bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward a Rational and Mechanistic Account of Mental Effort
Authors: Shenhav Amitai , Musslick Sebastian , Lieder Falk , Kool Wouter , Griffiths Thomas L. , Cohen Jonathan D. , Botvinick Matthew M.
Published: April 2017

In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.
Coding the Ideological Direction and Content of Policies
Authors: Clinton Joshua D.
Published: April 2017

Many of the questions that are central to political science involve understanding either the causes or consequences of policy change. Scholars have relied on both data-driven and model-driven approaches to characterize the content and direction of policy. This review briefly describes several prominent measures from each approach, and it highlights important limitations that scholars continue to face in the hope of prompting continued contributions to this difficult, but essential, task.
Adaptation to Climate Change
Authors: Fankhauser Sam
Published: April 2017

This article reviews the economic and analytical challenges of adaptation to climate change. Adaptation to climate risks that can no longer be avoided is an important aspect of the global response to climate change. Humans have always adapted to changing climatic conditions, and there is growing, if still patchy, evidence of widespread adaptation behavior. However, adaptation is not autonomous as sometimes claimed. It requires knowledge, planning, coordination, and foresight. There are important knowledge gaps, behavioral barriers, and market failures that hold back effective adaptation and require policy intervention. We identify the most urgent adaptation priorities, including areas where delay might lock in future vulnerability, and outline the decision-making challenges of adapting to an unknown future climate. We also highlight the strong interlinkages between adaptation and economic development, pointing out that decisions on industrial strategy, urban planning, and infrastructure investment all have a strong bearing on future vulnerability to climate change. We review the implications of these links for adaptation finance and what the literature tells us about the balance between adaptation and mitigation.
Redesigning a course to help students achieve higher-order cognitive thinking skills: from goals and mechanics to student outcomes
Authors: Casagrand Janet , Semsar Katharine
Published: April 2017

Here we describe a 4-yr course reform and its outcomes. The upper-division neurophysiology course gradually transformed from a traditional lecture in 2004 to a more student-centered course in 2008, through the addition of evidence-based active learning practices, such as deliberate problem-solving practice on homework and peer learning structures, both inside and outside of class. Due to the incremental nature of the reforms and absence of pre-reform learning assessments, we needed a way to retrospectively assess the effectiveness of our efforts. To do this, we first looked at performance on 12 conserved exam questions. Students performed significantly higher post-reform on questions requiring lower-level cognitive skills and those requiring higher-level cognitive skills. Furthermore, student performance on conserved questions was higher post-reform in both the top and bottom quartiles of students, although lower-quartile student performance did not improve until after the first exam. To examine student learning more broadly, we also used Bloom’s taxonomy to quantify a significant increase in the Bloom’s level of exams, with students performing equally well post-reform on exams that had over twice as many questions at higher cognitive skill levels. Finally, we believe that four factors provided critical contributions to the success of the course reform, including: transformation efforts across multiple course components, alignment between formative and evaluative course materials, student buy-in to course instruction, and instructional support. This reform demonstrates both the effectiveness of incorporating student-centered, active learning into our course, and the utility of using Bloom’s level as a metric to assess course reform.
An Exploration of Traditional Chinese Medicinal Plants with Anti‐Inflammatory Activities
Authors: Fan Chao , Jin Hui-zi , Wu Lehao , Zhang Yu , Ye Richard D. , Zhang Weidong , Zhang Yan
Published: April 2017

In a continuing effort to discover more anti‐inflammatory medicinal plants in China, the anti‐inflammatory activities of 101 extracts from different parts of 84 traditional medicinal plants were evaluated by a panel of in vitro and in vivo assays. Nuclear factor‐kappa B (NF‐κB) inhibitory effects were determined by luciferase assay in stably transfected Hela cells. Cytotoxic activities were assessed using the MTT assay. Inhibitory effects on LPS‐induced nitric oxide production and proinflammatory mediators were assessed by Griess reaction and Real‐Time PCR analysis, respectively. In vivo anti‐inflammatory activities were examined by xylene‐induced mice ear edema model. In total, 22 extracts showed promising NF‐κB inhibitory effects whereas 9 of them did not affect the cell viability. The 9 hit extracts were active in at least one of the subsequently performed in vitro pharmacological test systems. The extract from Hemerocallis minor (root) was selected to perform the in vivo study because it demonstrated significant suppressive effects in all the in vitro assays. Results showed that the extract of Hemerocallis minor (Root) was able to alleviate ear edema effectively in xylene‐induced mice ear edema mode. Collectively, our study provides evidence for the potential anti‐inflammatory effects of the medicinal plants traditionally used in China. Further phytochemical and pharmacological studies remain to be clarified.
One‐Dimension Nonisentropic Model for the Flow of Aluminized Explosive Products
Authors: Duan Ji , Wu Cheng , An Fengjiang , Liao Shasha , Liu Hengzhu , Dai Lihui
Published: April 2017

A new analytic model of aluminized explosive products based on the method of characteristics for planar isentropic flow is proposed herein. The contribution of Al oxidation in the explosion products is investigated analytically. The flow behind the detonation front cannot be treated as isentropic due to the Al oxidation in the products. To solve the nonisentropic flow field of aluminized explosives products analytically, the assumption of local isentropic process is proposed. Based on this assumption, the flow field behind the detonation front of aluminized explosive is a function of only the reacted aluminum mass fraction in each time range. The metal plate test was conducted with the metal plate driven by RDX/Al/wax (76/20/4) and RDX/LiF/wax (76/20/4). The reacted aluminum mass can be obtained indirectly from the experiment results. The reacted aluminum mass was then applied to the analytic model, and the velocity of metal plate driven by RDX/Al/wax (76/20/4) and RDX/LiF/wax (76/20/4) was calculated. The final velocity of the metal plate driven by RDX/Al/wax was 7.8% higher than that driven by RDX/LiF/wax.
Multimodal Sensing Interface for Haptic Interaction
Authors: Diaz Carlos , Payandeh Shahram
Published: April 2017

This paper investigates the integration of a multimodal sensing system for exploring limits of vibrato tactile haptic feedback when interacting with 3D representation of real objects. In this study, the spatial locations of the objects are mapped to the work volume of the user using a Kinect sensor. The position of the user’s hand is obtained using the marker-based visual processing. The depth information is used to build a vibrotactile map on a haptic glove enhanced with vibration motors. The users can perceive the location and dimension of remote objects by moving their hand inside a scanning region. A marker detection camera provides the location and orientation of the user’s hand (glove) to map the corresponding tactile message. A preliminary study was conducted to explore how different users can perceive such haptic experiences. Factors such as total number of objects detected, object separation resolution, and dimension-based and shape-based discrimination were evaluated. The preliminary results showed that the localization and counting of objects can be attained with a high degree of success. The users were able to classify groups of objects of different dimensions based on the perceived haptic feedback.
Role of Acupoint Area Collagen Fibers in Anti‐Inflammation of Acupuncture Lifting and Thrusting Manipulation
Authors: Wang Fan , Cui Guang-wei , Kuai Le , Xu Jian-min , Zhang Ting-ting , Cheng Huai-jin , Dong Hong-sheng , Dong Gui-rong
Published: April 2017

The role of the acupoint area collagen fibers in the efficacy of acupuncture lifting and thrusting (L&T) manipulation will be explored in this paper. 30 male NZW rabbits were randomly divided into 6 groups: sham operation group (Group N), model group (Group M), acupuncture without manipulation group (Group W), acupuncture L&T manipulation group (Group A), collagenase pretreatment group (Group JM), and collagenase pretreatment + acupuncture L&T manipulation group (Group JA). The bacterial endotoxin was used to generate the rabbit fever models. Acupuncture was applied at IL‐11. The levels of IL‐1β, TNF‐α, and IL‐4 and the rectal temperature were measured at 2 h, 4 h, and 6 h after modeling and the collagen fiber morphology at acupoint area was observed after 6 hours. Results. As compared with Group N, the levels of IL‐1β and TNF‐α in Group M were significantly higher; the level of IL‐4 was significantly lower (P < 0.05). As compared with Group M, IL‐1β and TNF‐α in Groups W and A were significantly lower and IL‐4 was significantly higher (P < 0.05). As compared with Group W, IL‐1β and TNF‐α in Group A were lower and IL‐4 was higher (P < 0.05). The collagen fiber in Group A was slightly rough, distorted, and fractured. As shown in studies, the endotoxin‐induced inflammatory response can be significantly inhibited by acupuncture whose efficacy can also be significantly improved by the manipulations. Collagenase pretreatment may be the first receptor to the mechanical force of the L&T manipulation.
Feature Extraction and Classification on Esophageal X-Ray Images of Xinjiang Kazak Nationality
Authors: Yang Fang , Hamit Murat , Yan Chuan B. , Yao Juan , Kutluk Abdugheni , Kong Xi M. , Zhang Sui X.
Published: April 2017

Esophageal cancer is one of the fastest rising types of cancers in China. The Kazak nationality is the highest-risk group in Xinjiang. In this work, an effective computer-aided diagnostic system is developed to assist physicians in interpreting digital X-ray image features and improving the quality of diagnosis. The modules of the proposed system include image preprocessing, feature extraction, feature selection, image classification, and performance evaluation. 300 original esophageal X-ray images were resized to a region of interest and then enhanced by the median filter and histogram equalization method. 37 features from textural, frequency, and complexity domains were extracted. Both sequential forward selection and principal component analysis methods were employed to select the discriminative features for classification. Then, support vector machine andK-nearest neighbors were applied to classify the esophageal cancer images with respect to their specific types. The classification performance was evaluated in terms of the area under the receiver operating characteristic curve, accuracy, precision, and recall, respectively. Experimental results show that the classification performance of the proposed system outperforms the conventional visual inspection approaches in terms of diagnostic quality and processing time. Therefore, the proposed computer-aided diagnostic system is promising for the diagnostics of esophageal cancer.
PV-Powered CoMP-Based Green Cellular Networks with a Standby Grid Supply
Authors: Jahid Abu , Shams Abdullah Bin , Hossain Md. Farhad
Published: April 2017

This paper proposes a novel framework for PV-powered cellular networks with a standby grid supply and an essential energy management technique for achieving envisaged green networks. The proposal considers an emerging cellular network architecture employing two types of coordinated multipoint (CoMP) transmission techniques for serving the subscribers. Under the proposed framework, each base station (BS) is powered by an individual PV solar energy module having an independent storage device. BSs are also connected to the conventional grid supply for meeting additional energy demand. We also propose a dynamic inter-BS solar energy sharing policy through a transmission line for further greening the proposed network by minimizing the consumption from the grid supply. An extensive simulation-based study in the downlink of a Long-Term Evolution (LTE) cellular system is carried out for evaluating the energy efficiency performance of the proposed framework. System performance is also investigated for identifying the impact of various system parameters including storage factor, storage capacity, solar generation capacity, transmission line loss, and different CoMP techniques.
An Investigation on the Aggregation and Rheodynamics of Human Red Blood Cells Using High Performance Computations
Authors: Xu Dong , Ji Chunning , Avital Eldad , Kaliviotis Efstathios , Munjiza Ante , Williams John
Published: April 2017

Studies on the haemodynamics of human circulation are clinically and scientifically important. In order to investigate the effect of deformation and aggregation of red blood cells (RBCs) in blood flow, a computational technique has been developed by coupling the interaction between the fluid and the deformable RBCs. Parallelization was carried out for the coupled code and a high speedup was achieved based on a spatial decomposition. In order to verify the code’s capability of simulating RBC deformation and transport, simulations were carried out for a spherical capsule in a microchannel and multiple RBC transport in a Poiseuille flow. RBC transport in a confined tube was also carried out to simulate the peristaltic effects of microvessels. Relatively large-scale simulations were carried out of the motion of 49,512 RBCs in shear flows, which yielded a hematocrit of 45%. The large-scale feature of the simulation has enabled a macroscale verification and investigation of the overall characteristics of RBC aggregations to be carried out. The results are in excellent agreement with experimental studies and, more specifically, both the experimental and simulation results show uniform RBC distributions under high shear rates (60–100/s) whereas large aggregations were observed under a lower shear rate of 10/s.
Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ
Authors: Davis Ruth J. , Moore Ellen C. , Clavijo Paul E. , Friedman Jay , Cash Harrison , Chen Zhong , Silvin Chris , Van Waes Carter , Allen Clint
Published: April 2017

Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell–inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte–dependent primary tumor growth delay and prolonged survival only in T-cell–inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607–19. ©2017 AACR.
E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer
Authors: Nicholson Judith , Jevons Sarah J. , Groselj Blaz , Ellermann Sophie , Konietzny Rebecca , Kerr Martin , Kessler Benedikt M. , Kiltie Anne E.
Published: April 2017

The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer. Cancer Res; 77(11); 3027–39. ©2017 AACR.
ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma
Authors: Schmitt Anna , Knittel Gero , Welcker Daniela , Yang Tsun-Po , George Julie , Nowak Michael , Leeser Uschi , Büttner Reinhard , Perner Sven , Peifer Martin , Reinhardt Hans Christian
Published: April 2017

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040–56. ©2017 AACR.
Behind the Scenes: Endo/Exocytosis in the Acquisition of Metastatic Traits
Authors: Lanzetti Letizia , Di Fiore Pier Paolo
Published: April 2017

Alterations of endo/exocytic proteins have long been associated with malignant transformation, and genes encoding membrane trafficking proteins have been identified as bona fide drivers of tumorigenesis. Focusing on the mechanisms underlying the impact of endo/exocytic proteins in cancer, a scenario emerges in which altered trafficking routes/networks appear to be preferentially involved in the acquisition of prometastatic traits. This involvement in metastasis frequently occurs through the integration of programs leading to migratory/invasive phenotypes, survival and resistance to environmental stresses, epithelial-to-mesenchymal transition, and the emergence of cancer stem cells. These findings might have important implications in the clinical setting for the development of metastasis-specific drugs and for patient stratification to optimize the use of available therapies. Cancer Res; 77(8); 1813–7. ©2017 AACR.
Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation
Authors: Frazier Jason P. , Bertout Jessica A. , Kerwin William S. , Moreno-Gonzalez Alicia , Casalini Joey R. , Grenley Marc O. , Beirne Emily , Watts Kori L. , Keener Andy , Thirstrup Derek J. , Tretyak Ilona , Ditzler Sally H. , Tripp Chelsea D. , Choy Kevin , Gillings Sarah , Breit Megan N. , Meleo Karri A. , Rizzo Vanessa , Herrera Chamisa L. , Perry James A. , Amaravadi Ravi K. , Olson James M. , Klinghoffer Richard A.
Published: April 2017

The vision of a precision medicine–guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869–80. ©2017 AACR.
Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models
Authors: Suominen Mari I. , Fagerlund Katja M. , Rissanen Jukka P. , Konkol Yvonne M. , Morko Jukka P. , Peng ZhiQi , Alhoniemi Esa J. , Laine Salla K. , Corey Eva , Mumberg Dominik , Ziegelbauer Karl , Käkönen Sanna-Maria , Halleen Jussi M. , Vessella Robert L. , Scholz Arne
Published: April 2017

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.

Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12–17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.

Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.

Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335–46. ©2017 AACR.
A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in MetastaticBRAF-Mutant Colorectal Cancer
Authors: van Geel Robin M.J.M. , Tabernero Josep , Elez Elena , Bendell Johanna C. , Spreafico Anna , Schuler Martin , Yoshino Takayuki , Delord Jean-Pierre , Yamada Yasuhide , Lolkema Martijn P. , Faris Jason E. , Eskens Ferry A.L.M. , Sharma Sunil , Yaeger Rona , Lenz Heinz-Josef , Wainberg Zev A. , Avsar Emin , Chatterjee Arkendu , Jaeger Savina , Tan Eugene , Maharry Kati , Demuth Tim , Schellens Jan H.M.
Published: April 2017

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.

Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610–9. ©2017 AACR.

See related commentary by Sundar et al., p. 558.

This article is highlighted in the In This Issue feature, p. 539
Refined Internal Limiting Membrane Inverted Flap Technique for Intractable Macular Detachment with Optic Disc Pit
Authors: Hara Rumiko , Tsukahara Yasutomo , Simoyama Tsuyoshi , Mori Soutarou
Published: April 2017

Purpose: To report a surgical technique for retinal detachment associated with optic disc pit (ODP) by using an internal limiting membrane (ILM) inverted flap as an obstacle between the vitreous cavity and subretinal space. Case Presentation: A 43-year-old man presented with decreased visual acuity in the right eye for 1 week due to macular detachment associated with ODP. After 2 unsuccessful surgeries, the retina was reattached by vitrectomy with an ILM inverted flap onto the ODP. Conclusion: Covering the pit with an inverted ILM flap is a reliable method for intercepting fluid from the vitreous cavity. Immediate absorption of subretinal fluid may lead to early macular attachment. This technique would be effective in managing ODP.
Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction
Authors: Silva-filho Antônio F. , Sena Wanessa L.B. , Lima Luiza R.A. , Carvalho Lidiane V.N. , Pereira Michelly C. , Santos Lucas G.S. , Santos Renata V.C. , Tavares Lucas B. , Pitta Maira G.R. , Rêgo Moacyr J. B. M.
Published: April 2017

Post-translational and co-translational enzymatic addition of glycans (glycosylation) to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.
Two new Neotropical species of the Dasyhelea mutabilis group (Culicomorpha: Ceratopogonidae)
Authors: Díaz Florentina , Felippe-Bauer Maria Luiza , Spinelli Gustavo Ricardo
Published: April 2017

Two new species of Dasyhelea Kieffer, Dasyhelea jorgei Diaz, Felippe-Bauer & Spinelli sp. nov. and Dasyhelea mineira Diaz, Felippe-Bauer & Spinelli sp. nov. are described, illustrated and photographed from Peru and Brazil respectively, based on male and female adults. These species are typical members of mutabilis species group and are compared with similar species within the group.
Diet of Dendropsophus microcephalus and Scarthyla vigilans (Anura: Hylidae) at a locality in north-western Venezuela with notes on microhabitat occupation
Authors: Fonseca-Pérez Kimberlyn Andreina , Molina César , Tárano Zaida
Published: April 2017

The coexistence of species with similar ecological requirements (food, space, time) has typically drawn attention of researchers because competition for resources is expected to be high. The diet and microhabitat occupation of two morphologically and ecologically similar species of Hylidae (Anura), Dendropsophus microcephalus and Scarthyla vigilans, were analyzed at a locality in north-western Venezuela, with the aim of addressing the potential for space and food competition between them. Diet was estimated through the analysis of stomach contents and microhabitat occupation was estimated through recordings of perch type, height and horizontal distance to water. Thirty-six prey categories (32 families, 4 orders) of arthropods were identified: 30 categories in D. microcephalus and 21 categories in S. vigilans. The most important prey (RII) in D. microcephalus were Agelenidae (11.1%), Tachinidae (9.32%) and Lepidoptera-larvae (7.96%). Gryllidae (14.13%), Cicadidae (9.1%), Cicadellidae (8.3%) and Delphacidae (8.02%) were the most important in S. vigilans. Diet overlap was relatively low (0.32). Both species have relatively generalist diets. Both species occupied the same type of perches (leaves and stems of Dicotyledons and Monocotyledons) and heights (average: S. vigilans, 24 ± 16.2 cm; D. microcephalus, 22.7 ± 9.5 cm). The potential for space competition is high if perches are limited and food competition is expected to be low.
A subadult maxilla of a Tyrannosauridae from the Two Medicine Formation, Montana, United States
Authors: Delcourt Rafael
Published: April 2017

Daspletosaurus is a Campanian genus of Tyrannosauridae from North America. This genus occupied the same geographic area of Albertosaurus, but remains of Albertosaurus are more abundant than Daspletosaurus. Here is described a subadult maxilla (AMNH FARB 5477) of Daspletosaurus sp. from Montana (USA) and possibly from the Two Medicine Formation. The description is based on Carr (1999) that described cranial ontogenetic variations in tyrannosaurids. The maxilla belongs to the ontogenetic Stage 3 sensu Carr (1999), in which the maxilla is thick, the lateral surface of the bone well sculptured, and the maxillary fenestra is subcircular and well separated from the anterior edge of antorbital fossa. Possibly there were more than one species of Daspletosaurus and the locality of the here described subadult specimen suggests that Daspletosaurus species occurred more southern than Albertosaurus.
Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor
Authors: Klarin Derek , Emdin Connor A. , Natarajan Pradeep , Conrad Mark F. , Kathiresan Sekar
Published: April 2017

Background—

UK Biobank is the world’s largest repository for phenotypic and genotypic information for individuals of European ancestry. Here, we leverage UK Biobank to understand the inherited basis for venous thromboembolism (VTE), a leading cause of cardiovascular mortality.

Methods and Results—

We identified 3290 VTE cases and 116 868 controls through billing code–based phenotyping. We performed a genome-wide association study for VTE with ≈9 000 000 imputed single-nucleotide polymorphisms. We performed a phenome-wide association study for a genetic risk score of 10 VTE-associated variants. To assess whether obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a genetic risk score instrument composed of 68 body mass index–associated variants. The genome-wide association study for VTE replicated previous findings at the
F5
,
F2
,
ABO
,
F11
, and
FGG
loci. We identified 1 new locus—
ZFPM2
rs4602861—at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07–1.15;
P
=4.9×10
−10
) and a new independent variant at the
F2
locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06–1.13;
P
=7.60×10
−9
). In a phenome-wide association study, a 10 single-nucleotide polymorphism VTE genetic risk score was associated with coronary artery disease (odds ratio, 1.08; 95% confidence interval, 1.05–1.10 per unit increase in VTE odds;
P
=1.08×10
−9
). In a Mendelian randomization analysis, genetically elevated body mass index (a 1 SD increase) was associated with 57% higher risk of VTE (odds ratio, 1.57; 95% confidence interval, 1.08–1.97;
P
=0.003).

Conclusions—

For common diseases such as VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference.
Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial
Authors: Upadhya Bharathi , Rocco Michael , Lewis Cora E. , Oparil Suzanne , Lovato Laura C. , Cushman William C. , Bates Jeffrey T. , Bello Natalie A. , Aurigemma Gerard , Fine Lawrence J. , Johnson Karen C. , Rodriguez Carlos J. , Raj Dominic S. , Rastogi Anjay , Tamariz Leonardo , Wiggers Alan , Kitzman Dalane W.
Published: April 2017

Background—

Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age ≥75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (≤132 versus >132 to <145 versus ≥145 mm Hg).

Methods and Results—

ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46–0.85;
P
value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age≥75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (
P
<0.001) in cardiovascular death.

Conclusions—

Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01206062
Glycemic Control Status After Percutaneous Coronary Intervention and Long-Term Clinical Outcomes in Patients With Type 2 Diabetes Mellitus
Authors: Hwang Jin Kyung , Lee Seung Hwa , Song Young Bin , Ahn Joonghyun , Carriere Keumhee , Jang Mi Ja , Park Taek Kyu , Choi Seung-Hyuk , Yang Jeong Hoon , Choi Jin-Ho , Lee Sang Hoon , Gwon Hyeon-Cheol , Hahn Joo-Yong
Published: April 2017

Background—

Data on the association between glycemic control after percutaneous coronary intervention and clinical outcomes are limited and controversial in diabetic patients.

Methods and Results—

We studied 980 patients with type 2 diabetes mellitus undergoing percutaneous coronary intervention using drug-eluting stents. Based on 2-year glycosylated hemoglobin A (HbA1c) levels, we divided patients into 2 groups of HbA1c<7.0 (n=489) and HbA1c≥7.0 (n=491). Propensity score–matched analysis was performed in 322 pairs. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of cardiac death, myocardial infarction, repeat revascularization, or stroke. Median follow-up duration was 5.4 years. The 7-year incidence of MACCE was lower in the HbA1c<7.0 group than in the HbA1c≥7.0 group (26.9% versus 40.3%; adjusted hazard ratio, 0.75; 95% confidence interval, 0.57–0.98;
P
=0.03). After propensity score matching, the 7-year incidence of MACCE was still lower in the HbA1c<7.0 group than in the HbA1c≥7.0 group (27.5% versus 37.4%; hazard ratio, 0.71; 95% confidence interval, 0.52–0.97;
P
=0.03), mainly because of a reduction in repeat revascularization (19.9% versus 29.5%; hazard ratio, 0.66; 95% confidence interval, 0.47–0.93;
P
=0.02). In subgroup analyses, the benefit of glycemic control for MACCE was more prominent in patients with residual SYNTAX score (Synergy Between PCI With Taxus and Cardiac Surgery) >4 than in those with the residual SYNTAX score ≤4 (
P
interaction
=0.004).

Conclusions—

HbA1c<7.0 measured 2 years after percutaneous coronary intervention was associated with a reduced rate of MACCE. Our data suggest that high HbA1c levels 2 years after percutaneous coronary intervention may identify a population at increased risk of adverse events, especially repeat revascularization.
Diagnostic Accuracy of 3.0‐T Magnetic Resonance T1 and T2 Mapping and T2‐Weighted Dark‐Blood Imaging for the Infarct‐Related Coronary Artery in Non–ST‐Segment Elevation Myocardial Infarction
Authors: Layland Jamie , Rauhalammi Samuli , Lee Matthew M. Y. , Ahmed Nadeem , Carberry Jaclyn , Teng Yue May Vannesa , Watkins Stuart , McComb Christie , Mangion Kenneth , McClure John D. , Carrick David , O'Donnell Anna , Sood Arvind , McEntegart Margaret , Oldroyd Keith G. , Radjenovic Aleksandra , Berry Colin
Published: April 2017

Background

Patients with recent non–ST‐segment elevation myocardial infarction commonly have heterogeneous characteristics that may be challenging to assess clinically.

Methods and Results

We prospectively studied the diagnostic accuracy of 2 novel (T1, T2 mapping) and 1 established (T2‐weighted short tau inversion recovery [T2W‐
STIR
]) magnetic resonance imaging methods for imaging the ischemic area at risk and myocardial salvage in 73 patients with non–ST‐segment elevation myocardial infarction (mean age 57±10 years, 78% male) at 3.0‐T magnetic resonance imaging within 6.5±3.5 days of invasive management. The infarct‐related territory was identified independently using a combination of angiographic,
ECG
, and clinical findings. The presence and extent of infarction was assessed with late gadolinium enhancement imaging (gadobutrol, 0.1 mmol/kg). The extent of acutely injured myocardium was independently assessed with native T1, T2, and T2W‐
STIR
methods. The mean infarct size was 5.9±8.0% of left ventricular mass. The infarct zone T1 and T2 times were 1323±68 and 57±5 ms, respectively. The diagnostic accuracies of T1 and T2 mapping for identification of the infarct‐related artery were similar (
P
=0.125), and both were superior to T2W‐
STIR
(
P
<0.001). The extent of myocardial injury (percentage of left ventricular volume) estimated with T1 (15.8±10.6%) and T2 maps (16.0±11.8%) was similar (
P
=0.838) and moderately well correlated (
r
=0.82,
P
<0.001). Mean extent of acute injury estimated with T2W‐
STIR
(7.8±11.6%) was lower than that estimated with T1 (
P
<0.001) or T2 maps (
P
<0.001).

Conclusions

In patients with non–ST‐segment elevation myocardial infarction, T1 and T2 magnetic resonance imaging mapping have higher diagnostic performance than T2W‐
STIR
for identifying the infarct‐related artery. Compared with conventional
STIR
, T1 and T2 maps have superior value to inform diagnosis and revascularization planning in non–ST‐segment elevation myocardial infarction.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
02073422.
Myocardial Damage Detected by Late Gadolinium Enhancement Cardiac Magnetic Resonance Is Uncommon in Peripartum Cardiomyopathy
Authors: Schelbert Erik B. , Elkayam Uri , Cooper Leslie T. , Givertz Michael M. , Alexis Jeffrey D. , Briller Joan , Felker G. Michael , Chaparro Sandra , Kealey Angela , Pisarcik Jessica , Fett James D. , McNamara Dennis M. ,   the Investigations of Pregnancy Associated Cardiomyopathy (IPAC) Investigators
Published: April 2017

Background

In peripartum cardiomyopathy, the prevalence of focal myocardial damage detected by late gadolinium enhancement (
LGE
) cardiovascular magnetic resonance is important to elucidate mechanisms of myocardial injury and cardiac dysfunction.
LGE
equates irreversible myocardial injury, but
LGE
prevalence in peripartum cardiomyopathy is uncertain.

Methods and Results

Among 100 women enrolled within the Investigations of Pregnancy Associated Cardiomyopathy cohort, we recruited 40 women at 13 centers to undergo
LGE
cardiovascular magnetic resonance, enrolled within the first 13 weeks postpartum. Follow‐up scans occurred at 6 months postpartum, and death/transplant rates at 12 months. Baseline characteristics did not differ significantly in the parent cohort according to cardiovascular magnetic resonance enrollment except for mechanical circulatory support.
LGE
was noted only in 2 women (5%) at baseline. While left ventricular dysfunction with enlargement was prevalent at baseline cardiovascular magnetic resonance scans (eg, ejection fraction 38% [Q1–Q3 31–50%], end diastolic volume index=108 mL/m
2
[Q1–Q3 83–134 mL/m
2
]), most women demonstrated significant improvements at 6 months, consistent with a low prevalence of
LGE
.
LGE
was not related to baseline clinical variables, ejection fraction, New York Heart Association heart failure class, or mortality. Neither of the 2 women who died exhibited
LGE
.
LGE
was inversely associated with persistent left ventricular ejection fraction at 6 months (
P
=0.006).

Conclusions

Factors other than focal myocardial damage detectable by
LGE
explain the initial transient depressions in baseline left ventricular ejection fraction, yet focal myocardial damage may contribute to persistent myocardial dysfunction and hinder recovery in a small minority. Most women exhibit favorable changes in ventricular function over 6 months.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01085955.
Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress
Authors: Wakayama Kouji , Shimamura Munehisa , Suzuki Jun-ichi , Watanabe Ryo , Koriyama Hiroshi , Akazawa Hiroshi , Nakagami Hironori , Mochizuki Hideki , Isobe Mitsuaki , Morishita Ryuichi
Published: April 2017

Background and Purpose—

Medication nonadherence is one of major risk factors for the poor outcome in ischemic stroke. Vaccination is expected to solve such a problem because of its long-lasting effects, but its effect on ischemic brain damage is still unknown. Here, we focused on vaccination for renin–angiotensin system and examined the effects of angiotensin II (Ang II) peptide vaccine in permanent middle cerebral artery occlusion model in rats.

Methods—

Male Wistar rats were exposed to permanent middle cerebral artery occlusion after 3× injections of Ang II peptide vaccine, and the serum or brain level of anti–Ang II antibody was examined. The effects of the vaccine were evaluated by differences in infarction volume, brain renin–angiotensin system components, and markers for neurodegeneration and oxidative stress.

Results—

Ang II vaccination successfully produced anti–Ang II antibodies in serum without concomitant change in blood pressure. Sufficient production of serum anti–Ang II antibody led to reduction of infarct volume and induced the penetration of anti–Ang II antibody in ischemic hemisphere, with suppressed expression of Ang II type 1 receptor mRNA. Vaccinated rats with sufficient antibody production showed the reduction of Fluoro-Jade B–positive cells, spectrin fragmentation, 4-hydroxynonenal-positive cells, and
Nox 2
mRNA expression.

Conclusions—

Our findings indicate that Ang II vaccination exerts neuroprotective and antioxidative effects in cerebral ischemia, with renin–angiotensin system blockade by penetration of anti–Ang II antibodies into ischemic brain lesion. Ang II peptide vaccination could be a promising approach to treat ischemic stroke.
Does Europeanization Foster Constructive Individualization?
Authors: Genov Nikolai
Published: April 2017

This paper aims at explaining changes in the conditions for individualization in ten central and eastern European (cee) countries after they have joined the European Union in 2004 and 2007. The expected changes had to follow the transfer of theeu’sacquis communautaireto theceeand the accompanying Europeanization understood as upgrading of governance. Indicators used in longitudinal studies are identified in order to test the assumption. Synchronic and diachronic comparison of outcomes of studies on the topic is carried out. The results don’t support the hypothesis about relevant changes in the conditions of individualization in theceecountries due to their Europeanization. The upgrading of governance quality affects the individualization in the old and neweumember states similarly. Declining quality of the conditions for individualization appears in both groups of countries with the same frequency and intensity too.