bluuebunny/crossref_metadata_2025 huggingface dataset:
SemDaServ: A Systematic Approach for Semantic Data Specification of AI-Based Smart Service Systems
Authors: Preidel Maurice , Stark Rainer
Published: June 2021

To develop smart services to successfully operate as a component of smart service systems (SSS), they need qualitatively and quantitatively sufficient data. This is especially true when using statistical methods from the field of artificial intelligence (AI): training data quality directly determines the quality of resulting AI models. However, AI model quality is only known when AI training can take place. Additionally, the creation of not yet available data sources (e.g., sensors) takes time. Therefore, systematic specification is needed alongside SSS development. Today, there is a lack of systematic support for specifying data relevant to smart services. This gap can be closed by realizing the systematic approach SemDaServ presented in this article. The research approach is based on Blessing’s Design Research Methodology (literature study, derivation of key factors, success criteria, solution functions, solution development, applicability evaluation). SemDaServ provides a three-step process and five accompanying artifacts. Using domain knowledge for data specification is critical and creates additional challenges. Therefore, the SemDaServ approach systematically captures and semantically formalizes domain knowledge in SysML-based models for information and data. The applicability evaluation in expert interviews and expert workshops has confirmed the suitability of SemDaServ for data specification in the context of SSS development. SemDaServ thus offers a systematic approach to specify the data requirements of smart services early on to aid development to continuous integration and continuous delivery scenarios.
Metagenomic Discovery and Characterization of Multi-Functional and Monomodular Processive Endoglucanases as Biocatalysts
Authors: Fan Ming Z. , Wang Weijun , Cheng Laurence , Chen Jiali , Fan Wenyi , Wang Min
Published: June 2021

Biomass includes cellulose, hemicelluloses, pectin and lignin; constitutes the components of dietary fibre of plant and alge origins in animals and humans; and can potentially provide inexhaustible basic monomer compounds for developing sustainable biofuels and biomaterials for the world. Development of efficacious cellulases is the key to unlock the biomass polymer and unleash its potential applications in society. Upon reviewing the current literature of cellulase research, two characterized and/or engineered glycosyl hydrolase family-5 (GH5) cellulases have displayed unique properties of processive endoglucanases, including GH5-tCel5A1 that was engineered and was originally identified via targeted genome sequencing of the extremely thermophilic Thermotoga maritima and GH5-p4818Cel5_2A that was screened out of the porcine hindgut microbial metagenomic expression library. Both GH5-tCel5A1 and GH5-p4818Cel5_2A have been characterized as having small molecular weights with an estimated spherical diameter at or < 4.6 nm; being monomodular without a required carbohydrate-binding domain; and acting as processive β-1,4-endoglucanases. These two unique GH5-tCel5A1 and GH5-p4818Cel5_2A processive endocellulases are active in hydrolyzing natural crystalline and pre-treated cellulosic substrates and have multi-functionality towards several hemicelluloses including β-glucans, xylan, xylogulcans, mannans, galactomannans and glucomannans. Therefore, these two multifunctional and monomodular GH5-tCel5A1 and GH5-p4818Cel5_2A endocellulases already have promising structural and functional properties for further optimization and industrial applications.
Assessment of the Urban Impact on Surface and Screen-Level Temperature in the ALADIN-Climate Driven SURFEX Land Surface Model for Budapest
Authors: Zsebeházi Gabriella , Mahó Sándor István
Published: June 2021

Land surface models with detailed urban parameterization schemes provide adequate tools to estimate the impact of climate change in cities, because they rely on the results of the regional climate model, while operating on km scale at low cost. In this paper, the SURFEX land surface model driven by the evaluation and control runs of ALADIN-Climate regional climate model is validated over Budapest from the aspect of urban impact on temperature. First, surface temperature of SURFEX with forcings from ERA-Interim driven ALADIN-Climate was compared against the MODIS land surface temperature for a 3-year period. Second, the impact of the ARPEGE global climate model driven ALADIN-Climate was assessed on the 2 m temperature of SURFEX and was validated against measurements of a suburban station for 30 years. The spatial extent of surface urban heat island (SUHI) is exaggerated in SURFEX from spring to autumn, because the urbanized gridcells are generally warmer than their rural vicinity, while the observed SUHI extent is more variable. The model reasonably simulates the seasonal means and diurnal cycle of the 2 m temperature in the suburban gridpoint, except summer when strong positive bias occurs. However, comparing the two experiments from the aspect of nocturnal UHI, only minor differences arose. The thorough validation underpins the applicability of SURFEX driven by ALADIN-Climate for future urban climate projections.
O3 Concentration and Its Relation with BVOC Emissions in a Subtropical Plantation
Authors: Bai Jianhui
Published: June 2021

An empirical model of O3 is developed using the measurements of emissions of biogenic volatile organic compounds (BVOCs), O3 concentration, global solar radiation, photosynthetically active radiation (PAR) and meteorological variables in a subtropical Pinus plantation, China, during 2013–2016. In view of the different structures of isoprene and monoterpenes, two empirical models of O3 concentration are developed, considering PAR absorption and scattering due to gases, liquids and particles (GLPs), as well as PAR attenuation caused by O3 and BVOCs. The estimated O3 is in agreement with the observations, and validation of the O3 empirical model is conducted. O3 concentrations are more sensitive to changes in PAR and water vapor than S/Q (horizontal diffuse to global solar radiation) and BVOC emissions. O3 is positive to changes in isoprene emission at low light and high GLPs, or negative at high light and low GLPs; O3 is negative to changes in monoterpene emissions. O3 are positive with the changes of PAR, water vapor and S/Q. It is suggested to control human-induced high BVOC emissions, regulate plant cutting, and reduce NOx and SO2 emissions more strictly than ever before. There are inverted U-shape interactions between O3 and its driving factors, and S/Q controls their turning points.
Air Quality Modeling for Sustainable Clean Environment Using ANFIS and Machine Learning Approaches
Authors: Taylan Osman , Alkabaa Abdulaziz S. , Alamoudi Mohammed , Basahel Abdulrahman , Balubaid Mohammed , Andejany Murad , Alidrisi Hisham
Published: June 2021

Air quality monitoring and assessment are essential issues for sustainable environmental protection. The monitoring process is composed of data collection, evaluation, and decision-making. Several important pollutants, such as SO2, CO, PM10, O3, NOx, H2S, location, and many others, have important effects on air quality. Air quality should be recorded and measured based on the total effect of pollutants that are collectively prescribed by a numerical value. In Canada, the Air Quality Health Index (AQHI) is used which is one numerical value based on the total effect of some concentrations. Therefore, evolution is required to consider the complex, ill-defined air pollutants, hence several naive and noble approaches are used to study AQHI. In this study, three approaches such as hybrid data-driven ANN, nonlinear autoregressive with external (exogenous) input (NARX) with a neural network, and adaptive neuro-fuzzy inference (ANFIS) approaches are used for estimating the air quality in an urban area (Jeddah city—industrial zone) for public health concerns. Over three years, 1771 data were collected for pollutants from 1 June 2016 until 30 September 2019. In this study, the Levenberg-Marquardt (LM) approach was employed as an optimization method for ANNs to solve the nonlinear least-squares problems. The NARX employed has a two-layer feed-forward ANN. On the other hand, the back-propagation multi-layer perceptron (BPMLP) algorithm was used with the steepest descent approach to reduce the root mean square error (RMSE). The RMSEs were 4.42, 0.0578, and 5.64 for ANN, NARX, and ANFIS, respectively. Essentially, all RMSEs are very small. The outcomes of approaches were evaluated by fuzzy quality charts and compared statistically with the US-EPA air quality standards. Due to the effectiveness and robustness of artificial intelligent techniques, the public’s early warning will be possible for avoiding the harmful effects of pollution inside the urban areas, which may reduce respiratory and cardiovascular mortalities. Consequently, the stability of air quality models was correlated with the absolute air quality index. The findings showed notable performance of NARX with a neural network, ANN, and ANFIS-based AQHI model for high dimensional data assessment.
Modeling Focused-Ultrasound Response for Non-Invasive Treatment Using Machine Learning
Authors: Arif Tariq Mohammad , Ji Zhiming , Rahim Md Adilur , Nunna Bharath Babu
Published: June 2021

The interactions between body tissues and a focused ultrasound beam can be evaluated using various numerical models. Among these, the Rayleigh–Sommerfeld and angular spectrum methods are considered to be the most effective in terms of accuracy. However, they are computationally expensive, which is one of the underlying issues of most computational models. Typically, evaluations using these models require a significant amount of time (hours to days) if realistic scenarios such as tissue inhomogeneity or non-linearity are considered. This study aims to address this issue by developing a rapid estimation model for ultrasound therapy using a machine learning algorithm. Several machine learning models were trained on a very-large dataset (19,227 simulations), and the performance of these models were evaluated with metrics such as Root Mean Squared Error (RMSE), R-squared (R2), Akaike Information Criterion (AIC), and Bayesian Information Criterion (BIC). The resulted random forest provides superior accuracy with an R2 value of 0.997, an RMSE of 0.0123, an AIC of −82.56, and a BIC of −81.65 on an external test dataset. The results indicate the efficacy of the random forest-based model for the focused ultrasound response, and practical adoption of this approach will improve the therapeutic planning process by minimizing simulation time.
Integrated Proteomic and Metabolomic Analysis of the Testes Characterizes BDE-47-Induced Reproductive Toxicity in Mice
Authors: Xu Liang , Gao Songyan , Zhao Hongxia , Wang Liupeng , Cao Yiyi , Xi Jing , Zhang Xinyu , Dong Xin , Luan Yang
Published: June 2021

A representative congener of polybrominated diphenyl ethers in the environment, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), is associated with male reproductive toxicity, yet the underlying mechanisms remain largely unclear. In this study, mice were administered environmentally relevant concentrations of BDE-47 for six weeks. Histopathological observations showed that BDE-47 induced inflammatory reactions and damaged the testes. By conducting an integrated proteomic and metabolomic analysis coupled with a bioinformatic analysis using ingenuity pathway analysis (IPA) methods, we found that BDE-47 mainly affected the molecules involved in free radical scavenging, cell death and survival, neurological disease, and inflammatory response. IPA canonical pathways showed inflammatory and apoptosis pathways, including hepatic fibrosis/hepatic stellate cell activation, the GP6 signaling pathway, tight junction signaling, acute phase response signaling, LXR/RXR activation, unfolded protein response, and FXR/RXR activation, which are related to male reproductive toxicity. Key transcriptional regulator networks were activated via a focus on upstream regulator analysis. The expression of MYC and Clu as the core transcriptional factor and targeted protein, respectively, was verified. It is further proposed that MYC may contribute to the etiology of male reproductive toxicity. These findings will improve our understanding of the mechanisms responsible for BDE-47-induced male reproductive toxicity, which may promote the discovery of useful biomarkers indicative of BDE-47 exposure.
Triazole-Modified Nucleic Acids for the Application in Bioorganic and Medicinal Chemistry
Authors: Baraniak Dagmara , Boryski Jerzy
Published: June 2021

This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs.
Electroencephalography (EEG) Reveals Increased Frontal Activity in Social Presence
Authors: Soiné Anna , Flöck Alessandra , Walla Peter
Published: June 2021

It remains an unsolved conundrum how social presence affects the neural processes involved in adaptive situation-specific decision-making mechanisms. To investigate this question, brain potential changes via electroencephalography (EEG) and skin conductance responses (SCR) were taken within this study, while participants were exposed to pre-rated pleasant, neutral, and unpleasant pictures, which they had to rate in terms of their perceived arousal. Crucially, they had to—in respective runs—do this alone and in the presence of a significant other. Contrasting respective event-related potentials (ERPs) revealed significantly more negative going potentials peaking at 708 ms post stimulus onset at mid-frontal electrode locations (around FPz and AFz), when participants were exposed to neutral pictures while in the presence of a significant other. SCR results demonstrate higher states of arousal in the presence of a significant other regardless of picture emotion category. Self-reported arousal turned out to be highest in response to neutral pictures within the significant other condition, whereas in the alone condition in response to the pleasant pictures. In light of existing literature on social aspects and the anterior cingulate cortex (ACC), the ERP finding in the significant other condition, while rating emotionally neutral pictures, is interpreted as reflecting heightened ACC activation, which is supported by electrode locations showing significant brain activity differences as well as by source localization results. Neutral pictures are inherently ambiguous, and the current results indicate the presence of another person to change the way one processes, perceives, and acts on them. This is in support for theories proposing the ACC to be part of a larger signal-specification network that gauges relevant stimuli for adequate execution of control.
Comparative Study of a Continuous Train of Theta-Burst Stimulation for a Duration of 20 s (cTBS 300) versus a Duration of 40 s (cTBS 600) in a Pre-Stimulation Relaxed Condition in Healthy Volunteers
Authors: Haeckert Jan , Rothwell John , Hannah Ricci , Hasan Alkomiet , Strube Wolfgang
Published: June 2021

As variable after effects have been observed following phasic muscle contraction prior to continuous theta-burst stimulation (cTBS), we here investigated two cTBS protocols (cTBS300 and cTBS600) in 20 healthy participants employing a pre-relaxed muscle condition including visual feedback on idle peripheral surface EMG activity. Furthermore, we assessed corticospinal excitability measures also from a pre-relaxed state to better understand the potential impact of these proposed contributors to TBS. Motor-evoked potential (MEP) magnitude changes were assessed for 30 min. The linear model computed across both experimental paradigms (cTBS300 and cTBS600) revealed a main effect of TIME COURSE (p = 0.044). Separate exploratory analysis for cTBS300 revealed a main effect of TIME COURSE (p = 0.031), which did not maintain significance after Greenhouse–Geisser correction (p = 0.073). For cTBS600, no main effects were observed. An exploratory analysis revealed a correlation between relative SICF at 2.0 ms (p = 0.006) and after effects (relative mean change) of cTBS600, which did not survive correction for multiple testing. Our findings thereby do not support the hypothesis of a specific excitability modulating effect of cTBS applied to the human motor-cortex in setups with pre-relaxed muscle conditions.
Whole-Lesion Apparent Diffusion Coefficient Histogram Analysis: Significance for Discriminating Lung Cancer from Pulmonary Abscess and Mycobacterial Infection
Authors: Usuda Katsuo , Iwai Shun , Yamagata Aika , Iijima Yoshihito , Motono Nozomu , Matoba Munetaka , Doai Mariko , Hirata Keiya , Uramoto Hidetaka
Published: June 2021

Diffusion-weighted magnetic resonance imaging (DWI) can differentiate malignant from benign pulmonary nodules. However, it is difficult to differentiate pulmonary abscesses and mycobacterial infections (PAMIs) from lung cancers because PAMIs show restricted diffusion in DWI. The study purpose is to establish the role of ADC histogram for differentiating lung cancer from PAMI. There were 41 lung cancers (25 adenocarcinomas, 16 squamous cell carcinomas), and 19 PAMIs (9 pulmonary abscesses, 10 mycobacterial infections). Parameters more than 60% of the area under the ROC curve (AUC) were ADC, maximal ADC, mean ADC, median ADC, most frequency ADC, kurtosis of ADC, and volume of lesion. There were significant differences between lung cancer and PAMI in ADC, mean ADC, median ADC, and most frequency ADC. The ADC (1.19 ± 0.29 × 10−3 mm2/s) of lung cancer obtained from a single slice was significantly lower than that (1.44 ± 0.54) of PAMI (p = 0.0262). In contrast, mean, median, or most frequency ADC of lung cancer which was obtained in the ADC histogram was significantly higher than the value of each parameter of PAMI. ADC histogram could discriminate PAMIs from lung cancers by showing that AUCs of several parameters were more than 60%, and that several parameters of ADC of PAMI were significantly lower than those of lung cancer. ADC histogram has the potential to be a valuable tool to differentiate PAMI from lung cancer.
Modulation of Early Neutrophil Granulation: The Circulating Tumor Cell-Extravesicular Connection in Pancreatic Ductal Adenocarcinoma
Authors: Charles Jacob Harrys , Charles Richard John , Signorelli Rossana , Kashuv Tyler , Lavania Shweta , Vaish Utpreksha , Boopathy Ranjitha , Middleton Ashley , Boone Melinda , Sundaram Ramakrishnan , Dudeja Vikas , Saluja Ashok
Published: June 2021

Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters.
Optimizing External Beam Radiotherapy as per the Risk Group of Localized Prostate Cancer: A Nationwide Multi-Institutional Study (KROG 18-15)
Authors: Choi Seo Hee , Kim Young Seok , Yu Jesang , Nam Taek-Keun , Kim Jae-Sung , Jang Bum-Sup , Kim Jin Ho , Kim Youngkyong , Jeong Bae Kwon , Chang Ah Ram , Park Young-Hee , Lee Sung Uk , Cho Kwan Ho , Kim Jin Hee , Kim Hunjung , Choi Youngmin , Kim Yeon Joo , Lee Dong Soo , Shin Young Ju , Shim Su Jung , Park Won , Cho Jaeho
Published: June 2021

Purpose: This nationwide multi-institutional study analyzed the patterns of care and outcomes of external beam radiotherapy (EBRT) in localized prostate cancer patients. We compared various risk classification tools and assessed the need for refinements in current radiotherapy (RT) schemes. Methods and Materials: We included non-metastatic prostate cancer patients treated with primary EBRT from 2001 to 2015 in this study. Data of 1573 patients from 17 institutions were analyzed and re-grouped using a risk stratification tool with the highest predictive power for biochemical failure-free survival (BCFFS). We evaluated BCFFS, overall survival (OS), and toxicity rates. Results: With a median follow-up of 75 months, 5- and 10-year BCFFS rates were 82% and 60%, and 5- and 10-year OS rates were 95% and 83%, respectively. NCCN risk classification revealed the highest predictive power (AUC = 0.556, 95% CI 0.524–0.588; p < 0.001). Gleason score, iPSA < 12 ng/mL, intensity-modulated RT (IMRT), and ≥179 Gy1.5 (EQD2, 77 Gy) were independently significant for BCFFS (all p < 0.05). IMRT and ≥179 Gy1.5 were significant factors in the high-risk group, whereas ≥170 Gy1.5 (EQD2, 72 Gy) was significant in the intermediate-risk group and no significant impact of dose was observed in the low-risk group. Both BCFFS and OS improved significantly when ≥179 Gy1.5 was delivered using IMRT and hypofractionation in the high-risk group without increasing toxicities. Conclusions: With NCCN risk classification, dose escalation with modern high-precision techniques might increase survivals in the high-risk group, but not in the low-risk group, although mature results of prospective studies are awaited.
Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis
Authors: Riddiough Georgina E. , Fifis Theodora , Walsh Katrina A. , Muralidharan Vijayaragavan , Christophi Christopher , Tran Bang M. , Vincan Elizabeth , Perini Marcos V.
Published: June 2021

(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.
The Value of Intraoperative Ultrasound in Selective Lateral Cervical Neck Lymphadenectomy for Papillary Thyroid Cancer: A Prospective Pilot Study
Authors: Di Meo Giovanna , Prete Francesco Paolo , De Luca Giuseppe Massimiliano , Pasculli Alessandro , Sgaramella Lucia Ilaria , Minerva Francesco , Logoluso Francesco Antonio , Calculli Giovanna , Gurrado Angela , Testini Mario
Published: June 2021

(1) Background: Lymph node metastases from papillary thyroid cancer (PTC) are frequent. Selective neck dissection (SND) is indicated in PTC with clinical or imaging evidence of lateral neck nodal disease. Both preoperative ultrasound (PreUS) and intraoperative palpation or visualization may underestimate actual lateral neck nodal involvement, particularly for lymph-nodes located behind the sternocleidomastoid muscle, where dissection may also potentially increase the risk of postoperative complications. The significance of diagnostic IOUS in metastatic PTC is under-investigated. (2) Methods: We designed a prospective diagnostic study to assess the diagnostic accuracy of IOUS compared to PreUS in detecting metastatic lateral neck lymph nodes from PTC during SND. (3) Results: There were 33 patients with preoperative evidence of lateral neck nodal involvement from PTC based on PreUS and fine-needle cytology. In these patients, IOUS guided the excision of additional nodal compartments that were not predicted by PreUS in nine (27.2%) cases, of which eight (24.2%) proved to harbor positive nodes at pathology. The detection of levels IIb and V increased, respectively, from 9% (PreUS) to 21% (IOUS) (p < 0.0001) and from 15% to 24% (p = 0.006). (4) Conclusions: In the context of this study, IOUS showed higher sensitivity and specificity than PreUS scans in detecting metastatic lateral cervical nodes. This study showed that IOUS may enable precise SND to achieve oncological radicality, limiting postoperative morbidity.
Stem Cell Theory of Cancer: Implications of a Viral Etiology in Certain Malignancies
Authors: Tu Shi-Ming
Published: June 2021

In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell origin of cancer.
Making Patient-Specific Treatment Decisions Using Prognostic Variables and Utilities of Clinical Outcomes
Authors: Msaouel Pavlos , Lee Juhee , Thall Peter F.
Published: June 2021

We argue that well-informed patient-specific decision-making may be carried out as three consecutive tasks: (1) estimating key parameters of a statistical model, (2) using prognostic information to convert these parameters into clinically interpretable values, and (3) specifying joint utility functions to quantify risk–benefit trade-offs between clinical outcomes. Using the management of metastatic clear cell renal cell carcinoma as our motivating example, we explain the role of prognostic covariates that characterize between-patient heterogeneity in clinical outcomes. We show that explicitly specifying the joint utility of clinical outcomes provides a coherent basis for patient-specific decision-making.
CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion
Authors: Jeong Miran , Wang Yi-Yue , Choi Ju-Yeon , Lim Myong Cheol , Choi Jung-Hye
Published: June 2021

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.
Current Status and Challenges of US-Guided Radiofrequency Ablation of Thyroid Nodules in the Long Term: A Systematic Review
Authors: Bernardi Stella , Palermo Andrea , Grasso Rosario Francesco , Fabris Bruno , Stacul Fulvio , Cesareo Roberto
Published: June 2021

Background: US-guided minimally-invasive techniques, such as radiofrequency ablation (RFA) have emerged as an alternative treatment for benign and malignant thyroid nodules. This systematic review aims to provide an overview on the long-term outcomes of US-guided RFA in patients with benign and malignant thyroid nodules. Methods: We systematically searched PubMed/MEDLINE, EMBASE, and Scopus to identify articles reporting the outcomes of thyroid RFA after a follow-up of at least 3 years. Results: A total of 20 studies met the inclusion criteria and were included in the review. In patients with benign thyroid nodules, RFA significantly reduced nodule volume and this was generally maintained for the following 5 years. However, a small but not negligible proportion of nodules regrew and some of them required further treatments over time. In patients with malignant nodules, RFA has been used not only to treat differentiated thyroid cancer (DTC) neck recurrences, but also to treat papillary thyroid microcarcinoma (PTMC). In most patients with PTMC, RFA led to complete disappearance of the tumor. When it was compared to surgery, RFA was not inferior in terms of oncologic efficacy but it had a lower complication rate. However, RFA did not allow for final pathology, disease staging and accurate risk stratification. Conclusions: US-guided RFA significantly reduces benign thyroid nodules and destroys most PTMC, and this is generally maintained for at least 5 years after the initial treatment. Further studies addressing the risk of regrowths in patients with benign thyroid nodules, as well as the risk of recurrence in patients with PTMC are needed.
Protein Kinases in Leukemias
Authors: De Sepulveda Paulo , Pasquet Jean-Max
Published: June 2021

Protein kinases (PK) make up around 2% of the human genome and their expression profile varies depending on the organ and tissue [...]
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
Authors: Uribe Mary Luz , Marrocco Ilaria , Yarden Yosef
Published: June 2021

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.
Associations between Prediagnostic Circulating Bilirubin Levels and Risk of Gastrointestinal Cancers in the UK Biobank
Authors: Seyed Khoei Nazlisadat , Wagner Karl-Heinz , Carreras-Torres Robert , Gunter Marc J. , Murphy Neil , Freisling Heinz
Published: June 2021

We investigated associations between serum levels of bilirubin, an endogenous antioxidant, and gastrointestinal cancer risk. In the UK Biobank, prediagnostic serum levels of total bilirubin were measured in blood samples collected from 440,948 participants. In multivariable-adjusted Cox proportional hazard regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between bilirubin levels and gastrointestinal cancer risk (colorectum, esophagus, stomach, mouth, pancreas, and liver). After a median follow-up of 7.1 years (interquartile range: 1.4), 5033 incident gastrointestinal cancer cases were recorded. In multivariable-adjusted models, bilirubin levels were negatively associated with risk of esophageal adenocarcinoma (EAC, HR per 1-SD increment in log-total bilirubin levels 0.72, 95%CI 0.56–0.92, p = 0.01). Weak and less robust negative associations were observed for colorectal cancer (CRC, HR per 1-SD increment in log-total bilirubin levels 0.95, 95%CI 0.88–1.02, p = 0.14). Bilirubin levels were positively associated with risk of hepatocellular carcinoma (HCC, HR per 1-SD increment in log-total bilirubin levels 2.07, 95%CI 1.15–3.73, p = 0.02) and intrahepatic bile duct (IBD) cancer (HR per 1-SD increment 1.67, 95%CI 1.07–2.62, p = 0.03). We found no associations with risks of stomach, oral, and pancreatic cancers. Prediagnostic serum levels of bilirubin were negatively associated with risk of EAC and positively associated with HCC and IBD cancer. Further studies are warranted to replicate our findings for specific GI cancers.
Human Adipose-Derived Stem/Stromal Cells Promote Proliferation and Migration in Head and Neck Cancer Cells
Authors: Sharaf Kariem , Eggersmann Tanja K. , Haider Stefan P. , Schwenk-Zieger Sabina , Zhou Jiefu , Gires Olivier , Lechner Axel , Canis Martin , Haubner Frank
Published: June 2021

Human adipose-derived stem/stromal cells (ASCs) are increasingly used as auto-transplants in regenerative medicine to restore tissue defects or induce wound healing, especially in cancer patients. The impact of ASCs on squamous cell carcinoma of the upper aerodigestive tract (UAT) including head and neck and esophageal squamous cell carcinoma (HNSCC and ESCC) is not yet fully understood. ASCs were cultured from subcutaneous, abdominal lipoaspirates of five patients, who received auto-transplants to the head and neck. Supernatants were tested for paracrine effects in functional in vitro assays of proliferation of HNSCC tumor cell line FaDu and ESCC cell line Kyse30, and their cell migration/invasion capacities in Boyden chambers, in addition to endothelial tube formation assay using human umbilical vein endothelial cells (HUVECs). All ASC-derived supernatants enhanced proliferation of FaDu cells, invasive migration, and tube formation by HUVECs, compared to controls. Of five patients’ lipoaspirates, ASC-derived supernatants of four patients increased proliferation and invasive migration in Kyse30 cells. The data suggests that ASCs can promote tumor cell proliferation, invasiveness, and neo-angiogenesis in these tumor cell lines of the UAT and HUVEC in a paracrine manner. Although clinical studies on the subject of oncological safety are still needed, these findings emphasize the importance of complete tumor removal before ASCs are used in the head and neck.
Analysis of Relationships between Immune Checkpoint and Methylase Gene Polymorphisms and Outcomes after Unrelated Bone Marrow Transplantation
Authors: Takahashi Hidekazu , Okayama Naoko , Yamaguchi Natsu , Nomura Moe , Miyahara Yuta , Mahbub MH , Hase Ryosuke , Morishima Yasuo , Suehiro Yutaka , Yamasaki Takahiro , Tamada Koji , Takahashi Satoshi , Tojo Arinobu , Tanabe Tsuyoshi
Published: June 2021

Unrelated bone marrow transplantation (uBMT) is performed to treat blood disorders, and it uses bone marrow from an unrelated donor as the transplant source. Although the importance of HLA matching in uBMT has been established, that of other genetic factors, such as single-nucleotide polymorphisms (SNPs), remains unclear. The application of immunoinhibitory receptors as anticancer drugs has recently been attracting attention. This prompted us to examine the importance of immunoinhibitory receptor SNPs in uBMT. We retrospectively genotyped five single-nucleotide polymorphisms (SNPs) in the immune checkpoint genes, BTLA, PD-1, LAG3, and CTLA4, and two SNPs in the methylase genes, DNMT1 and EZH2, in 999 uBMT donor–recipient pairs coordinated through the Japan Marrow Donor Program matched at least at HLA-A, -B, and -DRB1. No correlations were observed between these SNPs and post-uBMT outcomes (p > 0.005). This result questions the usefulness of these immune checkpoint gene polymorphisms for predicting post-BMT outcomes. However, the recipient EZH2 histone methyltransferase gene SNP, which encodes the D185H substitution, exhibited a low p-value in regression analysis of grade 2–4 acute graft-versus-host disease (p = 0.010). Due to a low minor allele frequency, this SNP warrants further investigation in a larger-scale study.
A Model of Catalytic Cracking: Product Distribution and Catalyst Deactivation Depending on Saturates, Aromatics and Resins Content in Feed
Authors: Nazarova Galina Y. , Ivashkina Elena N. , Ivanchina Emiliya D. , Vosmerikov Alexander V. , Vosmerikova Ludmila N. , Antonov Artem V.
Published: June 2021

The problems of catalyst deactivation and optimization of the mixed feedstock become more relevant when the residues are involved as a catalytic cracking feedstock. Through numerical and experimental studies of catalytic cracking, we optimized the composition of the mixed feedstock in order to minimize the catalyst deactivation by coke. A pure vacuum gasoil increases the yields of the wet gas and the gasoline (56.1 and 24.9 wt%). An increase in the ratio of residues up to 50% reduces the gasoline yield due to the catalyst deactivation by 19.9%. However, this provides a rise in the RON of gasoline and the light gasoil yield by 1.9 units and 1.7 wt% Moreover, the ratio of residue may be less than 50%, since the conversion is limited by the regenerator coke burning ability.
DisA Limits RecG Activities at Stalled or Reversed Replication Forks
Authors: Torres Rubén , Gándara Carolina , Carrasco Begoña , Baquedano Ignacio , Ayora Silvia , Alonso Juan C.
Published: June 2021

The DNA damage checkpoint protein DisA and the branch migration translocase RecG are implicated in the preservation of genome integrity in reviving haploid Bacillus subtilis spores. DisA synthesizes the essential cyclic 3′, 5′-diadenosine monophosphate (c-di-AMP) second messenger and such synthesis is suppressed upon replication perturbation. In vitro, c-di-AMP synthesis is suppressed when DisA binds DNA structures that mimic stalled or reversed forks (gapped forks or Holliday junctions [HJ]). RecG, which does not form a stable complex with DisA, unwinds branched intermediates, and in the presence of a limiting ATP concentration and HJ DNA, it blocks DisA-mediated c-di-AMP synthesis. DisA pre-bound to a stalled or reversed fork limits RecG-mediated ATP hydrolysis and DNA unwinding, but not if RecG is pre-bound to stalled or reversed forks. We propose that RecG-mediated fork remodeling is a genuine in vivo activity, and that DisA, as a molecular switch, limits RecG-mediated fork reversal and fork restoration. DisA and RecG might provide more time to process perturbed forks, avoiding genome breakage.
Hypoxia Inducible Factor-1α Attenuates Ischemic Brain Damage by Modulating Inflammatory Response and Glial Activity
Authors: Amin Nashwa , Chen Shijia , Ren Qiannan , Tan Xiaoning , Botchway Benson O. A. , Hu Zhiying , Chen Fengpei , Ye Shan , Du Xiaoxue , Chen Zuobing , Fang Marong
Published: June 2021

Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.
Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets
Authors: Burroughs Garcìa Jessica , Eufemiese Rosa Alba , Storti Paola , Sammarelli Gabriella , Craviotto Luisa , Todaro Giannalisa , Toscani Denise , Marchica Valentina , Giuliani Nicola
Published: June 2021

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon.
Pulmonary Fibroelastotic Remodelling Revisited
Authors: Braubach Peter , Werlein Christopher , Verleden Stijn E. , Maerzke Isabell , Gottlieb Jens , Warnecke Gregor , Dettmer Sabine , Laenger Florian , Jonigk Danny
Published: June 2021

Pulmonary fibroelastotic remodelling occurs within a broad spectrum of diseases with vastly divergent outcomes. So far, no comprehensive terminology has been established to adequately address and distinguish histomorphological and clinical entities. We aimed to describe the range of fibroelastotic changes and define stringent histological criteria. Furthermore, we wanted to clarify the corresponding terminology in order to distinguish clinically relevant variants of pulmonary fibroelastotic remodelling. We revisited pulmonary specimens with fibroelastotic remodelling sampled during the last ten years at a large European lung transplant centre. Consensus-based definitions of specific variants of fibroelastotic changes were developed on the basis of well-defined cases and applied. Systematic evaluation was performed in a steps-wise algorithm, first identifying the fulcrum of the respective lesions, and then assessing the morphological changes, their distribution and the features of the adjacent parenchyma. We defined typical alveolar fibro-elastosis as collagenous effacement of the alveolar spaces with accompanying hyper-elastosis of the remodelled and paucicellular alveolar walls, independent of the underlying disease in 45 cases. Clinically, this pattern could be seen in (idiopathic) pleuroparenchymal fibro-elastosis, interstitial lung disease with concomitant alveolar fibro-elastosis, following hematopoietic stem cell and lung transplantation, autoimmune disease, radio-/chemotherapy, and pulmonary apical caps. Novel in-transit and activity stages of fibroelastotic remodelling were identified. For the first time, we present a comprehensive definition of fibroelastotic remodelling, its anatomic distribution, and clinical associations, thereby providing a basis for stringent patient stratification and prediction of outcome.