bluuebunny/crossref_metadata_2025 huggingface dataset:
The Variation in 3D Face Shapes of Dutch Children for Mask Design
Authors: Goto Lyè , Lee Wonsup , Huysmans Toon , Molenbroek Johan F. M. , Goossens Richard H. M.
Published: July 2021

The use of 3D anthropometric data of children’s heads and faces has great potential in the development of protective gear and medical products that need to provide a close fit in order to function well. Given the lack of detailed data of this kind, the aim of this study is to map the size and shape variation of Dutch children’s heads and faces and investigate possible implications for the design of a ventilation mask. In this study, a dataset of heads and faces of 303 Dutch children aged six months to seven years consisting of traditional measurements and 3D scans were analysed. A principal component analysis (PCA) of facial measurements was performed to map the variation of the children’s face shapes. The first principal component describes the overall size, whilst the second principal component captures the more width related variation of the face. After establishing a homology between the 3D scanned face shapes, a second principal component analysis was done on the point coordinates, revealing the most prominent variations in 3D shape within the sample.
A Comparative Analysis of Arabic Text Steganography
Authors: Thabit Reema , Udzir Nur Izura , Yasin Sharifah Md , Asmawi Aziah , Roslan Nuur Alifah , Din Roshidi
Published: July 2021

Protecting sensitive information transmitted via public channels is a significant issue faced by governments, militaries, organizations, and individuals. Steganography protects the secret information by concealing it in a transferred object such as video, audio, image, text, network, or DNA. As text uses low bandwidth, it is commonly used by Internet users in their daily activities, resulting a vast amount of text messages sent daily as social media posts and documents. Accordingly, text is the ideal object to be used in steganography, since hiding a secret message in a text makes it difficult for the attacker to detect the hidden message among the massive text content on the Internet. Language’s characteristics are utilized in text steganography. Despite the richness of the Arabic language in linguistic characteristics, only a few studies have been conducted in Arabic text steganography. To draw further attention to Arabic text steganography prospects, this paper reviews the classifications of these methods from its inception. For analysis, this paper presents a comprehensive study based on the key evaluation criteria (i.e., capacity, invisibility, robustness, and security). It opens new areas for further research based on the trends in this field.
An Integrated Model for the Harvest, Storage, and Distribution of Perishable Crops
Authors: Giallombardo Giovanni , Mirabelli Giovanni , Solina Vittorio
Published: July 2021

Coordination of the production and distribution activities represents a significant opportunity to cut costs and limit waste in the food supply chains. In this paper, we propose two mathematical models. The first one aims to integrate the harvesting, storage, and distribution activities of an agricultural company dealing with perishable products. The second one promotes horizontal collaboration between heterogeneous agri-companies for the distribution phase, in order to achieve cost savings. Computational experiments, conducted on a set of real-life instances, confirm the effectiveness and efficiency of the proposed models, which provide multi-level support. At the tactical level, managerial insights suggest the most profitable parameter setting, in terms of harvesting frequency and quality of service. At the operational level, the use of a heuristic framework can support the decision-making of the companies, suggesting when collaboration is profitable.
De-Noising Process in Room Impulse Response with Generalized Spectral Subtraction
Authors: Chen Min , Lee Chang-Myung
Published: July 2021

The generalized spectral subtraction algorithm (GBSS), which has extraordinary ability in background noise reduction, is historically one of the first approaches used for speech enhancement and dereverberation. However, the algorithm has not been applied to de-noise the room impulse response (RIR) to extend the reverberation decay range. The application of the GBSS algorithm in this study is stated as an optimization problem, that is, subtracting the noise level from the RIR while maintaining the signal quality. The optimization process conducted in the measurements of the RIRs with artificial noise and natural ambient noise aims to determine the optimal sets of factors to achieve the best noise reduction results regarding the largest dynamic range improvement. The optimal factors are set variables determined by the estimated SNRs of the RIRs filtered in the octave band. The acoustic parameters, the reverberation time (RT), and early decay time (EDT), and the dynamic range improvement of the energy decay curve were used as control measures and evaluation criteria to ensure the reliability of the algorithm. The de-noising results were compared with noise compensation methods. With the achieved optimal factors, the GBSS contributes to a significant effect in terms of dynamic range improvement and decreases the estimation errors in the RTs caused by noise levels.
A Barber-Surgeon’s Instrument Case: Seeing the Iconography of Thomas Becket through a Netherlandish Lens
Authors: Hampson Louise , Jenkins John
Published: July 2021

The triple anniversary in 2020 of Thomas Becket’s birth, death and translation has been an occasion to review and revisit many of the artefacts associated with the saint and his cult in England and across Europe. Many of these are items directly associated with his veneration in churches or in private devotions, but one object which served in neither capacity is an instrument case currently in the collection of the Worshipful Company of Barbers in London. This unusual object has been studied for its fine silver work, and possible royal associations, but little academic attention has so far been paid to the some of the iconography, particularly that of the scene of the murder of Thomas Becket depicted on the back of the box, the side to be worn against the body. In this article, we show how seemingly unusual elements in the iconography draw on particularly Flemish representations of Becket’s murder that, to date, have received little attention in Anglophone scholarship. From this, we discuss this scene and its significance in understanding the role the iconography may have been intended to serve, and the interplay between the decorative schema and what the surgeon thought about his own role with regard to the use of the case and its tools.
Human Blood Serum Induces p38-MAPK- and Hsp27-Dependent Migration Dynamics of Adult Human Cardiac Stem Cells: Single-Cell Analysis via a Microfluidic-Based Cultivation Platform
Authors: Höving Anna L. , Schmitz Julian , Schmidt Kazuko E. , Greiner Johannes F. W. , Knabbe Cornelius , Kaltschmidt Barbara , Grünberger Alexander , Kaltschmidt Christian
Published: July 2021

Migratory capabilities of adult human stem cells are vital for assuring endogenous tissue regeneration and stem cell-based clinical applications. Although human blood serum has been shown to be beneficial for cell migration and proliferation, little is known about its impact on the migratory behavior of cardiac stem cells and underlying signaling pathways. Within this study, we investigated the effects of human blood serum on primary human cardiac stem cells (hCSCs) from the adult heart auricle. On a technical level, we took advantage of a microfluidic cultivation platform, which allowed us to characterize cell morphologies and track migration of single hCSCs via live cell imaging over a period of up to 48 h. Our findings showed a significantly increased migration distance and speed of hCSCs after treatment with human serum compared to control. Exposure of blood serum-stimulated hCSCs to the p38 mitogen-activated protein kinase (p38-MAPK) inhibitor SB239063 resulted in significantly decreased migration. Moreover, we revealed increased phosphorylation of heat shock protein 27 (Hsp27) upon serum treatment, which was diminished by p38-MAPK-inhibition. In summary, we demonstrate human blood serum as a strong inducer of adult human cardiac stem cell migration dependent on p38-MAPK/Hsp27-signalling. Our findings further emphasize the great potential of microfluidic cultivation devices for assessing spatio-temporal migration dynamics of adult human stem cells on a single-cell level.
Use of Continuous Positive Airway Pressure (CPAP) to Limit Diaphragm Motion—A Novel Approach for Definitive Radiation Therapy for Inoperable Pleural Mesothelioma: A Pilot Study
Authors: Moore Assaf , Kindler Marc J. , Allen Aaron Max
Published: July 2021

Malignant pleural mesothelioma (MPM) is a deadly disease and radiotherapy (RT) plays an important role in its management. Recent developments in technique have made it is possible to deliver RT to MPM in the intact lung. However, it is imperative to reduce normal lung doses. We present a pilot study examining the use of CPAP and VMAT radiotherapy to reduce toxicity when treating MPM, involving three consecutive patients with MPM, not amenable to surgery, who were treated according to Helsinki committee approval. Patients were simulated using four-dimentional CT simulation with the assistance of CPAP lung inflation, then were treated using both IMRT and VMAT techniques. Radiation lung dose was optimized based on accepted lung dose constraints. Patients were followed for toxicity as well as local control and survival. Results: Three patients were treated with CPAP-based IMRT treatment. These patients tolerated the treatment and DVH constraints were able to be met. The comparison plans among the four VMAT arcs and the IMRT static field treatment were able to accomplish the treatment planning objectives without significant advantages with either technique. The treatment combined with CPAP reduced the normal lung dose in MPM patients with intact lungs. This technique is worthy of further investigation.
Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia
Authors: Wierońska Joanna M , Cieślik Paulina , Kalinowski Leszek
Published: July 2021

Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO•-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO• synthases and the stabilization of HIF-1α activity.
Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis
Authors: Huang Tsui-Chin , Peng Kuan-Chieh , Kuo Tzu-Ting , Lin Li-Chun , Liu Bai-Chia , Ye Shu-Ping , Chu Chien-Chou , Hsia Shih-Min , Chang Hsin-Yi
Published: July 2021

5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.
Standardized Method for the Assessment of Behavioral Responses of Zebrafish Larvae
Authors: Maeda Hideyuki , Fukushima Noritoshi , Hasumi Akihiro
Published: July 2021

Zebrafish are easy to breed in a laboratory setting as they are extremely fertile and produce dozens of eggs per set. Because zebrafish eggs and the skin of the early-stage larvae are transparent, their embryos and the hearts and muscles of their larvae can be easily observed. Multiple rapid analyses of heart rate and behavior can be performed on these larvae simultaneously, enabling investigation of the influence of neuroactive substances on abnormal behavior, death, and associated pathogenetic mechanisms. Zebrafish larvae are becoming increasingly popular among researchers and are used in laboratories worldwide to study various vertebrate life phenomena; more experimental systems using zebrafish will undoubtedly be developed in the future. However, based on the available literature, we believe that the conceptualization of a protocol based on scientific evidence is necessary to achieve standardization. We exposed zebrafish larvae at 6–7 days post-fertilization to 50 repeated light–dark stimuli at either 15-min or 5-min intervals. We measured the traveled distance and habituation time through a video tracking apparatus. The traveled distance stabilized after the 16th repetition when the zebrafish were exposed to light–dark stimuli at 15-min intervals and after the 5th repetition when exposed at 5-min intervals. Additionally, at 15-min intervals, the peak of the traveled distance was reached within the first minute in a dark environment, whereas at 5-min intervals, it did not reach the peak even after 5 min. The traveled distance was more stable at 5-min intervals of light/dark stimuli than at 15-min intervals. Therefore, if one acclimatizes zebrafish larvae for 1 h and collects data from the 5th repetition of light/dark stimuli at intervals of 5 min in the light/dark test, a stable traveled distance result can be obtained. The establishment of this standardized method would be beneficial for investigating substances of unknown lethal concentration.
On-Chip Glucose Detection Based on Glucose Oxidase Immobilized on a Platinum-Modified, Gold Microband Electrode
Authors: Madden Julia , Barrett Colm , Laffir Fathima R. , Thompson Michael , Galvin Paul , O’ Riordan Alan
Published: July 2021

We report the microfabrication and characterization of gold microband electrodes on silicon using standard microfabrication methods, i.e., lithography and etching techniques. A two-step electrodeposition process was carried out using the on-chip platinum reference and gold counter electrodes, thus incorporating glucose oxidase onto a platinum-modified, gold microband electrode with an o-phenylenediamine and ß-cyclodextrin mixture. The as-fabricated electrodes were studied using optical microscopy, scanning electron microscopy, and atomic force microscopy. The two-step electrodeposition process was conducted in low sample volumes (50 µL) of both solutions required for biosensor construction. Cyclic voltammetry and electrochemical impedance spectroscopy were utilised for electrochemical characterization at each stage of the deposition process. The enzymatic-based microband biosensor demonstrated a linear response to glucose from 2.5–15 mM, using both linear sweep voltammetry and chronoamperometric measurements in buffer-based solutions. The biosensor performance was examined in 30 µL volumes of fetal bovine serum. Whilst a reduction in the sensor sensitivity was evident within 100% serum samples (compared to buffer media), the sensor demonstrated linear glucose detection with increasing glucose concentrations (5–17 mM).
Differential Long-Term Population Responses of Two Closely Related Human-Associated Sparrow Species with Respect to Urbanization
Authors: Jokimäki Jukka , Suhonen Jukka , Kaisanlahti-Jokimäki Marja-Liisa
Published: July 2021

Urban planning and management need long-term population level studies for evaluating how urbanization influences biodiversity. Firstly, we reviewed the current population trends of the House Sparrow (Passer domesticus) and the Eurasian Tree Sparrow (Passer montanus) in Europe, and evaluated the usefulness of citizens’ science projects to monitor these species in Finland. Secondly, we conducted a long-term (1991–2020) winter field study in 31 urban settlements along a 950 km north–south extent in Finland to study how latitude, weather and urbanization influence on sparrow’s growth rates. The House Sparrow is declining in 15 countries, and increasing in 5, whereas the Eurasian Tree Sparrow is declining in 12 and increasing in 9 European countries. The trend of the House Sparrow was significantly negative in continental Europe. However, the trend of the Eurasian Tree Sparrow was not significant. Both species have declined simultaneously in six countries, whereas in four countries, their trends are opposite. Citizen-based, long-term (2006–2020) winter season project data indicated that House Sparrow has decreased, whereas Eurasian Tree Sparrow has increased in Finland. However, the short-term (2013–2020) breeding season citizen-based project data did not indicate significant changes in the occupation rate of sparrows. Our long-term (1991–2020) field study indicated that wintering populations of the House Sparrow have decreased, whereas the Eurasian Tree Sparrows have both expanded their wintering range and increased their population size. Based on our winter count data, latitude and weather did not significantly influence the growth rates of sparrows. When the human population increased within the study plot, House Sparrow populations decreased, and vice versa. There was also a trend that a decreasing number of feeding sites has decreased the House Sparrow numbers. Urban-related factors did not influence the growth rate of the Eurasian Tree Sparrow. Our results indicate that the colonization of a new, even closely related species does not influence negatively on earlier urbanized species. It is probable that the niches of these sparrow species are different enough for allowing them to co-occur. The House Sparrow mainly nests on buildings, whereas the Eurasian Tree Sparrow can easily accept, e.g., nest boxes. Urban planning should take care of both the food availability and nest sites availability for both sparrow species.
Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury
Authors: Sysoev Yuriy I. , Prikhodko Veronika A. , Chernyakov Roman T. , Idiyatullin Ruslan D. , Musienko Pavel E. , Okovityi Sergey V.
Published: July 2021

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain’s electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg−1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 μg∙kg−1 did not affect the brain’s electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.
Validation of the Japanese Version of the Center for Epidemiologic Studies Depression Scale—Revised: A Preliminary Analysis
Authors: Tsuboi Hirohito , Takakura Yui , Tsujiguchi Hiromasa , Miyagi Sakae , Suzuki Keita , Nguyen Thao Thi Thu , Pham Kim Oanh , Shimizu Yukari , Kambayashi Yasuhiro , Yoshida Naoko , Hara Akinori , Nakamura Hiroyuki
Published: July 2021

To make the Japanese version of the CESD-R—a revised version of the Center for Epidemiologic Studies depression scale (CES-D)—in the assessment of depressive symptoms in a general population. The English version of CESD-R was translated into Japanese, and back-translated into English by three native speakers of Japanese and English; then, we selected the version most completely consistent with the original items. The CESD-R was applied to 398 community-dwelling people (191 men: 48.0%, and 207 women: 52.0%) who were over 40 years old. The Japanese version of the CES-D was also carried out in the same population. Factor analysis was performed. Additionally, the correlations between the CESD-R and CES-D results were identified. The CESD-R scores showed a significantly positive correlation with CES-D scores (r = 0.74, p < 0.0005). Analysis of the CESD-R yielded a Cronbach’s alpha result of 0.90. Factor analysis revealed one principal factor in the CESD-R, whereas the original CES-D had two factors because of reversed items. The Japanese version of the CESD-R appears to have the reliability to be applicable for assessing depressive symptoms in population-based samples. However, because the Japanese expressions for some items might be unusual, our study population was also limited; further studies on other populations and on incorporating improved Japanese terminology will be needed.
Preparation and Carbonization of Glucose and Pyromellitic Dianhydride Crosslinked Polymers
Authors: Caldera Fabrizio , Moramarco Antonella , Cesano Federico , Anceschi Anastasia , Damin Alessandro , Zanetti Marco
Published: July 2021

In this work, four types of nanosponges were prepared from pyromellitic dianhydride (PMDA) and D-glucose (GLU) with different molar ratios (1.5:1, 2:1, 2.5:1 and 3:1). The obtained PMDA/GLU nanosponges were then pyrolyzed at 800 °C for 30 min under N2 gas flow. The prepared polymeric nanosponges were investigated by FTIR spectroscopy, elemental and thermogravimetric analyses to unravel the role played by the different molar ratio of the precursors in the formation of the polymer. The pyrolyzed nanosponges were investigated by means of porosity measurements, X-ray diffraction analysis, Raman spectroscopy and high-resolution transmission electron microscopy. Notably, no significant correlation of the amounts of used precursors with the porous texture and structure was evidenced. The results corroborate that PMDA and GLU can be easily combined to prepare nanosponges and that the carbon materials produced by their pyrolysis can be associated with glassy carbons with a microporous texture and relatively high surface area. Such hard carbons can be easily obtained and shrewdly used to segregate relatively small molecules and organic contaminants; in this study methylene blue adsorption was investigated.
Novel Insights of T2-Weighted Imaging: Significance for Discriminating Lung Cancer from Benign Pulmonary Nodules and Masses
Authors: Usuda Katsuo , Iwai Shun , Yamagata Aika , Iijima Yoshihito , Motono Nozomu , Matoba Munetaka , Doai Mariko , Hirata Keiya , Uramoto Hidetaka
Published: July 2021

Diffusion-weighted imaging is useful for discriminating lung cancer from benign pulmonary nodules and masses (BPNMs), however the diagnostic capability is not perfect. The aim of this research was to clarify whether T2-weighted imaging (T2WI) is efficient in discriminating lung cancer from BPNMs, especially from pulmonary abscesses. A T2 contrast ratio (T2 CR) for a pulmonary nodule is defined as the ratio of T2 signal intensity of a pulmonary nodule divided by the T2 signal intensity of the rhomboid muscle. There were 52 lung cancers and 40 inflammatory BPNMs (mycobacteria disease 12, pneumonia 13, pulmonary abscess 9, other 6) and seven non-inflammatory BPNMs. The T2 CR (2.14 ± 0.63) of lung cancers was significantly lower than that (2.68 ± 1.04) of BPNMs (p = 0.0021). The T2 CR of lung cancers was significantly lower than that (2.93 ± 0.26) of pulmonary abscesses (p = 0.011). When the optical cutoff value of T2 CR was set as 2.44, the sensitivity was 0.827 (43/52), the specificity 0.596 (28/47), the accuracy 0.717 (71/99), the positive predictive value 0.694 (43/62), and the negative predictive value 0.757 (28/37). T2 CR of T2WI is useful in discriminating lung cancer from BPNMs. Pulmonary abscesses, which show strong restricted diffusion in DWI, can be differentiated from lung cancers using T2WI.
The DNA Damage Response Is Differentially Involved in HPV-Positive and HPV-Negative Radioresistant Head and Neck Squamous Cell Carcinoma
Authors: Bamps Marieke , Dok Rüveyda , Nuyts Sandra
Published: July 2021

Radioresistance is a major cause of recurrences and radiotherapy (RT) failure in head and neck squamous cell carcinoma (HNSCC). DNA damage response (DDR) is known to be important for RT response, but its role in radioresistance is not fully understood. Here, we assessed the role of DDR in the radioresistance process of HNSCC by generating radioresistant clones from both HPV-positive SCC154 and HPV-negative SCC61 cells. We show that fractionated RT decreased RT response of HPV-positive and HPV-negative radioresistant clones in vitro and in vivo. Moreover, HPV-positive and HPV-negative radioresistant clones were characterized by differential DDR response. HPV-positive radioresistant clones showed less residual double-strand break damage and increased G2/M arrest recovery after RT, indicating an acquisition of increased DDR kinetics. In contrast, HPV-negative radioresistant clones showed less micronucleated cells after RT and increased survival upon checkpoint inhibition, indicating an increased replicative capacity. Inhibiting key factors of DDR in combination with RT rescued the radioresistant phenotype of both HPV-positive and HPV-negative radioresistant clones. Altogether, our results not only highlight the importance of DDR response in the radioresistance process of HPV-positive and HPV-negative HNSCC, but also provide possibilities for new therapies for HNSCC patients in recurrent settings.
Site-Specific Variation in Radiomic Features of Head and Neck Squamous Cell Carcinoma and Its Impact on Machine Learning Models
Authors: Liu Xiaoyang , Maleki Farhad , Muthukrishnan Nikesh , Ovens Katie , Huang Shao Hui , Pérez-Lara Almudena , Romero-Sanchez Griselda , Bhatnagar Sahir Rai , Chatterjee Avishek , Pusztaszeri Marc Philippe , Spatz Alan , Batist Gerald , Payabvash Seyedmehdi , Haider Stefan P. , Mahajan Amit , Reinhold Caroline , Forghani Behzad , O’Sullivan Brian , Yu Eugene , Forghani Reza
Published: July 2021

Current radiomic studies of head and neck squamous cell carcinomas (HNSCC) are typically based on datasets combining tumors from different locations, assuming that the radiomic features are similar based on histopathologic characteristics. However, molecular pathogenesis and treatment in HNSCC substantially vary across different tumor sites. It is not known if a statistical difference exists between radiomic features from different tumor sites and how they affect machine learning model performance in endpoint prediction. To answer these questions, we extracted radiomic features from contrast-enhanced neck computed tomography scans (CTs) of 605 patients with HNSCC originating from the oral cavity, oropharynx, and hypopharynx/larynx. The difference in radiomic features of tumors from these sites was assessed using statistical analyses and Random Forest classifiers on the radiomic features with 10-fold cross-validation to predict tumor sites, nodal metastasis, and HPV status. We found statistically significant differences (p-value ≤ 0.05) between the radiomic features of HNSCC depending on tumor location. We also observed that differences in quantitative features among HNSCC from different locations impact the performance of machine learning models. This suggests that radiomic features may reveal biologic heterogeneity complementary to current gold standard histopathologic evaluation. We recommend considering tumor site in radiomic studies of HNSCC.
Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors
Authors: Jacome Sanz Dafne , Raivola Juuli , Karvonen Hanna , Arjama Mariliina , Barker Harlan , Murumägi Astrid , Ungureanu Daniela
Published: July 2021

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.
Differentiated Thyroid Cancer in Children and Adolescents: Long Term Outcome and Risk Factors for Persistent Disease
Authors: Sapuppo Giulia , Hartl Dana , Fresneau Brice , Hadoux Julien , Breuskin Ingrid , Baudin Eric , Rigaud Charlotte , Guerlain Joanne , Al Ghuzlan Abir , Leboulleux Sophie , Schlumberger Martin , Lamartina Livia
Published: July 2021

Background: Pediatric differentiated thyroid cancer (P-DTC) frequently presents with advanced disease. The study aim was to evaluate the outcome of P-DTC and a modified 2015 American Thyroid Association risk classification (ATA-R). Methods: A retrospective study of consecutive P-DTC patients was performed. The ATA-R for P-DTC was used with a cut-off of ≤ 5 N1a for low-risk. The outcome could be excellent response (ER) (thyroglobulin < 1 ng/mL and no evidence of disease (EoD) at imaging), biochemical incomplete response (BIR) (thyroglobulin ≥ 1 ng/mL and no EoD at imaging) or structural incomplete response (SIR) (EoD at imaging). Results: We studied 260 P-DTC (70% females; median age at diagnosis 14 years; 93% total thyroidectomy and 82% lymph node dissection). The ATA-R was low in 30% cases, intermediate in 15% and high in 55%, including 31.5% with distant metastases. Radioiodine treatment was administered in 218 (83.8%), and further radioiodine and surgery was performed in 113 (52%) and 76 (29%) patients, respectively. After a median follow-up of 8.2 years, the outcome was ER in 193 (74.3%), BIR in 17 (6.5%) and SIR in 50 (19.2%). Independent predictors of SIR or BIR at first and last visits were ATA-R intermediate or high. Conclusion: P-DTC has an excellent prognosis. Modified ATA-R is a useful prognostic tool in P-DTC to guide management.
Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression
Authors: Proctor Martina , Gonzalez Cruz Jazmina L. , Daignault-Mill Sheena M. , Veitch Margaret , Zeng Bijun , Ehmann Anna , Sabdia Muhammed , Snell Cameron , Keane Colm , Dolcetti Riccardo , Haass Nikolas K. , Wells James W. , Gabrielli Brian
Published: July 2021

Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8+ T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4+ and CD8+ T cells retained strong anti-tumour activity. Despite increased CD8+ T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3+ NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response.
Radiation-Induced Dyspnea in Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy
Authors: Cella Laura , Monti Serena , Thor Maria , Rimner Andreas , Deasy Joseph O. , Palma Giuseppe
Published: July 2021

In this study, we investigated the prognostic factors for radiation-induced dyspnea after hypo-fractionated radiation therapy (RT) in 106 patients treated with Stereotactic Body RT for Non-Small-Cell Lung Cancer (NSCLC). The median prescription dose was 50 Gy (range: 40–54 Gy), delivered in a median of four fractions (range: 3–12). Dyspnea within six months after SBRT was scored according to CTCAE v.4.0. Biologically Effective Dose (α/β = 3 Gy) volume histograms for lungs and heart were extracted. Dosimetric parameters along with patient-specific and treatment-related factors were analyzed, multivariable logistic regression method with Leave-One-Out (LOO) internal validation applied. Model performance was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plot parameters. Fifty-seven patients (53.8%) out of 106 developed dyspnea of any grade after SBRT (25/57 grade ≥ 2 cases). A three-variable predictive model including patient comorbidity (COPD), heart volume and the relative lungs volume receiving more than 15 Gy was selected. The model displays an encouraging performance given by a training ROC-AUC = 0.71 [95%CI 0.61–0.80] and a LOO-ROC-AUC = 0.64 [95%CI 0.53–0.74]. Further modeling efforts are needed for dyspnea prediction in hypo-fractionated treatments in order to identify patients at high risk for developing lung toxicity more accurately.
Targeting RB1 Loss in Cancers
Authors: Linn Paing , Kohno Susumu , Sheng Jindan , Kulathunga Nilakshi , Yu Hai , Zhang Zhiheng , Voon Dominic , Watanabe Yoshihiro , Takahashi Chiaki
Published: July 2021

Retinoblastoma protein 1 (RB1) is encoded by a tumor suppressor gene that was discovered more than 30 years ago. Almost all mitogenic signals promote cell cycle progression by braking on the function of RB1 protein through mono- and subsequent hyper-phosphorylation mediated by cyclin-CDK complexes. The loss of RB1 function drives tumorigenesis in limited types of malignancies including retinoblastoma and small cell lung cancer. In a majority of human cancers, RB1 function is suppressed during tumor progression through various mechanisms. The latter gives rise to the acquisition of various phenotypes that confer malignant progression. The RB1-targeted molecules involved in such phenotypic changes are good quarries for cancer therapy. Indeed, a variety of novel therapies have been proposed to target RB1 loss. In particular, the inhibition of a number of mitotic kinases appeared to be synthetic lethal with RB1 deficiency. A recent study focusing on a neighboring gene that is often collaterally deleted together with RB1 revealed a pharmacologically targetable vulnerability in RB1-deficient cancers. Here we summarize current understanding on possible therapeutic approaches targeting functional or genomic aberration of RB1 in cancers.
Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions
Authors: Hossain Fokhrul , Majumder Samarpan , David Justin , Miele Lucio
Published: July 2021

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
Adjuvant Radiotherapy Significantly Increases Neck Control and Survival in Early Oral Cancer Patients with Solitary Nodal Involvement: A National Cancer Registry Database Analysis
Authors: Tsai Chia-Jen , Kuo Yu-Hsuan , Wu Hung-Chang , Ho Chung-Han , Chen Yi-Chen , Yang Ching-Chieh
Published: July 2021

We assessed the role of adjuvant radiotherapy on neck control and survival in patients with early oral cancer with solitary nodal involvement. We identified pT1-2N1 oral cancer patients with or without adjuvant radiotherapy from the 2007–2015 Taiwan Cancer Registry database. The effect of adjuvant radiotherapy on 5-year neck control, overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan–Meier method, log-rank tests, and Cox regression analysis. Of 701 patients identified, 505 (72.0%) received adjuvant radiotherapy and 196 (28.0%) had surgery alone. Patients receiving adjuvant radiotherapy were more likely to be aged <65 years, pT2 stage, poorly graded and without comorbid conditions (all, p < 0.05). The 5-year OS and DFS differed significantly by receipt of adjuvant radiotherapy. Multivariable analysis showed adjuvant radiotherapy significantly associated with better 5-year OS (adjusted hazard ratio (aHR), 0.72; 95% confidence interval (CI), 0.54–0.97; p = 0.0288) and DFS (aHR, 0.64; 95% CI, 0.48–0.84; p = 0.0016). Stratified analysis indicated the greatest survival advantage for both 5-year OS and DFS in those with pT2 classification (p = 0.0097; 0.0009), and non-tongue disease (p = 0.0195; 0.0158). Moreover, adjuvant radiotherapy significantly protected against neck recurrence (aHR, 0.30; 95% CI, 0.18–0.51; p < 0.0001). Thus, adjuvant radiotherapy is associated with improved neck control and survival in these early oral cancer patients.
Image-Based Identification and Genomic Analysis of Single Circulating Tumor Cells in High Grade Serous Ovarian Cancer Patients
Authors: Salmon Carolin , Levermann Janina , Neves Rui P. L. , Liffers Sven-Thorsten , Kuhlmann Jan Dominik , Buderath Paul , Kimmig Rainer , Kasimir-Bauer Sabine
Published: July 2021

In Ovarian Cancer (OC), the analysis of single circulating tumor cells (sCTCs) might help to investigate genetic tumor evolution during the course of treatment. Since common CTC identification features failed to reliably detect CTCs in OC, we here present a workflow for their detection and genomic analysis. Blood of 13 high-grade serous primary OC patients was analyzed, using negative immunomagnetic enrichment, followed by immunofluorescence staining and imaging for Hoechst, ERCC1, CD45, CD11b and cytokeratin (CK) and sCTC sorting with the DEPArrayTM NxT. The whole genome of single cells was amplified and profiled for copy number variation (CNV). We detected: Type A-cells, epithelial (Hoechstpos, ERCC1pos, CD45neg, CD11bpos, CKpos); Type B-cells, potentially epithelial (Hoechstpos, ERCC1pos, CD45neg, CD11bpos, CKneg) and Type C-cells, potentially mesenchymal (Hoechstpos, ERCC1pos, CD45neg, CD11bneg, CKneg). In total, we identified five (38.5%) patients harboring sCTCs with an altered CN profile, which were mainly Type A-cells (80%). In addition to inter-and intra-patient genomic heterogeneity, high numbers of Type B- and C-cells were identified in every patient with their aberrant character only confirmed in 6.25% and 4.76% of cases. Further identification markers and studies in the course of treatment are under way to expand sCTC analysis for the identification of tumor evolution in OC.
Targeted Liposomal Chemotherapies to Treat Triple-Negative Breast Cancer
Authors: Si Yingnan , Zhang Ya , Ngo Hanh Giai , Guan Jia-Shiung , Chen Kai , Wang Qing , Singh Ajeet Pal , Xu Yuanxin , Zhou Lufang , Yang Eddy S. , Liu Xiaoguang (Margaret)
Published: July 2021

Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.
Methanol to Formaldehyde: An Overview of Surface Studies and Performance of an Iron Molybdate Catalyst
Authors: Malik Muhammad Irfan , Abatzoglou Nicolas , Achouri Inès Esma
Published: July 2021

Formaldehyde is a primary chemical in the manufacturing of various consumer products. It is synthesized via partial oxidation of methanol using a mixed oxide iron molybdate catalyst (Fe2(MoO4)3–MoO3). This is one of the standard energy-efficient processes. The mixed oxide iron molybdate catalyst is an attractive commercial catalyst for converting methanol to formaldehyde. However, a detailed phase analysis of each oxide phase and a complete understanding of the catalyst formulation and deactivation studies is required. It is crucial to correctly formulate each oxide phase and influence the synthesis methods precisely. A better tradeoff between support and catalyst and oxygen revival on the catalyst surface is vital to enhance the catalyst’s selectivity, stability, and lifetime. This review presents recent advances on iron molybdate’s catalytic behaviour for formaldehyde production—a deep recognition of the catalyst and its critical role in the processes are highlighted. Finally, the conclusion and prospects are presented at the end.
Immobilization of Camel Liver Catalase on Nanosilver-Coated Cotton Fabric
Authors: Al-Bar Omar A. M. , El-Shishtawy Reda M. , Mohamed Saleh A.
Published: July 2021

Nanoparticles have the advantage of a superior surface area to volume ratio, and thus such materials are useful for enzyme immobilization. A silver nanoparticle coated cotton fabric (AgNp-CF) is used to immobilize camel liver catalase in the present work. The effect of loading levels of AgNp inside cotton fabrics on the immobilization of catalase was investigated. The results revealed that a 6 mL loading level of AgNp precursor (silver nitrate, 2 mM) at pH 8 showed the maximum immobilization efficiency (76%). The morphological properties of the cotton fabric (CF), AgNp-CF and AgNp-CF-catalase were characterized by SEM. The reusability of the immobilized enzyme was tested over ten reuses to show a 67% retained function of its initial activity. Compared with the soluble enzyme’s working pH (6.5), a rather broader working pH (6.5–7.0) was observed for the immobilized catalase. Additionally, the optimum working temperature increased from 30 for the soluble enzyme to 40 °C for the immobilized one, indicating thermal stability. The free and immobilized catalase enzyme’s Km values were 22.5 and 25 mM H2O2, respectively, reflecting the enzyme’s effective properties. The inhibitory effect of metal ions on the enzyme activity was higher toward soluble catalase than the immobilized catalase. This work has developed a method for immobilizing catalase to be useful for several applications.