bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations
Authors: Li Na , Qiu Simei , Fang Ying , Wu Jianhua , Li Quhuan
Published: July 2021

Integrin αvβ3 interacting with the short Arg-Gly-Asp (RGD) motif plays a critical role in the progression of several types of tumors. However, the effects of the RGD structure (cyclic or linear) with integrin αvβ3 at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin αvβ3 in complex with a linear or cyclic pentapeptide by steered molecular dynamics simulations. Compared with cyclic RGD, the linear RGD peptide triggers instability of the configurational changes, mainly resting with the RGD domain due to its flexibility. The main interaction energy between Mg2+ and cyclic RGD is much stronger than that of the linear RGD system by the well shield to lessen attacks by free water molecules. The force-dependent dissociation results show that it is easier for linear RGD peptides to leave the active site and much quicker than the cyclic RGD ligand, whereas it is harder to enter the appropriate active binding site in linear RGD. The Ser123-AspRGD bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of αvβ3 interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy.
Genomic Selection for End-Use Quality and Processing Traits in Soft White Winter Wheat Breeding Program with Machine and Deep Learning Models
Authors: Sandhu Karansher , Aoun Meriem , Morris Craig , Carter Arron
Published: July 2021

Breeding for grain yield, biotic and abiotic stress resistance, and end-use quality are important goals of wheat breeding programs. Screening for end-use quality traits is usually secondary to grain yield due to high labor needs, cost of testing, and large seed requirements for phenotyping. Genomic selection provides an alternative to predict performance using genome-wide markers under forward and across location predictions, where a previous year’s dataset can be used to build the models. Due to large datasets in breeding programs, we explored the potential of the machine and deep learning models to predict fourteen end-use quality traits in a winter wheat breeding program. The population used consisted of 666 wheat genotypes screened for five years (2015–19) at two locations (Pullman and Lind, WA, USA). Nine different models, including two machine learning (random forest and support vector machine) and two deep learning models (convolutional neural network and multilayer perceptron) were explored for cross-validation, forward, and across locations predictions. The prediction accuracies for different traits varied from 0.45–0.81, 0.29–0.55, and 0.27–0.50 under cross-validation, forward, and across location predictions. In general, forward prediction accuracies kept increasing over time due to increments in training data size and was more evident for machine and deep learning models. Deep learning models were superior over the traditional ridge regression best linear unbiased prediction (RRBLUP) and Bayesian models under all prediction scenarios. The high accuracy observed for end-use quality traits in this study support predicting them in early generations, leading to the advancement of superior genotypes to more extensive grain yield trails. Furthermore, the superior performance of machine and deep learning models strengthens the idea to include them in large scale breeding programs for predicting complex traits.
Synthetic Biology: Old and New Dilemmas—The Case of Artificial Life
Authors: Kolisis Nikolaos , Kolisis Fragiskos
Published: July 2021

This article aims to examine some of the ethical questions emerging from the use of already existing biotechnological tools and the issues which might occur by synthetic biology’s potential future possibilities. In the first part, the essence of synthetic biology and its relation to the contemporary biotechnological research is analyzed. In the second part, the article examines whether the new biotechnological inventions pose new or revive old moral questions about the ethics of science, engineering, and technology in general. After briefly addressing some of the various issues which are raised by experts, philosophers, but also the general public, concerning synthetic biology in general, it focuses on the topic of “artificial life creation” and presents moral reasons which may or may not allow it. The topic is approached by referring to consequentialist, deontological, but also, virtue theory arguments for and against it and the possibility of a partial permission of “artificial life” experiments, asking whether the benefits outweigh the risks and moral implications is explored. Finally, it proposes an argument in favor of the future exploration of biological innovation, underlying the need for a more balanced access to its beneficial results.
Episodic Memory Encoding and Retrieval in Face-Name Paired Paradigm: An fNIRS Study
Authors: Yu Qian , Cheval Boris , Becker Benjamin , Herold Fabian , Chan Chetwyn C. H. , Delevoye-Turrell Yvonne N. , Guérin Ségolène M. R. , Loprinzi Paul , Mueller Notger , Zou Liye
Published: July 2021

Background: Episodic memory (EM) is particularly sensitive to pathological conditions and aging. In a neurocognitive context, the paired-associate learning (PAL) paradigm, which requires participants to learn and recall associations between stimuli, has been used to measure EM. The present study aimed to explore whether functional near-infrared spectroscopy (fNIRS) can be employed to determine cortical activity underlying encoding and retrieval. Moreover, we examined whether and how different aspects of task (i.e., novelty, difficulty) affects those cortical activities. Methods: Twenty-two male college students (age: M = 20.55, SD = 1.62) underwent a face-name PAL paradigm under 40-channel fNIRS covering fronto-parietal and middle occipital regions. Results: A decreased activity during encoding in a broad network encompassing the bilateral frontal cortex (Brodmann areas 9, 11, 45, and 46) was observed during the encoding, while an increased activity in the left orbitofrontal cortex (Brodmann area 11) was observed during the retrieval. Increased HbO concentration in the superior parietal cortices and decreased HbO concentration in the inferior parietal cortices were observed during encoding while dominant activation of left PFC was found during retrieval only. Higher task difficulty was associated with greater neural activity in the bilateral prefrontal cortex and higher task novelty was associated with greater activation in occipital regions. Conclusion: Combining the PAL paradigm with fNIRS provided the means to differentiate neural activity characterising encoding and retrieval. Therefore, the fNIRS may have the potential to complete EM assessments in clinical settings.
An Update on Hepatocellular Carcinoma in Chronic Kidney Disease
Authors: Fabrizi Fabrizio , Cerutti Roberta , Alfieri Carlo M. , Ridruejo Ezequiel
Published: July 2021

Chronic kidney disease is a major public health issue globally and the risk of cancer (including HCC) is greater in patients on long-term dialysis and kidney transplant compared with the general population. According to an international study on 831,804 patients on long-term dialysis, the standardized incidence ratio for liver cancer was 1.2 (95% CI, 1.0–1.4) and 1.5 (95% CI, 1.3–1.7) in European and USA cohorts, respectively. It appears that important predictors of HCC in dialysis population are hepatotropic viruses (HBV and HCV) and cirrhosis. 1-, 3-, and 5-year survival rates are lower in HCC patients on long-term dialysis than those with HCC and intact kidneys. NAFLD is a metabolic disease with increasing prevalence worldwide and recent evidence shows that it is an important cause of liver-related and extra liver-related diseases (including HCC and CKD, respectively). Some longitudinal studies have shown that patients with chronic hepatitis B are aging and the frequency of comorbidities (such as HCC and CKD) is increasing over time in these patients; it has been suggested to connect these patients to an appropriate care earlier. Antiviral therapy of HBV and HCV plays a pivotal role in the management of HCC in CKD and some combinations of DAAs (elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir-based regimens) are now available for HCV positive patients and advanced chronic kidney disease. The interventional management of HCC includes liver resection. Some ablative techniques have been suggested for HCC in CKD patients who are not appropriate candidates to surgery. Transcatheter arterial chemoembolization has been proposed for HCC in patients who are not candidates to liver surgery due to comorbidities. The gold standard for early-stage HCC in patients with chronic liver disease and/or cirrhosis is still liver transplant.
Pyroptosis in Cancer: Friend or Foe?
Authors: Lu Xiuxia , Guo Tianhui , Zhang Xing
Published: July 2021

Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity.
HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements
Authors: Camuzi Diego , Buexm Luisa Aguirre , Lourenço Simone de Queiroz Chaves , Esposti Davide Degli , Cuenin Cyrille , Lopes Monique de Souza Almeida , Manara Francesca , Talukdar Fazlur Rahman , Herceg Zdenko , Ribeiro Pinto Luis Felipe , Soares-Lima Sheila Coelho
Published: July 2021

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.
D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy
Authors: Barra Jonathan , Cerda-Infante Javier , Sandoval Lisette , Gajardo-Meneses Patricia , Henriquez Jenny F. , Labarca Mariana , Metz Claudia , Venegas Jaime , Retamal Claudio , Oyanadel Claudia , Cancino Jorge , Soza Andrea , Cuello Mauricio A. , Roa Juan Carlos , Montecinos Viviana P. , Gonzalez Alfonso
Published: July 2021

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.
Stakeholder Perceptions of Key Aspects of High-Quality Cancer Care to Assess with Patient Reported Outcome Measures: A Systematic Review
Authors: Stover Angela M. , Kurtzman Rachel , Walker Bissram Jennifer , Jansen Jennifer , Carr Philip , Atkinson Thomas , Ellis C. Tyler , Freeman Ashley T. , Turner Kea , Basch Ethan M.
Published: July 2021

Performance measurement is the process of collecting, analyzing, and reporting standardized measures of clinical performance that can be compared across practices to evaluate how well care was provided. We conducted a systematic review to identify stakeholder perceptions of key symptoms and health domains to test as patient-reported performance measures in oncology. Stakeholders included cancer patients, caregivers, clinicians, and healthcare administrators. Standard review methodology was used, consistent with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). MEDLINE/PubMed, EMBASE, and the Cochrane Library were searched to identify relevant studies through August 2020. Four coders independently reviewed entries and conflicts were resolved by a fifth coder. Efficacy and effectiveness studies, and studies focused exclusively on patient experiences of care (e.g., communication skills of providers) were excluded. Searches generated 1813 articles and 1779 were coded as not relevant, leaving 34 international articles for extraction. Patients, caregivers, clinicians, and healthcare administrators prioritize psychosocial care (e.g., distress) and symptom management for patient-reported performance measures. Patients and caregivers also perceive that maintaining physical function and daily activities are critical. Clinicians and administrators perceive control of specific symptoms to be critical (gastrointestinal symptoms, pain, poor sleep). Results were used to inform testing at six US cancer centers.
Development of Multidrug Resistance in Acute Myeloid Leukemia Is Associated with Alterations of the LPHN1/GAL-9/TIM-3 Signaling Pathway
Authors: Kocibalova Zuzana , Guzyova Martina , Borovska Ivana , Messingerova Lucia , Copakova Lucia , Sulova Zdena , Breier Albert
Published: July 2021

P-glycoprotein (known as ABCB1 transporter) expression in myeloid blasts of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) leads to the commonly observed multidrug resistance. Overexpression of latrophilin-1 was detected in leukemic cells from AML patients. In a previous study, we showed that ABCB1 overexpression is associated with decreased latrophilin-1 expression in MOLM-13/VCR and SKM-1/VCR AML cell variants derived from MOLM-13 and SKM-1 cells by vincristine selection/adaptation. In the present study, we found that if ABCB1 overexpression occurs in myeloid blasts of newly diagnosed MDS patients, latrophilin-1 expression is attenuated. Latrophilin-1 may initiate TIM-3- and galectin-9-mediated immune escape. We demonstrated changes in the expression of both proteins by comparing ABCB1-positive cell variants (MOLM-13/VCR, SKM-1/VCR) with their ABCB1-negative counterparts. Galectin-9 was present in our cell lines in eight protein isoforms for which we identified the respective transcription variants resulting from alternative splicing, and we verified their structure by sequencing. The isoform profile of galectin-9 was different between ABCB1-positive and ABCB1-negative cell variants. The interaction partner of galectin-9 is CD44, and its expression was altered in the ABCB1-positive variants MOLM-13/VCR and SKM-1/VCR compared to their ABCB1-negative counterparts.
Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI
Authors: Kubo Akinori , Suda Goki , Kimura Megumi , Maehara Osamu , Tokuchi Yoshimasa , Kitagataya Takashi , Ohara Masatsugu , Yamada Ren , Shigesawa Taku , Suzuki Kazuharu , Kawagishi Naoki , Nakai Masato , Sho Takuya , Natsuizaka Mitsuteru , Morikawa Kenichi , Ogawa Koji , Ohnishi Shunsuke , Sakamoto Naoya
Published: July 2021

In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study analyzed the prevalence, characteristics, response to lenvatinib, and CTNNB-1 mutation frequency in unresectable HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. In 52 patients with unresectable HCC treated with lenvatinib, the prevalence of iso-high intensity in the hepatobiliary phase of EOB-MRI was 13%. All patients had multiple HCCs, and 3 patients had multiple HCCs with iso-high intensity in the hepatobiliary phase of EOB-MRI. Lenvatinib response to progression-free survival and overall survival were similar between patients with or without iso-high intensity in the hepatobiliary phase of EOB-MRI. Seven patients (three and four patients who had unresectable HCC with or without iso-high intensity in the hepatobiliary phase of EOB-MRI, respectively) underwent genetic analyses. Among these, two (67%, 2/3) who had HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI carried a CTNNB-1 mutation, while all four patients who had HCC without iso-high intensity in the hepatobiliary phase of EOB-MRI did not carry the CTNNB-1 mutation. This study’s findings have clinical implications for the detection and treatment of HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI.
Two Dimensional-Difference in Gel Electrophoresis (2D-DIGE) Proteomic Approach for the Identification of Biomarkers in Endometrial Cancer Serum
Authors: Ura Blendi , Biffi Stefania , Monasta Lorenzo , Arrigoni Giorgio , Battisti Ilaria , Di Lorenzo Giovanni , Romano Federico , Aloisio Michelangelo , Celsi Fulvio , Addobbati Riccardo , Valle Francesco , Rampazzo Enrico , Brucale Marco , Ridolfi Andrea , Licastro Danilo , Ricci Giuseppe
Published: July 2021

Endometrial cancer is the most common gynecologic malignancy arising from the endometrium. Identification of serum biomarkers could be beneficial for its early diagnosis. We have used 2D-Difference In Gel Electrophoresis (2D-DIGE) coupled with Mass Spectrometry (MS) procedures to investigate the serum proteome of 15 patients with endometrial cancer and 15 non-cancer subjects. We have identified 16 proteins with diagnostic potential, considering only spots with a fold change in %V ≥ 1.5 or ≤0.6 in intensity, which were statistically significant (p < 0.05). Western blotting data analysis confirmed the upregulation of CLU, ITIH4, SERPINC1, and C1RL in endometrial and exosome cancer sera compared to those of control subjects. The application of the logistic regression constructed based on the abundance of these four proteins separated the controls from the cancers with excellent levels of sensitivity and specificity. After a validation phase, our findings support the potential of using the proposed algorithm as a diagnostic tool in the clinical stage.
Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors
Authors: Kelly Deirdre , Rose April A. N. , Muniz Thiago Pimentel , Hogg David , Butler Marcus O. , Saibil Samuel D. , King Ian , Kamil Zaid Saeed , Ghazarian Danny , Ross Kendra , Iafolla Marco , Araujo Daniel V. , Waldron John , Laperriere Normand , Krema Hatem , Spreafico Anna
Published: July 2021

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.
Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer
Authors: Dayde Delphine , Gunther Jillian , Hirayama Yutaka , Weksberg David C. , Boutin Adam , Parhy Gargy , Aguilar-Bonavides Clemente , Wang Hong , Katayama Hiroyuki , Abe Yuichi , Do Kim-Anh , Hara Kazuo , Kinoshita Takashi , Komori Koji , Shimizu Yasuhiro , Tajika Masahiro , Niwa Yasumasa , Wang Y. Alan , DePinho Ronald , Hanash Samir , Krishnan Sunil , Taguchi Ayumu
Published: July 2021

The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.
Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation
Authors: Tsukamoto Shinji , Righi Alberto , Mavrogenis Andreas F. , Akahane Manabu , Honoki Kanya , Tanaka Yasuhito , Donati Davide Maria , Errani Costantino
Published: July 2021

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB of the extremities, admitted and treated at two institutions between January 1980 and December 2019. Overall, 4 patients with primary malignant GCTB, 4 patients with missing data, 3 patients with a history of radiotherapy, 22 patients with a follow-up of less than 6 months, and 36 patients who received denosumab were excluded. Accordingly, 461 patients were included for further analysis. Malignant transformation was observed in 15 of 461 patients (3.3%) at a median follow-up period of 192 months. The median follow-up duration was 89.4 months. Multivariate analysis revealed that local recurrence was an independent prognostic factor for unfavorable malignant transformation (Hazard ratio [HR], 11.33; 95% confidence interval [CI] 2.33–55.13; p = 0.003 for once versus none and HR, 11.24; 95% CI, 1.76–71.96; and p = 0.011 for twice or more versus none). The interval between the last surgery to local recurrence and malignant transformation was longer than that to local recurrence of benign GCTB, with a median of 15.2 years (interquartile range [IQR], 5.2–25.4) versus 1.3 months (IQR, 0.8–2.6), respectively (p < 0.001). Late local recurrence of GCTB is associated with a higher risk of malignant transformation.
Conversion of Green Methanol to Methyl Formate
Authors: Kaiser Doreen , Beckmann Luise , Walter Jan , Bertau Martin
Published: July 2021

Methyl formate is a key component for both defossilized industry and mobility. The current industrial production via carbonylation of methanol has various disadvantages such as high requirements on reactant purity and low methanol conversion rates. In addition, there is a great interest in replacing the conventional homogeneous catalyst with a heterogeneous one, among other things to improve the downstream processing. This is why new approaches for methyl formate are sought. This review summarizes promising approaches for methyl formate production using methanol as a reactant.
A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies
Authors: von Loeffelholz Christian , Coldewey Sina M. , Birkenfeld Andreas L.
Published: July 2021

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.
Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer’s Disease Neuroimaging Initiative
Authors: Plini Emanuele R. G. , O’Hanlon Erik , Boyle Rory , Sibilia Francesca , Rikhye Gaia , Kenney Joanne , Whelan Robert , Melnychuk Michael C. , Robertson Ian H. , Dockree Paul M.
Published: July 2021

The noradrenergic theory of Cognitive Reserve (Robertson, 2013–2014) postulates that the upregulation of the locus coeruleus—noradrenergic system (LC–NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer’s disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD—an objective measure, which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.
PlA2 Polymorphism of Platelet Glycoprotein IIb/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg–Calvé–Perthes Disease
Authors: García-Alfaro María Dolores , Pérez-Nuñez María Isabel , Amigo María Teresa , Arbona Carmelo , Ballesteros María Ángeles , González-Lamuño Domingo
Published: July 2021

The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin F2 gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase (MTHFR) gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the ‘A2’ allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg–Calvé–Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2–47.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the MTHFR gene and the rs5918(C) variant of the platelet glycoprotein IIb/IIIa were associated with more severe forms of Perthes disease (Catterall III–IV) (p < 0.05). The four children homozygous for mutated MTHFR had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV–V).
Atmospheric-Pressure Air Plasma Jet and Its Striation Discharge Mode for Treatment of Thermally Sensitive Materials
Authors: Hong Yong-Cheol
Published: July 2021

A hollow inner electrode covered with a dielectric tube was inserted into an outer electrode and airflow was fed through the inner electrode. The electrodes were then connected to a transformer operated at an alternating voltage with sinusoidal waveform at a frequency of 20 kHz. The resulting discharge is ejected out of the outer electrode from a 0.7 mm hole in the form of a plasma jet into ambient air. The attributes of the discharged plasma jet were evaluated by monitoring the voltage and current behavior and by investigating the optical emissions. The discharge patterns in the atmospheric-pressure air plasma jet in the form of striations could be observed by the naked eye. Furthermore, we reported the striation mechanism by ion acoustic wave propagation by utilizing a simple calculation.
TiN/NbN Nanoscale Multilayer Coatings Deposited by High Power Impulse Magnetron Sputtering to Protect Medical-Grade CoCrMo Alloys
Authors: Sugumaran Arunprabhu Arunachalam , Purandare Yashodhan , Shukla Krishnanand , Khan Imran , Ehiasarian Arutiun , Hovsepian Papken
Published: July 2021

This study describes the performance of nanoscale multilayer TiN/NbN coatings deposited on CoCrMo medical-grade alloys by utilising novel mixed high power impulse magnetron sputtering (HIPIMS) and direct current unbalanced magnetron sputtering (UBM) technique in an industrial size vacuum coater. Scanning electron microscopy analysis showed that these coatings were extremely dense without any intercolumnar voids. The coating exhibited high hardness of 28 GPa, as well as low friction and wear coefficient of 0.7 and 1.4 × 10−14 m3·N−1·m−1, respectively, as compared to the bare material. Scratch tests revealed superior coating to substrate adhesion due to the HIPIMS etching prior to coating deposition. Energy-dispersive X-ray analysis of the wear debris generated during the impact test together with focused ion beam cross-section analysis in different locations of the impact crater revealed the coating failure mechanism and further confirmed the excellent coating to substrate bonding strength. Potentiodynamic polarisation tests in NaCl and Hank’s solutions revealed the clear passivation behaviour, several orders of magnitude lower corrosion currents, and high pitting potentials of the coating, which guarantee excellent protection to the base alloy in such aggressive environments. Inductively coupled plasma mass spectrometry analysis of Hank’s solution containing corrosion debris of the coated sample revealed that the leaching of harmful metal ions from the base material was reduced to below the detection limit of the technique, thus demonstrating the high barrier properties of the coating.
Special Issue “Wood Modification: Characterization, Modelling, and Applications”
Authors: Sandak Anna , Sandak Jakub
Published: July 2021

Wood has been recognized as an attractive alternative to several other traditional construction solutions, and it is often called the “building material of the 21st century” [...]
Tetrabromoethane as σ-Hole Donor toward Bromide Ligands: Halogen Bonding between C2H2Br4 and Bromide Dialkylcyanamide Platinum(II) Complexes
Authors: Cheranyova Anna M. , Ivanov Daniil M.
Published: July 2021

The complexes trans-[PtBr2(NCNR2)2] (R2 = Me21, (CH2)52) were cocrystallized with 1,1,2,2-tetrabromoethane (tbe) in CH2Cl2 forming solvates 1·tbe and 2·tbe, respectively. In both solvates, tbe involved halogen bonding, viz. the C–Br···Br–Pt interactions, were detected by single-crystal X-ray diffractions experiments. Appropriate density functional theory calculations (M06/def2-TZVP) performed for isolated molecules and complex-tbe clusters, where the existence of the interactions and their noncovalent nature were confirmed by electrostatic potential surfaces (ρ = 0.001 a.u.) for isolated molecules, topology analysis of electron density, electron localization function and HOMO-LUMO overlap projections for clusters.
Correction: Ratnayake et al. Assessment of Breast Cancer Surgery in Manitoba: A Descriptive Study. Curr. Oncol. 2021, 28, 581–592
Authors: Ratnayake Iresha , Hebbard Pamela , Feely Allison , Biswanger Natalie , Decker Kathleen
Published: July 2021

The authors wish to make a correction to this paper due to a minor change in indicator definition [...]
Patterns of Relapse in Small Cell Lung Cancer: Competing Risks of Thoracic versus CNS Relapse
Authors: Ellis Peter M. , Swaminath Anand , Pond Gregory R.
Published: July 2021

Introduction: Treatment algorithms for small cell lung cancer (SCLC) are determined largely by the Veterans Affairs Lung Cancer Staging Group (VALCSG) staging (limited (LS) versus extensive (ES) stage). Relapse occurs frequently; however, patterns of relapse, in particular the competing risk of thoracic and central nervous system relapse, are not well described. This study describes patterns of relapse in SCLC patients treated at a large tertiary institution in Ontario, Canada. Materials and Methods: A retrospective cohort of SCLC patients treated at the Juravinski Cancer Centre was reviewed. Data were abstracted from the medical record on demographic, disease, treatment and outcome variables. The primary outcome was a description of the patterns of relapse stratified by disease stage. Multivariate analysis was performed to identify prognostic variables for thoracic and CNS relapse. Results: Two hundred and twenty nine patients were treated during the study period (LS—83, ES—146). Relapse occurred in the majority of patients (isolated thoracic—28%, isolated CNS—9%, extrathoracic—9%, thoracic/extrathoracic—14%, systemic and CNS—13%). The median OS was consistent with published data (LS—21.8 months, ES—8.9 months). ES disease and elevated LDH were prognostic for increased thoracic relapse, whereas poor PS and older age were prognostic for lower central nervous system (CNS) relapse. Discussion: Thoracic relapse and CNS relapse represent competing risks for patients with SCLC. Decisions about incorporating thoracic or CNS radiation are complex. More research is needed to incorporate performance status and LDH into treatment algorithms.
Multi-Layout Invoice Document Dataset (MIDD): A Dataset for Named Entity Recognition
Authors: Baviskar Dipali , Ahirrao Swati , Kotecha Ketan
Published: July 2021

The day-to-day working of an organization produces a massive volume of unstructured data in the form of invoices, legal contracts, mortgage processing forms, and many more. Organizations can utilize the insights concealed in such unstructured documents for their operational benefit. However, analyzing and extracting insights from such numerous and complex unstructured documents is a tedious task. Hence, the research in this area is encouraging the development of novel frameworks and tools that can automate the key information extraction from unstructured documents. However, the availability of standard, best-quality, and annotated unstructured document datasets is a serious challenge for accomplishing the goal of extracting key information from unstructured documents. This work expedites the researcher’s task by providing a high-quality, highly diverse, multi-layout, and annotated invoice documents dataset for extracting key information from unstructured documents. Researchers can use the proposed dataset for layout-independent unstructured invoice document processing and to develop an artificial intelligence (AI)-based tool to identify and extract named entities in the invoice documents. Our dataset includes 630 invoice document PDFs with four different layouts collected from diverse suppliers. As far as we know, our invoice dataset is the only openly available dataset comprising high-quality, highly diverse, multi-layout, and annotated invoice documents.
High-Speed Video Microscopy for Primary Ciliary Dyskinesia Diagnosis: A Study of Ciliary Motility Variations with Time and Temperature
Authors: Reula Ana , Pitarch-Fabregat Javier , Milara Javier , Cortijo Julio , Mata-Roig Manuel , Milian Lara , Armengot Miguel
Published: July 2021

Primary ciliary dyskinesia (PCD) is a rare disease resulting from a defect in ciliary function that generates, among other issues, chronic upper and lower respiratory tract infections. European guidelines recommend studying ciliary function (pattern (CBP) and frequency (CBF)), together with characteristic clinical symptoms, as one of the definitive tests. However, there is no “gold standard”. The present study aims to use high-speed video microscopy to describe how CBF and CBP alter over time and at different temperatures to reduce the error rate in the diagnosis of PCD. Samples of nasal epithelium from 27 healthy volunteers were studied to assess CBF and CBP at 0, 3, 24, 48, and 72 h, at room temperature and 4 °C. It was observed that CBF increased while CBP became dyskinetic, both at room temperature and at 4 °C, as time passed, especially after 3 h. In order to preserve all ciliary function parameters and to perform a reliable analysis to improve the diagnostic process of PCD, analysis should be performed within the first 3 h of sample collection, preferably in reference centers.
Ischemic Stroke Risk Assessment by Multiscale Entropy Analysis of Heart Rate Variability in Patients with Persistent Atrial Fibrillation
Authors: Chairina Ghina , Yoshino Kohzoh , Kiyono Ken , Watanabe Eiichi
Published: July 2021

It has been recognized that heart rate variability (HRV), defined as the fluctuation of ventricular response intervals in atrial fibrillation (AFib) patients, is not completely random, and its nonlinear characteristics, such as multiscale entropy (MSE), contain clinically significant information. We investigated the relationship between ischemic stroke risk and HRV with a large number of stroke-naïve AFib patients (628 patients), focusing on those who had never developed an ischemic/hemorrhagic stroke before the heart rate measurement. The CHA2DS2−VASc score was calculated from the baseline clinical characteristics, while the HRV analysis was made from the recording of morning, afternoon, and evening. Subsequently, we performed Kaplan–Meier method and cumulative incidence function with mortality as a competing risk to estimate the survival time function. We found that patients with sample entropy (SE(s)) ≥ 0.68 at 210 s had a significantly higher risk of an ischemic stroke occurrence in the morning recording. Meanwhile, the afternoon recording showed that those with SE(s) ≥ 0.76 at 240 s and SE(s) ≥ 0.78 at 270 s had a significantly lower risk of ischemic stroke occurrence. Therefore, SE(s) at 210 s (morning) and 240 s ≤ s ≤ 270 s (afternoon) demonstrated a statistically significant predictive value for ischemic stroke in stroke-naïve AFib patients.
Representation of a Monotone Curve by a Contour with Regular Change in Curvature
Authors: Havrylenko Yevhen , Kholodniak Yuliia , Halko Serhii , Vershkov Oleksandr , Miroshnyk Oleksandr , Suprun Olena , Dereza Olena , Shchur Taras , Śrutek Mścisław
Published: July 2021

The problem of modelling a smooth contour with a regular change in curvature representing a monotone curve with specified accuracy is solved in this article. The contour was formed within the area of the possible location of a convex curve, which can interpolate a point series. The assumption that if a sequence of points can be interpolated by a monotone curve, then the reference curve on which these points have been assigned is monotone, provides the opportunity to implement the proposed approach to estimate the interpolation error of a point series of arbitrary configuration. The proposed methods for forming a convex regular contour by arcs of ellipses and B-spline ensure the interpolation of any point series in parts that can be interpolated by a monotone curve. At the same time, the deflection of the contour from the boundaries of the area of the possible location of the monotone curve can be controlled. The possibilities of the developed methods are tested while solving problems of the interpolation of a point series belonging to monotone curves. The problems are solved in the CAD system of SolidWorks with the use of software application created based on the methods developed in the research work.