bluuebunny/crossref_metadata_2025 huggingface dataset:
Power‐Splitting Scheme for Nonlinear Energy Harvesting AF Relaying with Direct Link
Authors: Bai Xiaobo , Shao Jingfeng , Tian Jiangang , Shi Liqin
Published: July 2018

Simultaneous wireless information and power transfer (SWIPT) is a promising technique to prolong the lifetime of energy‐constrained relay systems. Most previous works optimize power‐splitting (PS) scheme based on a linear or a simple two‐piecewise linear energy harvesting (EH) model, while the employed EH model may not characterize the properties of practical EH harvesters well. This leads to a mismatch between the existing PS scheme and the practical EH harvester available for relay systems. Motivated by this, this paper is devoted to the design of PS scheme in a nonlinear EH amplify‐and‐forward energy‐constrained relay system in the presence of a direct link between the source and the destination. In particular, we formulate an optimization problem to maximize the system capacity according to the instantaneous channel state information, subject to a nonlinear EH model based on the logistic function. The objective function of the formulated problem is proven to be unimodal and there is no closed‐form expression for the optimal PS ratio due to the complexity of logistic function. In order to reduce overhead cost of optimizing PS ratio, a simpler nonlinear EH model based on the inverse proportional function is employed to replace the nonlinear EH model based on the logistic function and we further derive the closed‐form expression for the optimal PS ratio. Simulation results reveal that a higher system capacity can be achieved when the PS scheme is optimized based on nonlinear EH models instead of the linear EH model, and that there is only a marginal difference between the capacity under the two optimal PS schemes optimized for two different nonlinear EH models.
The Role of Microbial Aspartic Protease Enzyme in Food and Beverage Industries
Authors: Mamo Jermen , Assefa Fassil
Published: July 2018

Proteases represent one of the three largest groups of industrial enzymes and account for about 60% of the total global enzymes sale. According to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology, proteases are classified in enzymes of class 3, the hydrolases, and the subclass 3.4, the peptide hydrolases or peptidase. Proteases are generally grouped into two main classes based on their site of action, that is, exopeptidases and endopeptidases. Protease has also been grouped into four classes based on their catalytic action: aspartic, cysteine, metallo, and serine proteases. However, lately, three new systems have been defined: the threonine-based proteasome system, the glutamate-glutamine system of eqolisin, and the serine-glutamate-aspartate system of sedolisin. Aspartic proteases (EC 3.4.23) are peptidases that display various activities and specificities. It has two aspartic acid residues (Asp32 and Asp215) within their active site which are useful for their catalytic activity. Most of the aspartic proteases display best enzyme activity at low pH (pH 3 to 4) and have isoelectric points in the pH range of 3 to 4.5. They are inhibited by pepstatin. The failure of the plant and animal proteases to meet the present global enzyme demand has directed to an increasing interest in microbial proteases. Microbial proteases are preferred over plant protease because they have most of the characteristics required for their biotechnological applications. Aspartic proteases are found in molds and yeasts but rarely in bacteria. Aspartic protease enzymes from microbial sources are mainly categorized into two groups: (i) the pepsin-like enzymes produced byAspergillus,Penicillium,Rhizopus, andNeurosporaand (ii) the rennin-like enzymes produced byEndothiaandMucorspp., such asMucor miehei,M. pusillus, andEndothia parasitica. Aspartic proteases of microbial origin have a wide range of application in food and beverage industries. These include as milk-clotting enzyme for cheese manufacturing, degradation of protein turbidity complex in fruit juices and alcoholic liquors, and modifying wheat gluten in bread by proteolysis.
Evidence of Exponential Speed‐Up in the Solution of Hard Optimization Problems
Authors: Traversa Fabio L. , Cicotti Pietro , Sheldon Forrest , Di Ventra Massimiliano
Published: July 2018

Optimization problems pervade essentially every scientific discipline and industry. A common form requires identifying a solution satisfying the maximum number among a set of many conflicting constraints. Often, these problems are particularly difficult to solve, requiring resources that grow exponentially with the size of the problem. Over the past decades, research has focused on developing heuristic approaches that attempt to find an approximation to the solution. However, despite numerous research efforts, in many cases even approximations to the optimal solution are hard to find, as the computational time for further refining a candidate solution also grows exponentially with input size. In this paper, we show a noncombinatorial approach to hard optimization problems that achieves an exponential speed-up and finds better approximations than the current state of the art. First, we map the optimization problem into a Boolean circuit made of specially designed, self-organizing logic gates, which can be built with (nonquantum) electronic elements with memory. The equilibrium points of the circuit represent the approximation to the problem at hand. Then, we solve its associated nonlinear ordinary differential equations numerically, towards the equilibrium points. We demonstrate this exponential gain by comparing a sequential MATLAB implementation of our solver with the winners of the 2016 Max‐SAT competition on a variety of hard optimization instances. We show empirical evidence that our solver scales linearly with the size of the problem, both in time and memory, and argue that this property derives from the collective behavior of the simulated physical circuit. Our approach can be applied to other types of optimization problems, and the results presented here have far‐reaching consequences in many fields.
Robust and Fragile Medical Image Watermarking: A Joint Venture of Coding and Chaos Theories
Authors: Rahman Atta Ur , Sultan Kiran , Musleh Dhiaa , Aldhafferi Nahier , Alqahtani Abdullah , Mahmud Maqsood
Published: July 2018

A secure spatial domain, hybrid watermarking technique for obtaining watermark (authentication information) robustness and fragility of the host medical image (content integrity) using product codes, chaos theory, and residue number system (RNS) is proposed. The proposed scheme is highly fragile and unrecoverable in terms of the host image, but it is significantly robust and recoverable in terms of the watermark. Altering the medical image may result in misdiagnosis, hence the watermark that may contain patient information and organization logo must be protected against certain attacks. The host medical image is separated into two parts, namely, the region of interest (ROI) and region of noninterest (RONI) using a rectangular region. The RONI part is used to embed the watermark information. Moreover, two watermarks are used: one to achieve authenticity of image and the other to achieve the robustness against both incidental and malicious attacks. Effectiveness in terms of security, robustness, and fragility of the proposed scheme is demonstrated by the simulations and comparison with the other state-of-the-art techniques.
Effects of Lime, Vermicompost, and Chemical P Fertilizer on Selected Properties of Acid Soils of Ebantu District, Western Highlands of Ethiopia
Authors: Bekele Abdissa , Kibret Kibebew , Bedadi Bobe , Yli-Halla Markku , Balemi Tesfaye
Published: July 2018

Soil acidity is one of the major factors limiting soil fertility and crop production in large areas of Ethiopia. A two-month incubation experiment was conducted to evaluate the effects of lime, vermicompost (VC), and chemical phosphorus (P) fertilizer on selected chemical properties of Dystric Nitisols in Ebantu District, Western Ethiopia. The treatments comprised of three rates of lime (2, 4, and 6 tons CaCO3·ha−1), VC (2.5, 5, and 7.5 tons·ha−1), and mineral P fertilizer (20, 40, and 60 kg·P·ha−1) each applied alone and in various combinations. The experiment was laid down in a completely randomized design with two replications. The results showed that the highest increment of pH from 4.83 at the control to 6.05 and reduction of exchangeable Al from 1.70 to 0.09 cmolc·kg−1were obtained from combined application of lime at 4 tons CaCO3·ha−1and VC at 7.5 tons·ha−1. The most significant decrease in exchangeable acidity (0.17 cmolc.kg-1) was observed in soil that was treated with 6 tons CaCO3·ha−1lime applied alone (93%) and combined application of lime at 4 tons CaCO3·ha−1with VC at 7.5 tons·ha−1by (81%). The highest contents of OM (4.1%) and total nitrogen (0.29%) were obtained from combined application of lime at 4 tons CaCO3·ha−1and VC at 7.5 tons·ha−1. Integrated application of chemical P (60 kg·P·ha−1) with lime (2 tons·ha−1) plus VC (7.5 tons·ha−1) resulted in Bray-II P increased by 45% relative to control. The various combinations of the treatments also improved exchangeable Ca2+and Mg2+. The results indicate that integrated use of lime, vermicompost, and chemical P fertilizer can improve soil acidity and availability of nutrients. However, the real potential of the amendments used in this experiment should be further assessed under field conditions using a test crop.
Investigation on the Neural Mechanism of Hypnosis-Based Respiratory Control Using Functional MRI
Authors: Liu Yanjun , Qin Wenjian , Li Rongmao , Yu Shaode , He Yini , Xie Yaoqin
Published: July 2018

Respiratory control is essential for treatment effect of radiotherapy due to the high dose, especially for thoracic-abdomen tumor, such as lung and liver tumors. As a noninvasive and comfortable way of respiratory control, hypnosis has been proven effective as a psychological technology in clinical therapy. In this study, the neural control mechanism of hypnosis for respiration was investigated by using functional magnetic resonance imaging (fMRI). Altered spontaneous brain activity as well as neural correlation of respiratory motion was detected for eight healthy subjects in normal state (NS) and hypnosis state (HS) guided by a hypnotist. Reduced respiratory amplitude was observed in HS (mean ± SD: 14.23 ± 3.40 mm in NS, 12.79 ± 2.49 mm in HS, p=0.0350), with mean amplitude deduction of 9.2%. Interstate difference of neural activity showed activations in the visual cortex and cerebellum, while deactivations in the prefrontal cortex and precuneus/posterior cingulate cortex (PCu/PCC) in HS. Within these regions, negative correlations of neural activity and respiratory motion were observed in visual cortex in HS. Moreover, in HS, voxel-wise neural correlations of respiratory amplitude demonstrated positive correlations in cerebellum anterior lobe and insula, while negative correlations were shown in the prefrontal cortex and sensorimotor area. These findings reveal the involvement of cognitive, executive control, and sensorimotor processing in the control mechanisms of hypnosis for respiration, and shed new light on hypnosis performance in interaction of psychology, physiology, and cognitive neuroscience.
A Piezoelectric‐Driven Rock‐Drilling Device for Extraterrestrial Subsurface Exploration
Authors: Li He , Shen Yi , Wang Qingchuan , Wang Yinchao , Bai Deen , Deng Zongquan
Published: July 2018

The rocks on extraterrestrial objects contain plenty of original geological and biological information. Drilling and sampling are an essential task in lunar exploration or future explorations of other planets like mars. Due to the limitation of payloads, energies, and drill pressure, the investigation of a lightweight and low‐powered rock‐drilling device is crucial for explorations of distant celestial bodies. The ultrasonic drill driven by piezoelectric ceramics is a new drilling device that can adapt to the arduous space rock‐drilling tasks in weak gravitational fields. An ultrasonic drill suitable for mounting on a planetary rover’s robotic arm is developed. The ultrasonic transducer’s energy conversion from electric energy to acoustic energy and the energy transmission from the horn’s high‐frequency vibration to the drill stem’s low‐frequency impact motion are analyzed to guide the design of the drill. To deeply understand the percussive drilling mechanism under high‐speed impact, the interaction between the drill stem and the rock is simulated using LS‐DYNA software. Drilling experiments on rocks with different hardness grades are conducted. The experiment results illustrate that the ultrasonic drill can penetrate into the hard rocks only taking a force of 6 N and a power consumption of 15 W. The study of ultrasonic drill will provide a reference method for sample collection of extraterrestrial rocks.
Discriminative and Quantitative Analysis of Antineoplastic Taxane Drugs Using a Handheld Raman Spectrometer
Authors: Lê Laetitia , Berge Marion , Tfayli Ali , Prognon Patrice , Caudron Eric
Published: July 2018

This study was conducted to evaluate the ability of Raman spectroscopy (RS) to control antineoplastic preparations used for chemotherapy in order to ensure its physical and chemical qualities. Three taxane drugs: cabazitaxel (CBX), docetaxel (DCX) and paclitaxel (PCX) at therapeutic concentration ranges were analyzed using a handheld spectrometer at 785 nm. Qualitative and quantitative models were developed and optimized using a calibration set (n=75 per drug) by partial least square discriminant analysis and regression and validated using a test set (n=27 per drug). All samples were correctly assigned with an accuracy of 100%. Despite optimization, quantitative analysis showed limited performances at the lowest concentrations. The root mean square error of predictions ranged from 0.012 mg/mL for CBX to 0.048 mg/mL for DCX with a minimal coefficient of determination of 0.9598. The linearity range was validated from 0.175 to 0.30 mg/mL for CBX, from 0.40 to 1.00 mg/mL for DCX and from 0.57 to 1.20 mg/mL for PCX. Despite some limitations, this study confirms the potential of RS to control these drugs and also provides substantial advantages to secure the activity for healthcare workers. As a result of its rapidity and the uncomplicated use of a handheld instrument, RS appears to be a promising method to augment security of the medication preparation process in hospitals.
A New Spray Approach to Produce Uniform Ultrafine Coatings
Authors: Qian Lijuan , Song Shaobo , Li Xiaolu
Published: July 2018

A new spray approach is proposed to overcome the disadvantages of the traditional single-orifice nozzle, such as uneven coatings, overspray, and low efficiency. Both the experimental measurements and numerical simulation are used to investigate the spray characteristics of the multiorifice nozzle. The results show the new nozzle structure is able to disperse the particles in a wider regime and reduce the central pressure. It is an effective way to produce uniform ultrafine coatings.
New Turns for High Efficiency Knock-In of Large DNA in Human Pluripotent Stem Cells
Authors: He Xiangjun , Li Yin-Xiong , Feng Bo
Published: July 2018

The groundbreaking CRISPR technology is revolutionizing biomedical research with its superior simplicity, high efficiency, and robust accuracy. Recent technological advances by a coupling CRISPR system with various DNA repair mechanisms have further opened up new opportunities to overcome existing challenges in knocking-in foreign DNA in human pluripotent stem cells, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). In this review, we summarized the very recent development of CRISPR-based knock-in strategies and discussed the results obtained as well as potential applications in human ESC and iPSC.
Change Point Detection for Piecewise Envelope Current Signal Based on Wavelet Transform
Authors: Wang Haiyan , Zhou Feng , Jiang Chunyang , Qin Ling , Zhang Huaiqing
Published: July 2018

One of the key issues of the accurate parameters analysis for the piecewise envelope current signal is to position the change point precisely. Discrete wavelet transform (DWT) modulus maxima method can detect change point, but the detection window of DWT will cause suspicious change point. Besides, the amount of calculated data is very large in actual process of envelope current signal. Therefore, in this paper, the envelope is used instead of the original sampling data for DWT so as to reduce the calculation amount. What is more, combined with the sliding dislocation window method, the change point can be located accurately and the pseudo-change point can be eliminated. The simulation results as well as the electric locomotive current and forging machine current examples show that it is feasible to detect the change point precisely through the proposed method, which provides possibilities for real-time online monitoring of change point.
Ka‐Band LTCC Stacked Substrate Integrated Waveguide Bandpass Filter
Authors: Zheng Peng , Liu Zhifu , Ma Mingsheng , Wang Yi , Liu Feng , Li Yongxiang
Published: July 2018

A Ka‐band substrate integrated waveguide bandpass filter has been designed and fabricated using low temperature co‐fired ceramic (LTCC) technology. The in‐house developed SICCAS‐K5F3 material with a permittivity of 6.2 and a loss tangent of 0.002 was used. The size and surface area of the proposed bandpass filter are reduced by exploiting vertical coupling in vertically laminated three‐dimensional structures. The coupling between adjacent cavities is realized by a narrow slot. A vertical transition structure between the coplanar‐waveguide feed line and the substrate integrated waveguide is adopted to facilitate the internal signal connection. The demonstrated third‐order filter has a compact size of 6.79 mm×4.13 mm×1.34 mm (0.63λ0  × 0.38λ0  × 0.12λ0) and exhibits good performance with a low insertion loss of 1.74 dB at 27.73 GHz and a 3 dB fractional bandwidth of 10 %.
Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population
Authors: Blyuss Oleg , Burnell Matthew , Ryan Andy , Gentry-Maharaj Aleksandra , Mariño Inés P. , Kalsi Jatinderpal , Manchanda Ranjit , Timms John F. , Parmar Mahesh , Skates Steven J. , Jacobs Ian , Zaikin Alexey , Menon Usha
Published: July 2018

Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the “Risk of Ovarian Cancer Algorithm” (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.

Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.

Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4–91.9] and PEB (88.5%; 95% CI, 80.6–93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6–80.8).

Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726–33. ©2018 AACR.
Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer
Authors: Karam Sana D. , Reddy Krishna , Blatchford Patrick J. , Waxweiler Tim , DeLouize Alicia M. , Oweida Ayman , Somerset Hilary , Marshall Carrie , Young Christian , Davies Kurtis D. , Kane Madeleine , Tan Aik Choo , Wang Xiao Jing , Jimeno Antonio , Aisner Dara L. , Bowles Daniel W. , Raben David
Published: July 2018

Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories.

Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25–200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care.

Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3–4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis.

Conclusions: Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. Clin Cancer Res; 24(20); 4949–59. ©2018 AACR.
Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
Authors: Ayers Leona W. , Barbachano-Guerrero Arturo , McAllister Shane C. , Ritchie Julie A. , Asiago-Reddy Elizabeth , Bartlett Linda C. , Cesarman Ethel , Wang Dongliang , Rochford Rosemary , Martin Jeffrey N. , King Christine A.
Published: July 2018

Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS–associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV.

Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine.

Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.

Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085–97. ©2018 AACR.
Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood–Brain Barrier
Authors: Kim Minjee , Ma Daniel J. , Calligaris David , Zhang Shuangling , Feathers Ryan W. , Vaubel Rachael A. , Meaux Isabelle , Mladek Ann C. , Parrish Karen E. , Jin Fang , Barriere Cedric , Debussche Laurent , Watters James , Tian Shulan , Decker Paul A , Eckel-Passow Jeanette E. , Kitange Gaspar J. , Johnson Aaron J. , Parney Ian F. , Anastasiadis Panos Z. , Agar Nathalie Y.R. , Elmquist William F. , Sarkaria Jann N.
Published: July 2018

Controversy exists surrounding whether heterogeneous disruption of the blood–brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. Mol Cancer Ther; 17(9); 1893–901. ©2018 AACR.
Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy
Authors: Lepikhova Tatiana , Karhemo Piia-Riitta , Louhimo Riku , Yadav Bhagwan , Murumägi Astrid , Kulesskiy Evgeny , Kivento Mikko , Sihto Harri , Grénman Reidar , Syrjänen Stina M. , Kallioniemi Olli , Aittokallio Tero , Wennerberg Krister , Joensuu Heikki , Monni Outi
Published: July 2018

There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus–negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series. Mol Cancer Ther; 17(9); 2060–71. ©2018 AACR.
Inhibition of Parp1 by BMN673 Effectively Sensitizes Cells to Radiotherapy by Upsetting the Balance of Repair Pathways Processing DNA Double-Strand Breaks
Authors: Soni Aashish , Li Fanghua , Wang You , Grabos Martha , Krieger Lisa Marie , Chaudhary Shipra , Hasan Mohammad Sharif Mortoga , Ahmed Mansoor , Coleman C. Norman , Teicher Beverly A. , Piekarz Richard L. , Wang Dian , Iliakis George E.
Published: July 2018

Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 μmol/L) or AG14361 (0.4 μmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 μmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (∼1 hour) and at pharmacologically achievable concentrations in vivo. BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end-joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. Mol Cancer Ther; 17(10); 2206–16. ©2018 AACR.
Identification of a Broad-Spectrum Peptidoglycan Hydrolase Associated with the Particle of Xanthomonas oryzae Phage Xop411
Authors: Weng Shu-Fen , Fu Yung-Chieh , Lin Juey-Wen , Tseng Tsai-Tien
Published: July 2018

Virion-associated peptidoglycan hydrolases (VAPGH) in bacteriophages are potential antimicrobials. Xop411 is a syphophage infecting the Gram-negative Xanthomonas oryzae pv. oryzae that causes bacterial leaf blight in rice plants. The Xop411 gp21 protein was identified here as a peptidoglycan glycohydrolase by Western blotting and zymogram assay, and localized to the phage tail by immunogold-labelling electron microscopy. This protein showed an apparent molecular mass of 17 kDa in SDS-polyacrylamide gels, larger than that calculated from the amino acid sequence, 15 kDa with 130 residues. The recombinant gp21 expressed in Escherichia coli formed inclusion bodies, which gained enzyme activity after in-gel renaturation. In contrast, the secreted recombinant protein (s-gp21His) expressed in Pichia pastoris was soluble and enzymatically active. Plate assays showed that s-gp21His was capable of killing 3 species of Xanthomonas, a genus containing 27 closely related plant pathogenic species, as well as the opportunistic Pseudomonas aeruginosa and Stenotrophomonas maltophilia causing nosocomial infections. These results indicate that the Xop411 gp21 has possible wide applications as an antimicrobial against xanthomonads and at least 2 opportunistic bacteria. Several other VAPGH from Xanthomonas phages were also identified by bioinformatic analysis, with 1 being confirmed by Western blotting.
Extra-Pulmonary Neuroendocrine Carcinomas: A Population-Based Study in the Netherlands
Authors: van der Zwan Jan Maarten , Siesling Sabine , van Velthuysen Loes , Links Thera , Walenkamp Annemiek , Tesselaar Margot
Published: July 2018

Background: Extra-pulmonary neuroendocrine carcinomas (EP-NEC) are rare tumours that require expertise for correct and timely diagnosis, which is essential for clinical decision making. The number of patients affected, treatment given, and the proportion surviving the disease is based on limited evidence. The aim of this study is to retrospectively analyse the incidence, treatment, and relative survival (RS) of EP-NEC patients in the Netherlands. Methods: Patients diagnosed between 2008–2012 with EP-NEC or NEC with unknown primary site (UP-NEC) were selected from the Netherlands Cancer Registry based on combinations of tumour localisation and morphology code. Incidence was studied using the European standardised (ESR) and world standardised rates, and RS was calculated using the Ederer II method. Results: In total, 1,544 cases were analysed, 1,045 EP-NEC and 499 UP-NEC. For EP-NEC, the incidence was 1.0 per 100,000 person-years (ESR), the mean age was 68 years, and the male to female ratio was 1: 0.6. Most frequent EP-NEC localisations were the bladder and the gastrointestinal tract, and the treatment most frequently given was surgery in combination with chemotherapy. The overall 5-year RS was 38% for patients with local/regional disease (n = 447), and 7% for patients with extensive disease (n = 582). For UP-NEC patients (n = 499), the 5-year RS was 6%. Conclusions: This study is the first nationwide study presenting an increase in the incidence of EP-NEC patients from 196 to 260 cases annually in the Netherlands. The best 5-year RS was found for EP-NEC patients with local disease located in the bladder, where the worst 5-year RS was found for patients with disease located in the oesophagus.
Impact of Insufficient Response with an Increase in Tumor Number in Predicting Transcatheter Arterial Chemoembolization Refractoriness for Hepatocellular Carcinoma
Authors: Furuta Mitsuhiro , Moriguchi Michihisa , Okuda Keiichiro , Kataoka Seita , Mizuno Naoki , Takemura Masashi , Taketani Hiroyoshi , Hara Tasuku , Seko Yuya , Umemura Atsushi , Nishikawa Taichiro , Yamaguchi Kanji , Yasui Koichiroh , Minami Masahito , Itoh Yoshito
Published: July 2018

Aim: In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after ≥2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of > 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness. Methods: Patients who underwent TACE for hepatocellular carcinomas > 3 cm in size or with > 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the “either” group, evaluated as either “ineffective” or “progressive,” and the “both” group, that is, both “ineffective” and “progressive.” Results: The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (n = 23) and both (n = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (p = 0.0295). Conclusions: Patients with both “ineffective” and “progressive” lesions are extremely likely to be TACE ­refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered.
Die Heterogenität des Prostatakrebses: Ein praxisorientierter Ansatz
Authors: Tolkach Yuri , Kristiansen Glen
Published: July 2018

Prostatakrebs ist in nahezu jeder Hinsicht ein beispielhaftes Tumormodell für Heterogenität. Seine klinische, räumliche und morphologische Heterogenität, dividiert durch die hochgradige molekular-genetische Diversität, umreißt die Komplexität dieses Krankheitsbildes im Klinik- und Forschungsumfeld. In dem vorliegenden Review fassen wir die Hauptaspekte der Heterogenität des Prostatakrebses auf verschiedenen Ebenen zusammen, unter besonderer Berücksichtigung der räumlichen Heterogenität innerhalb der Prostata sowie der morphologischen Standardheterogenität in Bezug auf Tumor-Grading und moderne Klassifikationen. Wir befassen uns auch mit der komplexen Frage der molekulargenetischen Heterogenität und diskutieren sie im Zusammenhang mit den aktuellen Erkenntnissen zur genetischen Charakterisierung von Prostatakarzinomen, mit der Heterogenität zwischen Patienten und Tumoren (multifokale Erkrankung) sowie der Heterogenität innerhalb eines Tumors, mit der Tumorklonalität und mit der Metastasierung. Die möglichen Konsequenzen für Klinik und Forschung werden zusammengefasst und dazu verwendet, die relevantesten Probleme zu diskutieren, die sich aus der extremen Heterogenität des Prostatakrebses ergeben. Übersetzung aus Tolkach Y, Kristiansen G: Pathobiology 2018;85:108-116.
Langfristige Vollremission mit Ipilimumab bei metastasiertem kastrationsresistentem Prostatakrebs: Fallbericht von zwei Patienten
Authors: Cabel Luc , Loir Elika , Gravis Gwenaelle , Lavaud Pernelle , Massard Christophe , Albiges Laurence , Baciarello Giulia , Loriot Yohann , Fizazi Karim
Published: July 2018

Hintergrund: Prostatakrebs ist eine der häufigsten Krebserkrankungen bei Männern und die vierthäufigste Ursache für Krebssterblichkeit weltweit. Obwohl in den letzten Jahren mit auf die Androgenrezeptorachse gezielten Wirkstoffen der nächsten Generation, Taxanen und auf die Knochen gerichteten Mitteln große Fortschritte bei Patienten mit metastasiertem kastrationsresistentem Prostatakrebs (mCRPC, metastatic castrate-resistant prostate cancer) erzielt wurden, ist die Immuntherapie noch nicht allgemein zur Behandlung von Prostatakrebs zugelassen und in Gebrauch. Zwei große Studien mit Ipilimumab, einem Antikörper gegen CTLA-4 (zytotoxisches T-Lymphozyten-Antigen 4), zeigten verbessertes progressionsfreies Überleben, aber kein statistisch verbessertes Gesamtüberleben bei der Primäranalyse (CA184 043 und CA184 095). Fallvorstellung: Hier berichten wir über zwei Patienten, die in diesen Studien Ipilimumab erhielten und immer noch in langfristiger Vollremission bei einer Nachbeobachtungszeit von 64 bzw. 52 Monaten nach Beginn der Behandlung mit Ipilimumab sind. Immunhistochemische Färbung auf hMLH1, hMSH2, hMSH6 und PMS2 wurde an archivierten Prostatabiopsieproben von einem der beiden Patienten durchgeführt; sie zeigten eine normale Proteinexpression. Interessanterweise wurde bei diesem Patienten in archivierten Prostatabiopsien hohe Infiltration mit CD3+- und CD8+-T-Zellen beobachtet, ebenso wie mit regulatorischen FoxP3+-Treg-Zellen. Schlussfolgerung: Ipilimumab zeigt klinische Aktivität bei Patienten mit CRPC, einschließlich Fällen sehr langen Ansprechens ohne nachweisbare Resterkrankung. Übersetzung aus J Immunother Cancer 2017;5:31.
Quality of Care in Ulcerative Colitis: A Modified Delphi Panel Approach
Authors: Peyrin-Biroulet Laurent , Baumgart Daniel C. , Armuzzi Alessandro , Gionchetti Paolo , Sebastian Shaji , Danese Silvio , Magro Fernando , Higgins Sophie , Yaworksy Andrew , Banderas Benjamin , Kachroo Sumesh
Published: July 2018

Objectives: To establish clinical consensus on important and relevant quality-of-care (QoC) attributes in ulcerative colitis (UC) treatment that may improve treatment outcomes and guide best practices. Methods: Thirty-eight QoC attributes were identified in a literature review. Sixteen European-based experts were selected based on their contributions to UC guidelines, publications, and patient care. A 3-round, modified Delphi panel was conducted including an interview round, and 2 web-based rounds to reach consensus and finalize a QoC attribute list. Results: The draft QoC attribute list derived from a literature review and Round 1, expert interviews, comprised 63 attributes. In Rounds 2 and 3, the QoC attributes frequently rated as critically important were diagnosis (n = 15, 93.8%), treatment adherence (n = 15, 93.8%), and access to care/treatment (Round 2: n = 14, 87.5%; Round 3: n = 15, 93.8%). The final QoC attribute list consisted of 61 attributes across 20 domains, with the most attributes reported in the “treatment goals” domain (n = 9). Conclusion: QoC is a complex and evolving concept that can improve outcomes while maximizing healthcare resources. Limited time and resources hamper clinicians’ ability to openly and empathetically communicate with patients; novel technology may help to offer solutions.
Atypical Glandular Cells: Interobserver Variability according to Clinical Management
Authors: Lepe Marcos , Eklund Claire M. , Quddus M. Ruhul , Paquette Cherie
Published: July 2018

Objective: The 2014 Bethesda System diagnostic criteria for atypical glandular cells (AGC) aids in classification of atypical cells in cervical cytology. There is limited literature regarding reproducibility and interobserver variability in the application of the 2014 AGC criteria. Our aim is to assess the interobserver variability of AGC with a focus on how diagnostic categories link with guideline-driven management. Study Design: Three observers re-reviewed 51 previously diagnosed AGC Papanicolaou tests. The diagnoses were categorized as follows: (1) according to guideline-specified management, and (2) as glandular vs. squamous lesions. The κ statistic was used to evaluate interobserver agreement. Results: The interobserver variability per guideline management by weighted 2-observer κ ranged from 0.009 to 0.530, with half of the interobserver pairings meeting the threshold for at least fair-moderate agreement. For categorization as glandular, squamous, or both, unweighted κ yielded at best fair interobserver agreement (κ = 0.250) in 1 pairing, with low κ scores in the remainder of reviewer pairs (range 0.015–0.152). Conclusions: There is significant interobserver variability in the diagnosis of AGC. The AGC cases when divided by clinical management had fair-moderate interobserver agreement, suggesting that diagnostic variability likely has a real effect on patient care. This diagnostic uncertainty should be understood by cytologists and clinicians.
Acute Lassa Virus Encephalitis with Lassa Virus in the Cerebrospinal Fluid but Absent in the Blood: A Case Report with a Positive Outcome
Authors: Okokhere Peter O. , Erameh Cyril O. , Alikah Francis , Akhideno Peter E. , Iruolagbe Christopher O. , Osazuwa Omoregie O. , Bankole Idowu A. , Adomeh Donatus I. , Odia Ikponmwosa , Aire Chris O. , Oyakhilome Jennifer , Agbukor Jacqueline , Atafo Rebecca O. , Asogun Danny A. , Happi Christian T. , Sabeti Pardis C. , Günther Stephan , Akpede George O.
Published: July 2018

It is rare both to have the central nervous system (CNS) as the main focus in the acute phase of Lassa fever infection without associated bleeding, and to find Lassa virus (LAV) in the cerebrospinal fluid (CSF) but not in the serum. We report the case of a 38-year-old Nigerian woman with mainly CNS manifestation of Lassa fever. She was admitted twice within 11 days because of persistent fever. A clinical diagnosis of acute LAV encephalitis was made because of a high index of suspicion and CNS involvement confirmed by positive reverse transcriptase polymerase chain reaction (RT-PCR) for LAV in the CSF, while her blood was repeatedly negative for LAV by RT-PCR test. She recovered fully following supportive care coupled with treatment with an 18-day course of ribavirin, and suffered no long-term neurological complication or relapse. Post-treatment CSF examination by RT-PCR did not detect LAV.
Executive Impairments in Binge Drinking: Evidence for a Specific Performance-Monitoring Difficulty during Alcohol-Related Processing
Authors: Lannoy Severine , Maurage Pierre , D’Hondt Fabien , Billieux Joel , Dormal Valerie
Published: July 2018

This study evaluated inhibition and performance-monitoring abilities through the explicit processing of alcohol cues. Twenty-two binge drinkers (BD) and 22 control participants performed a speeded Go/No-Go task using pictures of alcohol and soft cans as Go and No-Go targets. This task measures inhibitory control and performance monitoring (i.e., task adjustment through errors and feedback processing) during the explicit processing of alcohol cues. Groups did not significantly differ regarding inhibition abilities. However, BD had poorer performance-monitoring abilities, reflected by a difficulty to adjust after errors, especially when these errors were related to alcohol cues. These findings suggest that the explicit processing of alcohol cues negatively impacts cognitive abilities among BD.
Emerging Role of Exosomes in the Joint Diseases
Authors: Li Zeng , Wang Yingjie , Xiao Ke , Xiang Shuai , Li Zheng , Weng Xisheng
Published: July 2018

Exosomes are a subset of small, membrane-bound extracellular vesicles that are important for communication among cells. They originate from the cell membrane during endocytic internalization, and are stable in biological fluids, including blood and synovial fluids. Increasing knowledge is emerging about exosomes in joint diseases, including osteoarthritis, rheumatoid arthritis, osteonecrosis of the femoral head, and others. Exosomes in synovial fluid can lead to inflammation, degeneration of cartilage, and destruction of joints. Exosomes in blood have diagnostic value in the early disease stage or for complicated conditions of joint diseases. Exosomes from stem cells could delay diseases and repair joints. For a comprehensive understanding about the emerging role of exosomes in joint diseases, we introduced the isolation and verification of exosomes from synovial fluid, reviewed the physiological and pathological effects of exosomes on joints, and discussed the diagnostic value and therapeutic potential of exosomes in joint diseases. In the future, immunologically active exosomes and engineered exosomes will of interest in the joint diseases. Challenges in the field of exosomes in joint-disease research include complex and expensive isolation, detection of contributing molecular, effectiveness and safety evaluation. In summary, challenges remain, but the field of exosomes in joint diseases has potential, including in mechanisms, diagnoses and therapies.