bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the benefits of using a backward chaining decision support expert system for local flood forecasting and warning
Authors: Zhang Xiaoyin , Moynihan Gary P. , Ernest Andrew N. S. , Gutenson Joseph L.
Published: January 2018

Nationwide flood forecasting and warning are available through mass media. However, running the complex numerical models requires enormous computational resources. In addition, the comparatively low accuracy of prediction for a certain region such as a small town, a community, or a single house, causes false alarms and improper responses and thus the unnecessary loss of property and/or life. One potential solution to advance forecast accuracy without occupying substantial computational resources is to develop a stand‐alone local flood forecasting and warning expert system incorporating sufficient data on local hydraulic and hydrological factors and local historical experience. To date, there has been a limited amount of work developing expert systems in this area. In this paper, we discuss the development and implementation of an expert system for local flood forecasting and warning. With its extensible knowledge base combined with the information provided by users, this expert system provides reasoning routines and forecasting on the flood warning stages, possible consequences, and recommendations for community managers, landowners, or the public in general.
Inconsistent patterns of body size evolution in co‐occurring island reptiles
Authors: Itescu Yuval , Schwarz Rachel , Donihue Colin M. , Slavenko Alex , Roussos Stephanos A. , Sagonas Kostas , Valakos Efstratios D. , Foufopoulos Johannes , Pafilis Panayiotis , Meiri Shai
Published: January 2018

Aim

Animal body sizes are often remarkably variable across islands, but despite much research we still have a poor understanding of both the patterns and the drivers of body size evolution. Theory predicts that interspecific competition and predation pressures are relaxed on small, remote islands, and that these conditions promote body size evolution. We studied body size variation across multiple insular populations of 16 reptile species co‐occurring in the same archipelago and tested which island characteristics primarily drive body size evolution, the nature of the common patterns, and whether co‐occurring species respond in a similar manner to insular conditions.

Location

Aegean Sea islands.

Time period

1984–2016.

Major taxa studied

Reptiles.

Methods

We combined fieldwork, museum measurements and a comprehensive literature survey to collect data on nearly 10,000 individuals, representing eight lizard and eight snake species across 273 islands. We also quantified a large array of predictors to assess directly the effects of island area, isolation (both spatial and temporal), predation and interspecific competition on body size evolution. We used linear models and meta‐analyses to determine which predictors are informative for all reptiles, for lizards and snakes separately, and for each species.

Results

Body size varies with different predictors across the species we studied, and patterns differ within families and between lizards and snakes. Each predictor influenced body size in at least one species, but no general trend was recovered. As a group, lizards are hardly affected by any of the predictors we tested, whereas snake size generally increases with area and with competitor and predator richness, and decreases with isolation.

Main conclusions

No factor emerges as a predominant driver of Aegean reptile sizes. This contradicts theories of general body size evolutionary trajectories on islands. We conclude that overarching generalizations oversimplify patterns and processes of reptile body size evolution on islands. Instead, species’ autecology and island particularities interact to drive the course of size evolution.
Negativity Bias in Attention Allocation: Retail Investors’ Reaction to Stock Returns
Authors: Reyes Tomas
Published: January 2018

We argue that negative stock market performance attracts more attention from retail investors than comparable positive performance. Specifically, we test and confirm the hypothesis that retail investors pay more attention to negative extreme returns than positive ones. We present a measure of attention at the aggregate and company‐specific levels using Google's internet search volume indexes. These measures correlate with, but are different from, existing proxies of attention. Our empirical results strongly support the position that investors display a negativity bias in attention allocation with respect to extreme stock returns. Across all specifications, lagged negative extreme returns are stronger predictors of high attention at the individual‐stock and stock market levels than positive ones.
Wnt is here! Could Wnt signalling be promoted to protect against Alzheimer disease?
Authors: Garner Brett , Ooi Lezanne
Published: January 2018

This Editorial highlights an article in the current issue by Tapia‐Rojas and Inestrosa suggesting that attenuation of Wnt signalling may be a triggering factor for the pathogenesis of Alzheimer disease (AD) in the J20 mouse model of AD. Their study utilises Wnt signalling inhibitors that operate at different points in the signalling pathway. The molecular changes of several key Wnt signaling components are examined, along with a thorough analysis of both the amyloid and tau based pathologies in the mouse brain. Studies focusing on inhibition of Wnt signalling in AD mice have the potential to provide much needed information regarding the pathological mechanisms by which attenuated Wnt signalling impacts on AD.

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Alterations in wheat pollen lipidome during high day and night temperature stress
Authors: Narayanan Sruthi , Prasad P.V. Vara , Welti Ruth
Published: January 2018

Understanding the adaptive changes in wheat pollen lipidome under high temperature (HT) stress is critical to improving seed set and developing HT tolerant wheat varieties. We measured 89 pollen lipid species under optimum and high day and/or night temperatures using electrospray ionization‐tandem mass spectrometry in wheat plants. The pollen lipidome had a distinct composition compared with that of leaves. Unlike in leaves, 34:3 and 36:6 species dominated the composition of extraplastidic phospholipids in pollen under optimum and HT conditions. The most HT‐responsive lipids were extraplastidic phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol, phosphatidic acid, and phosphatidylserine. The unsaturation levels of the extraplastidic phospholipids decreased through the decreases in the levels of 18:3 and increases in the levels of 16:0, 18:0, 18:1, and 18:2 acyl chains. PC and PE were negatively correlated. Higher PC:PE at HT indicated possible PE‐to‐PC conversion, lower PE formation, or increased PE degradation, relative to PC. Correlation analysis revealed lipids experiencing coordinated metabolism under HT and confirmed the HT responsiveness of extraplastidic phospholipids. Comparison of the present results on wheat pollen with results of our previous research on wheat leaves suggests that similar lipid changes contribute to HT adaptation in both leaves and pollen, though the lipidomes have inherently distinct compositions.
The behavioral immune system: Current concerns and future directions
Authors: Ackerman Joshua M. , Hill Sarah E. , Murray Damian R.
Published: January 2018

The behavioral immune system is a motivational system that helps minimize infection risk by changing cognition, affect, and behavior in ways that promote pathogen avoidance. In the current paper, we review foundational concepts of the behavioral immune system and provide a brief summary of recent social psychological research on this topic. Next, we highlight current conceptual and empirical limitations of this work and delineate important questions that have the potential to drive major advances in the field. These questions include predicting the ontological development of the behavioral immune system, specifying the relationship between this system and the physiological immune system, and distinguishing conditions that elicit direct effects of situational pathogen threats versus effects that occur only in interaction with dispositional disease concerns. This discussion highlights significant challenges and underexplored topics to be addressed by the next generation of behavioral immune system research.
The Food Outlook: A World Imperative
Authors: Eastwood Ralph A.
Published: January 2018

Population has proved its propensity to grow faster than its food supply until a balance is reached at the Asiatic level of subsistence. The less-developed countries continue in nutritional crisis largely because of inadequate application of food production technology and the resource requirements imposed by child dependency. Developed countries show much more promise of avoiding this tragedy through management of resources and populations.

Increases are essential in research, teaching and extension education in the many competencies comprising the technologies of food production and public health if food supply is to gain on population. Mechanical engineers must lead if that technology is to be applied through mechanization to bring about desired increases in the economy, efficiency and effectiveness of the food industry, so people may heed their nutritional history and not relive it.

Paper published with permission.
Centralized Control Techniques for the Citrus Concentrating Plant
Authors: Stephenson Ed
Published: January 2018

There is a strong tendency within the citrus industry to regard the citrus concentrating plant as being a series of discrete operations. From the viewpoint of the instrument engineer the process is a continuous one, incorporating three major dead time areas:

(a) the fruit bins,

(b) the surge (evaporator feed) tanks, and

(c) the tank farm

At all other points in the process the product can be treated as a continuous flow.

Paper published with permission.
Economics of Supplemental Power Generation
Authors: Chamberland Richard L.
Published: January 2018

With the present high cost of fuel, industries are reassessing their in-house electrical generation capability and pump drive requirements. The decision on self-power generation must be based on economics. What was uneconomical in the past may result in a large saving today.

Paper published with permission.
Citrus in Brazil
Authors: Mayer Peter C.
Published: January 2018

The Citrus Engineering Conference Committee of the American Society of Mechanical Engineers is to be commended in choosing this timely subject, Citrus in Brazil.

As most of you know, and as this paper will confirm, Brazil is second only to Florida in the production of frozen concentrated orange juice.

One of the essential components of an effective marketing program is to know your competition so that effective strategies may be developed.

The purpose of this presentation is to give you an overview of citrus in Brazil and its relationship to the Florida industry.

Paper published with permission.
Condensate Reuse: Phase II
Authors: Hamilton Richard A.
Published: January 2018

During the 1976 edition of the Citrus Engineering Conference, Mr. Dave Hamrick, Technical Vice President of Tropicana Products, delivered a paper entitled “Condensate Reuse in Citrus Plants”. In this paper, he described the nature and composition of process condensate, showed the quantity which might be available for reuse, and recommended several areas where this water might be used.

Paper published with permission.
Industrial Control as Programmable Controllers
Authors: Reed Victor W.
Published: January 2018

Programmable controllers have come a long way since their original application in the control of the production of automobile parts. Todays programmable controllers are a viable tool when considering cost and ease of application for industrial manufacturing and process control systems.

Paper published with permission.
Florida’s Revised Water Quality Regulations
Authors: Bottcher John G.
Published: January 2018

On March 1, 1979 revisions to the Florida water quality regulations became effective. These revisions reflect over five years of work and comprise the first major modification to the regulations in their ten year history. Minor modifications have occurred sporadically throughout this time and will continue. Other parts have been challenged in court and further modifications, as a result, are a possibility. Also, as the department gains experience in implementing the rules and new scientific evidence indicates a need for a change, other modifications will be proposed. So it seems that these rules along with most other environmental standards are in a constant state of flux — changes being considered even before the ink drys on the last change.

Paper published with permission.
Solar Energy: Feasibility for the Citrus Industry
Authors: Lohkamp A. T.
Published: January 2018

This paper is intended only as a brief introduction to the use of Solar Energy for heating water or the generation of low pressure steam.

Paper published with permission.
Chlorine Dioxide: An Effective Biocide for Recycled or Reused Water Systems
Authors: Synan John F.
Published: January 2018

The desire and indeed the need of industry to recycle or reuse process waters wherever possible is becoming increasingly more urgent. Limited supplies of quality water in many parts of the country and more stringent EPA regulations for waste disposal and water discharge are but two of the many reasons for this.

Paper published with permission.
Effects of vibratory pile driver noise on echolocation and vigilance in bottlenose dolphins (Tursiops truncatus)
Authors: Branstetter Brian K. , Bowman Victoria F. , Houser Dorian S. , Tormey Megan , Banks Patchouly , Finneran James J. , Jenkins Keith
Published: January 2018

Vibratory pile drivers, used for marine construction, can produce sustained, high sound pressure levels (SPLs) in areas that overlap with dolphin habitats. Dolphins rely on echolocation for navigation, detecting predators and prey, and to coordinate group behavior. This study examined the effects of vibratory pile driver noise on dolphin sustained target detection capabilities through echolocation. Five dolphins were required to scan their enclosure and indicate the occurrences of phantom echoes during five different source levels of vibratory pile driver playback sound (no-playback control, 110, 120, 130, and 140 dB re 1 μPa). Three of the dolphins demonstrated a significant decrease in target detection performance at 140 dB playback level that was associated with an almost complete secession of echolocation activity. The performance of two dolphins was not affected. All dolphins rapidly returned to baseline levels of target detection performance by their second replication. However, an increased number of clicks was produced at the highest playback SPL. The data suggest that the decrease in vigilant behavior was due to the vibratory pile driver noise distracting the dolphins and decreasing their motivation to perform the task.
Generic uniform search grid generation algorithm for far-field source localization
Authors: Lee JeeSok , Chung Soo-Whan , Kang Hong-Goo , Choi Min-Seok
Published: January 2018

In this letter, a generic search grid generation algorithm for far-field source localization (SL) is proposed. Since conventional uniform regular grid structures only consider the resolution of the distribution, it is difficult to control the number of grid points to be distributed. The proposed algorithm generates a search grid by distributing a desired number of points evenly, depending on the target criterion, in either direction of arrival or time difference of arrival domain. The experimental results show that the proposed algorithm provides optimally distributed grid points given the number of desired points and the corresponding domain for SL processing.
Human service work, gender and antidepressant use: a nationwide register-based 19-year follow-up of 752 683 women and men
Authors: Buscariolli André , Kouvonen Anne , Kokkinen Lauri , Halonen Jaana I , Koskinen Aki , Väänänen Ari
Published: January 2018

Objectives

To examine antidepressant use among male and female human service professionals.

Methods

A random sample of individuals between 25 years and 54 years of age (n=752 683; 49.2% women; mean age 39.5 years). Information about each individual’s filled antidepressant prescriptions from 1995 to 2014 was provided by the Social Insurance Institution. First, antidepressant use in five broad human service categories was compared with that in all other occupations grouped together, separately for men and women. Then, each of the 15 human service professions were compared with all other occupations from the same skill/education level (excluding other human services professions). Cox models were applied and the results are presented as HRs for antidepressant use with 95% CIs.

Results

The hazard of antidepressant use was higher among men working in human service versus all other occupations with the same skill/occupational level (1.22, 95% CI 1.18 to 1.27), but this was not the case for women (0.99, 95% CI 0.98 to 1.01). The risks differed between professions: male health and social care professionals (including medical doctors, nurses, practical nurses and home care assistants), social workers, childcare workers, teachers and psychologists had a higher risk of antidepressant use than men in non-human service occupations, whereas customer clerks had a lower risk.

Conclusions

Male human service professionals had a higher risk of antidepressant use than men working in non-human service occupations. Gendered sociocultural norms and values related to specific occupations as well as occupational selection may be the cause of the elevated risk.
Photophysical and optical limiting properties at 532 nm of BODIPY dyes with p-benzyloxystyryl groups at the 3,5-positions
Authors: Ngoy Bokolombe P. , Hlatshwayo Zweli , Nwaji Njemuwa , Fomo Gertrude , Mack John , Nyokong Tebello
Published: January 2018

The synthesis and characterization of a series of 3,5-di-[Formula: see text]-benzyloxystyrylBODIPY dyes with different substituents at the meso-aryl position is reported. The photophysical and nonlinear optical properties are described. BODIPYs of this type are found to be suitable for optical limiting at 532 nm on the nanosecond timescale. An enhancement of the population of the T[Formula: see text] state through the incorporation of bromine atoms at the 2,6-positions does not result in an enhancement of the optical limiting properties on a nanosecond timescale. This suggests that, in contrast with phthalocyanines, access to excited state absorption (ESA) from the T[Formula: see text] state through the introduction of a heavy atom effect does not provide a significantly improved reverse saturable absorbance response compared to ESA from the S[Formula: see text] state.
Photophysical and optical limiting properties of a novel distyryl-BODIPY with fused crown ether moieties
Authors: May Aviwe K. , Stone Justin , Ngoy Bokolombe P. , Mack John , Nyokong Tebello , Kimura Mutsumi , Kobayashi Nagao
Published: January 2018

The synthesis and characterization of a crown-ether-substituted 3,5-distyrylBODIPY dye with a 4-dimethylaminophenyl group at the meso-position is reported. The optical limiting properties were investigated at 532 nm, and the dye was found to have enhanced reverse saturable absorption responses during z-scan measurements. Theoretical calculations suggest that this may be due to the large dipole moment that is introduced by the benzo-fused crown ether and 4-dimethylaminophenyl substituents.
Rapid insertion of bismuth radioactive isotopes into texaphyrin in aqueous media
Authors: Thiabaud Grégory , Radchenko Valery , Wilson Justin J. , John Kevin D. , Birnbaum Eva R. , Sessler Jonathan L.
Published: January 2018

Radioisotopes [Formula: see text]Bi and [Formula: see text]Bi were successfully inserted into a water-soluble and tumor-targeting texaphyrin ligand. The reaction with [Formula: see text]Bi(OAc)[Formula: see text] proceeds in about 15 min in aqueous media without the use of any organic base. The Bi(III) texaphyrin complex formed (3) is stable in aqueous media even in the presence of an excess of competitive chelators (EDTA or citric acid), as well as in human blood plasma. These results validate texaphyrins as potential candidates for coordinating bismuth radionuclides and set the stage for their use in targeted alpha therapy (TAT).
Functionalization of chlorins towards potential photosensitizers for photodynamic therapy
Authors: Pont Francesc , Montforts Franz-Peter
Published: January 2018

Photophysical properties of chlorins predestine this type of hydroporphyrins for photodynamic therapy and other diagnostic/therapeutic applications. Artificial chlorins 3a and 4a derived from the red blood pigment heme form a platform for functionalizations with respect towards potentially biologically active photosensitizers and fluorescense markers. Chlorin estrogen derivatives 8a, 8b might be useful as sensitizers which bind selectively to (tumor) cell tissue containing estrogen receptors, [Formula: see text] breast cancer cells.
Iodinated cobalt corroles
Authors: Sudhakar Kolanu , Mahammed Atif , Fridman Natalia , Gross Zeev
Published: January 2018

Cobalt(III) complexes of selectively [Formula: see text]-pyrrole-iodinated corroles were prepared and characterized for the first time. X-ray crystallographic data reveals that the corrole macrocycle remains quite planar despite of the presence of multiple iodine substituents. The redox potentials increase linearly with the number of iodine substituents, much more for reduction than for oxidation, in a similar pattern to that of previously reported gold(III), gallium(III), and aluminum(III) complexes of [Formula: see text]-pyrrole-iodinated corroles. Their effect on reduction potential is much larger than what is observed for analogous gallium(III) and aluminum(III) corroles, wherein the chelated element is not redox active. Interestingly, the effect of iodine is similar to that of the much more electronegative halides, which is attributed to a stronger [Formula: see text]-back donation by the latter. One advantage of achieving selective iodination, in terms of the number and positioning, is that is provides an entry to further functionalization of the corrole skeleton via nucleophilic aromatic substitution.
Communication Complexity of Statistical Distance
Authors: Watson Thomas
Published: January 2018

We prove nearly matching upper and lower bounds on the randomized communication complexity of the following problem: Alice and Bob are each given a probability distribution over
n
elements, and they wish to estimate within ±ε the statistical (total variation) distance between their distributions. For some range of parameters, there is up to a log
n
factor gap between the upper and lower bounds, and we identify a barrier to using information complexity techniques to improve the lower bound in this case. We also prove a side result that we discovered along the way: the randomized communication complexity of
n
-bit Majority composed with
n
-bit Greater Than is Θ (
n
log
n
).
Actin polymerization contributes to enhanced pulmonary vasoconstrictor reactivity after chronic hypoxia
Authors: Weise-Cross Laura , Sands Michelle A. , Sheak Joshua R. , Broughton Brad R. S. , Snow Jessica B. , Gonzalez Bosc Laura V. , Jernigan Nikki L. , Walker Benjimen R. , Resta Thomas C.
Published: January 2018

Chronic hypoxia (CH) augments basal and endothelin-1 (ET-1)-induced pulmonary vasoconstrictor reactivity through reactive oxygen species (ROS) generation and RhoA/Rho kinase (ROCK)-dependent myofilament Ca2+ sensitization. Because ROCK promotes actin polymerization and the actin cytoskeleton regulates smooth muscle tension, we hypothesized that actin polymerization is required for enhanced basal and ET-1-dependent vasoconstriction after CH. To test this hypothesis, both end points were monitored in pressurized, endothelium-disrupted pulmonary arteries (fourth-fifth order) from control and CH (4 wk at 0.5 atm) rats. The actin polymerization inhibitors cytochalasin and latrunculin attenuated both basal and ET-1-induced vasoconstriction only in CH vessels. To test whether CH directly alters the arterial actin profile, we measured filamentous actin (F-actin)-to-globular actin (G-actin) ratios by fluorescent labeling of F-actin and G-actin in fixed pulmonary arteries and actin sedimentation assays using homogenized pulmonary artery lysates. We observed no difference in actin polymerization between groups under baseline conditions, but ET-1 enhanced actin polymerization in pulmonary arteries from CH rats. This response was blunted by the ROS scavenger tiron, the ROCK inhibitor fasudil, and the mDia (RhoA effector) inhibitor small-molecule inhibitor of formin homology domain 2. Immunoblot analysis revealed an effect of CH to increase both phosphorylated (inactive) and total levels of the actin disassembly factor cofilin but not phosphorylated cofilin-to-total cofilin ratios. We conclude that actin polymerization contributes to increased basal pulmonary arterial constriction and ET-1-induced vasoconstrictor reactivity after CH in a ROS- and ROCK-dependent manner. Our results further suggest that enhanced ET-1-mediated actin polymerization after CH is dependent on mDia but independent of changes in the phosphorylated cofilin-to-total cofilin ratio.

NEW & NOTEWORTHY This research is the first to demonstrate a role for actin polymerization in chronic hypoxia-induced basal pulmonary arterial constriction and enhanced agonist-induced vasoconstrictor activity. These results suggest that a reactive oxygen species-Rho kinase-actin polymerization signaling pathway mediates this response and may provide a mechanistic basis for the vasoconstrictor component of pulmonary hypertension.
Transcriptional profiling reveals gland-specific differential expression in the three major salivary glands of the adult mouse
Authors: Gao Xin , Oei Maria S. , Ovitt Catherine E. , Sincan Murat , Melvin James E.
Published: January 2018

RNA-Seq was used to better understand the molecular nature of the biological differences among the three major exocrine salivary glands in mammals. Transcriptional profiling found that the adult murine parotid, submandibular, and sublingual salivary glands express greater than 14,300 protein-coding genes, and nearly 2,000 of these genes were differentially expressed. Principle component analysis of the differentially expressed genes revealed three distinct clusters according to gland type. The three salivary gland transcriptomes were dominated by a relatively few number of highly expressed genes (6.3%) that accounted for more than 90% of transcriptional output. Of the 912 transcription factors expressed in the major salivary glands, greater than 90% of them were detected in all three glands, while expression for ~2% of them was enriched in an individual gland. Expression of these unique transcription factors correlated with sublingual and parotid specific subsets of both highly expressed and differentially expressed genes. Gene ontology analyses revealed that the highly expressed genes common to all glands were associated with global functions, while many of the genes expressed in a single gland play a major role in the function of that gland. In summary, transcriptional profiling of the three murine major salivary glands identified a limited number of highly expressed genes, differentially expressed genes, and unique transcription factors that represent the transcriptional signatures underlying gland-specific biological properties.
miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer
Authors: Yan Ting-Ting , Ren Lin-Lin , Shen Chao-Qin , Wang Zhen-Hua , Yu Ya-Nan , Liang Qian , Tang Jia-Yin , Chen Ying-Xuan , Sun Dan-Feng , Zgodzinski Witold , Majewski Marek , Radwan Piotr , Kryczek Ilona , Zhong Ming , Chen Jinxian , Liu Qiang , Zou Weiping , Chen Hao-Yan , Hong Jie , Fang Jing-Yuan
Published: January 2018

Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.

Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.
Forkhead Box F2 Suppresses Gastric Cancer through a Novel FOXF2–IRF2BPL–β-Catenin Signaling Axis
Authors: Higashimori Akira , Dong Yujuan , Zhang Yanquan , Kang Wei , Nakatsu Geicho , Ng Simon S.M. , Arakawa Tetsuo , Sung Joseph J.Y. , Chan Francis K.L. , Yu Jun
Published: January 2018

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1–S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients.

Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res; 78(7); 1643–56. ©2018 AACR.
Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer
Authors: Li Lifeng , Wang Liping , Li Jieyao , Fan Zhirui , Yang Li , Zhang Zhen , Zhang Chaoqi , Yue Dongli , Qin Guohui , Zhang Tengfei , Li Feng , Chen Xinfeng , Ping Yu , Wang Dan , Gao Qun , He Qianyi , Huang Lan , Li Hong , Huang Jianmin , Zhao Xuan , Xue Wenhua , Sun Zhi , Lu Jingli , Yu Jane J. , Zhao Jie , Zhang Bin , Zhang Yi
Published: January 2018

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α and subsequently suppressed hypoxia-inducible factor α, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients.

Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779–91. ©2018 AACR.
The Strategy of PIKing a Target: What Is AKTually Most Effective?
Authors: Costa Carlotta , Bosch Ana
Published: January 2018

Breast and gynecologic cancers harboring PIK3CA mutations showed no significant responses to AZD5363, a pan-AKT catalytic inhibitor, in contrast with previous in vitro data showing activity of the drug in this subset of cancers. These results raise the question of how to select the most accurate predictive biomarkers of response. Clin Cancer Res; 24(9); 2029–31. ©2018 AACR.

See related article by Banerji et al., p. 2050
The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer
Authors: Miyamoto Sho , Kochin Vitaly , Kanaseki Takayuki , Hongo Ayumi , Tokita Serina , Kikuchi Yasuhiro , Takaya Akari , Hirohashi Yoshihiko , Tsukahara Tomohide , Terui Takeshi , Ishitani Kunihiko , Hata Fumitake , Takemasa Ichiro , Miyazaki Akihiro , Hiratsuka Hiroyoshi , Sato Noriyuki , Torigoe Toshihiko
Published: January 2018

Colorectal cancer consists of a small number of cancer stem cells (CSC) and many non-CSCs. Although rare in number, CSCs are a target for cancer therapy, because they survive conventional chemo- and radiotherapies and perpetuate tumor formation in vivo. In this study, we conducted an HLA ligandome analysis to survey HLA-A24 peptides displayed by CSCs and non-CSCs of colorectal cancer. The analysis identified an antigen, ASB4, which was processed and presented by a CSC subset but not by non-CSCs. The ASB4 gene was expressed in CSCs of colorectal cancer, but not in cells that had differentiated into non-CSCs. Because ASB4 was not expressed by normal tissues, its peptide epitope elicited CD8+ cytotoxic T-cell (CTL) responses, which lysed CSCs of colorectal cancer and left non-CSCs intact. Therefore, ASB4 is a tumor-associated antigen that can elicit CTL responses specific to CSCs and can discriminate between two cellular subsets of colorectal cancer. Adoptively transferred CTLs specific for the CSC antigen ASB4 could infiltrate implanted colorectal cancer cell tumors and effectively prevented tumor growth in a mouse model. As the cancer cells implanted in these mice contained very few CSCs, the elimination of a CSC subset could be the condition necessary and sufficient to control tumor formation in vivo. These results suggest that CTL-based immunotherapies against colorectal CSCs might be useful for preventing relapses. Cancer Immunol Res; 6(3); 358–69. ©2018 AACR.
Importance of Proactive Treatment of Depression in Lewy Body Dementias: The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study
Authors: Gatt Ariana , Ekonomou Antigoni , Somani Alyma , Thuret Sandrine , Howlett David , Corbett Anne , Johnson Mary , Perry Elaine , Attems Johannes , Francis Paul , Aarsland Dag , Ballard Clive
Published: January 2018

Objective: To examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). Methods: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). Results: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin-positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. Conclusion: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients.
Osteocardiology: Defining the Go/No-Go Time Point for Therapy
Authors: Rajamannan Nalini M.
Published: January 2018

Recent epidemiological studies have revealed that the risk factors associated with coronary artery calcification (CAC), including male gender, smoking, hypertension, and elevated serum cholesterol, are similar to the risk factors associated with the development of calcific aortic valve disease (CAVD). The results of the experimental and clinical studies demonstrate that traditional risk factors initiate early atherosclerosis which over time differentiates to form bone in the heart causing clinical CAC and CAVD. Understanding the cellular mechanisms of cardiovascular calcification, the end-stage process of the atherosclerosis will help define the specific time point to modify this cellular process of bone formation in the heart termed osteocardiology. This time point between subclinical atherosclerosis and clinical calcification is the go/no-go time point, or the point of no return with severe clinical calcification in the heart. This review will summarize the development of bone formation in the heart termed osteocardiology, to define the go/no-go time point for therapy initiation to slow the progression of cardiovascular calcification.
Saccular Impairment in Alzheimer’s Disease Is Associated with Driving Difficulty
Authors: Wei Eric X. , Oh Esther S. , Harun Aisha , Ehrenburg Matthew , Agrawal Yuri
Published: January 2018

Background/Aims: Patients with Alzheimer’s disease (AD) experience increased rates of vestibular loss. Recent studies suggest that saccular impairment in mild cognitive impairment (MCI) and AD patients is associated with impaired spatial cognitive function. However, the impact of saccular impairment on everyday behaviors that rely on spatial cognitive function is unknown. Methods: We recruited 60 patients (21 MCI and 39 AD) from an interdisciplinary Memory Clinic. Saccular function was measured, and a visuospatial questionnaire was administered to assess whether participants experienced impairments in terms of driving difficulty, losing objects, falls, and fear of falling. Results: In multiple logistic regression analyses, MCI and AD patients with bilateral saccular impairment had a significant, greater than 12-fold odds of driving difficulty (OR 12.1, 95% CI 1.2, 117.7) compared to MCI and AD patients with normal saccular function, and the association appears to be mediated by spatial cognition as measured by the Money Road Map Test. Conclusion: This study suggests a novel link between saccular impairment and driving difficulty in MCI and AD patients and demonstrates that driving difficulty may be a real-world manifestation of impaired spatial cognition associated with saccular impairment.
Arterial Stiffness in Chronic Kidney Disease and End-Stage Renal Disease
Authors: London Gerard M.
Published: January 2018

Accelerated ageing is observed in patients with chronic kidney disease (CKD)/end-stage renal disease. Premature vascular aging and arterial stiffening are the most characteristic features of this “progeria” that is already observed in those with the early stages of CKD. Aortic stiffening is associated with high characteristic impedance, left ventricular hypertrophy, decreased coronary perfusion, and is a strong prognostic marker of mortality and cardiovascular morbidity. With aging, the arterial stiffening is more pronounced in the aorta and central arteries than in peripheral conduit arteries. This leads to progressive decrease and inversion of the arterial stiffness gradient and systemic reflection coefficient, leading to less protection of the microcirculation in the event of high-pressure transmission towards it Arterial stiffening is multifactorial with systemic microinflammation being one of the most important associated factors primarily associated with vascular calcifications.
Magnesium in Chronic Kidney Disease: Should We Care?
Authors: van de Wal-Visscher Esther R. , Kooman Jeroen P. , van der Sande Frank M.
Published: January 2018

Background: Magnesium (Mg) is an essential cation for multiple processes in the body. The kidney plays a major role in regulating the Mg balance. In a healthy individual, total-body Mg content is kept constant by interactions among intestine, bones and the kidneys. Summary: In case of chronic kidney disease (CKD), renal regulatory mechanisms may be insufficient to balance intestinal Mg absorption. Usually Mg remains normal; however, when glomerular filtration rate declines, changes in serum Mg are observed. Patients with end-stage renal disease on dialysis are largely dependent on the dialysate Mg concentration for maintaining serum Mg and Mg homeostasis. A low Mg is associated with several complications such as hypertension, and vascular calcification, and also associated with an increased risk for both cardiovascular disease (CVD) and non-CVD mortality. Severe hypermagnesaemia is known to cause cardiac conduction defects, neuromuscular effects and muscle weakness; a slightly elevated Mg has been suggested to be beneficial in patients with end-stage renal disease. Key Messages: The role of both low and high Mg, in general, but especially in relation to CKD and dialysis patients is discussed.
Higher Serum Endocan Level Is Associated with Alzheimer Disease
Authors: Varan Hacer Dogan , Guner Gurkan , Kizilarslanoglu Muhammet Cemal , Sumer Fatih , Dogrul Rana Tuna , Sagir Aykut , Ozsurekci Cemile , Caliskan Hatice , Balci Cafer , Aycicek Gozde Sengul , Akbiyik Filiz , Halil Meltem , Cankurtaran Mustafa , Yavuz Burcu Balam
Published: January 2018

Background: The novel molecule endocan, which is released by endothelium and is regulated by proangiogenic and proinflammatory cytokines, may have a role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to evaluate the relationship between serum endocan levels and AD. Methods: A total of 134 patients (47 AD, 42 amnestic mild cognitive impairment [aMCI], and 45 control patients) 65 years of age and older were recruited in this study. Cognitive status of the patients was evaluated by performing the Montreal Cognitive Assessment (MOCA) and the Mini-Mental State Examination (MMSE). Serum endocan levels were measured with an enzyme-linked immunosorbent assay kit. Results: Median serum endocan level was significantly higher in AD patients (380.1 ng/mL) than in both aMCI patients (247.7 ng/mL) and controls (277.6 ng/mL; p < 0.01). Serum endocan level had a weak but significant correlation with MMSE and MOCA scores (r = –0.219 and r = –0.232; p = 0.012 and p = 0.01, respectively). Serum endocan level was detected as a factor independently associated with AD. The cutoff serum level of endocan predicting AD was >288.94 ng/mL in receiver operating characteristic curve analysis (area under the curve 0.71, 95% CI 66.7–90.9, sensitivity 80.9%, specificity 59.8%; p < 0.01). Conclusion: Higher serum endocan levels may be associated with the pathogenesis of AD.
Acute Menopausal Symptoms in Young Cancer Survivors Immediately following Chemotherapy
Authors: Cameron Katherine E. , Kole Martha B. , Sammel Mary D. , Ginsberg Jill P. , Gosiengfiao Yasmin , Mersereau Jennifer E. , Su H. Irene , Gracia Clarisa R.
Published: January 2018

Purpose: The aim of this study was to evaluate the prevalence of menopausal symptoms in young cancer survivors immediately following the completion of chemotherapy. Methods: This prospective cohort study followed 124 young females with a new diagnosis of cancer requiring chemotherapy to assess symptoms of menopause before treatment and immediately following chemotherapy. Symptoms were compared before and after treatment using the McNemar test and between cancer patients and 133 similar-aged healthy controls using Pearson χ2 and Fisher’s exact tests. Results: Participants undergoing cancer therapy reported more menopausal symptoms compared to controls prior to the initiation of any treatment (hot flashes or night sweats 33 vs. 7%, p < 0.01, trouble sleeping 57 vs. 31%, p < 0.01, headaches 50 vs. 35%, p = 0.02, and decreased libido 36 vs. 16%, p < 0.01) and also reported a greater prevalence of symptoms immediately after cancer therapy compared to pretreatment prevalence (vasomotor symptoms, p < 0.01, vaginal dryness, p < 0.01, decreased concentration, p < 0.01, and body aches, p = 0.01). Cancer patients with lower anti-Müllerian hormone (AMH) levels after treatment (<0.10 ng/mL) had an increased risk of vasomotor symptoms (OR 2.2, p = 0.04), mood swings (OR 2.4, p = 0.03), feeling sad (OR 2.2, p = 0.04), trouble sleeping (OR 2.7, p = 0.02), and decreased libido (OR 3.0, p = 0.03) when controlled for age and cancer type, and the incidence of these symptoms was not affected by the use of systemic hormones or psychiatric medications. Treatment length, use of alkylating agents, pelvic radiation, and marital status were also not associated with the prevalence of menopausal symptoms. Conclusions: Premenopausal women with a new cancer diagnosis have more menopausal symptoms than females of similar age before and after cancer treatment, the effects of which are not mitigated by systemic hormone use. Decreased AMH levels were associated with an increased likelihood of reporting physiologic symptoms after therapy. Implications for Cancer Survivors: This information is imperative for counseling; ultimately, improved symptom management during and after cancer therapies will improve quality of life in young cancer survivors.
Association of Optic Nerve Head Drusen with Best Vitelliform Macular Dystrophy: A Case Series
Authors: White Robert J. , Watson Daniel J. , Koozekanani Dara D. , Montezuma Sandra R.
Published: January 2018

Purpose: To report the association of optic nerve head (ONH) drusen with Best vitelliform macular dystrophy (BVMD). Methods: Chart review. Patients: Five patients from 3 families. Results: Multimodal imaging and ophthalmic examination demonstrated findings consistent with ONH drusen, in association with BVMD, in 5 patients. Conclusion: We report the association of BVMD with ONH drusen in 5 patients. This combination has previously been reported only once. We recommend that patients with a diagnosis of BVMD undergo autofluorescence and ultrasound imaging of the optic nerve to help facilitate this diagnosis, as some ONH drusen can be buried.