bluuebunny/crossref_metadata_2025 huggingface dataset:
Silver Nanoparticles Complexed with Bovine Submaxillary Mucin Possess Strong Antibacterial Activity and Protect against Seedling Infection
Authors: Makarovsky Daria , Fadeev Ludmila , Salam Bolaji Babajide , Zelinger Einat , Matan Ofra , Inbar Jacob , Jurkevitch Edouard , Gozin Michael , Burdman Saul
Published: November 2017

A simple method for the synthesis of nanoparticles (NPs) of silver (Ag) in a matrix of bovine submaxillary mucin (BSM) was reported previously by some of the authors of this study. Based on mucin characteristics such as long-lasting stability, water solubility, and surfactant and adhesive characteristics, we hypothesized that these compounds, named BSM-Ag NPs, may possess favorable properties as potent antimicrobial agents. The goal of this study was to assess whether BSM-Ag NPs possess antibacterial activity, focusing on important plant-pathogenic bacterial strains representing both Gram-negative (
Acidovorax
and
Xanthomonas
) and Gram-positive (
Clavibacter
) genera. Growth inhibition and bactericidal assays, as well as electron microscopic observations, demonstrate that BSM-Ag NPs, at relatively low concentrations of silver, exert strong antimicrobial effects. Moreover, we show that treatment of melon seeds with BSM-Ag NPs effectively prevents seed-to-seedling transmission of
Acidovorax citrulli
, one of the most threatening pathogens of cucurbit production worldwide. Overall, our findings demonstrate strong antimicrobial activity of BSM-Ag NPs and their potential application for reducing the spread and establishment of devastating bacterial plant diseases in agriculture.

IMPORTANCE
Bacterial plant diseases challenge agricultural production, and the means available to manage them are limited. Importantly, many plant-pathogenic bacteria have the ability to colonize seeds, and seed-to-seedling transmission is a critical route by which bacterial plant diseases spread to new regions and countries. The significance of our study resides in the following aspects: (i) the simplicity of the method of BSM-Ag NP synthesis, (ii) the advantageous chemical properties of BSM-Ag NPs, (iii) the strong antibacterial activity of BSM-Ag NPs at relatively low concentrations of silver, and (iv) the fact that, in contrast to most studies on the effects of metal NPs on plant pathogens, the proof of concept for the novel compound is supported by
in planta
assays. Application of this technology is not limited to agriculture; BSM-Ag NPs potentially could be exploited as a potent antimicrobial agent in a wide range of industrial areas, including medicine, veterinary medicine, cosmetics, textiles, and household products.
Pseudouridine-Free Escherichia coli Ribosomes
Authors: O'Connor Michael , Leppik Margus , Remme Jaanus
Published: November 2017

Pseudouridine (Ψ) is present at conserved, functionally important regions in the ribosomal RNAs (rRNAs) from all three domains of life. Little, however, is known about the functions of Ψ modifications in bacterial ribosomes. An
Escherichia coli
strain has been constructed in which all seven rRNA Ψ synthases have been inactivated and whose ribosomes are devoid of all Ψs. Surprisingly, this strain displays only minor defects in ribosome biogenesis and function, and cell growth is only modestly affected. This is in contrast to a strong requirement for Ψ in eukaryotic ribosomes and suggests divergent roles for rRNA Ψ modifications in these two domains.

IMPORTANCE
Pseudouridine (Ψ) is the most abundant posttranscriptional modification in RNAs. In the ribosome, Ψ modifications are typically located at conserved, critical regions, suggesting they play an important functional role. In eukarya and archaea, rRNAs are modified by a single pseudouridine synthase (PUS) enzyme, targeted to rRNA via a snoRNA-dependent mechanism, while bacteria use multiple stand-alone PUS enzymes. Disruption of Ψ modification of rRNA in eukarya seriously impairs ribosome function and cell growth. We have constructed an
E. coli
multiple deletion strain lacking all Ψ modifications in rRNA. In contrast to the equivalent eukaryotic mutants, the
E. coli
strain is only modestly affected in growth, decoding, and ribosome biogenesis, indicating a differential requirement for Ψ modifications in these two domains.
Accelerated in vitro model for occlusion of biliary stents: investigating the role played by dietary fibre
Authors: Surwase Sachin , Balakrishnan Harishankar , Acharya Subrat K , Makharia Govind K , Kumaraswamy Guruswamy , Prasad Bhagavatula L V
Published: November 2017

Background

To develop a new accelerated in vitro model that has implications for investigating the mechanism of biliary stent occlusion and help in the development of new materials that can alleviate this problem.

Methods

We employ a combination of reconstituted animal bile, bacteria and cellulose fibres optimised to reproducibly generate accelerated occlusion of stents, and produce occlusions that closely mimic those found in clinical studies.

Results

Our model affords repeatable, highly accelerated occlusion (within 2–3 days, compared with between about a week to 2 months in previous models). Our results highlight the role of dietary fibre in blockage of stents and demonstrate their importance in the onset of occlusion.

Conclusions

This accelerated model may have implications for developing biliary stents with enhanced patency.
Cost-effectiveness of a preferred intensity exercise programme for young people with depression compared with treatment as usual: an economic evaluation alongside a clinical trial in the UK
Authors: Turner David , Carter Tim , Sach Tracey , Guo Boliang , Callaghan Patrick
Published: November 2017

Objectives

To assess the cost-effectiveness of preferred intensity exercise programme for young people with depression compared with a treatment as usual control group.

Design

A ‘within trial’ cost-effectiveness and cost-utility analysis conducted alongside a randomised controlled trial. The perspective of the analysis was the UK National Health Service and social services.

Setting

The intervention was provided in a community leisure centre setting.

Participants

86 young people aged 14–17 years attending Tier 2 and Tier 3 CAMHS (Child and Adolescent Mental Health Services) outpatient services presenting with depression.

Interventions

The intervention comprised 12 separate sessions of circuit training over a 6-week period. Sessions were supervised by a qualified exercise therapist. Participants also received treatment as usual. The comparator group received treatment as usual.

Results

We found improvements in the Children’s Depression Inventory-2 (CDI-2) and estimated cost-effectiveness at £61 per point improvement in CDI-2 for the exercise group compared with control. We found no evidence that the exercise intervention led to differences in quality-adjusted life years (QALY). QALYs were estimated using the EQ-5D-5L (5-level version of EuroQol-5 dimension).

Conclusions

There is evidence that exercise can be an effective intervention for adolescents with depression and the current study shows that preferred intensity exercise could also represent a cost-effective intervention in terms of the CDI-2.

Trial registration number

NCT01474837.
Constrictive pericarditis: diagnosis, management and clinical outcomes
Authors: Welch Terrence D
Published: November 2017

Constrictive pericarditis (CP) is a form of diastolic heart failure that arises because an inelastic pericardium inhibits cardiac filling. This disorder must be considered in the differential diagnosis for unexplained heart failure, particularly when the left ventricular ejection fraction is preserved. Risk factors for the development of CP include prior cardiac surgery and radiation therapy, but most cases are still deemed to be idiopathic. Making the diagnosis may be challenging and requires meticulous echocardiographic assessment, often supplemented by cross-sectional cardiac imaging and haemodynamic catheterisation. The key pathophysiological concepts, which serve as the basis for many of the diagnostic criteria, remain: (1) dissociation of intrathoracic and intracardiac pressures and (2) enhanced ventricular interaction. Complete surgical pericardiectomy is the only effective treatment for chronic CP. A subset of patients with subacute inflammatory CP, often identified by cardiac MRI, may respond to anti-inflammatory treatments.
To sell or not to sell: cigarette sales in alcohol-licenced premises
Authors: Burton Suzan , Ludbrooke Mark , Williams Kelly , Walsberger Scott C , Egger Sam
Published: November 2017

Objective

To obtain insight into tobacco retailing by alcohol-licenced premises, in order to understand the financial importance of tobacco sales for such retailers.

Method

Data were collected by a telephone survey of 1042 clubs, hotels and packaged liquor outlets in New South Wales, Australia. The response rate was 86.1%. Qualitative and quantitative data were obtained. Logistic and linear regression were used to determine factors associated with the probability of selling and stopping selling and the importance of cigarette sales.

Results

More than a third (36.4%) of premises contacted did not sell cigarettes. 147 (an estimated 18.1% of those who had ever sold) had stopped selling. There were significant differences in the probability of selling, in the reported importance of cigarette sales and in the probability of stopping selling, between different outlet types and other outlet characteristics (number of gaming machines, proximity of nearest alternative tobacco retailer and remoteness). Outlets where alcohol can be consumed were more likely to rate cigarette sales as ‘not important’ than ‘important’.

Conclusions

Despite claims by tobacco companies that tobacco sales are important for many Australian retailers, tobacco sales appear to be of limited importance for alcohol-licenced premises. This means that opposition to stopping tobacco sales where alcohol is consumed and/or sold may be less than expected.
Prediction of resilient modulus of frozen unbound road materials using soil-freezing characteristic curve
Authors: Ren Junping , Vanapalli Sai K.
Published: November 2017

The resilient modulus is a key parameter required in the mechanistic design of pavements. Experimental determination of the resilient modulus requires elaborate equipment for testing and requires trained personnel; for this reason, it is expensive. There are several models for predicting the resilient modulus for unbound road materials that take into account the influence of wetting and drying conditions. However, well-established models are not available for the prediction of the resilient modulus of these materials in a frozen state. In this paper, a semi-empirical model, which uses a soil-freezing characteristic curve as a tool, is proposed for predicting the variation of the resilient modulus with subzero temperature and the associated cryogenic suction for frozen soils. Experimental data on seven different pavement unbound materials were used to validate the proposed model. It is shown that the model can reasonably predict the resilient modulus of the investigated soils that are in a frozen state. More investigations on different types of soils would be useful to better understand the strengths and limitations of the proposed model.
Diversity of parasitoid and parasitic wasps across a latitudinal gradient: Using public DNA records to work within a taxonomic impediment
Authors: Eagalle Thanushi , Smith M. Alex
Published: November 2017

The diversity of insect parasitoids (Hymenoptera) has long been thought to be anomalous because it doesn’t appear to increase rapidly with decreasing latitude. However, due to the presence of undiscovered cryptic species and the under-sampling of hyper-diverse tropical areas, such apparently anomalous gradients may, in fact, be artifacts of limited geographic and taxonomic sampling. We attempted to circumvent such taxonomic impediments by elucidating a diversity/latitude relationship for parasitoid wasps, using publicly available DNA sequences to quantify diversity (via a species proxy molecular operational taxonomic unit (the DNA Barcode Index Number) and phylogenetic diversity) across a latitudinal gradient of ∼5000 km. We compared these diversity values to the abiotic factors (temperature and precipitation) that may drive the diversity/latitude relationship. We found no significant relationship between either diversity measure with latitude or with the environmental variables. Although ours is the first work to enumerate different DNA-based measures of parasitoid diversity across this geographic scale in a standardized fashion using publicly available sequences, further standardized collections over long time periods and a rapid movement of sequences into the public arena are needed to facilitate the further testing of macroecological trends elucidated with public DNA sequence libraries.
FACTORS RELATED TO THE RISK OF A SUBSTANTIAL INCOME DECREASE BETWEEN 2006 AND 2008 IN SOUTH KOREA
Authors: HONG EUNICE JIHYUN , HANNA SHERMAN D.
Published: November 2017

Between 2006 and 2008, 9% of Korean households had an income decrease of 50% or more, a rate almost identical to the U.S. despite the much lower impact of the global financial crisis on Korea. We ran a logistic regression to determine factors related to the likelihood of a substantial income decrease between 2006 and 2008 for Korean households. The likelihood of a substantial decrease was low for households below the 75th percentile of 2006 income, probably due to differences in composition of income. Households with college education were less likely than those without college to have a substantial decrease.
Quasi-stationary states and fermion pair creation from a vacuum in supercritical Coulomb field
Authors: Khalilov V. R.
Published: November 2017

Creation of charged fermion pair from a vacuum in so-called supercritical Coulomb potential is examined for the case when fermions can move only in the same (one) plane. In which case, quantum dynamics of charged massive or massless fermions can be described by the two-dimensional Dirac Hamiltonians with an usual [Formula: see text] Coulomb potential. These Hamiltonians are singular and require the additional definition in order for them to be treated as self-adjoint quantum-mechanical operators. We construct the self-adjoint two-dimensional Dirac Hamiltonians with a Coulomb potential and determine the quantum-mechanical states for such Hamiltonians in the corresponding Hilbert spaces of square-integrable functions. We determine the scattering amplitude in which the self-adjoint extension parameter is incorporated and then obtain equations implicitly defining possible discrete energy spectra of the self-adjoint Dirac Hamiltonians with a Coulomb potential. It is shown that this quantum system becomes unstable in the presence of a supercritical Coulomb potential which manifests in the appearance of quasi-stationary states in the lower (negative) energy continuum. The energy spectrum of those states is quasi-discrete, consists of broadened levels with widths related to the inverse lifetimes of the quasi-stationary states as well as the probability of creation of charged fermion pair by a supercritical Coulomb field. Explicit analytical expressions for the creation probabilities of charged (massive or massless) fermion pair are obtained in a supercritical Coulomb field.
Modified Bridgeless SEPIC Rectifier for Power Factor Correction with Reduced Switch Stress Operating in Continuous Conduction Mode
Authors: Kommukuri Vinaya Sagar , Mohanty Kanungo Barada , Chatterjee Aditi , Thakre Kishor
Published: November 2017

In this paper, a high performance single-phase modified bridgeless AC–DC converter with reduced switch voltage stress for power factor correction (PFC) is introduced. The proposed converter is based on a single-ended primary-inductance converter (SEPIC) to meet the demands of PFC to unity and output voltage regulation. To reduce the number of components, the input bridge is combined with the SEPIC converter since the conventional SEPIC PFC is suffering with high conduction losses. It offers many advantages, such as fewer semiconductor devices in current flowing path which lead to improve the thermal management, low stress on each component, improved efficiency, high power factor compared to classical converter. Detailed analysis and design equations of the converter are presented. Simulation and experimental results are discussed for a 300[Formula: see text]W prototypeunder the universal input voltage (85–235[Formula: see text]V) to validate the performance of the converter.
Numerical Solution of Diffusion and Reaction–Diffusion Partial Integro-Differential Equations
Authors: Aziz Imran , Khan Imran
Published: November 2017

In this paper, a collocation method based on Haar wavelet is developed for numerical solution of diffusion and reaction–diffusion partial integro-differential equations. The equations are parabolic partial integro-differential equations and we consider both one-dimensional and two-dimensional cases. Such equations have applications in several practical problems including population dynamics. An important advantage of the proposed method is that it can be applied to both linear as well as nonlinear problems with slide modification. The proposed numerical method is validated by applying it to various benchmark problems from the existing literature. The numerical results confirm the accuracy, efficiency and robustness of the proposed method.
Photoconductive behavior of binary porphyrin crystalline assemblies
Authors: Borders Bryan , Adinehnia Morteza , Rosenkrantz Naomi , van Zijll Marshall , Hipps K. W. , Mazur Ursula
Published: November 2017

The mechanism of photoconductivity in a crystalline photoconductor synthesized from 1:1 ratio of meso-tetra(4-pyridyl)porphyrin (TPyP) and meso-tetra(4-sulfonatophenyl)porphyrin (TSPP) ionic tectons was examined. The rod-like crystals of TPyP:TSPP insulate in the dark but become photoconducting on illumination and a portion of the photoinduced current persists after the laser light is turned off. This persistent photoconductivity (PPC) is investigated as a function of laser illumination wavelength, laser power, and sample temperature. The primary charge carriers in the TPyP:TSPP upon photoexcitation are electrons and the charge recombination mechanism follows monomolecular kinetics. The number of electrons contributing to the photocurrent is directly proportional to the number of photons absorbed thus, the mechanisms of the photoconductivity resulting from excitations within the Soret band and the Q-band are the same. The PPC is interpreted to be the result of the formation of photoinduced metastable defects that allow for Miller–Abrahams-like hopping conductivity. The TPyP:TSPP has an incommensurately modulated crystal lattice and its proposed model structure is based on both ionic and neutral porphyrin tectons. The thermogravimetric analysis shows that the porphyrin crystals undergo dehydration on heating (˜50 ∘C) by losing water molecules located in the crystalline channels. Temperature dependent XRD indicates that dehydration causes irreversible changes to the crystal structure. The loss of crystallinity observed with heating the TPyP:TSPP crystals above 90 ∘C causes approximately 25% loss in photoconductivity but has little effect on the lifetime associated with the persistent photoconductivity.
Structural, spectroscopic and electrochemical investigations on fluorinated meso-tetraaryl porphyrins
Authors: Arunkumar Chellaiah , Kooriyaden Fasalu Rahman , Sujatha Subramaniam
Published: November 2017

Two series of meso-phenyl fluorinated porphyrins and their metal complexes, 5,10,15,20-tetrakis(2[Formula: see text],4[Formula: see text],6[Formula: see text]-trifluorophenyl)porphyrin, MT(2[Formula: see text],4[Formula: see text],6[Formula: see text]-TFP)Ps (2a–2d) and 5,10,15,20-tetrakis[3[Formula: see text],5[Formula: see text]-bis(trifluoromethylphenyl)]porphyrin, MT(3[Formula: see text],5[Formula: see text]-BTFMP)Ps (3a–3d); where M [Formula: see text] 2H; Ni(II); Cu(II) and Zn(II) have been synthesized and characterized using various spectroscopic techniques including UV-visible, fluorescence and [Formula: see text]H NMR and mass spectrometry. Electronic absorption spectra of porphyrins show the typical Soret (B) and visible (Q) bands. Free ligands and zinc(II) derivatives display two well-defined emission bands around 600–660 nm and 650–720 nm upon exciting the Soret band. Porphyrins, 1d, 2a, 2b, 2c, 3a and 3d were structurally characterized by single crystal XRD analysis, and various intermolecular interactions present in them were quantified on the basis of Hirshfeld surfaces and 2D fingerprint plots. Electrochemical studies were performed and the HOMO–LUMO energy gap is high for all the porphyrins compared to MTPPs.
SMT-based schedulability analysis using RMTL-∫
Authors: de Matos Pedro André , Pereira David , Pinho Luís Miguel , Pinto Jorge Sousa
Published: November 2017

Several methods have been proposed for performing schedulability analysis for both uni-processor and multi-processor real-time systems. Very few of these works use the power of formal logic to write unambiguous specifications and to allow the usage of theorem provers for building the proofs of interest with greater correctness guarantees. In this paper we address this challenge by: 1) defining a formal language that allows to specify periodic resource models; 2) describe a transformational approach to reasoning about timing properties of resource models by transforming the latter specifications into a
satisfiability modulo theories
problem.
Fraxinus: A Plant with Versatile Pharmacological and Biological Activities
Authors: Sarfraz Iqra , Rasul Azhar , Jabeen Farhat , Younis Tahira , Zahoor Muhammad Kashif , Arshad Muhammad , Ali Muhammad
Published: November 2017

Fraxinus, a member of the Oleaceae family, commonly known as ash tree is found in northeast Asia, north America, east and western France, China, northern areas of Pakistan, India, and Afghanistan. Chemical constituents of Fraxinus plant include various secoiridoids, phenylethanoids, flavonoids, coumarins, and lignans; therefore, it is considered as a plant with versatile biological and pharmacological activities. Its tremendous range of pharmacotherapeutic properties has been well documented including anticancer, anti‐inflammatory, antioxidant, antimicrobial, and neuroprotective. In addition, its bioactive phytochemicals and secondary metabolites can be effectively used in cosmetic industry and as a competent antiaging agent. Fraxinus presents pharmacological effectiveness by targeting the novel targets in several pathological conditions, which provide a spacious therapeutic time window. Our aim is to update the scientific research community with recent endeavors with specifically highlighting the mechanism of action in different diseases. This potentially efficacious pharmacological drug candidate should be used for new drug discovery in future. This review suggests that this plant has extremely important medicinal utilization but further supporting studies and scientific experimentations are mandatory to determine its specific intracellular targets and site of action to completely figure out its pharmacological applications.
Thyroid Carcinoma on the Side of the Absent Lobe in a Patient with Thyroid Hemiagenesis
Authors: Sato Hiroki , Tsukahara Kiyoaki , Motohashi Ray , Wakiya Midori , Serizawa Hiromi , Kurata Atsushi
Published: November 2017

Background. Thyroid carcinoma complicated by hemiagenesis is very rare, and previous reports have not described this cancer on the side of the absent lobe. Methods and Results. We report the case of a 64-year-old woman in whom left thyroid hemiagenesis was discovered incidentally during investigations of abnormal sensation during swallowing. A tumorous 1.4 cm lesion was also found on the side of the absent lobe, left of the isthmus. Fine-needle aspiration biopsy revealed class V papillary carcinoma, but no lymph node metastases. Total thyroidectomy was performed for stage cT1bN0M0 carcinoma. Histopathology revealed normal thyroid tissues in the right lobe and isthmus, while the left lobe was absent. The mostly papillary carcinoma was adjacent to the truncated thyroid tissue, with a portion histologically consistent with poorly differentiated carcinoma. Conclusions. All previously reported cases of thyroid cancer complicated by hemiagenesis have represented carcinoma occurring within the present lobe. This case is extremely rare.
A Comparison of Er:YAG Laser with Photon-Initiated Photoacoustic Streaming, Nd:YAG Laser, and Conventional Irrigation on the Eradication of Root Dentinal Tubule Infection by Enterococcus faecalis Biofilms: A Scanning Electron Microscopy Study
Authors: Ozses Ozkaya Burcu , Gulsahi Kamran , Ungor Mete , Gocmen Julide Sedef
Published: November 2017

This study evaluated the antimicrobial efficacy of Er:YAG laser activation with photon-initiated photoacoustic streaming (PIPS), Nd:YAG laser disinfection, and conventional irrigation on Enterococcus faecalis biofilms using scanning electron microscopy (SEM). Biofilms were grown on 110 root halves and divided into the following: Groups 1 and 2 (saline and 1% NaOCl with apical position of PIPS, resp.), Groups 3 and 4 (saline and 1% NaOCl with coronal position of PIPS, resp.), Groups 5 and 6 (Nd:YAG laser after saline and 1% NaOCl irrigation, resp.) and Groups 7, 8, and 9 (conventional irrigation with 1% NaOCl, 6% NaOCl, and saline, resp.). SEM images of the apical, middle, and coronal levels were examined using a scoring system. Score differences between Groups 1 and 2 were insignificant at all levels in the remaining biofilm. Group 4 had significantly greater bacterial elimination than Group 3 at all levels. Differences in Nd:YAG laser irradiation between Groups 5 and 6 were insignificant. Groups 7 and 8 were insignificantly different, except at the middle level. Saline group had a higher percentage of biofilms than the others. In this study, PIPS activation with NaOCl eliminates more E. faecalis biofilms in all root canals regardless of the position of the fiber tip.
A Variational Level Set Approach Based on Local Entropy for Image Segmentation and Bias Field Correction
Authors: Tang Jian , Jiang Xiaoliang
Published: November 2017

Image segmentation has always been a considerable challenge in image analysis and understanding due to the intensity inhomogeneity, which is also commonly known as bias field. In this paper, we present a novel region-based approach based on local entropy for segmenting images and estimating the bias field simultaneously. Firstly, a local Gaussian distribution fitting (LGDF) energy function is defined as a weighted energy integral, where the weight is local entropy derived from a grey level distribution of local image. The means of this objective function have a multiplicative factor that estimates the bias field in the transformed domain. Then, the bias field prior is fully used. Therefore, our model can estimate the bias field more accurately. Finally, minimization of this energy function with a level set regularization term, image segmentation, and bias field estimation can be achieved. Experiments on images of various modalities demonstrated the superior performance of the proposed method when compared with other state-of-the-art approaches.
Modification of the Integrated Sasang Constitutional Diagnostic Model
Authors: Nam Jiho , Jang Jun-Su , Kim Honggie , Kim Jong Yeol , Do Jun-Hyeong
Published: November 2017

In 2012, the Korea Institute of Oriental Medicine proposed an objective and comprehensive physical diagnostic model to address quantification problems in the existing Sasang constitutional diagnostic method. However, certain issues have been raised regarding a revision of the proposed diagnostic model. In this paper, we propose various methodological approaches to address the problems of the previous diagnostic model. Firstly, more useful variables are selected in each component. Secondly, the least absolute shrinkage and selection operator is used to reduce multicollinearity without the modification of explanatory variables. Thirdly, proportions of SC types and age are considered to construct individual diagnostic models and classify the training set and the test set for reflecting the characteristics of the entire dataset. Finally, an integrated model is constructed with explanatory variables of individual diagnosis models. The proposed integrated diagnostic model significantly improves the sensitivities for both the male SY type (36.4% → 62.0%) and the female SE type (43.7% → 64.5%), which were areas of limitation of the previous integrated diagnostic model. The ideas of these new algorithms are expected to contribute not only to the scientific development of Sasang constitutional medicine in Korea but also to that of other diagnostic methods for traditional medicine.
Apoptotic Protease Activating Factor‐1 Inhibitor Mitigates Myocardial Ischemia Injury via Disturbing Procaspase‐9 Recruitment by Apaf‐1
Authors: Wang Ying , Zhang Qiuyan , Zhong Liangjie , Lin Mingshen , Luo Xiaoling , Liu Siyu , Xu Peng , Liu Xinhua , Zhu Yi Zhun
Published: November 2017

(2S,3S,4S,5R,6R)‐6‐(4‐((4‐guanidinobutoxy)carbonyl)‐2,6‐dihydroxyphenoxy)‐3,4,5‐trihydroxytetrahydro‐2H‐pyran‐2‐carboxylic acid (ZYZ‐488) was discovered as a novel inhibitor of apoptotic protease activating factor‐1 (Apaf‐1). In present work, a surface plasmon resonance (SPR) assay confirms the direct binding between ZYZ‐488 and Apaf‐1 and this interaction was found to be able to block the recruitment of procaspase‐9 by Apaf‐1. This study also shows that the treatment of MI (myocardial infarction) mice with this novel Apaf‐1 inhibitor remarkably reduces the infarct size, improves cardiac functions, and attenuates the histopathology changes caused by MI. Meanwhile, here it is shown that ZYZ‐488 decreases myocardial enzyme release, inhibits cardiomyocyte apoptosis, and suppresses the activation of the downstream cascade of caspases. Moreover, in silico prediction validated the drug‐like properties of ZYZ‐488. In conclusion, our findings present the first piece of evidence indicating the interaction between Apaf‐1 and procaspase‐9 as a novel therapeutic target in myocardial infarction and suggesting ZYZ‐488 as a promising therapeutic option for myocardial infarction disease.
MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels
Authors: Lu Yunqi , Hu Zhongyi , Mangala Lingegowda S. , Stine Zachary E. , Hu Xiaowen , Jiang Dahai , Xiang Yan , Zhang Youyou , Pradeep Sunila , Rodriguez-Aguayo Cristian , Lopez-Berestein Gabriel , DeMarzo Angelo M. , Sood Anil K. , Zhang Lin , Dang Chi V.
Published: November 2017

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.

Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64–74. ©2017 AACR.
Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer
Authors: Carey Jason. P.W. , Karakas Cansu , Bui Tuyen , Chen Xian , Vijayaraghavan Smruthi , Zhao Yang , Wang Jing , Mikule Keith , Litton Jennifer K. , Hunt Kelly K. , Keyomarsi Khandan
Published: November 2017

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial–mesenchymal transition and cancer stem-like cell phenotypes. Notably, dinaciclib resensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon, and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

Significance: Dual targeting of MYC-regulated homologous recombination and PARP-mediated DNA repair yields potent synthetic lethality in triple-negative breast tumors and other aggressive tumors characterized by MYC overexpression. Cancer Res; 78(3); 742–57. ©2017 AACR.
Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes
Authors: Loree Jonathan M. , Pereira Allan A.L. , Lam Michael , Willauer Alexandra N. , Raghav Kanwal , Dasari Arvind , Morris Van. K , Advani Shailesh , Menter David G. , Eng Cathy , Shaw Kenna , Broaddus Russell , Routbort Mark J. , Liu Yusha , Morris Jeffrey S. , Luthra Rajyalakshmi , Meric-Bernstam Funda , Overman Michael J. , Maru Dipen , Kopetz Scott
Published: November 2017

Purpose: Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is unclear if this division is optimal and whether precise tumor location provides further information.

Experimental Design: In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients.

Results: Mutation prevalence differed by side and location for TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN. Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, RAS mutations decreased from 70% for cecal, to 43% for hepatic flexure location (P = 0.0001), while BRAFV600 mutations increased from 10% to 22% between the same locations (P < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more TP53 mutations (P = 0.027), less PIK3CA (P = 0.0009), BRAF (P = 0.0033), or CTNNB1 mutations (P < 0.0001), and less MSI (P < 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally.

Conclusions: Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations. Clin Cancer Res; 24(5); 1062–72. ©2017 AACR.

See related commentary by Dienstmann, p. 989
A Case of Crescentic Glomerulonephritis Complicated with Hypocomplementemic Urticarial Vasculitis Syndrome and ANCA-Associated Vasculitis
Authors: Tanaka Marenao , Moniwa Norihito , Mita Tomohiro , Tobisawa Toshiyuki , Matsumoto Tamaki , Mochizuki Atsushi , Yamashita Tomohisa , Yano Toshiyuki , Furuhashi Masato , Miura Tetsuji
Published: November 2017

Systemic urticaria in a 64-year-old woman was diagnosed as leukocytoclastic vasculitis by a punch biopsy of the skin. Her physical findings improved after prescription of prednisolone at a dose of 20 mg/day, but the skin rash relapsed with renal dysfunction, proteinuria, and hematuria when the dose of prednisolone was reduced over a period of 9 months to 1 mg/day. She was admitted to our institute for further examination, when urinary protein and plasma creatinine levels were 0.8 g/day and 1.7 mg/dL, respectively. Complement analysis showed that levels of total hemolytic component, component C3 fraction, and component C4 fraction were 30∼60% of normal values and the titer of anti-neutrophil cytoplasmic antibody for myeloperoxidase (MPO-ANCA) was 89 EU (normal range, <10 EU), though there were no immunologic disorders such as systemic lupus erythematosus. Cellular crescentic glomerulonephritis was observed by light microscopy, and immunofluorescent studies showed positive staining for IgG, IgM, C3, C4, and C1q. Electron microscopy showed mesangial and subendothelial deposits with circumferential mesangial interposition. She fulfilled the diagnostic criteria for hypocomplementemic urticarial vasculitis syndrome (HUV), and ANCA-associated vasculitis (AAV) was also indicated by small vessel vasculitis and positive MPO-ANCA. Steroid pulse therapy with methylprednisolone followed by oral prednisolone improved her general condition and hypocomplementemia, and MPO-ANCA became negative. HUV and AAV are distinct clinical disorders, though both affect small blood vessels. Here we report a case of AAV-complicated HUV with crescentic glomerulonephritis.
Synchronous Primary Renal Cell Carcinoma and Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review
Authors: Mahfoud Tarik , Tanz Rachid , Khmamouche Mohamed Réda , Allaoui Mohamed , Belbaraka Rhizlane , Khouchani Mouna , Ichou Mohamed
Published: November 2017

Synchronous primary cancers involving the pancreas and kidney are extremely rare and poorly documented. We report the first case of this association treated with chemotherapy and tyrosine kinase inhibitor. A 70-year-old woman presented with a 2-month history of epigastric pain with weight loss of 12 kg. Two weeks previously, she had presented with jaundice and pelvic pain. A computed tomography (CT) scan of the body revealed the presence of an irregular mass in the body of the pancreas, encasing the celiac trunk, with dilatation of the biliary tract. CT also revealed a heterogeneously right renal mass with bone metastasis in the left acetabular cup and the left iliac wing. A biliary metallic prosthesis was performed with a pancreatic mass biopsy. Histology revealed a moderately differentiated pancreatic ductal adenocarcinoma. Another biopsy was performed in the right iliac wing. Pathological examination with immunohistochemistry confirmed the diagnosis of bone metastasis from clear cell renal cell carcinoma. The patient was treated with a combination of gemcitabine, sunitinib, and denosumab. She had a stabilization disease and a prolonged progression-free survival of 9 months. Side effects were manageable and included grade 2 fatigue and grade 2 hypertension. The patient died at 13 months from diagnosis after disease progression. This report suggests that the appropriate treatment for this association in metastatic or unresectable disease is chemotherapy for pancreatic cancer and tyrosine kinase inhibitor for kidney cancer. We also review the appropriate literature concerning that association.
Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio as Prognostic Predictors for Hepatocellular Carcinoma Patients with Various Treatments: a Meta-Analysis and Systematic Review
Authors: Zheng Jun , Cai Jianye , Li Hui , Zeng Kaining , He Liying , Fu Hongyuan , Zhang Jiebin , Chen Liang , Yao Jia , Zhang Yingcai , Yang Yang
Published: November 2017

Background/Aims: Systemic inflammatory response (SIR) is widely considered as a preoperative risk factor for hepatocellular carcinoma (HCC) outcomes. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), two of the prognostic indices, have been investigated in post-therapeutic recurrence and survival of HCC. Here, we quantify the prognostic value of these two biomarkers and evaluate their consistency in different HCC therapies. Methods: A systematic review of electronic database of the Web of Science, Embase, PubMed and the Cochrane Library was conducted to search for associations between the NLR and PLR in the blood and clinical outcomes of HCC. Overall survival (OS) and recurrence-free survival (RFS) were the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were explored as effect measures. Subgroup analyses were performed to explore the heterogeneity of different therapies. Results: A total of 24 articles comprising 6318 patients were included in the meta-analysis. Overall, the pooled outcomes revealed that a high NLR before treatment predicted a poor OS (HR: 1.54, 95% CI: 1.34 to 1.76, p<0.001) and poor RFS (HR: 1.45, 95% CI: 1.16 to 1.82, p=0.001). Moreover, an increased PLR predicted a poor OS (HR: 1.63, 95% CI: 1.34 to 1.98, p<0.001) and earlier HCC recurrence (HR: 1.52, 95% CI: 1.21 to 1.91, p<0.001). In addition, both the NLR and PLR were identified as independent risk factors for predicting OS and RFS in HCC patients in a subgroup analysis of different treatment types, including curative or palliative therapy; however, these results were not found in the sorafenib subgroup due to limited clinical research. Conclusion: An increased NLR or PLR indicated poor outcomes for patients with HCC. The NLR and PLR may be considered as reliable and inexpensive biomarkers for making clinical decisions regarding HCC treatment.
Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer
Authors: Wang Lin , Wei Yingfeng , Fang Weijia , Lu Chong , Chen Jianing , Cui Guangying , Diao Hongyan
Published: November 2017

Background/Aims: Cetuximab is a chimeric IgG1 monoclonal antibody which targets the extracellular domain of epidermal growth factor receptor. This antibody is widely used for colorectal cancer (CRC) treatment but its influence on the immune system is incompletely understood. Methods: The immune influence of cetuximab therapy in CRC patients was investigated by analyzing peripheral blood mononuclear cells using flow cytometry. We undertook in vitro cytotoxicity and cytokine-profile assays to ascertain the immunomodulatory effect of cetuximab treatment. Results: The number of CD3+ T, CD8+ T, and natural killer (NK) cells was increased significantly and T-regulatory cells reduced gradually after cetuximab treatment. Percentage of CD4+ T, natural killer T (NKT)-like, invariant NKT, and dendritic cells was similar between baseline patients and cetuximab patients. Expression of CD137 on NK and CD8+ T cells was increased significantly after 4 weeks of cetuximab therapy. In vitro cetuximab treatment markedly increased expression of CD137 and CD107a on NK and CD8+ T cells. Cetuximab treatment promoted the cytotoxic activity of NK and CD8+ T cells against tumor cells. Conclusion: Cetuximab treatment promotes activation of the immune response but alleviates immunosuppression: this might be the underlying anti-CRC effect of cetuximab.
Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction
Authors: Liu Yihua , Yang Xiaoxi , Maureira Pablo , Falanga Aude , Marie Vanessa , Gauchotte Guillaume , Poussier Sylvain , Groubatch Frederique , Marie Pierre-Yves , Tran Nguyen
Published: November 2017

Background: The mismatch between traditional in vitro cell culture conditions and targeted chronic hypoxic myocardial tissue could potentially hamper the therapeutic effects of implanted bone marrow mesenchymal stem cells (BMSCs). This study sought to address (i) the extent of change to BMSC biological characteristics in different in vitro culture conditions and (ii) the effectiveness of permanent hypoxic culture for cell therapy in treating chronic myocardial infarction (MI) in rats. Methods: rat BMSCs were harvested and cultured in normoxic (21% O2, n=27) or hypoxic conditions (5% O2, n=27) until Passage 4 (P4). Cell growth tests, flow cytometry, and Bio-Plex assays were conducted to explore variations in the cell proliferation, phenotype, and cytokine expression, respectively. In the in vivo set-up, P3-BMSCs cultured in normoxia (n=6) or hypoxia (n=6) were intramyocardially injected into rat hearts that had previously experienced 1-month-old MI. The impact of cell therapy on cardiac segmental viability and hemodynamic performance was assessed 1 month later by 2-Deoxy-2[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) imaging and pressure-volume catheter, respectively. Additional histomorphological examinations were conducted to evaluate inflammation, fibrosis, and neovascularization. Results: Hypoxic preconditioning significantly enhanced rat BMSC clonogenic potential and proliferation without altering the multipotency. Different profiles of inflammatory, fibrotic, and angiogenic cytokine secretion were also documented, with a marked correlation observed between in vitro and in vivo proangiogenic cytokine expression and tissue neovessels. Hypoxic-preconditioned cells presented a beneficial effect on the myocardial viability of infarct segments and intrinsic contractility. Conclusion: Hypoxic-preconditioned BMSCs were able to benefit myocardial perfusion and contractility, probably by modulating the inflammation and promoting angiogenesis.
Hybrid Complexes of High and Low Molecular Weight Hyaluronans Highly Enhance HASCs Differentiation: Implication for Facial Bioremodelling
Authors: Stellavato Antonietta , La Noce Marcella , Corsuto Luisana , Pirozzi Anna Virginia Adriana , De Rosa Mario , Papaccio Gianpaolo , Schiraldi Chiara , Tirino Virginia
Published: November 2017

Background/Aims: Adipose-derived Stem Cells (ASCs) are used in Regenerative Medicine, including fat grafting, recovery from local tissue ischemia and scar remodeling. The aim of this study was to evaluate hyaluronan based gel effects on ASCs differentiation and proliferation. Methods: Comparative analyses using high (H) and low (L) molecular weight hyaluronans (HA), hyaluronan hybrid cooperative complexes (HCCs), and high and medium cross-linked hyaluronan based dermal fillers were performed. Human ASCs were characterized by flow cytometry using CD90, CD34, CD105, CD29, CD31, CD45 and CD14 markers. Then, cells were treated for 7, 14 and 21 days with hyaluronans. Adipogenic differentiation was evaluated using Oil red-O staining and expression of leptin, PPAR-γ, LPL and adiponectin using qRT-PCR. Adiponectin was analyzed by immunofluorescence, PPAR-γ and adiponectin were analyzed using western blotting. ELISA assays for adiponectin and leptin were performed. Results: HCCs highly affected ASCs differentiation by up-regulating adipogenic genes and related proteins, that were also secreted in the culture medium. H-HA and L-HA induced a lower level of ASCs differentiation. Conclusion: HCCs-based formulations clearly enhance adipogenic differentiation and proliferation, when compared with linear HA and cross-linked hyaluronans. Injection of HCCs in subdermal fat compartment may recruit and differentiate stem cells in adipocytes, and considerably improving fat tissue renewal.