bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyses of Molecular Characteristics and Enzymatic Activities of Ovine HSD17B3
Authors: Islam Mohammad Sayful , Uwada Junsuke , Hayashi Junki , Kikuya Kei-ichiro , Muranishi Yuki , Watanabe Hiroyuki , Yaegashi Kazuhide , Hasegawa Kazuya , Ida Takanori , Sato Takahiro , Imamichi Yoshitaka , Kitano Takeshi , Miyashiro Yoshimichi , Khan Rafiqul Islam , Takahashi Satoru , Umezawa Akihiro , Suzuki Nobuo , Sekiguchi Toshio , Yazawa Takashi
Published: October 2021

17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) converts androstenedione (A4) into testosterone (T), which regulates sex steroid production. Because various mutations of the HSD17B3 gene cause disorder of sex differentiation (DSD) in multiple mammalian species, it is very important to reveal the molecular characteristics of this gene in various species. Here, we revealed the open reading frame of the ovine HSD17B3 gene. Enzymatic activities of ovine HSD17B3 and HSD17B1 for converting A4 to T were detected using ovine androgen receptor-mediated transactivation in reporter assays. Although HSD17B3 also converted estrone to estradiol, this activity was much weaker than those of HSD17B1. Although ovine HSD17B3 has an amino acid sequence that is conserved compared with other mammalian species, it possesses two amino acid substitutions that are consistent with the reported variants of human HSD17B3. Substitutions of these amino acids in ovine HSD17B3 for those in human did not affect the enzymatic activities. However, enzymatic activities declined upon missense mutations of the HSD17B3 gene associated with 46,XY DSD, affecting amino acids that are conserved between these two species. The present study provides basic information and tools to investigate the molecular mechanisms behind DSD not only in ovine, but also in various mammalian species.
Organic Selenium (OH-MetSe) Effect on Whole Body Fatty Acids and Mx Gene Expression against Viral Infection in Gilthead Seabream (Sparus aurata) Juveniles
Authors: Tseng Yiyen , Dominguez David , Bravo Jimena , Acosta Felix , Robaina Lidia , Geraert Pierre-André , Kaushik Sadasivam , Izquierdo Marisol
Published: October 2021

The supplementation of fish diets with OH-SeMet reduces oxidative stress and modulates immune response against bacterial infection. However, despite the importance of essential polyunsaturated fatty acids in fish nutrition and their high risk of oxidation, the potential protective effect of OH-SeMet on these essential fatty acids has not been studied in detail. Moreover, while viral infection is very relevant in seabream production, no studies have focused the Se effects against viral infection. The aim of the present study was to assess the impact of dietary supplementation with OH-SeMet on gilthead seabream fatty acid profiles, growth performance and response against viral infection. Gilthead seabream juveniles (21.73 ± 0.27 g) were fed for 91 days with three experimental diets, a control diet without supplementation of Se (0.29 mg Se kg diet−1) and two diets supplemented with OH-SeMet (0.52 and 0.79 mg Se kg diet−1). A crowding stress test was performed at week 7 and an anti-viral response challenge were conducted at the end of the feeding trial. Selenium, proximate and fatty acid composition of diets and body tissues were analyzed. Although fish growth was not affected, elevation in dietary Se proportionally raised Se content in body tissues, increased lipid content in the whole body and promoted retention and synthesis of n-3 polyunsaturated fatty acids. Specifically, a net production of DHA was observed in those fish fed diets with a higher Se content. Additionally, both monounsaturated and saturated fatty acids were significantly reduced by the increase in dietary Se. Despite the elevation of dietary Se to 0.79 mg kg−1 not affecting basal cortisol levels, 2 h post-stress plasma cortisol levels were markedly increased. Finally, at 24 h post-stimulation, dietary OH-SeMet supplementation significantly increased the expression of the antiviral response myxovirus protein gene, showing, for the first time in gilthead seabream, the importance of dietary Se levels on antiviral defense.
Rational Pharmacotherapy in Infectious Diseases: Issues Related to Drug Residues in Edible Animal Tissues
Authors: Canton Lucila , Lanusse Carlos , Moreno Laura
Published: October 2021

Drugs are used in veterinary medicine to prevent or treat animal diseases. When rationally administered to livestock following Good Veterinary Practices (GVP), they greatly contribute to improving the production of food of animal origin. Since humans can be exposed chronically to veterinary drugs through the diet, residues in food are evaluated for effects following chronic exposures. Parameters such as an acceptable daily intake (ADI), the no-observed-adverse-effect level (NOAEL), maximum residue limits (MRLs), and the withdrawal periods (WPs) are determined for each drug used in livestock. Drug residues in food exceeding the MRLs usually appear when failing the GVP application. Different factors related either to the treated animal or to the type of drug administration, and even the type of cooking can affect the level of residues in edible tissues. Residues above the MRLs can have a diverse negative impact, mainly on the consumer’s health, and favor antimicrobial resistance (AMR). Drug residue monitoring programmes are crucial to ensure that prohibited or authorized substances do not exceed MRLs. This comprehensive review article addresses different aspects of drug residues in edible tissues produced as food for human consumption and provides relevant information contributing to rational pharmacotherapy in food-producing animals.
Effect of Gender on Meat Quality from Adult Obsolescent Horses
Authors: Razmaitė Violeta , Šveistienė Rūta , Račkauskaitė Alma , Jatkauskienė Virginija
Published: October 2021

The objective of the study was to assess the influence of gender, age, and carcass weight on the properties of meat from adult horses slaughtered in Lithuania. M. pectoralis profundus of twenty-six obsolescent horses from 3 to 21 years of age were used in the experiment. Gender appeared to affect the horse meat properties. Stallions demonstrated (p < 0.01 and p < 0.05, respectively) lower content of dry matter and also considerably lower (p < 0.001 and p < 0.01) intramuscular fat content compared with mares and geldings and higher (p < 0.01) cholesterol content compared with mares. The meat of stallions showed the highest pH; however, a significant (p < 0.01) difference was obtained only in comparison with mares. Meat lightness (L*) and yellowness (b*) of stallions were lower (p < 0.05) compared with geldings. Meat toughness of stallions was also lower (p < 0.01) than the meat of mares and geldings. The highest (p < 0.05 and p < 0.01, respectively) proportion of total polyunsaturated fatty acids (PUFA), higher (p < 0.05) and more favorable PUFA/SFA ratio, and also the highest (p < 0.05) but least favorable n-6/n-3 PUFA ratio, were detected in the muscles of stallions compared with mares and geldings. The differences in horse ages did not exhibit any effect on the properties of M. pectoralis profundus. Despite the age differences at the decline of horse life, the properties of the horse meat exhibited good quality and showed that horse meat is potentially highly beneficial to human health.
Climatological Study of Ozone over Saudi Arabia
Authors: Al-Kallas Saleha , Al-Mutairi Motirh , Abdel Basset Heshmat , Abdeldym Abdallah , Morsy Mostafa , Badawy Ayman
Published: October 2021

In this work, analysis of the variability of total column ozone (TCO) over the Kingdom of Saudi Arabia (KSA) has been conducted during the 1979–2020 period based on the ECMWF-ERA5 dataset. It is found that the highest values of TCO appear in the spring and winter months especially over north KSA, while the lowest values of TCO occur in the autumn months. The highest values of the coefficient of variation (COV) for TCO occur in winter and spring as they gradually decrease southward, while the lowest COV values appear in summer and autumn. The Mann–Kendall test indicates that the positive trend values are dominant for the annual and seasonal TCO values over KSA, and they gradually increase southward. The study of long-term variability of annual TCO at KSA stations shows negative trend values are the dominant behavior during the 1979–2004 period, while positive trend values are the dominant behavior during the 2004–2020 period. The Mann–Whitney test assessed the abrupt change of the annual TCO time series at 28 stations in KSA and confirmed that there is an abrupt change towards increasing values around 2000, 2005, and 2014. The climatological monthly mean of the ozone mass mixing ratio (OMR) is studied at three stations representing the north, middle, and south of KSA. The highest values of OMR are found in the layer between 20 and 4 hPa with the maximum in summer and early autumn, while the lowest values are found below 100 hPa.
Spectra of Temperature Fluctuations in the Solar Wind
Authors: Němeček Zdeněk , Šafránková Jana , Němec František , Ďurovcová Tereza , Pitňa Alexander , Alterman Benjamin L. , Voitenko Yuriy M. , Pavlů Jiří , Stevens Michael L.
Published: October 2021

Turbulent cascade transferring the free energy contained within the large scale fluctuations of the magnetic field, velocity and density into the smaller ones is probably one of the most important mechanisms responsible for heating of the solar corona and solar wind, thus the turbulent behavior of these quantities is intensively studied. The temperature is also highly fluctuating quantity but its variations are studied only rarely. There are probably two reasons, first the temperature is tensor and, second, an experimental determination of temperature variations requires knowledge of the full velocity distribution with an appropriate time resolution but such measurements are scarce. To overcome this problem, the Bright Monitor of the Solar Wind (BMSW) on board Spektr-R used the Maxwellian approximation and provided the thermal velocity with a 32 ms resolution, investigating factors influencing the temperature power spectral density shape. We discuss the question whether the temperature spectra determined from Faraday cups are real or apparent and analyze mutual relations of power spectral densities of parameters like the density, parallel and perpendicular components of the velocity and magnetic field fluctuations. Finally, we compare their spectral slopes with the slopes of the thermal velocity in both inertial and kinetic ranges and their evolution in course of solar wind expansion.
Tracking Airborne Pollution with Environmental Magnetism in A Medium-Sized African City
Authors: Dawaï Daouda , Macouin Mélina , Rousse Sonia , Léon Jean-François , Gountié Dedzo Merlin , Drigo Loïc
Published: October 2021

As in other parts of the world, air pollution over West and Central Africa has major health and meteorological impacts. Air quality assessment and its possible sanitary impact have become essential even in medium-sized towns, therefore amplifying the need for easy-to-implement monitoring methods with low environmental impact. We present here the potential of magnetic methods to monitor air quality at street level in the medium-sized city of Maroua (northern Cameroon) affected by dust-laden desert winds. More than five hundred (544) samples of bark and leaves taken from Neem trees in Maroua were analyzed. Magnetic susceptibility, saturation remanence, and S-ratio were found to determine the concentration and nature of magnetic particles. They are dominated by magnetite-like particle signals as a part of particulate emissions due to urban activities, including both traffic, composed of a substantial proportion of motorcycles, and wood burning for food preparation. We show that both bark and leaves from Neem trees are adequate passive bio-recorders. The use of both enables different times and heights to be sampled, allowing for the high-resolution monitoring, in terms of spatialization, of various urban environments. Particle emissions require assessment and screening that could be carried out rapidly and efficiently by magnetic methods on bio-recorders, even in cities impacted by dust-laden wind.
Understanding the Trend of NO2, SO2 and CO over East Africa from 2005 to 2020
Authors: Opio Ronald , Mugume Isaac , Nakatumba-Nabende Joyce
Published: October 2021

The atmospheric chemistry constituents of nitrogen dioxide (NO2), sulphur dioxide (SO2) and carbon monoxide (CO) are associated with air pollution and climate change. In sub-Saharan Africa, a lack of sufficient ground-based and aircraft observations has, for a long time, limited the study of these species. This study thus utilized satellite observations as an alternative source of data to study the abundance of these species over the East African region. The instruments used included the Ozone Monitoring Instrument (OMI), the Atmospheric InfraRed Sounder (AIRS), and the TROPOspheric Monitoring Instrument (TROPOMI). An investigation of trends in the data series from 2005 to 2020 was carried out using the sequential Mann-Kendall test while the Pearson correlation coefficient was used to compare the data records of the instruments. The analysis revealed no trend in NO2 (p > 0.05), a decreasing trend in SO2 (p < 0.05), a decreasing trend (p < 0.05) in CO closer to the surface (850 hPa to 500 hPa) and an increasing trend (p < 0.05) in CO higher up in the atmosphere (400 hPa to 1 hPa). There is likely a vertical ascent of CO. The correlation between the instrument records was 0.54 and 0.77 for NO2 and CO, respectively. Furthermore, seasonal fires in the savanna woodlands were identified as the major source of NO2 and CO over the region, while cities such as Kampala, Nairobi, and Bujumbura and towns such as Dar es Salaam and Mombasa were identified as important NO2 hotspots. Similarly, the active volcano at Mt. Nyiragongo near Goma was identified as the most important SO2 hotspot.
Biofabrication of Artificial Stem Cell Niches in the Anterior Ocular Segment
Authors: Hidalgo-Alvarez Veronica , Dhowre Hala S. , Kingston Olivia A. , Sheridan Carl M. , Levis Hannah J.
Published: October 2021

The anterior segment of the eye is a complex set of structures that collectively act to maintain the integrity of the globe and direct light towards the posteriorly located retina. The eye is exposed to numerous physical and environmental insults such as infection, UV radiation, physical or chemical injuries. Loss of transparency to the cornea or lens (cataract) and dysfunctional regulation of intra ocular pressure (glaucoma) are leading causes of worldwide blindness. Whilst traditional therapeutic approaches can improve vision, their effect often fails to control the multiple pathological events that lead to long-term vision loss. Regenerative medicine approaches in the eye have already had success with ocular stem cell therapy and ex vivo production of cornea and conjunctival tissue for transplant recovering patients’ vision. However, advancements are required to increase the efficacy of these as well as develop other ocular cell therapies. One of the most important challenges that determines the success of regenerative approaches is the preservation of the stem cell properties during expansion culture in vitro. To achieve this, the environment must provide the physical, chemical and biological factors that ensure the maintenance of their undifferentiated state, as well as their proliferative capacity. This is likely to be accomplished by replicating the natural stem cell niche in vitro. Due to the complex nature of the cell microenvironment, the creation of such artificial niches requires the use of bioengineering techniques which can replicate the physico-chemical properties and the dynamic cell–extracellular matrix interactions that maintain the stem cell phenotype. This review discusses the progress made in the replication of stem cell niches from the anterior ocular segment by using bioengineering approaches and their therapeutic implications.
A Novel Screw Drive for Allogenic Headless Position Screws for Use in Osteosynthesis—A Finite-Element Analysis
Authors: Lifka Sebastian , Baumgartner Werner
Published: October 2021

Due to their osteoconductive properties, allogenic bone screws made of human cortical bone have advantages regarding rehabilitation compared to other materials such as stainless steel or titanium. Since conventional screw drives like hexagonal or hexalobular drives are difficult to manufacture in headless allogenic screws, an easy-to-manufacture screw drive is needed. In this paper, we present a simple drive for headless allogenic bone screws that allows the screw to be fully inserted. Since the screw drive is completely internal, no threads are removed. In order to prove the mechanical strength, we performed simulations of the new drive using the Finite-Element method (FEM), validated the simulations with a prototype screw, tested the novel screw drive experimentally and compared the simulations with conventional drives. The validation with the prototype showed that our simulations provided valid results. Furthermore, the simulations of the new screw drive showed good performance in terms of mechanical strength in allogenic screws compared to conventional screw drives. The presented screw drive is simple and easy to manufacture and is therefore suitable for headless allogenic bone screws where conventional drives are difficult to manufacture.
Screening of Parkinson’s Disease Using Geometric Features Extracted from Spiral Drawings
Authors: Chandra Jay , Muthupalaniappan Siva , Shang Zisheng , Deng Richard , Lin Raymond , Tolkova Irina , Butts Dignity , Sul Daniel , Marzouk Sammer , Bose Soham , Chen Alexander , Bhaskar Anushka , Mantena Sreekar , Press Daniel Z.
Published: September 2021

Conventional means of Parkinson’s Disease (PD) screening rely on qualitative tests typically administered by trained neurologists. Tablet technologies that enable data collection during handwriting and drawing tasks may provide low-cost, portable, and instantaneous quantitative methods for high-throughput PD screening. However, past efforts to use data from tablet-based drawing processes to distinguish between PD and control populations have demonstrated only moderate classification ability. Focusing on digitized drawings of Archimedean spirals, the present study utilized data from the open-access ParkinsonHW dataset to improve existing PD drawing diagnostic pipelines. Random forest classifiers were constructed using previously documented features and highly-predictive, newly-proposed features that leverage the many unique mathematical characteristics of the Archimedean spiral. This approach yielded an AUC of 0.999 on the particular dataset we tested on, and more importantly identified interpretable features with good promise for generalization across diverse patient cohorts. It demonstrated the potency of mathematical relationships inherent to the drawing shape and the usefulness of sparse feature sets and simple models, which further enhance interpretability, in the face of limited sample size. The results of this study also inform suggestions for future drawing task design and data analytics (feature extraction, shape selection, task diversity, drawing templates, and data sharing).
The Potential Impact of Digital Biomarkers in Multiple Sclerosis in The Netherlands: An Early Health Technology Assessment of MS Sherpa
Authors: Cloosterman Sonja , Wijnands Inez , Huygens Simone , Wester Valérie , Lam Ka-Hoo , Strijbis Eva , den Teuling Bram , Versteegh Matthijs
Published: October 2021

(1) Background: Monitoring of Multiple Sclerosis (MS) with eHealth interventions or digital biomarkers provides added value to the current care path. Evidence in the literature is currently scarce. MS sherpa is an eHealth intervention with digital biomarkers, aimed at monitoring symptom progression and disease activity. To show the added value of digital biomarker–based eHealth interventions to the MS care path, an early Health Technology Assessment (eHTA) was performed, with MS sherpa as an example, to assess the potential impact on treatment switches. (2) Methods: The eHTA was performed according to the Dutch guidelines for health economic evaluations. A decision analytic MS model was used to estimate the costs and benefits of MS standard care with and without use of MS sherpa, expressed in incremental cost-effectiveness ratios (ICERs) from both societal and health care perspectives. The efficacy of MS sherpa on early detection of active disease and the initiation of a treatment switch were modeled for a range of assumed efficacy (5%, 10%, 15%, 20%). (3) Results: From a societal perspective, for the efficacy of 15% or 20%, MS sherpa became dominant, which means cost-saving compared to the standard of care. MS sherpa is cost-effective in the 5% and 10% scenarios (ICERs EUR 14,535 and EUR 4069, respectively). From the health care perspective, all scenarios were cost-effective. Sensitivity analysis showed that increasing the efficacy of MS sherpa in detecting active disease early leading to treatment switches be the most impactful factor in the MS model. (4) Conclusions: The results indicate the potential of eHealth interventions to be cost-effective or even cost-saving in the MS care path. As such, digital biomarker–based eHealth interventions, like MS sherpa, are promising cost-effective solutions in optimizing MS disease management for people with MS, by detecting active disease early and helping neurologists in decisions on treatment switch.
Compensatory and Lifestyle-Based Brain Health Program for Subjective Cognitive Decline: Self-Implementation versus Coaching
Authors: Liou Harris , Stonnington Cynthia M. , Shah Amit A. , Buckner-Petty Skye A. , Locke Dona E. C.
Published: October 2021

Although recent studies have explored the potential of multidomain brain health programs, there is a dearth of literature on operationalizing this research to create a clinical treatment program specifically for subjective cognitive decline (SCD). Patients seen by geriatricians in primary care and by behavioral neurology services at our institution presenting with SCD were recruited via a patient-appropriate flyer. After all participants had a 1-h brain health consultation with a neuropsychologist and were provided with program materials, they were randomized to attend a 10-week intervention designed to support program implementation (N = 10) or the control group of implementing the program on their own (N = 11). The program included (1) a calendar-based executive and memory support system for compensatory training and (2) training in healthy lifestyle. There were no significant differences between groups for any outcomes. Participants across both groups showed significant improvements with moderate effect sizes in compensatory strategy use, anxiety symptoms, and daily functioning, which were sustained through 6-month follow-up. They also increased physical activity by the end of the intervention period but did not sustain this through 6-month follow-up. Our pilot study demonstrates preliminary feasibility of a cognitive compensatory and lifestyle-based brain health program. Additional research is recommended to further develop two potentially scalable implementation strategies—coaching and self-implementation after brief consultation.
Cognitive Functions in Patients after Carotid Artery Revascularization—A Narrative Review
Authors: Piegza Magdalena , Więckiewicz Gniewko , Wierzba Dawid , Piegza Jacek
Published: October 2021

Carotid revascularization may lead to improved cognitive function beyond stroke prevention. This article summarizes the conclusions from available studies on the effects of carotid reperfusion procedures on cognitive function. The papers cited used different neuropsychological tests for cognitive assessment, resulting in different methodologies and the results obtained were not always convergent. However, most studies reported an improvement in neurocognitive abilities after both vascular interventions, but a more precise assessment of the specific benefits is still awaited. Clinical determinants to predict the effects of these treatments on cognitive function are still being sought, but results are not yet satisfactory. In view of these studies, carotid stenosis seems to be an independent risk factor for cognitive deterioration, and the main mechanisms responsible are embolism and cerebral hypoperfusion. The aim of this study is to order the knowledge about the effects of carotid artery stenting (CAS) and endarterectomy (CEA) on neurocognitive functions and to verify the usefulness of using these treatments.
Considering Preventative Care in a Native vs. Non-native Language: A Foreign Language Effect
Authors: Hayakawa Sayuri , Pan Yue , Marian Viorica
Published: October 2021

Every day, multilinguals around the world make important healthcare decisions while using a foreign language. The present study examined how the use of a native vs. non-native language shapes evaluations and decisions about preventative care. Bilinguals were randomly assigned to evaluate a series of medical scenarios in either their native or non-native language. Each scenario described potential adverse effects of a medical condition and a preventative treatment, as well as the population risk of disease- or treatment-related complications. Participants judged the perceived negativity and likelihood of experiencing adverse effects and indicated how willing they would be to accept the preventative treatment. We found that bilinguals using a foreign language perceived disease symptoms and treatment side effects to be less negative than those using their native tongue. Foreign language users were also more likely to account for the objective risks associated with medical conditions and treatments when making decisions about preventative care. We conclude that the use of a native vs. foreign language changes how people evaluate the consequences of accepting and declining preventative treatment, with potential implications for millions of providers and patients who routinely make medical choices in their non-native tongue.
Understanding Architectural Designers’ Continuous Use Intention Regarding BIM Technology: A China Case
Authors: Cui Qinghong , Hu Xiancun , Liu Xiao , Zhao Lingmin , Wang Guangbin
Published: September 2021

Despite BIM technology influencing architectural design companies profoundly, there has still been an under-representation of architectural designers’ continuous use intention (CUI) regarding it. This paper aims to empirically examine what factors can potentially affect architectural designers’ CUI of BIM through the integration of a technology acceptance model (TAM) and an expectation confirmation theory (ECT). Sample data for empirical research were collected from architectural design companies in Qingdao, China. A total of 207 valid questionnaires were analyzed by using a structural equation modeling method. The findings show that the proposed theoretical model has good explanatory abilities for architectural designers’ CUI. Perceived ease of use and satisfaction significantly and directly affect CUI, whereas perceived usefulness and conformation have an indirect influence on CUI via satisfaction. This study contributes to a deepened understanding of architectural designers’ CUI regarding BIM. In order to further promote continuous use practices of BIM, valuable insights are provided for designers, companies, and software developers.
Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer
Authors: Kim Chang Woo , Chon Hong Jae , Kim Chan
Published: September 2021

Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. (1) They are poorly immunogenic because of their low tumor mutation burden; (2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8+ T cell immunity; (3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and (4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.
Comparison of the Metastasis Predictive Potential of mRNA and Long Non-Coding RNA Profiling in Systemically Untreated Breast Cancer
Authors: Do Thi T. N. , Block Ines , Burton Mark , Sørensen Kristina P. , Larsen Martin J. , Bak Martin , Cold Søren , Thomassen Mads , Tan Qihua , Kruse Torben A.
Published: September 2021

Several gene expression signatures based on mRNAs and a few based on long non-coding RNAs (lncRNAs) have been developed to provide prognostic information beyond clinical evaluation in breast cancer (BC). However, the comparison of such signatures for predicting recurrence is very scarce. Therefore, we compared the prognostic utility of mRNAs and lncRNAs in low-risk BC patients using two different classification strategies. Frozen primary tumor samples from 160 lymph node negative and systemically untreated BC patients were included; 80 developed recurrence—i.e., regional or distant metastasis while 80 remained recurrence-free (mean follow-up of 20.9 years). Patients were pairwise matched for clinicopathological characteristics. Classification based on differential mRNA or lncRNA expression using seven individual machine learning methods and a voting scheme classified patients into risk-subgroups. Classification by the seven methods with a fixed sensitivity of ≥90% resulted in specificities ranging from 16–40% for mRNA and 38–58% for lncRNA, and after voting, specificities of 38% and 60% respectively. Classifier performance based on an alternative classification approach of balanced accuracy optimization also provided higher specificities for lncRNA than mRNA at comparable sensitivities. Thus, our results suggested that classification followed by voting improved prognostic power using lncRNAs compared to mRNAs regardless of classification strategy.
Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring
Authors: Reita Damien , Pabst Lucile , Pencreach Erwan , Guérin Eric , Dano Laurent , Rimelen Valérie , Voegeli Anne-Claire , Vallat Laurent , Mascaux Céline , Beau-Faller Michèle
Published: September 2021

Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.
The Role of BiP and the IRE1α–XBP1 Axis in Rhabdomyosarcoma Pathology
Authors: Aghaei Mahmoud , Nasimian Ahmad , Rahmati Marveh , Kawalec Philip , Machaj Filip , Rosik Jakub , Bhushan Bhavya , Bathaie S. Zahra , Azarpira Negar , Los Marek J. , Samali Afshin , Perrin David , Gordon Joseph W. , Ghavami Saeid
Published: October 2021

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. Methods: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. Results: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). Conclusions: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease.
Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach
Authors: Dauvé Jonathan , Belloy Nicolas , Rivet Romain , Etique Nicolas , Nizet Pierre , Pietraszek-Gremplewicz Katarzyna , Karamanou Konstantina , Dauchez Manuel , Ramont Laurent , Brézillon Stéphane , Baud Stéphanie
Published: October 2021

Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.
Robotic Cancer Surgery
Authors: Hoeppner Jens
Published: October 2021

Cancer kills millions of people around the world every year [...]
PMEPA1/TMEPAI Is a Unique Tumorigenic Activator of AKT Promoting Proteasomal Degradation of PHLPP1 in Triple-Negative Breast Cancer Cells
Authors: Haque Md. Anwarul , Abdelaziz Mohammed , Puteri Meidi Utami , Vo Nguyen Thanh Thao , Kudo Kosei , Watanabe Yukihide , Kato Mitsuyasu
Published: October 2021

Transmembrane prostate androgen-induced protein (TMEPAI), also known as PMEPA1, is highly expressed in many types of cancer and promotes oncogenic abilities. However, the mechanisms whereby TMEPAI facilitates tumorigenesis are not fully understood. We previously established TMEPAI-knockout (KO) cells from human triple-negative breast cancer (TNBC) cell lines and found that TMEPAI-KO cells showed reduced tumorigenic abilities. Here, we report that TMEPAI-KO cells upregulated the expression of pleckstrin homology (PH) domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and suppressed AKT Ser473 phosphorylation, which was consistent with TCGA dataset analysis. Additionally, the knockdown (KD) of PHLPP1 in TMEPAI-KO cells partially but significantly rescued AKT Ser473 phosphorylation, as well as in vitro and in vivo tumorigenic activities, thus showing that TMEPAI functions as an oncogenic protein through the regulation of PHLPP1 subsequent to AKT activation. Furthermore, we demonstrated that TMEPAI PPxY (PY) motifs are essential for binding to NEDD4-2, an E3 ubiquitin ligase, and PHLPP1-downregulatory ability. Moreover, TMEPAI enhanced the complex formation of PHLPP1 with NEDD4-2 and PHLPP1 polyubiquitination, which leads to its proteasomal degradation. These findings indicate that the PY motifs of TMEPAI suppress the amount of PHLPP1 and maintain AKT Ser473 phosphorylation at high levels to enhance the tumorigenic potentiality of TNBC.
Organ-Specific Uptake of Extracellular Vesicles Secreted by Urological Cancer Cells
Authors: Linxweiler Johannes , Kolbinger Anja , Himbert Dirk , Zeuschner Philip , Saar Matthias , Stöckle Michael , Junker Kerstin
Published: October 2021

Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In this study, we analyzed the organ-specific uptake of EVs secreted by urological cancer cells using an innovative in-vivo approach. EVs from benign and malignant prostate, kidney, and bladder cells were isolated using ultracentrifugation, fluorescence-labeled and injected intravenously in immunodeficient mice. After 12 or 24 h, the animals were sacrificed, their organs were harvested and analyzed for the presence of EVs by high-resolution fluorescence microscopy. Across all entities, EVs were taken up fast (12 h > 24 h), and EVs from malignant cells were taken up more efficiently than EVs from benign cells. Though not entirely organ-specific, EVs were incorporated in different amounts, depending on the entity (prostate: lung > liver > brain; kidney: brain > lung > liver; bladder: lung > liver > brain). EV uptake in other organs than lung, liver, brain, and spleen was not observed. Our results suggest a role of EVs in the formation of premetastatic niches and an organotropism in EV uptake, which have to be examined in more detail in further studies.
Use of FOLFIRINOX or Nab-Paclitaxel Plus Gemcitabine for the Treatment of Locally Advanced Pancreatic Adenocarcinoma: A Single Institution Observational Study
Authors: Servetto Alberto , Santaniello Antonio , Napolitano Fabiana , Foschini Francesca , Marciano Roberta , Mozzillo Eleonora , Cascetta Priscilla , Amato Anna Rita , Augurio Maria Rosaria , Maresca Lucia , De Placido Pietro , De Placido Sabino , Formisano Luigi , Bianco Roberto
Published: October 2021

Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II–III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3–4 side effects. Higher rates of thrombocytosis (p < 0.0001) and peripheral edema (p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.
A Geant4-DNA Evaluation of Radiation-Induced DNA Damage on a Human Fibroblast
Authors: Shin Wook-Geun , Sakata Dousatsu , Lampe Nathanael , Belov Oleg , Tran Ngoc Hoang , Petrovic Ivan , Ristic-Fira Aleksandra , Dordevic Milos , Bernal Mario A. , Bordage Marie-Claude , Francis Ziad , Kyriakou Ioanna , Perrot Yann , Sasaki Takashi , Villagrasa Carmen , Guatelli Susanna , Breton Vincent , Emfietzoglou Dimitris , Incerti Sebastien
Published: October 2021

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application “molecularDNA”, an example for users of Geant4-DNA, will soon be distributed through Geant4.
Anti-GD2 Based Immunotherapy Prevents Late Events in High-Risk Neuroblastoma Patients over 18 Months at Diagnosis
Authors: Tas Michelle L. , Dootjes Lisa W. , Fiocco Marta , de Krijger Ronald R. , Dierselhuis Miranda P. , van Eijkelenburg Natasha K. A. , van Grotel Martine , Kraal Kathelijne C. J. M. , Peek Annemarie M. L. , Tytgat Godelieve A. M. , van Noesel Max M.
Published: October 2021

Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the long-term efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with single-agent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy. Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 ± 7% and 49 ± 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 ± 7% and 41 ± 8%, respectively (p = 0.16). In the subgroup of patients ≥ 18 months, 5-yr OS was 63 ± 8% and 39 ± 9, respectively (p = 0.04) and EFS 54 ± 8% and 29 ± 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events. Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.
FAP and FAPI-PET/CT in Malignant and Non-Malignant Diseases: A Perfect Symbiosis?
Authors: Dendl Katharina , Koerber Stefan A. , Kratochwil Clemens , Cardinale Jens , Finck Rebecca , Dabir Mardjan , Novruzov Emil , Watabe Tadashi , Kramer Vasko , Choyke Peter L. , Haberkorn Uwe , Giesel Frederik L.
Published: October 2021

A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.