bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting Label Smoothing Regularization with Knowledge Distillation
Authors: Wang Jiyue , Zhang Pei , He Qianhua , Li Yanxiong , Hu Yongjian
Published: May 2021

Label Smoothing Regularization (LSR) is a widely used tool to generalize classification models by replacing the one-hot ground truth with smoothed labels. Recent research on LSR has increasingly focused on the correlation between the LSR and Knowledge Distillation (KD), which transfers the knowledge from a teacher model to a lightweight student model by penalizing their output’s Kullback–Leibler-divergence. Based on this observation, a Teacher-free Knowledge Distillation (Tf-KD) method was proposed in previous work. Instead of a real teacher model, a handcrafted distribution similar to LSR was used to guide the student learning. Tf-KD is a promising substitute for LSR except for its hard-to-tune and model-dependent hyperparameters. This paper develops a new teacher-free framework LSR-OS-TC, which decomposes the Tf-KD method into two components: model Output Smoothing (OS) and Teacher Correction (TC). Firstly, the LSR-OS extends the LSR method to the KD regime and applies a softer temperature to the model output softmax layer. Output smoothing is critical for stabilizing the KD hyperparameters among different models. Secondly, in the TC part, a larger proportion is assigned to the uniform distribution teacher’s right class to provide a more informative teacher. The two-component method was evaluated exhaustively on the image (dataset CIFAR-100, CIFAR-10, and CINIC-10) and audio (dataset GTZAN) classification tasks. The results showed that LSR-OS can improve LSR performance independently with no extra computational cost, especially on several deep neural networks where LSR is ineffective. The further training boost by the TC component showed the effectiveness of our two-component strategy. Overall, LSR-OS-TC is a practical substitution of LSR that can be tuned on one model and directly applied to other models compared to the original Tf-KD method.
Using Fuzzy Control for Feed Rate Scheduling of Computer Numerical Control Machine Tools
Authors: Lin Cheng-Jian , Lin Chun-Hui , Wang Shyh-Hau
Published: May 2021

In industrial processing, workpiece quality and processing time have recently become important issues. To improve the machining accuracy and reduce the cutting time, the cutting feed rate will have a significant impact. Therefore, how to plan a dynamic cutting feed rate is very important. In this study, a fuzzy control system for feed rate scheduling based on the curvature and curvature variation is proposed. The proposed system is implemented in actual cutting, and to verify the data an optical three-dimensional scanner is used to measure the cutting trajectory of the workpiece. Experimental results prove that the proposed fuzzy control system for dynamic cutting feed rate scheduling increases the cutting accuracy by 41.8% under the same cutting time; moreover, it decreases the cutting time by 50.8% under approximately the same cutting accuracy.
Viñamecum: A Computer-Aided Method for Diagnoses of Pests and Diseases in the Vineyard
Authors: García-García Juan Ignacio , Marín-Aragón Daniel , Maciá Hanael , Jiménez-Cantizano Ana
Published: May 2021

Information and telecommunication technologies (ICTs) offer new opportunities to provide more timely information services to farmers. This work aims to present a progressive web app (PWA) for mobile devices, which incorporates updated technical information on the pests and diseases of grapevines. In its development, it generated a database with content related to and photographs of grapevine pests and diseases for access by users using mobile devices. In addition, using an Expert System, the application allows the diagnosis of pathologies and the identification of pests by answering questions that are asked. This PWA is mainly addressed to technicians, students, and winegrowers who want to implement more environmentally friendly crop management strategies. Viñamecum is currently freely.
Machine Learning Approach to Real-Time 3D Path Planning for Autonomous Navigation of Unmanned Aerial Vehicle
Authors: Tullu Abera , Endale Bedada , Wondosen Assefinew , Hwang Ho-Yon
Published: May 2021

The need for civilian use of Unmanned Aerial Vehicles (UAVs) has drastically increased in recent years. Their potential applications for civilian use include door-to-door package delivery, law enforcement, first aid, and emergency services in urban areas, which put the UAVs into obstacle collision risk. Therefore, UAVs are required to be equipped with sensors so as to acquire Artificial Intelligence (AI) to avoid potential risks during mission execution. The AI comes with intensive training of an on-board machine that is responsible to autonomously navigate the UAV. The training enables the UAV to develop humanoid perception of the environment it is to be navigating in. During the mission, this perception detects and localizes objects in the environment. It is based on this AI that this work proposes a real-time three-dimensional (3D) path planner that maneuvers the UAV towards destination through obstacle-free path. The proposed path planner has a heuristic sense of A⋆ algorithm, but requires no frontier nodes to be stored in a memory unlike A⋆. The planner relies on relative locations of detected objects (obstacles) and determines collision-free paths. This path planner is light-weight and hence a fast guidance method for real-time purposes. Its performance efficiency is proved through rigorous Software-In-The-Loop (SITL) simulations in constrained-environment and preliminary real flight tests.
Reliability-Based Design Optimization of Structures Using Complex-Step Approximation with Sensitivity Analysis
Authors: Chun Junho
Published: May 2021

Structural optimization aims to achieve a structural design that provides the best performance while satisfying the given design constraints. When uncertainties in design and conditions are taken into account, reliability-based design optimization (RBDO) is adopted to identify solutions with acceptable failure probabilities. This paper outlines a method for sensitivity analysis, reliability assessment, and RBDO for structures. Complex-step (CS) approximation and the first-order reliability method (FORM) are unified in the sensitivity analysis of a probabilistic constraint, which streamlines the setup of optimization problems and enhances their implementation in RBDO. Complex-step approximation utilizes an imaginary number as a step size to compute the first derivative without subtractive cancellations in the formula, which have been observed to significantly affect the accuracy of calculations in finite difference methods. Thus, the proposed method can select a very small step size for the first derivative to minimize truncation errors, while achieving accuracy within the machine precision. This approach integrates complex-step approximation into the FORM to compute sensitivity and assess reliability. The proposed method of RBDO is tested on structural optimization problems across a range of statistical variations, demonstrating that performance benefits can be achieved while satisfying precise probabilistic constraints.
Immunohistochemical Expression Patterns of Tight Junction Proteins, Pro-Apoptotic and Anti-Apoptotic Factors on Progression of Intestinal Mucositis of Onco-Hematological Patients under Epirubicin-Based Chemotherapy
Authors: Cotoraci Coralia , Sasu Alciona , Miutescu Eftimie , Iovanescu Dana , Gharbia Sami , Ciceu Alina , Herman Hildegard , Hermenean Anca
Published: May 2021

Chemotherapy and radiation are often accompanied by complications such as intestinal mucositis. The aim of this study was to assess by immunohistochemical assay the consequences of epirubicin-based therapy applied to onco-hematological patients, on the mucosal cells that undergo apoptosis and on the tight junction proteins, immediately before and after a short time of chemotherapy administration. We assessed the protein expression and distribution of the pro-apoptotic Bax, anti-apoptotic Bcl-2 and effector Caspase-3 as key proteins in apoptosis pathways and the changes in immunopositivity of Claudin-1 and ZO-1 tight junction proteins. Results show that the Bcl-2 family is involved in intestinal damage via Caspase-3 dependent apoptosis of epithelial cells. Additionally, the intestinal mucositis activates other injurious pathways through a dramatic drop in Claudin-1 and ZO-1 expressions, contributing for a while to a structural and functional integrity disruption of the intestinal epithelium.
Anti-Inflammatory and Antioxidant Effects of Soroseris hirsuta Extract by Regulating iNOS/NF-κB and NRF2/HO-1 Pathways in Murine Macrophage RAW 264.7 Cells
Authors: Lee Woo Jin , Li Wan Yi , Lee Sang Woo , Jung Sung Keun
Published: May 2021

Until now, the physiological effects of Soroseris hirsuta were primarily unknown. Here we have evaluated the anti-inflammatory and antioxidant effects of Soroseris hirsuta extract (SHE) on lipopolysaccharide (LPS)-activated murine macrophages RAW 264.7 cells. SHE inhibited nitric oxide expression and inducible nitric oxide synthase expression in RAW 264.7 cells treated with LPS. Moreover, SHE suppressed LPS-induced phosphorylation of IκB kinase, inhibitor of kappa B, p65, p38, and c-JUN N-terminal kinase. Western blot and immunofluorescence analyses showed that SHE suppressed p65 nuclear translocation induced by LPS. Furthermore, SHE inhibited the reactive oxygen species in LPS-treated RAW 264.7 cells. SHE significantly increased heme oxygenase-1 expression and the nuclear translocation of nuclear factor erythroid 2-related factor 2. SHE suppressed LPS-induced interleukin-1β mRNA expression in RAW 264.7 cells. Thus, SHE is a promising nutraceutical as it displays anti-inflammatory and antioxidant properties.
Dry Spells in Croatia: Observed Climate Change and Climate Projections
Authors: Marinović Ivana , Cindrić Kalin Ksenija , Güttler Ivan , Pasarić Zoran
Published: May 2021

This study performs a systematic analysis of the recent and future changes of dry spells (DS) in Croatia. DS are defined as consecutive sequences of days with daily precipitation less than 5 mm of the precipitation-per-day threshold (DS5). Daily precipitation data come from a dense national rain gauge network (covering seven regions) and span the period 1961–2015. The spatial and temporal changes of the observed mean (MDS5) and maximum (MxDS5) seasonal and annual dry spells were analysed by means of the Kendall tau method and the partial trend method. Future changes of DS5 were assessed by employing the three regional climate models (RegCM4, CCLM4 and RCA4) covering the EURO-CORDEX domain with a 12.5-km horizontal resolution, resulting in a realistic orography and land–sea border over Croatia. The models were forced at their boundaries by the four CMIP5 global climate models. For the reference period 1971–2000, the observed, as well as modelled, DS5 were analysed, and the systematic model errors were assessed. Finally, the projections and future changes of the DS5 statistics based on simulations under the high and medium greenhouse gases concentration scenarios (i.e., RCP8.5 and RCP4.5) with a focus on the climate change signal between 1971–2000 and two future periods, 2011–2040 and 2041–2070, were examined. A prevailing increasing trend of MDS5 was found in the warm part of the year, being significant in the mountainous littoral and North Adriatic coastal region. An increasing trend of MxDS5 was also found in the warm part of the year (both the spring and summer), and it was particularly pronounced along the Adriatic coast, while a coherent negative trend pattern was found in the autumn. By applying the partial trend methodology, an increase was found in the very long DS5 (above the 90th percentile) in the recent half of the analysed 55-year period in all seasons, except in the autumn when shortening in the DS5 was detected. The climate change signal during the two analysed future periods was positive for the summer in all regions, weakly negative for the winter and not conclusive for the spring, autumn and year. It was found that no RCM-GCM combination is the best in all cases, since the most successful model combinations depend on the season and location.
The Implications of Post-Harvest Storage Time and Temperature on the Phytochemical Composition and Quality of Japanese-Styled Green Tea Grown in Australia: A Food Loss and Waste Recovery Opportunity
Authors: Krahe James , Krahe Michelle A. , Naumovski Nenad
Published: May 2021

The increases in consumer awareness of the potential health benefits of green tea have driven global demand for green tea products. This study investigated the effect of post-harvest processing and storage of Japanese-styled green tea (Camellia sinensis var. sinensis) grown in NSW, Australia. Harvested material underwent a processing delay of 6, 12, 18 or 24 h at temperatures of 0, 5 and 25 °C. Targeted green tea constituents: theanine, caffeine and catechins were determined using HPLC with UV detection. Product quality and commercial value were determined using the Quality Index (QI) Tool. Reductions in constituent levels were evident within all storage delays, with nominal quality preservation achieved by reducing the temperature. The green tea material stored at 25 °C for 24 h created the most commercially valued product, despite it having visual characteristics more akin to a semi-fermented tea. These visual characteristics are traditionally considered markers of green tea damage and are discarded; however, QI-Tool scoring suggests that this raw material presents as a commercially favourable source of food loss and waste (FLW). The findings of this study extend our understanding of post-harvest processing delays and storage on green tea quality and suggest the viability of a commercially valuable semi-fermented produced from FLW.
An Assessment of the Competitive Position of the Emergent Uruguayan Wine Industry: A Preliminary Netnographic Baseline Study
Authors: Camillo Angelo A. , Kim Woo Gon
Published: May 2021

This study investigates the competitive position of the Uruguayan wine industry and its potential to become a player in the global wine trade. The study adopts an exploratory, holistic, and qualitative research design, applying desk research, cyberethnography, and electronic correspondence with stakeholders. The research, based on the theory of global business competitiveness, aims to determine the opportunities Uruguay’s wine industry could exploit, based on its competencies, to become a player in the worldwide wine business landscape. The results show that Uruguay is a young wine-producing country; however, it has the potential to become a global competitor. Critical factors identified in the study are geographic location, favorable climate, terrain, hydropower and the high density of the hydrographic network, available agricultural land, the available and well-educated workforce, unique land infrastructure, and the newness of the grape varietal (Tannat) being introduced to the world market with promising results. The paper contributes to the body of knowledge of competitive strategy in wine business research and adds to the scarce literature on the Uruguayan wine industry. Finally, it assesses Uruguay’s current positioning of wine production and competitiveness. The results will benefit stakeholders in the Uruguayan wine industry, researchers, and practitioners in the field.
All That Glitters Is Not Gold: The Other Insects That Fall into the Asian Yellow-Legged Hornet Vespa velutina ‘Specific’ Traps
Authors: Sánchez Omar , Arias Andrés
Published: May 2021

The introduction of invasive species is considered one of the major threats to the biodiversity conservation worldwide. In recent years, an Asian invasive species of wasp has set off alarms in Europe and elsewhere in the world, Vespa velutina. The Asian wasp was accidentally introduced in France around 2004 and shortly thereafter it was able to colonise practically all of Europe, including the Iberian Peninsula. The ecological and economic implications of V. velutina invasion and its high colonisation ability have triggered widespread trapping campaigns, usually supported by beekeepers and local governments, with the aim of diminishing its population and its negative impacts. Among the most used control methods are the capture traps, which use a sugary attractant to catch the invasive wasps. However, the species-specific selectivity and efficiency of these traps has been little studied. In this paper, we have analysed the specific identity of the unintentionally trapped insect species from northern Spain (covering one-year period), as well as we have assessed the provided ecosystem services by them. A total of 74 non-target taxa of insects were caught by the V. velutina studied traps, most of them correspond to the orders Diptera, Hymenoptera and Lepidoptera, the dipterans being the most abundant group. Surprisingly, the most abundant trapped species was the invasive fly, Drosophila suzukii that represented the 36.07% of the total catches. Furthermore, we reported the first record of ectoparasitic mites of the genus Varroa on V. velutina, constituting a newly recorded symbiotic association. Hopefully, the provided information helps to develop new protocols and management tools to control this invasive species in the Iberian Peninsula and other temperate areas of western Europe and the Mediterranean basin.
Subcutaneous Adipose Tissue Measured by B-Mode Ultrasound to Assess and Monitor Obesity and Cardio–Metabolic Risk in Children and Adolescents
Authors: Schmid-Zalaudek Karin , Brix Bianca , Sengeis Marietta , Jantscher Andreas , Fürhapter-Rieger Alfred , Müller Wolfram , Matjuda Edna N. , Mungamba Muhau M. , Nkeh-Chungag Benedicta , Fredriksen Per Morten , Goswami Nandu
Published: May 2021

Monitoring of children at heightened risk of cardio–metabolic diseases raises the need for accurate assessment of obesity. A standardized approach for measuring subcutaneous adipose tissue (SAT) by bright-mode ultrasound was evaluated in relation to body indices and anthropometry in a cross-sectional sample of 76 South African children (7–10 years) and 86 adolescents (13–17 years) to assess cardio–metabolic risk. SAT was higher in girls as compared to boys (children: 50.0 ± 21.7 mm > 34.42 ± 15.8 mm, adolescents: 140.9 ± 59.4 mm > 79.5 ± 75.6 mm, p < 0.001) and up to four times higher in adolescents than in children. In children, measures of relative body weight showed only a poor correlation to SAT (BMI: r = 0.607, p < 0.001), while in adolescents, BMI correlated high with SAT (r = 0.906, p < 0.001) based on high rates of overweight and obesity (41.8%). Children with identical BMIs may have large differences (>2–3-fold) in their amount of SAT. The moderate association to systolic (r = 0.534, r = 0.550, p < 0.001) and diastolic blood pressure (r = 0.402, r = 0.262, p < 0.001) further substantiates that SAT measured by ultrasound provides an accurate, safe and easy applicable approach for monitoring in children and adolescents at cardio–metabolic risk.
Gene Polymorphisms of the Renin-Angiotensin-Aldosterone System as Risk Factors for the Development of In-Stent Restenosis in Patients with Stable Coronary Artery Disease
Authors: Azova Madina , Timizheva Kalima , Ait Aissa Amira , Blagonravov Mikhail , Gigani Olga , Aghajanyan Anna , Tskhovrebova Leyla
Published: May 2021

This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. Patients were divided into two groups: with in-stent restenosis (ISR) and without it. The patients with ISR were classified into subgroups by the terms of the restenosis development and age. Real-time PCR and Restriction Fragment Length Polymorphism-PCR were used to genotype the study participants for RAAS gene polymorphisms. We found that the development of restenosis is generally associated with the minor A allele for renin (REN) rs2368564 and the major TT genotype for angiotensinogen (AGT) rs699. The heterozygous genotype for AGT rs4762 acts as a protective marker. A minor A allele for angiotensin II type 2 receptor (AGTR2) rs1403543 is associated with a risk of restenosis in people under 65 years old. Among patients with the early ISR, heterozygotes for angiotensin II type 1 receptor (AGTR1) rs5186 are more frequent, as well as A allele carriers for AGTR2 rs1403543. A minor homozygous genotype for REN rs41317140 and heterozygous genotype for aldosterone synthase (CYP11B2) rs1799998 are predisposed to the late restenosis. Thus, to choose the effective treatment tactics for patients with coronary artery disease, it is necessary to genotype patients for the RAAS polymorphisms, which, along with age and clinical characteristics, will allow a comprehensive assessment of the risk of the restenosis development after stenting.
Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas
Authors: Nunvar Jaroslav , Pagacova Lucie , Vojtechova Zuzana , Azevedo Nayara Trevisan Doimo de , Smahelova Jana , Salakova Martina , Tachezy Ruth
Published: May 2021

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs.
Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?
Authors: Griffiths Courtney , Aikins James , Warshal David , Ostrovsky Olga
Published: May 2021

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications.
Multi-Omic Meta-Analysis of Transcriptomes and the Bibliome Uncovers Novel Hypoxia-Inducible Genes
Authors: Ono Yoko , Bono Hidemasa
Published: May 2021

Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.
Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery
Authors: Boisguérin Prisca , Konate Karidia , Josse Emilie , Vivès Eric , Deshayes Sébastien
Published: May 2021

Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV.
Highly Sensitive Colorimetric Assay of Cortisol Using Cortisol Antibody and Aptamer Sandwich Assay
Authors: Kim Yoonjae , Yang Jongmin , Hur Hyeyeon , Oh Seungju , Lee Hyun Ho
Published: May 2021

In this study, cortisol, which is a key stress hormone, could be detected sensitively via the colorimetric assay of a polycarbonate (PC) and glass substrate by the sandwich assay of cortisol monoclonal antibody (c-Mab) and cortisol specific binding aptamer (c-SBA). A highly sensitive change in colorimetry with a limit of detection (LOD) of cortisol of 100 fM could be attained on the optically transparent substrate using the antibody aptamer sandwich (AAS) assay by corresponding stacks of 5 nm gold nanoparticles (Au NPs). The Au NPs were conjugated by the c-SBA and the c-Mab was tethered on the PC and glass substrates. For the AAS method, a simple UV-Vis spectrophotometer was adopted to quantify the cortisol concentrations at an absorbance wavelength of 520 nm. Therefore, this study demonstrates the versatility of the AAS method to measure very low concentrations of cortisol in diagnostic applications.
Mean Operating Temperature (MOT) of Commercial Roof Assembly and Its Impact on the Energy Performance
Authors: Molleti Sudhakar , Carrigan Logan , van Reenen David
Published: May 2021

In the thermal design of low sloped roofing assemblies, two parameters are overlooked, one is the surface temperature of the roof assemblies which provides the required temperature gradient for heat flow, and the other is the mean operating temperature of the roof assembly, which has direct implications on the thermal performance of the insulation. An in situ field study was conducted in collaboration with Alberta Roofing Contractors Association (ARCA) on their headquarters building located in Calgary, to generate data on the mean operating temperature of the roof assemblies and to determine whether the thermal design of roofing assemblies using conventional methods is an accurate portrayal of in-service thermal performance. For the present study, two roof assemblies insulated with polyisocyanurate insulation, one with a white reflective roof membrane and the other with the black membrane were selected and instrumented. During the monitoring period, the mean operating temperature (MOT) of the roof assembly whether it is calculated as the average of interior and exterior ambient (MOTAIR,) or the average of surface temperatures (MOTSurface), was found to be below 24 °C (75 °F), which opposes the current roof thermal designs that are being designed using label R-value (thermal resistance) of the insulation reported at the mean temperature of 24 °C (75 °F) rather than temperature-dependent thermal resistance. The comparison of two energy transfer theoretical models, QConvention and QMOT, with the measured data indicated that the conventional approach of roof thermal design underestimates the energy performance of the roof assembly on average by 30%. The use of roof surface temperatures and the corresponding temperature-dependent thermal resistance of the insulation as in QMOT has been demonstrated to improve predictions of the energy performance. In addition the loss in thermal resistance due to blowing agent diffusion in polyisocyanurate was evaluated after two years of in situ installation.
Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy
Authors: Gao Chao , Jin Guangxu , Forbes Elizabeth , Mangala Lingegowda S. , Wang Yingmei , Rodriguez-Aguayo Cristian , Amero Paola , Bayraktar Emine , Yan Ye , Lopez-Berestein Gabriel , Broaddus Russell R. , Sood Anil K. , Xue Fengxia , Zhang Wei
Published: May 2021

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK’s role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.
RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer
Authors: Bonavida Benjamin
Published: May 2021

Since its original cloning by Yeung et al [...]
Response and Toxicity to the Second Course of 3 Cycles of 177Lu-PSMA Therapy Every 4 Weeks in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Rasul Sazan , Wollenweber Tim , Zisser Lucia , Kretschmer-Chott Elisabeth , Grubmüller Bernhard , Kramer Gero , Shariat Shahrokh F. , Eidherr Harald , Mitterhauser Markus , Vraka Chrysoula , Langsteger Werner , Hacker Marcus , Haug Alexander R.
Published: May 2021

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients. Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87–1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan–Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival. Results: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6–1926 µg/L, p = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer (p = 0.02), whereas the patients with bone metastases had a shorter survival (p = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS (p < 0.05, hazard ratio 2.43, 95% CI 1.01–5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, p = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, p = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded. Conclusion: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS.
The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy
Authors: Chargui Abderrahman , Belaid Amine , Ndiaye Papa Diogop , Imbert Véronique , Samson Michel , Guigonis Jean-Marie , Tauc Michel , Peyron Jean-François , Poujeol Philippe , Brest Patrick , Hofman Paul , Mograbi Baharia
Published: May 2021

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.
Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells
Authors: Kladnik Jerneja , Coverdale James P. C. , Kljun Jakob , Burmeister Hilke , Lippman Petra , Ellis Francesca G. , Jones Alan M. , Ott Ingo , Romero-Canelón Isolda , Turel Iztok
Published: May 2021

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G1 cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.
Long-Term Survival Effect of the Interval between Postoperative Chemotherapy and Radiotherapy in Patients with Completely Resected Pathological N2 Non-Small-Cell Lung Cancer
Authors: Lin Shih-Min , Ku Hsiu-Ying , Hsu Che-Yu , Wang Chih-Liang , Chang Gee-Chen , Chang Cheng-Shyong , Liu Tsang-Wu
Published: May 2021

(1) Purpose: To investigate the effects of the time interval between initiation of adjuvant chemotherapy and radiotherapy on survival outcomes in patients with completely resected stage IIIA pN2 non-small-cell lung cancer (NSCLC); (2) Methods: Data on 2515 patients with completely resected stage IIIA pN2 NSCLC in 2007–2017 were extracted from the Taiwan Cancer Registry Database. The survival outcomes in patients who underwent concurrent chemoradiotherapy (CCRT) and sequential chemotherapy and radiotherapy (SCRT) with either a short (SCRT1) or long (SCRT2) interval between treatments were estimated using Kaplan–Meier, Cox regression, and propensity score matching (PSM); (3) Results: Multivariate analyses of OS showed that SCRT2 (hazard ratio [HR] 0.64, p = 0.017) was associated with improved overall survival (OS). After PSM, the median OS periods were 64 and 75 months in the SCRT1 and SCRT2 groups, respectively, which differed significantly from that of 58 months in the CCRT group (p = 0.003). In elderly patients, SCRT2 significantly improved survival relative to CCRT before PSM (p = 0.024) and after PSM (p = 0.002); (4) Conclusions: A longer interval between initiation of adjuvant chemotherapy and postoperative radiotherapy (PORT; SCRT2) improved OS relative to CCRT; the benefits were greater in elderly patients (age >60 years).
Recent Progress in Dendritic Cell-Based Cancer Immunotherapy
Authors: Matsuo Kazuhiko , Yoshie Osamu , Kitahata Kosuke , Kamei Momo , Hara Yuta , Nakayama Takashi
Published: May 2021

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.
Differential Prognosis and Response of Denovo vs. Secondary Muscle-Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis
Authors: Pones Mario , D’Andrea David , Mori Keiichiro , Abufraj Mohammad , Moschini Marco , Comperat Eva , Shariat Shahrokh F.
Published: May 2021

To evaluate oncological outcomes of primary versus secondary muscle-invasive bladder cancer treated with radical cystectomy. Medline, Embase, Scopus and Cochrane Library were searched for eligible studies. Hazard ratios for overall survival (OS), cancer specific survival (CSS) and progression free survival (PFS) were calculated using survival data extracted from Kaplan-Meier curves. A total of 16 studies with 5270 patients were included. Pooled analysis showed similar 5-year and 10-year OS (HR 1, p = 0.96 and HR 1, p = 0.14) and CSS (HR 1.02, p = 0.85 and HR 0.99, p = 0.93) between primMIBC and secMIBC. Subgroup analyses according to starting point of follow-up and second-look transurethral resection revealed similar results. Subgroup analyses of studies in which neoadjuvant chemotherapy was administered demonstrated significantly worse 5-year CSS (HR 1.5, p = 0.04) but not 10-year CSS (HR 1.36, p = 0.13) in patients with secMIBC. Patients with secMIBC had significantly worse PFS at 5-year (HR 1.41, p = 0.002) but not at 10-year follow-up (HR 1.25, p = 0.34). This review found comparable oncologic outcomes between primMIBC and secMIBC patients treated with RC regarding OS and CSS. Subgroup analysis showed worse 5-year CSS but not 10-year CSS for neoadjuvant chemotherapy in the secMIBC group. Prospective clinical trials incorporating molecular markers, that allow precise risk stratification of secMIBC and further research uncovering underlying molecular and clinical drivers of the heterogeneous group of secMIBC is needed.
Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs
Authors: Capuano Cristina , Pighi Chiara , Battella Simone , De Federicis Davide , Galandrini Ricciarda , Palmieri Gabriella
Published: May 2021

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.
Evaluation of the Ginsburg Scheme: Where Is Significant Prostate Cancer Missed?
Authors: Sigle August , Jilg Cordula A. , Kuru Timur H. , Binder Nadine , Michaelis Jakob , Grabbert Markus , Schultze-Seemann Wolfgang , Miernik Arkadiusz , Gratzke Christian , Benndorf Matthias , Suarez-Ibarrola Rodrigo
Published: May 2021

Background: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS’s blind sectors where sPCa is missed is crucial to improve biopsy strategies. Methods: We analyzed cancer detection rates in 1084 patients that underwent MR-TB and SB. Cancerous lesions that were missed or underestimated by GBS were re-localized onto a prostate map encompassing Ginsburg sectors and blind-sectors (anterior, central, basodorsal and basoventral). Logistic regression analysis (LRA) and prostatic configuration analysis were applied to identify predictors for missing sPCa with the GBS. Results: GBS missed sPCa in 39 patients (39/1084, 3.6%). In 27 cases (27/39, 69.2%), sPCa was missed within a blind sector, with 17/39 lesions localized in the anterior region (43.6%). Neither LRA nor prostatic configuration analysis identified predictors for missing sPCa with the GBS. Conclusions: This is the first study to analyze the distribution of sPCa missed by the GBS. GBS misses sPCa in few men only, with the majority localized in the anterior region. Adding blind sectors to GBS defined a new sector map of the prostate suited for reporting histopathological biopsy results.
CAR T-Cells for CNS Lymphoma: Driving into New Terrain?
Authors: Karschnia Philipp , Blobner Jens , Teske Nico , Schöberl Florian , Fitzinger Esther , Dreyling Martin , Tonn Joerg-Christian , Thon Niklas , Subklewe Marion , von Baumgarten Louisa
Published: May 2021

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.