bluuebunny/crossref_metadata_2025 huggingface dataset:
The Quality of Life of Patients with Hereditary Nonpolyposis Colorectal Cancer Undergoing Preoperative Chemoradiation
Authors: Chirica Valeriu Aurelian , Matei Mioara , Postolica Roxana , Chelaru Liliana , Esanu Irina Mihaela , Sanduleac Lidia , Porumb Vlad , Boanca Mihaela , Coman Elena Adorata , Azoicai Doina
Published: September 2020

Of all the neoplastic sites, colorectal cancer (CRC) is one of the most common cancers in the family. Studies estimate that approximately 30% of all the CRC cases are a hereditary form of the disease with a potentially high impact on the quality of life (QoL), with a high risk of recurrence, and with bio–psycho–social functioning. The aim of the study was to assess the QoL of colorectal cancer patients with genetic risk by using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire version QLQ-CR29. Materials and methods: The cross-sectional, single-center study was performed on a group of 32 patients with genetic risk of colorectal cancer, who underwent preoperative chemoradiation and surgery. Results: The series of values for the scores on the symptom scale varied between 15 and 30, and the average level of symptom scores did not differ significantly between gender (22.0 vs. 22.75; p = 0.636), highlighting a moderate impairment of QoL. Scores for the emotional functioning scale were significantly lower in men (10.33 vs. 13.25; p = 0.049), as were the scores for the physical functions (15.67 vs. 19.15; p = 0.039), showing a decrease in QoL. Conclusions: The overall score showed an average QoL in patients with colorectal cancer with genetic risk, highlighting significant differences in psycho-emotional functioning between women and men.
Computer-Aided Environmental Assessment Applied for Estimation of Ecological Impacts Derived from Topological Pathways Based on Lignocellulosic Biomass Transformation
Authors: Meramo-Hurtado Samir Isaac , Puello Plinio , Rodríguez Julio
Published: September 2020

The growing awareness to include sustainability goals in the chemical process design has been making palpable since many governments and research institutions have made many efforts precisely to progress new ways to transform available resources into valuable chemicals. In this sense, this work is presenting a computer-aided evaluation based on environmental impact assessment and comparison of technical parameters for estimating the potential effects of two biorefinery designs. The first process involved a multiproduct production of acetone, butanol, and ethanol from cassava waste, while the second biorefinery comprised of succinic acid and bioethanol production from a mixture of cassava waste and banana rachis. These residues are highly available in the North Colombia region due to the agroindustrial activities of that zone. The developed environmental analysis employed the waste reduction algorithm (WAR) for estimating impact generation and output rates considering atmospheric and toxicological categories. Otherwise, process simulation of biorefineries showed production of 546.3 kg/h of acetone, 280.0 kg/h of ethanol, and 1305 kg/h of butanol for topology 1, while topology 2 delivered a synthesis of 13,865.7 kg/h of acetic acid and 2277.9 kg/h of ethanol. Data generated from process simulation allowed performing a technical comparison between evaluated biorefineries, showing a higher performance of evaluated indicators for topology 2. These evaluated variables included resource energy efficiency, and production yield, among others. The environmental analysis provided relevant information, indicating that topology 2 is a better alternative from an ecological viewpoint since this design would emit substances with lower effects than topology 1.
Mechanical Properties and Flexural Behavior of Sustainable Bamboo Fiber-Reinforced Mortar
Authors: Maier Marcus , Javadian Alireza , Saeidi Nazanin , Unluer Cise , Taylor Hayden K. , Ostertag Claudia P.
Published: September 2020

In this study, a sustainable mortar mixture is developed using renewable by-products for the enhancement of mechanical properties and fracture behavior. A high-volume of fly ash—a by-product of coal combustion—is used to replace Portland cement while waste by-products from the production of engineered bamboo composite materials are used to obtain bamboo fibers and to improve the fracture toughness of the mixture. The bamboo process waste was ground and size-fractioned by sieving. Several mixes containing different amounts of fibers were prepared for mechanical and fracture toughness assessment, evaluated via bending tests. The addition of bamboo fibers showed insignificant losses of strength, resulting in mixtures with compressive strengths of 55 MPa and above. The bamboo fibers were able to control crack propagation and showed improved crack-bridging effects with higher fiber volumes, resulting in a strain-softening behavior and mixture with higher toughness. The results of this study show that the developed bamboo fiber-reinforced mortar mixture is a promising sustainable and affordable construction material with enhanced mechanical properties and fracture toughness with the potential to be used in different structural applications, especially in developing countries.
Mooring-Failure Monitoring of Submerged Floating Tunnel Using Deep Neural Network
Authors: Kwon Do-Soo , Jin Chungkuk , Kim MooHyun , Koo Weoncheol
Published: September 2020

This paper presents a machine learning method for detecting the mooring failures of SFT (submerged floating tunnel) based on DNN (deep neural network). The floater-mooring-coupled hydro-elastic time-domain numerical simulations are conducted under various random wave excitations and failure/intact scenarios. Then, the big-data is collected at various locations of numerical motion sensors along the SFT to be used for the present DNN algorithm. In the input layer, tunnel motion-sensor signals and wave conditions are inputted while the output layer provides the probabilities of 21 failure scenarios. In the optimization stage, the numbers of hidden layers, neurons of each layer, and epochs for reliable performance are selected. Several activation functions and optimizers are also tested for the present DNN model, and Sigmoid function and Adamax are respectively adopted to enhance the classification accuracy. Moreover, a systematic sensitivity test with respect to the numbers and arrangements of sensors is performed to find the appropriate sensor combination to achieve target prediction accuracy. The technique of confusion matrix is used to represent the accuracy of the DNN algorithms for various cases, and the classification accuracy as high as 98.1% is obtained with seven sensors. The results of this study demonstrate that the DNN model can effectively monitor the mooring failures of SFTs utilizing real-time sensor signals.
Sensitivity of Simulated PM2.5 Concentrations over Northeast Asia to Different Secondary Organic Aerosol Modules during the KORUS-AQ Campaign
Authors: Lee Hyo-Jung , Jo Hyun-Young , Song Chang-Keun , Jo Yu-Jin , Park Shin-Young , Kim Cheol-Hee
Published: September 2020

A numerical sensitivity study on secondary organic aerosol formation has been carried out by employing the WRF-Chem (Weather Research and Forecasting model coupled with Chemistry). Two secondary organic aerosol formation modules, the Modal Aerosol Dynamics model for Europe/Volatility Basis Set (MADE/VBS) and the Modal Aerosol Dynamics model for Europe/Secondary Organic Aerosol Model (MADE/SORGAM) were employed in the WRF-Chem model, and surface PM2.5 (particulate matter less than 2.5 μm in size) mass concentration and the composition of its relevant chemical sources, i.e., SO42−, NO3−, NH4+, and organic carbon (OC) were simulated during the Korea-United States Air Quality (KORUS-AQ) campaign period (1 May to 12 June 2016). We classified the KORUS-AQ period into two cases, the stagnant period (16–21 May) which was dominated by local emission and the long-range transport period (25–31 May) which was affected by transport from the leeward direction, and focused on the differences in OC secondary aerosol formation between two modules over Northeast Asia. The simulated surface PM2.5 chemical components via the two modules showed the largest systematic biases in surface OC, with a mean bias of 4.5 μg m−3, and the second largest in SO42− abundance of 2.2 μg m−3 over Seoul. Compared with surface observations at two ground sites located near the western coastal Korean Peninsula, MADE/VBS exhibited the overpredictions in OC by 170–180%, whereas MADE/SORGAM showed underpredictions by 49–65%. OC and sulfate via MADE/VBS were simulated to be much higher than that simulated by MADE/SORGAM by a factor of 2.8–3.5 and 1.5–1.9, respectively. Model verification against KORUS-AQ aircraft measurements also showed large discrepancies in simulated non-surface OC between the two modules by a factor of five, with higher OC by MADE/VBS and lower IC by MADE/SORGAM, whereas much closer MADE/VBS simulations to the KORUS-AQ aircraft measurements were found. On the basis of the aircraft measurements, the aggregated bias (sum of four components) for PM2.5 mass concentrations from the MADE/VBS module indicated that the simulation was much closer to the measurements, nevertheless more elaborate analysis on the surface OC simulation performance would be needed to improve the ground results. Our findings show that significant inconsistencies are present in the secondary organic aerosol formation simulations, suggesting that PM2.5 forecasts should be considered with great caution, as well as in the context of policymaking in the Northeast Asia region.
Evaluation of the Four-Dimensional Ensemble-Variational Hybrid Data Assimilation with Self-Consistent Regional Background Error Covariance for Improved Hurricane Intensity Forecasts
Authors: Zhang Shixuan , Pu Zhaoxia
Published: September 2020

The feasibility of a hurricane initialization framework based on the Gridpoint Statistical Interpolation (GSI)-based four-dimensional ensemble-variational (GSI-4DEnVar) hybrid data assimilation system for the Hurricane Weather Research and Forecasting model (HWRF) model is evaluated in this study. The system considers the temporal evolution of error covariances via the use of four-dimensional ensemble perturbations that are provided by high-resolution, self-consistent HWRF ensemble forecasts. It is different from the configuration of the GSI-based three-dimensional ensemble-variational (GSI-3DEnVar) hybrid data assimilation system, similar to that used in the operational HWRF, which employs background error covariances provided by coarser-resolution global ensembles from the National Centers for Environmental Prediction (NCEP) Global Forecast System (GFS) ensemble Kalman filtering data assimilation system. In addition, our proposed initialization framework discards the empirical intensity correction in the vortex initialization package that is employed by the GSI-3DEnVar initialization framework in operational HWRF. Data assimilation and numerical simulation experiments for Hurricanes Joaquin (2015), Patricia (2015), and Matthew (2016) are conducted during their intensity changes. The impacts of two initialization frameworks on the HWRF analyses and forecasts are compared. It is found that GSI-4DEnVar leads to a reduction in track, minimum sea level pressure (MSLP), and maximum surface wind (MSW) forecast errors in all of the HWRF simulations, compared with the GSI-3DEnVar initialization framework. With assimilating high-resolution observations within the hurricane inner-core region, GSI-4DEnVar can produce the initial hurricane intensity reasonably well without the empirical vortex intensity correction. Further diagnoses with Hurricane Joaquin indicate that GSI-4DEnVar can significantly alleviate the imbalances in the initial conditions and enhance the performance of the data assimilation and subsequent hurricane intensity and precipitation forecasts.
Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues
Authors: Perišić Ognjen
Published: September 2020

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.
Special Issue: Juvenile Onset Huntington’s Disease
Authors: Nopoulos Peg C.
Published: September 2020

[...]
The Involvement of Hypothalamus–Pituitary–Adrenal (HPA) Axis in Suicide Risk
Authors: Berardelli Isabella , Serafini Gianluca , Cortese Natalia , Fiaschè Federica , O’Connor Rory C , Pompili Maurizio
Published: September 2020

Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction.
Mitigating Effects of Liriope platyphylla on Nicotine-Induced Behavioral Sensitization and Quality Control of Compounds
Authors: Yoon Dahye , Ryu In Soo , Shin Woo Cheol , Ka Minhan , Kim Hyoung-Geun , Jang Eun Young , Kim Oc-Hee , Lee Young-Seob , Seo Joung-Wook , Lee Dae Young
Published: September 2020

In this study we investigated the mitigating effects of Liriope platyphylla Wang et Tang extract on behavioral sensitization and the quantification of its major compounds. The extract of L. platyphylla reduces the expression of tyrosine hydroxylase (TH) protein, which is increased by nicotine, back to normal levels, and increases the expression of dopamine transporter (DAT) protein, which is reduced by nicotine, back to normal levels in PC12 cells. In this study, rats received nicotine (0.4 mg/kg, subcutaneously) only for seven days and then received extract of L. platyphylla (200 or 400 mg/kg, oral) 1 h prior to nicotine administration for an additional seven days. The extract of L. platyphylla reduced locomotor activity compared to the nicotine control group in rats. The extract of L. platyphylla significantly attenuated the repeated nicotine-induced DAT protein expression in the nucleus accumbens (NAc), but there was no effect on increased TH protein expression in the dorsal striatum. These findings suggest that L. platyphylla extract has a mitigating effect on nicotine-induced behavioral sensitization by modulating DAT protein expression in the NAc. For quality control of L. plathyphylla, spicatoside A and D, which are saponin compounds, were quantified in the L. platyphylla extract. The amounts of spicatoside A and D in L. platyphylla extract obtained from ultra-high-performance liquid chromatography with tandem mass spectrometry were 0.148 and 0.272 mg/g, respectively. The identification of these compounds in L. platyphylla, which can be used for quality control, provides important information for the development of drugs to treat nicotine dependence.
Non-Immersive Virtual Reality for Post-Stroke Upper Extremity Rehabilitation: A Small Cohort Randomized Trial
Authors: Miclaus Roxana , Roman Nadinne , Caloian Silviu , Mitoiu Brindusa , Suciu Oana , Onofrei Roxana Ramona , Pavel Ecaterina , Neculau Andrea
Published: September 2020

Immersive and non-immersive virtual reality (NIVR) technology can supplement and improve standard physiotherapy and neurorehabilitation in post-stroke patients. We aimed to use MIRA software to investigate the efficiency of specific NIVR therapy as a standalone intervention, versus standardized physiotherapy for upper extremity rehabilitation in patients post-stroke. Fifty-five inpatients were randomized to control groups (applying standard physiotherapy and dexterity exercises) and experimental groups (applying NIVR and dexterity exercises). The two groups were subdivided into subacute (six months to four years post-stroke survival patients). The following standardized tests were applied at baseline and after two weeks post-therapy: Fugl–Meyer Assessment for Upper Extremity (FMUE), the Modified Rankin Scale (MRS), Functional Independence Measure (FIM), Active Range of Motion (AROM), Manual Muscle Testing (MMT), Modified Ashworth Scale (MAS), and Functional Reach Test (FRT). The Kruskal–Wallis test was used to determine if there were significant differences between the groups, followed with pairwise comparisons. The Wilcoxon Signed-Rank test was used to determine the significance of pre to post-therapy changes. The Wilcoxon Signed-Rank test showed significant differences in all four groups regarding MMT, FMUE, and FIM assessments pre- and post-therapy, while for AROM, only experimental groups registered significant differences. Independent Kruskal–Wallis results showed that the subacute experimental group outcomes were statistically significant regarding the assessments, especially in comparison with the control groups. The results suggest that NIVR rehabilitation is efficient to be administered to post-stroke patients, and the study design can be used for a further trial, in the perspective that NIVR therapy can be more efficient than standard physiotherapy within the first six months post-stroke.
Adjuvant Chemotherapy for Stage III Colon Cancer
Authors: Taieb Julien , Gallois Claire
Published: September 2020

In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC.
Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors
Authors: Kobayashi Akira
Published: September 2020

The physiological roles of the NRF2-related transcription factor NRF3 (NFE2L3) have remained unknown for decades. The remarkable development of human cancer genome databases has led to strong suggestions that NRF3 has functional significance in cancer; specifically, high NRF3 mRNA levels are induced in many cancer types, such as colorectal cancer and pancreatic adenocarcinoma, and are associated with poor prognosis. On the basis of this information, the involvement of NRF3 in tumorigenesis and cancer malignancy has been recently proposed. NRF3 confers cancer cells with selective growth advantages by enhancing 20S proteasome assembly through induction of the chaperone gene proteasome maturation protein (POMP) and consequently promoting degradation of the tumor suppressors p53 and retinoblastoma (Rb) in a ubiquitin-independent manner. This new finding offers insight into the proteasomal but not the genetic inactivation mechanism of tumor suppressors. Moreover, NRF3 promotes cancer malignancy-related processes, including metastasis and angiogenesis. Finally, the molecular mechanisms underlying NRF3 activation have been elucidated, and this knowledge is expected to provide many insights that are useful for the development of anticancer drugs that attenuate NRF3 transcriptional activity. Collectively, the evidence indicates that NRF3 confers cells with six so-called “hallmarks of cancer”, implying that it exhibits cancer driver gene-like function. This review describes recent research advances regarding the newly discovered addiction of cancer cells to NRF3 compared to NRF2.
Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer
Authors: He Zongsheng , Khatib Abdel-Majid , Creemers John W. M.
Published: September 2020

In triple negative breast cancer (TNBC) cell lines, the proprotein convertase Furin cleaves and then activates several protein precursors involved in oncogenesis. However, the in vivo role of Furin in the mammary gland and how mammary gland-specific Furin knockout specifically influences tumor initiation and progression of TNBC is unknown. Here, we report that Furin is frequently overexpressed in TNBC tumors and this correlates with poor prognosis in patients with TNBC tumors. In a whey acidic protein (WAP)-induced mammary epithelial cell-specific Furin knockout mouse model, mice show normal mammary development. However, loss of Furin in mammary glands inhibits primary tumor growth and lung metastasis in an oncogene-induced TNBC mouse model. Further analysis of TNBC mice lacking Furin revealed repressed maturation of the Furin substrates proIGF1R and proIR that are associated with reduced expression and activation of their downstream effectors PI3K/AKT and MAPK/ERK1/2. In addition, these tissues showed enhanced apoptotic signaling. In conclusion, our findings reveal that upregulated Furin expression reflects the poor prognosis of TNBC patients and highlights the therapeutic potential of inhibiting Furin in TNBC tumors.
RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A)
Authors: Roßwag Sven , Thiede Gitta , Sleeman Jonathan P. , Thaler Sonja
Published: September 2020

The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ERα expression and function in ERα-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ERα expression and activity. Here we report that RASSF1A acts as an inhibitor of ERα-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ERα expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ERα+ breast cancer initiation and progression.
FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer
Authors: Lin Che-Hsuan , Lee Hsun-Hua , Chang Wei-Min , Lee Fei-Peng , Chen Lung-Che , Lu Long-Sheng , Lin Yuan-Feng
Published: September 2020

Radiotherapy is commonly used to treat oral cancer patients in the current clinics; however, a subpopulation of patients shows poor radiosensitivity. Therefore, the aim of this study is to identify a biomarker or druggable target to enhance the effectiveness of radiotherapy on oral cancer patients. By performing an in silico analysis against public databases, we found that the upregulation of FOXD1, a gene encoding forkhead box d1 (Foxd1), is extensively detected in primary tumors compared to normal tissues and associated with a poor outcome in oral cancer patients receiving irradiation treatment. Moreover, our data showed that the level of FOXD1 transcript is causally relevant to the effective dosage of irradiation in a panel of oral cancer cell lines. The FOXD1 knockdown (FOXD1-KD) dramatically suppressed the colony-forming ability of oral cancer cells after irradiation treatment. Differentially expressed genes analysis showed that G3BP2, a negative regulator of p53, is predominantly repressed after FOXD1-KD and transcriptionally regulated by Foxd1, as judged by a luciferase-based promoter assay in oral cancer cells. Gene set enrichment analysis significantly predicted the inhibition of E2F-related signaling pathway but the activation of the interferons (IFNs) and p53-associated cellular functions, which were further validated by luciferase reporter assays in the FOXD1-KD oral cancer cells. Robustly, our data showed that FOXD1-KD fosters the expression of TXNIP, a downstream effector of IFN signaling and activator of p53, in oral cancer cells. These findings suggest that FOXD1 targeting might potentiate the anti-cancer effectiveness of radiotherapy and promote immune surveillance on oral cancer.
Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder
Authors: van Wilpe Sandra , Gerretsen Eveline C. F. , van der Heijden Antoine G. , de Vries I. Jolanda M. , Gerritsen Winald R. , Mehra Niven
Published: September 2020

The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC. Current evidence indicates that a high density of tumor-infiltrating CD8+ T cells is a favorable prognostic factor, whereas PD-L1 expression and tumor-associated macrophages are unfavorable prognostic features. While PD-L1 expression appears unsuccessful as a biomarker for the response to checkpoint inhibitors, there are some indications that high CD8+ T cell infiltration, low transforming growth factor-beta signaling and low densities of myeloid-derived suppressor cells are associated with response. Future studies should focus on combinations of biomarkers to accurately predict survival and response to treatment.
Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis
Authors: Ferri-Borgogno Sammy , Barui Sugata , McGee Amberly M. , Griffiths Tamara , Singh Pankaj K. , Piett Cortt G. , Ghosh Bidyut , Bhattacharyya Sanchari , Singhi Aatur , Pradhan Kith , Verma Amit , Nagel Zac , Maitra Anirban , Gupta Sonal
Published: September 2020

Background & Aims: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. Methods: Pancreas-specific mutant Arid1a-driven GEM model (Ptf1a-Cre; KrasG12D; Arid1af/f or “KAC”) was generated by crossing Ptf1a-Cre; KrasG12D (“KC”) mice with Arid1af/f mice and characterized histologically with timed necropsies. Arid1a was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. Results: Retention of Arid1a is critical for early progression of mutant Kras-driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in “KAC” as compared to “KC” mice. Enforced deletion of Arid1a in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of “KAC” mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous “KAC” mice revealed various compensatory (“escaper”) mechanisms to overcome the growth suppressive effects of Arid1a loss. Conclusions: Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of “escaper” mechanisms drive progression.
Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
Authors: van Beijnum Judy R. , Weiss Andrea , Berndsen Robert H. , Wong Tse J. , Reckman Louise C. , Piersma Sander R. , Zoetemelk Marloes , de Haas Richard , Dormond Olivier , Bex Axel , Henneman Alexander A. , Jimenez Connie R. , Griffioen Arjan W. , Nowak-Sliwinska Patrycja
Published: September 2020

Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED5–25) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC.
RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives
Authors: Kang Donghee , Lee Yerim , Lee Jae-Seon
Published: September 2020

RNA-binding proteins (RBPs) crucially regulate gene expression through post-transcriptional regulation, such as by modulating microRNA (miRNA) processing and the alternative splicing, alternative polyadenylation, subcellular localization, stability, and translation of RNAs. More than 1500 RBPs have been identified to date, and many of them are known to be deregulated in cancer. Alterations in the expression and localization of RBPs can influence the expression levels of oncogenes, tumor-suppressor genes, and genome stability-related genes. RBP-mediated gene regulation can lead to diverse cancer-related cellular phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and epithelial-mesenchymal transition (EMT)/invasion/metastasis. This regulation can also be associated with cancer prognosis. Thus, RBPs can be potential targets for the development of therapeutics for the cancer treatment. In this review, we describe the molecular functions of RBPs, their roles in cancer-related cellular phenotypes, and various approaches that may be used to target RBPs for cancer treatment.
Advances in Research on Human Meningiomas
Authors: Torp Sverre Helge , Scheie David
Published: September 2020

Meningiomas are the most common intracranial tumours in humans, constituting more than one third [...]
Editorial Catalysts: Special Issue on Novel Enzyme and Whole-Cell Biocatalysts
Authors: Sunna Anwar , Daniellou Richard
Published: September 2020

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Iron-Catalyzed Carbonyl–Alkyne and Carbonyl–Olefin Metathesis Reactions
Authors: Grau Benedikt W. , Tsogoeva Svetlana B.
Published: September 2020

Construction of carbon–carbon bonds is one of the most important tools for the synthesis of complex organic molecules. Among multiple possibilities are the carbonyl–alkyne and carbonyl–olefin metathesis reactions, which are used to form new carbon–carbon bonds between carbonyl derivatives and unsaturated organic compounds. As many different approaches have already been established and offer reliable access to C=C bond formation via carbonyl–alkyne and carbonyl–olefin metathesis, focus is now shifting towards cost efficiency, sustainability and environmentally friendly metal catalysts. Iron, which is earth-abundant and considered as an eco-friendly and inexpensive option in comparison to traditional metal catalysts, fulfils these requirements. Hence, the focus of this review is on recent advances in the iron-catalyzed carbonyl–alkyne, carbonyl–olefin and related C–O/C–O metathesis reactions. The still large research potential for ecologically and economically attractive and sustainable iron-based catalysts is demonstrated.
Neutrophils and Neutrophil Extracellular Traps Regulate Immune Responses in Health and Disease
Authors: Mulay Shrikant R. , Anders Hans-Joachim
Published: September 2020

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...]
NRF2 Is an Upstream Regulator of MYC-Mediated Osteoclastogenesis and Pathological Bone Erosion
Authors: Park Peter Sang Uk , Mun Se Hwan , Zeng Steven L. , Kim Haemin , Bae Seyeon , Park-Min Kyung-Hyun
Published: September 2020

Osteoclasts are the sole bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathogenic bone destruction such as inflammatory arthritis. Pharmacologically targeting osteoclasts has been a promising approach to alleviating bone disease, but there remains room for improvement in mitigating drug side effects and enhancing cell specificity. Recently, we demonstrated the crucial role of MYC and its downstream effectors in driving osteoclast differentiation. Despite these advances, upstream regulators of MYC have not been well defined. In this study, we identify nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor known to regulate the expression of phase II antioxidant enzymes, as a novel upstream regulator of MYC. NRF2 negatively regulates receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis through the ERK and p38 signaling-mediated suppression of MYC transcription. Furthermore, the ablation of MYC in osteoclasts reverses the enhanced osteoclast differentiation and activity in NRF2 deficiency in vivo and in vitro in addition to protecting NRF2-deficient mice from pathological bone loss in a murine model of inflammatory arthritis. Our findings indicate that this novel NRF2-MYC axis could be instrumental for the fine-tuning of osteoclast formation and provides additional ways in which osteoclasts could be therapeutically targeted to prevent pathological bone erosion.
Parental Attitudes toward Artificial Intelligence-Driven Precision Medicine Technologies in Pediatric Healthcare
Authors: Sisk Bryan A. , Antes Alison L. , Burrous Sara , DuBois James M.
Published: September 2020

Precision medicine relies upon artificial intelligence (AI)-driven technologies that raise ethical and practical concerns. In this study, we developed and validated a measure of parental openness and concerns with AI-driven technologies in their child’s healthcare. In this cross-sectional survey, we enrolled parents of children <18 years in 2 rounds for exploratory (n = 418) and confirmatory (n = 386) factor analysis. We developed a 12-item measure of parental openness to AI-driven technologies, and a 33-item measure identifying concerns that parents found important when considering these technologies. We also evaluated associations between openness and attitudes, beliefs, personality traits, and demographics. Parents (N = 804) reported mean openness to AI-driven technologies of M = 3.4/5, SD = 0.9. We identified seven concerns that parents considered important when evaluating these technologies: quality/accuracy, privacy, shared decision making, convenience, cost, human element of care, and social justice. In multivariable linear regression, parental openness was positively associated with quality (beta = 0.23), convenience (beta = 0.16), and cost (beta = 0.11), as well as faith in technology (beta = 0.23) and trust in health information systems (beta = 0.12). Parental openness was negatively associated with the perceived importance of shared decision making (beta = −0.16) and being female (beta = −0.12). Developers might support parental openness by addressing these concerns during the development and implementation of novel AI-driven technologies.
Pain Symptomatology and Management in Pediatric Ehlers–Danlos Syndrome: A Review
Authors: Feldman Estée C. H. , Hivick Daniel P. , Slepian P. Maxwell , Tran Susan T. , Chopra Pradeep , Greenley Rachel Neff
Published: September 2020

Ehlers–Danlos syndromes (EDS) are a group of connective tissue disorders that manifest with hyperextensibility of joints and skin, and general tissue fragility. While not a major criterion for clinical diagnosis, pain is a frequently endorsed symptom across subtypes of EDS. As such, the present review aims to summarize research to date on pain characteristics and management, and the relationship between such pain symptomatology and quality of life in pediatric EDS. Characteristics of pain, including theorized etiology, relative intensity and extent of pain are described, as well as descriptions of frequently endorsed pain sites (musculoskeletal, and non-musculoskeletal). Interventions related to the management of musculoskeletal (e.g., pharmaceutical intervention, physical therapy) and non-musculoskeletal pain (e.g., pharmaceutical and psychological interventions) are discussed, highlighting the need for additional research related to pediatric pain management in the context of hypermobility syndromes. In addition, the relationship between pain in pediatric EDS and quality of life is described. Finally, limitations of literature to date are described and recommendations for future lines of research are outlined.
Na2SO4 + V2O5 Corrosion Behavior of BaNd2Ti3O10 for Thermal Barrier Coating Applications
Authors: She Yajuan , Guo Yiwen , Tan Zanxian , Liao Kai
Published: September 2020

BaNd2Ti3O10 has been considered as a promising thermal barrier coating (TBC) candidate material, which reveals many advantages over the widely used TBC material of yttria partially stabilized zirconia, such as lower thermal conductivity, better high-temperature capability, and higher resistance to environmental deposits corrosion. In this study, the hot corrosion behavior of BaNd2Ti3O10 in Na2SO4 + V2O5 molten salt at 900 °C and 1000 °C is investigated. Exposed to the salt for 4 h at 900 °C, BaNd2Ti3O10 pellets had an obvious reaction with the salt, forming corrosion products of NdVO4, TiO2, and BaSO4, and the reaction layer was ~30 μm, beneath which no salt trace could be found. Prolonging the corrosion time to 20 h, the type of the corrosion products had no change. At an elevated corrosion temperature of 1000 °C for 4 h, the corrosion products were still NdVO4, TiO2, and BaSO4, but NdVO4 revealed a significant growth, which fully covered the pellet surface. The mechanisms by which the corrosion reaction between BaNd2Ti3O10 and the molten salt occurred were discussed.
Formation of Tribofilm in the Friction of Fluorinated Diamond-Like Carbon (FDLC) Film against Ti6Al4V in Bovine Serum Albumin (BSA) Solution
Authors: Zhang Tengfei , Xu Zhaoying , Su Yongyao , Wang Jinbiao , Li Lu , Chong Kok Boon , Hou Xiaodong , Paddea Sanjooram
Published: September 2020

A route to reducing the wear of the metal counterpart in the friction of meatal against diamond-like carbon (DLC) is to form a lubricating tribofilm on the metal counterface. However, in liquid lubricating conditions, the formation of tribofilm can be influenced by both the lubricating medium and the counterpart material. Here we report the effect of lubricating biomolecule and doping fluorine element on the formation of tribofilm in fluorinated DLC (FDLC)-Ti6Al4V friction system. A group of ball-on-disc frictional experiments with different sliding speeds and normal loads were performed in phosphate buffer solution (PBS) and bovine serum albumin (BSA) solution. The results showed the formation of tribofilm was inhibited by the absorption of biomolecules on the frictional surface, thus improving the friction coefficient and wear of Ti6Al4V counterpart. Doping fluorine into DLC film also can restrain the formation of tribofilm on Ti6Al4V counterface. As a result, tribofilm is difficult to form when Ti6Al4V counterface slides against FDLC in BSA solution. Fluorinated DLC film should be considered carefully for the anti-wear use in body fluid containing biomolecules because it might cause severe wear of the counterpart material.
Artificial Superhydrophobic and Antifungal Surface on Goose Down by Cold Plasma Treatment
Authors: Kapica Ryszard , Markiewicz Justyna , Tyczkowska-Sieroń Ewa , Fronczak Maciej , Balcerzak Jacek , Sielski Jan , Tyczkowski Jacek
Published: September 2020

Plasma treatment, especially cold plasma generated under low pressure, is currently the subject of many studies. An important area using this technique is the deposition of thin layers (films) on the surfaces of different types of materials, e.g., textiles, polymers, metals. In this study, the goose down was coated with a thin layer, in a two-step plasma modification process, to create an artificial superhydrophobic surface similar to that observed on lotus leaves. This layer also exhibited antifungal properties. Two types of precursors for plasma enhanced chemical vapor deposition (PECVD) were applied: hexamethyldisiloxane (HMDSO) and hexamethyldisilazane (HMDSN). The changes in the contact angle, surface morphology, chemical structure, and composition in terms of the applied precursors and modification conditions were investigated based on goniometry (CA), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy in attenuated total reflectance mode (FTIR-ATR), and X-ray photoelectron spectroscopy (XPS). The microbiological analyses were also performed using various fungal strains. The obtained results showed that the surface of the goose down became superhydrophobic after the plasma process, with contact angles as high as 161° ± 2°, and revealed a very high resistance to fungi.
Fabrication of Silver- and Zinc-Doped Hydroxyapatite Coatings for Enhancing Antimicrobial Effect
Authors: Predoi Daniela , Iconaru Simona Liliana , Predoi Mihai Valentin
Published: September 2020

This study develops, for the first time, composite coatings based on silver and zinc doped hydroxyapatite in chitosan matrix (AgZnHApCs). The AgZnHApCs composite coatings were prepared by dip coating method. The hydroxyapatite (HAp), biocompatible material for regenerating and strengthening damaged bones were doped with silver and zinc ions and coated with chitosan in order to produce a uniform and homogenous coating with biocompatibility and antimicrobial properties. The stability of AgZnHApCs suspensions was evaluated by ultrasound measurements. The value of stability parameters of AgZnHApCs suspension is in good agreement with the value of bidistilled water used as reference fluid. Homogeneously dispersed solutions of AgZnHApCs were synthesized to endeavor to optimize the physico-chemical and biological characteristics of the coatings obtained at room temperature. The AgZnHApCs composite suspension and coatings were analyzed using various investigation techniques, such as X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR), MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte-2H-tetrazolium bromide) assay and antimicrobial studies. The optical spectroscopy, atomic force microscopy (AFM), metallographic examination and X-ray photoelectron spectroscopy (XPS) on AgZnHApCs composite coatings were also conducted. Cell culture and MTT assays demonstrate that AgZnHApCs composite suspension and coatings have no negative effect on the cell viability and proliferation. The cell morphology was not affected in presence of AgZnHApCs composite suspension and coatings. The antimicrobial assays conducted against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Candida albicans ATCC 90029 microbial strains revealed that both the AgZnHApCs composite suspension and coatings exhibited great antimicrobial properties.