bluuebunny/crossref_metadata_2025 huggingface dataset:
In VitroAntiproliferative Effect of the Acetone Extract ofRubus fairholmianusGard. Root on Human Colorectal Cancer Cells
Authors: Plackal Adimuriyil George Blassan , Tynga Ivan Mfouo , Abrahamse Heidi
Published: May 2015

Plants and plant derived products exert chemopreventive effects on various cancer cell lines by the induction of cell death mechanisms. The effects of root acetone extract ofRubus fairholmianus(RFRA) on the proliferation of human colorectal cancer (Caco-2) cells have been investigated in this study. The extract led to a dose dependent decrease in both viability and proliferation and increased cytotoxicity using trypan blue exclusion, adenosine 5′-triphosphate (ATP), and lactate dehydrogenase (LDH) assay. The morphological features of the treated cells were supportive for the antiproliferative activity. The Annexin V/propidium iodide staining indicated thatR. fairholmianusinduced toxic effects in Caco-2 cells and the percentages of the early and late apoptotic population significantly increased when compared with control cells. Also we studied the apoptosis inducing ability of the extract by analysing caspase 3/7 activity and the induction of cell death via the effector caspases was confirmed; the activity increased in treated cells compared with control. Thus the present findings highlight that theR. fairholmianusroot acetone extract exhibits antiproliferative activity on Caco-2 cells by the induction of apoptosis via caspase dependent pathway.
A Case Report and Review of the Literature of Adult Gastric Duplication Cyst
Authors: Samona Scott , Berri Richard
Published: May 2015

Gastrointestinal (GI) duplication cysts are a rare congenital disease. They may involve any level of the alimentary tract, but they most commonly involve the ileum, esophagus, and jejunum. Gastric duplication cysts represent approximately 4–8% of GI duplication cysts, the majority of which present in early childhood. We present a rare case of adult gastric duplication cyst in a 25-year-old female found to have abdominal mass on computed tomography imaging. There are several potential methods to diagnose gastric duplication cyst and treatment of choice is complete surgical resection.
A Butterfly-Shaped Wideband Microstrip Patch Antenna for Wireless Communication
Authors: Sun Liling , He Maowei , Hu Jingtao , Zhu Yunlong , Chen Hanning
Published: May 2015

A novel butterfly-shaped patch antenna for wireless communication is introduced in this paper. The antenna is designed for wideband wireless communications and radio-frequency identification (RFID) systems. Two symmetrical quasi-circular arms and two symmetrical round holes are incorporated into the patch of a microstrip antenna to expand its bandwidth. The diameter and position of the circular slots are optimized to achieve a wide bandwidth. The validity of the design concept is demonstrated by means of a prototype having a bandwidth of about 40.1%. The return loss of the butterfly-shaped antenna is greater than 10 dB between 4.15 and 6.36 GHz. The antenna can serve simultaneously most of the modern wireless communication standards.
Adaptive Output Tracking Control for Nonlinear Systems with Failed Actuators and Aircraft Flight System Applications
Authors: Hou Chuanjing , Hu Lisheng , Zhang Yingwei
Published: May 2015

An adaptive failure compensation scheme using output feedback is proposed for a class of nonlinear systems with nonlinearities depending on the unmeasured states of systems. Adaptive high-gain K-filters are presented to suppress the nonlinearities while the proposed backstepping adaptive high-gain controller guarantees the stability of the closed-loop system and small tracking errors. Simulation results verify that the adaptive failure compensation scheme is effective.
Constrictive Pericarditis in the Presence of Remaining Remnants of a Left Ventricular Assist Device in a Heart Transplanted Patient
Authors: Rivinius R. , Helmschrott M. , Koch V. , Sedaghat-Hamedani F. , Fortner P. , Darche F. F. , Thomas D. , Ruhparwar A. , Schmack B. , Karck M. , Akhavanpoor M. , Erbel C. , Gleissner C. A. , Buss S. J. , Mereles D. , Ehlermann P. , Katus H. A. , Doesch A. O.
Published: May 2015

Constrictive pericarditis (CP) is a severe subform of pericarditis with various causes and clinical findings. Here, we present the unique case of CP in the presence of remaining remnants of a left ventricular assist device (LVAD) in a heart transplanted patient. A 63-year-old man presented at the Heidelberg Heart Center outpatient clinic with progressive dyspnea, fatigue, and loss of physical capacity. Heart transplantation (HTX) was performed at another heart center four years ago and postoperative clinical course was unremarkable so far. Pharmacological cardiac magnetic resonance imaging (MRI) stress test was performed to exclude coronary ischemia. The test was negative but, accidentally, a foreign body located in the epicardial adipose tissue was found. The foreign body was identified as the inflow pump connection of an LVAD which was left behind after HTX. Echocardiography and cardiac catheterization confirmed the diagnosis of CP. Surgical removal was performed and the epicardial tubular structure with a diameter of 30 mm was carefully removed accompanied by pericardiectomy. No postoperative complications occurred and the patient recovered uneventfully with a rapid improvement of symptoms. On follow-up 3 and 6 months later, the patient reported about a stable clinical course with improved physical capacity and absence of dyspnea.
Damage Characteristics of Surrounding Rock Subjected to VCR Mining Blasting Shock
Authors: Jiang Nan , Zhou Chuanbo , Luo Xuedong , Lu Shiwei
Published: May 2015

For limiting the damage range caused by explosive shock loads in vertical crater retreat (VCR) mining, the blasting damage characteristics of surrounding rock were studied by two methods: numerical simulation and ultrasonic testing. Combined with the mining blasting in Dongguashan Copper Mine of China, the VCR blasting shock characteristics under different conditions are obtained by using LSDYNA. Based on statistical fracture mechanics and damage mechanics theories, a damage constitutive model for rock mass subjected to blasting shock load was established. Then by using the fast Lagrange analysis codes (FLAC3D), the blasting damage characteristics of surrounding rock were analyzed by applying the blasting shock loads obtained from the VCR mining and the damage zone is obtained. At last, the relationship between the amount of explosives and the radius of damaged surrounding rock mass was discussed, and its formula was also derived. The research provides a theoretical basis for rationally controlling stope boundaries and optimizing mining blasting parameters.
Chemotherapy in the Setting of Severe Liver Dysfunction in Patients with Metastatic Colorectal Cancer
Authors: Kasi Pashtoon Murtaza , Thanarajasingam Gita , Finnes Heidi D. , Villasboas Bisneto Jose C. , Hubbard Joleen M. , Grothey Axel
Published: May 2015

The liver is the dominant site of metastases for patients with metastatic colorectal cancer (mCRC). Depending on the timing of diagnosis and the biology of the disease, it is not uncommon for these patients to present with visceral crisis in the form of severe liver dysfunction. Treatment of these individuals is, however, difficult and challenging. The decision to consider chemotherapy in these dire circumstances entails consideration of numerous factors. If we were to focus on just the metabolism of the different drugs and biologic agents available to treat mCRC, both 5-fluorouracil and oxaliplatin alone or in combination with a monoclonal antibody are reasonable choices. Specifically, FOLFOX is a feasible and safe option in patients with mCRC with severe liver dysfunction. Choice of the biologic agent to add to the doublet chemotherapy could be individualized based on the RAS status and the clinical scenario. Based on the divergent experience of treating 2 cases and other prior reports, a summary of recommendations with a model in the form of a “therapeutic triad” is presented. The paper highlights the therapeutic challenges in patients with mCRC and severe liver dysfunction. The choice of chemotherapeutic agents and reports of other cases/series is also presented.
Cognitive Functions and Depression in Patients with Irritable Bowel Syndrome
Authors: Farup Per G. , Hestad Knut
Published: May 2015

Background. Irritable bowel syndrome (IBS) is associated with depression and depression with impaired cognitive functions. The primary aim was to study associations between depression and cognitive functions in patients with IBS.Methods. IBS (according to the Rome III criteria), cognitive functions (evaluated with a set of neuropsychological tests), and depression (measured with Beck Depression Inventory II and Montgomery-Åsberg Depression Scale) were analysed in patients with idiopathic depression and in patients with unspecified neurological symptoms.Results. 18 and 48 patients with a mean age of 47 and 45 years were included in the “Depression” and “Neurological” group, respectively. In the “Depression” group, the degree of depression was significantly higher in patients with IBS than in those without. Depression was associated with impaired cognitive function in 6 out of 17 neuropsychological tests indicating reduced set shifting, verbal fluency, attention, and psychomotor speed. IBS was statistically significantly associated with depression but not with any of the tests for cognitive functions.Conclusions. IBS was associated with depression but not with impaired cognitive functions. Since the idiopathic depression was associated with cognitive deficits, the findings could indicate that the depression in patients with IBS differs from an idiopathic depression.
Blast-Induced Damage on Millisecond Blasting Model Test with Multicircle Vertical Blastholes
Authors: Ma Qin-yong , Yuan Pu , Zhang Jing-shuang , Ma Rui-qiu , Han Bo
Published: May 2015

To investigate the blast-induced damage effect on surrounding rock in vertical shaft excavation, 4 kinds of millisecond blasting model tests with three-circle blastholes were designed and carried out with excavation blasting in vertical shaft as the background. The longitudinal wave velocity on the side of concrete model was also measured before and after blasting. Then blast damage factor was then calculated by measuring longitudinal wave velocity before and after blasting. The test results show that the blast-induced damage factor attenuated gradually with the centre of three-circle blastholes as centre. With the threshold value of 0.19 for blast-induced damage factor, blast-induced damage zones for 4 kinds of model tests are described and there is an inverted cone blast-induced damage zone in concrete model. And analyses of cutting effect and blast-induced damage zone indicate that in order to minimize the blast-induced damage effect and ensure the cutting effect the reasonable blasting scheme for three-circle blastholes is the inner two-circle blastholes initiated simultaneously and the outer third circle blastholes initiated in a 25 ms delay.
Effect of Fe3O4Nanoparticles on Skin Tumor Cells and Dermal Fibroblasts
Authors: Alili Lirija , Chapiro Swetlana , Marten Gernot U. , Schmidt Annette M. , Zanger Klaus , Brenneisen Peter
Published: May 2015

Iron oxide (Fe3O4) nanoparticles have been used in many biomedical approaches. The toxicity of Fe3O4nanoparticles on mammalian cells was published recently. Though, little is known about the viability of human cells after treatment with Fe3O4nanoparticles. Herein, we examined the toxicity, production of reactive oxygen species, and invasive capacity after treatment of human dermal fibroblasts (HDF) and cells of the squamous tumor cell line (SCL-1) with Fe3O4nanoparticles. These nanoparticles had an average size of 65 nm. Fe3O4nanoparticles induced oxidative stress via generation of reactive oxygen species (ROS) and subsequent initiation of lipid peroxidation. Furthermore, the question was addressed of whether Fe3O4nanoparticles affect myofibroblast formation, known to be involved in tumor invasion. Herein, Fe3O4nanoparticles prevent the expression alpha-smooth muscle actin and therefore decrease the number of myofibroblastic cells. Moreover, our data showin vitrothat concentrations of Fe3O4nanoparticles, which are nontoxic for normal cells, partially reveal a ROS-triggered cytotoxic but also a pro-invasive effect on the fraction of squamous cancer cells surviving the treatment with Fe3O4nanoparticles. The data herein show that the Fe3O4nanoparticles appear not to be adequate for use in therapeutic approaches against cancer cells, in contrast to recently published data with cerium oxide nanoparticles.
Impact Analysis of Window-Wall Ratio on Heating and Cooling Energy Consumption of Residential Buildings in Hot Summer and Cold Winter Zone in China
Authors: Yang Qiaoxia , Liu Meng , Shu Chang , Mmereki Daniel , Uzzal Hossain Md. , Zhan Xiang
Published: May 2015

In order to assess the optimal window-wall ratio and the proper glazing type in different air conditioning system operation modes of residential buildings for each orientation in three typical cities in hot summer and cold winter zone: Chongqing, Shanghai, and Wuhan simulation models were built and analyzed using Designer’s Simulation Toolkit (DeST). The study analyzed the variation of annual heating energy demand, annual cooling energy demand, and the annual total energy consumption in different conditions, including different orientations, patterns of utilization of air conditioning system, window-wall ratio, and types of windows. The results show that the total energy consumption increased when the window-wall ratio is also increased. It appears more obvious when the window orientation is east or west. Furthermore, in terms of energy efficiency, low-emissivity (Low-E) glass performs better than hollow glass. From this study, it can be concluded that the influence and sensitivity of window-wall ratio on the total energy consumption are related to the operation mode of air conditioning system, the orientation of outside window, and the glazing types of window. The influence of the factors can be regarded as reference mode for the window-wall ratio when designing residential buildings.
A Local Estimate for the Maximal Function in Lebesgue Spaces with EXP-Type Exponents
Authors: Fiorenza Alberto
Published: May 2015

It is proven that if1≤p(·)<∞in a bounded domainΩ⊂Rnand ifp(·)∈EXPa(Ω)for somea>0, then givenf∈Lp(·)(Ω), the Hardy-Littlewood maximal function off,Mf, is such thatp(·)log(Mf)∈EXPa/(a+1)(Ω). Becausea/(a+1)<1, the thesis is slightly weaker than(Mf)λp(·)∈L1(Ω)for someλ>0. The assumption thatp(·)∈EXPa(Ω)for somea>0is proven to be optimal in the framework of the Orlicz spaces to obtainp(·)log(Mf)in the same class of spaces.
Warning Method of Coal Bursting Failure Danger by Electromagnetic Radiation
Authors: Liu Guang-Jian , Lu Cai-Ping , Wang Hong-Yu , Liu Peng-Fei , Liu Yang
Published: May 2015

Electromagnetic radiation (EMR) can reflect the stress state and deformation level of coal, yet its warning indexes correlated with coal properties and roof caving is poorly understood. The laboratory observations of EMR effects of coal samples bursting failure and in situ investigations in the process of roof caving are presented in this paper. EMR peak with increasing stress is discussed when the failure of coal samples happens, which provides an explanation to EMR signals positively correlated well with the stress loaded. The linearly increasing relation is also found between EMR intensity and the uniaxial compressive strength, and EMR maximum amplitudes and pulses behave a logarithmic accretion tendency with bursting energy indexes of coal. By in situ investigations, it is well found that EMR amplitude can effectively warn coal deformation and failure based on the critical value 120 mV proposed from experiments.
Research on Polarization Cancellation of Nonstationary Ionosphere Clutter in HF Radar System
Authors: Mao Xingpeng , Hong Hong , Deng Weibo , Liu Yongtan
Published: May 2015

Oblique projection polarization filter (OPPF) can be applied as an effective approach for interference cancellation in high-frequency surface wave radar (HFSWR) and other systems. In order to suppress the nonstationary ionosphere clutter further, a novel OPPF based clutter suppressing scheme is proposed in this paper. The polarization and nonstationary characteristic of the clutter are taken into account in the algorithms referred to as range-Doppler domain polarization suppression (RDDPS) and the range-time domain polarization suppression (RTDPS) method, respectively. The RDDPS is designed for weak ionosphere clutter and implemented in the range-Doppler domain directly, whereas the RTDPS algorithm is designed to suppress the powerful ionosphere clutter with a multisegment estimation and suppression scheme. About 15–23 dB signal to interference ratio (SIR) improvement can be excepted when using the proposed method, whereas the targets can be more easily detected in the range-Doppler map. Experimental results demonstrate that the scheme proposed is effective for nonstationary ionosphere clutter and is proven to be a practical interference cancellation technique for HFSWR.
Malakoplakia of the Pancreas with Simultaneous Colon Involvement: Case Report and Review of the Literature
Authors: Guha Surya , Liu Haiyan
Published: May 2015

Although malakoplakia has been reported to occur at various body sites, pancreatic malakoplakia with simultaneous colonic involvement is very rare. Lesions of malakoplakia can masquerade as tumor masses leading to unwanted resections. Nevertheless, malakoplakia can occur in association with frank carcinomas, especially in the colon. By reporting a case of pancreatic malakoplakia diagnosed by fine needle aspiration cytology, this paper aims to describe cytologic features of malakoplakia and to further review findings from previous reported cases of pancreatic malakoplakia in the literature. With advances in minimally invasive, image-guided aspiration technologies, cytomorphological analyses can diagnose lesions of malakoplakia. This may help avoid surgeries that would have otherwise been carried out due to a misleading impression of tumor. However challenges remain as to the further management of patients diagnosed with this condition. More studies are necessary to determine the probability of malignancies arising in association with malakoplakia, in order to devise appropriate treatment protocols.
A Nonlinear Exact Disturbance Observer Inspired by Sliding Mode Techniques
Authors: Chen Xinkai
Published: May 2015

Inspired by sliding mode techniques, a nonlinear exact disturbance observer is proposed. The disturbance and its derivatives up to the second order are assumed to be bounded. However, the bounds of the disturbance and its derivatives are unknown, and they are adaptively estimated online during the observation of the disturbances. The exact convergence of the disturbance observer to the genuine disturbance is assured theoretically. The convergence speed of the disturbance estimation error is controlled by design parameters. The proposed method is robust to the type of disturbance and is easy to be implemented. Computer simulation results show the superiority and effectiveness of the proposed formulation.
Effects of Fine Gangue on Strength, Resistivity, and Microscopic Properties of Cemented Coal Gangue Backfill for Coal Mining
Authors: Qi Tingye , Feng Guorui , Li Yanrong , Guo Yuxia , Guo Jun , Zhang Yujiang
Published: May 2015

The cemented coal gangue backfill (CGB) in coal mining is normally made of gangue (particle size of 0–15 mm), fly ash, cement, and water. In this study, the effects of the weight content (ranging from 20% to 60%) of fine gangue (0–5 mm) on the microscopic characteristics, resistivity, and compressive strength of CGB were investigated at 3 d and 28 d curing times, respectively. The test results indicate that the strengths of the CGB, regardless of the curing time, increased with fine gangue content changing from 20% up to 40%. Further increase in fine gangue introduced a decrease in the strength. Another observation is that, at 3 days, a general increasing trend of CGB resistivity was noted with fine gangue content. At 28 days, the resistivity of CGB decreased with increase in the fine gangue content. Correlations between the resistivity and compression strength of CGB show a concave pattern, which attribute to the various micromechanism influenced on the resistivity and strength of CGB with different fine gangue content. It indicates that using resistivity to derive strength of CGB is not appropriate.
Mechanism of Roof Shock in Longwall Coal Mining under Surface Gully
Authors: Fan Gangwei , Zhang Dongsheng , Wang Xufeng
Published: May 2015

The paper presents an interpretation on the abnormal roof shock in longwall coal mining under gullies using physical modeling, numerical modeling, and mechanical analysis. The modeling results show that the roof movement causes the shock load onto the stope in longwall coal mining under surface gully. The triggering mechanism of shock load depends on the direction of the face retreat with respect to the bottom of the surface gully. The slope tends to slide along the interface plane with a long periodical weighting intervals when mining towards the bottom of the gully (downslope direction), while the overburden strata may be split into blocks and tend to topple towards the free face of gully when mining away from the bottom of the gully (upslope direction). The mechanical models showed that, during the period of mining in downslope direction, planar sliding and key fragmental blocks cause a sudden roof shearing off which could result in shock load and, during the period of mining in upslope direction, the overburden blocks may become unstable due to shearing off which could resulted in large shock pressure onto the stope.
Absence of Clinical and Hemodynamic Consequences due to Posterior Tibial Artery Congenital Aplasia
Authors: Karaolanis Georgios , Galyfos George , Karanikola Evridiki , Palla Viktoria Varvara , Filis Konstantinos
Published: May 2015

The exact knowledge of popliteal artery and its branches’ anatomic variations is important for the clinical practice of angiology, vascular surgery, and interventional procedures. Congenital absence of the artery leads, in some cases, to early malformations of the extremity in the childhood; however, it may also remain asymptomatic. We present an unusual case of a 76-year-old male patient complaining of paraesthesia in both limbs and bilateral aplasia of posterior tibial artery (PTA). Physical examination, ankle-brachial indexes, before and after exercise, arterial duplex scan, and magnetic resonance arteriography were performed. Arterial pulses for PTA at the level of the ankle were normal; arterial duplex study showed biphasic arterial flow at the level of the ankle. Color duplex ultrasound as well as magnetic resonance arteriography revealed the absence of the PTA in both limbs. The vascularization of the fibula was bilaterally normal. The patient underwent also neurological examination and electromyography, which were normal. The evaluation of the possible clinical signs and symptoms and the hemodynamic consequences of this condition are further discussed.
Psychometric Properties of the Serbian Version of the Maslach Burnout Inventory‐Human Services Survey: A Validation Study among Anesthesiologists from Belgrade Teaching Hospitals
Authors: Matejić Bojana , Milenović Miodrag , Kisić Tepavčević Darija , Simić Dušica , Pekmezović Tatjana , Worley Jody A.
Published: May 2015

We report findings from a validation study of the translated and culturally adapted Serbian version of Maslach Burnout Inventory‐Human Services Survey (MBI‐HSS), for a sample of anesthesiologists working in the tertiary healthcare. The results showed the sufficient overall reliability (Cronbach’s α = 0.72) of the scores (items 1–22). The results of Bartlett’s test of sphericity (χ2 = 1983.75, df = 231, p < 0.001) and Kaiser‐Meyer‐Olkin measure of sampling adequacy (0.866) provided solid justification for factor analysis. In order to increase sensitivity of this questionnaire, we performed unfitted factor analysis model (eigenvalue greater than 1) which enabled us to extract the most suitable factor structure for our study instrument. The exploratory factor analysis model revealed five factors with eigenvalues greater than 1.0, explaining 62.0% of cumulative variance. Velicer’s MAP test has supported five‐factor model with the smallest average squared correlation of 0,184. This study indicated that Serbian version of the MBI‐HSS is a reliable and valid instrument to measure burnout among a population of anesthesiologists. Results confirmed strong psychometric characteristics of the study instrument, with recommendations for interpretation of two new factors that may be unique to the Serbian version of the MBI‐HSS.
A Comparison of Mine Seismic Discriminators Based on Features of Source Parameters to Waveform Characteristics
Authors: Ma Ju , Zhao Guoyan , Dong Longjun , Chen Guanghui , Zhang Chuxuan
Published: May 2015

To find efficient methods for classifying mine seismic events, two features extraction approaches were proposed. Features of source parameters including the seismic moment, the seismic energy, the energy ratio of S- to P-wave, the static stress drop, time of occurrence, and the number of triggers were selected, counted, and analyzed in approach I. Waveform characteristics consisting of two slope values and the coordinates of the first peak and the maximum peak were extracted as the discriminating parameters in approach II. The discriminating performance of the two approaches was compared and discussed by applying the Bayes discriminant analysis to the characteristic parameters extracted. Classification results show that 83.5% of the original grouped cases are correctly classified by approach I, and 97.1% of original grouped cases are correctly classified by approach II. The advantages and limitations pertaining to each classifier were discussed by plotting the event magnitude versus sample number. Comparative analysis shows that the proposed method of approach II not only has a low misjudgment rate but also displays relative constancy when the testing samples fluctuate with seismic magnitude and energy.
Outbreak Control and Clinical, Pathological, and Epidemiological Aspects and Molecular Characterization of a Bovine Herpesvirus Type 5 on a Feedlot Farm in São Paulo State
Authors: Megid Jane , Ferreira Vicente Acácia , Appolinario Camila Michele , Allendorf Susan Dora , de Souza Ribeiro Mioni Mateus , Gasparini Baraldi Thaís , Cortez Adriana , Bryan Heinemann Marcos , Reinaldo Silva Fonseca Clovis , Cristina Pelícia Vanessa , Devidé Ribeiro Bruna Leticia , Hiromi Okuda Liria , Pituco Edviges Maristela
Published: May 2015

This paper describes the control, epidemiological, pathological, and molecular aspects of an outbreak of meningoencephalitis in calves due to bovine herpesvirus 5 at a feedlot with 540 animals in São Paulo State, Brazil. The introduction of new animals and contact between the resident animals and the introduced ones were most likely responsible for virus transmission. Bovine herpesvirus 1 vaccine was used, resulting in the efficacy of the outbreak control, although two bovine herpesvirus 1 positive animals, vaccinated and revaccinated, presented meningoencephalitis, thereby characterizing vaccinal failure.
Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer
Authors: Zhu Yezi , Liu Chengfei , Armstrong Cameron , Lou Wei , Sandher Amandeep , Gao Allen C.
Published: May 2015

Purpose: Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel.

Experimental Design: ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo.

Results: We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel-resistant and androgen receptor (AR)–negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel-resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status.

Conclusions: We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer. Clin Cancer Res; 21(18); 4133–42. ©2015 AACR.
Growth Factor Receptor Fusions Predict Therapeutic Sensitivity
Authors: Ahluwalia Manmeet S. , Rich Jeremy N.
Published: May 2015

Dysregulated growth factor pathways promote tumor growth in many cancers, but receptor-targeting strategies frequently offer limited benefit despite activation by receptor overexpression or amplification. In contrast, tumors harboring growth factor receptor fusions display exquisite dependence on receptor activity, providing predictive markers for patient response to inform precise oncology treatment. Clin Cancer Res; 21(14); 3105–7. ©2015 AACR.

See related article by Di Stefano et al., p. 3307
23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity
Authors: Proia Theresa , Jiang Feng , Bell Alisa , Nicoletti Richard , Kong Lingxin , Kreuter Kelly , Poling Laura , Winston William M. , Flaherty Meghan , Weiler Solly , Perino Samantha , O'Hagan Ronan , Lin Jie , Gyuris Jeno , Okamura Heidi
Published: May 2015

Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.
ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM
Authors: Liu Xue-Song , Genet Matthew D. , Haines Jenna E. , Mehanna Elie K. , Wu Shaowei , Chen Hung-I Harry , Chen Yidong , Qureshi Abrar A. , Han Jiali , Chen Xiang , Fisher David E. , Pandolfi Pier Paolo , Yuan Zhi-Min
Published: May 2015

The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated downregulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, downregulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens.

Implications: Together, these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications. Mol Cancer Res; 13(8); 1206–17. ©2015 AACR.
Diameter of Parathyroid Glands Measured by Computed Tomography as a Predictive Indicator for Response to Cinacalcet in Dialysis Patients with Secondary Hyperparathyroidism
Authors: Hong Yu Ah , Cho Yoo Sun , Kim Sun Woo , Jung Mi Yeon , Lee Eun Ah , Ko Gang Jee , Pyo Heui Jung , Hwang Soon Young , Suh Sangil , Kwon Young Joo
Published: May 2015

Background/Aims: Cinacalcet is one of the important treatments of secondary hyperparathyroidism (SHPT). We evaluated the role of computed tomography (CT) for parathyroid glands (PTGs) to determine the response to cinacalcet therapy in dialysis patients. Methods: In study 1, we compared the predictive cutoff values of the largest volume or diameter of PTGs on ultrasonography or CT for achievement of target intact parathyroid hormone (iPTH) level according to K/DOQI guideline after cinacalcet treatment in a single dialysis center. In study 2, the role of the cutoff diameter of PTGs on CT in predicting responsive to cinacalcet therapy was reevaluated in dialysis patients with SHPT in multiple centers. Results: In study 1, among the total population of 26 patients, the number of patients with baseline iPTH over 600 pg/mL was 16 (61%). In study 2, it was 45 (54%), among 82 patients. In study 1, the number of PTGs equal to or larger than the cutoff value (≥ 11.2 mm) on CT, not ultrasonography, was significantly higher in non-responders than in responders (p=0.038). In study 2, the proportion of patients with PTGs ≥ 11.2 mm on CT was significantly higher in non-responders than responders (p=0.003). Multivariate analysis showed that pretreatment iPTH (odds ratio [OR] 1.498, p=0.003) and the existence of enlarged PTGs on CT (OR 8.940, p=0.015) were significant clinical factors affecting the response to cinacalcet. Conclusions: The diameter of PTGs on CT could predict the response to cinacalcet in dialysis patients with SHPT.
Downregulation of β-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein: Proteomics-Based Identification in Early-Stage Prion Disease
Authors: Lin Zhu , Zhao Deming , Wang Yunsheng , Zhao Wei , Yin Xiaomin , Zhou Xiangmei , Zhang Zhongqiu , Yang Lifeng
Published: May 2015

Prion diseases are known as neurodegenerative diseases of the central nervous system with a long incubation period. Alzheimer's disease (AD) and prion diseases share the hallmark of severe neuronal loss, although their pathogenic mechanisms are similarly incomplete. It appears that these two neurodegenerative diseases share a complex deterioration of function involved in the onset of neuronal loss. To investigate presymptomatic biochemical changes indicative of the initial stage of prion diseases and decipher the pathophysiological mechanisms of these two neurodegenerative diseases, we performed a differential proteomic analysis on brain tissues of 263K-infected hamsters during the presymptomatic period and transgenic APPSWE, PSEN1dE9 mice (a mouse model of AD). We identified 7 differentially expressed proteins including the β-soluble N-ethylmaleimide-sensitive factor attachment protein (β-SNAP) by 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The β-SNAP expression patterns in the brains of cases and controls were further quantified by Western blotting. β-SNAP showed an early decrease followed by a progressive depletion. The expression of β-SNAP was also significantly downregulated in the mouse model of AD. β-SNAP is brain-specific and known to bind to the SNAP receptors and is therefore involved in the control of neurotransmitter release as well as in constitutive vesicular transport. Our results suggest that presynaptic failure and abnormalities in neurotransmission may be early events in the development of neuronal dysfunction.
HIF-1α as a Regulator of BMP2-Induced Chondrogenic Differentiation, Osteogenic Differentiation, and Endochondral Ossification in Stem Cells
Authors: Zhou Nian , Hu Ning , Liao Jun-Yi , Lin Liang-Bo , Zhao Chen , Si Wei-Ke , Yang Zhong , Yi Shi-Xiong , Fan Ting-Xu , Bao Wei , Liang Xi , Wei Xu , Chen Hong , Chen Cheng , Chen Qiang , Lin Xin , Huang Wei
Published: May 2015

Background/Aims: Joint cartilage defects are difficult to treat due to the limited self-repair capacities of cartilage. Cartilage tissue engineering based on stem cells and gene enhancement is a potential alternative for cartilage repair. Bone morphogenetic protein 2 (BMP2) has been shown to induce chondrogenic differentiation in mesenchymal stem cells (MSCs); however, maintaining the phenotypes of MSCs during cartilage repair since differentiation occurs along the endochondral ossification pathway. In this study, hypoxia inducible factor, or (HIF)-1α, was determined to be a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral bone formation. Methods: BMP2 was used to induce chondrogenic and osteogenic differentiation in stem cells and fetal limb development. After HIF-1α was added to the inducing system, any changes in the differentiation markers were assessed. Results: HIF-1α was found to potentiate BMP2-induced Sox9 and the expression of chondrogenesis by downstream markers, and inhibit Runx2 and the expression of osteogenesis by downstream markers in vitro. In subcutaneous stem cell implantation studies, HIF-1α was shown to potentiate BMP2-induced cartilage formation and inhibit endochondral ossification during ectopic bone/cartilage formation. In the fetal limb culture, HIF-1α and BMP2 synergistically promoted the expansion of the proliferating chondrocyte zone and inhibited chondrocyte hypertrophy and endochondral ossification. Conclusion: The results of this study indicated that, when combined with BMP2, HIF-1α induced MSC differentiation could become a new method of maintaining cartilage phenotypes during cartilage tissue engineering.
Long-Term Low Intensity Physical Exercise Attenuates Heart Failure Development in Aging Spontaneously Hypertensive Rats
Authors: Pagan Luana U. , Damatto Ricardo L. , Cezar Marcelo D.M. , Lima Aline R.R. , Bonomo Camila , Campos Dijon H.S. , Gomes Mariana J. , Martinez Paula F. , Oliveira Jr Silvio A. , Gimenes Rodrigo , Rosa Camila M. , Guizoni Daniele M. , Moukbel Yasmin C. , Cicogna Antonio C. , Okoshi Marina P. , Okoshi Katashi
Published: May 2015

Background: Physical exercise is a strategy to control hypertension and attenuate pressure overload-induced cardiac remodeling. The influence of exercise on cardiac remodeling during uncontrolled hypertension is not established. We evaluated the effects of a long-term low intensity aerobic exercise protocol on heart failure (HF) development and cardiac remodeling in aging spontaneously hypertensive rats (SHR). Methods: Sixteen month old SHR (n=50) and normotensive Wistar-Kyoto (WKY, n=35) rats were divided into sedentary (SED) and exercised (EX) groups. Rats exercised in treadmill at 12 m/min, 30 min/day, 5 days/week, for four months. The frequency of HF features was evaluated at euthanasia. Statistical analyses: ANOVA and Tukey or Mann-Whitney, and Goodman test. Results: Despite slightly higher systolic blood pressure, SHR-EX had better functional capacity and lower HF frequency than SHR-SED. Echocardiography and tissue Doppler imaging showed no differences between SHR groups. In SHR-EX, however, left ventricular (LV) systolic diameter, larger in SHR-SED than WKY-SED, and endocardial fractional shortening, lower in SHR-SED than WKY-SED, had values between those in WKY-EX and SHR-SED not differing from either group. Myocardial function, assessed in LV papillary muscles, showed improvement in SHR-EX over SHR-SED and WKY-EX. LV myocardial collagen fraction and type I and III collagen gene expression were increased in SHR groups. Myocardial hydroxyproline concentration was lower in SHR-EX than SHR-SED. Lysyl oxidase gene expression was higher in SHR-SED than WKY-SED. Conclusion: Exercise improves functional capacity and reduces decompensated HF in aging SHR independent of elevated arterial pressure. Improvement in functional status is combined with attenuation of LV and myocardial dysfunction and fibrosis.
Nrp1, a Neuronal Regulator, Enhances DDR2-ERK-Runx2 Cascade in Osteoblast Differentiation via Suppression of DDR2 Degradation
Authors: Zhang Yan , Su Jin , Teng Yue , Zhang Jian , Wang Jiang , Li Kun , Yao Libo , Li Xu
Published: May 2015

Background: Osteoblastogenesis is under delicate control by multiple factors and hormones. Recent reports indicated the involvement of immunological and neuronal regulators. However, the role of neuropilin 1 (Nrp1) in osteoblastogenesis remains obscure. Methods: Real-time PCR was carried out to detect the mRNA of osteoblastic markers, Nrp1, and discoidin domain receptor 2 (DDR2). Immunoblot was performed to test the protein of Nrp1 and DDR2. Osteogenic differentiation was evaluated by mRNA analysis of osteogenic markers, and determination of ALP activity and OCN secretion. The intercellular signaling effectors were examined by immunoblot. Immunofluorescent assays were performed to detect the localization of Nrp1 and DDR2. Half-life determination assay was executed to test the DDR2 stability. Results: The expression of Nrp1 paralleled with that of DDR2 during osteoblastogensis. Nrp1 overexpression enhanced DDR2-induced stimulation of osteoblastogensis, whereas Nrp1 silencing caused attenuation. Nrp1 overexpression increased the phosphorylation of DDR2, ERK1/2 and Runx2. Nrp1 co-localized with DDR2 in the cellular membrane of differentiated MC3T3-E1. Enhanced or attenuated Nrp1 expression did not alter the mRNA transcript of DDR2. Nrp1 overexpression prolonged the half-life of DDR2 protein. Conclusion: Our results originally demonstrated the stimulatory role of Nrp1 in DDR2-induced osteoblast differentiation, providing molecular evidence for exploiting Nrp1 and DDR2 as targets to treat bone-related disease.
Effects of Donor Age, Long-Term Passage Culture, and Cryopreservation on Tonsil-Derived Mesenchymal Stem Cells
Authors: Choi Jin-Sik , Lee Byung-Joo , Park Hee-Young , Song Ji-Sun , Shin Sung-Chan , Lee Jin-Choon , Wang Soo-Geun , Jung Jin Sup
Published: May 2015

Objectives: Human mesenchymal stem cells (MSCs) are efficacious in various cellular therapeutic applications and have been isolated from several tissues. Recent studies have reported that human tonsil tissue contains a new source of progenitor cells, potentially applicable for cell-based therapies. Information about the effects of donor age, long-term passage and cryopreservation are essential for clinical applications and cell-based therapies. Therefore, the authors investigated how the morphology, cell-surface markers, proliferation potential and differentiation capacity of tonsil-derived MSCs (T-MSCs) were affected by donor age, long-term passage, and cryopreservation. Materials and Methods: T-MSCs were isolated from tonsillar tissue of 20 patients undergoing tonsillectomy. Authors evaluated the effects of donor-age, long-term passage, and cryopreservation on the morphology, surface markers, proliferation potential and differentiation capacities of T-MSCs. Results: T-MSCs exhibited a fibroblast-like, spindle-shaped appearance. There were no significant morphological differences according to donor age, long-term passage or cryopreservation. T-MSCs isolated from donors of various ages were positive for markers CD90, CD44, and CD73, but negative for CD45, CD31, and HLA-DR. There were no significant differences in the expression of positive and negative surface markers as a function of donor age, long-term passage and cryopreservation. T-MSCs from different donor age groups showed similar proliferation potentials after passage 2. After long-term passage and cryopreservation, there were no significant morphological differences. Cryopreservation did not affect the proliferation potential of T-MSCs, but there was a significant decrease in the proliferation potential in long-term passage T-MSCs (passage 15). The effect of donor age, long-term passage and cryopreservation on the in vitro adipogenic, osteogenic, and chondrogenic differentiation potential of T-MSCs was not significant. Conclusion: The effect of donor age, long-term passage culture, and cryopreservation on T-MSC properties are negligible, except for the proliferation capacity of long-term cultured T-MSCs. Therefore, T-MSCs are considered to be promising MSCs that can be used as future alternative sources for autologous or allogenic MSCs.
The Functional Variant in the 3'UTR of PTPRT with the Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population
Authors: Yao Yongliang , Shao Jie , Wu Jianhong , Zhang Qinghui , Wang Jianjun , Xiao Daping , Huang Feng
Published: May 2015

Background/Aims: PTPRT is an essential tumor suppressor that plays crucial roles in regulating the mechanisms of tumorigenesis. Polymorphisms in PTPRT have been reported associated with human longevity, but their association with the risk of esophageal squamous cell carcinoma (ESCC) has not been found so far. In this study, we focused on the miRNAs associated SNPs in the 3'-UTR of PTPRT to investigate the further relationship of the SNPs with miRNAs among Chinese ESCC patients. Methods: We performed case-control study including 790 ESCC patients and 749 cancer-free controls. Genotyping, real time PCR assay, cell transfection and the dual luciferase reporter assay were used in our study. Results: We found that patients suffering from smoking exposure, drinking exposure and the history of cancer indicated to be the susceptible population by comparing with controls. Besides, SNP rs2866943 in PTPRT 3'-UTR was involved in the occurrence of ESCC by acting as a protective factor while rs6029959 acting a risk factor. SNP rs2866943 was also could be regulated by miR-218 which caused a down-regulation of PTPRT in patients with CT and TT genotype. Furthermore, the carriers of CT and TT genotype presented a small tumor size as well as the low probability of metastasis. Conclusion: Our findings have shown that the SNP rs2866943 in PTPRT 3'-UTR, through disrupting the regulatory role of miR-218 in PTPRT expression, rs2866943 in PTPRT might act as a protective factor in the pathogenesis of ESCC.