bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis
Authors: Liu Rui , Han Cheng , Wu Di , Xia Xinghai , Gu Jianqiu , Guan Haixia , Shan Zhongyan , Teng Weiping
Published: November 2015

We systematically identified the prevalence of hyperuricemia and gout in mainland China and provided informative data that can be used to create appropriate local public health policies. Relevant articles from 2000 to 2014 were identified by searching 5 electronic databases: PubMed, Google Scholar, Chinese Wanfang, CNKI, and Chongqing VIP. All of the calculations were performed using the Stata 11.0 and SPSS 20.0 software. The eligible articles (n=36; 3 in English and 33 in Chinese) included 44 studies (38 regarding hyperuricemia and 6 regarding gout). The pooled prevalence of hyperuricemia and gout was 13.3% (95% CI: 11.9%, 14.6%) and 1.1% (95% CI: 0.7%, 1.5%), respectively. Although publication bias was observed, the results did not change after a trim and fill test, indicating that that impact of this bias was likely insignificant. The prevalence of hyperuricemia and gout was high in mainland China. The subgroup analysis suggested that the geographical region, whether the residents dwell in urban or rural and coastal or inland areas, the economic level, and sex may be associated with prevalence.
System Behaviour Charts Inform an Understanding of Biodiversity Recovery
Authors: Black Simon A.
Published: November 2015

Practitioners working with species and ecosystem recovery typically deal with the complexity of, on one hand, lack of data or data uncertainties and, on the other hand, demand for critical decision-making and intervention. The control chart methods of commercial and industrial and environmental monitoring can complement an ecological understanding of wildlife systems including those situations which incorporate human activities and land use. Systems Behaviour Charts are based upon well-established control chart methods to provide conservation managers with an approach to using existing data and enable insight to aid timely planning of conservation interventions and also complement and stimulate research into wider scientific and ecological questions. When the approach is applied to existing data sets in well-known wildlife conservation cases, the subsequent Systems Behaviour Charts and associated analytical criteria demonstrate insights which would be helpful in averting problems associated with each case example.
Changes of Plantar Pressure and Gait Parameters in Children with Mild Cerebral Palsy Who Used a Customized External Strap Orthosis: A Crossover Study
Authors: Chang Wen-Dien , Chang Nai-Jen , Lin Hung-Yu , Lai Ping-Tung
Published: November 2015

Toe-in gait and crouch gait can make children with mild cerebral palsy fall and suffer improper balance during walking or ambulation training. A customized external strap orthosis for correcting leg alignment was used to resolve this problem. The purpose of this study was to research the immediate effects while wearing the customized external strap orthosis. Pressure platform was used to assess the plantar pressure through static and dynamic assessments and to record the changes in path of pressure trajectory. Motion image analysis system was used to record the gait parameters, which included gait speed, stride length, and cadence. The influence of both wearing and removing the orthosis on the dominant leg of children with mild cerebral palsy was analyzed. Nine children with mild cerebral palsy, who all had a dominant right leg, were recruited. After wearing the orthosis, all gait parameters improved, and foot motion changed in the stance phase of the gait cycle. The path of pressure trajectory closing to the midline was also observed during dynamic assessment. Changes in plantar pressure and path of pressure trajectory were observed and the orthosis device could provide immediate assistance to correct the leg alignment and improve the gait performance in children with mild cerebral palsy.
Probing Mixing of Photons and Axion-Like Particles by Geometric Phase
Authors: Capolupo A. , Lambiase G. , Vitiello G.
Published: November 2015

We find that a geometric phase characterizes the phenomenon of mixing of photons with axion-like particles (ALPs). The laboratory observation of such a phase may provide a novel tool able to detect such a mixing phenomenon. We show that the geometric phase is dependent on the axion-like particle mass and coupling constant. We discuss an interferometric experiment able to detect the geometric phase associated with the ALPs-photon mixing.
The Effect of Therapeutic Blockades of Dust Particles‐Induced Ca2+ Signaling and Proinflammatory Cytokine IL‐8 in Human Bronchial Epithelial Cells
Authors: Yoon Ju Hee , Jeong Sung Hwan , Hong Jeong Hee
Published: November 2015

Bronchial epithelial cells are the first barrier of defense against respiratory pathogens. Dust particles as extracellular stimuli are associated with inflammatory reactions after inhalation. It has been reported that dust particles induce intracellular Ca2+ signal, which subsequently increases cytokines production such as interleukin‐ (IL‐) 8. However, the study of therapeutic blockades of Ca2+ signaling induced by dust particles in human bronchial epithelial cells is poorly understood. We investigated how to modulate dust particles‐induced Ca2+ signaling and proinflammatory cytokine IL‐8 expression. Bronchial epithelial BEAS‐2B cells were exposed to PM10 dust particles and subsequent mediated intracellular Ca2+ signaling and reactive oxygen species signal. Our results show that exposure to several inhibitors of Ca2+ pathway attenuated the PM10‐induced Ca2+ response and subsequent IL‐8 mRNA expression. PM10‐mediated Ca2+ signal and IL‐8 expression were attenuated by several pharmacological blockades such as antioxidants, IP3‐PLC blockers, and TRPM2 inhibitors. Our results show that blockades of PLC or TRPM2 reduced both of PM10‐mediated Ca2+ signal and IL‐8 expression, suggesting that treatment with these blockades should be considered for potential therapeutic trials in pulmonary epithelium for inflammation caused by environmental events such as seasonal dust storm.
Bilateral Malrotation and a Congenital Pelvic Kidney with Varied Vasculature and Altered Hilar Anatomy
Authors: Singh J. , Singh N. , Kapoor K. , Sharma M.
Published: November 2015

Variations of structure and position of the kidney along with variations of renal vessels are most frequently reported. Rotational variations form a rare entity that are not cited in most embryology textbooks. During an educational cadaveric dissection of a 42-year-old male, a complex picture of bilateral anatomical variants was encountered. Malrotation of both kidneys and a left lobulated ectopic kidney along with open hilum was observed. The left kidney showed a pelvic position in front of sacral promontory with three renal arteries retaining its embryological aortoiliac branches and two renal veins draining into right common iliac vein. These variations have an embryological base. Pelvic kidney with rotational variation though comparatively rare assumes great importance in view of present-day surgical procedures like laparoscopic radical nephrectomy, percutaneous nephrectomy, and renal transplantation.
2-Mercaptobenzimidazole, 2-Mercaptobenzothiazole, and Thioglycolic Acid in an Electroless Nickel-Plating Bath
Authors: Gezerman Ahmet Ozan , Çorbacıoğlu Burcu Didem
Published: November 2015

The use of three different materials, 2-mercaptobenzimidazole, 2-mercaptobenzothiazole, and thioglycolic acid, was investigated to improve the performance of electroless nickel-plating baths. By changing the concentrations of these materials, sample plates were coated. Optical microscope images were obtained by selecting representative coated plates. From the results of the investigations, the effects of these materials on electroless nickel plating were observed, and the most appropriate amounts of these materials for nickel plating were determined. Moreover, the nickel plating speed observed with the bath solution containing 2-mercaptobenzimidazole, 2-mercaptobenzothiazole, and thioglycolic acid is higher than that in the case of traditional electroless plating baths, but the nickel consumption amount in the former case is lower. In order to minimize the waste water generated from electroless nickel-plating baths, we determined the lowest amounts of the chemicals that can be used for the concentrations reported in the literature.
Sub-Millimeter-Wave 10 dB Directional Coupler Based on Micromachining Technique
Authors: Liu Shuang , Hu Jiang , Zhang Yong , Liu Yupeng , Ren Tianhao , Xu Ruimin , Xue Quan
Published: November 2015

A waveguide 10 dB directional coupler operating from 325 GHz to 400 GHz is designed based on the short-slot Riblet-type coupling configuration and fabricated using the deep reactive ion etching (DRIE) silicon micromachining technique. The skin depth and the conductivity of the gold film with the roughness of 0.2 μm are investigated at 300~1000 GHz frequency band for the higher accuracy. In order to measure the small-size four-port coupler using the two-port VNA with big-size flanges, three testing topologies are designed, in which the terahertz (THz) wedged-type absorbing material terminals are adopted as the waveguide matching loads. The measured average insertion loss is 0.5 dB after deducting the intrinsic loss and the measured average isolation is better than 25 dB, which are in good agreement with simulations. The analysis and the design are verified to be accurate and valuable for the high-performance sub-millimeter-wave waveguide components.
Amyand’s Hernia with Appendicitis: A Case Report and Integrative Review
Authors: Feitosa Cavalcante Jéssica , Melo Teixeira Batista Hermes , Cavalcante Pita Neto Ivo , Fernandes Frutuoso Jairo , Rodrigues Pinheiro Woneska , Maria Pinheiro Bezerra Italla , de Abreu Luiz Carlos , de Menezes Silveira Gylmara Bezerra
Published: November 2015

Introduction.Inguinal hernia is a common disorder with an estimated prevalence of 1.2% of the entire population and it is 12 times more common in males.Objective.To describe a case of appendix with signs of inflammation in the hernia sac, condition that is rare and difficult to diagnose, and to perform literature review, describing the most relevant aspects and the main controversies.Method.Report of a case and search in PubMed on June 1, 2015, using the terms “Appendix” [MeSH term] AND “hernia, inguinal” [MeSH term].Results.The search resulted in 38 articles in total, and after deleting the articles that were not part of the inclusion criteria, there were 26 case reports remaining.Discussion.The search resulted in a total of 38 articles and after deleting the articles that were not part of the inclusion criteria, there were 26 case reports remaining.Conclusion.Amyand’s hernia is a rare and difficult to diagnose condition, being commonly found occasionally in surgical procedures. It should be remembered in the presence of cases of incarcerated hernia, due to its possible complications if not diagnosed.
Improved Pre-miRNA Classification by Reducing the Effect of Class Imbalance
Authors: Zhong Yingli , Xuan Ping , Han Ke , Zhang Weiping , Li Jianzhong
Published: November 2015

MicroRNAs (miRNAs) play important roles in the diverse biological processes of animals and plants. Although the prediction methods based on machine learning can identify nonhomologous and species-specific miRNAs, they suffered from severe class imbalance on real and pseudo pre-miRNAs. We propose a pre-miRNA classification method based on cost-sensitive ensemble learning and refer to it as MiRNAClassify. Through a series of iterations, the information of all the positive and negative samples is completely exploited. In each iteration, a new classification instance is trained by the equal number of positive and negative samples. In this way, the negative effect of class imbalance is efficiently relieved. The new instance primarily focuses on those samples that are easy to be misclassified. In addition, the positive samples are assigned higher cost weight than the negative samples. MiRNAClassify is compared with several state-of-the-art methods and some well-known classification models by testing the datasets about human, animal, and plant. The result of cross validation indicates that MiRNAClassify significantly outperforms other methods and models. In addition, the newly added pre-miRNAs are used to further evaluate the ability of these methods to discover novel pre-miRNAs. MiRNAClassify still achieves consistently superior performance and can discover more pre-miRNAs.
Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review
Authors: Seyedan Atefehalsadat , Alshawsh Mohammed Abdullah , Alshagga Mustafa Ahmed , Koosha Sanaz , Mohamed Zahurin
Published: November 2015

Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity.
Estrogen Replacement Reduces Oxidative Stress in the Rostral Ventrolateral Medulla of Ovariectomized Rats
Authors: Hao Fan , Gu Ying , Tan Xing , Deng Yu , Wu Zhao-Tang , Xu Ming-Juan , Wang Wei-Zhong
Published: November 2015

Cardiovascular disease prevalence rises rapidly after menopause, which is believed to be derived from the loss of estrogen. It is reported that sympathetic tone is increased in postmenopause. The high level of oxidative stress in the rostral ventrolateral medulla (RVLM) contributes to increased sympathetic outflow. The focus of this study was to determine if estrogen replacement reduces oxidative stress in the RVLM and sympathetic outflow in the ovariectomized (OVX) rats. The data of this study showed that OVX rat increased oxidative stress in the RVLM and sympathetic tone; estrogen replacement improved cardiovascular functions but also reduced the level of oxidative stress in the RVLM. These findings suggest that estrogen replacement decreases blood pressure and sympathoexcitation in the OVX rats, which may be associated with suppression in oxidative stress in the RVLM through downregulation of protein expression of NADPHase (NOX4) and upregulation of protein expression of SOD1. The data from this study is beneficial for our understanding of the mechanism of estrogen exerting cardiovascular protective effects on postmenopause.
Markers of Antioxidant Defense in Patients with Type 2 Diabetes
Authors: Gawlik K. , Naskalski J. W. , Fedak D. , Pawlica-Gosiewska D. , Grudzień U. , Dumnicka P. , Małecki M. T. , Solnica B.
Published: November 2015

Aims. Diabetes is considered a state of increased oxidative stress. This study evaluates blood concentrations of selected markers of antioxidant defense in patients with type 2 diabetes. Methods. The study included 80 type 2 diabetes patients and 79 apparently healthy controls. Measured markers included ferric reducing ability of plasma (FRAP), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), γ‐glutamyltransferase (GGT) and uric acid serum, and plasma and/or hemolysate levels. Results. FRAP, uric acid, CRP, and GGT levels were significantly higher in patients with diabetes. Plasma and hemolysate GR was significantly higher whereas GPx activity was significantly lower in patients with diabetes. There were no significant differences in antioxidant defense markers between patients with and without chronic diabetes complications. Fasting serum glucose correlated with plasma GPx, plasma and hemolysate GR, FRAP, and serum GGT, and HbA1c correlated with serum GGT. Only FRAP and serum uric acid were significantly higher in obese (BMI > 30 kg/m2) patients with diabetes than in nonobese patients. Conclusions. Some components of antioxidant defense such as GR, uric acid, and GGT are increased in patients with type 2 diabetes. However, the whole system cannot compensate for an enhanced production of ROS as reflected by the trend toward decreased erythrocytes GSH.
Redox Modulations, Antioxidants, and Neuropsychiatric Disorders
Authors: Fraunberger Erik A. , Scola Gustavo , Laliberté Victoria L. M. , Duong Angela , Andreazza Ana C.
Published: November 2015

Although antioxidants, redox modulations, and neuropsychiatric disorders have been widely studied for many years, the field would benefit from an integrative and corroborative review. Our primary objective is to delineate the biological significance of compounds that modulate our redox status (i.e., reactive species and antioxidants) as well as outline their current role in brain health and the impact of redox modulations on the severity of illnesses. Therefore, this review will not enter into the debate regarding the perceived medical legitimacy of antioxidants but rather seek to clarify their abilities and limitations. With this in mind, antioxidants may be interpreted as natural products with significant pharmacological actions in the body. A renewed understanding of these often overlooked compounds will allow us to critically appraise the current literature and provide an informed, novel perspective on an important healthcare issue. In this review, we will introduce the complex topics of redox modulations and their role in the development of select neuropsychiatric disorders.
Curcumin Supplementation Decreases Intestinal Adiposity Accumulation, Serum Cholesterol Alterations, and Oxidative Stress in Ovariectomized Rats
Authors: Morrone Maurilio da Silva , Schnorr Carlos Eduardo , Behr Guilherme Antônio , Gasparotto Juciano , Bortolin Rafael Calixto , da Boit Martinello Katia , Saldanha Henkin Bernardo , Rabello Thallita Kelly , Zanotto-Filho Alfeu , Gelain Daniel Pens , Moreira José Cláudio Fonseca
Published: November 2015

The aim of this study was to investigate the potential of curcumin oral supplementation (50 and 100 mg/Kg/day, for 30 days) in circumventing menopause‐associated oxidative stress and lipid profile dysfunctions in a rat ovariectomy (OVX) model. Female Wistar rats were operated and randomly divided into either sham‐operated or OVX groups. Sham‐operated group (n = 8) and one OVX group (n = 11) were treated with vehicle (refined olive oil), and the other two OVX groups received curcumin at 50 or 100 mg/Kg/day doses (n = 8/group). OVX vehicle‐treated animals presented a higher deposition of intestinal adipose tissue as well as increased serum levels of IL‐6, LDL, and total cholesterol when compared to sham‐operated rats. In addition, several oxidative stress markers in serum, blood, and liver (such as TBARS, carbonyl, reduced‐sulphydryl, and nonenzymatic antioxidant defenses) were altered toward a prooxidant status by OVX. Interestingly, curcumin supplementation attenuated most of these parameters to sham comparable values. Thus, the herein presented results show that curcumin may be useful to ameliorate lipid metabolism alterations and oxidative damage associated with hormone deprivation in menopause.
Interaction of Hydrogen Sulfide with Nitric Oxide in the Cardiovascular System
Authors: Nagpure B. V. , Bian Jin-Song
Published: November 2015

Historically acknowledged as toxic gases, hydrogen sulfide (H2S) and nitric oxide (NO) are now recognized as the predominant members of a new family of signaling molecules, “gasotransmitters” in mammals. While H2S is biosynthesized by three constitutively expressed enzymes (CBS, CSE, and 3‐MST) from L‐cysteine and homocysteine, NO is generated endogenously from L‐arginine by the action of various isoforms of NOS. Both gases have been transpired as the key and independent regulators of many physiological functions in mammalian cardiovascular, nervous, gastrointestinal, respiratory, and immune systems. The analogy between these two gasotransmitters is evident not only from their paracrine mode of signaling, but also from the identical and/or shared signaling transduction pathways. With the plethora of research in the pathophysiological role of gasotransmitters in various systems, the existence of interplay between these gases is being widely accepted. Chemical interaction between NO and H2S may generate nitroxyl (HNO), which plays a specific effective role within the cardiovascular system. In this review article, we have attempted to provide current understanding of the individual and interactive roles of H2S and NO signaling in mammalian cardiovascular system, focusing particularly on heart contractility, cardioprotection, vascular tone, angiogenesis, and oxidative stress.
Induction of Expression of p75 Neurotrophin Receptor Intracellular Domain Does Not Induce Expression or Enhance Activity of Mitochondrial Complex II
Authors: Yang Yaoli Pu , Lotta Louis , Beutner Gisela , Li Xingguo , Schor Nina F.
Published: November 2015

Fenretinide is a chemotherapeutic agent in clinical trials for the treatment of neuroblastoma, among the most common and most deadly cancers of childhood. Fenretinide induces apoptosis in neuroblastoma cells through accumulation of mitochondrial reactive oxygen species released from Complex II. The neurotrophin receptor, p75NTR, potentiates this effect. The signaling activity of p75NTR is dependent upon its cleavage to its intracellular domain, p75ICD, trafficking of p75ICD to the nucleus, and functioning of p75ICD as a transcription factor. Mitochondrial Complex II comprises 4 subunits, all of which are encoded by nuclear DNA. We therefore hypothesized that the fenretinide‐potentiating effects of p75NTR are the result of transcriptional enrichment of Complex II by p75ICD. However, the present studies demonstrate that neither induced expression of p75ICD or its active fragments nor overexpression of p75NTR results in altered expression or activity of Complex II.
Relationship of Hemoglobin A1c withβCell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients
Authors: Hou Xinguo , Liu Jinbo , Song Jun , Wang Chuan , Liang Kai , Sun Yu , Ma Zeqiang , Yang Weifang , Li Chengqiao , Zhang Xiuping , Lin Peng , Gong Lei , Wang Meijian , Liu Fuqiang , Li Wenjuan , Yan Fei , Qin Jun , Wang Lingshu , Liu Jidong , Zhao Ruxing , Chen Shihong , Chen Li
Published: November 2015

Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those inβcell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them.Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5–7%, 7-8%, 8-9%, and ≥9%). The homeostasis model assessment (HOMA) was used to evaluate pancreaticβcell function (HOMA-β) and insulin resistance (HOMA-IR). ANOVA,t-tests, and binary logistic regression analysis were used for data analysis.Results. Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5–7% exhibited an increased HOMA-βindex. However, the HOMA-βindex was significantly decreased at A1c values ≥7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8-9%. As A1c increased to ≥9%, a 62% reduction inβcell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values.Conclusions. Elevated A1c values (≥7%) were associated with substantial reductions inβcell function.
PAN‐811 Blocks Chemotherapy Drug‐Induced In Vitro Neurotoxicity, While Not Affecting Suppression of Cancer Cell Growth
Authors: Jiang Zhi-Gang , Fuller Steven A. , Ghanbari Hossein A.
Published: November 2015

Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN‐811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5‐fluorouracil (5‐FU), or cisplatin (CDDP) in the absence or presence of PAN‐811·Cl·H2O. The effect of PAN‐811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN‐811 dose‐dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN‐811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN‐811 did not inhibit MTX‐induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5‐FU or CDDP in reducing cancer cell viability. Thus, PAN‐811 can be a potent drug candidate for chemotherapy‐induced cognitive impairment.
Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers
Authors: Kaczkowski Bogumil , Tanaka Yuji , Kawaji Hideya , Sandelin Albin , Andersson Robin , Itoh Masayoshi , Lassmann Timo , Hayashizaki Yoshihide , Carninci Piero , Forrest Alistair R.R.
Published: November 2015

Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression. Cancer Res; 76(2); 216–26. ©2015 AACR.
Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer
Authors: Yang Yijun , Jia Dingwu , Kim Hogyoung , Abd Elmageed Zakaria Y. , Datta Amrita , Davis Rodney , Srivastav Sudesh , Moroz Krzysztof , Crawford Byron E. , Moparty Krishnarao , Thomas Raju , Hudson Robert S. , Ambs Stefan , Abdel-Mageed Asim B.
Published: November 2015

Purpose: The causes of disproportionate incidence and mortality of prostate cancer among African Americans (AA) remain elusive. The purpose of this study was to investigate the mechanistic role and assess clinical utility of the splicing factor heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate cancer progression among AA men.

Experimental Design: We employed an unbiased functional genomics approach coupled with suppressive subtractive hybridization (SSH) and custom cDNA microarrays to identify differentially expressed genes in microdissected tumors procured from age- and tumor grade–matched AA and Caucasian American (CA) men. Validation analysis was performed in independent cohorts and tissue microarrays. The underlying mechanisms of hnRNPH1 regulation and its impact on androgen receptor (AR) expression and tumor progression were explored.

Results: Aberrant coexpression of AR and hnRNPH1 and downregulation of miR-212 were detected in prostate tumors and correlate with disease progression in AA men compared with CA men. Ectopic expression of miR-212 mimics downregulated hnRNPH1 transcripts, which in turn reduced expression of AR and its splice variant AR-V7 (or AR3) in prostate cancer cells. hnRNPH1 physically interacts with AR and steroid receptor coactivator-3 (SRC-3) and primes activation of androgen-regulated genes in a ligand-dependent and independent manner. siRNA silencing of hnRNPH1 sensitized prostate cancer cells to bicalutamide and inhibited prostate tumorigenesis in vivo.

Conclusions: Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. Targeted disruption of the hnRNPH1-AR axis may have therapeutic implications to improve clinical outcomes in patients with advanced prostate cancer, especially among AA men. Clin Cancer Res; 22(7); 1744–56. ©2015 AACR.
Folate Receptor–Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple-Negative Breast Cancer
Authors: Paulmurugan Ramasamy , Bhethanabotla Rohith , Mishra Kaushik , Devulapally Rammohan , Foygel Kira , Sekar Thillai V. , Ananta Jeyarama S. , Massoud Tarik F. , Joy Abraham
Published: November 2015

Triple-negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off-target effects and poor bioavailability of the FDA-approved antiobesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here, we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor–targeted micellar nanoparticles (NP) carrying orlistat, which improved the solubility (70–80 μg/mL) of this water-insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in a nude mouse model. We prepared HEA–EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence-activated cell sorting (FACS) analysis of TNBC cells indicated a dose-dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor–targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase-3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, folate receptor–targeted Fol-DyLight747-orlistat NP–treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. Mol Cancer Ther; 15(2); 221–31. ©2015 AACR.
Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer
Authors: Lund Amanda W. , Medler Terry R. , Leachman Sancy A. , Coussens Lisa M.
Published: November 2015

Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, and are important contributors to malignancy and potential biomarkers and targets for immunotherapy.

Significance: The tumor microenvironment and tumor-associated inflammation are now appreciated not only for their role in cancer progression but also for their response to therapy. The lymphatic vasculature is a less-appreciated component of this microenvironment that coordinates local inflammation and immunity and thereby critically shapes local responses. A mechanistic understanding of the complexities of lymphatic vessel function in the unique context of skin provides a model to understand how regional immune dysfunction drives cutaneous malignancies, and as such lymphatic vessels represent a biomarker of cutaneous immunity that may provide insight into cancer prognosis and effective therapy. Cancer Discov; 6(1); 22–35. ©2015 AACR.
Real-Time GnRH Gene Transcription in GnRH Promoter-Driven Luciferase-Expressing Transgenic Mice: Effect of Kisspeptin
Authors: Choe Han Kyoung , Chun Sung Kook , Kim Jeongah , Kim Doyeon , Kim Hee-Dae , Kim Kyungjin
Published: November 2015

Pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) is indispensable for controlling proper pituitary gonadotrope functions; however, the mechanism underlying GnRH pulse generation remains largely unknown. It is important to understand the cellular oscillator in individual GnRH neurons and temporal synchronization among GnRH neurons. In this brief review, we summarize our recent findings on episodic GnRH gene transcription at the single GnRH neuron level and in synchronized multicellular burst in relation to the temporal pattern of GnRH secretion. We also detail the effects of kisspeptin on ultradian rhythmic GnRH gene transcription and secretion. We extend our discussion to the hierarchical interaction between circadian and ultradian rhythms. Taken together, the current review elucidates the genomic control of GnRH pulse generation in hypothalamic neurons.
Novel Application of Laparoscopic Ultrasound for Fetoscopic Laser Ablation in Twin-Twin Transfusion Syndrome with Complete Anterior Placenta
Authors: Jarboe Marcus D. , Berman Deborah R. , Wright Tiffany , Treadwell Marjorie C. , Mychaliska George B.
Published: November 2015

Fetoscopic laser coagulation of the placental communicating vessels has become the standard treatment for monochorionic/diamniotic twin pregnancies complicated by severe twin-twin transfusion syndrome. Fetoscopic trocar placement can be performed with transabdominal ultrasound guidance with a posterior placenta and most anterior placentas that have a safe avascular window for entry. However, trocar insertion is challenging in cases of a complete anterior placenta without an avascular window. Current techniques to deal with this situation include mini-laparotomy with exteriorization to allow for dorsal entry, percutaneous lateral entry under transabdominal ultrasound/Doppler guidance, and laparoscopic assisted access with direct visualization of trocar entry. We describe a modified technique of laparoscopic assisted fetoscopic trocar placement using a laparoscopic ultrasound probe, which allows for precise, real-time guidance of trocar placement.
Sextant-Specific Analysis of Detection and Tumor Volume by HistoScanning™
Authors: Porres Daniel , Kuru Timur Hasan , Epplen Robin , Eck Andreas , Zugor Vahudin , Kennes Lieven Niels , Afram Samir , Braunschweig Till , Knüchel-Clarke Ruth , Pfister David , Heidenreich Axel
Published: November 2015

Introduction: Published results of HistoScanning™ (HS) for prostate cancer (PCa) diagnostics are inconsistent and their value remains unclear. We prospectively analyzed the detection rate and tumor volume concordance in PCa patients. Material and Methods: Two hundred and eighty-two patients with biopsy-proven PCa scheduled for radical prostatectomy (RP) were included. All patients underwent ultrasonographical examination by HS prior to surgery. HS was evaluated compared to RP specimen as to (1) the prediction of overall tumor volume and (2) accuracy of HS in detection of PCa lesions larger than 0.2/0.5 ml, separated for each sextant. For each sextant, receiver operating characteristic (ROC)-analysis and area under the curve were determined. Sensitivity and specificity were calculated and visualized in ROC-curves. Results: HS tends to underestimate volume of cancerous lesions, particularly larger lesions >8 ml. Using a 0.2 ml detection threshold, specificity and sensitivity of HS were between 29-68% and 46-78%. For a 0.5 ml detection threshold, sextant-specific specificity increased to 59-92% and sensitivity decreased to 16-54%. Stratification according to pre-operational PSA values did not improve performance characteristics of HS. Conclusions: Our results do not support a significant contribution of HS to PCa diagnostics.
Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine
Authors: Vogel Arndt , Kullmann Frank , Kunzmann Volker , Al-Batran Salah-Eddin , Oettle Helmut , Plentz Ruben , Siveke Jens , Springfeld Christoph , Riess Hanno
Published: November 2015

In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.
Impact of p16 Alterations and Pretreatment Anemia on Toxicity in Head and Neck Cancer Patients Undergoing Definitive Radiochemotherapy
Authors: Becker-Schiebe Martina , Sperling Matthias , Pinkert Uwe , Hoffmann Wolfgang
Published: November 2015

Background: Human papilloma virus (HPV) infection, p16 expression and hypoxia may play important roles in the carcinogenesis, treatment response and toxicities of head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to assess whether there is any correlation between pre-radiotherapy (RT) anemia, p16 expression and toxicities and local control for patients undergoing definitive therapy. Methods: 79 HNSCC patients who had undergone radiochemotherapy (RCT) or RT-antibody therapy were retrospectively analyzed. p16 (INK4A) expression was detected by immunohistochemical analysis. Factors predisposing for acute side effects were examined by uni- and multivariate analysis. Results: p16 overexpression was detected in 32 cases. Pretreatment anemia was present in one third of patients. Only 5% of patients were characterized by both pre-RT anemia and p16 overexpression. p16 expression was significantly associated with acute grade 3 toxicity. 47% of p16-positive patients developed grade ≥ 3 radiodermatitis compared to 26% of p16-negative patients (p = 0.04). A reduced risk of severe skin toxicities was noted for patients with hypoxic blood values before RT. p16 expression was significantly correlated with local control (p = 0.002). Conclusions: p16 expression is associated with better response to definitive combined treatment (RCT, RT + cetuximab), but also significantly related to acute high-grade toxicity.
Subpubic Arch Angle and Mode of Delivery in Low-Risk Nulliparous Women
Authors: Youssef Aly , Ghi Tullio , Martelli Federica , Montaguti Elisa , Salsi Ginevra , Bellussi Federica , Pilu Gianluigi , Rizzo Nicola
Published: November 2015

Objective: To assess whether subpubic arch angle (SPA) measurement before labor onset can predict labor outcome among low-risk pregnant women. Methods: 3D ultrasound volume was transperineally acquired from a series of nulliparous women with uncomplicated pregnancy at term before the onset of labor. SPA was measured offline using Oblique View Extended Imaging (OVIX) on each volume performed by an investigator not involved in the clinical management. Labor outcome was prospectively investigated in the whole study group. Results: Overall, 145 women were enrolled in the study. Of these, 83 underwent spontaneous vaginal delivery, whereas obstetric intervention was performed in 62 cases (Cesarean section in 40 and vacuum extraction in 22). The SPA appeared to be significantly narrower in the women submitted to obstetric intervention compared with those undergoing spontaneous vaginal delivery (116.8 ± 10.3° vs. 123.7 ± 9.6°, p < 0.01). At multivariate analysis SPA and maternal age were identified as independent predictors of the mode of delivery. On the other hand, the duration of labor did not show a significant relationship with SPA. Conclusions: In low-risk nulliparous women at term gestation, SPA measurement obtained by 3D ultrasound before the onset of labor seems to predict the likelihood of an obstetric intervention but not the duration of labor.
Long‐Term Risk of Stroke in Patients With Type 1 and Type 2 Diabetes Following Coronary Artery Bypass Grafting
Authors: Nyström Thomas , Holzmann Martin J. , Sartipy Ulrik
Published: November 2015

Background

We performed a nationwide population‐based cohort study to investigate the long‐term risk of stroke after coronary artery bypass grafting in patients with type 1 and type 2 diabetes.

Methods and Results

All patients who underwent primary coronary artery bypass grafting in Sweden from 2000 through 2011 were included from the
SWEDEHEART
register. We excluded patients with prior stroke, and patients who had a stroke or died within 30 days of surgery. The National Diabetes Register was used to identify patients with type 1 and type 2 diabetes. Incident stroke (ischemic and hemorrhagic), and all‐cause mortality was obtained by record linkage with the National Patient Register and the Cause of Death register. We used multivariable Cox regression to estimate the risk of stroke in relation to type of diabetes. A total of 53 820 patients (type 1 diabetes [n=714], type 2 diabetes [n=10 054], no diabetes [n=43 052]) were included. During a mean follow‐up of 7.4 years (398 337 person‐years), in total, 8.0% (n=4296) of the patients had a stroke: 7.3% (n=52) in patients with type 1 diabetes, 9.1% (n=915) in patients with type 2 diabetes, and 7.7% (n=3329) in patients with no diabetes. The multivariable adjusted hazard ratio (95% CI) for all stroke was 1.59 (1.20–2.11) in type 1 diabetes, and 1.32 (1.23–1.43) in type 2 diabetes.

Conclusions

The long‐term risk for stroke after coronary artery bypass grafting was increased in patients with type 1 and type 2 diabetes, compared to patients with no diabetes.
Cancer and Its Association With the Development of Coronary Artery Calcification: An Assessment From the Multi‐Ethnic Study of Atherosclerosis
Authors: Whitlock Matthew C. , Yeboah Joseph , Burke Gregory L. , Chen Haiying , Klepin Heidi D. , Hundley W. Gregory
Published: November 2015

Background

Although cancer and its corresponding therapies are associated with increased ischemic heart disease, the temporal relationship between cancer and the development of coronary artery calcium (
CAC
), a marker of subclinical atherosclerosis, is unknown.

Methods and Results

Among 3122 men and women free of cardiovascular disease and cancer in the Multi‐Ethnic Study of Atherosclerosis trial,
CAC
scoring was performed at baseline (2000–2002) and at follow‐up (2010–2012). Over this 10‐year period, 85 men (age 63.6±8.3 years) and 50 women (age 62.1±9.8 years) were diagnosed with cancer (predominantly breast, lung, or uterine [52%] in women and prostate or colorectal [78%] in men). The other 2987 subjects (age 59.6±9.2 years for men, 59.7±9.4 years for women) remained cancer free. The incidence of new
CAC
(baseline Agatston score of zero converting to detectable
CAC
) was modeled with relative risk regression and compared for cancer versus no cancer. Increase in pre‐existing
CAC
was compared in these groups using linear regression of log transformed
CAC
. The incidence of
CAC
was independently associated with cancer history (relative risk 1.32 [
P
=0.04] and 1.29 [
P
=0.01] for women and men, respectively). In participants with
CAC
at baseline, a clear difference of
CAC
progression was not observed between cancer and noncancer participants (
P
=0.6 for women,
P
=0.2 for men).

Conclusions

A diagnosis of cancer is associated with the development of
CAC
even after accounting for atherosclerotic risk factors. However, in individuals with pre‐existing
CAC
, it is not clear whether the presence of cancer accelerates
CAC
over time.
Coronary Artery Vessel Healing Pattern, Short and Long Term, After Implantation of the Everolimus‐Eluting Bioresorbable Vascular Scaffold
Authors: Kraak Robin P. , de Boer Hans H. , Elias Joëlle , Ambarus Carmen A. , van der Wal Allard C. , de Winter Robbert J. , Wykrzykowska Joanna J.
Published: November 2015

Background

Although the Absorb bioresorbable vascular scaffold is increasingly used in daily clinical practice for the treatment of coronary artery disease, the exact vascular healing pattern and the resorption process in humans is unknown because histological data are derived only from animal studies.

Methods and Results

We have obtained 4 autopsies (5 scaffolds) since August 2013. Duration of bioresorbable vascular scaffold implantation ranged from 3 to 501 days. All autopsies and histological assessments were performed by dedicated cardiovascular pathologists. At 1 week after bioresorbable vascular scaffold implantation, struts were covered with a fine layer of fibrin and platelets. At 113 days, the scaffold struts were fully covered with smooth muscle cells. Hyaline eosinophilic and proteoglycan material infiltrating the scaffold struts was observed at 501 days after implantation. At all time points, we observed the presence of multinuclear foreign body giant cells adjacent to the scaffold struts.

Conclusions

Resorption and healing processes after bioresorbable vascular scaffold implantation in human patients mirror those observed in porcine models. The presence of multinucleated foreign body giant cells at both short‐ and long‐term follow‐up needs further investigation and may be related to a low‐grade absorptive inflammatory response to the polymer.