bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Five-Year Treatment with Testosterone Undecanoate on Metabolic and Hormonal Parameters in Ageing Men with Metabolic Syndrome
Authors: Francomano Davide , Lenzi Andrea , Aversa Antonio
Published: February 2014

Metabolic and hormonal modifications after long-term testosterone (T) treatment have never been investigated. 20 hypogonadal men (mean T = 241 ng/dL–8.3 nmol/L) with metabolic syndrome (MS, mean age 58) were treated with T-undecanoate injections every 12 weeks for 60 months. 20 matched subjects in whom T was unaccepted or contraindicated served as controls. Primary endpoints were variations from baseline of metabolic and hormonal parameters. In T-group, significant reductions in waist circumference (−9.6±3.8 cm,P<0.0001), body weight (−15±2.8 Kg,P<0.0001), and glycosylated hemoglobin (−1.6 ± 0.5%,P<0.0001) occurred, along with improvements in insulin sensitivity (HOMA-I;−2.8 ± 0.6,P<0.0001), lipid profile (total/HDL-cholesterol ratio−2.9±1.5,P<0.0001), systolic and diastolic blood pressure (−23±10and−16±8mm Hg,P<0.0001, resp.), and neck and lumbar T-scores (+0.5±0.15 gr/cm2,P<0.0001;+0.7±0.8,P<0.0001, resp.). Also, serum vitamin D (+14.0±1.3 ng/mL,P<0.01), TSH (− 0.9±0.3 mUI/mL,P<0.01), GH (0.74±0.2 ng/mL,P<0.0001), and IGF1 (105±11 ng/mL,P<0.01) levels changed in T-group but not in controls. Normalization of T levels in men with MS improved obesity, glycemic control, blood pressure, lipid profile, and bone mineral density compared with controls. Amelioration in hormonal parameters, that is, vitamin D, growth hormone, and thyrotropin plasma levels, were reported.
Protection of Steel Corrosion in Concrete Members by the Combination of Galvanic Anode and Nitrite Penetration
Authors: Aoyama Minobu , Miyazato Shinichi , Kawamura Mitsunori
Published: February 2014

Chloride induced-corrosion of steel bars in concrete can make cracks and exfoliation in near-surface regions in reinforced concrete structures. In this paper, we described the basic concept and practice of steel bars corrosion protection method by the combination of galvanic anode (zinc wire) and the penetration of nitrite ions from mortar layers containing a large amount of lithium nitrite.
Multilinear Singular Integrals and Commutators on Herz Space with Variable Exponent
Authors: Hussain Amjad , Gao Guilian
Published: February 2014

The paper establishes some sufficient conditions for the boundedness of singular integral operators and their commutators from products of
variable exponent Herz spaces to variable exponent Herz spaces.
Recombinant Human Trefoil Factor 3 Ameliorates Bowel Injury: Its Anti-Inflammatory Effect on Experimental Necrotizing Enterocolitis
Authors: Shi Lei , Zhou Pang-Hu , Xi Juan-Li , Yu Hong-Gang , Zhang Bing-Hong
Published: February 2014

Aim. Recombinant human trefoil factor 3 (intestinal trefoil factor) has been suggested to be partially protective against necrotizing enterocolitis (NEC), but the mechanisms of this protection have not been defined. We investigated whether the protective effects of rhTFF3 are the result of an anti-inflammatory response.Methods. The rats were killed on day 4, the distal ileum was harvested for morphological studies and immunohistochemistry for NF-κB (p65), and the amounts of IL-1β, IL-6, and IL-10 in the intestinal tissue were measured using commercial ELISA assay kits.Results. In the neonatal NEC, IL-1β, IL-6, and IL-10 were significantly higher than in normal group. In normal group, IL-1βand IL-6 were significantly decreased, and the amount of IL-10 was markedly increased compared with NEC group. In the NEC model, immunohistochemical staining for NF-κB (p65) was demonstrated to be of a strong brown color and was distributed in the intestinal epithelium. Treatment with rhTFF3 significantly decreased the immunoreactivity of NF-κB (p65) in the NEC model.Conclusions. Intestinal inflammation was ameliorated after rhTFF3 was injected. rhTFF3 may protect against the intestinal injury of the neonatal rat NEC model by suppression of the inflammatory response.
Novel Approaches to Improve Iris Recognition System Performance Based on Local Quality Evaluation and Feature Fusion
Authors: Chen Ying , Liu Yuanning , Zhu Xiaodong , Chen Huiling , He Fei , Pang Yutong
Published: February 2014

For building a new iris template, this paper proposes a strategy to fuse different portions of iris based on machine learning method to evaluate local quality of iris. There are three novelties compared to previous work. Firstly, the normalized segmented iris is divided into multitracks and then each track is estimated individually to analyze the recognition accuracy rate (RAR). Secondly, six local quality evaluation parameters are adopted to analyze texture information of each track. Besides, particle swarm optimization (PSO) is employed to get the weights of these evaluation parameters and corresponding weighted coefficients of different tracks. Finally, all tracks’ information is fused according to the weights of different tracks. The experimental results based on subsets of three public and one private iris image databases demonstrate three contributions of this paper. (1) Our experimental results prove that partial iris image cannot completely replace the entire iris image for iris recognition system in several ways. (2) The proposed quality evaluation algorithm is a self-adaptive algorithm, and it can automatically optimize the parameters according to iris image samples’ own characteristics. (3) Our feature information fusion strategy can effectively improve the performance of iris recognition system.
Organic/Inorganic Superabsorbent Hydrogels Based on Xylan and Montmorillonite
Authors: Zhang Shuang , Guan Ying , Fu Gen-Que , Chen Bo-Yang , Peng Feng , Yao Chun-Li , Sun Run-Cang
Published: February 2014

The unique organic/inorganic superabsorbent hydrogels based on xylan and inorganic clay montmorillonite (MMT) were prepared via grafting copolymerization of acrylic acid (AA) and 2‐acrylamido‐2‐methylpropanesulfonic acid (AMPS) with N,N‐methylenebisacrylamide (MBA) as a cross‐linking agent and potassium persulfate (KPS) as an initiator. The effect of variables on the swelling capacity of the hydrogels, such as the weight ratios of MMT/xylan, MBA/xylan, and AMPS/AA, was systematically optimized. The results indicated that the superabsorbent hydrogels comprised a porous cross‐linking structure of MMT and xylan with side chains that carry carboxylate, carboxamide, and sulfate. The hydrogels exhibit the high compressive modulus (E), about 35–55 KPa, and the compression strength of the hydrogels increased with an increment of the MMT content. The effect of various cationic salt solutions (LiCl, CaCl2, and FeCl3) on the swelling has the following order: Li+ > Ca2+ > Fe3+. Furthermore, the influence of pH values on swelling behaviors showed that the superabsorbent composites retained around 1000 g g−1 over a wide pH range of 6.0–10.0. The xylan‐based hydrogels with the high mechanical and swelling properties are promising for the applications in the biomaterials area.
Current Neonatal Resuscitation Practices among Paediatricians in Gujarat, India
Authors: Bansal Satvik C. , Nimbalkar Archana S. , Patel Dipen V. , Sethi Ankur R. , Phatak Ajay G. , Nimbalkar Somashekhar M.
Published: February 2014

Aim. We assessed neonatal resuscitation practices among paediatricians in Gujarat.Methods. Cross-sectional survey of 23 questions based on guidelines of Neonatal Resuscitation Program (NRP) and Navjaat Shishu Suraksha Karyakram (NSSK) was conducted using web-based tool. Questionnaire was developed and consensually validated by three neonatologists.Results. Total of 142 (21.2%) of 669 paediatricians of Gujarat, India, whose e-mail addresses were available, attempted the survey and, from them, 126 were eligible. Of these, 74 (58.7%) were trained in neonatal resuscitation. Neonatal Intensive Care Unit with mechanical ventilation facilities was available for 54% of respondents. Eighty-eight (69.8%) reported correct knowledge and practice regarding effective bag and mask ventilation (BMV) and chest compressions. Knowledge and practice about continuous positive airway pressure use in delivery room were reported in 18.3% and 30.2% reported use of room air for BMV during resuscitation. Suctioning oral cavity before delivery in meconium stained liquor was reported by 27.8% and 38.1% cut the cord after a minute of birth. Paediatricians with NRP training used appropriate method of tracheal suction in cases of nonvigorous newborns than those who were not trained.Conclusions. Contemporary knowledge about neonatal resuscitative practices in paediatricians is lacking and requires improvement. Web-based tools provided low response in this survey.
Acute Liver Failure Secondary to Niacin Toxicity
Authors: Ellsworth Marc A. , Anderson Katelyn R. , Hall David J. , Freese Deborah K. , Lloyd Robin M.
Published: February 2014

A 17-year-old male was transferred to the pediatric intensive care unit for evaluation of acute liver failure. He was recently released from an alcohol treatment center with acute onset of chest pain. Cardiac workup was negative but he was found to have abnormal coagulation studies and elevated liver transaminases. Other evaluations included a normal toxicology screen and negative acetaminophen level. Autoimmune and infectious workups were normal providing no identifiable cause of his acute liver failure. He initially denied any ingestions or illicit drug use but on further query he admitted taking niacin in an attempt to obscure the results of an upcoming drug test. Niacin has been touted on the Internet as an aid to help pass urine drug tests though there is no evidence to support this practice. Niacin toxicity has been associated with serious multisystem organ failure and fulminant hepatic failure requiring liver transplantation. Pediatric providers should be aware of the risks associated with niacin toxicity and other experimental medical therapies that may be described on the Internet or other nonreputable sources.
A Spinal Arteriovenous Fistula in a 3-Year Old Boy
Authors: Crijnen Thomas E. M. , van Gijlswijk Sandra , De Dooy Jozef , Voormolen Maurits H. J. , Robert Dominique , Jorens Philippe G. , Ramet Jose
Published: February 2014

We present a case of a 3-year-old boy with neurodegeneration. Family history reveals Rendu-Osler-Weber disease. Magnetic resonance imaging (MRI) of the spinal cord and spinal angiography showed a spinal arteriovenous fistula with venous aneurysm, causing compression of the lumbar spinal cord. Embolisation of the fistula was executed, resulting in clinical improvement. A week after discharge he was readmitted with neurologic regression. A second MRI scan revealed an intraspinal epidural haematoma and increase in size of the aneurysm with several new arterial feeders leading to it. Coiling of the aneurysm and fistulas was performed. Postoperative, the spinal oedema increased despite corticoids, causing more extensive paraplegia of the lower limbs and a deterioration of his mental state. A laminectomy was performed and the aneurysm was surgically removed. Subsequently, the boy recovered gradually. A new MRI scan after two months showed less oedema and a split, partly affected spinal chord. This case shows the importance of excluding possible arteriovenous malformations in a child presenting with progressive neurodegeneration. In particular when there is a family history for Rendu-Osler-Weber disease, scans should be performed instantly to rule out this possibility. The case also highlights the possibility of good recovery of paraplegia in paediatric Rendu-Osler-Weber patients.
Translation, Creation and Annihilation of Poles and Zeros with the Biernacki and Ruscheweyh Operators, Acting on Meijer's G-Functions
Authors: Pishkoo Amir , Darus Maslina
Published: February 2014

Meijer's G-functions are studied by the Biernacki and Ruscheweyh operators. These operators are special cases of the Erdélyi-Kober operators (for m=1). The effect of operators on Meijer's G-functions can be shown as the change in the distribution of poles and zeros on the complex plane. These poles and zeros belong to the integrand, a ratio of gamma functions, defining the Meijer's G-function. Displacement in position and increasing or decreasing in number of poles and zeroes are expressed by the transporter, creator, and annihilator operators. With special glance, three basic univalent Meijer's G-functions, Koebe, and convex functions are considered.
An Exploration of the Range of Noise Intensity That Affects the Membrane Potential of Neurons
Authors: Wang Rubin , Wang Guanzheng , Zheng Jinchao
Published: February 2014

Neuronal activity in the human brain occurs in a complex physiologic environment, and noise from all aspects in this physiologic environment affects all aspects of nervous-system function. An essential issue of neural information processing is whether the environmental noise in a neural system can be estimated and quantified in a proper way. In this paper, we calculated the neural energy to estimate the range of critical values of thermal noise intensity that markedly affect the membrane potential and the energy waveform, in order to define such a noisy environment which neuronal activity relies on.
A Rare Tumor in a Patient with Hepatic Hydatic Cyst: Adrenal Hepatoid Adenocarcinoma
Authors: Malya Fatma Umit , Bozkurt Suleyman , Hasbahceci Mustafa , Cipe Gokhan , Ahmad Issam Cheikh , Gucin Zuhal , Karatepe Oguzhan , Muslumanoglu Mahmut
Published: February 2014

Hepatoid adenocarcinoma (HAC) is a very rare type of extrahepatic adenocarcinoma which has a clinicopathologic and morphologic similarity to hepatocellular carcinoma (HCC). Although it is not common, it can be seen in organs other than the liver. The correct diagnosis can be a challenge because of its clinically similarity to HCC and the diagnosis is usually achieved by pathological examination following the surgery. We present a 48-year-old woman who was following with the diagnosis of stage 5 hepatic hydatic cyst. In her routine blood examinations, her alpha feta protein level was found higher than normal and her abdominal computed tomography and magnetic resonance findings did not reveal any pathological findings rather than hepatic hydatic cysts. There was a high activity of FDG on PET CT in the hepatic region so we performed a right lateral hepatectomy to the patient and final pathology was adrenal hepatoid adenocarcinoma. In this paper we aimed to present a rare case of hepatoid carcinoma of the adrenal gland.
An Overview of Systematic Reviews of Shenmai Injection for Healthcare
Authors: Lu Ling-yan , Zheng Guo-qing , Wang Yan
Published: February 2014

Shenmai injection (SMI) is widely applied in clinical practice as an organ protector. This overview is to evaluate the current evidence from systematic reviews (SRs) of SMI for healthcare. The literature searches were carried out in 6 databases without language restrictions until December 2012. The quality of the primary studies from the respective SRs was evaluated by using Jadad score. The overview quality assessment questionnaire (OQAQ) was used to evaluate the methodological quality of all included SRs. Twenty eligible SRs were identified. They reported a wide range of conditions, including SMI for cardio/cerebrovascular diseases, viral myocarditis, tumor chemotherapy, and adverse drug reactions. Most of the primary studies were of good quality only in 1 SR of non‐small‐cell lung cancer. According to the OQAQ scores, the quality of included SRs was variable and six reviews were of high quality with a score of 5 points. Two SRs showed that SMI had low adverse drug reaction occurrence. In conclusion, there is mixed evidence to support efficacy of SMI for an adjunct therapy to tumor chemotherapy and premature evidence for the use of SMI for cardio/cerebrovascular disorders and viral myocarditis. SMI seems generally safe for clinical application. Further large sample‐size and well‐designed RCTs are needed.
Detection of Abnormal Item Based on Time Intervals for Recommender Systems
Authors: Gao Min , Yuan Quan , Ling Bin , Xiong Qingyu
Published: February 2014

With the rapid development of e-business, personalized recommendation has become core competence for enterprises to gain profits and improve customer satisfaction. Although collaborative filtering is the most successful approach for building a recommender system, it suffers from “shilling” attacks. In recent years, the research on shilling attacks has been greatly improved. However, the approaches suffer from serious problem in attack model dependency and high computational cost. To solve the problem, an approach for the detection of abnormal item is proposed in this paper. In the paper, two common features of all attack models are analyzed at first. A revised bottom-up discretized approach is then proposed based on time intervals and the features for the detection. The distributions of ratings in different time intervals are compared to detect anomaly based on the calculation ofchisquare distribution (χ2). We evaluated our approach on four types of items which are defined according to the life cycles of these items. The experimental results show that the proposed approach achieves a high detection rate with low computational cost when the number of attack profiles is more than 15. It improves the efficiency in shilling attacks detection by narrowing down the suspicious users.
Learning Curves of Macintosh Laryngoscope in Nurse Anesthetist Trainees Using Cumulative Sum Method
Authors: Rujirojindakul Panthila , McNeil Edward , Rueangchira-urai Rongrong , Siripunt Niranuch
Published: February 2014

Background. Tracheal intubation is a potentially life-saving procedure. This skill is taught to many anesthetic healthcare professionals, including nurse anesthetists. Our goal was to evaluate the learning ability of nurse anesthetist trainees in their performance of orotracheal intubation with the Macintosh laryngoscope.Methods. Eleven nurse anesthetist trainees were enrolled in the study during the first three months of their training. All trainees attended formal lectures and practice sessions with manikins at least one time on performing successful tracheal intubation under supervision of anesthesiology staff. Learning curves for each nurse anesthetist trainee were constructed with the standard cumulative summation (cusum) methods.Results. Tracheal intubation was attempted on 388 patients. Three hundred and six patients (78.9%) were successfully intubated on the trainees’ first attempt and 17 patients (4.4%) on the second attempt. The mean±SD number of orotracheal intubations per trainee was35.5 ± 5.1(range 30–47). Ten (90.9%) of 11 trainees crossed the 20% acceptable failure rate line. A median of 22 procedures was required to achieve an 80% orotracheal intubations success rate.Conclusion. At least 22 procedures were required to reach an 80% success rate for orotracheal intubation using Macintosh laryngoscope in nonexperienced nurse anesthetist trainees.
Prevalence of Dental Caries in relation to Body Mass Index, Daily Sugar Intake, and Oral Hygiene Status in 12-Year-Old School Children in Mathura City: A Pilot Study
Authors: Gupta Prahlad , Gupta Nidhi , Singh Harkanwal Preet
Published: February 2014

Aim. To correlate the prevalence of dental caries to body mass index, daily sugar intake, and oral hygiene status of 12-year-old school children of Mathura city.Material and Methods. The study design was cross-sectional and included 100 school children aged 12 years (n=50boys andn=50girls) who were randomly selected from two schools based upon inclusion and exclusion criteria. Body weight/height was recorded and BMI was calculated and plotted on CDC-BMI for age growth charts/curves for boys and girls to obtain percentile ranking. Dental caries was recorded using WHO criteria. Oral hygiene status of the study subjects was assessed using oral hygiene index-simplified. Data regarding the daily sugar intake was recorded using 24-hour recall diet frequency chart. The data obtained was analysed using SPSS version 11.5 for windows.Result. Only 27 subjects were affected by caries. The mean DMFT/dmft was 0.37 ± 0.79 and 0.12 ± 0.60, respectively. Statistical analysis by means of a logistic regression model revealed that only oral hygiene status had a significant effect on caries prevalence (OR = 5.061,P=0.004), whereas daily sugar intake and body mass index had no significant effect.Conclusion. From the analysis, it was concluded that oral hygiene status had a significant effect on caries prevalence of 12-year-old school children of Mathura city.
Resistin: A Potential Biomarker for Periodontitis Influenced Diabetes Mellitus and Diabetes Induced Periodontitis
Authors: Devanoorkar Archana , Kathariya Rahul , Guttiganur Nagappa , Gopalakrishnan D. , Bagchi Paulami
Published: February 2014

Biomarkers are highly specific and sensitive indicators of disease activity. Resistin is a recently discovered adipocytokine, having a potent biomarker quality. Initially resistin was thought to be produced by adipocytes alone; however, emerging evidence suggests that it is also produced in abundance by various cells of the immunoinflammatory system, indicating its role in various chronic inflammatory diseases. Data suggests that resistin plays a role in obesity, insulin resistance, cardiovascular diseases, and periodontitis. Resistin derived its name from the original observation that it induced insulin resistance (resist-in: resist insulin) in mice and is downregulated in mature murine adipocytes cultured in the presence of insulin sensitizing drugs like thiazolidinediones. It is well recognized that obesity, is associated with insulin resistance and diabetes. A three-way relationship has been established between diabetes, obesity and periodontitis. Recent evidence also suggests an association between obesity and increased risk for periodontitis. Our previous research showed incremental elevation of resistin with periodontal disease activity and a reduced level of resistin, after periodontal therapy. Thus resistin would be one of the molecular links connecting obesity, periodontitis, and diabetes and may serve as a marker that links periodontal disease with other systemic diseases. A Medline/PubMed search was carried out for keywords “Diabetes Mellitus,” “Periodontitis,” and “Resistin,” and all relevant research papers from 1990 in English were shortlisted and finalized based on their importance. This review provides an insight into the biological action of resistin and its possible role in periodontitis influenced diabetes mellitus and diabetes induced periodontitis.
NonfragileH∞Control for Stochastic Systems with Markovian Jumping Parameters and Random Packet Losses
Authors: Wang Jing , Zhang Ke
Published: February 2014

This paper is concerned with the nonfragileH∞control problem for stochastic systems with Markovian jumping parameters and random packet losses. The communication between the physical plant and controller is assumed to be imperfect, where random packet losses phenomenon occurs in a random way. Such a phenomenon is represented by a stochastic variable satisfying the Bernoulli distribution. The purpose is to design a nonfragile controller such that the resulting closed-loop system is stochastically mean square stable with a guaranteedH∞performance levelγ. By using the Lyapunov function approach, some sufficient conditions for the solvability of the previous problem are proposed in terms of linear matrix inequalities (LMIs), and a corresponding explicit parametrization of the desired controller is given. Finally, an example illustrating the effectiveness of the proposed approach is presented.
Improved Robust Stability Criterion of Networked Control Systems with Transmission Delays and Packet Loss
Authors: Xiao Shenping , Wang Liyan , Zeng Hongbing , Cheng Wubin
Published: February 2014

The problem of stability analysis for a class of networked control systems (NCSs) with network-induced delay and packet dropout is investigated in this paper. Based on the working mechanism of zero-order holder, the closed-loop NCS is modeled as a continuous-time linear system with input delay. By introducing a novel Lyapunov-Krasovskii functional which splits both the lower and upper bounds of the delay into two subintervals, respectively, and utilizes reciprocally convex combination technique, a new stability criterion is derived in terms of linear matrix inequalities. Compared with previous results in the literature, the obtained stability criterion is less conservative. Numerical examples demonstrate the validity and feasibility of the proposed method.
Numerical Investigation of Pressure Fluctuation in Centrifugal Pump Volute Based on SAS Model and Experimental Validation
Authors: Si Qiaorui , Yuan Jianping , Yuan Shouqi , Wang Wenjie , Zhu Lei , Bois Gérard
Published: February 2014

This paper presents an investigation of pressure fluctuation of a single-suction volute-type centrifugal pump, particularly volute casing, by using numerical and experimental methods. A new type of hybrid Reynolds-averaged Navier-Stokes/Large Eddy Simulation, referred to as the shear stress transport-scale-adaptive simulation (SAS) model, is employed to study the unsteady flow. Statistical analysis method is adopted to show the pressure fluctuation intensity distribution in the volute channel. A test rig for pressure pulsation measurement is built to validate the numerical simulation results using eight transient pressure sensors in the middle section of the volute wall. Results show that the SAS model can accurately predict the inner flow field of centrifugal pumps. Radial force acting on the impeller presents a star distribution related to the blade number. Pressure fluctuation intensity is strongest near the tongue and shows irregular distribution in the pump casing. Pressure fluctuation is distributed symmetrically at the cross-section of the volute casing because the volute can eliminate the rotational movement of the liquid discharged from the impeller. Blade passing frequency and its multiples indicate the dominant frequency of the monitoring points within the volute, and the low-frequency pulsation, particularly in the shaft component, increases when it operates at off-design condition, particularly with a small flow rate. The reason is that the vortex wave is enhanced at the off-design condition, which has an effect on the axle and is presented in the shaft component in the frequency domain.
Vaccine-Mediated Immunotherapy Directed against a Transcription Factor Driving the Metastatic Process
Authors: Ardiani Andressa , Gameiro Sofia R. , Palena Claudia , Hamilton Duane H. , Kwilas Anna , King Thomas H. , Schlom Jeffrey , Hodge James W.
Published: February 2014

Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid tumor progression, metastasis, and drug resistance. Several transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many carcinomas and other tumor types. The role of Twist in experimental cancer metastases has been principally studied in the 4T1 mammary tumor model, where silencing of Twist in vitro has been shown to greatly reduce in vivo metastatic spread. Transcription factors such as Twist are generally believed to be “undruggable” because of their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to drug therapy targeting transcription factors driving the metastatic process is T-cell–mediated immunotherapy. A therapeutic vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing tumor-associated antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire Twist protein, which is capable of inducing both CD8+ and CD4+ Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1 tumors and had an even greater antitumor effect on lung metastases of the same mice, which was dependent on Twist-specific CD8+ T cells. These studies provide the rationale for vaccine-induced T-cell–mediated therapy of transcription factors involved in driving the metastatic process. Cancer Res; 74(7); 1945–57. ©2014 AACR.
Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids
Authors: Perrino Elena , Steiner Martina , Krall Nikolaus , Bernardes Gonçalo J.L. , Pretto Francesca , Casi Giulio , Neri Dario
Published: February 2014

It is generally thought that the anticancer efficacy of antibody–drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569–78. ©2014 AACR.
Tumor-Infiltrating Myeloid Cells Activate Dll4/Notch/TGF-β Signaling to Drive Malignant Progression
Authors: Ohnuki Hidetaka , Jiang Kan , Wang Dunrui , Salvucci Ombretta , Kwak Hyeongil , Sánchez-Martín David , Maric Dragan , Tosato Giovanna
Published: February 2014

Myeloid cells that orchestrate malignant progression in the tumor microenvironment offer targets for a generalized strategy to attack solid tumors. Through an analysis of tumor microenvironments, we explored an experimental model of lung cancer that uncovered a network of Dll4/Notch/TGF-β1 signals that links myeloid cells to cancer progression. Myeloid cells attracted to the tumor microenvironment by the tumor-derived cytokines CCL2 and M-CSF expressed increased levels of the Notch ligand Dll4, thereby activating Notch signaling in the tumor cells and amplifying tumor-intrinsic Notch activation. Heightened Dll4/Notch signaling in tumor cells magnified TGF-β–induced pSMAD2/3 signaling and was required to sustain TGF-β–induced tumor cell growth. Conversely, Notch blockade reduced TGF-β signaling and limited lung carcinoma tumor progression. Corroborating these findings, by interrogating RNAseq results from tumor and adjacent normal tissue in clinical specimens of human head and neck squamous carcinoma, we found evidence that TGF-β/Notch crosstalk contributed to progression. In summary, the myeloid cell-carcinoma signaling network we describe uncovers novel mechanistic links between the tumor microenvironment and tumor growth, highlighting new opportunities to target tumors where this network is active. Cancer Res; 74(7); 2038–49. ©2014 AACR.
Phase I Trial of a Bivalent Gangliosides Vaccine in Combination with β-Glucan for High-Risk Neuroblastoma in Second or Later Remission
Authors: Kushner Brian H. , Cheung Irene Y. , Modak Shakeel , Kramer Kim , Ragupathi Govind , Cheung Nai-Kong V.
Published: February 2014

Purpose: To report on a phase I trial designed to find the maximally tolerated dose in children of the immunologic adjuvant OPT-821 in a vaccine containing neuroblastoma-associated antigens (GD2 and GD3; Clinicaltrials.gov NCT00911560). Secondary objectives were to obtain preliminary data on immune response and activity against minimal residual disease (MRD). Treatment also included the immunostimulant β-glucan.

Experimental Design: Patients with neuroblastoma in ≥2nd complete/very good partial remission received vaccine subcutaneously (weeks 1–2–3–8–20–32–52). Vaccine contained 30 μg each of GD2 and GD3 stabilized as lactones and conjugated to the immunologic carrier protein keyhole limpet hemocyanin; and OPT-821, which was dose escalated as 50, 75, 100, and 150 μg/m2 per injection. Oral β-glucan (40 mg/kg/day, 14 days on/14 days off) started week 6.

Results: The study was completed with 15 patients because there was no dose-limiting toxicity at 150 μg/m2 of OPT-821 (the dosing used in adults). Thirteen of fifteen patients received the entire protocol treatment, including 12 who remain relapse-free at 24+ to 39+ (median 32+) months and 1 who relapsed (single node) at 21 months. Relapse-free survival was 80% ± 10% at 24 months. Vaccine and β-glucan were well tolerated. Twelve of fifteen patients had antibody responses against GD2 and/or GD3. Disappearance of MRD was documented in 6 of 10 patients assessable for response.

Conclusions: This immunotherapy program lacks major toxicity and is transportable to any outpatient clinic. Patient outcome is encouraging but the efficacy is uncertain because of the complexity and heterogeneity of prior therapies. A larger phase II trial is underway. Clin Cancer Res; 20(5); 1375–82. ©2014 AACR.
Beneficial Effects of RAF Inhibitor in Mutant BRAF Splice Variant–Expressing Melanoma
Authors: Hartsough Edward J. , Basile Kevin J. , Aplin Andrew E.
Published: February 2014

Resistance to RAF inhibitors such as vemurafenib and dabrafenib is a major clinical problem in the treatment of melanoma. Patients with mutant BRAF melanoma that progress on RAF inhibitors have limited treatment options, and drug removal from resistant tumors may elicit multiple effects. A frequent mechanism of resistance to RAF inhibitors is caused by expression of mutant BRAF splice variants. RAF inhibitor–resistant cell lines, generated in vivo, were tested as to whether or not mutant BRAF splice variants confer a fitness advantage in the presence of RAF inhibitor. Critically, cells expressing distinct mutant BRAF splice variants grow more efficiently in vitro and in vivo in the presence of the vemurafenib analog, PLX4720, compared with in the absence of inhibitor. PLX4720-treated BRAF splice variant–expressing cells exhibited levels of phospho-extracellular signal–regulated kinase (ERK)1/2 comparable to untreated parental cells. In addition, a reduction in phospho-ERK1/2 levels following treatment with the MEK inhibitor, trametinib (GSK1120212) phenocopied the fitness benefit provided by PLX4720. These data indicate that mutant BRAF splice variant–expressing melanoma cells are benefited by defined concentrations of RAF inhibitors.

Implications: This study provides evidence that RAF inhibitor–resistant melanoma cells benefit from continued therapy. Mol Cancer Res; 12(5); 795–802. ©2014 AACR.
Pubertal Bisphenol A Exposure Alters Murine Mammary Stem Cell Function Leading to Early Neoplasia in Regenerated Glands
Authors: Wang Danhan , Gao Hui , Bandyopadhyay Abhik , Wu Anqi , Yeh I-Tien , Chen Yidong , Zou Yi , Huang Changjiang , Walter Christi A. , Dong Qiaoxiang , Sun Lu-Zhe
Published: February 2014

Perinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell–mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. Cancer Prev Res; 7(4); 445–55. ©2014 AACR.
Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment
Authors: Yue Wen , Yang Chung S. , DiPaola Robert S. , Tan Xiang-Lin
Published: February 2014

Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. Cancer Prev Res; 7(4); 388–97. ©2014 AACR.
Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade
Authors: da Silva Ines Pires , Gallois Anne , Jimenez-Baranda Sonia , Khan Shaukat , Anderson Ana C. , Kuchroo Vijay K. , Osman Iman , Bhardwaj Nina
Published: February 2014

The immunoregulatory protein T-cell immunoglobulin- and mucin-domain–containing molecule-3 (Tim-3) mediates T-cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases, including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, the role of Tim-3 in modulating the function of these innate effector cells remains unclear, particularly in human diseases. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted, and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels were correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK-cell exhaustion marker in advanced melanoma and support the development of Tim-3–targeted therapies to restore antitumor immunity. Cancer Immunol Res; 2(5); 410–22. ©2014 AACR.
Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes
Authors: Jeanbart Laura , Ballester Marie , de Titta Alexandre , Corthésy Patricia , Romero Pedro , Hubbell Jeffrey A. , Swartz Melody A.
Published: February 2014

The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in non–tumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8+ T-cell responses, both locally and systemically, than non–tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436–47. ©2014 AACR.
Effects of Sex on the Incidence of Cardiac Tamponade After Catheter Ablation of Atrial Fibrillation
Authors: Michowitz Yoav , Rahkovich Michael , Oral Hakan , Zado Erica S. , Tilz Roland , John Silke , Denis Arnaud , Di Biase Luigi , Winkle Roger A. , Mikhaylov Evgeny N. , Ruskin Jeremy N. , Yao Yan , Josephson Mark E. , Tanner Hildegard , Miller John M. , Champagne Jean , Della Bella Paolo , Kumagai Koichiro , Defaye Pascal , Luria David , Lebedev Dmitry S. , Natale Andrea , Jais Pierre , Hindricks Gerhard , Kuck Karl-Heinz , Marchlinski Francis E. , Morady Fred , Belhassen Bernard
Published: February 2014

Background—

Cardiac tamponade is the most dramatic complication observed during atrial fibrillation (AF) ablation and the leading cause of procedure-related mortality. Female sex is a known risk factor for complications during AF ablation; however, it is unknown whether women have a higher risk of tamponade.

Methods and Results—

A systematic Medline search was used to locate academic electrophysiological centers that reported cases of tamponade occurring during AF ablation. Centers were asked to provide information on cases of acute tamponade according to sex and their mode of management including any case of related mortality. Nineteen electrophysiological centers provided information on 34 943 ablation procedures involving 25 261 (72%) men. Overall, 289 (0.9%) cases of tamponade were reported: 120 (1.24%) in women and 169 (0.67%) in men (odds ratio, 1.83;
P
<0.001). There was a reciprocal association between center volume and the occurrence of tamponade with substantially lower risk in high-volume centers. Most cases of tamponade occurred during catheter manipulation or ablation; women tended to develop more tamponades during transseptal catheterization. No sex difference in the mode of management was observed. However, 16% cases of tamponade required surgery with lower rates in high-volume centers. Three cases of tamponade (1%) culminated in death.

Conclusions—

Tamponade during AF ablation procedures is relatively rare. Women have an ≈2-fold higher risk for developing this complication. The risk of tamponade among women decreases substantially in high-volume centers. Surgical backup and acute management skills for treating tamponade are important in centers performing AF ablation.
Usefulness of N-Terminal Pro–B-Type Natriuretic Peptide Levels for Stroke Risk Prediction in Anticoagulated Patients With Atrial Fibrillation
Authors: Roldán Vanessa , Vílchez Juan Antonio , Manzano-Fernández Sergio , Jover Eva , Gálvez Josefa , Puche Carmen M. , Valdés Mariano , Vicente Vicente , Lip Gregory Y.H. , Marín Francisco
Published: February 2014

Background and Purpose—

Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF.

Methods—

We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0–3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves.

Results—

Median levels (interquartile range) of NT-proBNP were 610 (318–1037) pg/mL. Median follow-up was 1007 (806–1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71;
P
=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85;
P
=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66;
P
=0.006). No association with bleeding was found (
P
=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age≥75 (doubled), Diabetes mellitus, Stroke (doubled)–Vascular disease and Sex category (female); CHA
2
DS
2
–VASc score for predicting embolic events (relative IDI, 2.8%;
P
=0.001) and all-cause death (relative IDI, 1.8%;
P
=0.001).

Conclusions—

In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA
2
DS
2
–VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.