bluuebunny/crossref_metadata_2025 huggingface dataset:
Second-order centrality correlation in scale-free networks
Authors: Lv Meilei , Guo Xinling , Chen Jiaquan , Lu Zhe-Ming , Nie Tingyuan
Published: January 2015

Scale-free networks in which the degree displays a power-law distribution can be classified into assortative, disassortative, and neutral networks according to their degree–degree correlation. The second-order centrality proposed in a distributed computation manner is quick-calculated and accurate to identify critical nodes. We explore the second-order centrality correlation (SOC) for each type of the scale-free networks. The SOC–SOC correlation in assortative network and neutral network behaves similarly to the degree–degree correlation, while it behaves an apparent difference in disassortative networks. Experiments show that the invulnerability of most of scale-free networks behaves similarly under the node removal ordering by SOC centrality and degree centrality, respectively. The netscience network and the Yeast network behave a little differently because they are native disconnecting networks.
Prediction of the permeability of proppant packs under load
Authors: Bikulov Dmitry , Saratov Anton , Grachev Eugene
Published: January 2015

The calculation of proppant pack properties under load is useful to determine the optimal material parameters and grain size distribution. A simple, yet effective model for simulation of both mechanical deformation and permeability of the pack in specific case of polymeric proppant is presented. The mechanical deformation modeling is similar to the discrete elements method, where permeability is calculated with the lattice Boltzmann method. The simulation imitates the standard procedure for measuring the conductivity of a proppant. Permeabilities for different loads and different grain size distributions are obtained.
Probing the string landscape: Implications, applications, and altercations
Authors: Dienes Keith R.
Published: January 2015

In keeping with the "Perspectives" theme of this volume, this Chapter provides a personal perspective on the string landscape. Along the way, the perspectives of many other physicists are discussed as well. No attempt is made to provide a thorough and balanced review of the field, and indeed there is a slight emphasis on my own contributions to this field, as these contributions have been critical to forming my perspective. This Chapter is adapted from a Colloquium which I have delivered at a number of institutions worldwide, and I have attempted to retain the informal and non-technical spirit and style of this Colloquium presentation as much as possible.
Cluster assisted generation of the isolated attosecond sources
Authors: Feng Li-Qiang , Chu Tianshu
Published: January 2015

A promising method to generate the intense isolated attosecond sources has been theoretically investigated emerging from the two-dimensional Ar+cluster driven in the two-color polarized gating pulse. The results show that with the introduction of the Ar+cluster model, not only the harmonic cutoffs are extended, but also the harmonic yields are enhanced by at least two orders of magnitude compared with the single atom model. Further, by properly choosing the number of ions surrounding the central atom, the internuclear distance as well as the laser parameters, two isolated pulses with durations of 53 as and 46 as can be obtained.
A holographic bound on the total number of computations in the visible universe
Authors: van Putten Maurice H. P. M.
Published: January 2015

Information I in holographic imaging of massive particles by star-like screens is shown to represent the probability of detection based on their propagator. Results are derived for screens in the shape of a plane, cube and sphere from unitarity in the exponentially small transition probability for a detection outside. We derive I = 2πΔφ in log 2 bits for the imaging of a particle by a spherical screen at a relative de Broglie phase Δφ. Encoding mass, charge, angular momentum or radiation requires at minimum four bits. Minimal screens at maximal information density hereby recover Reissner–Nordström and extremal Kerr black holes. Applied to the visible Universe, the Hubble flow of galaxies through the cosmological event horizon leaves 10121 computations in the future.
AUTOMATED CHARACTERIZATION AND DETECTION OF DIABETIC RETINOPATHY USING TEXTURE MEASURES
Authors: MOOKIAH MUTHU RAMA KRISHNAN , TAN JEN HONG , CHUA CHUA KUANG , NG E. Y. K. , LAUDE AUGUSTINUS , TONG LOUIS
Published: January 2015

The chronic and uncontrolled diabetes mellitus (DM) damages the retinal blood vessels leading to diabetic retinopathy (DR). The advanced stage of DR leads to loss of vision and subsequently blindness. The morphological changes during the progression of DR can be diagnosed using digital fundus images. The pathological changes in the retina influence the variations in pixel patterns which can be quantified using texture measures. In this paper, we have explored different texture measures namely statistical moments, gray level co-occurrence matrix (GLCM), gray level run length matrix (GLRLM), local binary pattern (LBP), laws mask energy (LME), fractal dimension (FD), fourier spectrum (FS) and Gabor wavelet to characterize and classify the normal and DR classes. We have tabulated 109 texture parameters for the normal and DR classes. Further, these features were subjected to empirical receiver operating characteristic (ROC) based ranking to select optimal feature set. The ranked nested features were fed to the support vector machine (SVM) classifier with different kernel functions to evaluate the highest performance measure using the least number of features to discriminate normal and DR classes. Our proposed system was evaluated using two different databases Kasturba Medical College Hospital (KMCH) and Tan Tock Seng Hospital (TTSH), each with 340 images (170 normal and 170 DR). We have also formulated an integrated index called as diabetic retinopathy risk index (DRRI) using selected texture features to discriminate normal and DR classes using single number. The proposed frame work can be used to help the clinicians and also for mass DR screening programs.
MECHANICAL TEST OF HUMAN CEREBRAL ANEURYSM SPECIMENS OBTAINED FROM SURGICAL CLIPPING
Authors: VALENCIA ALVARO , CONTENTE ALVARO , IGNAT MIGUEL , MURA JORGE , BRAVO EDUARDO , RIVERA RODRIGO , SORDO JUAN
Published: January 2015

The walls of the blood vessels involved with cerebral aneurysms present different mechanical properties, when compared with those of normal artery. Consequently the models which may describe then predict an aneurysm rupture need as input their mechanical properties. This paper describes the experimental determination of the mechanical properties of the tissues of the blood vessels affected with a cerebral aneurysm. In particular, we determine and discuss the critical elongation and the rupture strength. The affected tissues were obtained from surgical clipping and extraction; six specimens were tested. The mechanical tests were performed in a tensile device. The experimental data was fitted numerically with a Mooney–Rivlin hyper elastic model. The model was compared with previous published data.
An efficient multiple kernel learning in reproducing kernel Hilbert spaces (RKHS)
Authors: Xu Lixiang , Luo Bin , Tang Yuanyan , Ma Xiaohua
Published: January 2015

The reproducing kernel Hilbert space construction is a bijection or transform theory which associates a positive definite kernel with a Hilbert space of functions. Recently, reproducing kernel Hilbert space (RKHS) has come wildly alive in the pattern recognition and machine learning community. In this paper, we propose a novel method named multiple kernel learning with reproducing property (MKLRP) to achieve some classification tasks. The MKLRP consists of two major steps. First, we find the basic solution of a generalized differential operator by delta function, and prove this basic solution is a new specific reproducing kernel called H2-reproducing kernel (HRK) in RKHS. Second, in RKHS, we prove that the HRK satisfies the condition of Mercer kernel. Furthermore, a novel specific multiple kernel learning (MKL) called MKLRP, which is based on reproducing kernel is proposed. We perform an extensive experimental evaluation on synthetic and real-world data, which shows the effectiveness of the proposed approach.
Measuring effects of different noises in a model using ISI-distance methods
Authors: Qu Jingyi , Wang Rubin , Du Ying
Published: January 2015

This paper examines the effects of current and conductance noises in a minimal Hodgkin–Huxley type model of a cold receptor neuron. Current noise enters the membrane equation directly while conductance noise is propagated through the activation variables. Compared with common used interspike interval method, ISI-distance is a simple complementary approach to measure the different effects of current and conductance noises. ISI-distance extracts information from the interspike intervals by evaluating the ratio of instantaneous firing rates, which is parameter-free, time scale-independent and easy to visualize. Simulation results show that the most significant differences between different noise implementations in a pacemaker-like tonic firing regime at the transition to chaotic burst discharges.
Hydroxy-α sanshool induces colonic motor activity in rat proximal colon: a possible involvement of KCNK9
Authors: Kubota Kunitsugu , Ohtake Nobuhiro , Ohbuchi Katsuya , Mase Akihito , Imamura Sachiko , Sudo Yuka , Miyano Kanako , Yamamoto Masahiro , Kono Toru , Uezono Yasuhito
Published: January 2015

Various colonic motor activities are thought to mediate propulsion and mixing/absorption of colonic content. The Japanese traditional medicine daikenchuto (TU-100), which is widely used for postoperative ileus in Japan, accelerates colonic emptying in healthy humans. Hydroxy-α sanshool (HAS), a readily absorbable active ingredient of TU-100 and a KCNK3/KCNK9/KCNK18 blocker as well as TRPV1/TRPA1 agonist, has been investigated for its effects on colonic motility. Motility was evaluated by intraluminal pressure and video imaging of rat proximal colons in an organ bath. Distribution of KCNKs was investigated by RT-PCR, in situ hybridization, and immunohistochemistry. Current and membrane potential were evaluated with use of recombinant KCNK3- or KCNK9-expressing Xenopus oocytes and Chinese hamster ovary cells. Defecation frequency in rats was measured. HAS dose dependently induced strong propulsive “squeezing” motility, presumably as long-distance contraction (LDC). TRPV1/TRPA1 agonists induced different motility patterns. The effect of HAS was unaltered by TRPV1/TRPA1 antagonists and desensitization. Lidocaine (a nonselective KCNK blocker) and hydroxy-β sanshool (a geometrical isomer of HAS and KCNK3 blocker) also induced colonic motility as a rhythmic propagating ripple (RPR) and a LDC-like motion, respectively. HAS-induced “LDC,” but not lidocaine-induced “RPR,” was abrogated by a neuroleptic agent tetrodotoxin. KCNK3 and KCNK9 were located mainly in longitudinal smooth muscle cells and in neural cells in the myenteric plexus, respectively. Administration of HAS or TU-100 increased defecation frequency in normal and laparotomy rats. HAS may evoke strong LDC possibly via blockage of the neural KCNK9 channel in the colonic myenteric plexus.
Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis
Authors: Wang Shusheng , Zhu Hong-Yan , Jin Yi , Zhou Youlang , Hu Shufen , Liu Tong , Jiang Xinghong , Xu Guang-Yin
Published: January 2015

The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation.
Low-frequency stimulation regulates metabolic gene expression in paralyzed muscle
Authors: Petrie Michael , Suneja Manish , Shields Richard K.
Published: January 2015

The altered metabolic state after a spinal cord injury compromises systemic glucose regulation. Skeletal muscle atrophies and transforms into fast, glycolytic, and insulin-resistant tissue. Osteoporosis is common after spinal cord injury and limits the ability to exercise paralyzed muscle. We used a novel approach to study the acute effect of two frequencies of stimulation (20 and 5 Hz) on muscle fatigue and gene regulation in people with chronic paralysis. Twelve subjects with chronic (>1 yr) and motor complete spinal cord injury (ASIA A) participated in the study. We assessed the twitch force before and after a single session of electrical stimulation (5 or 20 Hz). We controlled the total number of pulses delivered for each protocol (10,000 pulses). Three hours after the completion of the electrical stimulation (5 or 20 Hz), we sampled the vastus lateralis muscle and examined genes involved with metabolic transcription, glycolysis, oxidative phosphorylation, and mitochondria remodeling. We discovered that the 5-Hz stimulation session induced a similar amount of fatigue and a five- to sixfold increase ( P < 0.05) in key metabolic transcription factors, including PGC-1α, NR4A3, and ABRA as the 20-Hz session. Neither session showed a robust regulation of genes for glycolysis, oxidative phosphorylation, or mitochondria remodeling. We conclude that a low-force and low-frequency stimulation session is effective at inducing fatigue and regulating key metabolic transcription factors in human paralyzed muscle. This strategy may be an acceptable intervention to improve systemic metabolism in people with chronic paralysis.
Blockade of neurokinin-1 receptors in the ventral respiratory column does not affect breathing but alters neurochemical release
Authors: Muere Clarissa , Neumueller Suzanne , Olesiak Samantha , Miller Justin , Hodges Matthew R. , Pan Lawrence , Forster Hubert V.
Published: January 2015

Substance P (SP) and its receptor, neurokinin-1 (NK1R), have been shown to be excitatory modulators of respiratory frequency and to stabilize breathing regularity. Studies in anesthetized mice suggest that tonic activation of NK1Rs is particularly important when other excitatory inputs to the pre-Bötzinger complex in the ventral respiratory column (VRC) are attenuated. Consistent with these findings, muscarinic receptor blockade in the VRC of intact goats elicits an increase in breathing frequency associated with increases in SP and serotonin concentrations, suggesting an involvement of these substances in neuromodulator compensation. To gain insight on the contribution to breathing of endogenous SP and NK1R activation, and how NK1R modulates the release of other neurochemicals, we individually dialyzed antagonists to NK1R (133, 267, 500 μM Spantide; 3 mM RP67580) throughout the VRC of awake and sleeping goats. We found that NK1R blockade with either Spantide at any dose or RP67580 had no effect on breathing or regularity. Both antagonists significantly ( P < 0.001) increased SP, while RP67580 also increased serotonin and glycine and decreased thyrotropin-releasing hormone concentrations in the dialysate. Taken together, these data support the concept of neuromodulator interdependence, and we believe that the loss of excitatory input from NK1Rs was locally compensated by changes in other neurochemicals.
Predicting the response of the injured lung to the mechanical breath profile
Authors: Smith Bradford J. , Lundblad Lennart K. A. , Kollisch-Singule Michaela , Satalin Joshua , Nieman Gary , Habashi Nader , Bates Jason H. T.
Published: January 2015

Mechanical ventilation is a crucial component of the supportive care provided to patients with acute respiratory distress syndrome. Current practice stipulates the use of a low tidal volume (Vt) of 6 ml/kg ideal body weight, the presumptive notion being that this limits overdistension of the tissues and thus reduces volutrauma. We have recently found, however, that airway pressure release ventilation (APRV) is efficacious at preventing ventilator-induced lung injury, yet APRV has a very different mechanical breath profile compared with conventional low-Vt ventilation. To gain insight into the relative merits of these two ventilation modes, we measured lung mechanics and derecruitability in rats before and following Tween lavage. We fit to these lung mechanics measurements a computational model of the lung that accounts for both the degree of tissue distension of the open lung and the amount of lung derecruitment that takes place as a function of time. Using this model, we predicted how tissue distension, open lung fraction, and intratidal recruitment vary as a function of ventilator settings both for conventional low-Vt ventilation and for APRV. Our predictions indicate that APRV is more effective at recruiting the lung than low-Vt ventilation, but without causing more overdistension of the tissues. On the other hand, low-Vt ventilation generally produces less intratidal recruitment than APRV. Predictions such as these may be useful for deciding on the relative benefits of different ventilation modes and thus may serve as a means for determining how to ventilate a given lung in the least injurious fashion.
Pressure-limited sustained inflation vs. gradual tidal inflations for resuscitation in preterm lambs
Authors: Tingay David G. , Polglase Graeme R. , Bhatia Risha , Berry Clare A. , Kopotic Robert J. , Kopotic Clinton P. , Song Yong , Szyld Edgardo , Jobe Alan H. , Pillow J. Jane
Published: January 2015

Support of the mechanically complex preterm lung needs to facilitate aeration while avoiding ventilation heterogeneities: whether to achieve this gradually or quickly remains unclear. We compared the effect of gradual vs. constant tidal inflations and a pressure-limited sustained inflation (SI) at birth on gas exchange, lung mechanics, gravity-dependent lung volume distribution, and lung injury in 131-day gestation preterm lambs. Lambs were resuscitated with either 1) a 20-s, 40-cmH2O pressure-limited SI (PressSI), 2) a gradual increase in tidal volume (Vt) over 5-min from 3 ml/kg to 7 ml/kg (IncrVt), or 3) 7 ml/kg Vt from birth. All lambs were subsequently ventilated for 15 min with 7 ml/kg Vt with the same end-expiratory pressure. Lung mechanics, gas exchange and spatial distribution of end-expiratory volume (EEV), and tidal ventilation (electrical impedance tomography) were recorded regularly. At 15 min, early mRNA tissue markers of lung injury were assessed. The IncrVt group resulted in greater tissue hysteresivity at 5 min ( P = 0.017; two-way ANOVA), higher alveolar-arterial oxygen difference from 10 min ( P < 0.01), and least uniform gravity-dependent distribution of EEV. There were no other differences in lung mechanics between groups, and the PressSI and 7 ml/kg Vt groups behaved similarly throughout. EEV was more uniformly distributed, but Vt least so, in the PressSI group. There were no differences in mRNA markers of lung injury. A gradual increase in Vt from birth resulted in less recruitment of the gravity-dependent lung with worse oxygenation. There was no benefit of a SI at birth over mechanical ventilation with 7 ml/kg Vt.
Tumor Endothelial Cells with Distinct Patterns of TGFβ-Driven Endothelial-to-Mesenchymal Transition
Authors: Xiao Lin , Kim Dae Joong , Davis Clayton L. , McCann James V. , Dunleavey James M. , Vanderlinden Alissa K. , Xu Nuo , Pattenden Samantha G. , Frye Stephen V. , Xu Xia , Onaitis Mark , Monaghan-Benson Elizabeth , Burridge Keith , Dudley Andrew C.
Published: January 2015

Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimulation. Although some TECs strikingly upregulate α smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGFβ treatment. Compared with NECs, SMA+ TECs were 40% less motile in wound-healing assays and formed more stable vascular-like networks in vitro when challenged with TGFβ. Lineage tracing using ZsGreenCdh5-Cre reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA+ TECs, suggesting that not all endothelial cells (EC) respond identically to TGFβ in vivo. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to upregulate others. ECs challenged with TGFβ secrete bFGF, which blocks SMA expression in secondary cultures, suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature. Cancer Res; 75(7); 1244–54. ©2015 AACR.
Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage
Authors: Wu Wenwen , Nishikawa Hiroyuki , Fukuda Takayo , Vittal Vinayak , Asano Masahide , Miyoshi Yasuo , Klevit Rachel E. , Ohta Tomohiko
Published: January 2015

Stable retention of BRCA1/BARD1 complexes at sites of DNA damage is required for the proper response to DNA double-strand breaks (DSB). Here, we demonstrate that the BRCT domain of BARD1 is crucial for its retention through interaction with HP1. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent but RNF168-independent manner. This interaction is mediated primarily by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacted with the chromoshadow domain of HP1 in vitro. Mutations in this motif (or simultaneous depletion of all three HP1 isoforms) disrupted retention of BARD1, BRCA1, and CtIP at DSB sites and allowed ectopic accumulation of RIF1, an effector of nonhomologous end-joining, at damaged loci in S-phase. UNC0638, a small-molecule inhibitor of histone lysine methyltransferase (HKMT), abolished retention and cooperated with the PARP inhibitor olaparib to block cancer cell growth. Taken together, our findings show how BARD1 promotes retention of the BRCA1/BARD1 complex at damaged DNA sites and suggest the use of HKMT inhibitors to leverage the application of PARP inhibitors to treat breast cancer. Cancer Res; 75(7); 1311–21. ©2015 AACR.
Cancer Fear: Facilitator and Deterrent to Participation in Colorectal Cancer Screening
Authors: Vrinten Charlotte , Waller Jo , von Wagner Christian , Wardle Jane
Published: January 2015

Background: Cancer fear has been associated with higher and lower screening uptake across different studies, possibly because different aspects of cancer fear have different effects on intentions versus behavior. The present study examined associations of three aspects of cancer fear with intention and uptake of endoscopic screening for colorectal cancer.

Methods: A subsample of UK Flexible Sigmoidoscopy (FS) Trial participants received a baseline questionnaire that included three cancer fear items from a standard measure asking if: (i) cancer was feared more than other diseases, (ii) cancer worry was experienced frequently, and (iii) thoughts about cancer caused discomfort. Screening intention was assessed by asking participants whether, if invited, they would accept an invitation for FS screening. Positive responders were randomized to be invited or not in a 1:2 ratio. The behavioral outcome was clinic-recorded uptake. Control variables were age, gender, ethnicity, education, and marital status.

Results: The questionnaire return rate was 60% (7,971/13,351). The majority (82%) intended to attend screening; 1,920 were randomized to receive an invitation, and 71% attended. Fearing cancer more than other diseases (OR = 2.32, P < 0.01) and worrying a lot about cancer (OR = 2.34, P < 0.01) increased intentions to attend screening, but not uptake. Finding thoughts about cancer uncomfortable did not influence intention, but predicted lower uptake (OR = 0.72, P < 0.01).

Conclusions: Different aspects of cancer fear have different effects on the decision and action processes leading to screening participation.

Impact: Knowledge of the different behavioral effects of cancer fear may aid the design of effective public health messages. Cancer Epidemiol Biomarkers Prev; 24(2); 400–5. ©2015 AACR.
Cancer Risk and Subsequent Survival after Hospitalization for Intermittent Claudication
Authors: Onega Tracy , Baron John A. , Johnsen Søren P. , Pedersen Lars , Farkas Dóra K. , Sørensen Henrik T.
Published: January 2015

Background: Intermittent claudication, muscle ischemia due to reduced arterial circulation, may be associated with an increased risk of cancer risk and death due to neoplasm-induced hypercoagulability and angiogenesis, or to shared risk factors, but the relation is not well understood.

Methods: We conducted a population-based cohort study using the Danish National Registry of Patients to identify patients with intermittent claudication from 1980 to 2011 and no history of cancer. We followed these patients for incident cancers using the Danish Cancer Registry and compared cancer incidence among patients with intermittent claudication to that expected in the general population. We also compared the survival of patients with cancer with and without claudication, matched for sex, cancer site, stage, age at diagnosis, and diagnosis year.

Results: A total of 53,762 patients with intermittent claudication were identified. We observed 6,270 incident cancers over a total 269,430 years of follow-up (mean, 5.0), compared with 4,306 cancer cases expected [standardized incidence ratio = 1.46; 95% confidence interval (CI), 1.42–1.49]. Cancer risk also increased after the exclusion of patients with a prior diagnosis of cerebrovascular disease, myocardial infarction, or diabetes, particularly for tobacco-related cancers. The elevated cancer risk persisted over 10 years of follow-up. For patients with cancer, diagnosis of intermittent claudication within 3 months preceding the cancer diagnosis did not influence survival, but before 3 months, was associated with modestly worse survival (mortality rate ratio = 1.19; 95% CI, 1.14–1.25).

Conclusions: Intermittent claudication is associated with an increased risk of cancer and poorer subsequent survival.

Impact: Clinical attention following intermittent claudication diagnosis may reveal incident cancers. Cancer Epidemiol Biomarkers Prev; 24(4); 744–8. ©2015 AACR.
Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma
Authors: Qiu Zhijuan , Huang Huakang , Grenier Jeremy M. , Perez Oriana A. , Smilowitz Henry M. , Adler Barbara , Khanna Kamal M.
Published: January 2015

The presence of tumor-infiltrating CD8+ T cells is associated with tumor regression and better prognosis. Cytomegalovirus (CMV) infection elicits a robust and long-lasting CD8+ T-cell response, which makes CMV a potentially promising vaccine vector against cancer. In the current study, we used recombinant murine CMV (MCMV) strains as prophylactic and therapeutic vaccines in an aggressive B16 lung metastatic melanoma model. Immunization with MCMV-expressing ovalbumin (OVA) induced a potent OVA-specific CD8+ T-cell response and was effective in protecting mice from OVA-expressing B16 melanoma in an antigen-dependent manner. We engineered MCMV to express a modified B16 melanoma antigen gp100 (MCMV-gp100KGP). Immunization with MCMV-gp100KGP was highly effective in overcoming immune tolerance to self-antigen and induced a strong, long-lasting gp100-specific CD8+ T-cell response even in the presence of preexisting anti-CMV immunity. Furthermore, both prophylactic and therapeutic vaccinations of mice with MCMV-gp100KGP effectively protected mice from highly aggressive lung B16-F10 melanoma, and the protection was mediated by gp100-specific CD8+ T cells. We showed that MCMV is a superior vaccine vector compared with a commonly used vesicular stomatitis virus vector. Collectively, our studies demonstrate that CMV is a promising vaccine vector to prevent and treat tumors. Cancer Immunol Res; 3(5); 536–46. ©2015 AACR.
Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering
Authors: Portron Sophie , Hivernaud Vincent , Merceron Christophe , Lesoeur Julie , Masson Martial , Gauthier Olivier , Vinatier Claire , Beck Laurent , Guicheux Jérôme
Published: January 2015

Background/Aims: Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O2) or hypoxic (5%O2) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.
PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis
Authors: Zhang Xudong , Tan Zhongming , Wang Youjing , Tang Junwei , Jiang Runjiu , Hou Jiajie , Zhuo Han , Wang Xiaochen , Ji Jie , Qin Xihu , Sun Beicheng
Published: January 2015

Background/Aims: PTPRO (protein tyrosine phosphatase, receptor type O) is implicated in diverse physiological and pathological processes in cancer and hepatic ischemia/reperfusion injury, although little is known about its role in hepatic fibrosis. Methods: Here, by using genetically deficient mice, we reported that PTPRO knockout (PTPRO-/-) significantly attenuated liver injury, release of inflammatory factors, tissue remodeling, and liver fibrosis in two experimental mouse models of fibrogenesis induced by bile-duct ligation or carbon tetrachloride administration. Results: However, we proved that PTPRO expression was strongly downregulated in clinical and experimental liver fibrosis specimens. Further investigations revealed that stimulation of primary hepatic stellate cells (HSCs) and hepatocytes with specific activator platelet-derived growth factor (PDGF)-BB increased PTPRO transcription in HSCs but had the opposite effect in primary hepatocytes. More importantly, synthetic short hairpin RNA targeting PTPRO significantly neutralized PDGF-BB-induced HSC proliferation and myofibroblast marker expression through downregulated phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Conclusion: These observations confirm that PTPRO plays a critical role in liver fibrogenesis by affecting PDGF signaling in HSC activation and might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.
Regulation of Autophagy of Prostate Cancer Cells by β-Catenin Signaling
Authors: Lin Rongkai , Feng Jiayu , Dong Shaoliang , Pan Runyang , Zhuang Huiqiang , Ding Zhenyu
Published: January 2015

Background/Aims: Autophagy is a cellular degradation process for the recycling of damaged or superfluous intracellular compartments to provide an alternative energy source during periods of metabolic stress for maintaining cell homeostasis and viability. Although autophagy in different contexts have been shown to use similar signaling pathways, the exact molecular regulation of autophagy has been found to be cell-type dependent. Methods: We used rapamycin to trigger autophagy and used nitric oxide (NO) to inhibit autophagy in prostate cancer cells. IWP-2 was used to inhibit β-catenin signaling. Autophagy-associated proteins were examined by Western blot. Results: We found that nitric oxide (NO), a potent cellular messenger, impaired rapamycin-induced autophagy in prostate cancer cells. Further analyses showed that NO induced nuclear accumulation of β-catenin, a key factor of Wnt signaling pathway, to inhibit autophagy in prostate cancer cells. Conclusions: We demonstrate involvement of β-catenin signaling in the regulation of autophagy of prostate cancer cells. Our results shed light on a previously unappreciated β-catenin signaling pathway for regulating autophagy in prostate cancer.
Altered MiRNA Expression in Gastric Cancer: a Systematic Review and Meta-Analysis
Authors: Wang Qi-Xian , Zhu You-Qing , Zhang Hu , Xiao Jun
Published: January 2015

Background/Aims: Aberrant microRNA expression has the potential to be used for early diagnosis of gastric cancer or to predict survival and treatment response. This study performed a systematic review and meta-analysis of altered miRNAs in gastric cancer in order to assess the use of miRNAs as novel biomarkers for early detection and prognosis prediction of gastric cancer. Methods: We retrieved published articles from the PubMed online database and obtained different sets of data on miRNAs expression profiling in gastric cancer and highlighted the most frequently dysregulated miRNAs in gastric cancer. We then extracted studies that used quantitative RT-PCR and then pooled them together by using meta-disc software (version 1.4). Results: We found that there were 47 aberrantly expressed miRNAs in gastric cancer (29 up-regulated and 18 down-regulated) that were most frequently reported in the literature. In publications that provided information on specific miRNA expression vs. diagnostic value, the pooled data showed good sensitivity and specificity as well as high levels of overall accuracy. However, specimen types could be a factor that introduces substantial heterogeneity. Published studies also showed association of altered miRNA expression with clinicopathological data from gastric cancer patients. Conclusion: Thus, various miRNAs are differentially expressed in gastric cancer and some of them could be further evaluated as biomarkers for early diagnosis of gastric cancer and prediction of prognosis or treatment response.
Integrative Cognitive Reserve
Authors: Jiang Wenfei , Pan Weidong
Published: January 2015

The cognitive reserve (CR) against cognitive damage stems from a series of observations. The purpose of this study is to perform a systematic review to summarize the concept of CR. A variety of factors such as age, education level, reading ability, and vocabulary have an impact on the reserve according to a large amount of research and may influence CR. Furthermore, due to measurement difficulties, efforts to explore CR have been hindered. This is why different methods have been used to quantify reserve, such as multiple indicators multiple causes, residual variance in episodic memory performance, the Sole-Padulles Childhood Enrichment measure, the Mini-Mental State Examination, the Peabody Picture Vocabulary Test, the Hollingshead Two-Factor Index of Social Position, the Cattell Culture Fair Intelligence Test, and the Digit Span Subtests of the Wechsler Memory Scale. In addition, numerous studies explored the role of CR in various diseases, such as multiple sclerosis, hepatitis C, obesity, and sleep onset/maintenance difficulties. CR plays a significant role in the morbidity of these diseases, and since integrative medicine may be able to modify CR, it might be an effective tool to prevent these serious diseases.
Oxybutynin for the Treatment of Primary Hyperhidrosis: Current State of the Art
Authors: Campanati Anna , Gregoriou Stamatis , Kontochristopoulos George , Offidani Annamaria
Published: January 2015

Oxybutynin is an anticholinergic drug with an emerging role in the treatment of hyperhidrosis. Several recent studies have documented that it is effective both in focal and generalized hyperhidrosis and shows universally good response among different groups of patients regardless of age, gender, and weight. The most common adverse event is dry mouth reported by almost all patients treated. The way this might affect long-term compliance and tolerability should be better investigated in the future.
High Levels of Soluble Tumor Necrosis Factor Receptors 1 and 2 and Their Association with Mortality in Patients Undergoing Hemodialysis
Authors: Carlsson Axel C. , Carrero Juan-Jesús , Stenvinkel Peter , Bottai Matteo , Barany Peter , Larsson Anders , Ärnlöv Johan
Published: January 2015

Objective: Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients. Research Design and Methods: This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality. Results: The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-α. Conclusions: Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.
Bilateral Heel Numbness due to External Compression during Obstetric Epidural Analgesia
Authors: Kamphuis Vivian P. , Zegers Marie P.A. , Koppen Hille
Published: January 2015

We describe the case of a 32-year-old woman who developed bilateral heel numbness after obstetric epidural analgesia. We diagnosed her with bilateral neuropathy of the medial calcaneal nerve, most likely due to longstanding pressure on both heels. Risk factors for the development of this neuropathy were prolonged labour with spinal analgesia and a continuation of analgesia during episiotomy. Padded footrests decrease pressure and can possibly prevent this neuropathy.
Comparison of a Novel Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent
Authors: Windecker Stephan , Haude Michael , Neumann Franz-Josef , Stangl Karl , Witzenbichler Bernhard , Slagboom Ton , Sabaté Manel , Goicolea Javier , Barragan Paul , Cook Stéphane , Piot Christophe , Richardt Gert , Merkely Béla , Schneider Henrik , Bilger Johannes , Erne Paul , Waksman Ron , Zaugg Serge , Jüni Peter , Lefèvre Thierry
Published: January 2015

Background—

Biodegradable polymers for release of antiproliferative drugs from drug-eluting stents aim to improve vascular healing. We assessed noninferiority of a novel ultrathin strut drug-eluting stent releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) compared with the durable polymer Xience Prime everolimus-eluting stent (X-EES) in terms of the primary end point in-stent late lumen loss at 9 months.

Methods and Results—

A total of 452 patients were randomly assigned 2:1 to treatment with O-SES (298 patients, 332 lesions) or X-EES (154 patients, 173 lesions) in a multicenter, noninferiority trial. The primary end point was in-stent late loss at 9 months. O-SES was noninferior to X-EES for the primary end point (0.10±0.32 versus 0.11±0.29 mm; difference=0.00063 mm; 95% confidence interval, −0.06 to 0.07;
P
noninferiority
<0.0001). Clinical outcome showed similar rates of target-lesion failure at 1 year (O-SES 6.5% versus X-EES 8.0%; hazard ratio=0.82; 95% confidence interval, 0.40–1.68; log-rank test:
P
=0.58) without cases of stent thrombosis. A subgroup of patients (n=55) underwent serial optical coherence tomography at 9 months, which demonstrated similar neointimal thickness among lesions allocated to O-SES and X-EES (0.10±0.04 mm versus 0.11±0.04 mm; −0.01 [−0.04, −0.01];
P
=0.37). Another subgroup of patients (n=56) underwent serial intravascular ultrasound at baseline and 9 months indicating a potential difference in neointimal area at follow-up (O-SES, 0.16±0.33 mm
2
versus X-EES, 0.43±0.56 mm
2
;
P
=0.04).

Conclusions—

Compared with durable polymer X-EES, novel biodegradable polymer–based O-SES was found noninferior for the primary end point in-stent late lumen loss at 9 months. Clinical event rates were comparable without cases of stent thrombosis throughout 1 year of follow-up.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01356888.
Ischemic Stroke Phenotype in Patients With Nonsustained Atrial Fibrillation
Authors: Arsava Ethem M. , Bas Demet F. , Atalar Enver , Has Arzu C. , Oguz Kader K. , Topcuoglu Mehmet A.
Published: January 2015

Background and Purpose—

The widespread use of ambulatory cardiac monitoring has not only increased the detection of high-risk arrhythmias like persistent and paroxysmal atrial fibrillation (AF), but also made it possible to identify other aberrations such as short-lasting (<30 seconds) irregular runs of supraventricular tachycardia. Ischemic stroke phenotype might be helpful in understanding whether these nonsustained episodes play a similar role in stroke pathophysiology like their persistent and paroxysmal counterparts.

Methods—

In a consecutive series of patients with ischemic stroke, we retrospectively determined clinical and imaging features associated with nonsustained AF (n=126), defined as <30-second-lasting supraventricular tachyarrhythmias with irregular RR interval on 24-hour Holter monitoring, and compared them to patients with persistent/paroxysmal AF (n=239) and no AF (n=246).

Results—

Patients with persistent/paroxysmal AF significantly differed from patients with nonsustained AF by a higher prevalence of female sex (odds ratio [95% confidence interval], 1.8 [1.1–2.9]), coronary artery disease (1.9 [1.1–3.0]), and embolic imaging features (2.7 [1.1–6.5]), and lower frequency of smoking (0.4 [0.2–0.8]) and hyperlipidemia (0.5 [0.3–0.8]). In contrast, patients with no AF were younger (0.5 [0.4–0.6] per decade) and more likely to be male (1.7 [1.0–2.8]) in comparison with nonsustained AF population. The prevalence of nonsustained AF was similar among cryptogenic and noncryptogenic stroke patients (32% versus 29%). Voxel-wise comparison of lesion probability maps revealed no significant difference between cryptogenic stroke patients with and without nonsustained AF.

Conclusions—

Clinical features of patients with nonsustained AF exhibited an intermediary phenotype in between patients with persistent/paroxysmal AF and no AF. Furthermore, imaging features did not entirely resemble patterns observed in patients with longer durations of AF.
Alcohol Consumption at Midlife and Risk of Stroke During 43 Years of Follow-Up
Authors: Kadlecová Pavla , Andel Ross , Mikulík Robert , Handing Elizabeth P. , Pedersen Nancy L.
Published: January 2015

Background and Purpose—

Although alcohol–stroke association is well known, the age-varying effect of alcohol drinking at midlife on subsequent stroke risk across older adulthood has not been examined. The effect of genetic/early-life factors is also unknown. We used cohort and twin analyses of data with 43 years of follow-up for stroke incidence to help address these gaps.

Methods—

All 11 644 members of the population-based Swedish Twin Registry born 1886 to 1925 with alcohol data aged ≤60 years were included. The interaction of midlife alcohol consumption by age at stroke was evaluated in Cox-regression and analyses of monozygotic twins were used. Covariates were baseline age, sex, cardiovascular diseases, diabetes mellitus, stress reactivity, depression, body mass index, smoking, and exercise.

Results—

Altogether 29% participants developed stroke. Compared with very-light drinkers (<0.5 drink/d), heavy drinkers (>2 drinks/d) had greater risk of stroke (hazard ratio, 1.34;
P
=0.02) and the effect for nondrinkers approached significance (hazard ratio, 1.11;
P
=0.08). Age increased stroke risk for nondrinkers (
P
=0.012) and decreased it for heavy drinkers (
P
=0.040). Midlife heavy drinkers were at high risk from baseline until the age of 75 years when hypertension and diabetes mellitus grew to being the more relevant risk factors. In analyses of monozygotic twin-pairs, heavy drinking shortened time to stroke by 5 years (
P
=0.04).

Conclusions—

Stroke-risk associated with heavy drinking (>2 drinks/d) in midlife seems to predominate over well-known risk factors, hypertension and diabetes, until the age of ≈75 years and may shorten time to stroke by 5 years above and beyond covariates and genetic/early-life factors. Alcohol consumption should be considered an age-varying risk factor for stroke.