bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mcm2-7 Replicative Helicase: A Promising Chemotherapeutic Target
Authors: Simon Nicholas E. , Schwacha Anthony
Published: August 2014

Numerous eukaryotic replication factors have served as chemotherapeutic targets. One replication factor that has largely escaped drug development is the Mcm2-7 replicative helicase. This heterohexameric complex forms the licensing system that assembles the replication machinery at origins during initiation, as well as the catalytic core of the CMG (Cdc45-Mcm2-7-GINS) helicase that unwinds DNA during elongation. Emerging evidence suggests that Mcm2-7 is also part of the replication checkpoint, a quality control system that monitors and responds to DNA damage. As the only replication factor required for both licensing and DNA unwinding, Mcm2-7 is a major cellular regulatory target with likely cancer relevance. Mutations in at least one of the sixMCMgenes are particularly prevalent in squamous cell carcinomas of the lung, head and neck, and prostrate, andMCMmutations have been shown to cause cancer in mouse models. Moreover various cellular regulatory proteins, including the Rb tumor suppressor family members, bind Mcm2-7 and inhibit its activity. As a preliminary step toward drug development, several small molecule inhibitors that target Mcm2-7 have been recently discovered. Both its structural complexity and essential role at the interface between DNA replication and its regulation make Mcm2-7 a potential chemotherapeutic target.
Systemic Treatment with Strontium Ranelate Accelerates the Filling of a Bone Defect and Improves the Material Level Properties of the Healing Bone
Authors: Zacchetti Giovanna , Dayer Romain , Rizzoli René , Ammann Patrick
Published: August 2014

Rapid bone defect filling with normal bone is a challenge in orthopaedics and dentistry. Strontium ranelate (SrRan) has been shown to in vitro decrease bone resorption and increase bone formation, and represents a potential agent with the capacity to accelerate bone defect filling. In this study, bone tibial defects of 2.5 mm in diameter were created in 6-month-old female rats orally fed SrRan (625 mg/kg/d; 5/7 days) or vehicle for 4, 8, or 12 weeks (10 rats per group per time point) from the time of surgery. Tibias were removed. Micro-architecture was determined by micro-computed tomography (µCT) and material level properties by nanoindentation analysis.µCT analysis showed that SrRan administration significantly improved microarchitecture of trabecular bone growing into the defect after 8 and 12 weeks of treatment compared to vehicle. SrRan treatment also accelerated the growth of cortical bone over the defect, but with different kinetics compared to trabecular bone, as the effects were already significant after 4 weeks. Nanoindentation analysis demonstrated that SrRan treatment significantly increased material level properties of both trabecular bone and cortical bone filling the defect compared to vehicle. SrRan accelerates the filling of bone defect by improving cortical and trabecular bone microarchitecture both quantitatively and qualitatively.
A Parametric Study of the Impact of the Cooling Water Site Specific Conditions on the Efficiency of a Pressurized Water Reactor Nuclear Power Plant
Authors: Ibrahim Mohamed M. A. , Badawy Mohamed R.
Published: August 2014

In this study, the thermal analysis for the impact of the cooling seawater site specific conditions on the thermal efficiency of a conceptual pressurized water reactor nuclear power plant (PWR NPP) is presented. The PWR NPP thermal performance depends upon the heat transfer analysis of steam surface condenser accounting for the key parameters such as the cooling seawater salinity and temperature that affect the condenser overall heat transfer coefficient and fouling factor. The study has two aspects: the first one is the impact of the temperature and salinity within a range of (290 K–310 K and 0.00–60000 ppm) on the seawater thermophysical properties such as density, specific heat, viscosity, and thermal conductivity that reflect a reduction in the condenser overall heat transfer coefficient from 2.25 kW/m2 K to 1.265 kW/m2 K at temperature and salinity of 290 K and 0.00 ppm and also from 2.35 kW/m2 K to 1.365 kW/m2 K at temperature and salinity of 310 K and 60000 ppm, whereas the second aspect is the fouling factor variations due to the seawater salinity. The analysis showed that the two aspects have a significant impact on the computation of the condenser overall heat transfer coefficient, whereas the increase of seawater salinity leads to a reduction in the condenser overall heat transfer coefficient.
Creatine, L-Carnitine, andω3 Polyunsaturated Fatty Acid Supplementation from Healthy to Diseased Skeletal Muscle
Authors: D’Antona Giuseppe , Nabavi Seyed Mohammad , Micheletti Piero , Di Lorenzo Arianna , Aquilani Roberto , Nisoli Enzo , Rondanelli Mariangela , Daglia Maria
Published: August 2014

Myopathies are chronic degenerative pathologies that induce the deterioration of the structure and function of skeletal muscle. So far a definitive therapy has not yet been developed and the main aim of myopathy treatment is to slow the progression of the disease. Current nonpharmacological therapies include rehabilitation, ventilator assistance, and nutritional supplements, all of which aim to delay the onset of the disease and relieve its symptoms. Besides an adequate diet, nutritional supplements could play an important role in the treatment of myopathic patients. Here we review the most recentin vitroandin vivostudies investigating the role supplementation with creatine, L-carnitine, andω3 PUFAs plays in myopathy treatment. Our results suggest that these dietary supplements could have beneficial effects; nevertheless continued studies are required before they could be recommended as a routine treatment in muscle diseases.
Structural Performance of a Hybrid FRP-Aluminum Modular Triangular Truss System Subjected to Various Loading Conditions
Authors: Zhang Dongdong , Huang Yaxin , Zhao Qilin , Li Fei , Li Feng , Gao Yifeng
Published: August 2014

A novel hybrid FRP-aluminum truss system has been employed in a two-rut modular bridge superstructure composed of twin inverted triangular trusses. The actual flexural behavior of a one-rut truss has been previously investigated under the on-axis loading test; however, the structural performance of the one-rut truss subjected to an off-axis load is still not fully understood. In this paper, a geometrical linear finite element model is introduced and validated by the on-axis loading test; the structural performance of the one-rut truss subjected to off-axis load was numerically obtained; the dissimilarities of the structural performance between the two different loading cases are investigated in detail. The results indicated that (1) the structural behavior of the off-axis load differs from that of the on-axis load, and the off-axis load is the critical loading condition controlling the structural performance of the triangular truss; (2) under the off-axis load, the FRP trussed members and connectors bear certain out-of-plane bending moments and are subjected to a complicated stress state; and (3) the stress state of these members does not match that of the initial design, and optimization for the redesign of these members is needed, especially for the pretightened teeth connectors.
New Described Dermatological Disorders
Authors: Gönül Müzeyyen , Cevirgen Cemil Bengu , Keseroglu Havva Ozge , Kaya Akis Havva
Published: August 2014

Many advances in dermatology have been made in recent years. In the present review article, newly described disorders from the last six years are presented in detail. We divided these reports into different sections, including syndromes, autoinflammatory diseases, tumors, and unclassified disease. Syndromes included are “circumferential skin creases Kunze type” and “unusual type of pachyonychia congenita or a new syndrome”; autoinflammatory diseases include “chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome,” “pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome,” and “pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) syndrome”; tumors include “acquired reactive digital fibroma,” “onychocytic matricoma and onychocytic carcinoma,” “infundibulocystic nail bed squamous cell carcinoma,” and “acral histiocytic nodules”; unclassified disorders include “saurian papulosis,” “symmetrical acrokeratoderma,” “confetti-like macular atrophy,” and “skin spicules,” “erythema papulosa semicircularis recidivans.”
Substance Use in the Club Scene of Rome: A Pilot Study
Authors: Vento Alessandro Emiliano , Martinotti Giovanni , Cinosi Eduardo , Lupi Matteo , Acciavatti Tiziano , Carrus Dario , Santacroce Rita , Chillemi Eleonora , Bonifaci Ludovica , di Giannantonio Massimo , Corazza Ornella , Schifano Fabrizio
Published: August 2014

Objective. Over the last few years, a wide number of unregulated substances have been marketed on the Web and in smart and head shops; they are usually advertised as legal alternatives to commonly known drugs and are defined as “smart drugs,” “legal highs,” and “novel psychoactive substances” (NPS). Aim of our work is to describe use habits and distribution of NPS in a population of young adults in Rome club scene.Methods. A self-administered questionnaire was proposed to subjects over 18 years of age at the entrance of 5 nightclubs in Rome. Socioeconomic characteristics and substance use were investigated.Results. Preliminary results give evidence that 78% of respondents have a lifetime history of NPS use. In addition, 56% of the sample has consumed illicit drugs in the past and 39% has used psychoactive substances in the 12 hours preceding the questionnaire administration.Conclusions. A significant proportion of subjects report use of novel psychoactive substances; traditional illicit drugs consumption, particularly cocaine, appears to be very high as well in the club scene. These data highlight a serious public health challenge, since pharmacological, toxicological, and psychopathological effects linked to interactions among all these substances may be unpredictable and sometimes fatal in vulnerable individuals.
A Conservative Treatment Approach to Replacing a Missing Anterior Tooth
Authors: Singh Kunwarjeet , Gupta Nidhi , Unnikrishnan Nandini , Kapoor Vikram , Arora Dhruv , Khinnavar Poonam K.
Published: August 2014

An implant-supported crown or conventionally fixed partial denture is the most common treatment modality to replace a missing anterior tooth but a more conservative approach, with a fiber reinforced composite resin FPD, can be used to replace a missing anterior tooth in young patients or when the patient does not agree for an implant, or conventional FPD or RPD therapy. It is an esthetic, conservative single sitting chairside procedure which can be used as a definitive treatment alternative in certain clinical situations for esthetic and functional replacement of a missing anterior tooth. To achieve desirable results, putty matrix was used for proper positioning of the pontic during direct fabrication of FRCFPD.
The Potential of MicroRNAs in Personalized Medicine against Cancers
Authors: Saumet Anne , Mathelier Anthony , Lecellier Charles-Henri
Published: August 2014

MicroRNAs orchestrate the expression of the genome and impact many, if not all, cellular processes. Their deregulation is thus often causative of human malignancies, including cancers. Numerous studies have implicated microRNAs in the different steps of tumorigenesis including initiation, progression, metastasis, and resistance to chemo/radiotherapies. Thus, microRNAs constitute appealing targets for novel anticancer therapeutic strategies aimed at restoring their expression or function. As microRNAs are present in a variety of human cancer types, microRNA profiles can be used as tumor-specific signatures to detect various cancers (diagnosis), to predict their outcome (prognosis), and to monitor their treatment (theranosis). In this review, we present the different aspects of microRNA biology that make them remarkable molecules in the emerging field of personalized medicine against cancers and provide several examples of their industrial exploitation.
Arthroscopic Fixation of Cell Free Polymer-Based Cartilage Implants with a Bioinspired Polymer Surface on the Hip Joint: A Cadaveric Pilot Study
Authors: Lahner Matthias , Duif Christian , Ficklscherer Andreas , Kaps Christian , Kalwa Lukas , Seidl Tobias
Published: August 2014

This study investigates the adhesion capacity of a polyglycolic acid- (PGA-) hyaluronan scaffold with a structural modification based on a planar polymer (PM) surface in a cadaver cartilage defect model. Two cadaver specimens were used to serially test multiple chondral matrices. In a cadaver hip model, cell free polymer-based cartilage implants with a planar bioinspired PM surface (PGA-PM-scaffolds) were implanted arthroscopically on 10 mm × 15 mm full-thickness femoral hip cartilage lesions. Unprocessed cartilage implants without a bioinspired PM surface were used as control group. The cartilage implants were fixed without and with the use of fibrin glue on femoral hip cartilage defects. After 50 movement cycles and removal of the distraction, a rearthroscopy was performed to assess the outline attachment and integrity of the scaffold. The fixation techniques without and with fibrin fixation showed marginal differences for outline attachment, area coverage, scaffold integrity, and endpoint fixation after 50 cycles. The PGA-PM-scaffolds with fibrin fixation achieved a higher score in terms of the attachment, integrity, and endpoint fixation than the PGA-scaffold on the cartilage defect. Relating to the outline attachment, area coverage, scaffold integrity, and endpoint fixation, the fixation with PGA-PM-scaffolds accomplished significantly better results compared to the PGA-scaffolds(P=0.03752, P=0.03078, P=0.00512, P=0.00512). PGA-PM-scaffolds demonstrate increased observed initial fixation strength in cadaver femoral head defects relative to PGA-scaffold, particularly when fibrin glue is used for fixation.
Possible Use of Bacteriophages Active againstBacillus anthracisand OtherB. cereusGroup Members in the Face of a Bioterrorism Threat
Authors: Jończyk-Matysiak Ewa , Kłak Marlena , Weber-Dąbrowska Beata , Borysowski Jan , Górski Andrzej
Published: August 2014

Anthrax is an infectious fatal disease with epidemic potential. Nowadays, bioterrorism usingBacillus anthracisis a real possibility, and thus society needs an effective weapon to neutralize this threat. The pathogen may be easily transmitted to human populations. It is easy to store, transport, and disseminate and may survive for many decades. Recent data strongly support the effectiveness of bacteriophage in treating bacterial diseases. Moreover, it is clear that bacteriophages should be considered a potential incapacitative agent against bioterrorism using bacteria belonging toB. cereusgroup, especiallyB. anthracis. Therefore, we have reviewed the possibility of using bacteriophages active againstBacillus anthracisand other species of theB. cereusgroup in the face of a bioterrorism threat.
Time-Dependent Global Attractor for a Class of Nonclassical Parabolic Equations
Authors: Zhang Fang-hong
Published: August 2014

Based on the recent theory of time-dependent global attractors in the works of Conti et al. (2013) and di Plinio et al. (2011), we prove the existence of time-dependent global attractors as well as the regularity of the time-dependent global attractor for a class of nonclassical parabolic equations.
Cr(VI) Removal from Aqueous by Adsorption on Amine-Functionalized Mesoporous Silica Prepared from Silica Fume
Authors: Li Xitong , Han Caiyun , Zhu Wenjie , Ma Wenhui , Luo Yongming , Zhou Yang , Yu Jie , Wei Kuixian
Published: August 2014

Amino-functionalized mesoporous silica MCM-41 materials have been prepared to develop efficient adsorbents of Cr(VI) in wastewater, using silica fume as silica source. Functionalization with amino groups has been carried out by using grafting method. The materials have been characterized by means of X-ray diffraction (XRD), nitrogen (N2) adsorption-desorption, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). Adsorption potential of the material for Cr(VI) removal from aqueous solution was investigated by varying experimental conditions such as pH, initial metal concentration, and contact time. The equilibrium data were analyzed using the Langmuir and Freundlich isotherm by linear regression analysis, and the results show that the adsorption equilibrium data obeyed the Langmuir model. In addition, the kinetics analysis revealed that the overall adsorption process was successfully fitted with the pseudo-second-order kinetic model.
Nonunion of the First Sternocostal Synchondrosis Accompanied by Sternoclavicular Joint Synovitis
Authors: Takeuchi Makoto , Goto Tomohiro , Yukata Kiminori , Suzue Naoto , Hamada Daisuke , Nishisho Toshihiko , Tonogai Ichiro , Matsuura Tetsuya , Sairyo Koichi
Published: August 2014

Injury to the sternocostal synchondrosis of the first rib is quite rare. We report one such case in a 50-year-old man with nonunion of the first sternocostal synchondrosis accompanied by synovitis of the sternoclavicular joint. He first underwent arthroscopic surgery of the left sternoclavicular joint. Postoperatively, the patient’s symptoms decreased by half, but another pain and crepitus at the inferior lateral portion of the sternoclavicular joint developed. Since MRI and functional CT reexaminations revealed nonunion of the first sternocostal synchondrosis, resection arthroplasty of the first sternocostal joint was performed. This resulted in immediate resolution of the symptoms. At 2-year follow-up, his symptoms disappeared entirely with no limited range of motion of the shoulder.
Systematic Evaluation and Mechanistic Investigation of Antioxidant Activity of Fullerenols Using β‐Carotene Bleaching Assay
Authors: Ueno Hiroshi , Yamakura Shizuka , Arastoo Riya S. , Oshima Takumi , Kokubo Ken
Published: August 2014

Antioxidant activity of hydroxylated fullerenes, so‐called fullerenols, against lipid peroxyl radical was evaluated by β‐carotene bleaching assay. All samples showed moderate to high antioxidant activity (%AOA), especially for C60(OH)12 (70.1) and C60(OH)44 (66.0) as compared with 8, 24, 26, and 36 hydroxylated ones (31.7–62.8). The detection of the possible products was conducted in the model reaction of both fullerenols and C60 with methyl linoleate by MALDI‐TOF‐MS. These results suggested that the two possible mechanisms, such as C‐addition to double bonds and H‐abstraction from –OH groups, are involved in the present radical scavenging reaction.
Niosomes of Ascorbic Acid and α-Tocopherol in the Cerebral Ischemia-Reperfusion Model in Male Rats
Authors: Varshosaz Jaleh , Taymouri Somayeh , Pardakhty Abbas , Asadi-Shekaari Majid , Babaee Abodolreza
Published: August 2014

The objective of the present study was to prepare a stableivinjectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluatedin vitro. Forin vivoevaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4–8°C.In vivostudies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.
Improvement of the Asymptotic Properties of Zero Dynamics for Sampled-Data Systems in the Case of a Time Delay
Authors: Zeng Cheng , Liang Shan , Zhong Jiaqi , Su Yingying
Published: August 2014

It is well known that the existence of unstable zero dynamics is recognized as a major barrier in many control systems, and deeply limits the achievable control performance. When a continuous-time system with relative degree greater than or equal to three is discretized using a zero-order hold (ZOH), at least one of the zero dynamics of the resulting sampled-data model is obviously unstable for sufficiently small sampling periods, irrespective of whether they involve time delay or not. Thus, attention is here focused on continuous-time systems with time delay and relative degree two. This paper analyzes the asymptotic behavior of zero dynamics for the sampled-data models corresponding to the continuous-time systems mentioned above, and further gives an approximate expression of the zero dynamics in the form of a power series expansion up to the third order term of sampling period. Meanwhile, the stability of the zero dynamics is discussed for sufficiently small sampling periods and a new stability condition is also derived. The ideas presented here generalize well-known results from the delay-free control system to time-delay case.
Summation Formulas Obtained by Means of the Generalized Chain Rule for Fractional Derivatives
Authors: Gaboury S. , Tremblay R.
Published: August 2014

In 1970, several interesting new summation formulas were obtained by using a generalized chain rule for fractional derivatives. The main object of
this paper is to obtain a presumably new general formula. Many special cases involving special functions of mathematical physics such as the generalized hypergeometric functions, the Appell F1 function, and the Lauricella functions of several variables FD(n) are given.
Pharmacokinetics of Two Alkaloids after Oral Administration of Rhizoma Coptidis Extract in Normal Rats and Irritable Bowel Syndrome Rats
Authors: Gong Zipeng , Chen Ying , Zhang Ruijie , Wang Yinghan , Yang Qing , Guo Yan , Weng Xiaogang , Gao Shuangrong , Wang Hailin , Zhu Xiaoxin , Dong Yu , Li Yujie , Wang Yajie
Published: August 2014

A comparative pharmacokinetic study of berberine and palmatine after oral administration of Rhizoma Coptidis extract (96 mg/kg, containing berberine 22 mg/kg and palmatine 5 mg/kg based on body weight) was performed in normal and postinflammation irritable bowel syndrome (PI‐IBS) rats, induced by intracolonic instillation of acetic acid and restraint stress. Quantification of berberine and palmatine in rat plasma was achieved by using a sensitive and rapid UPLC‐MS/MS method. Plasma samples were collected at 13 different time points and the pharmacokinetic parameters were analyzed by WinNonlin software. The significant differences in the pharmacokinetic behaviors, such as Cmax⁡, AUC(0–t), Vd/F, and CL/F, of berberine and palmatine were found between normal and PI‐IBS model rats. The results indicated that PI‐IBS pathological conditions in rats could alter the pharmacokinetic behavior of drug. Preclinical pharmacokinetic studies are usually carried out on healthy animals. However, we should pay more attention to the fact that the change of pharmacokinetic behavior plays an important role on efficacy. It is essential to investigate the pharmacokinetics of the drug in disease status.
Fast SAR Image Change Detection Using Bayesian Approach Based Difference Image and Modified Statistical Region Merging
Authors: Zhang Han , Ni Weiping , Yan Weidong , Bian Hui , Wu Junzheng
Published: August 2014

A novel fast SAR image change detection method is presented in this paper. Based on a Bayesian approach, the prior information that speckles follow the Nakagami distribution is incorporated into the difference image (DI) generation process. The new DI performs much better than the familiar log ratio (LR) DI as well as the cumulant based Kullback-Leibler divergence (CKLD) DI. The statistical region merging (SRM) approach is first introduced to change detection context. A new clustering procedure with the region variance as the statistical inference variable is exhibited to tailor SAR image change detection purposes, with only two classes in the final map, the unchanged and changed classes. The most prominent advantages of the proposed modified SRM (MSRM) method are the ability to cope with noise corruption and the quick implementation. Experimental results show that the proposed method is superior in both the change detection accuracy and the operation efficiency.
Violence in Intimate Relationships: A Comparison between Married and Dating Couples
Authors: Machado Carla , Martins Carla , Caridade Sónia
Published: August 2014

This study examines the attitudes about intimate violence and compares the prevalence of abuse reported by married and dating participants, by type of abuse and sex of respondent. A sample of 3,716 participants, aged 15 to 67 years, filled in one attitudinal questionnaire and a self-report instrument on abuse perpetration and victimization. Attitudinal data revealed a general disapproval of violence use, with greater violence support among males and married participants. When comparing violence in both relational contexts, we found that, in terms of perpetration, more dating partners reported physical abuse and severe forms of physical abuse than married partners. Suggestions for future research are discussed.
Clinical Nonlinear Laser Imaging of Human Skin: A Review
Authors: Cicchi Riccardo , Kapsokalyvas Dimitrios , Pavone Francesco Saverio
Published: August 2014

Nonlinear optical microscopy has the potential of being usedin vivoas a noninvasive imaging modality for both epidermal and dermal imaging. This paper reviews the capabilities of nonlinear microscopy as a noninvasive high-resolution tool for clinical skin inspection. In particular, we show that two-photon fluorescence microscopy can be used as a diagnostic tool for characterizing epidermal layers by means of a morphological examination. Additional functional information on the metabolic state of cells can be provided by measuring the fluorescence decay of NADH. This approach allows differentiating epidermal layers having different structural and cytological features and has the potential of diagnosing pathologies in a very early stage. Regarding therapy follow-up, we demonstrate that nonlinear microscopy could be successfully used for monitoring the effect of a treatment. In particular, combined two-photon fluorescence and second-harmonic generation microscopy were usedin vivofor monitoring collagen remodeling after microablative fractional laser resurfacing and for quantitatively monitoring psoriasis on the basis of the morphology of epidermal cells and dermal papillae. We believe that the described microscopic modalities could find in the near future a stable place in a clinical dermatological setting for quantitative diagnostic purposes and as a monitoring method for various treatments.
Global Stabilization of High-Order Time-Delay Nonlinear Systems under a Weaker Condition
Authors: Zhang Nengwei , Zhang Enbin , Gao Fangzheng
Published: August 2014

Under the weaker condition on the system growth, this paper further investigates the problem of global stabilization by state feedback for a class of high-order nonlinear systems with time-varying delays. By skillfully using the homogeneous domination approach, a continuous state feedback controller is successfully designed, which preserves the equilibrium at the origin and guarantees the global asymptotic stability of the resulting closed-loop system. A simulation example is given to demonstrate the effectiveness of the proposed design procedure.
Characterizations of MV-Algebras Based on the Theory of Falling Shadows
Authors: Yang Yongwei , Xin Xiaolong , He Pengfei
Published: August 2014

Based on the falling shadow theory, the concept of falling fuzzy (implicative) ideals as a generalization of that of aT∧-fuzzy (implicative) ideal is proposed in MV-algebras. The relationships between falling fuzzy (implicative) ideals andT-fuzzy (implicative) ideals are discussed, and conditions for a falling fuzzy (implicative) ideal to be aT∧-fuzzy (implicative) ideal are provided. Some characterizations of falling fuzzy (implicative) ideals are presented by studying proprieties of them. The product⊛and the up product⊚operations on falling shadows and the upset of a falling shadow are established, by whichT-fuzzy ideals are investigated based on probability spaces.
Small Cell Carcinoma of the Uterine Cervix in a Pregnant Patient Diagnosed with Liquid Based Cytology and Cell Block Immunocytochemistry
Authors: Attipoe Mawuli F. , Sturgis Charles D.
Published: August 2014

Definitive cytomorphologic diagnosis of small cell carcinoma of the uterine cervix is possible but can be challenging in routine cervicovaginal cancer screening specimens. Several small series of reported cases of cervical small cell carcinoma have shown this uncommon malignancy to represent fewer than 2% of all invasive cervical cancers. This tumor type is associated with poor prognosis and rapid disease progression and can develop to an advanced stage in the interval between screening visits. Only rare case reports of small cell carcinoma arising in gravid cervices are known. In the current case a 29-year-old, gravida 6, para 2, pregnant (10-week gestation) female presented with postcoital bleeding. A definitive diagnosis of small cell carcinoma of the cervix was made possible by liquid based Pap testing with ancillary cell block preparation allowing for immunocytochemical characterization of the lesional cell population.
Metastatic Heterogeneity of Breast Cancer Cells Is Associated with Expression of a Heterogeneous TGFβ-Activating miR424–503 Gene Cluster
Authors: Li Yun , Li Wei , Ying Zhe , Tian Han , Zhu Xun , Li Jun , Li Mengfeng
Published: August 2014

TGFβ signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFβ activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFβ signaling can be overactivated and sustained. To better understand how the TGFβ inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424–503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFβ signaling, leading to enhanced TGFβ signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424–503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424–503 cluster contributed to the heterogeneity of TGFβ activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424–503 cluster, underlying TGFβ activation and metastasis of human breast cancer. Cancer Res; 74(21); 6107–18. ©2014 AACR.
Zfx Facilitates Tumorigenesis Caused by Activation of the Hedgehog Pathway
Authors: Palmer Colin J. , Galan-Caridad Jose M. , Weisberg Stuart P. , Lei Liang , Esquilin Jose M. , Croft Gist F. , Wainwright Brandon , Canoll Peter , Owens David M. , Reizis Boris
Published: August 2014

The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies. Cancer Res; 74(20); 5914–24. ©2014 AACR.
Promoting Thiol Expression Increases the Durability of Antitumor T-cell Functions
Authors: Kesarwani Pravin , Al-Khami Amir A. , Scurti Gina , Thyagarajan Krishnamurthy , Kaur Navtej , Husain Shahid , Fang Quan , Naga Osama S. , Simms Patricia , Beeson Gyda , Voelkel-Johnson Christina , Garrett-Mayer Elizabeth , Beeson Craig C. , Nishimura Michael I. , Mehrotra Shikhar
Published: August 2014

Ex vivo–expanded CD8+ T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (TEM cells). With regard to therapeutic applications, two undesired features of this phenotype in vivo are limited persistence and reduced antitumor efficacy, relative to CD8+ T cells with a central memory-like phenotype (TCM cells). Furthermore, there is incomplete knowledge about all the differences between TEM and TCM cells that may influence tumor treatment outcomes. Given that TCM cells survive relatively longer in oxidative tumor microenvironments, we investigated the hypothesis that TCM cells possess relatively greater antioxidative capacity than TEM cells. Here, we report that TCM cells exhibit a relative increase compared with TEM cells in the expression of cell surface thiols, a key target of cellular redox controls, along with other antioxidant molecules. Increased expression of redox regulators in TCM cells inversely correlated with the generation of reactive oxygen and nitrogen species, proliferative capacity, and glycolytic enzyme levels. Notably, T-cell receptor–transduced T cells pretreated with thiol donors, such as N-acetyl cysteine or rapamycin, upregulated thiol levels and antioxidant genes. A comparison of antitumor CD8+ T-cell populations on the basis of surface thiol expression showed that thiol-high cells persisted longer in vivo and exerted superior tumor control. Our results suggest that higher levels of reduced cell surface thiols are a key characteristic of T cells that can control tumor growth and that profiling this biomarker may have benefits to adoptive T-cell immunotherapy protocols. Cancer Res; 74(21); 6036–47. ©2014 AACR.
Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence
Authors: Payne Ania W. , Pant Dhruv K. , Pan Tien-Chi , Chodosh Lewis A.
Published: August 2014

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTC) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that ceramide kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously upregulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly upregulated in tumor cells following HER2/neu downregulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu downregulation. Consistent with our observations in mouse models, analysis of gene expression profiles from more than 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. In addition, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are estrogen receptor–negative, HER2+, basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathologic variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this prosurvival pathway. Cancer Res; 74(21); 6352–63. ©2014 AACR.
The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness
Authors: Thangavel Chellappagounder , Boopathi Ettickan , Ciment Steve , Liu Yi , O' Neill Raymond , Sharma Ankur , McMahon Steve B. , Mellert Hestia , Addya Sankar , Ertel Adam , Birbe Ruth , Fortina Paolo , Dicker Adam P. , Knudsen Karen E. , Den Robert B.
Published: August 2014

Purpose: Perturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance.

Experimental Design: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts.

Results: Loss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P < 0.05).

Conclusions: Loss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy. Clin Cancer Res; 20(21); 5468–82. ©2014 AACR.
Identification of Differentially Expressed Long Noncoding RNAs in Bladder Cancer
Authors: Peter Stefan , Borkowska Edyta , Drayton Ross M. , Rakhit Callum P. , Noon Aidan , Chen Wei , Catto James WF
Published: August 2014

Purpose: Loss of epigenetic gene regulation through altered long noncoding RNA (lncRNA) expression seems important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer. Here, we identify differentially expressed lncRNAs with potential regulatory functions in urothelial cancer.

Experimental Design: The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs.

Results: We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation.

Conclusions: We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease. Clin Cancer Res; 20(20); 5311–21. ©2014 AACR.
Functional and Manometric Outcomes after Redo-Ileal Pouch Anal Anastomosis in Patients with Ulcerative Colitis
Authors: Araki Toshimitsu , Okita Yoshiki , Fujikawa Hiroyuki , Uchida Keiichi , Mohri Yasuhiko , Kusunoki Masato
Published: August 2014

Aim: To retrospectively analyze manometric findings in patients with ulcerative colitis who underwent redo-ileo anal anastomosis for pouch-related complications. Methods: Functional and anal manometric parameters were analyzed before, immediately after, and 6 months after the procedure in 17 patients who underwent redo-ileo anal anastomosis between 2001 and 2012. Results: Of the 17 patients, 13 showed stoma closure and 9 have maintained gastrointestinal continuity with functional pouches. Manometric findings were similar before and immediately after redo-ileo anal anastomosis, including length of high-pressure zone (p = 0.11) and maximum resting and (p = 0.060) squeezing (p = 0.69) pressures, but maximum resting pressure improved significantly 6 months later (p = 0.021). Univariate analysis showed that ulcerative colitis duration <3 years before ileo anal anastomosis (p = 0.0073), interval between pouch-related complications and ileo anal anastomosis <2 years (p = 0.040), and persistent abscess before diversion ileostomy (p = 0.0024) were significant risk factors for pouch failure after redo-ileo anal anastomosis. Conclusions: Although maximum resting pressure was significantly reduced 3 months after redo-ileo anal anastomosis, it returned to preoperative levels after 6 months. The length of the high-pressure zone and the maximum squeezing pressure were not affected by this procedure.
A Low‐Frequency Variant in
MAPK14
Provides Mechanistic Evidence of a Link With Myeloperoxidase: A Prognostic Cardiovascular Risk Marker
Authors: Waterworth Dawn M. , Li Li , Scott Robert , Warren Liling , Gillson Christopher , Aponte Jennifer , Sarov‐Blat Lea , Sprecher Dennis , Dupuis Josée , Reiner Alex , Psaty Bruce M. , Tracy Russell P. , Lin Honghuang , McPherson Ruth , Chissoe Stephanie , Wareham Nick , Ehm Margaret G.
Published: August 2014

Background

Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen‐activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in

MAPK
11/14

genes by exome sequencing and follow‐up genotyping or imputation in participants well‐phenotyped for cardiovascular and metabolic traits.

Methods and Results

Investigation of genetic variation in

MAPK
11

and

MAPK
14

genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of
RS
2859144 in

MAPK
14

with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study),
P
=2.3×10
−6
). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta‐
P
=0.003), leading to a meta‐
P
value of 9.96×10
−7
in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population‐based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case–control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (
P
=0.002) and risk of obesity (body mass index ≥30 kg/m
2
,
P
=0.004).

Conclusions

As myeloperoxidase is a prognostic marker of coronary events, the

MAPK
14

variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.
Dead Wrong?: Battle Deaths, Military Medicine, and Exaggerated Reports of War's Demise
Authors: Fazal Tanisha M.
Published: August 2014

Is war in decline? Recent scholarship suggests that it is. The empirical basis for this argument is a decline in battle deaths over the past several centuries, a standard metric for counting wars and armed conflicts. Dramatic improvements in medical care in conflict zones—in preventive medicine, battlefield medicine, evacuation, and protective equipment—have raised the likelihood of surviving battle wounds today compared with past eras. Thus the fact that war has become less fatal does not necessarily mean that it has become less frequent. Original data on wounded-to-killed ratios, supplemented by medical research and interviews with physicians from the military and nongovernmental communities, is used to advance this claim. The results show that the decline in war is likely not as dramatic as some scholars have argued. These findings question the foundation of existing datasets on war and armed conflict. They also highlight the growing need for policy focused on the battle wounded.
The Minotaur’s Labyrinth: Third State Intervention before the International Court of Justice
Authors: Uchkunova Inna
Published: August 2014

The procedure for intervention before the International Court of Justice has been little explored in literature, which may be explained by the uncertainties that inhabit it.

In fact, this is the reason why States have had little recourse to it – and worse yet – only a few applications for intervention have been successful. The present article seeks to throw light on the most problematic aspects of third State intervention, with a view to finding the thread which will guide a way out of the labyrinth of uncertainty.