bluuebunny/crossref_metadata_2025 huggingface dataset:
Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer
Authors: Zhang Jiajia , Wolfgang Christopher , Zheng Lei
Published: January 2018

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.
Carbon-Supported Copper-Based Nitrogen-Containing Supramolecule as an Efficient Oxygen Reduction Reaction Catalyst in Neutral Medium
Authors: Zhao Yuanyuan , Chu Ya , Ju Xiuping , Zhao Jinsheng , Kong Lingqian , Zhang Yan
Published: January 2018

In this work, a nitrogen-containing bidentate ligand named 5,5′-(9-octyl-9H-carbazole-2,7-diyl)bis(1,10-phenanthroline) (OCBP) was synthesized as a nitrogen precursor for making an oxygen reduction catalyst. The 1,10-phenanthroline unit provides a coordination site for copper ions, and the resulting Cu-Nx unit may be responsible for the catalytic activities of the catalyst. Carbon black was selected as a support to improve the electroconductibility of the resulting catalyst. The metallo-supramolecule (Cu-SOCBP) was dispersed on the surface of Vulcan XC-72 carbon and was used as a catalyst (designated as Cu-SOCBP/C) for the oxygen reduction reaction (ORR). The microscope structure and surface components of the catalyst were acquired via scanning electron microscopy and X-ray photoelectron spectroscopy, as well as X-ray powder diffraction. The electrochemical property and ORR mechanism of Cu-SOCBP/C were analyzed using a variety of electroanalytical methods including cyclic voltammetry, electrochemical impedance spectroscopy, and linear sweep voltammetry. These results show that Cu-SOCBP/C was successfully synthesized and that ORR was achieved mainly via a four-electron transfer process to water. Thus, Cu-SOCBP/C was an effective catalyst and might have potential application as a cathodic catalyst in microbial fuel cells, which operate in an aqueous medium.
Fault Attacks on the Authenticated Encryption Stream Cipher MORUS
Authors: Salam Iftekhar , Simpson Leonie , Bartlett Harry , Dawson Ed , Koon-Ho Wong Kenneth
Published: January 2018

This paper investigates the application of fault attacks to the authenticated encryption stream cipher algorithm MORUS. We propose fault attacks on MORUS with two different goals: one to breach the confidentiality component, and the other to breach the integrity component. For the fault attack on the confidentiality component of MORUS, we propose two different types of key recovery. The first type is a partial key recovery using a permanent fault model, except for one of the variants of MORUS where the full key is recovered with this model. The second type is a full key recovery using a transient fault model, at the cost of a higher number of faults compared to the permanent fault model. Finally, we describe a fault attack on the integrity component of MORUS, which performs a forgery using the bit-flipping fault model.
A Study of Extended Defects in Surface Damaged Crystals
Authors: Ferrari Claudio , Ghica Corneliu , Rotunno Enzo
Published: January 2018

We have analyzed by transmission electron microscopy silicon and GaAs crystals polished with sandpapers of different grain size. The surface damage induced a crystal permanent convex curvature with a radius of the order of a few meters. The curvature is due to a compressive strain generated in the damaged zone of the sample. Contrary to what was reported in the literature, the only defects detected by transmission electron microscopy were dislocations penetrating a few microns from the surface. Assuming the surface damage as a kind of continuous indentation, a simple model able to explain the observed compressive strain is given.
Acknowledgement to Reviewers of Designs in 2017
Authors:   Designs Editorial Office
Published: January 2018

Peer review is an essential part in the publication process, ensuring that Designs maintains high quality standards for its published papers[...]
Spectral and Energy Efficient Low-Overhead Uplink and Downlink Channel Estimation for 5G Massive MIMO Systems
Authors: Khan Imran , Zafar Mohammad , Jan Mohammad , Lloret Jaime , Basheri Mohammed , Singh Dhananjay
Published: January 2018

Uplink and Downlink channel estimation in massive Multiple Input Multiple Output (MIMO) systems is an intricate issue because of the increasing channel matrix dimensions. The channel feedback overhead using traditional codebook schemes is very large, which consumes more bandwidth and decreases the overall system efficiency. The purpose of this paper is to decrease the channel estimation overhead by taking the advantage of sparse attributes and also to optimize the Energy Efficiency (EE) of the system. To cope with this issue, we propose a novel approach by using Compressed-Sensing (CS), Block Iterative-Support-Detection (Block-ISD), Angle-of-Departure (AoD) and Structured Compressive Sampling Matching Pursuit (S-CoSaMP) algorithms to reduce the channel estimation overhead and compare them with the traditional algorithms. The CS uses temporal-correlation of time-varying channels to produce Differential-Channel Impulse Response (DCIR) among two CIRs that are adjacent in time-slots. DCIR has greater sparsity than the conventional CIRs as it can be easily compressed. The Block-ISD uses spatial-correlation of the channels to obtain the block-sparsity which results in lower pilot-overhead. AoD quantizes the channels whose path-AoDs variation is slower than path-gains and such information is utilized for reducing the overhead. S-CoSaMP deploys structured-sparsity to obtain reliable Channel-State-Information (CSI). MATLAB simulation results show that the proposed CS based algorithms reduce the feedback and pilot-overhead by a significant percentage and also improve the system capacity as compared with the traditional algorithms. Moreover, the EE level increases with increasing Base Station (BS) density, UE density and lowering hardware impairments level.
Scaling-Laws of Flow Entropy with Topological Metrics of Water Distribution Networks
Authors: Santonastaso Giovanni , Di Nardo Armando , Di Natale Michele , Giudicianni Carlo , Greco Roberto
Published: January 2018

Robustness of water distribution networks is related to their connectivity and topological structure, which also affect their reliability. Flow entropy, based on Shannon’s informational entropy, has been proposed as a measure of network redundancy and adopted as a proxy of reliability in optimal network design procedures. In this paper, the scaling properties of flow entropy of water distribution networks with their size and other topological metrics are studied. To such aim, flow entropy, maximum flow entropy, link density and average path length have been evaluated for a set of 22 networks, both real and synthetic, with different size and topology. The obtained results led to identify suitable scaling laws of flow entropy and maximum flow entropy with water distribution network size, in the form of power–laws. The obtained relationships allow comparing the flow entropy of water distribution networks with different size, and provide an easy tool to define the maximum achievable entropy of a specific water distribution network. An example of application of the obtained relationships to the design of a water distribution network is provided, showing how, with a constrained multi-objective optimization procedure, a tradeoff between network cost and robustness is easily identified.
Particle Swarm Optimization and Uncertainty Assessment in Inverse Problems
Authors: Pallero José , Fernández-Muñiz María , Cernea Ana , Álvarez-Machancoses Óscar , Pedruelo-González Luis , Bonvalot Sylvain , Fernández-Martínez Juan
Published: January 2018

Most inverse problems in the industry (and particularly in geophysical exploration) are highly underdetermined because the number of model parameters too high to achieve accurate data predictions and because the sampling of the data space is scarce and incomplete; it is always affected by different kinds of noise. Additionally, the physics of the forward problem is a simplification of the reality. All these facts result in that the inverse problem solution is not unique; that is, there are different inverse solutions (called equivalent), compatible with the prior information that fits the observed data within similar error bounds. In the case of nonlinear inverse problems, these equivalent models are located in disconnected flat curvilinear valleys of the cost-function topography. The uncertainty analysis consists of obtaining a representation of this complex topography via different sampling methodologies. In this paper, we focus on the use of a particle swarm optimization (PSO) algorithm to sample the region of equivalence in nonlinear inverse problems. Although this methodology has a general purpose, we show its application for the uncertainty assessment of the solution of a geophysical problem concerning gravity inversion in sedimentary basins, showing that it is possible to efficiently perform this task in a sampling-while-optimizing mode. Particularly, we explain how to use and analyze the geophysical models sampled by exploratory PSO family members to infer different descriptors of nonlinear uncertainty.
Optimization of the Transesterification of Waste Cooking Oil with Mg-Al Hydrotalcite Using Response Surface Methodology
Authors: Costarrosa Laureano , Leiva-Candia David , Cubero-Atienza Antonio , Ruiz Juan , Dorado M.
Published: January 2018

Nowadays, biodiesel has become a very promising alternative to fossil diesel fuel, regarding environmental concerns and fuel resource depletion. Biodiesel is usually produced through homogeneous or heterogeneous transesterification of different fatty raw materials. Although main research has been carried out with homogenous catalysts, heterogeneous catalysts may be of interest due to ease of recovery and recycling, as well as readiness for continuous processing. In this work, calcined Mg-Al hydrotalcite (HT) was used for the heterogeneous transesterification of waste cooking oil. Three reaction parameters, namely, reaction time, amount of catalyst, and methanol-to-oil molar ratio, were optimized by means of Response Surface Methodology (RSM) at constant temperature (65 °C), using a Box-Behnken design. Optimal fatty acid methyl ester (FAME) content (86.23% w/w FAME/sample) was predicted by the model with an R-squared value of 98.45%, using 3.39 g of HT (8.5% w/w oil) and an 8:1 methanol-oil molar ratio, for a duration of 3.12 h. It was observed that calcination of HT, while avoiding the previous washing step, allowed the presence of chemical species that enhanced the effect of the catalyst. It can be concluded from this field trial that calcined and nonwashed Mg-Al hydrotalcite may be considered an effective basic catalyst for the production of biodiesel from waste cooking oil. Also, RSM proved to be a useful tool for predicting biodiesel yield.
A Generic Approach to Analyze the Impact of a Future Aircraft Design on the Boarding Process
Authors: Yildiz Bekir , Förster Peter , Feuerle Thomas , Hecker Peter , Bugow Stefan , Helber Stefan
Published: January 2018

The turnaround process constitutes an important part of the air transportation system. Airports often represent bottlenecks in air traffic management (ATM), thus operations related to the preparation of the aircraft for the next flight leg have to be executed smoothly and in a timely manner. The ATM significantly depends on a reliable turnaround process. Future paradigm changes with respect to airplane energy sources, aircraft design or propulsion concepts will also influence the airport layout. As a consequence, operational processes associated with the turnaround will be affected. Airlines aim for efficient and timely turnaround operations that are correlated with higher profits. This case study discusses an approach to investigate a new aircraft design with respect to the implications on the turnaround. The boarding process, as part of the turnaround, serves as an example to evaluate the consequences of new design concepts. This study is part of an interdisciplinary research to investigate future energy, propulsion and designs concepts and their implications on the whole ATM system. Due to these new concepts, several processes of the turnaround will be affected. For example, new energy storage concepts will influence the fueling process on the aircraft itself or might lead to a new infrastructure at the airport. This paper aims to evaluate the applied methodology in the case of a new boarding process, due to a new aircraft design, by means of a generic example. An agent-based boarding simulation is applied to assess passenger behavior during boarding, particularly with regard to cabin layout and seat configuration. The results of the generic boarding simulation are integrated into a simplified, deterministic and generic simulation of the turnaround process. This was done to assess the proposed framework for future investigations which on the one hand address the ATM system holistically and on the other, incorporate additional or adapted processes of the turnaround.
Brazilian Tensile Strength of Anisotropic Rocks: Review and New Insights
Authors: Ma Tianshou , Peng Nian , Zhu Zhu , Zhang Qianbing , Yang Chunhe , Zhao Jian
Published: January 2018

Strength anisotropy is one of the most distinct features of anisotropic rocks, and it also normally reveals strong anisotropy in Brazilian test Strength (“BtS”). Theoretical research on the “BtS” of anisotropic rocks is seldom performed, and in particular some significant factors, such as the anisotropic tensile strength of anisotropic rocks, the initial Brazilian disc fracture points, and the stress distribution on the Brazilian disc, are often ignored. The aim of the present paper is to review the state of the art in the experimental studies on the “BtS” of anisotropic rocks since the pioneering work was introduced in 1964, and to propose a novel theoretical method to underpin the failure mechanisms and predict the “BtS” of anisotropic rocks under Brazilian test conditions. The experimental data of Longmaxi Shale-I and Jixi Coal were utilized to verify the proposed method. The results show the predicted “BtS” results show strong agreement with experimental data, the maximum error is only ~6.55% for Longmaxi Shale-I and ~7.50% for Jixi Coal, and the simulated failure patterns of the Longmaxi Shale-I are also consistent with the test results. For the Longmaxi Shale-I, the Brazilian disc experiences tensile failure of the intact rock when 0° ≤ βw ≤ 24°, shear failure along the weakness planes when 24° ≤ βw ≤ 76°, and tensile failure along the weakness planes when 76° ≤ βw ≤ 90°. For the Jixi Coal, the Brazilian disc experiences tensile failure when 0° ≤ βw ≤ 23° or 76° ≤ βw ≤ 90°, shear failure along the butt cleats when 23° ≤ βw ≤ 32°, and shear failure along the face cleats when 32° ≤ βw ≤ 76°. The proposed method can not only be used to predict the “BtS” and underpin the failure mechanisms of anisotropic rocks containing a single group of weakness planes, but can also be generalized for fractured rocks containing multi-groups of weakness planes.
5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell
Authors: Ecsedi Szilvia , Rodríguez-Aguilera Jesús , Hernandez-Vargas Héctor
Published: January 2018

Recently described as the sixth base of the DNA macromolecule, the precise role of 5-hydroxymethylcytosine (5hmC) is the subject of debate. Early studies indicate that it is functionally distinct from cytosine DNA methylation (5mC), and there is evidence for 5hmC being a stable derivate of 5mC, rather than just an intermediate of demethylation. Moreover, 5hmC events correlate in time and space with key differentiation steps in mammalian cells. Such events span the three embryonic germ layers and multiple progenitor cell subtypes, suggesting a general mechanism. Because of the growing understanding of the role of progenitor cells in disease origin, we attempted to provide a detailed summary on the currently available literature supporting 5hmC as a key player in adult progenitor cell differentiation. This summary consolidates the emerging role for 5hmC in defining cellular fate.
Assessment of Educational Methods for Improving Children’s Awareness of Tsunamis and Other Natural Disasters: Focusing on Changes in Awareness and Regional Characteristics in Japan
Authors: Yasuda Mari , Muramoto Toshiaki , Nouchi Rui
Published: January 2018

In this research, a visiting class on disaster preparedness education for higher-grade elementary school students (10–11 years old) was conducted in Wakayama prefecture, which is exposed to Nankai Trough earthquakes, and in different parts of the three prefectures whose coasts were most affected by the 2011 Great East Japan Earthquake: Fukushima (Western inland), Miyagi (North side out of the tsunami inundation area and Northern inland), and Iwate (Medium inland). Group activities with game-like elements were conducted. To examine whether this initiative improves schoolchildren’s awareness of disaster-prevention, surveys were conducted before, immediately after, and one month after the classes. Results indicate differences in awareness depending on regional characteristics of the schoolchildren’s residential area. The data obtained at each school varied according to whether the school was in a region that had experienced disaster in the recent past, or if the school was in a region where there is a recognized risk of disaster in the future. Classes in regions with recent disaster experience showed increased awareness of threats and prevention after the disaster-prevention class; however, this effect was short-lived. Increased awareness lasted longer in those schools located in regions that had not suffered from disasters in the recent past, but that are predicted to experience a major disaster in the future. We therefore infer that the “previous history of disasters” defines the key difference between regions, even when the particular school concerned was located outside the afflicted area (the coastal zone in the 2011 Great East Japan earthquake and tsunami) and so not directly affected. The afflicted area was limited to the 2011 Great East Japan Earthquake; regions experiencing no direct damage, even if they were near damaged regions, saw an increased awareness of the threat of disasters as a result of disaster-prevention classes. Students also saw a decrease in their own confidence regarding evacuation behavior, while their expressed dependence on their families for help in evacuation situations strengthened. However, such effects were temporary. In the future, it would be desirable to develop disaster-prevention programs that consider such regional characteristics.
Assessment of a Simplified Connectivity Index and Specific Sediment Potential in River Basins by Means of Geomorphometric Tools
Authors: Grauso Sergio , Pasanisi Francesco , Tebano Carlo
Published: January 2018

Sediment connectivity is a major topic in recent research because of its relevance in the characterization of the morphology of river systems and assessing of sediment transport and deposition. Currently, the connectivity indices found in the literature are generally dimensionless and need to be coupled with quantitative soil-loss data for land management and design purposes. In the present work, a simple methodology is proposed to assess two different indices, namely, the simplified connectivity index (SCI) and the specific sediment potential (SSP), based on geomorphometric tools that are commonly available in commercial and open-source geographic information system (GIS) platforms. The proposed metrics allows us to easily assess both the SCI and the SSP as functions of the estimated soil erosion per unit area of the catchment and of the inverse distance of each unit area from the river outlet, this distance being measured along the network path. The proposed indices have been devised to express, respectively, the potential sediment transfer ability and the sediment mass potentially available at a given section of the drainage network. In addition to other parameters used to describe the catchment characteristics potentially affecting the river sediment delivery capacity, the SCI and SSP indices can help to refine theoretical models in order to assess the sediment yield (SY) in ungauged river basins.
Factors Influencing Global Health Related Quality of Life in Elderly Cancer Patients: Results of a Secondary Data Analysis
Authors: Schmidt Heike , Nordhausen Thomas , Boese Stephanie , Vordermark Dirk , Wheelwright Sally , Wienke Andreas , Johnson Colin
Published: January 2018

Cancer treatment for elderly patients is often complicated by poor physical condition, impaired functioning and comorbidities. Patient reported health related quality of life (HRQOL) can contribute to decisions about treatment goals and supportive therapy. Knowledge about factors influencing HRQOL is therefore needed for the development of supportive measures and care pathways. An exploratory secondary data analysis on 518 assessments of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC QLQ-C30) and the elderly module (EORTC QLQ-ELD14) was performed to identify factors predictive for global HRQOL. Preliminary simple and multivariable regression analyses were conducted resulting in a final model comprising sociodemographic and disease specific variables and scales of the QLQ-C30 and QLQ-ELD14. Age, sex and disease related variables explained only part of the variance of global HRQOL (adjusted R2 = 0.203). In the final model (adjusted R2 = 0.504) fatigue, social function, burden of illness and joint stiffness showed possible influence on global HRQOL. Fatigue, social function and burden of illness seem to have the largest impact on global HRQOL of elderly cancer patients. Further prospective studies should examine these domains. Actionable symptoms should be given special attention to initiate targeted supportive measures aiming to maximize HRQOL of older cancer patients.
Managing Early Childhood Caries for Young Children in China
Authors: Chen Kitty , Gao Sherry , Duangthip Duangporn , Lo Edward , Chu Chun
Published: January 2018

The latest national survey found that 70% of 5-year-old children in China had dental caries. The prevalence of early childhood caries (ECC) may not only be attributed to poor oral hygiene and unhealthy diet, but also to limited access to and availability of dental care. The prevailing preventive measures adopted by industrialised countries for ECC management are neither practical nor affordable in China. Hence, an alternative approach to ECC management is necessary. Atraumatic restorative treatment (ART) has been advocated because the simple and short operative time renders ART affordable. However, the success rate of ART in restoring anterior primary teeth is unfavourable. Although there is no water fluoridation in China, topical fluorides may be used to manage ECC. Tooth brushing with fluoride toothpaste is effective for caries control, but not all toothpastes in China are fluoridated. Professionally applied fluorides such as sodium fluoride varnish can be a cost-effective treatment for managing the high prevalence of ECC in China. Silver diamine fluoride (SDF) at 38% is suggested to be effective in arresting ECC in China. It can be a simple, non-invasive and low-cost treatment. However, it stains caries black. Children and their parents must be well informed before SDF treatment.
Do Working Conditions of Patients in Psychotherapeutic Consultation in the Workplace Differ from Those in Outpatient Care? Results from an Observational Study
Authors: Barrech Amira , Kilian Reinhold , Rottler Edit , Jerg-Bretzke Lucia , Hölzer Michael , Rieger Monika , Jarczok Marc , Gündel Harald , Rothermund Eva
Published: January 2018

In previous studies, it was found that patients treated at a psychosomatic outpatient clinic (PSOC) for common mental disorders showed more severe symptoms than those who used a psychotherapeutic consultation service at the workplace (PSIW). This study examines whether the higher symptom severity of the PSOC patients in comparison to their PSIW counterparts is also related to higher levels of occupational stress as measured by the demand-control-support model (DCS). N = 253 participants (PSIW n = 100; PSOC n = 153) provided self-reported data on demands, decision latitude, social support, and health before consultation. The association between mental health care setting, symptom level and demands, decision latitude, and social support was assessed by means of a path model. Results of the path model indicated that the higher level of depression in PSOC patients was related to higher levels of demands and lower levels of social support. Demands and social support were found to be indirectly associated with treatment setting. No interaction effect between demands, decision latitude, social support, and depression was found. Results of this study reveal that the working conditions influenced the pathway to care process via symptom severity.
Factors Associated with Pregnancy among Married Adolescents in Nepal: Secondary Analysis of the National Demographic and Health Surveys from 2001 to 2011
Authors: Pradhan Rina , Wynter Karen , Fisher Jane
Published: January 2018

Pregnancy-related morbidity and mortality are much more prevalent among adolescents than adults, particularly in low-income settings. Little is known about risk factors for pregnancy among adolescents in Nepal, but setting-specific evidence is needed to inform interventions. This study aimed to describe the prevalence, and identify factors associated with pregnancy among adolescents in Nepal between 2001 and 2011. Secondary analyses of Nepal Demographic Health Surveys (NDHS) data from 2001, 2006, and 2011 were completed. The outcome was any pregnancy or birth among married adolescents; prevalence was calculated for each survey year. Although the rate of marriage among adolescent women in Nepal decreased significantly from 2001 to 2011, prevalence of pregnancy and birth among married adolescent women in Nepal remains high (average 56%) in Nepal, and increased significantly between 2001 and 2011. Regression analyses of this outcome indicate higher risk was associated with living in the least resourced region, early sexual debut, and older husband. Despite national efforts to reduce pregnancies among married adolescent women in Nepal, prevalence remains high. Integrated, cross-sectoral prevention efforts are required. Poverty reduction and infrastructure improvements may lead to lower rates of adolescent pregnancy.
Ventilation Positive Pressure Intervention Effect on Indoor Air Quality in a School Building with Moisture Problems
Authors: Vornanen-Winqvist Camilla , Järvi Kati , Toomla Sander , Ahmed Kaiser , Andersson Maria , Mikkola Raimo , Marik Tamás , Kredics László , Salonen Heidi , Kurnitski Jarek
Published: January 2018

This case study investigates the effects of ventilation intervention on measured and perceived indoor air quality (IAQ) in a repaired school where occupants reported IAQ problems. Occupants’ symptoms were suspected to be related to the impurities leaked indoors through the building envelope. The study’s aim was to determine whether a positive pressure of 5–7 Pa prevents the infiltration of harmful chemical and microbiological agents from structures, thus decreasing symptoms and discomfort. Ventilation intervention was conducted in a building section comprising 12 classrooms and was completed with IAQ measurements and occupants’ questionnaires. After intervention, the concentration of total volatile organic compounds (TVOC) and fine particulate matter (PM2.5) decreased, and occupants’ negative perceptions became more moderate compared to those for other parts of the building. The indoor mycobiota differed in species composition from the outdoor mycobiota, and changed remarkably with the intervention, indicating that some species may have emanated from an indoor source before the intervention.
Naturally Occurring Canine Melanoma as a Predictive Comparative Oncology Model for Human Mucosal and Other Triple Wild-Type Melanomas
Authors: Hernandez Belen , Adissu Hibret , Wei Bih-Rong , Michael Helen , Merlino Glenn , Simpson R.
Published: January 2018

Melanoma remains mostly an untreatable fatal disease despite advances in decoding cancer genomics and developing new therapeutic modalities. Progress in patient care would benefit from additional predictive models germane for human disease mechanisms, tumor heterogeneity, and therapeutic responses. Toward this aim, this review documents comparative aspects of human and naturally occurring canine melanomas. Clinical presentation, pathology, therapies, and genetic alterations are highlighted in the context of current basic and translational research in comparative oncology. Somewhat distinct from sun exposure-related human cutaneous melanomas, there is growing evidence that a variety of gene copy number alterations and protein structure/function mutations play roles in canine melanomas, in circumstances more analogous to human mucosal melanomas and to some extent other melanomas with murine sarcoma viral oncogene homolog B (BRAF), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), and neurofibromin 1 tumor suppressor NF1 triple wild-type genotype. Gaps in canine genome annotation, as well as an insufficient number and depth of sequences covered, remain considerable barriers to progress and should be collectively addressed. Preclinical approaches can be designed to include canine clinical trials addressing immune modulation as well as combined-targeted inhibition of Rat Sarcoma Superfamily/Mitogen-activated protein kinase (RAS/MAPK) and/or Phosphatidylinositol-3-Kinase/Protein Kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal transduction, pathways frequently activated in both human and canine melanomas. Future investment should be aimed towards improving understanding of canine melanoma as a predictive preclinical surrogate for human melanoma and for mutually benefiting these uniquely co-dependent species.
Nanobody Based Dual Specific CARs
Authors: De Munter Stijn , Ingels Joline , Goetgeluk Glenn , Bonte Sarah , Pille Melissa , Weening Karin , Kerre Tessa , Abken Hinrich , Vandekerckhove Bart
Published: January 2018

Recent clinical trials have shown that adoptive chimeric antigen receptor (CAR) T cell therapy is a very potent and possibly curative option in the treatment of B cell leukemias and lymphomas. However, targeting a single antigen may not be sufficient, and relapse due to the emergence of antigen negative leukemic cells may occur. A potential strategy to counter the outgrowth of antigen escape variants is to broaden the specificity of the CAR by incorporation of multiple antigen recognition domains in tandem. As a proof of concept, we here describe a bispecific CAR in which the single chain variable fragment (scFv) is replaced by a tandem of two single-antibody domains or nanobodies (nanoCAR). High membrane nanoCAR expression levels are observed in retrovirally transduced T cells. NanoCARs specific for CD20 and HER2 induce T cell activation, cytokine production and tumor lysis upon incubation with transgenic Jurkat cells expressing either antigen or both antigens simultaneously. The use of nanobody technology allows for the production of compact CARs with dual specificity and predefined affinity.
Antioxidative and Anti-Melanogenic Activities of Bamboo Stems (Phyllostachys nigra variety henosis) via PKA/CREB-Mediated MITF Downregulation in B16F10 Melanoma Cells
Authors: Choi Moon-Hee , Jo Han-Gyo , Yang Ji , Ki Sung , Shin Hyun-Jae
Published: January 2018

Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. The anti-melanogenic and antioxidative activities of the EtOAc fraction (PN3) of a P. nigra stem extract were investigated in a cell-free system and in B16F10 melanoma cells. PN3 consisted of a mixture of flavonoids, such as catechin, chlorogenic acid, caffeic acid, and p-coumaric acid. The antioxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)), and hydroxyl radical scavenging) was evaluated, as well as the inhibition of reactive oxygen species (ROS) produced by the Fenton reaction. PN3 showed in vitro tyrosinase inhibition activity with the half maximal inbihitory concentration (IC50) values of 240 μg/mL, and in vivo cytotoxic concentration ranges > 100 μg/mL. The protein expression levels and mRNA transcription levels of TYR, TRP-1, and MITF were decreased in a dose-dependent manner by the treatment with PN3. PN3 interfered with the phosphorylation of intracellular protein kinase A (PKA)/cAMP response element-binding protein (CREB), demonstrating potent anti-melanogenic effects. PN3 could inhibit PKA/CREB and the subsequent degradation of microphthalmia-associated transcription factor (MITF), resulting in the suppression of melanogenic enzymes and melanin production, probably because of the presence of flavonoid compounds. These properties make it a candidate as an additive to whitening cosmetics.
Natural Anti-Estrogen Receptor Alpha Antibodies Able to Induce Estrogenic Responses in Breast Cancer Cells: Hypotheses Concerning Their Mechanisms of Action and Emergence
Authors: Leclercq Guy
Published: January 2018

The detection of human anti-estrogen receptor α antibodies (ERαABs) inducing estrogenic responses in MCF-7 mammary tumor cells suggests their implication in breast cancer emergence and/or evolution. A recent report revealing a correlation between the titer of such antibodies in sera from patients suffering from this disease and the percentage of proliferative cells in samples taken from their tumors supports this concept. Complementary evidence of the ability of ERαABs to interact with an epitope localized within the estradiol-binding core of ERα also argues in its favor. This epitope is indeed inserted in a regulatory platform implicated in ERα-initiated signal transduction pathways and transcriptions. According to some experimental observations, two auto-immune reactions may already be advocated to explain the emergence of ERαABs: one involving probably the idiotypic network to produce antibodies acting as estrogenic secretions and the other based on antibodies able to abrogate the action of a natural ERα inhibitor or to prevent the competitive inhibitory potency of released receptor degradation products able to entrap circulating estrogens and co-activators. All of this information, the aspect of which is mainly fundamental, may open new ways in the current tendency to combine immunological and endocrine approaches for the management of breast cancer.
In-Hospital Palliative Care: Should We Need to Reconsider What Role Hospitals Should Have in Patients with End-Stage Disease or Advanced Cancer?
Authors: Cotogni Paolo , Saini Andrea , De Luca Anna
Published: January 2018

Traditionally, palliative care (PC) systems focused on the needs of advanced cancer patients, but most patients needing PC have end-stage organ diseases. Similarly, PC models focus on the needs of patients in hospices or at home; however, in most cases PC is provided in acute hospitals. Indeed, the symptom burden that these patients experience in the last year of life frequently forces them to seek care in emergency departments. The majority of them are admitted to the hospital and many die. This issue poses important concerns. Despite the efforts of attending healthcare professionals, in-hospital patients do not receive optimal care near the end-of-life. Also, evidence is emerging that delay in identifying patients needing PC have a detrimental impact on their quality of life (QoL). Therefore, there is an urgent need to identify, early and properly, these patients among those hospitalized. Several trials reported the efficacy of PC in improving the QoL in these patients. Each hospital should ensure that a multidisciplinary PC team is available to support attending physicians to achieve the best QoL for both PC patients and their families. This review discusses the role and the impact of in-hospital PC in patients with end-stage disease or advanced cancer.
Evaluation of Colorectal Cancer Incidence Trends in the United States (2000–2014)
Authors: Ansa Benjamin , Coughlin Steven , Alema-Mensah Ernest , Smith Selina
Published: January 2018

Colorectal cancer (CRC) incidence rates have declined in recent years for people of all races/ethnicities; however, the extent to which the decrease varies annually by demographic and disease-related characteristics is largely unknown. This study examines trends and annual percent change (APC) in the incidence among persons diagnosed with CRC in the United States of America from 2000–2014. The data obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program were analyzed, and all persons (N = 577,708) with malignant CRC recorded in the SEER 18 database from 2000 to 2014 were characterized according to sex, race, age at diagnosis, disease site and stage. Incidence rates and APC were calculated for the entire study period. Overall, the incidence rate of CRC decreased from 54.5 in 2000 to 38.6 per 100,000 in 2014, with APC = −2.66 (p < 0.0001). Decline in rates was most profound between 2008 and 2011 from 46.0 to 40.7 per 100,000 (APC = −4.04; p < 0.0001). Rates were higher for males (vs. females; rate ratio (RR) = 1.33) and for blacks (vs. whites; RR = 1.23). Proximal colon cancers at the localized stage were the predominant cancers. An increase in rate was observed among people younger than 50 years (6.6 per 100,000, APC= 1.5). The annual rate of CRC has decreased over time. However, the development and implementation of interventions that further reduce the disparities among demographic and disease-related subgroups are warranted.
Taking the Occam’s Razor Approach to Hedgehog Lipidation and Its Role in Development
Authors: Manikowski Dominique , Kastl Philipp , Grobe Kay
Published: January 2018

All Hedgehog (Hh) proteins signal from producing cells to distant receiving cells despite being synthesized as N-and C-terminally lipidated, membrane-tethered molecules. To explain this paradoxical situation, over the past 15 years, several hypotheses have been postulated that tie directly into this property, such as Hh transport on cellular extensions called cytonemes or on secreted vesicles called lipophorins and exosomes. The alternative situation that tight membrane association merely serves to prevent unregulated Hh solubilization has been addressed by biochemical and structural studies suggesting Hh extraction from the membrane or proteolytic Hh release. While some of these models may act in different organisms, tissues or developmental programs, others may act together to specify Hh short- and long-range signaling in the same tissues. To test and rank these possibilities, we here review major models of Hh release and transport and hypothesize that the (bio)chemical and physical properties of firmly established, homologous, and functionally essential biochemical Hh modifications are adapted to specify and determine interdependent steps of Hh release, transport and signaling, while ruling out other steps. This is also described by the term “congruence”, meaning that the logical combination of biochemical Hh modifications can reveal their true functional implications. This combined approach reveals potential links between models of Hh release and transport that were previously regarded as unrelated, thereby expanding our view of how Hhs can steer development in a simple, yet extremely versatile, manner.
Influence of Modifying Mixtures on Si Crystal Formation in Al-7%Si Alloy
Authors: Zykova Anna , Kazantseva Lyudmila , Popova Natalya , Vorozhtsov Alexander , Kurzina Irina
Published: January 2018

Using scanning and transmission electron microscopy, we studied silicon particles formed during the solidification of Al-7%Si alloy when different modifying mixtures were introduced into the melt: (1) a mixture of ultrafine powders Na3AlF6 + K2ZrF6 + TiO2 + ZrO2; (2) K2ZrF6; and (3) the flux Arsal. By differential scanning calorimetry, it was established that modifying mixtures significantly influenced the temperature of the solidification processes. The formation of two types of Si crystals was established. The first type of Si crystals precipitated during the solidification of the eutectic mixture (α-Al + Si) in the form of needles or plates. The second type of Si crystals was segregated from eutectic Al-phases or segregated from the solid phase α-Al upon cooling in the solid state. The introduction of modifiers led to a shift in solidification temperatures. When fluoride salts were used, there was an increase in the temperature of eutectic solidification. Silicon crystals were large (up to 10 µm), with a local excess of aluminum concentration.
Formation of Deformation-Induced Products in a Metastable-β Titanium Alloy during High Temperature Compression
Authors: Samiee Alireza , Casillas Gilberto , Ahmed Mansur , Savvakin Dmytro , Naseri Ryan , Pereloma Elena
Published: January 2018

A metastable-β titanium alloy, Ti-10V-3Fe-3Al (wt. %), was subjected to thermo-mechanical processing including the compression test at 725 °C, which is below the β transus temperature (780 °C), and at strain rate of 10−3 s−1. The presence of phases was determined using transmission electron microscopy and X-ray diffraction. Although the dynamic recovery took place together with slip, both deformation-induced α” martensite and ω were detected as other operating mechanisms for the first time in metastable-β titanium alloy deformed in α + β region. The volume fraction of stress-induced α” was higher than that of the same alloy deformed at room temperature due to a higher strain applied. Stress-induced twinning was not operational, which could be related to the priority of slip mechanism at high temperature resulted from thermally-assisted nucleation and lateral migration of kink-pairs.
An Inhalable Powder Formulation Based on Micro- and Nanoparticles Containing 5-Fluorouracil for the Treatment of Metastatic Melanoma
Authors: Zatta Kelly , Frank Luiza , Reolon Luciano , Amaral-Machado Lucas , Egito Eryvaldo , Gremião Maria , Pohlmann Adriana , Guterres Silvia
Published: January 2018

Melanoma is the most aggressive and lethal type of skin cancer, with a poor prognosis because of the potential for metastatic spread. The aim was to develop innovative powder formulations for the treatment of metastatic melanoma based on micro- and nanocarriers containing 5-fluorouracil (5FU) for pulmonary administration, aiming at local and systemic action. Therefore, two innovative inhalable powder formulations were produced by spray-drying using chondroitin sulfate as a structuring polymer: (a) 5FU nanoparticles obtained by piezoelectric atomization (5FU-NS) and (b) 5FU microparticles of the mucoadhesive agent Methocel™ F4M for sustained release produced by conventional spray drying (5FU-MS). The physicochemical and aerodynamic were evaluated in vitro for both systems, proving to be attractive for pulmonary delivery. The theoretical aerodynamic diameters obtained were 0.322 ± 0.07 µm (5FU-NS) and 1.138 ± 0.54 µm (5FU-MS). The fraction of respirable particles (FR%) were 76.84 ± 0.07% (5FU-NS) and 55.01 ± 2.91% (5FU-MS). The in vitro mucoadhesive properties exhibited significant adhesion efficiency in the presence of Methocel™ F4M. 5FU-MS and 5FU-NS were tested for their cytotoxic action on melanoma cancer cells (A2058 and A375) and both showed a cytotoxic effect similar to 5FU pure at concentrations of 4.3 and 1.7-fold lower, respectively.
Catalytic Activity of Silicon Nanowires Decorated with Gold and Copper Nanoparticles Deposited by Pulsed Laser Ablation
Authors: Casiello Michele , Picca Rosaria , Fusco Caterina , D’Accolti Lucia , Leonardi Antonio , Lo Faro Maria , Irrera Alessia , Trusso Sebastiano , Cotugno Pietro , Sportelli Maria , Cioffi Nicola , Nacci Angelo
Published: January 2018

Silicon nanowires (SiNWs) decorated by pulsed laser ablation with gold or copper nanoparticles (labeled as AuNPs@SiNWs and CuNPs@SiNWs) were investigated for their catalytic properties. Results demonstrated high catalytic performances in the Caryl–N couplings and subsequent carbonylations for gold and copper catalysts, respectively, that have no precedents in the literature. The excellent activity, attested by the very high turn over number (TON) values, was due both to the uniform coverage along the NW length and to the absence of the chemical shell surrounding the metal nanoparticles (MeNPs). A high recyclability was also observed and can be ascribed to the strong covalent interaction at the Me–Si interface by virtue of metal “silicides” formation.