bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha Stable Distribution Based Morphological Filter for Bearing and Gear Fault Diagnosis in Nuclear Power Plant
Authors: Zhang Xinghui , Kang Jianshe , Xiao Lei , Zhao Jianmin
Published: April 2015

Gear and bearing play an important role as key components of rotating machinery power transmission systems in nuclear power plants. Their state conditions are very important for safety and normal operation of entire nuclear power plant. Vibration based condition monitoring is more complicated for the gear and bearing of planetary gearbox than those of fixed-axis gearbox. Many theoretical and engineering challenges in planetary gearbox fault diagnosis have not yet been resolved which are of great importance for nuclear power plants. A detailed vibration condition monitoring review of planetary gearbox used in nuclear power plants is conducted in this paper. A new fault diagnosis method of planetary gearbox gears is proposed. Bearing fault data, bearing simulation data, and gear fault data are used to test the new method. Signals preprocessed using dilation-erosion gradient filter and fast Fourier transform for fault information extraction. The length of structuring element (SE) of dilation-erosion gradient filter is optimized by alpha stable distribution. Method experimental verification confirmed that parameter alpha is superior compared to kurtosis since it can reflect the form of entire signal and it cannot be influenced by noise similar to impulse.
An Assessment of Human versus Climatic Impacts on Jing River Basin, Loess Plateau, China
Authors: He Yi , Wang Fei , Mu Xingmin , Yan Huiting , Zhao Guangju
Published: April 2015

The impacts of climate change and human activities on runoff and sediment load are too integrated to distinguish their own contributions. We develop a new method to assess the impact of human activities based on paired years with similar precipitation and evapotranspiration (ET0) conditions (SPEC) using a 55-year monthly data of climate, runoff, and sediment load in 1958–2012 at Zhangjiashan Hydrologic Station of Jing River, Loess Plateau, China. The SPEC of paired periods is defined by similar annual amounts (difference less than 2.0%) and similar process (linear correlations of monthly data less than 0.05) which could set a precondition fixing the possible influence of climate factors. The runoff declined in all nine paired years, but the sediment load and concentration decreased in seven (78%) and six (67%) paired years, respectively. The further analysis with available data of land use and land cover (LUC), Normalized Difference Vegetation Index (NDVI), and soil and water measures in this basin and the results could explain impacts of human activities well. The method could be used combining with the traditional methods in hydrological research.
Predictive Performance of a Seven-Plex Antibody Array in Prenatal Screening for Down Syndrome
Authors: Pennings Jeroen L. A. , Imholz Sandra , Zutt Ilse , Koster Maria P. H. , Siljee Jacqueline E. , de Vries Annemieke , Schielen Peter C. J. I. , Rodenburg Wendy
Published: April 2015

We evaluated the use of multiplex antibody array methodology for simultaneous measurement of serum protein markers for first trimester screening of Down Syndrome (DS) and other pregnancy outcomes such as preeclampsia. For this purpose, we constructed an antibody array for indirect (“sandwich”) measurement of seven serum proteins: pregnancy-associated plasma protein-A (PAPP-A), free beta subunit of human chorionic gonadotropin (fβ-hCG), alpha-fetoprotein (AFP), angiopoietin-like 3 (ANGPTL3), epidermal growth factor (EGF), insulin-like growth factor 2 (IGFII), and superoxide dismutase 1 (SOD1). This array was tested using 170 DS cases and 510 matched controls drawn during the 8th–13th weeks of pregnancy. Data were used for prediction modelling and compared to previously obtained AutoDELFIA immunoassay data for PAPP-A and fβ-hCG. PAPP-A and fβ-hCG serum concentrations obtained using antibody arrays were highly correlated with AutoDELFIA data. Moreover, DS prediction modeling using (log-MoMmed) antibody array and AutoDELFIA data gave comparable results. Of the other markers, AFP and IGFII showed significant changes in concentration, although adding these markers to a prediction model based on prior risk, PAPP-A and fβ-hCG did not improve the predictive performance. We conclude that implementation of antibody arrays in a prenatal screening setting is feasible but will require additional first trimester screening markers.
A New Approach for Flexible Molecular Docking Based on Swarm Intelligence
Authors: Fu Yi , Wu Xiaojun , Chen Zhiguo , Sun Jun , Zhao Ji , Xu Wenbo
Published: April 2015

Molecular docking methods play an important role in the field of computer-aided drug design. In the work, on the basis of the molecular docking program AutoDock, we present QLDock as a tool for flexible molecular docking. For the energy evaluation, the algorithm uses the binding free energy function that is provided by the AutoDock 4.2 tool. The new search algorithm combines the features of a quantum-behaved particle swarm optimization (QPSO) algorithm and local search method of Solis and Wets for solving the highly flexible protein-ligand docking problem. We compute the interaction of 23 protein-ligand complexes and compare the results with those of the QDock and AutoDock programs. The experimental results show that our approach leads to substantially lower docking energy and higher docking precision in comparison to Lamarckian genetic algorithm and QPSO algorithm alone. QPSO-ls algorithm was able to identify the correct binding mode of 74% of the complexes. In comparison, the accuracy of QPSO and LGA is 52% and 61%, respectively. This difference in performance rises with increasing complexity of the ligand. Thus, the novel algorithm QPSO-ls may be used to dock ligand with many rotatable bonds with high accuracy.
Vitamin D Deficiency Contributes to the Reduction and Impaired Function of NaïveCD45RA+Regulatory T Cell in Chronic Heart Failure
Authors: Ma Yan-hui , Zhou Yun-lan , Yue Chao-yan , Zhang Guang-hui , Deng Lin , Xie Guo-hua , Xu Wei-ping , Shen Li-song
Published: April 2015

The effect of vitamin D pertinent to cardiovascular health on the heart itself is considered to shift toward an anti-inflammatory response in chronic heart failure (CHF); however, its underlying mechanism is not completely understood. In this study, we demonstrated that plasma 25(OH)D level, negatively associated with NT-ProBNP, correlated with the decreased Treg in CHF compared to the patients with other cardiovascular diseases and healthy and older donors. Naïve Treg cell (CD4+CD45RA+Foxp3loT) subset, rather than whole Treg cells, contributes to the reduction of Treg in CHF. 1,25(OH)2D treatment maintained partial expression of CD45RA on CD4+T cell afterαCD3/CD28 monoclonal antibodies activation and ameliorated the impaired CD4+CD45RA+T cell function from CHF patients through upregulating Foxp3 expression and IL-10 secretionin vitro. Low level of vitamin D receptor (VDR) was detected in CD4+CD45RA+T cell of CHF than control, while 1,25(OH)2D treatment increased the VDR expression to exert its immunosuppression on T cell. The results of this study might provide tangible evidence to our knowledge of the impact of vitamin D supplementation on naïve Tregs, which may offer new means of preventing and treating CHF.
TLR3 Plays Significant Roles against HBV-Associated HCC
Authors: Chen Xiao-lan , Xu Yu-yin , Chen Li , Wang Gui-lan , Shen Yin
Published: April 2015

Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). The role of TLR3 in hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) infections is not well understood. To investigate the ability of TLR3 in regulating HBV replication in HCC, 80 cases of human HCC were collected and their tissue microarray was made. In HCC cells, the expression and location of TLR3, hepatitis-associated virus, and interstitial immunoreactive cells were assayed with immunohistochemical staining. The apoptosis of tumor cells was also detected by TUNEL stain. Correlations between TLR3 expression and HBV infection, interstitial immunoreactive cells, and cells apoptosis in HCC were investigated. In addition, we explored whether TLR3 agonist dsRNA can inhibit HepG2.2.15 cells secreting HBV. We found that the cytoplasmic expression of TLR3 in HCC is positively related to HBsAg infection and HCC with cirrhosis and promotes interstitial immunoreactive cells infiltration and cancer cells apoptosis. In HepG2.2.15 cells, dsRNA inhibited the secretion of HBV and induced apoptosis. These results indicate that TLR3 signaling activity may be involved in immune responses against HBV in HCC.
Changes of the eSheath Outer Dimensions Used for Transfemoral Transcatheter Aortic Valve Replacement
Authors: Koehler Till , Buege Michael , Schleiting Heinrich , Seyfarth Melchior , Tiroch Klaus , Vorpahl Marc
Published: April 2015

Innovative catheter systems with lower-profile sheaths and a dynamic expansion mechanism (DEM) were recently introduced for transcatheter aortic valve replacement (TAVR). However, the labeling of 14 F and 16 F eSheaths denote the inner nominal diameter. Exact changes of the clinically relevant outer diameters during usage are not available. eSheaths were measured every 30 mm using a digital caliper. Unused 14 F and 16 F eSheaths served as controls. Maximum eSheath diameters were measured after insertion of the Edwards Commander Delivery System (ECDS) into 14 F and 16 F eSheaths.Finally, eSheaths were retrieved and measured after TAVR. Outer diameters of control 14 F eSheaths were 5.8 mm and 6.50 mm for the 16 F eSheath. Introduction of the 23 mm and 26 mm ECDS into 14 F eSheaths showed a maximum diameter of 7.65 mm and 7.64 mm (P=NS). Introduction of the 29 mm ECDS into the 16 F eSheath showed the greatest diameter of 8.18 mm (P=0.03). After TAVR, diameters of the 14 F eSheaths were 7.14 mm (23 mm valve) and 7.26 mm (26 mm valve) (P=NS), while 16 F eSheaths were 8.10 mm (29 mm valve) (P≤0.03). Nominal 14 F and 16 F eSheaths showed a significant increase of the outer diameter during advancement of the ECDS and after TAVR implantation.
Responsivity Enhanced NMOSFET Photodetector Fabricated by Standard CMOS Technology
Authors: Wu Fuwei , Ji Xiaoli , Yan Feng
Published: April 2015

Increasing the responsivity is one of the important issues for a photodetector. In this paper, we demonstrate an improved NMOSFET photodetector by using deep-n-well (DNW) structure which can improve the responsivity of the photodetector significantly. The experimental results show that the responsivity can be enhanced greatly by the DNW structure and is much larger than the previous work when DNW is biased with 0.5 V, while the dark current exhibits almost no increase. Further characterization indicates that the diode formed by the bulk and DNW can efficiently absorb photons and has a large gain factor of the photocurrent especially under low light condition, which gives a more promising application for the detector to detect the weak light.
Ozone Treatment Improved the Resistive Switching Uniformity of HfAlO2Based RRAM Devices
Authors: Liu Lifeng , Hou Yi , Zhang Weibing , Han Dedong , Wang Yi
Published: April 2015

HfAlO2based resistive random access memory (RRAM) devices were fabricated using atomic layer deposition by modulating deposition cycles for HfO2and Al2O3. Effect of ozone treatment on the resistive switching uniformity of HfAlO2based RRAM devices was investigated. Compared to the as-fabricated devices, the resistive switching uniformity of HfAlO2based RRAM devices with the ozone treatment is significantly improved. The uniformity improvement of HfAlO2based RRAM devices is related to changes in compositional and structural properties of the HfAlO2resistive switching film with the ozone treatment.
Homogenized Poly(3-hexylthiophene)/Methanofullerene Film by Addition of End-Functionalized Compatibilizer and Its Application to Polymer Solar Cells
Authors: Huang Ping-Tsung , Chen Yi-Hao , Lin Bo-Yu , Chuang Wei-Ping
Published: April 2015

A uniformed poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) blended film prepared by using spin-coating process is achieved by addition of 10% hydroxyl group end-functionalized P3HT (HOC-P3HT-COH) as a compatibilizer. Ratio of P3HT/PCBM on a spin-coated film has been improved from 1 : 1.22 on the edge and 1 : 0.85 in the center of substrate (substrate size, 2 cm × 3 cm) to 1 : 1.03 on the edge and 1 : 0.94 in the center for P3HT/HOC-P3HT-COH/PCBM film (1 : 0.1 : 1). Homogeneous and reproducible polymer solar cell with an average of 3.71% power conversion efficiency under AM1.5G irradiation is fabricated with 10% HOC-P3HT-COH in P3HT/PCBM layer.
Structure-Aware Bayesian Compressive Sensing for Near-Field Source Localization Based on Sensor-Angle Distributions
Authors: Qin Si , Zhang Yimin D. , Wu Qisong , Amin Moeness G.
Published: April 2015

A novel technique for localization of narrowband near-field sources is presented. The technique utilizes the sensor-angle distribution (SAD) that treats the source range and direction-of-arrival (DOA) information as sensor-dependent phase progression. The SAD draws parallel to quadratic time-frequency distributions and, as such, is able to reveal the changes in the spatial frequency over sensor positions. For a moderate source range, the SAD signature is of a polynomial shape, thus simplifying the parameter estimation. Both uniform and sparse linear arrays are considered in this work. To exploit the sparsity and continuity of the SAD signature in the joint space and spatial frequency domain, a modified Bayesian compressive sensing algorithm is exploited to estimate the SAD signature. In this method, a spike-and-slab prior is used to statistically encourage sparsity of the SAD across each segmented SAD region, and a patterned prior is imposed to enforce the continuous structure of the SAD. The results are then mapped back to source range and DOA estimation for source localization. The effectiveness of the proposed technique is verified using simulation results with uniform and sparse linear arrays where the array sensors are located on a grid but with consecutive and missing positions.
Extramedullary Manifestation in Multiple Myeloma Bears High Incidence of Poor Cytogenetic Aberration and Novel Agents Resistance
Authors: Qu Xiaoyan , Chen Lijuan , Qiu Hairong , Lu Hua , Wu Hanxin , Qiu Hongxia , Liu Peng , Guo Rui , Li Jianyong
Published: April 2015

Extramedullary disease (EMD) in multiple myeloma (MM) patients is an uncommon event and more attention was directed toward the feature of these patients. Cytogenetic aberration is an important characteristic of MM and is associated with patients’ outcome. In this study, we aimed to compare the cytogenetic abnormality of patients with and without extramedullary manifestation, and to analyze the clinical outcomes of novel agents in EMD patients. We retrospectively investigated data from 41 MM patients. Our analyses showed del(17p13) in 31% of EMD versus 13% of medullary disease (P=0.03) and amp(1q21) in 55% versus 32% (P=0.019). No differences were shown in del(13q14) and t(4;14). 24/27 patients with EMD at diagnosis responded to the novel agents-containing regimens. However, when relapsed, 70% of patients did not benefit from the sequential use of novel agents as salvage therapy. In 14 patients who developed EMD at relapse phase, only 2 patients responded to novel agents therapy. Median overall survival of patients with extramedullary manifestations was 30 months, in comparison to 104 months for patients without EMD (P=0.002). Patients with extramedullary manifestation bore high incidence of poor cytogenetic aberration and novel agents resistance.
Getting Business Insights through Clustering Online Behaviors
Authors: Bang Jounghae , Cho Yoonho , Kim Min Sun
Published: April 2015

This study aimed to explore the online users’ behaviors. Since the Internet was introduced to the market, the various and frequent online activities have increased, and it becomes more important for the businesses to understand the online users. Therefore this study analyzed the online users’ behaviors and segmented the users by usingK-means clustering method using actual clickstream data. There were four different research questions and, thus, four different sets of segmentations. It was found that many people find much of entertaining from online using SNS, games, and so on. In addition, some people only have access to a few specific websites. Some use the online service regularly every day while others use it in a very irregular pattern. People were divided into two groups, weekday group and weekend group. People are likely to be using the Internet either on weekdays or at weekend. Teenagers and people in their 50s are more likely to use it during weekend. In addition, teenagers also show different time zone (e.g., overnight) to use the Internet from other age groups. These results can shed light on understanding what consumers do online and what they are interested in currently and on decision making in marketing strategy.
Mechanisms of Hydrogen Transport in Flexible‐Wall Narrow Carbon Nanotubes
Authors: Chen Bin-Hao , Kung Chieh , Chu I-Peng
Published: April 2015

Understanding the interaction between hydrogen and carbon nanotubes is crucial to enhancing the performance of hydrogen storage and nanofluidic carbon‐adsorbent systems. Accordingly, this study performs a series of molecular dynamics simulations to investigate the transport properties of hydrogen molecules confined within a flexible narrow carbon nanotube. The tube’s diameter is 10.8 Å at temperatures in the range of 100~800 K. The particle loadings inside carbon nanotubes are ranging from 0.01∼1 No/Å. The results show that the hydrogen molecules exhibit three distinct diffusion regimes, namely, single‐file, Fickian, and ballistic, depending on the value of the Knudsen number. In addition, it is shown that with the Knudsen number of less than 1, the tube‐wall long wavelength acoustic phonons induced Rayleigh traveling wave prompts a longitudinal wave slip and compression‐expansion of the hydrogen molecule crowds within the CNT, which leads to a significant increase in the mean square displacement of the molecules.
Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation
Authors: Veliça Pedro , Zech Mathias , Henson Sian , Holler Angelika , Manzo Teresa , Pike Rebecca , Santos e Sousa Pedro , Zhang Lei , Schiedlmeier Bernhard , Pule Martin , Stauss Hans , Chakraverty Ronjon
Published: April 2015

A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1low T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions. Cancer Res; 75(13); 2641–52. ©2015 AACR.
Combined Androgen and Estrogen Receptor Status in Breast Cancer: Treatment Prediction and Prognosis in a Population-Based Prospective Cohort
Authors: Elebro Karin , Borgquist Signe , Simonsson Maria , Markkula Andrea , Jirström Karin , Ingvar Christian , Rose Carsten , Jernström Helena
Published: April 2015

Purpose: To evaluate whether tumor androgen receptor (AR) expression was prognostic and/or predictive for endocrine treatment alone or in combination with estrogen receptor (ER). The AR has been hypothesized to have differential prognostic roles in breast cancer depending on tumor ER status, and to influence endocrine treatment response.

Experimental Design: A population-based prospective cohort of 1,026 patients diagnosed with primary invasive breast cancer in Lund, Sweden, between 2002 and 2012 was followed until June 2014. Associations between immunohistochemical AR expression in tumor tissue microarrays, patient and tumor characteristics, and AR genotypes were analyzed. Disease-free survival (DFS) by AR status, and combined ER/AR status was assessed in various treatment groups.

Results: AR expression was assessable in 913 tumors. AR+ tumors (85.0%) were associated with higher age (P = 0.036) and favorable tumor characteristics. The AR+ status was a prognostic marker for DFS (LogRank P = 0.025). There was an interaction between AR and ER expression with respect to prognosis (adjusted Pinteraction ≤ 0.024). Tumors with discordant hormone receptor expressions (ER+AR− or ER−AR+) demonstrated worse prognosis compared with concordant tumor expressions (ER+AR+ or ER−AR−) in multivariable models [adjusted HRs (95% confidence intervals); ≥1.99 (1.28–3.10), P ≤ 0.002]. ER+AR− indicated early treatment failure with aromatase inhibitors (AI) among chemonaïve patients aged 50 or older.

Conclusions: Prediction of breast cancer prognosis and treatment response was improved by combining AR and ER status. AR negativity predicted early treatment failure with AI but not tamoxifen, a finding that warrants confirmation in a randomized setting. Patients may benefit from anti-androgens or selective AR modulators. Clin Cancer Res; 21(16); 3640–50. ©2015 AACR.
Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer
Authors: Speers Corey , Zhao Shuang , Liu Meilan , Bartelink Harry , Pierce Lori J. , Feng Felix Y.
Published: April 2015

Purpose: An unmet clinical need in breast cancer management is the accurate identification of patients who will benefit from adjuvant radiotherapy. We hypothesized that integration of postradiation clonogenic survival data with gene expression data across breast cancer cell (BCC) lines would generate a radiation sensitivity signature (RSS) and identify patients with tumors refractive to conventional therapy.

Experimental Design: Using clonogenic survival assays, we identified the surviving fraction (SF-2Gy) after radiation across a range of BCC lines. Intrinsic radiosensitivity was correlated to gene expression using Spearman correlation. Functional analysis was performed in vitro, and enriched biologic concepts were identified. The RSS was generated using a Random Forest model and was refined, cross-validated, and independently validated in additional breast cancer datasets.

Results: Clonogenic survival identifies a range of radiosensitivity in human BCC lines (SF-2Gy 77%-17%) with no significant correlation to the intrinsic breast cancer subtypes. One hundred forty-seven genes were correlated with radiosensitivity. Functional analysis of RSS genes identifies previously unreported radioresistance-associated genes. RSS was trained, cross-validated, and further refined to 51 genes that were enriched for concepts involving cell-cycle arrest and DNA damage response. RSS was validated in an independent dataset and was the most significant factor in predicting local recurrence on multivariate analysis, outperfoming all clinically used clinicopathologic features.

Conclusions: We derive a human breast cancer–specific RSS with biologic relevance and validate this signature for prediction of locoregional recurrence. By identifying patients with tumors refractory to standard radiation this signature has the potential to allow for personalization of radiotherapy. Clin Cancer Res; 21(16); 3667–77. ©2015 AACR.
Safety and Tumor Specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer
Authors: Rosenthal Eben L. , Warram Jason M. , de Boer Esther , Chung Thomas K. , Korb Melissa L. , Brandwein-Gensler Margie , Strong Theresa V. , Schmalbach Cecelia E. , Morlandt Anthony B. , Agarwal Garima , Hartman Yolanda E. , Carroll William R. , Richman Joshua S. , Clemons Lisa K. , Nabell Lisle M. , Zinn Kurt R.
Published: April 2015

Purpose: Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer.

Experimental Design: A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology.

Results: There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels.

Conclusions: We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology. Clin Cancer Res; 21(16); 3658–66. ©2015 AACR.
Genetic Modulation of Neurocognitive Function in Glioma Patients
Authors: Liu Yanhong , Zhou Renke , Sulman Erik P. , Scheurer Michael E. , Boehling Nicholas , Armstrong Georgina N. , Tsavachidis Spiridon , Liang Fu-Wen , Etzel Carol J. , Conrad Charles A. , Gilbert Mark R. , Armstrong Terri S. , Bondy Melissa L. , Wefel Jeffrey S.
Published: April 2015

Purpose: Accumulating evidence supports the contention that genetic variation is associated with neurocognitive function in healthy individuals and increased risk for neurocognitive decline in a variety of patient populations, including cancer patients. However, this has rarely been studied in glioma patients.

Experimental Design: To identify the effect of genetic variants on neurocognitive function, we examined the relationship between the genotype frequencies of 10,967 single-nucleotide polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase) and neurocognitive function in 233 newly diagnosed glioma patients before surgical resection. Four neuropsychologic tests that measured memory (Hopkins Verbal Learning Test—Revised), processing speed (Trail Making Test A), and executive function (Trail Making Test B, Controlled Oral Word Association) were examined.

Results: Eighteen polymorphisms were associated with processing speed and 12 polymorphisms with executive function. For processing speed, the strongest signals were in IRS1 rs6725330 in the inflammation pathway (P = 2.5 × 10−10), ERCC4 rs1573638 in the DNA repair pathway (P = 3.4 × 10−7), and ABCC1 rs8187858 in metabolism pathway (P = 6.6 × 10−7). For executive function, the strongest associations were in NOS1 rs11611788 (P = 1.8 × 10−8) and IL16 rs1912124 (P = 6.0 × 10−7) in the inflammation pathway, and POLE rs5744761 (P = 6.0 × 10−7) in the DNA repair pathway. Joint effect analysis found significant gene polymorphism-dosage effects for processing speed (Ptrend = 9.4 × 10−16) and executive function (Ptrend = 6.6 × 10−15).

Conclusions: Polymorphisms in inflammation, DNA repair, and metabolism pathways are associated with neurocognitive function in glioma patients and may affect clinical outcomes. Clin Cancer Res; 21(14); 3340–6. ©2015 AACR.
IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors
Authors: Ab Olga , Whiteman Kathleen R. , Bartle Laura M. , Sun Xiuxia , Singh Rajeeva , Tavares Daniel , LaBelle Alyssa , Payne Gillian , Lutz Robert J. , Pinkas Jan , Goldmacher Victor S. , Chittenden Thomas , Lambert John M.
Published: April 2015

A majority of ovarian and non–small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody–drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N2′-deacetyl-N2′-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models. The level of expression of FRα on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non–small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors. Mol Cancer Ther; 14(7); 1605–13. ©2015 AACR.
Gluten-Related Disorders: Gluten Ataxia
Authors: Hadjivassiliou Marios , Sanders David D. , Aeschlimann Daniel P.
Published: April 2015

The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten-free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction.
Vaccination and Other Antigen-Specific Immunomodulatory Strategies in Celiac Disease
Authors: Rossi Mauro
Published: April 2015

Background: Celiac disease (CD) results from an alteration in the oral tolerance to dietary gluten. The response to gluten is normally tightly regulated and involves the secretion of TGF-β and IL-10 from different subtypes of regulatory T cells (Tregs). Interestingly, in addition to proinflammatory cytokines, the inflamed CD mucosa also contains high levels of T cell-derived IL-10 compared with treated CD patients or normal donors. Furthermore, most studies describe an increase in the number of Foxp3+ Tregs in the small intestinal mucosa in CD patients compared to controls. This paradoxical condition suggests that regulatory mechanisms might operate to counterbalance the abnormal gliadin-triggered immune activation in untreated mucosa. Indeed, addition of exogenous IL-10 to mucosal cultures from treated CD patients can suppress gliadin-induced T cell activation. Considering the central role of adaptive immunity in CD, the development of strategies to stimulate these mechanisms is a primary goal of efforts to restore gluten tolerance. Key Messages: Different immunomodulatory strategies have been explored. NexVax2, a desensitizing vaccine that uses three dominant gluten peptides administered subcutaneously to induce a tolerogenic response in CD patients, is under development. Alternatively, the potential of substituted, cyclic or dimeric peptide analogues as blockers to prevent HLA from binding to the immunodominant gliadin epitopes has been demonstrated in vitro. In line with these results, we recently found that modified (transamidated) gliadins influenced the immune response in intestinal biopsy samples from CD patients with overt disease by drastically reducing the production of IFN-γ. Notably, in a mouse model, transamidated gliadins reverted the phenotype of the gliadin-inducible immune response from an inflammatory phenotype to an anti-inflammatory phenotype. Conclusions: Various approaches are currently under investigation to recover gluten tolerance based on the use of both modified and native antigen molecules. More specific studies are now required to test the efficacy of such strategies for preventing CD.
Small Bowel, Celiac Disease and Adaptive Immunity
Authors: Sollid Ludvig M. , Iversen Rasmus , Steinsbø Øyvind , Qiao Shuo-Wang , Bergseng Elin , Dørum Siri , du Pré M. Fleur , Stamnaes Jorunn , Christophersen Asbjørn , Cardoso Inês , Hnida Kathrin , Chen Xi , Snir Omri , Lundin Knut E.A.
Published: April 2015

Background: Celiac disease is a multifactorial and polygenic disease with autoimmune features. The disease is caused by an inappropriate immune response to gluten. Elimination of gluten from the diet leads to disease remission, which is the basis for today's treatment of the disease. There is an unmet need for new alternative treatments. Key Messages: Genetic findings point to adaptive immunity playing a key role in the pathogenesis of celiac disease. MHC is by far the single most important genetic factor in the disease. In addition, a number of non-MHC genes, the majority of which have functions related to T cells and B cells, also contribute to the genetic predisposition, but each of them has modest effect. The primary MHC association is with HLA-DQ2 and HLA-DQ8. These HLA molecules present gluten epitopes to CD4+ T cells which can be considered to be the master regulators of the immune reactions that lead to the disease. The epitopes which the T cells recognize are usually deamidated, and this deamidation is mediated by the enzyme transglutaminase 2 (TG2). Celiac disease patients have disease-specific antibodies. In addition to antibodies to gluten, these include autoantibodies to TG2. Antibodies to deamidated gluten are nearly as specific for celiac disease as the anti-TG2 antibodies. Both types of antibodies appear only to be produced in subjects who are HLA-DQ2 or HLA-DQ8 when they are consuming gluten. Conclusion: It is hardly coincidental that TG2 is implicated in T-cell epitope formation and at the same time a target for autoantibodies. Understanding this connection is one of the major challenges for obtaining a complete understanding of how gluten causes tissue destruction and remodeling of the mucosa in the small bowel.
Small Bowel Imaging in Celiac Disease
Authors: Van Weyenberg Stijn J.B. , Mulder Chris J.J. , Van Waesberghe Jan Hein T.M.
Published: April 2015

Background: Modern small bowel imaging techniques allow detailed depiction of small-intestinal abnormalities. The role of these techniques in the investigation of celiac disease is increasing, especially in patients with suspected complicated celiac disease. Key Messages: In general, there is no need for radiological small bowel imaging in uncomplicated celiac disease. It is however important that clinicians and radiologists are aware of certain specific radiological findings that may suggest celiac disease, especially since celiac disease is often not considered in adult patients, and small bowel radiology may be performed before specific tests for celiac disease. Radiological abnormalities can be observed with both conventional small bowel radiology studies, like small bowel follow-through or double-contrast small bowel enteroclysis, and newer modalities, like computed tomography or magnetic resonance enterography or enteroclysis. These signs include a decreased number of jejunal folds, an increased number of ileal folds, small bowel dilatation, wall thickening and intussusception. Extraintestinal abnormalities include mesenteric lymphadenopathy, vascular changes and splenic atrophy. Abnormalities congruent with refractory celiac disease type II include a severe decrease in jejunal folds, infiltration of the mesenteric fat and thickening of the small bowel wall. Additionally, a severely decreased splenic volume may indicate complicated celiac disease. Malignant complications of celiac disease, such as enteropathy-associated T-cell lymphoma and small-intestinal adenocarcinoma, can be reliably investigated with cross-sectional enteroclysis techniques. Conclusions: Small bowel imaging and especially cross-sectional enteroclysis techniques are important extensions to the diagnostic workup of clinicians involved in the care of patients with celiac disease, especially those with suspected complicated disease.
Microscopic Colitis
Authors: Bouma Gerd , Münch Andreas
Published: April 2015

Microscopic colitis (MC) is the common denominator for lymphocytic and collagenous colitis (CC). It is now recognized as a relatively frequent cause of diarrhea that equals the prevalence of inflammatory bowel disease. Patients are typically middle-aged women, but disease may occur at every age. Patients with MC report watery, non-bloody diarrhea in the absence of endoscopic and radiologic abnormalities. Lymphocytic colitis is characterized by an increased number of intraepithelial lymphocytes, and CC by a thickened subepithelial collagen band, whereas in both an increased mononuclear infiltration of the lamina propria is found. The pathogenesis of MC is largely unknown, but may relate to autoimmunity, adverse reactions to drugs or (bacterial) toxins, and abnormal collagen metabolism in the case of CC. Budesonide is so far the only drug that has proven efficacy in randomized controlled trials both for the induction and maintenance of remission. Patients who are nonresponsive, dependent or who experience side effects on budesonide may benefit from thiopurine or anti-TNF treatment, but these options are still experimental. The long-term prognosis of MC is good; it does not appear to predispose to malignancies and can in some cases be self-limiting. Further research and randomized clinical trials are required to expand our understanding of the natural course and the pathogenesis of MC.
World Perspective and Celiac Disease Epidemiology
Authors: Catassi Carlo , Gatti Simona , Lionetti Elena
Published: April 2015

In Europe and the USA, the mean frequency of celiac disease (CD) in the general population is approximately 1%, with some regional differences, the reasons for which remain elusive. A similar disease prevalence has been found in other countries mostly populated by individuals of European origin, e.g. Australia and Argentina. In Western countries, a true rise in overall CD prevalence of CD has been documented. CD is a common disorder in North Africa, the Middle East and India; however, the diagnostic rate is low in these countries due to low availability of diagnostic facilities and poor disease awareness. The highest CD prevalence in the world (5.6%) has been described in an African population originally living in Western Sahara, the Saharawi, of Arab-Berber origin. The reasons for this high CD frequency are unclear but could be primarily related to recent dietary changes and genetic factors, given the high level of consanguinity of this population. Further studies are needed to quantify the incidence of the celiac condition in apparently ‘celiac-free' areas such as Sub-Saharan Africa and the Far East. In many developing countries, the frequency of CD is likely to increase in the near future given the diffuse tendency to adopt Western, gluten-rich dietary patterns. As most cases currently escape diagnosis all over the world, an effort should be made to increase the awareness of CD polymorphism. A cost-effective case-finding policy and new strategies of mass CD screening could significantly reduce the morbidity and mortality associated with untreated disease. The current high prevalence of CD is just the last link in a chain of events started about 10,000 years ago after wheat domestication and diffusion from the Middle East. We hypothesize different mechanisms to explain the so-called evolutionary celiac paradox of co-localization of gluten consumption and HLA CD-predisposing genotypes.
Interleukin-15, a Master Piece in the Immunological Jigsaw of Celiac Disease
Authors: Meresse Bertrand , Korneychuk Natalia , Malamut Georgia , Cerf-Bensussan Nadine
Published: April 2015

Background: The immune response causing celiac disease (CD) depends on the activation of intestinal CD4+ T cells by gluten-derived peptides presented by HLA-DQ2 or HLA-DQ8 molecules, the main genetic risk factor. However, additional factors are necessary to impair immune tolerance to dietary gluten, to stimulate intraepithelial lymphocytes (IEL) and to induce intestinal damage. Key Messages: Current data point to a central role of interleukin-15 (IL-15). In situ and ex vivo studies indicate that IL-15 stimulates the accumulation and cytotoxic activation of CD8+ T IEL in active CD, and that of the malignant innate-like IEL in type II refractory CD (RCDII). Other studies show that IL-15 impairs the immunoregulatory control of effector T cells, notably CD8+. Recently, animal models have been designed to investigate the respective role of CD4+ T cells and IL-15 in CD. We discuss more particularly our results in such a model, which shows that IL-15 produced in excess in the intestine can cooperate with CD4+ T cells specific for a dietary antigen to trigger a celiac-like enteropathy. In this mouse model, CD4+ T cells activated by dietary ovalbumin secreted IL-2 which, along with IL-15, stimulated the expansion of noncognate intestinal cytotoxic CD8+ T cells containing large amounts of granzyme B. In the presence of IL-15, the latter cells did not respond to regulatory T cells, and accumulated in the intestine close to epithelial damage. Conclusion: On the basis of these data, we propose that, in CD, gluten-specific CD4+ T cells synthesize cytokines that synergize with IL-15 to license the expansion and activation of cytotoxic IEL, which drive tissue damage. We suggest that IL-15 is a meaningful therapeutic target, notably in patients with RCDII in which malignant IEL can respond to IL-15 independently of signals provided by CD4+ T cells.
Host-Microbiota Interactions in the Intestine
Authors: Elson Charles O. , Alexander Katie L.
Published: April 2015

The comprehensive collection of bacterial species, termed microbiota, within human and other mammalian hosts has profound effects on both innate and adaptive immunity. Multiple host innate mechanisms contribute to intestinal homeostasis, including epithelial production of protective mucin layers maintaining spatial segregation in the intestine as well as epithelial cell secretion of a broad range of antimicrobial peptides. Additionally, epithelial cells employ autophagy to contain and eliminate invading bacteria; interestingly, genetic variants in specific autophagy genes are linked to susceptibility to Crohn's disease. Innate lymphoid cells, which rapidly respond to cytokine and microbial signals, have emerged as important regulators of the intestinal immune response to the microbiota. With regard to adaptive immunity, specific microbial species stimulate induction of regulatory T cells while others induce effector T cells within the gut. Such stimulation is subject to dysregulation during inflammation and disease, contributing to ‘dysbiosis' or an abnormal microbiota composition that has been associated with a variety of immune-mediated inflammatory disorders, including celiac disease. The microbiota communicates with the immune system and vice versa; thus, an abnormal microbiota composition likely translates into an altered host immune response, though the exact mechanisms of such are not yet clear. Immunoglobulin A plays a critical role in limiting bacterial access to the host and in maintaining mutualism with the microbiota. Perturbation of the mucosal barrier via infection or other means can induce effector T cells reactive to the intestinal microbiota, and these cells can persist as memory cells for extended periods of time and potentially serve as pathogenic effector cells upon re-encounter with antigen. Health is associated with a diverse microbiota that functions to maintain the balance between T effector and T regulatory cells in the intestine. Whether dysbiosis can be reversed in immune-mediated disease, thus restoring health, is a question of intense interest for this active area of research.