bluuebunny/crossref_metadata_2025 huggingface dataset:
Physico-Chemical and Sensory Quality of Oven-Dried and Dehydrator-Dried Apples of the Starkrimson, Golden Delicious and Florina Cultivars
Authors: Ghinea Cristina , Prisacaru Ancuta Elena , Leahu Ana
Published: February 2022

Apple fruits are high in phenolic compounds, sugar and dietary fiber content and are rich in malic acid and vitamins, with a significant impact on the organoleptic quality and its health-promoting properties. They can be turned out in value-added product such as apple chips due to the low cost of raw material. The aim of the study was to obtain apple chips, fat-free, healthy, traditionally dried and without added sugar, which can be easily obtained and capitalized economically, as well as the evaluation of their physico-chemical and sensory qualities. The apple chips were produced from three apple cultivars (‘Starkrimson’, ‘Golden Delicious’ and ‘Florina’) by drying the apple fruits in an oven and a dehydrator at 65 °C. To inactivate the browning enzymes, the apple slices were immersed in a solution of lemon salt (4%) for 7 min before drying. Apple chips were sensory-evaluated and relevant parameters were analyzed at defined intervals during storage at room temperature up to 21 days. The water activity (aw) values of apple chip samples dried in the oven ranged from 0.544 to 0.650, while for the samples dried in the dehydrator, aw values were between 0.374 and 0.426. During the storage, the pH of apple chips varied very little, while titratable acidity increased for all samples. Compared with fresh apple slices, it was observed that the total soluble solids (TSS) content of all dried apple chip samples decreased. Color parameters and browning and whitening indexes differed depending on the apple cultivars and dryer type used.
Cationic Curing of Epoxy–Aromatic Matrices for Advanced Composites: The Assets of Radiation Processing
Authors: Ranoux Guillaume , Tataru Gabriela , Coqueret Xavier
Published: February 2022

Cross-linking polymerization of multifunctional aromatic monomers initiated by exposure to high energy radiation continues to be explored as a promising alternative to thermal curing for the production of high-performance composite materials. High-energy radiation processing offers several advantages over thermosetting technology by allowing for fast and out-of-autoclave curing operations and for its adaptability in the manufacturing of large and complex structures at reduced energy costs. The present article covers the basic aspects of radiation curing by cationic polymerization of epoxy resins, providing a status report on recent investigations conducted in our group to improve the properties of epoxy matrices and gain better control over the process for producing composites. A selection of results based on blends prepared with different composition of epoxy aromatics, transfer agents, thermoplastic toughening agents and onium salt initiators exemplifies the importance of the composition on polymerization kinetics and on the properties of resulting materials. The superiority of radiation-triggered polymerization-induced phase separation of thermoplastic additives is emphasized by the obtained morphology of toughened materials. The low initial temperature and fast curing of the reactive blends limits the expansion of phase-separated thermoplastic domains, resulting in an enhancement of the toughness.
Study on the Dynamic Response Characteristics and p–y Curve of Straight and Inclined Pile Groups in Saturated Sands
Authors: Li Yurun , Zhang Jian , Chen Huabin , Qiang Dongfeng , Wang Yongzhi
Published: February 2022

This paper is based on a shaking table test of 2 × 2 straight pile groups and 2 × 2 inclined pile groups in non-liquefied sand and saturated sand with different thicknesses. Under the sine wave with a certain peak acceleration and frequency, the lateral dynamic response characteristics, the distribution law of the maximum bending moment envelope diagram, and the p–y curve of the straight and inclined pile groups are studied. The results show that the bending moment of the straight pile group is 3~4 times that of the inclined pile group at the bottom section of the pile in the 300 mm saturated sand. When the thickness of the saturated sand increases to 380 mm, the maximum bending moment of the straight pile group is 6~7 times that of the inclined pile group at the bottom section of the pile. Through the comparison of indicators, it shows that the inclined pile group can have better bending resistance when subjected to the same lateral dynamic load.
Assessing the State of Structural Foundations in Permafrost Regions by Means of Acoustic Testing
Authors: Syas’ko Vladimir , Shikhov Aleksandr
Published: February 2022

About 60% of the territory of the Russian Federation is covered by permafrost. Additionally, a large share of the country’s mineral and hydrocarbon deposits are located in the Arctic. Climate change that has been happening over the past few decades has had a serious impact on the conditions in which permafrost soils are found. Changes in temperatures in permafrost regions, along with the human impact from mining and processing, have led to an increase in accidents caused by the degradation of permafrost foundations. In this situation, timely detection of the degradation of permafrost foundations plays a pivotal role in ensuring the safe operation of buildings and structures. This article contains a theoretical review and describes the results of an experimental study of whether it is possible to use acoustic testing in solving problems associated with monitoring the state of permafrost foundations. In the course of the study, the relationships between the acoustic characteristics and the deformation and strength characteristics of permafrost soils were analysed. The results of the study made it possible to draw a preliminary conclusion that acoustic testing can be used to solve problems associated with condition monitoring of permafrost foundations.
Minimizing the Late Work of the Flow Shop Scheduling Problem with a Deep Reinforcement Learning Based Approach
Authors: Dong Zhuoran , Ren Tao , Weng Jiacheng , Qi Fang , Wang Xinyue
Published: February 2022

In the field of industrial manufacturing, assembly line production is the most common production process that can be modeled as a permutation flow shop scheduling problem (PFSP). Minimizing the late work criteria (tasks remaining after due dates arrive) of production planning can effectively reduce production costs and allow for faster product delivery. In this article, a novel learning-based approach is proposed to minimize the late work of the PFSP using deep reinforcement learning (DRL) and graph isomorphism network (GIN), which is an innovative combination of the field of combinatorial optimization and deep learning. The PFSPs are the well-known permutation flow shop problem and each job comes with a release date constraint. In this work, the PFSP is defined as a Markov decision process (MDP) that can be solved by reinforcement learning (RL). A complete graph is introduced for describing the PFSP instance. The proposed policy network combines the graph representation of PFSP and the sequence information of jobs to predict the distribution of candidate jobs. The policy network will be invoked multiple times until a complete sequence is obtained. In order to further improve the quality of the solution obtained by reinforcement learning, an improved iterative greedy (IG) algorithm is proposed to search the solution locally. The experimental results show that the proposed RL and the combined method of RL+IG can obtain better solutions than other excellent heuristic and meta-heuristic algorithms in a short time.
Probabilistic Models for Competence Assessment in Education
Authors: López de Aberasturi Gómez Alejandra , Sabater-Mir Jordi , Sierra Carles
Published: February 2022

Probabilistic models of competence assessment join the benefits of automation with human judgment. We start this paper by replicating two preexisting probabilistic models of peer assessment (PG1-bias and PAAS). Despite the use that both make of probability theory, the approach of these models is radically different. While PG1-bias is purely Bayesian, PAAS models the evaluation process in a classroom as a multiagent system, where each actor relies on the judgment of others as long as their opinions coincide. To reconcile the benefits of Bayesian inference with the concept of trust posed in PAAS, we propose a third peer evaluation model that considers the correlations between any pair of peers who have evaluated someone in common: PG-bivariate. The rest of the paper is devoted to a comparison with synthetic data from these three models. We show that PG1-bias produces predictions with lower root mean squared error (RMSE) than PG-bivariate. However, both models display similar behaviors when assessing how to choose the next assignment to be graded by a peer, with an “RMSE decreasing policy” reporting better results than a random policy. Fair comparisons among the three models show that PG1-bias makes the lowest error in situations of scarce ground truths. Nevertheless, once nearly 20% of the teacher’s assessments are introduced, PAAS sometimes exceeds the quality of PG1-bias’ predictions by following an entropy minimization heuristic. PG-bivariate, our new proposal to reconcile PAAS’ trust-based approach with PG1-bias’ theoretical background, obtains a similar percentage of error values to those of the original models. Future work includes applying the models to real experimental data and exploring new heuristics to determine which teacher’s grade should be obtained next to minimize the overall error.
Applied Biosciences: Application of Biological Science and Technology
Authors: Henry Robert J.
Published: February 2022

The 21st century has been defined as the age of biology [...]
“Alpha Females”: Feminist Transgressions in Industrial Music
Authors: Ballet Nicolas
Published: February 2022

Recycled, re-engineered and transformed pornography has often been appropriated by many of the industrial music movement’s female personalities who are invested in an anti-censorship discourse. This contrasts with the dominant form of feminism in the 1970s, which railed against the depiction of all aspects of sexuality. Artists Cosey Fanni Tutti, Lisa Carver, Diamanda Galás, Mïrka Lugosi, Antal Nemeth, Diana Rogerson and Jill Westwood challenged the codes of male domination by reconfiguring gender and overturning the violence perpetrated by men within the industrial movement. Following the artistic and cultural context of the 1970s and 1980s, such issues gave rise to the radical performances that are discussed throughout this article.
Assessment of Human Outdoor Thermal Comfort in a Palm Grove during the Date Palm Phenological Cycle
Authors: Matallah Mohamed Elhadi , Arrar Hicham Fawzi , Faci Mohammed , Mahar Waqas Ahmed , Ben Ratmia Fatima Zahra , Attia Shady
Published: February 2022

Oasis settlements in Saharan lands present a particular model of life for rural individuals’ adaptation to environmental challenges. This study investigated human outdoor thermal comfort in a palm grove of the Tolga region, Algeria, during the phenological cycle of the date palm. Date palms are the primary economic source of the cultivators, who mainly live in houses inside the cultivated area. For this study, an area of 21 hectares with 220 palm trees was selected. The phenological cycle of the date palm was divided into three growth stages, including seasonal variations as well. The cycle covers a period of 8 months from March to November. Therefore, on-site monitoring of the microclimate was performed during March–November 2021. The climatic factors of air temperature and humidity were monitored at an interval of 10 min. The discomfort index based on temperature ranges covering discomfort conditions was used. The results showed that the cultivators work under extreme temperatures for 5.5 months during the phenological cycle. The spring period was more comfortable, while slight to extreme discomfort was observed in the summer and fall seasons, especially between midday and 7 p.m. Temperatures below 25 °C are comfortable for the cultivators; however, severe discomfort occurs at 30 °C or above. Moreover, the humidity was not a dominant factor for discomfort. These findings can be helpful for architects and planners to devise solutions that can fulfil human comfort requirements and date palm cultivar conditions, specifically during extreme thermal situations.
Endoglin and Activin Receptor-like Kinase 1 (Alk1) Modify Adrenomedullin Expression in an Organ-Specific Manner in Mice
Authors: García-Sanmartín Josune , Narro-Íñiguez Judit , Rodríguez-Barbero Alicia , Martínez Alfredo
Published: February 2022

Hereditary hemorrhagic telangiectasia (HHT) is a rare disease characterized by vascular malformations and profuse bleeding. The disease is caused by mutations in the components of the BMP-9 receptor: endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes. Recently, we reported that HHT patients expressed higher serum levels of adrenomedullin (AM) than healthy volunteers; thus, we studied the expression of AM (by enzyme immunoassay, qRT-PCR, immunohistochemistry, and Western blotting) in mice deficient in either one of the receptor components to investigate whether these defects may be the cause of that elevated AM in patients. We found that AM expression is not affected by these mutations in a consistent pattern. On the contrary, in some organs (blood, lungs, stomach, pancreas, heart, kidneys, ovaries, brain cortex, hippocampus, foot skin, and microvessels), there were no significant changes, whereas in others we found either a reduced expression (fat, skin, and adrenals) or an enhanced production of AM (cerebellum and colon). These results contradict our initial hypothesis that the increased AM expression found in HHT patients may be due directly to the mutations, but open intriguing questions about the potential phenotypic manifestations of Eng and Acvrl1 mutants that have not yet been studied and that may offer, in the future, a new focus for research on HHT.
Anti-Osteoporotic Effect of Lactobacillus brevis AR281 in an Ovariectomized Mouse Model Mediated by Inhibition of Osteoclast Differentiation
Authors: Yu Jing , Hang Yiling , Sun Wenni , Wang Guangqiang , Xiong Zhiqiang , Ai Lianzhong , Xia Yongjun
Published: February 2022

Osteoporosis is a global disease characterized by weakened bone microarchitecture, leading to osteoporotic fractures. Estrogen replacement therapy is the traditional treatment for osteoporosis but carries with it an increased risk of cardiac events. In search of a safe and effective treatment, we used Lactobacillus brevis AR281, which has anti-inflammatory properties, to conduct a 7-week experiment, investigating its inhibitory effects on osteoporosis in an ovariectomized (ovx) mouse model. The results demonstrated that AR281 significantly improved bone microarchitecture and biomechanical strength in ovx mice by attenuating bone resorption. AR281 significantly decreased the critical osteoclast activator, the ratio of the receptor activator for nuclear factor kappa B (NF-κB) ligand (RANKL) to osteoprotegerin, and pro-inflammatory osteoclastogenic mediators, such as IL-1, IL-6, and IL-17, which can increase the RANKL expression. Moreover, AR281 modulated intestinal microbiota in ovx mice increased the abundance of Akkermansia, which is responsible for the improvement of gut epithelial barrier integrity. In an in vitro trial, AR281 suppressed the number of osteoclasts differentiated from the osteoclast precursor RAW264.7 cells caused by RANKL through the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6)/NF-κB/nuclear factor of activated T cells c1 (NFATc1) pathway. Therefore, AR281 may be a natural alternative for combating osteoporosis.
Special Issue on Bioinformatics and Machine Learning for Cancer Biology
Authors: Wan Shibiao , Jiang Chunjie , Li Shengli , Fan Yiping
Published: February 2022

Cancer is a leading cause of death worldwide, claiming millions of lives each year [...]
E-Cadherin Orthologues as Substrates for the Serine Protease High Temperature Requirement A (HtrA)
Authors: Bernegger Sabine , Hutterer Evelyn , Zarzecka Urszula , Schmidt Thomas P. , Huemer Markus , Widlroither Isabella , Posselt Gernot , Skorko-Glonek Joanna , Wessler Silja
Published: February 2022

Helicobacter pylori (H. pylori) expresses the serine protease and chaperone High temperature requirement A (HtrA) that is involved in periplasmic unfolded protein stress response. Additionally, H. pylori-secreted HtrA directly cleaves the human cell adhesion molecule E-cadherin leading to a local disruption of intercellular adhesions during pathogenesis. HtrA-mediated E-cadherin cleavage has been observed in response to a broad range of pathogens, implying that it is a prevalent mechanism in humans. However, less is known whether E-cadherin orthologues serve as substrates for bacterial HtrA. Here, we compared HtrA-mediated cleavage of human E-cadherin with murine, canine, and simian E-cadherin in vitro and during bacterial infection. We found that HtrA targeted mouse and dog E-cadherin equally well, whereas macaque E-cadherin was less fragmented in vitro. We stably re-expressed orthologous E-cadherin (Cdh1) in a CRISPR/Cas9-mediated cdh1 knockout cell line to investigate E-cadherin shedding upon infection using H. pylori wildtype, an isogenic htrA deletion mutant, or complemented mutants as bacterial paradigms. In Western blot analyses and super-resolution microscopy, we demonstrated that H. pylori efficiently cleaved E-cadherin orthologues in an HtrA-dependent manner. These data extend previous knowledge to HtrA-mediated E-cadherin release in mammals, which may shed new light on bacterial infections in non-human organisms.
Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models
Authors: Morale Mirian Galliote , Tamura Rodrigo Esaki , Rubio Ileana Gabriela Sanchez
Published: February 2022

Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I− symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.
Screening and Identification of Putative Long Non-Coding RNA in Childhood Obesity: Evaluation of Their Transcriptional Levels
Authors: Cabiati Manuela , Fontanini Martina , Giacomarra Manuel , Politano Gianfranco , Randazzo Emioli , Peroni Diego , Federico Giovanni , Del Ry Silvia
Published: February 2022

Background and Methods: Long non-coding RNAs (LncRNAs) and microRNAs are involved in the pathogenesis of obesity, a multifactorial disease that is characterized by inflammation, cardiometabolic complications, and increased cancer risk among other co-morbidities. The up/down regulation of LncRNAs and microRNAs may play an important role in this condition to identify new diagnostic/prognostic markers. The aim of the study was to identify circulating inflammatory LncRNAs in obese adolescents (n = 54) and to evaluate whether their expression behaved differently compared to normal-weight adolescents (n = 26). To have a more complete insight, the expression of some circulating miRNAs that are linked to obesity (miR-33a, miR-223, miR-142, miR-199a, miR-181a, and miR-4454) were also analyzed. Results: LncRNAs and miRNAs were extracted simultaneously from plasma samples and amplified by Real-Time PCR. Among the 86 LncRNAs that were analyzed with custom pre-designed plates, only four (RP11-347E10.1, RP11-10K16.1, LINC00657, and SNHG12) were amplified in both normal-weight and obese adolescents and only SNHG12 showed significantly lower expression compared to the normal-weight adolescents (p = 0.026). Circulating miRNAs showed a tendency to increase in obese subjects, except for miR-181a expression. LncRNAs and miRNAs correlated with some clinical and metabolic parameters. Conclusions: Our results suggest the importance of these new biomarkers to better understand the molecular mechanisms of childhood obesity and its metabolic disorder.
Secretin Receptor as a Target in Gastrointestinal Cancer: Expression Analysis and Ligand Development
Authors: Klussmeier Anja , Aurich Stefan , Niederstadt Lars , Wiedenmann Bertram , Grötzinger Carsten
Published: February 2022

Secretin was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from the pancreas and liver and delays gastric emptying. In disease, a secretin receptor (SCTR) was found to occur as a splice variant in gastrinoma and pancreatic adenocarcinoma. Overexpression of SCTR has been described for gastrinomas, carcinoid tumors of the lung and cholangiocarcinoma. SCTR therefore is considered a candidate target for molecular tumor imaging as well as for peptide receptor radioligand therapy (PRRT) in a number of oncological indications. The aim of this study was to characterize SCTR expression in esophageal and pancreatic cancer, demonstrating for the first time high SCTR overexpression in these tumor types. In total, 65 of 70 pancreatic ductal adenocarcinoma tissues stained strongly positive for SCTR in immunohistochemistry, as did most of the 151 esophageal cancer samples, with minor influence of grading in both entities. In addition, the aim of this study was to further delineate residues in human secretin that are critical for binding to and activation of human SCTR. For a potential development of short and metabolically stable analogs for clinical use, it was intended to probe the peptide for its capacity to incorporate deletions and substitutions without losing its affinity to SCTR. In a systematic approach, a library of 146 secretin variants containing single amino acid substitutions as well as truncations on either end was tested in β-arrestin2-GFP translocation and fluorescent ligand internalization assays employing high-content analysis, in cAMP assays which run in agonist and antagonist mode, and in radioligand binding. The main structural determinants of SCTR binding and activation were localized to the N-terminus, with His1, Asp3 being among the most sensitive positions, followed by Phe6, Thr7 and Leu10. Aminoterminal truncation caused a rapid decline in receptor activity and most of these variants proved to be partial agonists showing antagonistic properties. In this study, the most potent novel antagonist showed an IC50 of 309 ± 74 nM in the β-arrestin2-GFP translocation assay on human SCTR while remaining a weak partial agonist. Future studies will have to demonstrate the utility of further enhanced secretin analogues as tracers for in vivo imaging and therapy.
Immunotherapy in Advanced Prostate Cancer: Current Knowledge and Future Directions
Authors: López-Campos Fernando , Gajate Pablo , Romero-Laorden Nuria , Zafra-Martín Juan , Juan Manel , Hernando Polo Susana , Conde Moreno Antonio , Couñago Felipe
Published: February 2022

The advent of immunotherapy has revolutionized cancer treatment. Unfortunately, this has not been the case for metastatic castration-resistant prostate cancer (mCRPC), likely due to the heterogeneous and immune-suppressive microenvironment present in prostate cancer. The identification of molecular biomarkers that could predict response to immunotherapy represents one of the current challenges in this clinical scenario. The management of advanced castration-resistant prostate cancer is rapidly evolving and immunotherapy treatments, mostly consisting of immune checkpoint inhibitors combinations, BiTE® (bispecific T-cell engager) immune therapies, and chimeric antigen receptors (CAR) are in development with promising results. This review analyses the current evidence of immunotherapy treatments for mCRPC, evaluating past failures and promising approaches and discussing the directions for future research.
Polycystic Ovarian Syndrome: A Complex Disease with a Genetics Approach
Authors: Nautiyal Himani , Imam Syed Sarim , Alshehri Sultan , Ghoneim Mohammed M. , Afzal Muhammad , Alzarea Sami I. , Güven Emine , Al-Abbasi Fahad A. , Kazmi Imran
Published: February 2022

Polycystic ovarian syndrome (PCOS) is a complex endocrine disorder affecting females in their reproductive age. The early diagnosis of PCOS is complicated and complex due to overlapping symptoms of this disease. The most accepted diagnostic approach today is the Rotterdam Consensus (2003), which supports the positive diagnosis of PCOS when patients present two out of the following three symptoms: biochemical and clinical signs of hyperandrogenism, oligo, and anovulation, also polycystic ovarian morphology on sonography. Genetic variance, epigenetic changes, and disturbed lifestyle lead to the development of pathophysiological disturbances, which include hyperandrogenism, insulin resistance, and chronic inflammation in PCOS females. At the molecular level, different proteins and molecular and signaling pathways are involved in disease progression, which leads to the failure of a single genetic diagnostic approach. The genetic approach to elucidate the mechanism of pathogenesis of PCOS was recently developed, whereby four phenotypic variances of PCOS categorize PCOS patients into classic, ovulatory, and non-hyperandrogenic types. Genetic studies help to identify the root cause for the development of this PCOS. PCOS genetic inheritance is autosomal dominant but the latest investigations revealed it as a multigene origin disease. Different genetic loci and specific genes have been identified so far as being associated with this disease. Genome-wide association studies (GWAS) and related genetic studies have changed the scenario for the diagnosis and treatment of this reproductive and metabolic condition known as PCOS. This review article briefly discusses different genes associated directly or indirectly with disease development and progression.
The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?
Authors: Mitoma Hiroshi , Yamaguchi Kazuhiko , Honnorat Jerome , Manto Mario
Published: February 2022

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.
Indoor Daylight Performances of Optimized Transmittances with Electrochromic-Applied Kinetic Louvers
Authors: Kim Jae-Hyang , Han Seung-Hoon
Published: February 2022

Windows with low visible light transmittance (VLT) and g-values are preferred to reduce the building’s energy consumption. However, low VLT and g-value can create an unpleasant indoor daylight environment. A glass with freely adjustable VLT and g-value as required has been developed and is called smart glass. In this study, the recently developed VLT adjustable smart glass is targeted. Some studies were conducted on the VLT adjustment status of smart windows to create an appropriate indoor lighting environment. Although research on smart glass has been conducted through ecofriendly building certification systems such as LEED in the US, BREEAM in the UK, CASBEE in Japan, and GSEED in South Korea, it was pointed out that there is a limit to creating a uniformity. Therefore, the previous study analyzed the VLT conditions to create a minimal indoor daylight environment. The purpose of this study is to propose and analyze a louver-type electrochromic façade that can create a uniform indoor illuminance. A simulation method was used, and a range of changes in indoor illuminance that could be controlled through an electrochromic louver was derived. The simulation was performed using the Rhino 6′s Grasshopper program based on the Radiance engine. Electrochromic is a class of smart glass with high VLT variable range and durability. The conditions for deriving the optimal daylight environment according to the composition, VLT, and angle of the electrochromic louver were analyzed. The evaluation was made against the criteria of LEED v4.1. Data on the composition, VLT, and angle adjustment of the electrochromic louver that can obtain a high LEED v4.1 daylight score were derived, and organized in tables. Considering the composition and angle, it was found that the daylight environment of the electrochromic louver adjusted with a VLT of 25% to 45% was excellent in composition.
Analytical Reliability Evaluation Framework of Three-Dimensional Engineering Slopes
Authors: Zhang Genbao , Zhu Jianfeng , Chen Changfu , Tang Renhua , Zhu Shimin , Luo Xiao
Published: February 2022

An analytical three-dimensional slope reliability evaluation framework was developed in this work independent of use of numerical simulations. The slope stability analysis was necessarily carried out by utilizing an extended three-dimensional Morgenstern–Price method, which was characterized by analytical formulations and competitive computational efficiency. Incorporation of the presented stability analysis method into response surface methodology led to an effective slope reliability evaluation framework. The applicability and superiority of this framework was examined and validated using a real complicated landslide case reported in practice, and a hypothetical slope example widely adopted in the literature. The impact of correlation coefficients and probability distribution patterns on the slope reliability assessment results was further addressed to derive additional benefits of this framework.
Diffusion Microstructure Imaging to Analyze Perilesional T2 Signal Changes in Brain Metastases and Glioblastomas
Authors: Würtemberger Urs , Diebold Martin , Erny Daniel , Hosp Jonas A. , Schnell Oliver , Reinacher Peter C. , Rau Alexander , Kellner Elias , Reisert Marco , Urbach Horst , Demerath Theo
Published: February 2022

Purpose: Glioblastomas (GBM) and brain metastases are often difficult to differentiate in conventional MRI. Diffusion microstructure imaging (DMI) is a novel MR technique that allows the approximation of the distribution of the intra-axonal compartment, the extra-axonal cellular, and the compartment of interstitial/free water within the white matter. We hypothesize that alterations in the T2 hyperintense areas surrounding contrast-enhancing tumor components may be used to differentiate GBM from metastases. Methods: DMI was performed in 19 patients with glioblastomas and 17 with metastatic lesions. DMI metrics were obtained from the T2 hyperintense areas surrounding contrast-enhancing tumor components. Resected brain tissue was assessed in six patients in each group for features of an edema pattern and tumor infiltration in the perilesional interstitium. Results: Within the perimetastatic T2 hyperintensities, we observed a significant increase in free water (p < 0.001) and a decrease in both the intra-axonal (p = 0.006) and extra-axonal compartments (p = 0.024) compared to GBM. Perilesional free water fraction was discriminative regarding the presence of GBM vs. metastasis with a ROC AUC of 0.824. Histologically, features of perilesional edema were present in all assessed metastases and absent or marginal in GBM. Conclusion: Perilesional T2 hyperintensities in brain metastases and GBM differ significantly in DMI-values. The increased free water fraction in brain metastases suits the histopathologically based hypothesis of perimetastatic vasogenic edema, whereas in glioblastomas there is additional tumor infiltration.
Comparative Effectiveness and Safety of Standard-Dose and Low-Dose Pembrolizumab in Patients with Non-Small-Cell Lung Cancer: A Multi-Institutional Cohort Study in Taiwan
Authors: Chang Kai-Cheng , Shao Shih-Chieh , Chen Hui-Yu , Chan Yuk-Ying , Fang Yueh-Fu
Published: February 2022

Fixed doses at 200 mg of pembrolizumab or 2 mg/kg every 3 weeks are the standard dosages for first- and second-line treatment of non-small-cell lung cancer (NSCLC); however, in clinical practice, patients with NSCLC may receive lower doses of pembrolizumab due to drug product availability or economic factors. To date, the comparative effectiveness and safety of the standard dose and lower doses of pembrolizumab in these patients still remains limited. We conducted a retrospective cohort study by analyzing electronic medical records data from the largest multi-institutional hospital system in Taiwan. Advanced NSCLC patients newly receiving pembrolizumab with or without chemotherapy were included. Patients were classified into: (1) the standard-dose group (≥2 mg/kg), and (2) the low-dose group (<2 mg/kg). We applied inverse probability of treatment weighting (IPTW) to compare the overall survival (OS) and immune-related adverse events (irAEs) between the two treatment groups, and to evaluate the minimum clinically effective dose of pembrolizumab. We included a total of 147 NSCLC patients receiving standard-dose pembrolizumab (mean [range] age: 63.7 [58.0–73.0] years; male: 62.6%; mean [range] body weight: 60.5 [58.0–73.0] kg) and 95 patients receiving low-dose pembrolizumab (mean [range] age: 62.0 [50.0–68.8] years; male: 64.2%; mean [range] body weight: 63.9 [55.0–73.8] kg). After IPTW adjustments, the median OS was similar for both the standard-dose and low-dose pembrolizumab groups (19.3 vs. 14.3 months, log-rank p = 0.15). Also, the rate for all classes of irAEs was similar for both groups. We found that patients with a pembrolizumab dose ≥1.8 mg/kg were associated with better OS than those receiving <1.8 mg/kg. Our findings suggested no significant difference in OS and irAEs between patients receiving pembrolizumab ≥2 mg/kg and <2 mg/kg in clinical practice. A pembrolizumab dose ≥1.8 mg/kg may be the clinically most efficient dose.
Prolonged Exposure to Oxaliplatin during HIPEC Improves Effectiveness in a Preclinical Micrometastasis Model
Authors: Seyfried Nick , Yurttas Can , Burkard Markus , Oswald Benedikt , Tolios Alexander , Herster Franziska , Kauer Joseph , Jäger Tarkan , Königsrainer Ingmar , Thiel Karolin , Quante Markus , Rammensee Hans-Georg , Venturelli Sascha , Schwab Matthias , Königsrainer Alfred , Beckert Stefan , Löffler Markus W.
Published: February 2022

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based HIPEC. Constituting a complex multifactorial treatment, we investigated HIPEC in a preclinical model concerning the elimination of minimal tumor residues, thereby aiming to better understand the size of effects and respective clinical trial results. Patient samples of peritoneal perfusates obtained during HIPEC treatments and oxaliplatin-containing solutions at clinically relevant dosages, conforming with established HIPEC protocols, were assessed regarding their ability to eliminate modelled ~100 µm thickness cancer cell layers. Impedance-based real-time cell analysis and classical end-point assays were used. Flow cytometry was employed to determine the effect of different HIPEC drug solvents on tumor cell properties. Effectiveness of peritoneal perfusate patient samples and defined oxaliplatin-containing solutions proved limited but reproducible. HIPEC simulations for 30 min reduced the normalized cell index below 50% with peritoneal perfusates from merely 3 out of 9 patients within 72 h, indicating full-thickness cytotoxic effects. Instead, prolonging HIPEC to 1 h enhanced these effects and comprised 7 patients’ samples, while continuous drug exposure invariably resulted in complete cell death. Further, frequently used drug diluents caused approximately 25% cell size reduction within 30 min. Prolonging oxaliplatin exposure improved effectiveness of HIPEC to eliminate micrometastases in our preclinical model. Accordingly, insufficient penetration depth, short exposure time, and the physicochemical impact of drug solvents may constitute critical factors.
A Deep Learning Model for Cervical Cancer Screening on Liquid-Based Cytology Specimens in Whole Slide Images
Authors: Kanavati Fahdi , Hirose Naoki , Ishii Takahiro , Fukuda Ayaka , Ichihara Shin , Tsuneki Masayuki
Published: February 2022

Liquid-based cytology (LBC) for cervical cancer screening is now more common than the conventional smears, which when digitised from glass slides into whole-slide images (WSIs), opens up the possibility of artificial intelligence (AI)-based automated image analysis. Since conventional screening processes by cytoscreeners and cytopathologists using microscopes is limited in terms of human resources, it is important to develop new computational techniques that can automatically and rapidly diagnose a large amount of specimens without delay, which would be of great benefit for clinical laboratories and hospitals. The goal of this study was to investigate the use of a deep learning model for the classification of WSIs of LBC specimens into neoplastic and non-neoplastic. To do so, we used a dataset of 1605 cervical WSIs. We evaluated the model on three test sets with a combined total of 1468 WSIs, achieving ROC AUCs for WSI diagnosis in the range of 0.89–0.96, demonstrating the promising potential use of such models for aiding screening processes.
More than a Bubble: Extracellular Vesicle microRNAs in Head and Neck Squamous Cell Carcinoma
Authors: Panvongsa Wittaya , Pegtel D. Michiel , Voortman Jens
Published: February 2022

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a pivotal regulatory role in a broad variety of biological processes. Dysregulation of miRNAs is associated with several human diseases, particularly cancer. Extracellular vesicles (EVs) are crucial components in intercellular communication. As part of the cargo of EVs, miRNAs are involved in EV-mediated cell-to-cell interactions, including promotion or suppression of tumor development. The knowledge on the molecular mechanisms and clinical importance of EV-miRNAs in head and neck squamous cell carcinoma (HNSCC) has rapidly grown over the past years. In the present review, the current understanding regarding the effect of EV-miRNAs on HNSCC tumorigenesis is summarized, which includes effects on tumor proliferation, angiogenesis, invasion and metastasis, the tumor microenvironment, immune modulation, and treatment resistance. EV-miRNA-based biomarkers in liquid biopsies such as blood and saliva may open up new possibilities for employing EV-miRNAs for screening and early diagnostics as well as disease monitoring. Future perspectives include the promise of EV-miRNAs as a novel therapeutic target.
The Therapeutic Potential of FLASH-RT for Pancreatic Cancer
Authors: Okoro Chidi M. , Schüler Emil , Taniguchi Cullen M.
Published: February 2022

Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.
Comparison of Immune Response Assessment in Colon Cancer by Immunoscore (Automated Digital Pathology) and Pathologist Visual Scoring
Authors: Boquet Isabelle , Kassambara Alboukadel , Lui Alfred , Tanner Alicia , Latil Marie , Lovera Yoann , Arnoux Fanny , Hermitte Fabienne , Galon Jérôme , Catteau Aurelie
Published: February 2022

Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted digital pathology. The strong prognostic impact of the immune response, as assessed by IS, has been widely validated and IS can help to refine treatment decision making in early CC. In this study, we compared pathologist visual scoring to IS. Four pathologists evaluated tumor specimens from 50 early-stage CC patients and classified the CD3+ and CD8+ T-cell densities at the tumor site (T-score) into 2 (High/Low) categories. Individual and overall pathologist scoring of immune response (before and after training for immune response assessment) were compared to the reference IS (High/Low). Pathologists’ disagreement with the reference IS was observed in almost half of the cases (48%) and training only slightly improved the accuracy of pathologists’ classification. Agreement among pathologists was minimal with a Kappa of 0.34 and 0.57 before and after training, respectively. The standardized IS assay outperformed expert pathologist assessment in the clinical setting.
The Use of miRNAs in Predicting Response to Neoadjuvant Therapy in Oesophageal Cancer
Authors: Lang Cameron C. J. , Lloyd Megan , Alyacoubi Said , Rahman Saqib , Pickering Oliver , Underwood Tim , Breininger Stella P.
Published: February 2022

Oesophageal cancer (OC) is the ninth most common cancer worldwide. Patients receive neoadjuvant therapy (NAT) as standard of care, but less than 20% of patients with oesophageal adenocarcinoma (OAC) or a third of oesophageal squamous cell carcinoma (OSCC) patients, obtain a clinically meaningful response. Developing a method of determining a patient’s response to NAT before treatment will allow rational treatment decisions to be made, thus improving patient outcome and quality of life. (1) Background: To determine the use and accuracy of microRNAs as biomarkers of response to NAT in patients with OAC or OSCC. (2) Methods: MEDLINE, EMBASE, Web of Science and the Cochrane library were searched to identify studies investigating microRNAs in treatment naïve biopsies to predict response to NAT in OC patients. (3) Results: A panel of 20 microRNAs were identified as predictors of good or poor response to NAT, from 15 studies. Specifically, miR-99b, miR-451 and miR-505 showed the strongest ability to predict response in OAC patients along with miR-193b in OSCC patients. (4) Conclusions: MicroRNAs are valuable biomarkers of response to NAT in OC. Research is needed to understand the effects different types of chemotherapy and chemoradiotherapy have on the predictive value of microRNAs; studies also require greater standardization in how response is defined.
Radiolabeled Somatostatin Analogs—A Continuously Evolving Class of Radiopharmaceuticals
Authors: Fani Melpomeni , Mansi Rosalba , Nicolas Guillaume P. , Wild Damian
Published: February 2022

Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST2) being the predominantly and most frequently expressed. PET/CT imaging with 68Ga-labeled SST agonists, e.g., 68Ga-DOTA-TOC (SomaKit TOC®) or 68Ga-DOTA-TATE (NETSPOT®), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts 177Lu-DOTA-TOC or 177Lu-DOTA-TATE (Lutathera®). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST2 antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic α-emitters, such as 225Ac, or β- and Auger electrons, such as 161Tb, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with β--emitters.