bluuebunny/crossref_metadata_2025 huggingface dataset:
Crosstalk between Heme Oxygenase-1 and Iron Metabolism in Macrophages: Implications for the Modulation of Inflammation and Immunity
Authors: de Oliveira Joseana , Denadai Marina B. , Costa Diego L.
Published: April 2022

Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the degradation of heme, releasing equimolar amounts of carbon monoxide (CO), biliverdin (BV), and iron. The anti-inflammatory and antioxidant properties of HO-1 activity are conferred in part by the release of CO and BV and are extensively characterized. However, iron constitutes an important product of HO-1 activity involved in the regulation of several cellular biological processes. The macrophage-mediated recycling of heme molecules, in particular those contained in hemoglobin, constitutes the major mechanism through which living organisms acquire iron. This process is finely regulated by the activities of HO-1 and of the iron exporter protein ferroportin. The expression of both proteins can be induced or suppressed in response to pro- and anti-inflammatory stimuli in macrophages from different tissues, which alters the intracellular iron concentrations of these cells. As we discuss in this review article, changes in intracellular iron levels play important roles in the regulation of cellular oxidation reactions as well as in the transcriptional and translational regulation of the expression of proteins related to inflammation and immune responses, and therefore, iron metabolism represents a potential target for the development of novel therapeutic strategies focused on the modulation of immunity and inflammation.
IoT System for Detecting the Condition of Rotating Machines Based on Acoustic Signals
Authors: Radonjić Milutin , Vujnović Sanja , Krstić Aleksandra , Zečević Žarko
Published: April 2022

Modern predictive maintenance techniques have been significantly improved with the development of Industrial Internet of Things solutions which have enabled easier collection and analysis of various data. Artificial intelligence-based algorithms in combination with modular interconnected architecture of sensors, devices and servers, have resulted in the development of intelligent maintenance systems which outperform most traditional machine maintenance approaches. In this paper, a novel acoustic-based IoT system for condition detection of rotating machines is proposed. The IoT device designed for this purpose is mobile and inexpensive and the algorithm developed for condition detection consists of a combination of discrete wavelet transform and neural networks, while a genetic algorithm is used to tune the necessary hyperparameters. The performance of this system has been tested in a real industrial setting, on different rotating machines, in an environment with strong acoustic pollution. The results show high accuracy of the algorithm, with an average F1 score of around 0.99 with tuned hyperparameters.
Quantitative Seismic Geomorphology of Four Different Types of the Continental Slope Channel Complexes in the Canterbury Basin, New Zealand
Authors: Harishidayat Dicky , Raja Wasif Rehman
Published: April 2022

Modern marine seismic reflection data have allowed for the study of the morphology of submarine channels in a 3D perspective. This study presents a quantitative analysis of continental slope channel complexes morphology within the Canterbury Basin (New Zealand). It aims to characterize the morphology and seismic facies of submarine channels to better understand their formative sedimentary processes, paleoenvironment, and petroleum prospectivity. Submarine channel morphometric parameters are measured at 150 m intervals perpendicular to the axis of channels complexes. Based on the morphology analysis of erosional surfaces and seismic facies of channel complexes filling deposits, four types of continental slope channel complexes are found in the study area. These are vertical migrating channels, lateral migrating channels, V-shaped channels, and U-shaped channels. Furthermore, our work shows that channel morphometry varies over distances of 0.1 to 14 km in this continental slope system. These changes indicate a combination of submarine gravity flow process and channel wall collapse responsible for the development of continental slope channel complexes. Regionally, the evolution of the channels indicated less significant regional plate movement. This quantitative seismic geomorphology approach of characterizing submarine channels system has broader applications for better interpretation of paleoenvironment and petroleum prospectivity within frontier basins.
Research on the Crane Safety Assessment Method Based on the Cloud Model and ICWGT
Authors: Zhu Ze , Luo Yangyi , Xiao Hanbin , Xiong Chuchen , Chen Chentong
Published: April 2022

In crane safety assessment, both quantitative and qualitative indicators are inevitably influenced by the subjective influence of the evaluator, which is unfavorable to the objective requirements of safety assessment. In response to these problems, this study proposes a crane safety assessment method based on the cloud model and the improved combination weighting method of game theory (ICWGT). This evaluation method constructs a multi-level assessment index system for crane safety status by selecting suitable indicators in layers and groups, according to the crane safety assessment rules, and gives a method for constructing the cloud model of the commentary set, the selection and derivation of the membership function, and the determination of the fuzzy relationship matrix. When performing fuzzy synthetic calculations based on the cloud model, the synthetic operator enhances the effect of expectation on entropy and makes the cloud image significantly deformed; this method uses a fine-tuned synthetic operator to improve the algorithm. Compared with the traditional crane fuzzy synthesis assessment method, this method combines the cloud model and ICWGT to achieve finding a balance between expert experience and sample data information, calculating the combined optimization weights of each index and component layer by layer. In order to verify the effectiveness of the method, we take the metal structure system of the shipyard portal crane as an example to explore the applicability of the method in crane safety assessment. The results show that the assessment method can accurately reflect the safety level of the crane and can provide reference material for crane safety assessment.
Antioxidant and 5α-Reductase Inhibitory Activity of Momordica charantia Extract, and Development and Characterization of Microemulsion
Authors: Trakoolthong Patarapan , Ditthawuttikul Naphatsorn , Sivamaruthi Bhagavathi Sundaram , Sirilun Sasithorn , Rungseevijitprapa Wandee , Peerajan Sartjin , Chaiyasut Chaiyavat
Published: April 2022

Momordica charantia (M. charantia) is rich in flavonoids, which possess a strong antioxidant capacity and may help prevent hair loss. This study aims to develop the microemulsion of M. charantia with antioxidant activity and 5α-reductase (5aR) inhibitory activity. The total phenolic content (TPC), antioxidant activity, and 5aR inhibitory activity of ethanolic and aqueous extracts of the fruit were investigated. The preparation of M. charantia extract-loaded microemulsion (MELM) was optimized and characterized the MELM. The aqueous extract of M. charantia fruit flesh displayed a TPC of 780.75 ± 24.82 mg Gallic acid equivalence/g of extract. ABTS (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), DPPH (2,2-diphenyl-1-picrylhydrazyl), and nitric oxide (NO) radical scavenging activities were observed in all the extracts. About 0.461 ± 0.003 mg finasteride equivalence/g of extract of 5aR inhibitory activity was detected in the aqueous extract of the inner tissue of M. charantia fruit. Based on NO radical scavenging and 5aR inhibitory activity, an aqueous extract of the inner tissue (pericarp with seed) of M. charantia fruit was used to prepare the MELM. The MELM was prepared using a different ratio of tween 80 and ethanol as Smix. The results showed that the 1:1 ratio of tween 80: ethanol produced microemulsion of an optimum size, zeta potential, and polydispersity index. The MELM samples were stored at 5, 30, and 40 °C for 12 weeks, and the stability was assessed. The results revealed that the size, zeta potential, and polydispersity index of the formulated MELM remained unchanged during the investigated time. This study primarily reports the 5aR inhibitory activity of M. charantia extract and the development of microemulsion. The prepared MELM could be further developed into cosmetic or pharmacological preparations to manage hair loss.
Whitening CNN-Based Rotor System Fault Diagnosis Model Features
Authors: Miettinen Jesse , Nikula Riku-Pekka , Keski-Rahkonen Joni , Fagerholm Fredrik , Tiainen Tuomas , Sierla Seppo , Viitala Raine
Published: April 2022

Intelligent fault diagnosis (IFD) models have the potential to increase the level of automation and the diagnosis accuracy of machine condition monitoring systems. Many of the latest IFD models rely on convolutional layers for feature extraction from vibration data. The majority of these models employ batch normalisation (BN) for centring and scaling the input for each neuron. This study includes a novel examination of a competitive approach for layer input normalisation in the scope of fault diagnosis. Network deconvolution (ND) is a technique that further decorrelates the layer inputs reducing redundancy among the learned features. Both normalisation techniques are implemented on three common 1D-CNN-based fault diagnosis models. The models with ND mostly outperform the baseline models with BN in three experiments concerning fault datasets from two different rotor systems. Furthermore, the models with ND significantly outperform the baseline models with BN in the common CWRU bearing fault tests with load domain shifts, if the data from drive-end and fan-end sensors are employed. The results show that whitened features can improve the performance of CNN-based fault diagnosis models.
Ku-Band CMOS Power Amplifier with Three-Stack Power Stage to Enhance Output Power and Efficiency
Authors: Yang Junhyuk , Lee Jaeyong , Jang Seongjin , Jeong Hayeon , Kim Choulyoung , Park Changkun
Published: April 2022

In this study, we proposed a power amplifier structure with improved efficiency while securing high output power. First, the characteristics of the common-source and stack structures were investigated. In particular, the output power and output impedance characteristics of the stack structure were analyzed compared with the common-source structure. A common-source structure was applied to the driver stage to minimize dc power consumption, and a stack structure was applied to the power stage to ensure high output power. In order to verify the proposed structure, a Ku-band power amplifier was designed using the 65-nm RF CMOS process that provides nine metal layers. At the operating frequency of 15 GHz, saturation output power and maximum power-added efficiency were confirmed to be 22.1 dBm and 17.2%, respectively.
Molecular Dynamics Simulation of Bulk Cu Material under Various Factors
Authors: Trong Dung , Long Van , Ţălu Ştefan
Published: April 2022

In this paper, the molecular dynamics (MD) method was used to study the influence of factors of bulk Cu material, such as the effect of the number of atoms (N) at temperature (T), T = 300 K, temperature T, and annealing time (t) with Cu5324 on the structure properties, phase transition, and glass temperature Tg of the bulk Cu material. The obtained results showed that the glass transition temperature (Tg) of the bulk Cu material was Tg = 652 K; the length of the link for Cu-Cu had a negligible change; r = 2.475 Å; and four types of structures, FCC, HCP, BCC, Amor, always existed. With increasing the temperature the FCC, HCP, and BCC decrease, and Amorphous (Amor) increases. With an increasing number of atoms and annealing time, the FCC, HCP, and BCC increased, and Amor decreased. The simulated results showed that there was a great influence of factors on the structure found the gradient change, phase transition, and successful determination of the glass temperature point above Tg of the bulk Cu material. On the basis of these results, essential support will be provided for future studies on mechanical, optical, and electronic properties.
Chemical Speciation of Antarctic Atmospheric Depositions
Authors: Bertinetti Stefano , Berto Silvia , Malandrino Mery , Vione Davide , Abollino Ornella , Conca Eleonora , Marafante Matteo , Annibaldi Anna , Truzzi Cristina , Illuminati Silvia
Published: April 2022

Both inorganic and organic complexation of metal cations in clouds or rainwater is essential to describe the global biogeochemical cycles of metals, because complexation can increase metal solubility and stabilize some of their oxidation states. Within a Project of the National Research Program in the Antarctica, atmospheric depositions were collected during the Antarctic summer 2017–2018 in eight sampling sites. The main ionic components occurring in water extracts of these atmospheric depositions were quantified, and a chemical model was applied, in order to identify the main species occurring in the samples. The speciation study showed that most cations were present as aquoions, except for Fe, which occurred predominantly in hydrolytic forms. The model allowed us to foresee the effect of an increase in the concentration levels of all the solution components, by simulating what could happen when the original particles act as cloud condensation nuclei. The role of inorganic anions as complexing agents becomes important when increasing total concentrations of all the solutes by a factor >100 compared to the water extracts, while the presence of organic acids acquires significance for samples having organic acid concentration higher than 10−5 mol L−1. Moreover, it was possible to pinpoint the formation constants that mostly affect the chemical system, and to gain insight into the behavior of metals in wet depositions, which is fundamental knowledge in atmospheric photochemistry studies and in the modeling of the biogeochemical cycles of metal cations.
Identifying Anode and Cathode Contributions in Li-Ion Full-Cell Impedance Spectra
Authors: Heinrich Marco , Wolff Nicolas , Seitz Steffen , Krewer Ulrike
Published: April 2022

Measured impedance spectra of Li-ion battery cells are often reproduced with equivalent circuits or physical models to determine losses due to charge transfer processes at the electrodes. The identified model parameters can usually not readily or unambiguously be assigned to the anode and the cathode. A new measurement method is presented that enables the assignment of features of impedance spectra of full cells to single electrodes. To this end, temperature gradients are imprinted perpendicular to the electrode layers of a single-layered Li-ion battery cell while impedance spectra are measured. The method exploits different dependences of the charge transfer processes at the electrodes on temperature. An equivalent circuit model of RC-elements and the effect of temperature on the related electrode properties is discussed to demonstrate the feasibility of the method. A reliable assignment of the change of impedance spectra to the electrode processes is shown to be possible. The assignment can be used to identify if changes in an impedance spectrum originate from the anode or the cathode.
Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
Authors: Ilic Viktoria K. , Egorova Olga , Tsang Ernest , Gatto Milena , Wen Yi , Zhao Yong , Sheng Yi
Published: April 2022

The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain.
Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer
Authors: Liu Yaxuan , Helgadottir Hafdis T. , Kharaziha Pedram , Choi Jungmin , López-Giráldez Francesc , Mane Shrikant M. , Höiom Veronica , Juhlin Carl Christofer , Larsson Catharina , Bajalica-Lagercrantz Svetlana
Published: April 2022

Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17–35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.
Evaluation of the Surface Roughness of Bulk-Fill Composite Resins after Submission to Acidic and Abrasive Aggressions
Authors: Tărăboanță Ionuț , Buhățel Dan , Brînză Concită Corina Alexandra , Andrian Sorin , Nica Irina , Tărăboanță-Gamen Andra Claudia , Brânzan Răzvan , Stoleriu Simona
Published: April 2022

This in vitro study aimed to assess the erosive effect of hydrochloric acid in association with toothbrushing procedure on the surface condition of three bulk-fill composite resins used for direct restoration. A total of 480 samples (160 from each composite resin): X-tra Fil (VOCO, Germany)—group A, Filtek Bulk-fill Posterior (3M-ESPE, St. Paul, MN, USA)—group B, G-aenial Posterior (GC Japan)—group C were prepared, submitted to chemical attack for 60 min with hydrochloric acid 30% and, subsequently, submitted to the abrasive effect of toothbrushing using 10,000 cycles with medium and hard bristles, at three different times (immediately and after 30 min after acid attack or without any chemical attack). The surface roughness of the samples was measured using a noncontact profilometer (Dektak XT, Bruker, Billerica, MA, USA). The values were analyzed using ANOVA and post hoc Bonferroni tests, with a p < 0.05. Chemical attack for 60 min associated with one year of toothbrushing with toothbrushes having medium or hard bristles increase the surface roughness of tested bulk-fill composite resins. No differences were recorded between toothbrushing with medium or firm bristles immediately or 30 min after acidic challenge for each of the three bulk-fill composite resins. Exposure to hydrochloric acid determines no effect on surface roughness of bulk-fill composite resins.
Evaluation of the Interaction of Cinacalcet with Calf Thymus dsDNA: Use of Electrochemical, Spectrofluorimetric, and Molecular Docking Methods
Authors: Erkmen Cem , Unal Didem Nur , Kurbanoglu Sevinc , Eren Gokcen , Uslu Bengi
Published: April 2022

The binding of drugs to DNA plays a critical role in new drug discovery and is important for designing better drugs. In this study, the interaction and binding mode of calf-thymus double-stranded deoxyribonucleic acid (ct-dsDNA) with cinacalcet (CIN) from the calcimimetic drug that mimics the action of calcium on tissues group were investigated. The interaction of CIN with ct-dsDNA was observed by the differential pulse voltammetry (DPV) technique by following the decrease in electrochemical oxidation signals to deoxyguanosine and adenosine. A competitive study was performed on an indicator, methylene blue, to investigate the interaction of the drug with ct-dsDNA by fluorescence spectroscopy. Interaction studies have shown that the binding mode for the interaction of CIN with ct-dsDNA could be groove-binding. According to the results obtained, the binding constant values were found to be 6.30 × 104 M−1 and 3.16 × 105 M−1, respectively, at 25 °C as obtained from the cyclic voltammetry (CV) and spectroscopic techniques. Possible molecular interactions of CIN with dsDNA were explored via molecular docking experiments. The docked structure indicated that CIN could fit well into the minor groove of the DNA through H-bonding and π-π stacking contact with CIN.
“First Catch Your Hare”: Some Difficulties with, and Contextual Factors in, Understanding (In)Appropriate Workplace Relationships
Authors: Duck Steve
Published: April 2022

The article considers the contextual factors that lead to descriptions of workplace relationships as appropriate and inappropriate. It reviews viewpoint, context of activity, and the tension between social and personal relationships in environments based on task completion. If relationships are the sum of series of interactions, then interactions must be judged in context before compilation. The vantage point of viewers will complicate these assessments, as will the rhetorical purpose of the reporter.
Application of Iron Ore Tailings and Phosphogypsum to Create Artificial Rockfills Used in Rock-Filled Concrete
Authors: Han Guoxuan , Zhang Jingbin , Sun Haojie , Shen Dejian , Wu Zhoutong , An Xuehui , Meye Serges Mendomo , Huang Yongmou
Published: April 2022

Rock-filled concrete (RFC) has good performance in terms of energy savings, cost reduction, and CO2 emissions as a novel massive concrete construction technology. There have been studies into replacing natural rocks in RFC with large blocks of solid waste, and this method has been used on several construction sites. However, the granular and powdery solid waste utilized in RFC is limited, as a consequence of the special requirement of self-compacting concrete (SCC) in RFC. The goal of this paper is to increase the amount of granular and powdery solid waste in RFC. Iron ore tailing (IOT) and phosphogypsum (PG) were used separately as granular and powdery solid waste. The modified PG, ground blast-furnace slag (GBFS), steel slag, and cement clinker are combined to form parathion gypsum slag cement in a specific proportion, with the ratio of PG, GBFS, steel slag, and cement being 47:47:2:2. To replace the natural rocks in RFC, artificial rockfills made of IOT and parathion gypsum slag cement are used to increase the dosage of solid waste. The artificial rockfills were formed using three methods: compressing, roller compacting, and normal vibrating. When the compressive strength and material costs of the three types of artificial rockfills are compared, the compressing method is the best for maximizing the IOT. In artificial rockfills, the mass fraction of granular solid waste is 83.3%, and the mass fraction of total solid waste is 99.3%.
Identification of Urban Functional Areas Based on the Multimodal Deep Learning Fusion of High-Resolution Remote Sensing Images and Social Perception Data
Authors: Xie Lijian , Feng Xiuli , Zhang Chi , Dong Yuyi , Huang Junjie , Liu Kaikai
Published: April 2022

As the basic spatial unit of urban planning and management, it is necessary to know the distribution status of urban functional areas in time. Due to the complexity of urban land use, it is difficult to identify the urban functional areas using only remote sensing images. Social perception data can provide additional information for the identification of urban functional areas. However, the sources of remote sensing data and social perception data differ, with some differences in data forms. Existing methods cannot comprehensively consider the characteristics of these data for functional area identification. Therefore, in this study, we propose a multimodal deep learning method with an attention mechanism to fully utilize the data features of these two modalities and apply it to the recognition of urban functional areas. First, the pre-processed remote sensing images, points of interest, and building footprint data are divided into block-based target units of features by the road network. Next, the remote sensing image features and social perception data features of the target unit are extracted separately using a two-branch convolutional network. Finally, features are extracted sequentially along two separate dimensions, being channel and spatial, to generate an attention weight map for the identification and classification mapping of urban functional areas. The model framework was finally applied to the Ningbo dataset for testing, and the recognition accuracy was above 93%. The experimental results deduce, as a whole, that the prediction performance of the deep multimodal fusion model framework with an attention mechanism is comparatively superior to other traditional methods. It can provide a reference for the classification of urban land use and provide data support for urban planning and management.
Arginine Methyltransferase PRMT7 Deregulates Expression of RUNX1 Target Genes in T-Cell Acute Lymphoblastic Leukemia
Authors: Oksa Laura , Mäkinen Artturi , Nikkilä Atte , Hyvärinen Noora , Laukkanen Saara , Rokka Anne , Haapaniemi Pekka , Seki Masafumi , Takita Junko , Kauko Otto , Heinäniemi Merja , Lohi Olli
Published: April 2022

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with no well-established prognostic biomarkers. We examined the expression of protein arginine methyltransferases across hematological malignancies and discovered high levels of PRMT7 mRNA in T-ALL, particularly in the mature subtypes of T-ALL. The genetic deletion of PRMT7 by CRISPR-Cas9 reduced the colony formation of T-ALL cells and changed arginine monomethylation patterns in protein complexes associated with the RNA and DNA processing and the T-ALL pathogenesis. Among them was RUNX1, whose target gene expression was consequently deregulated. These results suggest that PRMT7 plays an active role in the pathogenesis of T-ALL.
EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures
Authors: Peindl Matthias , Göttlich Claudia , Crouch Samantha , Hoff Niklas , Lüttgens Tamara , Schmitt Franziska , Pereira Jesús Guillermo Nieves , May Celina , Schliermann Anna , Kronenthaler Corinna , Cheufou Danjouma , Reu-Hofer Simone , Rosenwald Andreas , Weigl Elena , Walles Thorsten , Schüler Julia , Dandekar Thomas , Nietzer Sarah , Dandekar Gudrun
Published: April 2022

Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRASG12C or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRASG12C inhibitor in KRASG12C mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
How Do the Outcomes of Radiation-Associated Pelvic and Sacral Bone Sarcomas Compare to Primary Osteosarcomas following Surgical Resection?
Authors: Lazarides Alexander L. , Burke Zachary D. C. , Gundavda Manit K. , Novak Rostislav , Ghert Michelle , Wilson David A. , Rose Peter S. , Wong Philip , Griffin Anthony M. , Ferguson Peter C. , Wunder Jay S. , Houdek Matthew T. , Tsoi Kim M.
Published: April 2022

Radiation-associated sarcoma of the pelvis and/or sacrum (RASB) is a rare but challenging disease process associated with a poor prognosis. We hypothesized that patients with RASB would have worse surgical and oncologic outcomes than patients diagnosed with primary pelvic or sacral bone sarcomas. This was a retrospective, multi-institution, comparative analysis. We reviewed surgically treated patients from multiple tertiary care centers who were diagnosed with a localized RASB. We also identified a comparison group including all patients diagnosed with a primary localized pelvic or sacral osteosarcoma/spindle cell sarcoma of bone (POPS). There were 35 patients with localized RASB and 73 patients with POPS treated with surgical resection. Patients with RASB were older than those with POPS (57 years vs. 38 years, p < 0.001). Patients with RASB were less likely to receive chemotherapy (71% for RASB vs. 90% for POPS, p = 0.01). Seventeen percent of patients with RASB died in the perioperative period (within 90 days of surgery) as compared to 4% with POPS (p = 0.03). Five-year disease-specific survival (DSS) (31% vs. 54% p = 0.02) was worse for patients with RASB vs. POPS. There was no difference in 5-year local recurrence free survival (LRFS) or metastasis free survival (MFS). RASB and POPS present challenging disease processes with poor oncologic outcomes. Rates of perioperative mortality and 5-year DSS are worse for RASB when compared to POPS.
Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA)
Authors: Joerger Markus , Metaxas Yannis , Zaman Khalil , Michielin Olivier , Mach Nicolas , Bettini Adrienne , Schmitt Andreas M. , Cantoni Nathan , Caspar Clemens B. , Stettler Sonja , Malval Roma , Pless Miklos , Britschgi Christian , Renner Christoph , Koeberle Dieter , Schulz Jessica D. , Kopp Christoph , Hayoz Stefanie , Stathis Anastasios , von Moos Roger
Published: April 2022

Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.
Intratumoral Platelets: Harmful or Incidental Bystanders of the Tumor Microenvironment?
Authors: Le Chapelain Ophélie , Ho-Tin-Noé Benoît
Published: April 2022

The tumor microenvironment (TME) has gained considerable interest because of its decisive impact on cancer progression, response to treatment, and disease recurrence. The TME can favor the proliferation, dissemination, and immune evasion of cancer cells. Likewise, there is accumulating evidence that intratumoral platelets could favor the development and aggressiveness of solid tumors, notably by influencing tumor cell phenotype and shaping the vascular and immune TME components. Yet, in contrast to other tumor-associated cell types like macrophages and fibroblasts, platelets are still often overlooked as components of the TME. This might be due, in part, to a deficit in investigating and reporting the presence of platelets in the TME and its relationships with cancer characteristics. This review summarizes available evidence from clinical and animal studies supporting the notion that tumor-associated platelets are not incidental bystanders but instead integral and active components of the TME. A particular emphasis is given to the description of intratumoral platelets, as well as to the functional consequences and possible mechanisms of intratumoral platelet accumulation.
Alternative Lengthening of Telomeres and Mediated Telomere Synthesis
Authors: Hou Kailong , Yu Yuyang , Li Duda , Zhang Yanduo , Zhang Ke , Tong Jinkai , Yang Kunxian , Jia Shuting
Published: April 2022

Telomeres are DNA–protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchymal and neuroepithelial origin, and ALT also frequently occurs during experimental cellular immortalization of mesenchymal cells. ALT is a process that relies on homologous recombination (HR) to elongate telomeres. However, some processes in the ALT mechanism remain poorly understood. Here, we review the most recent understanding of ALT mechanisms and processes, which may help us to better understand how the ALT pathway is activated in cancer cells and determine the potential therapeutic targets in ALT pathway-stabilized tumors.
Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma
Authors: Wan Peixing , Huang Siyu , Luo Yanting , Deng Caibin , Zhou Jiajian , Long Erping , Zhuo Yehong
Published: April 2022

Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management.
Ratiometric Fluorescence Probe of Vesicle-like Carbon Dots and Gold Clusters for Quantitation of Cholesterol
Authors: Hu Shun-Ruei , Yang Chang-Ruei , Huang Yu-Fen , Huang Chih-Ching , Chen Yen-Ling , Chang Huan-Tsung
Published: April 2022

We report a facile method for the preparation of vesicle-like carbon dots (VCDs) via dry-heating of surfactant solutions. Like most reported CDs, the VCDs possess interesting fluorescence properties. Entrapment of enzymes and gold nanoclusters (AuNCs) inside the VCDs allows for the development of fluorescent probes for the quantitation of various substrates, with the advantages of high sensitivity and selectivity. The AuNCs act as a probe, and the VCDs as an internal standard confine the AuNCs, enzyme, and analyte to provide high local concentrations to enhance the assay sensitivity. In this study, we employed cholesterol oxidase (ChOX) as a model enzyme for the quantitation of cholesterol. The as-formed hydrogen peroxide through the enzyme reaction inside the VCDs causes fluorescence quenching of AuNCs (excitation/emission wavelengths of 320/670 nm), but not that of the VCDs (excitation/emission wavelengths of 320/400 nm). To improve the sensitivity and linearity, the fluorescence ratios of AuNCs/VCDs are plotted against analyte concentration. The present ratiometric fluorescent method allows for the detection of hydrogen peroxide over the concentration range of 1–100 μM, with a detection limit of 0.673 μM, and cholesterol concentrations ranging from 5 to 100 μM, with a detection limit of 2.8 μM. The practicality of this fluorescent method has been further validated by evaluating cholesterol levels in human serum samples with sufficient accuracy and recovery, revealing its great prospective in diagnosis and biomedical applications.
Urinary Protein Array Analysis to Identify Key Inflammatory Markers in Children with IgA Vasculitis Nephritis
Authors: Marro Julien , Chetwynd Andrew J. , Wright Rachael D. , Dliso Silothabo , Oni Louise
Published: April 2022

Chronic kidney disease is a recognised complication of immunoglobulin A vasculitis, (IgAV; formerly Henoch–Schonlein purpura—HSP). The pathophysiology of IgAV and why some patients develop significant renal involvement remains largely unknown. Identifying urinary inflammatory markers could direct targets for earlier intervention. The aim of this cross-sectional exploratory study was to perform a large protein array analysis to identify urinary markers to provide insight into the mechanisms of kidney inflammation in children with established IgAV nephritis (IgAVN). Determination of the relative levels of 124 key proteins was performed using commercially available proteome profiler array kits. Twelve children were recruited: IgAVN, n = 4; IgAV without nephritis (IgAVwoN), n = 4; healthy controls (HCs), n = 4. The urinary concentrations of twenty proteins were significantly different in IgAVN compared to IgAVwoN. The largest fold changes were reported for B-cell activating factor (BAFF), Cripto-1, sex-hormone-binding globulin and angiotensinogen. The urinary levels of complement components C5/C5a and factor D were also significantly elevated in patients with IgAVN. A total of 69 urinary proteins significantly raised levels in comparisons made between IgAVN vs. HCs and nine proteins in IgAVwoN vs. HCs, respectively. This study identified key urinary proteins potentially involved in IgAVN providing new insight into the pathophysiology. Further longitudinal studies with larger cohorts are needed to quantitatively analyse these biomarkers.
Innovations in the Management of Vaginal Cancer
Authors: Kulkarni Anjali , Dogra Nupur , Zigras Tiffany
Published: April 2022

Primary vaginal cancer is a rare gynecologic malignancy. Given the rarity of the disease, standardized approaches to management are limited, and a great variety of therapeutic conditions are endorsed. This paper reviews advances in surgical approaches, radiation, chemoradiation, and immunotherapy. Advances in surgical management including the increasing use of laparoscopic and endoscopic approaches, as well as the novel techniques in vaginal reconstruction, are reviewed. Concurrent chemoradiation remains a mainstay of treatment for vaginal cancer and has improved local control of disease and overall survival. Additionally, with metastatic disease or situations where toxicity from CCRT is unacceptable, systemic therapies including immunotherapy approaches are reviewed.
An Estimated-Travel-Time Data Scraping and Analysis Framework for Time-Dependent Route Planning
Authors: Tee Hong-Le , Liew Soung-Yue , Wong Chee-Siang , Ooi Boon-Yaik
Published: April 2022

Generally, a courier company needs to employ a fleet of vehicles to travel through a number of locations in order to provide efficient parcel delivery services. The route planning of these vehicles can be formulated as a vehicle routing problem (VRP). Most existing VRP algorithms assume that the traveling durations between locations are time invariant; thus, they normally use only a set of estimated travel times (ETTs) to plan the vehicles’ routes; however, this is not realistic because the traffic pattern in a city varies over time. One solution to tackle the problem is to use different sets of ETTs for route planning in different time periods, and these data are collectively called the time-dependent estimated travel times (TD-ETTs). This paper focuses on a low-cost and robust solution to effectively scrape, process, clean, and analyze the TD-ETT data from free web-mapping services in order to gain the knowledge of the traffic pattern in a city in different time periods. To achieve the abovementioned goal, our proposed framework contains four phases, namely, (i) Full Data Scraping, (ii) Data Pre-Processing and Analysis, (iii) Fast Data Scraping, and (iv) Data Patching and Maintenance. In our experiment, we used the above framework to obtain the TD-ETT data across 68 locations in Penang, Malaysia, for six months. We then fed the data to a VRP algorithm for evaluation. We found that the performance of our low-cost approach is comparable with that of using the expensive paid data.
Can We Use Urinary Cytokine/Chemokine Analysis in Discriminating Ulcer-Type Interstitial Cystitis/Bladder Pain Syndrome?
Authors: Jiang Yuan-Hong , Jhang Jia-Fong , Kuo Hann-Chorng
Published: April 2022

Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) has ulcer (HIC) and non-ulcer subtypes. Differentiation of these two subtypes could only be based by cystoscopy. This study analyzed the urinary cytokines and chemokines among IC/BPS subtypes and controls for discriminating HIC from non-HIC and controls. Materials and Methods: A total of 309 consecutive patients with clinically diagnosed IC/BPS were enrolled. All patients received cystoscopic hydrodistention under anesthesia and urine samples were collected prior to the procedure. Enrolled patients were classified into subtypes based on the glomerulation grade, maximal bladder capacity (MBC), and presence of Hunner’s lesion. Inflammation-related cytokines and chemokines in urine samples, including interleukin-8 (IL-8), C-X-C motif chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), eotaxin-1 (eotaxin), IL-6, macrophage inflammatory protein-1 beta (MIP-1β), regulated upon activation, normally T-expressed, and presumably secreted (RANTES), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) were assayed using commercially available microspheres with the Milliplex® Human Cytokine/Chemokine Magnetic Bead-based Panel kit. The clinical data and urine levels of analytes between IC/BPS patients and controls, and among HIC, non-HIC, and controls were analyzed. Results: Among the 10 proteins, MCP-1, eotaxin, MIP-1β, TNF-α, and PGE2 were significantly different between IC/BPS and control, while IL-8, CXCL10, BDNF, IL-6, and RANTES were significantly higher in HIC than non-HIC patients. The receiver operating characteristic curve was used to analyze each urine biomarker in the patients with IC/BPS and controls. Among the 10 urine biomarkers, MIP-1β and TNF-α had an area under curve of >0.70 to predict IC/BPS from controls, however, the predictive values of these urine biomarkers to predict HIC from non-HIC were low. Combined cut-off values of MIP-1β and TNF-α can only have a 50% sensitivity and 39.6% specificity in identifying HIC from non-HIC. Conclusion: The results of this study demonstrate that urine cytokines and chemokines may be useful to discriminate patients with HIC from controls. An elevation of urine levels of IL-8, CXCL 10, BDNF, IL-6, and RANTES in IC/BPS patients should prompt physicians to consider the diagnosis of HIC.
Using a ResNet-18 Network to Detect Features of Alzheimer’s Disease on Functional Magnetic Resonance Imaging: A Failed Replication. Comment on Odusami et al. Analysis of Features of Alzheimer’s Disease: Detection of Early Stage from Functional Brain Changes in Magnetic Resonance Images Using a Finetuned ResNet18 Network. Diagnostics 2021, 11, 1071
Authors: Nicholas Peter J. , To Alex , Tanglay Onur , Young Isabella M. , Sughrue Michael E. , Doyen Stéphane
Published: April 2022

There is considerable interest in developing effective tools to detect Alzheimer’s Disease (AD) early in its course, prior to clinical progression [...]
Reply to Nicholas et al. Using a ResNet-18 Network to Detect Features of Alzheimer’s Disease on Functional Magnetic Resonance Imaging: A Failed Replication. Comment on “Odusami et al. Analysis of Features of Alzheimer’s Disease: Detection of Early Stage from Functional Brain Changes in Magnetic Resonance Images Using a Finetuned ResNet18 Network. Diagnostics 2021, 11, 1071”
Authors: Odusami Modupe , Maskeliūnas Rytis , Damaševičius Robertas , Krilavičius Tomas
Published: April 2022

We have studied the manuscript of Nicholas et al. [...]