bluuebunny/crossref_metadata_2025 huggingface dataset:
AnEx VivoModel in Human Femoral Heads for Histopathological Study and Resonance Frequency Analysis of Dental Implant Primary Stability
Authors: Hernández-Cortés Pedro , Monje Alberto , Galindo-Moreno Pablo , Catena Andrés , Ortega-Oller Inmaculada , Salas-Pérez José , Mesa Francisco , Gómez-Sánchez Rafael , Aguilar Mariano , Aguilar David , O'Valle Francisco
Published: June 2014

Objective. This study was designed to explore relationships of resonance frequency analysis (RFA)—assessed implant stability (ISQ values) with bone morphometric parameters and bone quality in anex vivomodel of dental implants placed in human femoral heads and to evaluate the usefulness of this model for dental implant studies.Material and Methods. Thisex vivostudy included femoral heads from 17 patients undergoing surgery for femoral neck fracture due to osteoporosis (OP) (n=7) or for total prosthesis joint replacement due to severe hip osteoarthrosis (OA) (n=10). Sixty4.5×13 mm Dentsply Astra implants were placed, followed by RFA. CD44 immunohistochemical analysis for osteocytes was also carried out.Results. As expected, the analysis yielded significant effects of femoral head type (OA versus OA) (P<0.001), but not of the implants (P=0.455) or of the interaction of the two factors (P=0.848). Bonferroni post hoc comparisons showed a lower mean ISQ for implants in decalcified (50.33±2.92) heads than in fresh (66.93±1.10) or fixated (70.77±1.32) heads (bothP<0.001). The ISQ score (fresh) was significantly higher for those in OA (73.52±1.92) versus OP (67.13±1.09) heads. However, mixed linear analysis showed no significant association between ISQ scores and morphologic or histomorphometric results (P>0.5in all cases), and no significant differences in ISQ values were found as a function of the length or area of the cortical layer (bothP>0.08).Conclusion. Although RFA-determined ISQ values are not correlated with morphometric parameters, they can discriminate bone quality (OP versus OA). Thisex vivomodel is useful for dental implant studies.
Broadband Bioimpedance Spectroscopy Based on a Multifrequency Mixed Excitation and Nuttall Windowed FFT Algorithm
Authors: Yang Yuxiang , Zhang Wen , Du Fangling , Tang Xuan , Wen He , Teng Zhaosheng
Published: June 2014

Bioimpedance spectroscopy (BIS) has become an important clinical indicator for monitoring the pathological status of biological tissues, and multifrequency simultaneous measurement of BIS may provide more accurate diagnostic information compared with the traditional frequency‐sweep measurement technology. This paper proposes a BIS multifrequency simultaneous measurement method based on multifrequency mixed (MFM) signal excitation and a Nuttall windowed interpolation FFT algorithm. Firstly, the excitation source adopts the nine‐frequency MFM signal f(9, t), which has excellent spectral characteristic and is very suitable for BIS measurement. On this basis, a Nuttall window is adopted to truncate sample data, and an interpolation FFT algorithm based on Nuttall window is built to perform spectral analysis, in which the parameter correction formula is provided based on polynomial approximation. A BIS measurement simulation experiment is performed on an RC three‐element equivalent circuit, and results on the 9 primary harmonic frequencies ranging from 3.9 kHz to 1 MHz show a high accuracy with the impedance amplitude relative error |Ez | < 0.3%, and the phase absolute error |Ep | < 0.1°. This paper validates the feasibility of BIS multifrequency simultaneous measurement method and establishes an algorithm foundation for the development of practical broadband BIS measurement system.
Forest Phenology Dynamics and Its Responses to Meteorological Variations in Northeast China
Authors: Yu Xinfang , Wang Qiankun , Yan Huimin , Wang Yong , Wen Kege , Zhuang Dafang , Wang Qiao
Published: June 2014

Based on time series of Moderate Resolution Imaging Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) data (2000–2009), we extracted forest phenological variables in Northeast China using a threshold-based method, which included the start of the growing season (SOS), end of the growing season (EOS), and length of the growing season (LOS). The spatial variation of phenological trends was analyzed using the linear regression method. In Northeast China, SOS was delayed at the rate of <1.5 days per year. The delay trend of EOS was well distributed in the entire region with almost the same rates. LOS increased slightly. The analysis of the relationship between forest phenology and meteorological variations shows that SOS was mainly affected by spring temperature, whereas SOS had a negative relationship with precipitation in the warm-temperate deciduous broadleaf forest region. The EOS in temperate steppe region was affected by temperature and precipitation in August, whereas the others were significantly affected by temperature. Because of the increased temperature in spring, the LOS of the temperate steppe region and temperate mixed forest region increased, and the LOS was positively correlated with the mean temperature of summer in the cool-temperate needleleaf forest region.
Translation and Initial Validation of the Chinese (Cantonese) Version of Community Integration Measure for Use in Patients with Chronic Stroke
Authors: Liu Tai-Wa , Ng Shamay S. M. , Ng Gabriel Y. F.
Published: June 2014

Objectives. To (1) translate and culturally adapt the English version Community Integration Measure into Chinese (Cantonese), (2) report the results of initial validation of the Chinese (Cantonese) version of CIM (CIM-C) including the content validity, internal consistency, test-retest reliability, and factor structure of CIM-C for use in stroke survivors in a Chinese community setting, and (3) investigate the level of community integration of stroke survivors living in Hong Kong.Design. Cross-sectional study.Setting. University-based rehabilitation centre.Participants. 62 (n=62) subjects with chronic stroke.Methods. The CIM-C was produced after forward-backward translation, expert panel review, and pretesting. 25 (n=25) of the same subjects were reassessed after a 1-week interval.Results. The items of the CIM-C demonstrated high internal consistency with a Cronbach’sαof 0.84. The CIM-C showed good test-retest reliability with an intraclass correlation coefficient (ICC) of 0.84 (95% confidence interval, 0.64–0.93). A 3-factor structure of the CIM-C including “relationship and engagement,” “sense of knowing,” and “independent living,” was consistent with the original theoretical model. Hong Kong stroke survivors revealed a high level of community integration as measured by the CIM-C (mean (SD): 43.48 (5.79)).Conclusions. The CIM-C is a valid and reliable measure for clinical use.
Intelligent Advisory Speed Limit Dedication in Highway Using VANET
Authors: Jalooli Ali , Shaghaghi Erfan , Jabbarpour Mohammad Reza , Md Noor Rafidah , Yeo Hwasoo , Jung Jason J.
Published: June 2014

Variable speed limits (VSLs) as a mean for enhancing road traffic safety are studied for decades to modify the speed limit based on the prevailing road circumstances. In this study the pros and cons of VSL systems and their effects on traffic controlling efficiency are summarized. Despite the potential effectiveness of utilizing VSLs, we have witnessed that the effectiveness of this system is impacted by factors such as VSL control strategy used and the level of driver compliance. Hence, the proposed approach called Intelligent Advisory Speed Limit Dedication (IASLD) as the novel VSL control strategy which considers the driver compliance aims to improve the traffic flow and occupancy of vehicles in addition to amelioration of vehicle’s travel times. The IASLD provides the advisory speed limit for each vehicle exclusively based on the vehicle’s characteristics including the vehicle type, size, and safety capabilities as well as traffic and weather conditions. The proposed approach takes advantage of vehicular ad hoc network (VANET) to accelerate its performance, in the way that simulation results demonstrate the reduction of incident detection time up to 31.2% in comparison with traditional VSL strategy. The simulation results similarly indicate the improvement of traffic flow efficiency, occupancy, and travel time in different conditions.
Giant Perineal Leiomyoma: A Case Report and Review of the Literature
Authors: von-Waagner Wolf , Liu Huifei , Picon Antonio I.
Published: June 2014

We report the case of a 40-year-old woman who presented with a large perineal mass with no rectal or vaginal involvement. Imaging could not rule out malignancy. She underwent wide surgical excision. Histological analysis revealed a large atypical leiomyoma, measuring 24 × 12 × 8 cm. Followup after two years showed no recurrence and she has been asymptomatic since surgery. This is the largest perineal leiomyoma reported so far.
The Application of Pattern Recognition in Electrofacies Analysis
Authors: Li Huan , Yang Xiao , Wei Wenhong
Published: June 2014

Pattern recognition is an important analytical tool in electrofacies analysis. In this paper, we study several commonly used clustering and classification algorithms. On the basis of advantages and disadvantages of existing algorithms, we introduce the KMRIC algorithm, which improves initial centers ofK-means. Also, we propose the AKM algorithm which automatically determines the number of clusters and apply support vector machine to classification. Finally, we apply these algorithms to electrofacies analysis, where the experiments on the real-world datasets are carried out to compare the merits of various algorithms.
Continuous Genetic Algorithm as a Novel Solver for Stokes and Nonlinear Navier Stokes Problems
Authors: Abo-Hammour Z. S. , Samhouri A. D. , Mubarak Y.
Published: June 2014

The one‐dimensional continuous genetic algorithm (CGA) previously developed by the principal author is extended and enhanced to deal with two‐dimensional spaces in this paper. The enhanced CGA converts the partial differential equations into algebraic equations by replacing the derivatives appearing in the differential equation with their proper finite difference formula in 2D spaces. This optimization methodology is then applied for the solution of steady‐state two‐dimensional Stokes and nonlinear Navier Stokes problems. The main advantage of using CGA for the solution of partial differential equations is that the algorithm can be applied to linear and nonlinear equations without any modification in its structure. A comparison between the results obtained using the 2D CGA and the known Galerkin finite element method using COMSOL is presented in this paper. The results showed that CGA has an excellent accuracy as compared to other numerical solvers.
Correlates of Cessation Success among Romanian Adults
Authors: Kaleta Dorota , Usidame Bukola , Dziankowska-Zaborszczyk Elżbieta , Makowiec-Dąbrowska Teresa
Published: June 2014

Background. Tobacco smoking and its consequences are a serious public health problem in Romania. Evidence-based data on factors associated with successful smoking cessation are crucial to optimize tobacco control. The aim of the study was to determine the sociodemographic and other factors associated with smoking cessation success among adults.Materials and Methods. Data was from a sample of 4,517 individuals derived from the Global Adult Tobacco Survey (GATS). GATS is a cross-sectional, nationally representative household survey implemented in Romania in 2011. Data was analyzed with logistic regression.Results. Among females, the quit rate was 26.3% compared with 33.1% in males (P<0.02). We found disparities in cessation success among the analyzed groups of respondents. Being economically active, being aged 40 and above, and having an awareness of smoking health consequences were associated with long-term quitting smoking among men, while initiating smoking at a later age increased the odds of quitting smoking among women. However, cohabitation with nonsmokers was the strongest predictor of successful cessation among both genders.Conclusion. Programs increasing quit rates and encourage cessation among groups less likely to quit, adopting voluntary smoke-free homes, and increasing the awareness of smoking and tobacco pollution risks are needed.
MiR-15b Targets Cyclin D1 to Regulate Proliferation and Apoptosis in Glioma Cells
Authors: Sun Guan , Shi Lei , Yan Shushan , Wan Zhengqiang , Jiang Nan , Fu Linshan , Li Min , Guo Jun
Published: June 2014

Aim. To investigate the role and mechanism of miR-15b in the proliferation and apoptosis of glioma.Methods. The miR-15b mimics were transfected into human glioma cells to upregulate the miR-15b expression. Cyclin D1 was determined by both western blotting analysis and luciferase reporter assay. Methylthiazol tetrazolium (MTT) and flow cytometry were employed to detect the cell proliferation, cell cycle, and apoptosis.Results. Overexpression of miR-15b inhibits proliferation by arrested cell cycle progression and induces apoptosis, possibly by directly targeting Cyclin D1. Both luciferase assay and bioinformatics search revealed a putative target site of miR-15b binding to the 3′-UTR of Cyclin D1. Moreover, expression of miR-15b in glioma tissues was found to be inversely correlated with Cyclin D1 expression. Enforced Cyclin D1 could abrogate the miR-15b-mediated cell cycle arrest and apoptosis.Conclusions. Our findings identified that miR-15b may function as a glioma suppressor by targeting the Cyclin D1, which may provide a novel therapeutic strategy for treatment of glioma.
Safety and Efficiency of Biomimetic Nanohydroxyapatite/Polyamide 66 Composite in Rabbits and Primary Use in Anterior Cervical Discectomy and Fusion
Authors: Xu Hui , Wang Yan , Su Xiaojing , Zhang Xuelian , Zhang Xuesong
Published: June 2014

This study was conducted to validate the safety and efficiency of biomimetic nanohydroxyapatite/polyamide 66 (n-HA/PA66) composite in animal model (rabbit) and report its application in anterior cervical discectomy and fusion (ACDF) for 4, 12, and 24 weeks. N-HA/PA66 composite was implanted into one-side hind femur defects and the control defects were kept empty as blank controls. A combination of macroscopic and histomorphometric studies was performed up to 24 weeks postoperatively and compared with normal healing. 60 cervical spondylosis myelopathy and radiculopathy patients who were subjected to ACDF using n-HA/PA66 and PEEK cage were involved in this study with six-month minimum follow-up. Their radiographic (cage subsidence, fusion status, and segmental sagittal alignment (SSA)) and clinical (VAS and JOA scales) data before surgery and at each follow-up were recorded and compared. Nanohydroxyapatite/polyamide 66 composite is safe and effective in animal experiment and ACDF.
Inducible Protective Processes in Animal Systems XIII: Comparative Analysis of Induction of Adaptive Response by EMS and MMS in Ehrlich Ascites Carcinoma Cells
Authors: Mahadimane Periyapatna Vishwaprakash , Vasudev Venkateshaiah
Published: June 2014

In order to investigate the presence of adaptive response in cancerous cells, two monofunctional alkylating agents, namely, ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS), were employed to treat Ehrlich ascites carcinoma (EAC) cellsin vivo. Conditioning dose of 80 mg/kg body weight of EMS or 50 mg/kg body weight of MMS and challenging dose of 240 mg/kg body weight of EMS or 150 mg/kg body weight of MMS were selected by pilot toxicity studies. Conditioned EAC cells when challenged after 8 h time lag resulted in significant reduction in chromosomal aberrations compared to challenging dose of respective agents. As has been proved in earlier studies with normal organisms, even in cancerous cells (EAC), there is presence of adaptive response to methylating and ethylating agents. Furthermore, it is also interesting to note in the present studies that the methylating agent, MMS, is a stronger inducer of the adaptive response than the ethylating agent, EMS.
Methods for Prediction of Temperature Distribution in Flashover Caused by Backdraft Fire
Authors: Zhang Guowei , Zhu Guoqing , Yuan Guanglin , Huang Lili
Published: June 2014

Accurately predicting temperature distribution in flashover fire is a key issue for evacuation and fire‐fighting. Now many good flashover fire experiments have be conducted, but most of these experiments are proceeded in enclosure with fixed openings; researches on fire development and temperature distribution in flashover caused by backdraft fire did not receive enough attention. In order to study flashover phenomenon caused by backdraft fire, a full‐scale fire experiment was conducted in one abandoned office building. Process of fire development and temperature distribution in room and corridor were separately recorded during the experiment. The experiment shows that fire development in enclosure is closely affected by the room ventilation. Unlike existing temperature curves which have only one temperature peak, temperature in flashover caused by backdraft may have more than one peak value and that there is a linear relationship between maximum peak temperature and distance away from fire compartment. Based on BFD curve and experimental data, mathematical models are proposed to predict temperature curve in flashover fire caused by backdraft at last. These conclusions and experiment data obtained in this paper could provide valuable reference to fire simulation, hazard assessment, and fire protection design.
Comparison of Venous Thromboembolism after Total Hip Arthroplasty between Ankylosing Spondylitis and Osteoarthritis
Authors: Shi Dongquan , Xu Xingquan , Song Kai , Xu Zhihong , Dai Jin , Chen Dongyang , Jiang Qing
Published: June 2014

Objective.Ankylosing spondylitis (AS), an inflammatory rheumatic disease, will gradually lead to severe hip joint dysfunction. Total hip arthroplasty is a useful method to improve patients’ quality of life. The aim of this study was to compare the incidence and risk factors of deep vein thrombosis (DVT) between AS and hip osteoarthritis.Methods.In a retrospective study, a total of 149 subjects who underwent cementless THA were studied. Clinical data, biochemical data, and surgery-related data were measured between AS and OA groups.Results.The incidence of DVT in AS group was lower than that of OA group, although no significant difference was detected (P=0.89). The patients of AS group were much younger (P<0.0001) and thinner (P=0.018) compared with those of OA group. AS patients had higher ejection fraction (EF) (P=0.016), higher platelet counts (P<0.0001), and lower hypertension rate (P=0.0004). The values of APTT, PT, and INR in AS patients were higher than those in OA patients (allP<0.0001). The values of D-dimer and APTT were both significantly higher in DVT subjects than those in non-DVT subjects.Conclusion.AS patients potentially had a lower incidence of DVT compared with OA patients.
Bipolar Disorder after Stroke in an Elderly Patient
Authors: Melo Raquel Calvão de , Lopes Rui , Alves José Carlos
Published: June 2014

The onset of bipolar disorder (BD) secondary to a stroke event is a rare clinical entity. Although it may be related to specific regions of the brain, several other factors have been linked to its expression such as subcortical atrophy or chronic vascular burden. While precise locations and cerebral circuits involved in the bipolarity expression after stroke still need to be determined, their investigation represents an opportunity to study brain function and BD etiopathogenesis. We present a BD secondary to multiple subcortical biparietal lacunar infarctions, a lacunar infarction in left putamen and an ischemic lesion at the cerebral trunk evolving the right median portion, in a 65-year-old male patient who experienced manic, hypomanic, and depressive episodes, after 6, 10, and 16 months, respectively, of the cerebrovascular events.
The Interplay between Inflammation and Fibrosis in Kidney Transplantation
Authors: Torres Irina B. , Moreso Francesc , Sarró Eduard , Meseguer Anna , Serón Daniel
Published: June 2014

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.
Recurrent Catastrophic Ceramic Femoral Head Failure in Total Hip Arthroplasty
Authors: Tai S. M. M. , Parker L. , de Roeck N. J. , Skinner J. A.
Published: June 2014

Fracture of a modern ceramic head component in total hip replacement is an uncommon but catastrophic complication. Hence, the occurrence of a second ceramic head fracture in the same hip replacement of an individual represents a perishingly rare event. We present the case as a means of highlighting potential risk factors for ceramic head fracture and suggest possible management strategies in such cases.
Study of Robust H∞ Filtering Application in Loosely Coupled INS/GPS System
Authors: Zhao Lin , Qiu Haiyang , Feng Yanming
Published: June 2014

Since a celebrate linear minimum mean square (MMS) Kalman filter in integration GPS/INS system cannot guarantee the robustness performance, a H∞ filtering with respect to polytopic uncertainty is designed. The purpose of this paper is to give an illustration of this application and a contrast with traditional Kalman filter. A game theory H∞ filter is first reviewed; next we utilize linear matrix inequalities (LMI) approach to design the robust H∞ filter. For the special INS/GPS
model, unstable model case is considered. We give an explanation for Kalman filter divergence under uncertain dynamic system and simultaneously investigate the relationship between H∞ filter and Kalman filter. A loosely coupled INS/GPS simulation system is given here to verify this application. Result shows that the robust H∞ filter has a better performance when system suffers uncertainty; also it is more robust compared to the conventional Kalman filter.
Preparation and Characterization of Novel Fe2O3-Flaky Coated Carbon Fiber by Electrospinning and Hydrothermal Methods
Authors: Chen Qing-Yun , Liu Lang , Wang Yun-Hai
Published: June 2014

A novel hierarchical nanostructure ofFe2O3-flaky coated carbon fibers was produced by the electrospinning process followed by a hydrothermal technique. First, electrospinning of a colloidal solution that consisted of ferric nitrate and polyacrylonitrile (PAN) was performed to produce PAN nanofibers. Then electrospun nanofiber was stabilized and calcinated in nitrogen at 800°C for 2 h to produce carbon nanofibers (CNFs) which were exploited to produceFe2O3-flaky structure using hydrothermal technique. The as-obtained products were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The results revealed thatFe2O3flakes were successfully grown on the CNFs substrates, and the coverage ofFe2O3flakes could be controlled by simply adjusting the hydrothermal pH value and time.Fe2O3-flaky coated carbon fibers displayed high photocatalytic activity toward degradation of methyl orange (MO) under visible light irradiation.
Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair
Authors: Ismail Ismail Hassan , Davidson Riley , Gagné Jean-Philippe , Xu Zhi Zhong , Poirier Guy G. , Hendzel Michael J.
Published: June 2014

The BRCA1-associated deubiquitylase BAP1 is mutated in several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis. In this study, we present evidence that BAP1 functions as part of the DNA damage response (DDR). We found that BAP1 mediates rapid poly(ADP-ribose)-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA damage. Furthermore, we identified BAP1 as a phosphorylation target for the DDR kinase ATM. Functionally, BAP1 promoted repair of DNA double-strand breaks, enhancing cell survival after DNA damage. Our results highlight the importance of ubiquitin turnover at sites of DNA damage, and they provide a mechanism to account for the tumor-suppressive function of BAP1. Cancer Res; 74(16); 4282–94. ©2014 AACR.
A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer
Authors: Vasan Neil , Boyer Julie L. , Herbst Roy S.
Published: June 2014

Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a “Ras renaissance,” signified by new Ras and Ras pathway–targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non–small cell lung cancer as a case example. Clin Cancer Res; 20(15); 3921–30. ©2014 AACR.
An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells
Authors: Bae Jeong A. , Yoon Somy , Park So-Yeon , Lee Jae Hyuk , Hwang Jun-Eul , Kim Hangun , Seo Young-Woo , Cha Yoon Jin , Hong Sung Pil , Kim Hoguen , Chung Ik Joo , Kim Kyung Keun
Published: June 2014

Purpose: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer.

Experimental Design: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity.

Results: We identified the KITENIN/ErbB4–Dvl2–c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy.

Conclusions: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.
Molecular Pathways: Targeting NRAS in Melanoma and Acute Myelogenous Leukemia
Authors: Johnson Douglas B. , Smalley Keiran S.M. , Sosman Jeffrey A.
Published: June 2014

Successful targeting of specific oncogenic “driver” mutations with small-molecule inhibitors has represented a major advance in cancer therapeutics over the past 10 to 15 years. The most common activating oncogene in human malignancy, RAS (rat sarcoma), has proved to be an elusive target. Activating mutations in RAS induce mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase–AKT pathway signaling and drive malignant progression in up to 30% of cancers. Oncogenic NRAS mutations occur in several cancer types, notably melanoma, acute myelogenous leukemia (AML), and less commonly, colon adenocarcinoma, thyroid carcinoma, and other hematologic malignancies. Although NRAS-mutant tumors have been recalcitrant to targeted therapeutic strategies historically, newer agents targeting MAP/ERK kinase 1 (MEK1)/2 have recently shown signs of clinical efficacy as monotherapy. Combination strategies of MEK inhibitors with other targeted agents have strong preclinical support and are being evaluated in clinical trials. This review discusses the recent preclinical and clinical studies about the role of NRAS in cancer, with a focus on melanoma and AML. Clin Cancer Res; 20(16); 4186–92. ©2014 AACR.
Cotargeting of Epidermal Growth Factor Receptor and PI3K Overcomes PI3K–Akt Oncogenic Dependence in Pancreatic Ductal Adenocarcinoma
Authors: Wong Matthew H. , Xue Aiqun , Julovi Sohel M. , Pavlakis Nick , Samra Jaswinder S. , Hugh Thomas J. , Gill Anthony J. , Peters Lyndsay , Baxter Robert C. , Smith Ross C.
Published: June 2014

Purpose: PI3K–Akt is overexpressed in 50% to 70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR coinhibition may be effective in PDAC with upregulated PI3K–Akt signaling.

Experimental Design: Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi)–resistant cell lines were found to have significantly overexpressed AKT2 gene, total Akt, and pAkt. In vitro erlotinib-resistant (ER) cell models (BxPC-ER and PANC-ER) with highly constitutively active PI3K–Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGFIR inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, Western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in vivo.

Results: Erlotinib acted synergistically with BYL in BxPC-ER (synergy index, SI = 1.71) and PANC-ER (SI = 1.44). Treatment of ER cell lines showing upregulated PI3K–Akt with erlotinib plus BYL caused significant G1 cell-cycle arrest (71%, P < 0.001; 58%, P = 0.003), inhibition of colony formation (69% and 72%, both P < 0.001), and necrosis and apoptosis (75% and 53%, both P < 0.001), more so compared with parent cell lines. In primary patient-derived tumor subrenal capsule (n = 90) and subcutaneous (n = 22) xenografts, erlotinib plus BYL significantly reduced tumor volume (P = 0.005). Strong pEGFR and pAkt immunostaining (2+/3+) was correlated with high and low responses, respectively, to both erlotinib and erlotinib plus BYL.

Conclusion: PDAC with increased expression of the PI3K–Akt pathway was susceptible to PI3K–EGFR coinhibition, suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential positive and negative predictive biomarkers is warranted. Clin Cancer Res; 20(15); 4047–58. ©2014 AACR.
Neuroblastoma Killing Properties of Vδ2 and Vδ2-Negative γδT Cells Following Expansion by Artificial Antigen-Presenting Cells
Authors: Fisher Jonathan P.H. , Yan Mengyong , Heuijerjans Jennifer , Carter Lisa , Abolhassani Ayda , Frosch Jennifer , Wallace Rebecca , Flutter Barry , Capsomidis Anna , Hubank Mike , Klein Nigel , Callard Robin , Gustafsson Kenth , Anderson John
Published: June 2014

Purpose: The majority of circulating human γδT lymphocytes are of the Vγ9Vδ2 lineage, and have T-cell receptor (TCR) specificity for nonpeptide phosphoantigens. Previous attempts to stimulate and expand these cells have therefore focused on stimulation using ligands of the Vγ9Vδ2 receptor, whereas relatively little is known about variant blood γδT subsets and their potential role in cancer immunotherapy.

Experimental Design: To expand the full repertoire of γδT without bias toward specific TCRs, we made use of artificial antigen-presenting cells loaded with an anti γδTCR antibody that promoted unbiased expansion of the γδT repertoire. Expanded cells from adult blood donors were sorted into 3 populations expressing respectively Vδ2 TCR chains (Vδ2+), Vδ1 chains (Vδ1+), and TCR of other δ chain subtypes (Vδ1negVδ2neg).

Results: Both freshly isolated and expanded cells showed heterogeneity of differentiation markers, with a less differentiated phenotype in the Vδ1 and Vδ1negVδ2neg populations. Expanded cells were largely of an effector memory phenotype, although there were higher numbers of less differentiated cells in the Vδ1+ and Vδ1negVδ2neg populations. Using neuroblastoma tumor cells and the anti-GD2 therapeutic mAb ch14.18 as a model system, all three populations showed clinically relevant cytotoxicity. Although killing by expanded Vδ2 cells was predominantly antibody dependent and proportionate to upregulated CD16, Vδ1 cells killed by antibody-independent mechanisms.

Conclusions: In conclusion, we have demonstrated that polyclonal-expanded populations of γδT cells are capable of both antibody-dependent and -independent effector functions in neuroblastoma. Clin Cancer Res; 20(22); 5720–32. ©2014 AACR.
Toll-like Receptor Agonist Imiquimod Facilitates Antigen-Specific CD8+ T-cell Accumulation in the Genital Tract Leading to Tumor Control through IFNγ
Authors: Soong Ruey-Shyang , Song Liwen , Trieu Janson , Knoff Jayne , He Liangmei , Tsai Ya-Chea , Huh Warner , Chang Yung-Nien , Cheng Wen-Fang , Roden Richard B.S. , Wu T.-C. , Trimble Cornelia L. , Hung Chien-Fu
Published: June 2014

Purpose: Imiquimod is a Toll-like receptor 7 agonist used topically to treat external genital warts and basal cell carcinoma. We examined the combination of topical imiquimod with intramuscular administration of CRT/E7, a therapeutic human papillomavirus (HPV) vaccine comprised of a naked DNA vector expressing calreticulin fused to HPV16 E7.

Experimental Design: Using an orthotopic HPV16 E6/E7+ syngeneic tumor, TC-1, as a model of high-grade cervical/vaginal/vulvar intraepithelial neoplasia, we assessed if combining CRT/E7 vaccination with cervicovaginal deposition of imiquimod could result in synergistic activities promoting immune-mediated tumor clearance.

Results: Imiquimod induced cervicovaginal accumulation of activated E7-specific CD8+ T cells elicited by CRT/E7 vaccination. Recruitment was not dependent upon the specificity of the activated CD8+ T cells, but was significantly reduced in mice lacking the IFNγ receptor. Intravaginal imiquimod deposition induced upregulation of CXCL9 and CXCL10 mRNA expression in the genital tract, which are produced in response to IFNγ receptor signaling and attract cells expressing their ligand, CXCR3. The T cells attracted by imiquimod to the cervicovaginal tract expressed CXCR3 as well as CD49a, an integrin involved in homing and retention of CD8+ T cells at mucosal sites. Our results indicate that intramuscular CRT/E7 vaccination in conjunction with intravaginal imiquimod deposition recruits antigen-specific CXCR3+ CD8+ T cells to the genital tract.

Conclusions: Several therapeutic HPV vaccination clinical trials using a spectrum of DNA vaccines, including vaccination in concert with cervical imiquimod, are ongoing. Our study identifies a mechanism by which these strategies could provide therapeutic benefit. Our findings support accumulating evidence that manipulation of the tumor microenvironment can enhance the therapeutic efficacy of strategies that induce tumor-specific T cells. Clin Cancer Res; 20(21); 5456–67. ©2014 AACR.
Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma
Authors: Zhao Zhiqiang , Yin Jun-qiang , Wu Man-si , Song Guohui , Xie Xian-biao , Zou Changye , Tang Qinglian , Wu Yuanzhong , Lu Jinchang , Wang Yongqian , Wang Jin , Kang Tiebang , Jia Qiang , Shen Jingnan
Published: June 2014

Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G2–M cell-cycle arrest, caused DNA damage, activated ATM–CHK2–H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKα and p38MAPK, as the activating AMPKα led to the inactivation of GSK3β in osteosarcoma cells. Moreover, GSK3β deletion or GSK3β inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38MAPK and the AMPKα–GSK3β–Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma. Cancer Prev Res; 7(9); 927–38. ©2014 AACR.
A New Clinical Scoring System to Define Pneumonia following Esophagectomy for Cancer
Authors: van der Sluis Pieter C. , Verhage Roy J.J. , van der Horst Sylvia , van der Wal Willem M. , Ruurda Jelle P. , van Hillegersberg Richard
Published: June 2014

Background: Pneumonia is a frequently observed complication following esophagectomy. The lack of a uniform definition of pneumonia leads to large variations of pneumonia rates in literature. This study was designed to develop a scoring system for diagnosing pneumonia following esophagectomy at the hospital ward. Methods: In a prospective cohort study of esophagectomy patients, known risk factors for pneumonia, temperature, leukocyte count, pulmonary radiography and sputum culture added were evaluated. Primary outcome was defined as the decision to treat suspected pneumonia. Multivariate Cox regression analysis with backward selection was used to identify predictors of pneumonia treatment. Results: The majority of postoperative pneumonia treatments (88.2%) occurred at the hospital ward, where treatment was observed in 67 (36.2%) of 185 patients. Independent diagnostic determinants for pneumonia treatment were temperature (hazard ratio (HR) = 1.283, p = 0.073), leukocyte count (HR = 1.040, p = 0.078) and pulmonary radiography (HR >11.0, p = 0.000). Sputum culture did not influence the decision to treat pneumonia. These findings were used to develop a scoring system which includes temperature, leukocyte count and pulmonary radiography. Conclusion: The decision to treat pneumonia is based on temperature, leukocyte count and pulmonary radiography findings. The proposed clinical scoring system for pneumonia following esophagectomy at the hospital ward has the potential to aid clinical practice and improve comparability of future research in esophageal cancer surgery.
Prevalence of Normal Liver Tests in Patients with Choledocholithiasis Undergoing Endoscopic Retrograde Cholangiopancreatography
Authors: Wilcox Charles Mel , Kim Hwasoon , Trevino Jessica , Ramesh Jayapal , Monkemuller Klaus , Varadarajulu Shyam
Published: June 2014

Background/Aims: Abnormal liver chemistry tests are a hallmark of common bile duct (CBD) stones. There is little information, however, on the prevalence of and predictors for normal liver chemistry tests in such patients. Methods: Over an 11-year period, all patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) at our Center were prospectively identified. Patients in this study were those with CBD stones found at ERCP and where the indication for ERCP was CBD stones seen on imaging studies or when CBD stones were highly suspected based upon clinical presentation and radiographic and laboratory findings. Liver chemistry tests were recorded from those taken at the time of initial presentation as well as the time closest to ERCP. Results: Of a total of 5,133 patients undergoing ERCP during the study period, the indication was suspicion for CBD stones or for radiographically identified CBD stones in 476 and 593, respectively, with 115 patients having both indications. Of these 1,184 patients, 765 had CBD stones of whom 541 had liver tests. Of these 541, 29 patients (5.4%) were found to consistently have normal liver chemistry tests. Multivariate analysis identified two factors predictive of normal liver tests including age >55 years and the presence of abdominal pain. Conclusions: Although rare, liver tests can be normal in patients with CBD stones. Patients most likely to have normal liver tests included older patients and those with abdominal pain.
Clinical Impact of the Extent of Lymph Node Micrometastasis in Undifferentiated-Type Early Gastric Cancer
Authors: Lee Tomohiro , Tanaka Hiroaki , Ohira Masaichi , Okita Yoshihiro , Yoshii Mami , Sakurai Katsunobu , Toyokawa Takahiro , Kubo Naoshi , Muguruma Kazuya , Tanaka Sayaka , Ohsawa Masahiko , Hirakawa Kosei
Published: June 2014

Objective: Lymph node (LN) metastasis is one of the most important prognostic factors for undifferentiated-type early gastric cancer (EGC). The aim of this study was to examine expansion of micrometastasis in regional LNs to clarify the importance of lymphadenectomy for undifferentiated-type EGC. Methods: Clinicopathological features of 307 patients with undifferentiated-type EGC who underwent gastrectomy with lymphadenectomy between 1997 and 2010 at the Department of Surgical Oncology, Osaka City University, were retrospectively reviewed. Micrometastasis in LNs was detected by immunohistochemistry using anticytokeratin antibody. Results: The incidence of LN metastasis was 1.8% in patients with mucosal (pT1a) tumors and 17.3% in those with submucosal (pT1b) tumors. Multivariate analysis revealed that lymphatic invasion and tumor depth were independently related to LN metastasis. Micrometastasis was found in 41 (13.3%) patients. Twenty-two patients with pN0 had micrometastasis in the perigastric region. Micrometastasis had spread to the area along the left gastric or common hepatic artery in 12 patients. Patients with an upgraded stage by micrometastasis had significantly worse disease-free survival. Conclusions: LN micrometastasis was observed beyond the perigastric LNs and correlated with poor outcomes in patients with undifferentiated-type EGC. These data underscore the importance of adequate lymphadenectomy for patients with undifferentiated-type EGC.
On Some Quantitative Properties of Czech ř in Newsreading
Authors: Pavlík Radoslav
Published: June 2014

This research examines the distributional characteristics of Czech ř in terms of the number of contacts (periods). The traditional claim that this consonant is produced with two or more contacts is challenged by the empirical evidence of ř realized in connected speech (newsreading style). The results of the study show that the most common variant of the (ř) variable is a one-contact alveolar sound, with the multiple-contact realization of ř being extremely rare. The role of eight linguistic variables is assessed in order to find out which factors are most likely to influence the number of contacts of Czech ř. Some questions are discussed concerning its current definition as a trill.
Complicated and Uncomplicated Peptic Ulcer Disease: Altered Symptom Response to a Nutrient Challenge Linked to Gastric Motor Dysfunction
Authors: Gururatsakul Montri , Holloway Richard H. , Bellon Max , Bartholomeusz Dylan , Talley Nicholas J. , Holtmann Gerald J.
Published: June 2014

Background: Bleeding peptic ulcer (BPU) frequently occurs in the absence of preceding dyspeptic symptoms. We have observed that patients with BPU had a diminished symptom response to nutrient challenge test compared to uncomplicated peptic ulcer disease (uPUD). We postulated that more symptoms are manifest in patients with uPUD than BPU because there are greater derangements in gastric motor function. Aim: To assess gastric emptying in patients with BPU, uPUD and healthy controls (HC). Methods: We studied 17 patients with BPU, 10 with uPUD, and 15 HC. After an 8-hour fast, subjects ingested 200 ml of an enteral feeding solution, containing 5 MBq 99mTc-rhenium sulphide colloid, every 5 min up to a cumulative volume of 800 ml. Gastric emptying was measured by scintigraphy for the total, proximal and distal stomach. Results: Patients with uPUD had significantly higher gastric retention in the proximal and total stomach at 100 min than HC and BPU, while BPU had similar percent retention to HC. Patients with uPUD had significantly higher cumulative symptom response to the nutrient challenge than did HC and BPU, while BPU had similar symptom responses to HC. Conclusions: Patients with uPUD have significantly delayed gastric emptying compared to HC and BPU. Data suggest that in addition to alterations of visceral sensory function, altered gastric motor function occurs during a nutrient challenge in uPUD but not BPU. Gastric motor function may contribute to the manifestation of dyspeptic symptoms in PUD.