bluuebunny/crossref_metadata_2025 huggingface dataset:
Fear Processing in Dental Phobia during Crossmodal Symptom Provocation: An fMRI Study
Authors: Hilbert Kevin , Evens Ricarda , Maslowski Nina Isabel , Wittchen Hans-Ulrich , Lueken Ulrike
Published: March 2014

While previous studies successfully identified the core neural substrates of the animal subtype of specific phobia, only few and inconsistent research is available for dental phobia. These findings might partly relate to the fact that, typically, visual stimuli were employed. The current study aimed to investigate the influence of stimulus modality on neural fear processing in dental phobia. Thirteen dental phobics (DP) and thirteen healthy controls (HC) attended a block-design functional magnetic resonance imaging (fMRI) symptom provocation paradigm encompassing both visual and auditory stimuli. Drill sounds and matched neutral sinus tones served as auditory stimuli and dentist scenes and matched neutral videos as visual stimuli. Group comparisons showed increased activation in the insula, anterior cingulate cortex, orbitofrontal cortex, and thalamus in DP compared to HC during auditory but not visual stimulation. On the contrary, no differential autonomic reactions were observed in DP. Present results are largely comparable to brain areas identified in animal phobia, but also point towards a potential downregulation of autonomic outflow by neural fear circuits in this disorder. Findings enlarge our knowledge about neural correlates of dental phobia and may help to understand the neural underpinnings of the clinical and physiological characteristics of the disorder.
Numerical Absorbing Boundary Conditions Based on a Damped Wave Equation for Pseudospectral Time-Domain Acoustic Simulations
Authors: Spa Carlos , Reche-López Pedro , Hernández Erwin
Published: March 2014

In the context of wave-like phenomena, Fourier pseudospectral time-domain (PSTD) algorithms are some of the most efficient time-domain numerical methods for engineering applications. One important drawback of these methods is the so-called Gibbs phenomenon. This error can be avoided by using absorbing boundary conditions (ABC) at the end of the simulations. However, there is an important lack of ABC using a PSTD methods on a wave equation. In this paper, we present an ABC model based on a PSTD damped wave equation with an absorption parameter that depends on the position. Some examples of optimum variation profiles are studied analytically and numerically. Finally, the results of this model are also compared to another ABC model based on an hybrid formulation of the scalar perfectly matched layer.
Bleeding Complication of Triple Therapy of Rivaroxaban, Prasugrel, and Aspirin: A Case Report and General Discussion
Authors: Gruenebaum Dane D. , Alsarah Ahmad , Alsara Osama , Laird-Fick Heather
Published: March 2014

Hemorrhagic side effects are the bane of oral anticoagulation. Despite careful selection of medications and close monitoring, some adverse events are unavoidable. The available literature about the risks of triple oral anticoagulation therapy versus dual antiplatelet therapy does not address all of the medication combinations currently available. This report describes a patient with atrial fibrillation and recent stent placement who developed severe, recurrent epistaxis on aspirin, prosugrel, and rivaroxaban. We believe this is the first case report of severe bleeding with this combination, and it may help provide insights into the risk for other patients.
Pain in Parkinson's Disease Associated withCOMTGene Polymorphisms
Authors: Li Wanjun , Chen Yongqian , Yin Bowen , Zhang Limei
Published: March 2014

Background. PD patients present high incidence of pain with unknown pathogenesis.Objective. We investigated the relation ofCOMTpolymorphismsrs4633andrs6267with PD pain.Subjects and Methods. One hundred PD patients and 105 controls were evaluated with simplified Mc GILL pain scale and VAS scale. PD patients were assessed with H&Y grade, UPDRS score, and HAMD scale. Polymorphismsrs4633andrs6267were detected by PCR and direct sequencing.Results. Fifty-seven percent of PD patients experienced pain, consisting of PD-related pain (64.91%) (the majority was dystonia pain) and non-PD-related pain (35.09%) (psychogenic pain was most frequent). The frequency ofrs6267genotype “GT/TT” and allele “T” was higher in PD pain. No difference was observed in frequencies ofrs4633between PD pain and without pain. UPDRS and depression score were higher in PD pain. The onset age was earlier in PD-related pain (57.43 ± 19.71) than non-PD-related pain (63.36 ± 6.88).Conclusion. PD patients possess a high prevalence of pain. Dystonia pain was the most frequent type of PD-related pain.COMTgeners6267allele “T” associated with PD pain. PD pain was influenced by disease severity and depression. PD onsets earlier in patients with PD-related pain than non-PD-related pain.
Experiences of Thrombolytic Therapy for Ischemic Stroke in Tuzla Canton, Bosnia and Herzegovina
Authors: Smajlović Dževdet , Salihović Denisa , Ibrahimagić Omer Ć. , Dostović Zikrija , Avdić Leila , Vidović Mirjana
Published: March 2014

Aim. To demonstrate our experiences of thrombolytic therapy in acute ischemic stroke. Subjects and Methods. Patients with ischemic stroke treated with rt-PA, admitted at the Department of Neurology, Tuzla, Bosnia and Herzegovina, in the period between April 1, 2008, and December 31, 2012, were included. Results. Between April 2008 and December 2012, intravenous rt-PA was given to 87 patients with acute ischemic stroke, which represents 3.2% of patients with acute ischemic stroke admitted to our department in that period. Hypertension was the leading stroke risk factor. The mean NIHSS score before thrombolysis was 12 (range 4–21). Large artery arteriosclerosis was the most common stroke etiology. The mean door-to-needle time was 72 minutes and onset-to-needle time 152 minutes. Half of patients (44/87) had a significant improvement within the first 24 hours. Parenchymal hemorrhage occurred in 5 patients (6%) and was fatal in two cases. At 3-month follow-up, 45% of patients (39/87) had good outcome (mRS 0 or 1). Sixteen patients were dead at 3 months, and mean baseline stroke severity was significantly higher in patients who died (NIHSS 16.5 versus 11, P=0.003). Conclusion. The number of patients with acute ischemic stroke treated using rt-PA in the Department of Neurology, Tuzla, is lower than in developed countries. Thrombolytic therapy is safe and leads to favorable outcome in half of the patients.
A Purified Recombinant Lipopeptide as Adjuvant for Cancer Immunotherapy
Authors: Song Ying-Chyi , Liu Hsueh-Hung , Chen I-Hua , Chen Hsin-Wei , Chong Pele , Leng Chih-Hsiang , Liu Shih-Jen
Published: March 2014

Synthetic lipopeptides have been widely used as vaccine adjuvants to enhance immune responses. The present study demonstrated that the tryptic N-terminal fragment of the lipoprotein rlipo-D1E3 (lipo-Nter) induces superior antitumor effects compared to a synthetic lipopeptide. The lipo-Nter was purified and formulated with protein or peptide vaccines to determine if lipo-Nter could be used as a novel adjuvant and could induce antitumor immunity in a cervical cancer model. Purified lipo-Nter activated the maturation of bone marrow-derived dendritic cells (BM-DCs), leading to the secretion of TNF-αthrough TLR2/6 but not TLR1/2. A recombinant mutant HPV16 E7 (rE7m) protein was mixed with lipo-Nter to immunize the mice; the anti-E7 antibody titers were increased, and the T helper cells were skewed toward the Th1 fate (increased IL-2 and decreased IL-5 secretion). Single-dose injection of rE7m and lipo-Nter inhibited tumor growth, but the injection of rE7m alone did not. Accordingly, lipo-Nter also enhanced the antitumor immunity of the E7-derived peptide but not the synthetic lipopeptide (Pam3CSK4). We demonstrated that the lipo-Nter of a bacterial-derived recombinant lipoprotein is a novel adjuvant that could be used for the development of a new generation of vaccines.
Impact of Preceding El Niño and the Indian Ocean Dipole on the Southern China Precipitation in Early Summer
Authors: Li Yan , Wang Yafei , Mu Lin , Wang Qingyuan , Song Jun , Wang Guosong
Published: March 2014

Delayed impacts of El Niño and the Indian Ocean Dipole in positive phase (P-IOD) on the South China early monsoon were investigated by observations and simulations. The most significant correlation between IOD index (IODI) and NINO3 appeared in boreal autumn. A new index (IODN3) related to the intensity of El Niño and IOD was created. Three indexes in boreal autumn were positively well correlated with the rainfall over the Yangtze River and its southern area (rain-YRBS) in next June. The most significant correlation appeared between IODN3 and rain-YRBS. Positive rain-YRBS anomalies in June tend to occur after P-IOD or El Niño solely matured in previous boreal autumn. However, when both events matured in boreal autumn, rain-YRBS anomalies tended to be more enhanced, which suggests that a delayed combined influence of both events on rain-YRBS in June was larger than that of either event alone. There was a low level anticyclonic circulation around the Philippines (PSAC) that developed in boreal autumn and was maintained until the following June when the single event occurred. However, a much stronger PSAC tended to occur when both events matured. The stronger PSAC could transport more water vapor to YRBS and cause more rainfall there in June.
Minimal Solution of Singular LR Fuzzy Linear Systems
Authors: Nikuie M. , Ahmad M. Z.
Published: March 2014

In this paper, the singular LR fuzzy linear system is introduced. Such systems are divided into two parts: singular consistent LR fuzzy linear systems and singular inconsistent LR fuzzy linear systems. The capability of the generalized inverses such as Drazin inverse, pseudoinverse, and {1}-inverse in finding minimal solution of singular consistent LR fuzzy linear systems is investigated.
Provenance Study of Archaeological Ceramics from Syria Using XRF Multivariate Statistical Analysis and Thermoluminescence Dating
Authors: Bakraji Elias Hanna , Abboud Rana , Issa Haissm
Published: March 2014

Thermoluminescence (TL) dating and multivariate statistical methods based on radioisotope X-ray fluorescence analysis have been utilized to date and classify Syrian archaeological ceramics fragment from Tel Jamous site. 54 samples were analyzed by radioisotope X-ray fluorescence; 51 of them come from Tel Jamous archaeological site in Sahel Akkar region, Syria, which fairly represent ceramics belonging to the Middle Bronze Age (2150 to 1600 B.C.) and the remaining three samples come from Mar-Takla archaeological site fairly representative of the Byzantine ceramics. We have selected four fragments from Tel Jamous site to determinate their age using thermoluminescence (TL) method; the results revealed that the date assigned by archaeologists was good. An annular 109Cd radioactive source was used to irradiate the samples in order to determine their chemical composition and the results were treated statistically using two methods, cluster and factor analysis. This treatment revealed two main groups; the first one contains only the three samples M52, M53, and M54 from Mar-Takla site, and the second one contains samples that belong to Tel Jamous site (local).
Aircraft Cockpit Ergonomic Layout Evaluation Based on Uncertain Linguistic Multiattribute Decision Making
Authors: Chen Junxuan , Yu Suihuai , Wang Shuxia , Lin Zhengze , Liu Guochang , Deng Li
Published: March 2014

In the view of the current cockpit information interaction, facilities and other characteristics are increasingly multifarious; the early layout evaluation methods based on single or partial components, often cause comprehensive evaluation unilateral, leading to the problems of long development period and low efficiency. Considering the fuzziness of ergonomic evaluation and diversity of evaluation information attributes, we refine and build an evaluation system based on the characteristics of the current cockpit man-machine layout and introduce the different types of uncertain linguistic multiple attribute combination decision making (DTULDM) method in the cockpit layout evaluation process. Meanwhile, we also establish an aircraft cockpit ergonomic layout evaluation model. Finally, an experiment about cockpit layout evaluation is given, and the result demonstrates that the proposed method about cockpit ergonomic layout evaluation is feasible and effective.
Detection of Tannery Effluents Induced DNA Damage in Mung Bean by Use of Random Amplified Polymorphic DNA Markers
Authors: Raj Abhay , Kumar Sharad , Haq Izharul , Kumar Mahadeo
Published: March 2014

Common effluent treatment plant (CETP) is employed for treatment of tannery effluent. However, the performance of CETP for reducing the genotoxic substances from the raw effluent is not known. In this study, phytotoxic and genotoxic effects of tannery effluents were investigated in mung bean (Vigna radiata(L.) Wilczek). For this purpose, untreated and treated tannery effluents were collected from CETP Unnao (UP), India. Seeds of mung bean were grown in soil irrigated with various concentrations of tannery effluents (0, 25, 50, 75, and 100%) for 15 days. Inhibition of seed germination was 90% by 25% untreated effluent and 75% treated effluent, compared to the control. Plant growth was inhibited by 51% and 41% when irrigated with untreated and treated effluents at 25% concentration. RAPD technique was used to evaluate the genotoxic effect of tannery effluents (untreated and treated) irrigation on the mung bean. The RAPD profiles obtained showed that both untreated and treated were having genotoxic effects on mung bean plants. This was discernible with appearance/disappearance of bands in the treatments compared with control plants. A total of 87 RAPD bands were obtained using eight primers and 42 (48%) of these showed polymorphism. Irrigating plants with untreated effluent caused 12 new bands to appear and 18 to disappear. Treated effluent caused 8 new bands and the loss of 15 bands. The genetic distances shown on the dendrogram revealed that control plants and those irrigated with treated effluent were clustered in one group (joined at distance of 0.28), whereas those irrigated with untreated effluent were separated in another cluster at larger distance (joined at distance of 0.42). This indicates that treated effluent is less genotoxic than the untreated. Nei’s genetic similarity indices calculated between the treatments and the control plants showed that the control and the plants irrigated with treated tannery effluent had a similarity index of 0.75, the control and plants irrigated with untreated 0.65, and between the treatments 0.68. We conclude that both untreated and treated effluents contain genotoxic substances that caused DNA damage to mung beans. CETP Unnao removes some, but not all, genotoxic substances from tannery effluent. Consequently, use of both untreated and treated wastewater for irrigation poses health hazard to human and the environment.
Ethnic Differences in MicroRNA-375 Expression Level and DNA Methylation Status in Type 2 Diabetes of Han and Kazak Populations
Authors: Chang Xiangyun , Li Siyuan , Li Jun , Yin Liang , Zhou Ting , Zhang Chen , Chen Xuan , Sun Kan
Published: March 2014

Han population is six times as likely as Kazak population to present with type 2 diabetes mellitus (T2DM) in China. We hypothesize that differential expression and CpG methylation of miR-375 may be an ethnic-related factor that influences the incidence of T2DM. The expression level of miR-375 was examined using real-time PCR on Kazak and Han T2DM plasma samples. Furthermore, the methylation levels of CpG sites of miR-375 promoter were determined by MassARRAY Spectrometry in these samples. The relative expression levels of plasma miR-375 in Kazak T2DM samples are 1, and the relative expression levels of plasma miR-375 in Han T2DM samples are 3. The mean level of miR-375 methylation, calculated from the methylation levels of the CpG sites, was 8.47% for the Kazak T2DM group and 10.38% for the Han T2DM group. Further, five CpG units showed a statistically significant difference between Kazak and Han T2DM samples, and, among them, four were hypomethylated and only one CpG unit showed hypermethylation in Kazak T2DM samples. These findings indicate that the expression levels of plasma miR-375 and its CpG methylation in the promoter region are ethnically different, which may contribute to the different incidence of diabetes observed in Kazak and Han populations.
Dark Photon Searches Using Displaced Vertices at Low Energye+e-Colliders
Authors: Bossi Fabio
Published: March 2014

The existence of a new, photon-like, massive particle, theγ′or dark photon, is postulated in several extensions of the Standard Model. These models are often advocated to explain some recent puzzling astrophysical observations, as well as to solve the so far unexplained deviation between the measured and calculated values of the muon anomaly. Dark photons can be produced ate+e-colliders both in continuum events and in vector meson transitions and can eventually decay into an electron-positron pair. For a proper choice of the parameters of the theory, aγ′can have a relatively long lifetime and can therefore be observed as ane+e-vertex well separated by the primary interaction point. This case is discussed in reference to very high luminositye+e-colliders either in construction or under study in several laboratories in the world. It is shown that a search strategy based on the detection of displaced vertices can be in principle very effective in covering a rather wide and to date unexplored region of the theoretical parameters space.
Effect of Reaction Rate and Calcination Time on CaNb2O6 Nanoparticles
Authors: Dudhe C. M. , Nagdeote S. B.
Published: March 2014

The properties of CaNb2O6 nanoparticles synthesized by coprecipitation method under controlled reaction rate and extended calcination time were studied. Analysis of the X-ray diffraction pattern shows single orthorhombic phase of the material with lattice parameters: a=15.0147 Å, b=5.74148 Å, and c=5.30296 Å. The morphology and size of particles was found to be improved due to the controlled reaction rate and extended calcination time. The average sizes of the particles were estimated as 40 nm and 90 nm for sintering temperatures 650°C and 800°C, respectively. The material was found to possess dielectric constant which is inversely proportional to the frequency. Surprisingly, the material shows ferroelectric behavior, the possible origin of which is discussed here.
Site-Specific Analysis of Inflammatory Markers in Discoid Lupus Erythematosus Skin
Authors: Thorpe Ryan B. , Gray Anna , Kumar Kirthi R. , Susa Joseph S. , Chong Benjamin F.
Published: March 2014

Prior studies identified T cells, B cells, and macrophages in the inflammatory infiltrate and up-regulation of their protein products in discoid lupus erythematosus (DLE) skin; however, they lacked rigorous analyses to define their specific locations in skin. Thus, we compared expressions of selected T cell, B cell, and macrophage markers in five areas of DLE, psoriasis, and normal skin. Immunostainings for CD3, CD4, CD8, CD20, CD68, CXCR3, CXCL10, and TIA-1 were performed in biopsies of 23 DLE lesional skin, 11 psoriasis lesional skin, and 5 normal skin. Three independent observers used a graded scale to rate each marker’s presence in the epidermis, dermatoepidermal junction (DEJ), perivascular area, periadnexal area, and deep dermis. DLE lesional skin contained an increased abundance of CD3+, CD8+, and CD68+cells at the DEJ, and CD20+and CD68+cells in the periadnexal area versus psoriasis and normal skin. CXCR3, CXCL10, and TIA-1 were elevated in periadnexal sites of DLE lesional skin versus psoriasis lesional skin. The aggregation of T cells, B cells, macrophages, and their protein products (CXCR3, CXCL10, and TIA-1) in the DEJ and periadnexal area of DLE lesional skin may contribute to the pathology of DLE through a coordinated, sophisticated process.
A Comprehensive Review on Metabolic Syndrome
Authors: Kaur Jaspinder
Published: March 2014

Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factorα, interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome’s definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.
Study on the Technical Efficiency of Creative Human Capital in China by Three-Stage Data Envelopment Analysis Model
Authors: Ma Jian , Ma Yueru , Bai Yong , Xia Bing
Published: March 2014

Previous researches have proved the positive effect of creative human capital and its development on the development of economy. Yet, the technical efficiency of creative human capital and its effects are still under research. The authors are trying to estimate the technical efficiency value in Chinese context, which is adjusted by the environmental variables and statistical noises, by establishing a three-stage data envelopment analysis model, using data from 2003 to 2010. The research results indicate that, in this period, the entirety of creative human capital in China and the technical efficiency value in different regions and different provinces is still in the low level and could be promoted. Otherwise, technical non-efficiency is mostly derived from the scale nonefficiency and rarely affected by pure technical efficiency. The research also examines environmental variables’ marked effects on the technical efficiency, and it shows that different environmental variables differ in the aspect of their own effects. The expansion of the scale of education, development of healthy environment, growth of GDP, development of skill training, and population migration could reduce the input of creative human capital and promote the technical efficiency, while development of trade and institutional change, on the contrary, would block the input of creative human capital and the promotion the technical efficiency.
Association of CHMP4B and Autophagy with Micronuclei: Implications for Cataract Formation
Authors: Sagona Antonia P. , Nezis Ioannis P. , Stenmark Harald
Published: March 2014

Autophagy is a mechanism of cellular self-degradation that is very important for cellular homeostasis and differentiation. Components of the endosomal sorting complex required for transport (ESCRT) machinery are required for endosomal sorting and also for autophagy and the completion of cytokinesis. Here we show that the ESCRT-III subunit CHMP4B not only localizes to normal cytokinetic bridges but also to chromosome bridges and micronuclei, the latter surrounded by lysosomes and autophagosomes. Moreover, CHMP4B can be co-immunoprecipitated with chromatin. Interestingly, a CHMP4B mutation associated with autosomal dominant posterior polar cataract abolishes the ability of CHMP4B to localize to micronuclei. We propose that CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. This may have implications for DNA degradation during lens cell differentiation, thus potentially protecting lens cells from cataract development.
Matrilin-2 Is a Widely Distributed Extracellular Matrix Protein and a Potential Biomarker in the Early Stage of Osteoarthritis in Articular Cartilage
Authors: Zhang Shukun , Peng Jinwu , Guo Yan , Javidiparsijani Sara , Wang Guirong , Wang Yichun , Liu Honggang , Liu Jingshi , Luo Junming
Published: March 2014

In this study, we first generated and characterized a polyclonal antibody against unique domain of matrlin-2 and then used this specific antibody to assess the expression pattern of matrilin-2 by immunohistochemistry. We found that marilin-2 is widely distributed in the connective tissues of many mouse tissues including heart, colon, penis, esophagus, lung, kidney, tracheal cartilage, developmental bone, and adult bone. The expression level of matrilin-2 was remarkably increased in the tissues of osteoarthritis developmental articular cartilage, compared to normal healthy tissues. Furthermore, we determined matrilin-2 expression in specific epithelial cells in stomach and ductal epithelial cells of salivary gland. In other tissues, the positive signals were mainly located around cardiac muscle cells and Purkinje fibers in the heart; corpus spongiosum in the penis; submucosa in the colon and esophagus; extracellular matrix of cartilage in the tracheal cartilage; and, glomerulus, the basement membrane of distal convoluted tubule and renal matrix in kidney. These observations indicated that the distribution pattern of matrilin-2 is heterogeneous in each tissue. Matrilin-2 may play an important role in the communication of matrix to matrix and matrix to cells and will be used as a potential biomarker in the early stage of osteoarthritis of articular cartilage.
Survival in Patients with High-Risk Prostate Cancer Is Predicted by miR-221, Which Regulates Proliferation, Apoptosis, and Invasion of Prostate Cancer Cells by Inhibiting IRF2 and SOCS3
Authors: Kneitz Burkhard , Krebs Markus , Kalogirou Charis , Schubert Maria , Joniau Steven , van Poppel Hein , Lerut Evelyne , Kneitz Susanne , Scholz Claus Jürgen , Ströbel Philipp , Gessler Manfred , Riedmiller Hubertus , Spahn Martin
Published: March 2014

A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high-risk prostate cancer, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness, and apoptosis in prostate cancer at least partially via STAT1/STAT3-mediated activation of the JAK/STAT signaling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signaling pathway. miR-221 expression sensitized prostate cancer cells for IFN-γ–mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk prostate cancer. Cancer Res; 74(9); 2591–603. ©2014 AACR.
COX-2 Drives Metastatic Breast Cells from Brain Lesions into the Cerebrospinal Fluid and Systemic Circulation
Authors: Allen Joshua E. , Patel Akshal S. , Prabhu Varun V. , Dicker David T. , Sheehan Jonas M. , Glantz Michael J. , El-Deiry Wafik S.
Published: March 2014

Breast cancer is among the most common malignancies that metastasize to the brain, with 15% to 20% of patients with metastatic breast cancer eventually developing brain metastases. We previously reported a method to enumerate tumor cells in the cerebrospinal fluid (CSF) of patients with breast cancer with central nervous system (CNS) metastases, a setting that lacks sufficiently informative biomarkers. Here, we show that breast cancer cells can spontaneously disseminate into the CSF from brain lesions in mice in a COX-2–dependent manner and can escape from the CNS to systemic circulation. Enumeration of tumor cells in the peripheral blood (circulating tumor cells, CTC) and CSF (cerebrospinal fluid tumor cells, CSFTC) of nine breast cancer patients with brain metastases revealed dynamic changes in tumor cell burden in both the peripheral blood and CSF compartments that correlated with clinical disease progression. Interestingly, four of the enrolled patients exhibited rapid intercompartmental transitioning of the disease reflected in the CTC and CSFTC counts that preceded corresponding evidence by clinical imaging or neurologic symptoms. Two of these patients had systemic disease recurrence involving the primary malignant site. Intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence that may involve tumor self-seeding. Our findings demonstrate the involvement of COX-2 in the genesis of CSFTCs and suggest that COX-2 inhibitors should be investigated in patients with breast cancer with brain metastases for their ability to reduce CSFTC counts and prevent systemic recurrence. Cancer Res; 74(9); 2385–90. ©2014 AACR.
Molecular Pathways: BRAF Induces Bioenergetic Adaptation by Attenuating Oxidative Phosphorylation
Authors: Haq Rizwan , Fisher David E. , Widlund Hans R.
Published: March 2014

Cancers acquire mutations in cooperating pathways that sustain their growth and survival. To support continued proliferation, tumor cells adapt their metabolism to balance energy production with their augmented biosynthetic needs. Although most normal differentiated cells use mitochondrial oxidative phosphorylation (OXPHOS) as the bioenergetic source, cancer cells have been proposed to rely principally on cytoplasmic glycolysis. The molecular basis for this shift, termed the Warburg effect, is the subject of intense investigation, because mechanistic understanding may lead to novel approaches to target the altered metabolism of cancer cells. Recently, mutations BRAF(V600E) have emerged as a major regulator of metabolic homeostasis. Melanoma cells may use a metabolic shift to circumvent BRAF(V600E)-induced senescence though limiting their reliance on OXPHOS and promote proliferation. Furthermore, BRAF(V600E) acts to suppress expression of the melanocyte master regulator microphthalmia-associated transcription factor (MITF) and the mitochondrial biogenesis coactivator PGC1α. Accordingly, therapeutic inhibition of BRAF(V600E) reverses metabolic reprogramming in melanoma cells and elevates OXPHOS through increased MITF–PGC1α levels. BRAF-targeted drugs modulate the metabolic state of malignant melanoma cells, and counteracting these adaptive responses using pharmacologic agents may prove useful in combinatorial therapeutic strategies. Clin Cancer Res; 20(9); 2257–63. ©2014 AACR.
Enhancement of Nab-Paclitaxel Antitumor Activity through Addition of Multitargeting Antiangiogenic Agents in Experimental Pancreatic Cancer
Authors: Awasthi Niranjan , Zhang Changhua , Schwarz Anna M. , Hinz Stefan , Schwarz Margaret A. , Schwarz Roderich E.
Published: March 2014

Nanoparticle albumin–bound paclitaxel (nab-paclitaxel, NPT) has recently shown efficacy in pancreatic ductal adenocarcinoma (PDAC). Targeting tumor angiogenesis is a sensible combination therapeutic strategy for cancer, including PDAC. We tested the hypothesis that NPT response in PDAC can be enhanced by the mechanistically different antiangiogenic agents bevacizumab (Bev) or sunitinib (Su), despite its inherently increased tumor penetration and drug delivery. Compared with controls (19 days), median animal survival was increased after NPT therapy (32 days, a 68% increase, P = 0.0008); other regimens with enhanced survival were NPT+Bev (38 days, a 100% increase, P = 0.0004), NPT+Su (37 days, a 95% increase, P = 0.0004), and NPT+Bev+Su (49 days, a 158% increase, P = 0.0001) but not bevacizumab, sunitinib, or Bev+Su therapy. Relative to controls (100 ± 22.8), percentage net local tumor growth was 28.2 ± 23.4 with NPT, 55.6 ± 18 (Bev), 38.8 ± 30.2 (Su), 11 ± 7.2 (Bev+Su), 32.8 ± 29.2 (NPT+Bev), 6.6 ± 10.4 (NPT+Su), and 13.8 ± 12.5 (NPT+Bev+Su). Therapeutic effects on intratumoral proliferation, apoptosis, microvessel density, and stromal density corresponded with tumor growth inhibition data. In AsPC-1 PDAC cells, NPT IC50 was reduced >6-fold by the addition of sunitinib (IC25) but not by bevacizumab. In human umbilical vein endothelial cells (HUVEC), NPT IC50 (82 nmol/L) was decreased to 41 nmol/L by bevacizumab and to 63 nmol/L by sunitinib. In fibroblast WI-38 cells, NPT IC50 (7.2 μmol/L) was decreased to 7.8 nmol/L by sunitinib, but not by bevacizumab. These findings suggest that the effects of one of the most active cytotoxic agents against PDAC, NPT, can be enhanced with antiangiogenic agents, which clinically could relate to greater responses and improved antitumor results. Mol Cancer Ther; 13(5); 1032–43. ©2014 AACR.
Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma
Authors: Ng Kevin Tak-Pan , Lo Chung Mau , Guo Dong Yong , Qi Xiang , Li Chang Xian , Geng Wei , Liu Xiao Bing , Ling Chang Chun , Ma Yuen Yuen , Yeung Wai Ho , Shao Yan , Poon Ronnie Tung-Ping , Fan Sheung Tat , Man Kwan
Published: March 2014

Chemoresistance is one of the major obstacles in systemic chemotherapy and targeted therapy for patients with advanced hepatocellular carcinoma. To identify novel chemoresistance-associated targets in hepatocellular carcinoma, chemoresistant hepatocellular carcinoma cell lines were established. By comparing the global gene expression profiles between chemoresistant and chemosensitive cell lines, eight novel chemoresistance-associated genes were identified to be significantly associated with the commonly augmented chemoresistance of hepatocellular carcinoma cells. One upregulated candidate named transmembrane protein 98 (TMEM98) was found to be overexpressed in 80 of 118 (67.80%) of patients with hepatocellular carcinoma. TMEM98 mRNA in tumor tissues was significantly higher than nontumor tissues of patients with hepatocellular carcinoma (P < 0.0001). Upregulation of TMEM98 was significantly correlated with advanced tumor stage (P = 0.048), high incidence of early tumor recurrence (P = 0.005), poor overall survival (P = 0.029), and poor disease-free survival (P = 0.011) of patients with hepatocellular carcinoma after hepatectomy. Importantly, upregulation of TMEM98 mRNA in patients with hepatocellular carcinoma who received transarterial chemoembolization (TACE) treatment was significantly higher than in patients without TACE treatment (P = 0.046). Moreover, patients with poor response to TACE treatment had higher degree of TMEM98 upregulation than the responsive patients. In vitro and in vivo studies showed that suppression of TMEM98 in chemoresistant hepatocellular carcinoma cells restored their chemosensitivity, while forced overexpression of TMEM98 enhanced their chemoresistance. The mechanism of TMEM98 in conferring chemoresistance of hepatocellular carcinoma might be possibly through activation of the AKT pathway and deactivation of p53. In conclusion, we identified a panel of novel common chemoresistance-associated genes and demonstrated that TMEM98 is a chemoresistance-conferring gene in hepatocellular carcinoma. Mol Cancer Ther; 13(5); 1285–97. ©2014 AACR.
Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials
Authors: Fritsch Christine , Huang Alan , Chatenay-Rivauday Christian , Schnell Christian , Reddy Anupama , Liu Manway , Kauffmann Audrey , Guthy Daniel , Erdmann Dirk , De Pover Alain , Furet Pascal , Gao Hui , Ferretti Stephane , Wang Youzhen , Trappe Joerg , Brachmann Saskia M. , Maira Sauveur-Michel , Wilson Christopher , Boehm Markus , Garcia-Echeverria Carlos , Chene Patrick , Wiesmann Marion , Cozens Robert , Lehar Joseph , Schlegel Robert , Caravatti Giorgio , Hofmann Francesco , Sellers William R.
Published: March 2014

Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kα may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Kα and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose- and time-dependent inhibition of PI3Kα signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials. Mol Cancer Ther; 13(5); 1117–29. ©2014 AACR.
ADAMTS-7 Expression Increases in the Early Stage of Angiotensin II-Induced Renal Injury in Elderly Mice
Authors: Gao Yan-Xiang , Yu Chang-An , Lu Jian-Hua , Gao Hong-Mei , Li Geng , Kong Wei , Zheng Jingang
Published: March 2014

Background/Aims: We investigated the recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), and matrix metalloproteinases (MMPs) as inflammatory mediators in inflammatory kidney damage by studying ADAMTS-1, -4, and -7 and MMP-9 expression in elderly mouse kidneys after angiotensin II (Ang II) administration. Methods: Ang II (2.5 µg/kg/min) or norepinephrine (8.3 µg/kg/min) was subcutaneously infused in old mice. Renal injury was assessed by hematoxylin-eosin staining, 24-h albuminuria, and immunohistochemistry to evaluate inflammatory cell markers. The mRNA and protein expression of ADAMTS-1, -4, and -7 and MMP-9 were determined using real-time PCR, Western blot, and immunohistochemistry 3 days after Ang II or norepinephrine administration. Results: Elderly mice in the Ang II group developed hypertension and pathological kidney damage. The mRNA and protein levels of ADAMTS-7 in the Ang II group were 3.3 ± 1.1 (P = 0.019) and 1.6 ± 0.1 (P = 0.047) vs. 1.0 ± 0.1 and 1.0 ± 0.1 in the control group on day 3. In contrast, treatment with the hypertensive agent norepinephrine did not lead to obvious renal damage or an increase in renal ADAMTS-7 expression. Conclusions: Renal ADAMTS-7 expression was induced by Ang II in elderly mice. The overexpression of ADATMTS-7 might contribute to early inflammatory kidney damage associated with aging.
Aging and Chronic Kidney Disease
Authors: Nitta Kosaku , Okada Kazuyoshi , Yanai Mitsuru , Takahashi Susumu
Published: March 2014

A recent report has dealt with geriatric nephrology, including epidemiology and pathophysiology of chronic kidney disease (CKD), attempting to get nephrologists to pay more attention to elderly CKD patients. The aims of this article are to summarize the morphological and functional properties of the aging kidney, and to better understand nephrology care for elderly CKD patients. The kidneys are affected by the aging process, which results in numerous effects on the renal system. In addition, the elderly population is hetereogenous - some have a decline in GFR explained by diseases that complicate aging such as arteriosclerosis with hypertension, whereas in the most of healthy adults the decline in GFR is much more modest and not inevitable. The values for normal estimated glomerular filtration rate (eGFR) in aging population have important implications for the diagnosis of CKD in the elderly. However, the MDRD equation underestimates mean eGFR by 25% and the CKD-EPI equation underestimates mean GFR by 16%. This bias may lead to misclassifying healthy older persons as having CKD. It is also still unknown whether and how age influences the predictive role of other risk factors for end-stage renal disease (ESRD) and death in referred as well as unreferred patients. The risk of ESRD was reported to be higher than the risk of death without ESRD for ages <60 years, and independent of eGFR. Proteinuria significantly increased the risk of ESRD with advancing age. In older patients on nephrology care, the risk of ESRD prevailed over mortality even when eGFR was not severely impaired. Proteinuria increases the risk of ESRD, while the predictive role of other modifiable risk factors was unchanged compared with younger patients. The decision to initiate renal replacement therapy in the elderly is complicated by more challenges than in younger patients. Calorie restriction and Klotho deficiency may be a candidate therapeutic target for attenuating kidney aging.
Long-Term Follow-Up After Catheter Ablation of Paroxysmal Atrial Fibrillation
Authors: Takigawa Masateru , Takahashi Atsushi , Kuwahara Taishi , Okubo Kenji , Takahashi Yoshihide , Watari Yuji , Takagi Katsumasa , Fujino Tadashi , Kimura Shigeki , Hikita Hiroyuki , Tomita Makoto , Hirao Kenzo , Isobe Mitsuaki
Published: March 2014

Background—

Although catheter ablation (CA) is a standard treatment for atrial fibrillation (AF), its long-term efficacy remains unclear. This study aimed to elucidate the incidences of AF recurrence and of progression from paroxysmal to persistent AF, after CA, in patients with paroxysmal AF.

Methods and Results—

We examined the incidence of AF recurrence and AF progression in 1220 consecutive patients (mean age, 61 years), with symptomatic paroxysmal AF, undergoing CA, based on extensive pulmonary vein isolation and focal ablation for nonpulmonary vein foci. AF recurrence–free survival probabilities at 5 years were 59.4% after the initial CA and 81.1% after the final CA (average, 1.3 procedures). During a median follow-up period of 47.9 (range, 5.3–123.3) months after the initial CA, AF progressed from paroxysmal to persistent in 15 (1.2%) patients (0.3%/y). The duration of AF history (hazard ratio [HR], 1.03;
P
<0.0001), number of ineffective antiarrhythmics (HR, 1.09;
P
=0.005), and left atrial diameter indexed by the body surface area (HR, 1.05;
P
=0.001) were significant predictors of AF recurrence. Patient age (HR, 1.12;
P
=0.0001) and left atrial diameter indexed by the body surface area (HR, 1.26;
P
=0.0006) were significantly associated with AF progression. Patients aged ≤65 years and with a left atrial diameter indexed by the body surface area of ≤24.0 mm/m
2
did not develop AF progression for ≤10 years after the initial CA.

Conclusions—

Although the long-term follow-up revealed the effect of CA on preventing AF recurrence, repeated CA sessions might be required. The rate of progression from paroxysmal to persistent AF was 0.3%/y.
Impact of Cardiac Resynchronization Therapy on Hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial
Authors: Gillis Anne M , Kerr Charles R. , Philippon François , Newton Gary , Talajic Mario , Froeschl Michael , Froeschl Sandra , Swiggum Elizabeth , Yetisir Elizabeth , Wells George A. , Tang Anthony S.
Published: March 2014

Background—

This study reports the impact of cardiac resynchronization therapy (CRT) on hospitalizations in patients randomized to implantable cardioverter-defibrillator (ICD) or ICD-CRT in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT).

Methods and Results—

Hospitalization rates and lengths of hospital stay were compared between the 2 groups. At the 18-month follow-up, the numbers of patients hospitalized for any cause were similar in the ICD (n=351, 38.8%) and ICD-CRT (n=331, 30.0%) groups. The number of patients hospitalized for heart failure was significantly lower in the ICD-CRT (n=101, 11.3%) compared with the ICD (n=141, 15.6%;
P
=0.003) group. The number of patients hospitalized for a device-related indication was similar in the ICD-CRT group (n=147, 16.4%) and ICD group (n=126, 13.9%;
P
=0.148). The total number of hospitalizations for any cause (n=1448 versus n=1553;
P
=0.042), any cardiovascular cause (n=667 versus n=790;
P
=0.017), and any heart failure cause (n=385 versus n=505;
P
<0.0001) was significantly lower in ICD-CRT group compared with the ICD group, whereas the number of hospitalizations for device-related causes was significantly higher in the ICD-CRT group compared with the ICD group (246 versus 159;
P
<0.001). Although the reduction in hospitalizations for heart failure in the CRT-ICD group was offset by an increased number of hospitalizations for device-related indications, the length of hospital stay for any cause was significantly shorter in the ICD-CRT group (8.83±13.30 days) compared with the ICD group (9.59±14.40 days;
P
=0.005).

Conclusion—

ICD-CRT therapy significantly reduces hospitalizations and total days in hospital in patients with New York Heart Association class II/III heart failure compared with ICD therapy despite increased admissions for device-related indications.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00251251.
Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice
Authors: Li Li , Wei Chuanyu , Kim Il-Kwon , Janssen-Heininger Yvonne , Gupta Sudhiranjan
Published: March 2014

Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with significant morbidity and mortality in patients with various lung and heart diseases. PAH is characterized by vascular obstruction which leads to a sustained increased pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure. Limited PAH therapies indicate that novel approaches are urgently needed for the treatment of PAH. Nuclear factor-κB (NF-κB) has been shown to play an important role in different cardiac pathologies; however, the role of NF-κB remains limited in the setting of PAH. Here, we investigated whether NF-κB inhibition in the lungs using Club (Clara) cell-10 promoter driving IκBα mutant had any effect in monocrotaline (MCT)-induced PAH mouse model. Our data revealed that MCT-induced PAH and right ventricular hypertrophy were associated with NF-κB activation, inflammatory response, and altered expression of bone morphogenetic protein receptor 2, inhibitor of differentiation, and Notch-3 signaling molecules in wild-type mice; and all these alterations were prevented in IκBα mutant mice treated with MCT. Moreover, endothelial cell apoptosis and endothelial-to-mesenchymal transition occurred in the lungs of MCT-treated wild-type mice and were restored in IκBα mutant+MCT mice, indicating an association with NF-κB signaling. In lung microvascular endothelial cells, IκBα (AA) mutant plasmid restored the decreased bone morphogenetic protein receptor 2 protein level and reversed the endothelial-to-mesenchymal transition process induced by transforming growth factor-β1. We conclude that NF-κB regulates bone morphogenetic protein receptor 2–inhibitor of differentiation–Notch-3 axis genes and the subsequent endothelial cell apoptosis and endothelial-to-mesenchymal transition events in the lungs, providing new mechanistic information about MCT-induced PAH and right ventricular hypertrophy.