4-11 AML cells with an IC50 of 0.2 uM, and inhibits MYC mRNA expression with an IC50 of 0.16 uM.

ZEN-3694 has also demonstrated strong activity against many solid tumor and hematological cell lines with sub-uM IC50 values. In vitro synergy with Standard of Care (SOC) agents has been shown in a wide variety of malignancies including Breast, Prostate, Lung, Melanoma, AML, and DLBCL. Xenograft studies conducted with ZEN-3694 in AML, prostate and breast cancer models have demonstrated that it is efficacious at well-tolerated doses, modulating target gene expression and halting tumor growth in a dose-dependent manner.

In the AR positive VCAP prostate cancer cell line, ZEN-3694 inhibits proliferation synergistically with the AR antagonists enzalutamide and ARN-509. In an in vitro enzalutamide resistance model characterized by the up-regulation of the glucocorticoid receptor (GR), GR expression was inhibited by ZEN-3694 in a dose-dependent manner. Sensitivity to ZEN-3694 was unaltered, suggesting that it could be a valid therapeutic approach in patients developing resistance to AR antagonists through GR induction.

Robust PD modulation has been observed across multiple matrices for ZEN-3694 and will be explored further in the clinic. Promising target validation data, excellent pharmacological properties, and robust activity of ZEN-3694 across a variety of hematological malignancy and solid tumor settings support the clinical development of ZEN-3694 in various oncologic indications.

Citation Format: Sarah Attwell, Eric Campeau, Ravi Jahagirdar, Olesya Kharenko, Karen Norek, Laura Tsujikawa, Cyrus Calosing, Reena Patel, Emily Gesner, Sanjay Lakhotia, Henrik Hansen. The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C86.
Abstract IA32: Optimizing kinase inhibitors to treat cancer
Authors: Bollag Gideon
Published: May 2016

Kinase inhibitors have become important therapeutic agents with at least 27 FDA-approved compounds currently available. While this success has brought important benefit to cancer patients, new challenges have been revealed. In particular, resistances to therapy and novel therapy-induced side effects have introduced rationale for optimizing next-generation treatment regimens. Two specific examples will be discussed: RAF and KIT inhibitors for BRAF- and KIT-driven cancers.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting MAPK pathway signaling independent of RAS activation. Efforts to develop agents to block mutated BRAF have brought substantial therapeutic improvement in personalized treatment of metastatic melanoma. Nonetheless, many patients relapse and relapsed tumors generally display MAPK pathway re-activation. The development of these agents also revealed an unexpected consequence of these targeted therapies: stimulated growth of certain cancers. Structurally-diverse ATP-competitive RAF kinase inhibitors can either inhibit or paradoxically activate the MAPK pathway depending whether the pathway is activated by a BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. We have identified next generation RAF inhibitors (dubbed “paradox breakers”) that inhibit mutant RAF cells without activating the MAPK pathway in cells containing an upstream activation event. These new inhibitors maintain efficacy in BRAF-driven cell and animal models. In addition, PLX8394 is able to overcome several known mechanisms of resistance to first generation RAF inhibitors. By dissociating MAPK pathway inhibition from pathway activation, the next generation RAF inhibitors may yield both improved safety and more durable efficacy than first generation RAF inhibitors.

KIT inhibitors are now standard therapy for advanced gastrointestinal stromal tumors, and indeed comprise 1st, 2nd and 3rd line treatments reflecting both the marked dependence of these tumors on KIT and also the facile development of resistance. Even with multiple compounds approved, resistance mutations - in exon 17 in particular - still limit the durability of clinical benefit. We have discovered PLX9486 as an effective inhibitor of mutant KIT, including exon 17 mutations, with the added feature of selectivity versus the wild-type KIT kinase activity. This compound shows potent activity against exon 17 mutant tumors both in vitro and in vivo. Anticipating the obstacle of polyclonal KIT mutations in standard TKI-resistant patients, clinical development plans include a study combining PLX9486 with PLX3397, a potent KIT inhibitor addressing complementary KIT mutational profiles.

Citation Format: Gideon Bollag. Optimizing kinase inhibitors to treat cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA32.
Abstract OT3-01-12: Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer
Authors: Barr JA , Sharma P , Fabian CJ , Yeh H , Baccaray S , Springer M , Khan QJ
Published: May 2016

Background:

Although the treatment of HER2 positive metastatic breast cancer (MBC) has improved with anti-HER2 agents and chemotherapy, most patients will eventually develop resistance to these agents. Preclinical studies have shown that mTOR inhibition may reverse trastuzumab resistance. We hypothesize that combining mTOR inhibitor everolimus with lapatinib will be an effective strategy for patients who have progressed on prior anti-HER2 therapies.

Trial Design:

We are conducting an open-label phase II pilot study of the combination of everolimus and lapatinib for pts with HER-2 positive MBC. Eligible pts must have histologically documented locally advanced (inoperable) or metastatic HER-2 positive breast cancer that have progressed on at least one HER-2 based regimen in the metastatic or locally advanced setting. Pts with disease progression during or within 12 mos of the completion of adjuvant trastuzumab are eligible. Pts with untreated asymptomatic brain metastases are allowed. Pts with symptomatic brain metastases are allowed to enroll after they have completed radiation and are off steroids. Eligible pts are started on everolimus 5 mg PO daily and lapatinib 1250 mg PO daily without interruption. Among subjects progressing on lapatinib, lapatinib is continued and everolimus initiated. Pts will continue to receive treatment until there is evidence of progressive disease (PD), unacceptable toxicity, or withdrawal of consent. Pts will have radiological evaluation every 8 weeks with CT, bone scan, and MRI brain (for pts with known brain metastasis at baseline).

Specific Aims:

Primary objective is to assess the effectiveness of the combination of RAD-001 and lapatinib as measured by the six-month Overall Response Rate in women with MBC who have progressed on trastuzumab and/or lapatinib based therapies. Secondary objectives are six-month PFS, safety and tolerability of the combination, six-month objective CNS response rate, six-month clinical benefit rate of systemic disease, and six-month clinical benefit rate in CNS.

Statistical methods:

The response rate of lapatinib monotherapy in heavily pre-treated patients is estimated to be 7% (Blackwell 2009). For an expected ORR of 17%, a sample size of 45 subjects will provide 79% power to detect the difference at 0.10 Type I error rate according to 1-sided exact binomial test.

Present accrual and target accrual:

The trial has accrued 20 patients with a target accrual of 45 patients.

Citation Format: Barr JA, Sharma P, Fabian CJ, Yeh H, Baccaray S, Springer M, Khan QJ. Phase II trial of lapatinib and everolimus for HER2 positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-12.
Functional Outcomes of Patients Treated with Intensive Medications for Bowel and Pain Control for Low-Lying Rectal Cancer Who Received Preoperative Chemoradiotherapy
Authors: Beppu Naohito , Fumihiko Kimura , Hiroshi Doi , Norihiko Kamikonya , Matsubara Nagahide , Tomita Naohiro , Yanagi Hidenori , Yamanaka Naoki
Published: May 2016

Purpose: The aim of this study was to assess the functional outcomes of patients treated with intensive medications for bowel and pain control for low-lying rectal cancer who received preoperative chemoradiotherapy (CRT). Methods: The inclusion criterion was sphincter-preserving surgery following CRT for T3 middle and low rectal cancer. Postoperative defecation control was conducted using calcium polycarbophil and loperamide, and anal pain control was conducted using oxycodone hydrochloride hydrate. The functional outcomes were determined by an annual questionnaire after stoma closure. Results: Of 64 patients evaluated, 33 were reconstructed using the double stapling technique (DST) and 31 were reconstructed using the intersphincteric resection (ISR) technique. The median Visual Analogue Scale at ISR was improved from 7 to 1.5 at 1 year after surgery. The median Wexner scores were 6.0, 6.0, 5.0 and 5.0 for DST and 14.5, 12.0, 10.0 and 8.0 for ISR for the first 4 years, respectively. The only independent predictor of a poor bowel function (Wexner score >10) according to a multivariate analyses was pelvic infection (OR 3.994, 95% CI 1.235-13.52, p = 0.021), while ISR was not a predictor. Conclusions: Anal pain following ISR can be controlled with oxycodone hydrochloride hydrate therapy. ISR is feasible following CRT for low-lying rectal cancer.
Allogeneic Liver Transplantation and Subsequent Syngeneic Hepatocyte Transplantation in a Rat Model: Proof of Concept for in vivo Tissue Engineering
Authors: Rohn Susanne , Schroeder Jan , Riedel Henriette , Polenz Dietrich , Stanko Katarina , Reutzel-Selke Anja , Tang Peter , Brusendorf Lydia , Raschzok Nathanael , Neuhaus Peter , Pratschke Johann , Sawitzki Birgit , Sauer Igor M. , Mogl Martina T.
Published: May 2016

Objectives: Stable long-term functioning of liver cells after transplantation in humans is still not achieved successfully. A new approach for successful engraftment of liver cells may be the transplantation of syngeneic cells into an allogeneic liver graft. We therefore developed a new rat model for combined liver and liver cell transplantation (cLCTx) under stable immunosuppression. Materials and Methods: After inducing a mitotic block, liver grafts from female donor rats (Dark Agouti) were transplanted into female recipients (Lewis). In male Lewis rats, liver cell proliferation was induced with subsequent cell isolation and transplantation into female recipients after organ transplantation. Y-chromosome detection of the transplanted male cells was performed by quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FisH) with localization of transplanted cells by immunohistochemistry. Results: Immunohistochemistry demonstrated the engraftment of transplanted cells, as confirmed by FisH, showing repopulation of the liver graft with 15.6% male cells (± 1.8 SEM) at day 90. qPCR revealed 14.15% (± 5.09 SEM) male DNA at day 90. Conclusion: Engraftment of transplanted syngeneic cells after cLCTx was achieved for up to 90 days under immunosuppression. Immunohistochemistry indicated cell proliferation, and the FisH results were partly confirmed by qPCR. This new protocol in rats appears feasible for addressing long-term functioning and eventually the induction of operational tolerance in the future.
Traumatic Brain Injury in Children: Role of CDRs-PECARN as a Clinical Predictive Resource for Evaluation of Intracranical Lesions and Neuropsychiatric Outcomes
Authors: Ferrara Pietro , Basile Maria Cristina , Dell'Aquila Livia , Vena Flaminia , Coppo Elena , Chiaretti Antonio , Verrotti Alberto , Paolini Fabrizio , Caldarelli Massimo
Published: May 2016

Cranial computed tomography (CT) is considered the gold standard for the diagnosis of traumatic brain injury (TBI). The aim of this study was to evaluate if the clinical decision rules proposed by the Pediatric Emergency Care Applied Research Network (CDRs-PECARN) are really able to identify the patients who do not need cranial CT. This study investigates the neuropsychiatric outcome after TBI according to a pediatric version of the Glasgow Outcome Scale-Extended (GOS-E Peds). We calculated the sensitivity, specificity, negative predictive value (NPV) and positive predictive value of the CDRs-PECARN in 2 age groups. Sensitivity was very high in both groups, and the NPV was very useful for predicting which subjects, of those who presented without CDRs- PECARN, would have a negative cranial CT. We also evaluated the correlations between the GOS-E Peds and Glasgow Coma Scale and between the GOS-E Peds and cranial CT scan. Our study confirms the validation of the PECARN TBI prediction rules as a clinical instrument which can play a significant role in CT decision-making for children with TBI. It also demonstrates that the GOS-E Peds is a valid pediatric outcome scale for children with TBI, despite some important limitations.
Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice
Authors: Westerterp Marit , Tsuchiya Kyoichiro , Tattersall Ian W. , Fotakis Panagiotis , Bochem Andrea E. , Molusky Matthew M. , Ntonga Vusisizwe , Abramowicz Sandra , Parks John S. , Welch Carrie L. , Kitajewski Jan , Accili Domenico , Tall Alan R.
Published: May 2016

Objective—

Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of
Abca1
and
Abcg1
.

Approach and Results—

Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding
Abca1

fl/fl

Abcg1

fl/fl

Ldlr

−/−

mice with the Tie2Cre strain, followed by irradiation and transplantation of
Abca1

fl/fl

Abcg1

fl/fl

bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-
Abca1
and
Abcg1
deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-
Abca1/g1
deficiency caused a significant further increase in lesion area at both sites. EC-
Abca1/g1
deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque.
Abca1/g1
deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by
ABCG1
deficiency in human aortic ECs.

Conclusions—

These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.
Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration
Authors: Williams Helen , Mill Carina A.E. , Monk Bethan A. , Hulin-Curtis Sarah , Johnson Jason L. , George Sarah J.
Published: May 2016

Objective—

Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening.

Approach and Results—

Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2
+/−
and WISP-1
−/−
mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus.

Conclusions—

Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure.
Procalcitonin and Midregional Proatrial Natriuretic Peptide as Markers of Ischemic Stroke
Authors: Katan Mira , Moon Yeseon P. , Paik Myunghee C. , Mueller Beat , Huber Andreas , Sacco Ralph L. , Elkind Mitchell S.V.
Published: May 2016

Background and Purpose—

Chronic infections and neuroendocrine dysfunction may be risk factors for ischemic stroke (IS). We hypothesized that selected blood biomarkers of infection (procalcitonin [PCT]), hypothalamic–pituitary–axis function (copeptin), and hemodynamic dysfunction (midregional proatrial natriuretic peptide [MRproANP]) are associated with incident IS risk in the multiethnic, urban Northern Manhattan Study (NOMAS) cohort.

Methods—

A nested case–control study was performed among initially stroke-free participants. Cases were defined as first IS (n=172). We randomly selected controls among those who did not develop an event (n=344). We calculated Cox proportional hazards models with inverse probability weighting to estimate the association of blood biomarkers with risk of stroke after adjusting for demographic, behavioral, and medical risk factors.

Results—

Those with PCT and MRproANP, but not copeptin, in the top quartile, compared with the lowest quartile, were associated with IS (for PCT adjusted hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0–3.8 and for MRproANP adjusted HR, 3.5; 95% CI, 1.6–7.5). The associations of PCT and MRproANP differed by stroke etiology; PCT levels in the top quartile were particularly associated with small vessel stroke (adjusted HR, 5.1; 95% CI, 1.4–18.7) and MRproANP levels with cardioembolic stroke (adjusted HR, 16.3; 95% CI, 3.7–70.9).

Conclusions—

Higher levels of PCT, a marker of infection, and MRproANP, a marker for hemodynamic stress, were independently associated with IS risk. PCT was specifically associated with small vessel and MRproANP with cardioembolic stroke risk. Further study is needed to validate these biomarkers and determine their significance in stroke risk prediction and prevention.
Utility of Computed Tomographic Perfusion in Thrombolysis for Minor Stroke
Authors: Ng Felix C. , Coote Skye , Frost Tanya , Bladin Chris , Choi Philip M.
Published: May 2016

Background and Purpose—

The use of thrombolysis in acute minor ischemic stroke (MIS) remains controversial. We sought to determine the safety and efficacy of intravenous tissue-type plasminogen activator (IV-tPA) in acute MIS patients with demonstrable penumbra on computed tomographic perfusion study.

Methods—

Consecutive MIS patients with National Institutes of Health Stroke Scale ≤3 were identified from a prospective single tertiary-center database over a 4.5-year period (2011–2015). Cases with demonstrable penumbra were analyzed according to treatment received: IV-tPA versus standard stroke-unit care without thrombolysis.

Results—

Seventy-three patients of 195 acute MIS admissions had a demonstrable penumbra (34 IV-tPA versus 39 standard stroke-unit care). Overall median National Institutes of Health Stroke Scale and premorbid modified Rankin Scale were 2 and 0, respectively. Median age was 73.2 (interquartile range, 67.3–82.8) years. There were no differences in baseline demographics, risk factors, stroke localization and cause, rates of vascular occlusion (38.2% versus 38.5%;
P
=1.000), or mean penumbral volume (41.3 versus 25.1 mL;
P
=0.150; IV-tPA versus standard stroke-unit care) between groups. There were no symptomatic intracerebral hemorrhages in either group. Patients treated with IV-tPA were more likely to have an excellent functional outcome at discharge (88.2% versus 53.9%;
P
=0.002) and 90 days (91.2% versus 71.8%;
P
=0.042). Ordinal analysis demonstrated a favorable shift in modified Rankin Scale with IV-tPA both at discharge (odds ratio, 5.23; 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35; 95% confidence interval, 1.77–11.36).

Conclusions—

In selected MIS patients with demonstrable penumbra on computed tomographic perfusion, IV-tPA is safe and associated with significant improvement in functional outcome at discharge and 90 days.
True bugs (Hemiptera-Heteroptera) of Botswana—Bibliographical inventory and new records
Authors: Krüger ANDREAS , Deckert JÜRGEN
Published: May 2016

The knowledge of insect biodiversity of Botswana is far from perfect. By 2015, there were only inventories publicly available for butterflies, dragonflies and grasshoppers. Here we report 331 species and subspecies of true bugs (Heteroptera), of which 242 records were extracted from scattered published literature and online sources, and 89 (27%) are new records for Botswana. These data significantly increase the number of insect species known from Botswana by roughly 30%.
Past and Projected Changes in Western North Pacific Tropical Cyclone Exposure
Authors: Kossin James P. , Emanuel Kerry A. , Camargo Suzana J.
Published: May 2016

The average latitude where tropical cyclones (TCs) reach their peak intensity has been observed to be shifting poleward in some regions over the past 30 years, apparently in concert with the independently observed expansion of the tropical belt. This poleward migration is particularly well observed and robust in the western North Pacific Ocean (WNP). Such a migration is expected to cause systematic changes, both increases and decreases, in regional hazard exposure and risk, particularly if it persists through the present century. Here, it is shown that the past poleward migration in the WNP has coincided with decreased TC exposure in the region of the Philippine and South China Seas, including the Marianas, the Philippines, Vietnam, and southern China, and increased exposure in the region of the East China Sea, including Japan and its Ryukyu Islands, the Korea Peninsula, and parts of eastern China. Additionally, it is shown that projections of WNP TCs simulated by, and downscaled from, an ensemble of numerical models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) demonstrate a continuing poleward migration into the present century following the emissions projections of the representative concentration pathway 8.5 (RCP8.5). The projected migration causes a shift in regional TC exposure that is very similar in pattern and relative amplitude to the past observed shift. In terms of regional differences in vulnerability and resilience based on past TC exposure, the potential ramifications of these future changes are significant. Questions of attribution for the changes are discussed in terms of tropical belt expansion and Pacific decadal sea surface temperature variability.
Can Beach Cleans Do More Than Clean-Up Litter? Comparing Beach Cleans to Other Coastal Activities
Authors: Wyles Kayleigh J. , Pahl Sabine , Holland Matthew , Thompson Richard C.
Published: May 2016

Coastal visits not only provide psychological benefits but can also contribute to the accumulation of rubbish. Volunteer beach cleans help address this issue, but may only have limited, local impact. Consequently, it is important to study any broader benefits associated with beach cleans. This article examines the well-being and educational value of beach cleans, as well as their impacts on individuals’ behavioral intentions. We conducted an experimental study that allocated students ( n = 90) to a beach cleaning, rock pooling, or walking activity. All three coastal activities were associated with positive mood and pro-environmental intentions. Beach cleaning and rock pooling were associated with higher marine awareness. The unique impacts of beach cleaning were that they were rated as most meaningful but linked to lower restorativeness ratings of the environment compared with the other activities. This research highlights the interplay between environment and activities, raising questions for future research on the complexities of person-environment interactions.
Emotional Resilience Mediates the Relationship Between Mindfulness and Emotion
Authors: Wang Yuzheng , Xu Wei , Luo Fei
Published: May 2016

Previous studies have shown that mindfulness promotes positive mood states and reduces negative ones; however, the underlying mechanisms are still controversial. This study assessed the role of emotional resilience as a mediator between mindfulness and emotional regulation. A total of 421 college students ( M age = 20.0 year, SD = 2.0; males/females/missing are 152/248/4) completed the Five-Facet Mindfulness Questionnaire, Profile of Mood States, and Adolescents’ Emotional Resilience Questionnaire (AERQ). The ability to generate positive emotion (GP) and the ability to recover from negative emotion (RN) are two subscales of the AERQ. A Structural Equation Modeling analysis indicated that emotional resilience mediated the connection between mindfulness and emotion. Specifically, GP mediated the relationship between mindfulness and both positive and negative emotions while RN mainly mediated the relationship between mindfulness and negative emotions. These findings suggest that mindfulness may play a role in regulating positive and negative emotions through the two different aspects of emotional resilience.
Sociology of Exclusion: Dalits in East Uttar Pradesh
Authors: Mallick Nirakar , Malik Bibhuti Bhushan
Published: May 2016

Social reality in India is pre-determined by a hierarchy of caste and class that denies rights to people living at the bottom of the Hindu social order. In this micro-regional study, we attempt to show how continuing caste rigidity hinders social interaction, which, in turn, strengthens social exclusion, thus preventing the growth and development of certain communities. We set out to examine and analyse how social interaction, and its effect on social exclusion, historically exists amongst the Dalits in Varanasi district of East Uttar Pradesh. The article, developed out of extensive empirical fieldwork and based on a primary data interview schedule, focused interviews and a quasi-participatory observation method, initially contextualises linkages between social interaction and social exclusion. Then, we observe the proximity and locations of different communities in the surveyed villages. Next, we examine the kinds of village activities the lower caste Dalits participate in or do not have access to, and the reasons for their non-participation. Finally, through some observations, we outline how equal access to services and society are imperative for democratic participation and the overall development of society.
Assessing the Potential Impact of Labor Law Reforms on University Faculty
Authors: Butovsky Jonah , Savage Larry , Webber Michelle
Published: May 2016

This article presents the findings of a survey of unionized professors and professional librarians at a public university in Southern Ontario to examine their views on the prospect and desirability of “right-to-work” legislation and “paycheck protection” laws. The purpose of the study is twofold: first, to assess the level of opposition to such legislative initiatives among unionized faculty, and, second, to determine the extent to which the passage of such laws would undermine the dues base of the faculty union. Based on the findings of a mixed methods survey, we found that a strong majority of the university professors and professional librarians surveyed were opposed to “right-to-work” and “paycheck protection” laws and that their passage would not deter them from paying dues or authorizing expenditures for political action.
Culturally Responsive Pyramid Model Practices
Authors: Allen Rosemarie , Steed Elizabeth A.
Published: May 2016

This conceptual article reviews current research on racial disparities in disciplinary practices in early childhood education and work to address these issues within a positive behavior support (PBS) framework. Building largely on the Pyramid Model, recommendations and a culturally responsive approach are suggested for use within a program-wide PBS framework in early childhood settings. Future directions are discussed to guide efforts toward reducing disparate racial discipline practices in early childhood programs.
Residential mobility
Authors: Morris Tim , Manley David , Sabel Clive E.
Published: May 2016

Research into health disparities has long recognized the importance of residential mobility as a crucial factor in determining health outcomes. However, a lack of connectivity between the health and mobility literatures has led to a stagnation of theory and application on the health side, which lacks the detail and temporal perspectives now seen as critical to understanding residential mobility decisions. Through a critical re-think of mobility processes with respect to health outcomes and an exploitation of longitudinal analytical techniques, we argue that health geographers have the potential to better understand and identify the relationship that residential mobility has with health.
pH-responsive amphiphilic macromolecular carrier for doxorubicin delivery
Authors: Gu Li , Wang Ning , Nusblat Leora M , Soskind Rose , Roth Charles M , Uhrich Kathryn E
Published: May 2016

In this work, pH-sensitive amphiphilic macromolecules are designed to possess good biocompatibility and drug loading while employing an acid-sensitive linkage to trigger drug release at tumor tissues. Specifically, two pH-sensitive amphiphilic macromolecules were synthesized with a hydrazone linkage between the hydrophobic and hydrophilic segments. The chemical structure, molecular weight, critical micelle concentration, micelle size, and pH-triggered cleavage of the amphiphilic macromolecules were characterized via matrix-assisted laser desorption/ionization time-of-flight, nuclear magnetic resonance, and dynamic light scattering techniques. Drug loading and release as well as cytotoxicity studies were performed using doxorubicin. Hydrodynamic diameters of the micelles formed with pH-sensitive amphiphilic macromolecules were within an optimal range for cellular uptake. The critical micelle concentration values were 10–8–10–6 M, indicating micellar stability upon dilution. The degradation products of the amphiphilic macromolecules after acidic incubation were identified using mass spectrometry, nuclear magnetic resonance, and dynamic light scattering methods. A pH-dependent release profile of the doxorubicin-encapsulated amphiphilic macromolecules was observed. Cytotoxicity studies against two cancer cell lines, MDA-MB-231 human breast cancer cells and A549 lung cancer cells, showed that doxorubicin encapsulated in pH-sensitive amphiphilic macromolecules decreased cell viability more efficiently than free doxorubicin, possibly due to the toxicity of the amphiphilic macromolecule degradation products. Resulting from enhanced release at acidic pH due to hydrolysis of the hydrazone linkage, pH-sensitive amphiphilic macromolecules also had improved efficacy toward cancer cells compared to other carriers (e.g. Pluronics®). These findings indicate that pH-sensitive amphiphilic macromolecules can potentially be applied as anticancer drug delivery vehicles to achieve controlled release and improved therapeutic effects.
Efficient trajectory parameterization for environmental optimization of departure flight paths using a genetic algorithm
Authors: Hartjes S , Visser HG
Published: May 2016

In this study, a genetic optimization algorithm is applied to the design of environmentally friendly aircraft departure trajectories. The environmental optimization has been primarily focused on noise abatement and local NOx emissions, whilst taking fuel burn into account as an economical criterion. In support of this study, a novel parameterization approach has been conceived for discretizing the lateral and vertical flight profiles, which reduces the need to include nonlinear side constraints in the multiparameter optimization problem formulation, while still permitting to comply with the complex set of operational requirements pertaining to departure procedures. The resulting formulation avoids infeasible solutions and hence significantly reduces the number of model evaluations required in the genetic optimization process. The efficiency of the developed approach is demonstrated in a case study involving the design of a noise abatement departure procedure at Amsterdam Airport Schiphol in The Netherlands.
Comparison of cytotoxicity test models for evaluating resin-based composites
Authors: Lim SM , Yap AUJ , Loo CSL , Ng J , Goh CY , Hong CHL , Toh WS
Published: May 2016

Objectives:

This study compared different cytotoxicity test models for evaluating resin-based composites (RBCs) and assessed the biocompatibility of standard and bulk-fill RBCs.

Methods:

A standard (spectrum TPH) and a bulk-fill (smart dentin replacement (SDR)) RBC were selected. Disc-shaped specimens (7 mm diameter) of 2 and 4 mm thickness were polymerized for 20 s with a LED curing light of 700 mW/cm2 irradiance. The specimens ( n = 5) were subjected to micro-hardness testing and three cytotoxicity test models (direct contact, indirect contact and extract tests) with the established L-929 cell line. Hardness ratios of top and bottom surfaces of specimens were computed to assess the effectiveness of cure. For the direct and indirect contact tests, the cells were stained and zones of inhibition were analyzed after material contact for 24 h. For the extract test, cells were exposed to extracts for 24 h, and cell viability was measured. Data was analyzed using analysis of variance/Scheffe’s post hoc test and Pearson’s correlation ( p < 0.05).

Results:

The lowest mean hardness ratio and highest cytotoxicity were observed for TPH at 4 mm. At 4-mm thickness, SDR was found to be biocompatible with all three models. Correlations between hardness ratio and cell viability ranged from r = 0.89–0.96 for the various tests. A significant correlation ( r = 0.97) was also observed between the three test models.

Conclusion:

Our data indicated consistency between direct contact, indirect contact and extract test models for cytotoxicity testing of RBCs. Bulk placement and curing at 4 mm for the bulk-fill RBC evaluated did not result in undue cytotoxicity.