bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteins Associated with Phagocytosis Alteration in Retinal Pigment Epithelial Cells Derived from Age-Related Macular Degeneration Patients
Authors: Voisin Audrey , Gaillard Afsaneh , Balbous Anaïs , Leveziel Nicolas
Published: April 2022

Age-related macular degeneration (AMD) is partially characterized by retinal pigment epithelial (RPE) cell dysfunction. This study focused on phagocytosis activity and its involvement in AMD. Phagocytic activity was analyzed by flow cytometry using porcine photoreceptor outer segment (POS) and fluorescent beads in basal and under oxidative stress condition induced by Fe-NTA in fifteen hiPSC-RPE cell lines (six controls, six atrophic AMD and three exudative AMD). Oxidative stress exposure inhibited phagocytosis in the same manner for control, atrophic AMD (AMDa) and exudative AMD (AMDe) cell lines. However, altered phagocytosis in basal condition in hiPSC-RPE AMDa/e was observed compared to control cell lines. Gene expression after 3 or 24 h of POS incubation was analyzed by RNA-Seq based transcriptomic profiling. Differential gene expression was observed by RNA seq after 3 and 24 h POS exposure. We have focused on the genes involved in mTOR/PI3K-AKT/MEK-ERK pathway. We investigated differences in gene expression by analyzing the expression levels and activity of the corresponding proteins by Western blot. We showed the involvement of three proteins essential for phagocytosis activity: fak, tuberin and rictor. These findings demonstrate that hiPSC-RPE AMDa/e cells have a typical disease phenotype characterized by alteration of the main function of RPE cells, phagocytosis activity.
Isolation, Characterization, Antioxidant Activity, Metal-Chelating Activity, and Protein-Precipitating Capacity of Condensed Tannins from Plum (Prunus salicina) Fruit
Authors: Zhang Liangliang , Zhang He , Tang Lihua , Hu Xinyu , Xu Man
Published: April 2022

The type of polymeric condensed tannins from plum fruit (Prunus salicina) (PCT), the degree of polymerization and the distribution of polymers were characterized by MALDI-TOF MS and NMR spectroscopy. The metal-binding capacity of PCT with five metal ions (Cu2+, Zn2+, Al3+, Fe2+, and Fe3+) was characterized by a fluorescence quenching method. The results demonstrated the following: epicatechin was the basic unit occurring in PCT, and A-type and B-type linkages were the most common between the structural units of the polymers. The PCT have a strong antioxidant activity, which is comparable with that of the synthetic antioxidant BHA. The quenching mechanism of the PCT’s fluorescence intensity by Zn2+, Cu2+, and Al3+ was different from that of Fe3+ and Fe2+. Fe3+, Al3+ and Fe2+ had much higher affinities for the PCT than Zn2+ and Cu2+. A simple UV-Vis spectra method was developed to determine the protein-precipitating capacity of tannins. Bovine serum albumin (BSA) was effectively precipitated by tannins isolated from plum fruits, Chinese gallnut, sorghum grain, and Platycarya strobilacea at pH values between 4.5 and 5.0. A statistically significant linear relationship (p < 0.0001 or p < 0.0003) existed between the amount of tannin–protein complex formed and the amount of tannins added to the reaction mixture. The slopes of these lines indicated the protein-precipitating capacity of tannins.
Lipid Extracts Obtained by Supercritical Fluid Extraction and Their Application in Meat Products
Authors: Šojić Branislav , Putnik Predrag , Danilović Bojana , Teslić Nemanja , Bursać Kovačević Danijela , Pavlić Branimir
Published: April 2022

Supercritical fluid extraction (SFE) has been recognized as the green and clean technique without any negative impact on the environment. Although this technique has shown high selectivity towards lipophilic bioactive compounds, very few case studies on the application of these extracts in final products and different food matrices were observed. Considering the recent developments in food science and the increasing application of supercritical extracts in meat products in the last decade (2012–2022), the aim of this manuscript was to provide a systematic review of the lipid extracts and bioactives successfully obtained by supercritical fluid extraction and their application in meat products as antioxidant and/or antimicrobial agents. Lipophilic bioactives from natural resources were explained in the first step, which was followed by the fundamentals of supercritical fluid extraction and application on recovery of these bioactives. Finally, the application of natural extracts and bioactives obtained by this technique as functional additives in meat and meat products were thoroughly discussed in order to review the state-of-the-art techniques and set the challenges for further studies.
Reciprocal Regulation of Shh Trafficking and H2O2 Levels via a Noncanonical BOC-Rac1 Pathway
Authors: Thauvin Marion , Amblard Irène , Rampon Christine , Mourton Aurélien , Queguiner Isabelle , Li Chenge , Gautier Arnaud , Joliot Alain , Volovitch Michel , Vriz Sophie
Published: April 2022

Among molecules that bridge environment, cell metabolism, and cell signaling, hydrogen peroxide (H2O2) recently appeared as an emerging but central player. Its level depends on cell metabolism and environment and was recently shown to play key roles during embryogenesis, contrasting with its long-established role in disease progression. We decided to explore whether the secreted morphogen Sonic hedgehog (Shh), known to be essential in a variety of biological processes ranging from embryonic development to adult tissue homeostasis and cancers, was part of these interactions. Here, we report that H2O2 levels control key steps of Shh delivery in cell culture: increased levels reduce primary secretion, stimulate endocytosis and accelerate delivery to recipient cells; in addition, physiological in vivo modulation of H2O2 levels changes Shh distribution and tissue patterning. Moreover, a feedback loop exists in which Shh trafficking controls H2O2 synthesis via a non-canonical BOC-Rac1 pathway, leading to cytoneme growth. Our findings reveal that Shh directly impacts its own distribution, thus providing a molecular explanation for the robustness of morphogenesis to both environmental insults and individual variability.
A Novel Sulfated Glycoprotein Elicitor Extracted from the Moroccan Green Seaweed Codium decorticatum Induces Natural Defenses in Tomato
Authors: Aitouguinane Meriem , El Alaoui-Talibi Zainab , Rchid Halima , Fendri Imen , Abdelkafi Slim , Ould El-Hadj Mohamed Didi , Boual Zakaria , Dubessay Pascal , Michaud Philippe , Le Cerf Didier , Rihouey Christophe , Pierre Guillaume , Delattre Cédric , El Modafar Cherkaoui
Published: April 2022

Sulfated glycoproteins extracted for the first time from the Moroccan green seaweed Codium decorticatum were investigated for their ability to induce a natural defense metabolism in the roots and the upper leaves of tomato seedlings. The crude (AGB) and the purified fractions (AGP) were characterized chemically (Colorimetric assays) and structurally (SEC-MALS, GC-EI/MS, ATR-FTIR). The elicitor aqueous solutions (1 g/L) were applied by foliar spray and syringe infiltration into the internodal middle of 45-day-old tomato seedlings. Phenylalanine ammonia-lyase (PAL) activity, polyphenols, and lignin contents were measured in the roots and the leaves after 0 h, 12, 24, 48, and 72 h of treatment. The AGB and AGP extracts contained 37.67% and 48.38% of the total carbohydrates, respectively, and were mainly composed of galactose, glucose, arabinose, and a minor amount of xylose and rhamnose. They were characterized by an important molecular weight (Mw) > of 2000 × 103 g·mol−1 and a high degree of sulfation and protein (12–23% (w/w)), indicating that the extracted polysaccharides could be an arabinogalactan-rich protein present in the cell wall of the green seaweed C. decorticatum. Both crude and purified fractions exhibited an elicitor effect by inducing the PAL activity, the accumulation of phenolic compounds and lignin contents in the roots and the leaves of tomato seedlings. These responses were systemic in both the methods used (injection and foliar spray) and were mobilized throughout tissues that are not directly treated (roots and/or leaves). Regarding the elicitor activities, AGB and AGP presented globally similar patterns, which revealed the importance of crude extracts in the stimulation of plant immunity. These results suggest the new application of sulfated glycoprotein isolated from green seaweed in agriculture as inducers of natural defenses of plants.
The Effect of Conductive Alginate Capsules Encapsulating Rejuvenator (HealRoad Capsules) on the Healing Properties of 10 mm Stone Mastic Asphalt Mix
Authors: Tabaković Amir , Faloon Christopher , O’Prey Declan
Published: April 2022

Conductive alginate capsules encapsulating a bitumen rejuvenator (HealRoad capsules) has demonstrated good healing abilities in pure bitumen and mortar mixes. HealRoad capsules can efficiently heal damage via induction heating. They also release the encapsulated rejuvenator, thereby rejuvenating aged bitumen. These findings indicate that HealRoad capsules and induction heating systems combined could represent a possible asphalt pavement maintenance method. This paper investigated the effect of HealRoad capsules on the mechanical performance of the 10 mm stone mastic asphalt mix and measured the damage repair (healing) efficiency of the capsules in an asphalt mix. The results indicate that in small amounts, >1%, HealRoad capsules do not degrade the mix performance (indirect tensile strength and rutting resistance) and in some cases, the HealRoad capsules actually improve mix performance, e.g., in terms of the indirect tensile strength ratio (water sensitivity). However, the HealRoad capsules are unable to stimulate induction healing due to the small volume of capsules within the mix. Further investigation demonstrated that increasing the capsules in the mix to >5% can stimulate induction heating effectively. However, it also indicated that a high content of HealRoad capsules reduces the asphalt mix strength. The study has shown that HealRoad capsules are an effective healing system for high bitumen content mixtures such as mortar mixtures but is an inefficient healing system for a full asphalt mix, such as the 10 mm stone mastic asphalt mix.
Influence of Lateral Multistage Unloading Intensity on Mechanical Properties of Reconstituted Coastal Soils Containing Silty Particles
Authors: Xia Changqing , Meng Fanli , Zhu Min , Tang Yan , Lu Chengyuan
Published: April 2022

The unclear understanding of the mechanical behavior of soil under unloading conditions is a significant reason for the frequent occurrence of accidents and difficulties in the deformation control of foundation pit engineering in coastal areas. This paper discusses the effect of multistage unloading intensity on the mechanical properties of reconstituted coastal soils containing silty particles through a series of laboratory tests, namely, the CU triaxial, bender-element, and permeability tests. Results indicate that, with an increase in unloading intensity, the shear strength and stiffness parameters decrease, while permeability slightly increases. The effect of unloading intensity on the mechanical properties of silt and mucky silty clay is more pronounced. Additional consideration should be given to the effect of a single excavation depth on the mechanical properties of fine-grained soil in foundation pit engineering in order to ensure the stability of the surrounding soil and the safety of adjacent structures.
Physiological Effect of Deep Pressure in Reducing Anxiety of Children with ASD during Traveling: A Public Transportation Setting
Authors: Afif Ilham Yustar , Manik Aloysius Raynaldo , Munthe Kristian , Maula Mohamad Izzur , Ammarullah Muhammad Imam , Jamari Jamari , Winarni Tri Indah
Published: April 2022

Traveling with children with autism can be very challenging for parents due to their reactions to sensory stimuli resulting in behavioral problems, which lead to self-injury and danger for themselves and others. Deep pressure was reported to have a calming effect on people with autism. This study was designed to investigate the physiological effect of deep pressure, which is an autism hug machine portable seat (AHMPS) in children with autism spectrum disorders (ASD) in public transportation settings. The study was conducted with 20 children with ASD (16 boys and 4 girls) at the Semarang Public Special School with an age ranging from 4 to 13 years (mean 10.9 ± 2.26 years), who were randomly assigned into two groups. The experiment consisted of group I who used the AHMPS inflatable wraps model and group II who used the AHMPS manual pull model. Heart rate (HR) and skin conductance (SC) were analyzed to measure the physiological calming effect using pulse oximeter oximetry and a galvanic skin response (GSR) sensor. Heart rate was significantly decreased during the treatment compared to the baseline (pre-test) session in group I (inflating wrap model) with p = 0.019, while no change of heart rate variability (HRV) was found in group II (manual pull model) with p = 0.111. There was no remaining effect of deep pressure using the HRV indicator after the treatment in both groups (group I with p = 0.159 and group II with p = 0.566). GSR captured the significant decrease in skin conductance during the treatment with p < 0.0001 in group I, but no significant decrease was recorded in group II with p = 0.062. A skin conductance indicator captured the remaining effect of deep pressure (after the treatment); it was better in group I (p = 0.003) than in group II (p = 0.773). In conclusion, the deep pressure of the AHMPS inflating wrap decreases physiological arousal in children with ASD during traveling.
Urine Hydrogen Peroxide Levels and Their Relation to Outcome in Patients with Sepsis, Septic Shock, and Major Burn Injury
Authors: Lipcsey Miklos , Bergquist Maria , Sirén Rebecca , Larsson Anders , Huss Fredrik , Pravda Jay , Furebring Mia , Sjölin Jan , Janols Helena
Published: April 2022

Hydrogen peroxide (H2O2) and oxidative stress have been suggested as possible instigators of both the systemic inflammatory response and the increased vascular permeability associated with sepsis and septic shock. We measured H2O2 concentrations in the urine of 82 patients with severe infections, such as sepsis, septic shock, and infections not fulfilling sepsis-3 criteria, in patients with major burn injury with associated systemic inflammation, and healthy subjects. The mean concentrations of H2O2 were found to be lower in patients with severe infections compared to burn injury patients and healthy subjects. Patients with acute kidney injury (AKI), vs. those without AKI, in all diagnostic groups displayed higher concentrations of urine H2O2 (p < 0.001). Likewise, urine concentrations of H2O2 were higher in non-survivors as compared to survivors (p < 0.001) at day 28 in all diagnostic groups, as well as in patients with severe infections and burn injury (p < 0.001 for both). In this cohort, increased H2O2 in urine is thus associated with mortality in patients with sepsis and septic shock as well as in patients with burn injury.
Development of Alzheimer’s Disease Biomarkers: From CSF- to Blood-Based Biomarkers
Authors: Mankhong Sakulrat , Kim Sujin , Lee Seongju , Kwak Hyo-Bum , Park Dong-Ho , Joa Kyung-Lim , Kang Ju-Hee
Published: April 2022

In the 115 years since the discovery of Alzheimer’s disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are not clinically used routinely, they help us to understand the mechanisms of this disease. This review charts the journey of AD biomarker discovery and development from cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau) biomarkers and imaging technologies to the next generation of biomarkers. We also discuss advanced high-sensitivity assay platforms for CSF Aβ42, T-tau, p-tau, and blood analysis. The recently proposed Aβ deposition/tau biomarker/neurodegeneration or neuronal injury (ATN) scheme might facilitate the definition of the biological status underpinning AD and offer a common language among researchers across biochemical biomarkers and imaging. Moreover, we highlight blood-based biomarkers for AD that offer a scalable alternative to CSF biomarkers through cost-saving and reduced invasiveness, and may provide an understanding of disease initiation and development. We discuss different groups of blood-based biomarker candidates, their advantages and limitations, and paths forward, from identification and analysis to clinical validation. The development of valid blood-based biomarkers may facilitate the implementation of future AD therapeutics and diagnostics.
Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer
Authors: Palmer Hannah , Nimick Mhairi , Mazumder Aloran , Taurin Sebastien , Rana Zohaib , Rosengren Rhonda J.
Published: April 2022

Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC50 values in PC3 cells. Additionally, the two drugs were synergistically cytotoxic toward the PC3, DU-145 and LNCaP cell lines. To determine the effect of the drug combination in vivo, an orthotopic model of CRPC was used. Male mice were injected with PC3 prostate cancer cells and then treated with vehicle (5 mL/kg), raloxifene (8.5 mg/kg, po), RL91 (8.5 mg/kg, po) or a combination of raloxifene and RL91 for six weeks. Sham animals were subjected to the surgical procedure but were not implanted with PC3 cells. The results showed that raloxifene decreased tumor size and weight as well as metastasis to renal lymph nodes. However, combination treatment reversed the efficacy of raloxifene as tumor volume and metastasis returned to control levels. The results suggest that raloxifene has tumor suppressive and anti-metastatic effects and has potential for further clinical use in AR-CRPC.
The Relationship between Crawling and Emotion Discrimination in 9- to 10-Month-Old Infants
Authors: Gehb Gloria , Vesker Michael , Jovanovic Bianca , Bahn Daniela , Kauschke Christina , Schwarzer Gudrun
Published: April 2022

The present study examined whether infants’ crawling experience is related to their sensitivity to fearful emotional expressions. Twenty-nine 9- to 10-month-old infants were tested in a preferential looking task, in which they were presented with different pairs of animated faces on a screen displaying a 100% happy facial expression and morphed facial expressions containing varying degrees of fear and happiness. Regardless of their crawling experiences, all infants looked longer at more fearful faces. Additionally, infants with at least 6 weeks of crawling experience needed lower levels of fearfulness in the morphs in order to detect a change from a happy to a fearful face compared to those with less crawling experience. Thus, the crawling experience seems to increase infants’ sensitivity to fearfulness in faces.
Disaster Assessment of Tall Buildings in Korea by K-Rapid Visual Screening System Focusing on Structural Safety
Authors: Park Min Jae , Ju Young K.
Published: April 2022

Multiple hazards, which threaten people’s lives and property, are the main concern for engineers in preventing dangers to buildings. In particular, densely populated areas, such as capital cities and tall buildings, are exposed to higher risks owing to multiple hazards. To rapidly evaluate the disaster assessment of tall buildings, the Federal Emergency Management Agency (FEMA) in the U.S. proposed the integrated rapid visual screening system (IRVS). However, the IRVS system only considers U.S. conditions. Therefore, a Korean-oriented rapid visual screening system should be developed because the number of buildings over 200 m in Korea ranked fourth in the world with the highest density (500 people per square kilometer) among the top five countries based on the Council on Tall Buildings and Urban Habitat’s (CTBUH) database. This study describes a Korea-rapid visual screening (K-RVS) system that focuses on the structural safety of tall buildings in Korea. The K-RVS system was modified based on the IRVS, considering the Korean design standard (KDS) and Korean conditions. With the weight value for each characteristic, the scores for each hazard and final scores combined from the scores by multi-hazard can be obtained to conduct a disaster assessment of tall buildings subjected to multiple hazards.
Long-Term Monitoring of Local Track Irregularity and Its Influence for Simply Supported Girder Bridge of HSR
Authors: Li Guolong , Yang Fei , Ke Zaitian , Sun Xianfu , Liu Bing , Zhao Wenbo , Zhou Yunlai
Published: April 2022

By analyzing dynamic track geometric irregularity data of high-speed railway (HSR) with ballast track in China, there is a peak of [5, 11] m wavelength for the longitudinal level at the beam joint of simply supported girder bridges. The difference between the absolute value of track longitudinal level at the beam joint and that at the midspan is one to three mm. Under annual temperature cycle, the ballast at the beam joint loosens because of the bridge–track interaction, which results in the longitudinal level at the beam joint gets larger in winter and smaller in summer, that means the longitudinal level is negatively correlated with temperature, and at the same time, the development of the track longitudinal level and Track Quality Index (TQI) with the temperature are given. In addition, the vertical acceleration of axle box and bogie, and wheel–rail vertical force are larger when the train passes the beam joint than when it passes the midspan, which threatens running safety significantly. This article established a three-dimensional vehicle–track–bridge finite element model (FEM), thus the thresholds of track longitudinal level at the beam joint for simply supported girder bridge with ballast track in 250 km/h HSR were proposed, i.e., the maximum of dynamic track longitudinal level is 14 mm, and the maximum of static value is 11 mm. Once one of the two thresholds exceeds the corresponding limit, the train speed should be reduced to 160 km/h or below.
Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells
Authors: Chen Ya-Hui , Wu Jyun-Xue , Yang Shun-Fa , Yang Chueh-Ko , Chen Tze-Ho , Hsiao Yi-Hsuan
Published: April 2022

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin β1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin β1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment.
Robust Validation and Comprehensive Analysis of a Novel Signature Derived from Crucial Metabolic Pathways of Pancreatic Ductal Adenocarcinoma
Authors: Gu Wenchao , Mo Shaocong , Wang Yulin , Kawabata-Iwakawa Reika , Zhang Wei , Yang Zongcheng , Sun Chenyu , Tsushima Yoshito , Xu Huaxiang , Nakajima Takahito
Published: April 2022

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a dismal prognosis. PDAC have extensively reprogrammed metabolic characteristics influenced by interactions with normal cells, the effects of the tumor microenvironment and oncogene-mediated cell-autonomous pathways. In this study, we found that among all cancer hallmarks, metabolism played an important role in PDAC. Subsequently, a 16-gene prognostic signature was established with genes derived from crucial metabolic pathways, including glycolysis, bile acid metabolism, cholesterol homeostasis and xenobiotic metabolism (gbcx). The signature was used to distinguish overall survival in multiple cohorts from public datasets as well as a validation cohort followed up by us at Shanghai Cancer Center. Notably, the gbcx-related risk score (gbcxMRS) also accurately predicted poor PDAC subtypes, such as pure-basal-like and squamous types. At the same time, it also predicted PDAC recurrence. The gbcxMRS was also associated with immune cells, especially CD8 T cells, Treg cells. Furthermore, a high gbcxMRS may indicate high drug sensitivity to irinotecan and docetaxel and CTLA4 inhibitor immunotherapy. Taken together, these results indicate a robust and reproducible metabolic-related signature based on analysis of the overall pathogenesis of pancreatic cancer, which may have excellent prognostic and therapeutic implications for PDAC.
Tissue Microarray Analyses Suggest Axl as a Predictive Biomarker in HPV-Negative Head and Neck Cancer
Authors: Busch Chia-Jung , Hagel Christian , Becker Benjamin , Oetting Agnes , Möckelmann Nikolaus , Droste Conrad , Möller-Koop Christina , Witt Melanie , Blaurock Markus , Loges Sonja , Rothkamm Kai , Betz Christian , Münscher Adrian , Clauditz Till S. , Rieckmann Thorsten
Published: April 2022

The receptor tyrosine kinase Axl is described to promote migration, metastasis and resistance against molecular targeting, radiotherapy, and chemotherapy in various tumor entities, including head and neck squamous cell carcinoma (HNSCC). Since clinical data on Axl and its ligand Gas6 in HNSCC are sparse, we assessed the association of Axl and Gas6 expression with patient survival in a single center retrospective cohort in a tissue microarray format. Expression was evaluated manually using an established algorithm and correlated with clinicopathological parameters and patient survival. A number of 362 samples yielded interpretable staining, which did not correlate with T- and N-stage. Protein expression levels were not associated with the survival of patients with p16-positive oropharyngeal SCC. In HPV-negative tumors, Axl expression did not impact patients treated with primary or adjuvant radio(chemo)therapy, but was significantly associated with inferior overall and recurrence-free survival in patients treated with surgery alone. Gas6 was a positive predictor of survival in patients whose treatment included radiotherapy. Associations remained significant in multivariable analysis. Our data question a meaningful contribution of the Axl/Gas6 pathway to radio-resistance in HNSCC and instead suggest that strong Axl expression identifies tumors requiring adjuvant radio(chemo)therapy after surgery.
Radiation-Induced Esophagitis in Non-Small-Cell Lung Cancer Patients: Voxel-Based Analysis and NTCP Modeling
Authors: Monti Serena , Xu Ting , Mohan Radhe , Liao Zhongxing , Palma Giuseppe , Cella Laura
Published: April 2022

The aim of our study is to characterize the risk of radiation-induced esophagitis (RE) in a cohort of Non-Small-Cell Lung Cancer (NSCLC) patients treated with concurrent chemotherapy and photon/proton therapy. For each patient, the RE was graded according to the CTCAE v.3. The esophageal dose-volume histograms (DVHs) were extracted. Voxel-based analyses (VBAs) were performed to assess the spatial patterns of the dose differences between patients with and without RE of grade ≥ 2. Two hierarchical NTCP models were developed by multivariable stepwise logistic regression based on non-dosimetric factors and on the DVH metrics for the whole esophagus and its anatomical subsites identified by the VBA. In the 173 analyzed patients, 76 (44%) developed RE of grade ≥ 2 at a median follow-up time of 31 days. The VBA identified regions of significant association between dose and RE in a region encompassing the thoracic esophagus. We developed two NTCP models, including the RT modality and a dosimetric factor: V55Gy for the model related to the whole esophagus, and the mean dose for the model designed on the thoracic esophagus. The cross-validated performance showed good predictions for both models (ROC-AUC of 0.70 and 0.73, respectively). The only slight improvement provided by the analysis of the thoracic esophageal subsites might be due to the relevant sparing of cervical and lower thoracic esophagus in the analyzed cohort. Further studies on larger cohorts and a more heterogeneous set of dose distributions are needed to validate these preliminary findings and shed further light on the spatial patterns of RE development.
Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin
Authors: Rochette Luc , Dogon Geoffrey , Rigal Eve , Zeller Marianne , Cottin Yves , Vergely Catherine
Published: April 2022

Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 possess both anti-inflammatory and anti-bacterial properties. The complex is a ligand of the toll-like receptor 4 (TLR4) and receptor for advanced glycation end (RAGE). At sites of infection and inflammation, CLP is a target for oxidation due to its co-localization with neutrophil-derived oxidants. In the heart, oxidative stress (OS) responses and S100 proteins are closely related and intimately linked through pathophysiological processes. Our review summarizes the roles of S100A8, S100A9 and CLP in the inflammation in relationship with vascular OS, and we examine the importance of CLP for the mechanisms driving in the protection of myocardium. Recent evidence interpreting CLP as a critical modulator during the inflammatory response has identified this alarmin as an interesting drug target.
Raman Spectroscopy as a Neuromonitoring Tool in Traumatic Brain Injury: A Systematic Review and Clinical Perspectives
Authors: Stevens Andrew R. , Stickland Clarissa A. , Harris Georgia , Ahmed Zubair , Goldberg Oppenheimer Pola , Belli Antonio , Davies David J.
Published: April 2022

Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care.
Therapeutic Efficacy of Pharmacological Ascorbate on Braf Inhibitor Resistant Melanoma Cells In Vitro and In Vivo
Authors: Niessner Heike , Burkard Markus , Leischner Christian , Renner Olga , Plöger Sarah , Meraz-Torres Francisco , Böcker Matti , Hirn Constanze , Lauer Ulrich M. , Venturelli Sascha , Busch Christian , Sinnberg Tobias
Published: April 2022

High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach to treating refractory melanomas, e.g., with secondary resistance to targeted BRAF inhibitor therapy. BRAF mutated melanoma cells were treated with ascorbate alone or in combination with the BRAF inhibitor vemurafenib. Viability, cell cycle, ROS production, and the protein levels of phospho-ERK1/2, GLUT-1 and HIF-1α were analyzed. To investigate the treatment in vivo, C57BL/6NCrl mice were subcutaneously injected with D4M.3A (BrafV600E) melanoma cells and treated with intraperitoneal injections of ascorbate with or without vemurafenib. BRAF mutated melanoma cell lines either sensitive or resistant to vemurafenib were susceptible to the induction of cell death by pharmacological ascorbate. Treatment of BrafV600E melanoma bearing mice with ascorbate resulted in plasma levels in the pharmacologically active range and significantly improved the therapeutic effect of vemurafenib. We conclude that intravenous high-dose ascorbate will be beneficial for melanoma patients by interfering with the tumor’s energy metabolism and can be safely combined with standard melanoma therapies such as BRAF inhibitors without pharmacological interference.
Evaluation of an Online Version of the CFT 20-R in Third and Fourth Grade Children
Authors: Visser Linda , Rothe Josefine , Schulte-Körne Gerd , Hasselhorn Marcus
Published: April 2022

There is growing demand for digital intelligence testing. In the current study, we evaluated the validity of an online version of the revised German Culture Fair Intelligence Test (CFT 20-R). A total of 4100 children from the third and fourth grades completed the online version using a smartphone or tablet. Subsequently, 220 of these children also completed the paper-pencil (PP) version. The internal consistency and construct validity of the online version appeared to be acceptable. The correlation between the raw scores and school grades in German and mathematics was slightly lower than expected. On average, the raw scores for the PP version were revealed to be higher, which was probably due to a learning effect. At the item level, the results show small differences for the subtests Series and Matrices, possibly caused by small differences in the presentation of the items. The correspondence between the versions did not depend on children’s levels of impulsivity or intelligence. Altogether, the results support the hypothesis that the online version of the CFT 20-R is a valid measure of general fluid intelligence and highlight the need for separate norms.
Pediatric Emergencies and Hospital Admissions in the First Six Months of the COVID-19 Pandemic in a Tertiary Children’s Hospital in Romania
Authors: Miron Victor Daniel , Gunșahin Deniz , Filimon Claudiu , Bar Gabriela , Craiu Mihai
Published: April 2022

The COVID-19 pandemic has had a significant impact on the pediatric population, particularly on their access to health services. We conducted a retrospective study to assess the influence that the pandemic, and its related containment and mitigation public health measures, had on pediatric emergencies and hospitalizations in a major tertiary pediatric hospital in Bucharest, Romania, during the first six months of the pandemic, March–August 2020, compared to the same period in 2019. In these first 6 months of the COVID-19 pandemic, the number of pediatric emergencies decreased 2.8-fold compared to the same period in 2019, but the proportion of major emergencies increased significantly (p < 0.001). The number of admissions also decreased 3.3-fold in 2020, compared to 2019, but the risk of admission for lower respiratory tract infections and respiratory failure increased 1.3- and 2.3-fold, respectively. In conclusion, the restrictions imposed by the pandemic containment and mitigation plan not only had a significant impact on reducing emergency department presentations, but also on pediatric admissions in Romania. These data highlight the importance of maintaining optimal access to child health services when confronted with a public health threat, such as the COVID-19 pandemic. Active communication with parents, involving general practitioners, pediatricians, and authorities, is essential for managing children with acute signs of illness in the case of future restrictions or lockdown measures.
Laminin 511-E8 Fragment Offers Superior Adhesion Properties for Gastric Cancer Cells Compared with Full-Length Laminin 511
Authors: Iwamuro Masaya , Shiraha Hidenori , Kobashi Mayu , Horiguchi Shigeru , Okada Hiroyuki
Published: April 2022

Background: The interaction between cancer cells and laminin (Ln) is a key event in tumor invasion and metastasis. Previously, we determined the effect of full-length Ln511 on gastric cancer cells. However, the interactions between the Ln511-E8 fragment, a truncated protein of Ln511, and gastric cancer cells have not been investigated. Methods: We investigated the adhesion properties of gastric cancer cells to full-length Ln511 and Ln511-E8 fragments. Results: The proliferation of four gastric cancer cell lines (SH-10-TC, MKN74, SC-6-JCK, and MKN45) was highest on the Ln511-E8 fragment. Further, a larger cytoplasm was observed in SH-10-TC and MKN74 cells cultured on full-length Ln511 or Ln511-E8 fragments. The percentage of adhesive cells was highest on the Ln511-E8 fragment in all four cell lines. Moreover, adhesion of the gastric cancer cells to Ln511-E8 fragment-coated plates was reduced by the Cdc42 GTPase inhibitor in a dose-dependent manner, suggesting the involvement of Cdc42 in the Ln511-E8 fragment-induced enhanced adhesion of gastric cancer cells. Conclusions: The Ln511-E8 fragment had a greater impact on the adhesion, morphology, and proliferation of gastric cancer cells than full-length laminin. Thus, the Ln511-E8 fragment is suitable for investigating the interaction between gastric cancer cells and extracellular matrices in tumor invasion and metastasis.
Comparison of Next-Generation Sequencing and Polymerase Chain Reaction for Personalized Treatment-Related Genomic Status in Patients with Metastatic Colorectal Cancer
Authors: Su Wei-Chih , Tsai Yi-Chen , Tsai Hsiang-Lin , Chang Tsung-Kun , Yin Tzu-Chieh , Huang Ching-Wen , Chen Yen-Cheng , Li Ching-Chun , Chen Po-Jung , Liu Yun-Ru , Hsieh Tsung-Han , Wang Jaw-Yuan
Published: April 2022

Personalized treatments based on the genetic profiles of tumors can simultaneously optimize efficacy and minimize toxicity, which is beneficial for improving patient outcomes. This study aimed to integrate gene alterations associated with predictive and prognostic outcomes in patients with metastatic colorectal cancer (mCRC) with polymerase chain reaction (PCR) and in-house next-generation sequencing (NGS) to detect KRAS, NRAS, and BRAF mutations. In the present study, 41 patients with mCRC were assessed between August 2017 and June 2019 at a single institution. The overall concordance between NGS and PCR results for detecting KRAS, NRAS, and BRAF mutations was considerably high (87.8–92.7%), with only 15 discrepant results between PCR and NGS. Our companion diagnostic test analyzes KRAS, NRAS, and BRAF as a panel of CRC molecular targets; therefore, it has the advantages of requiring fewer specimens and being more time and cost efficient than conventional testing for separate analyses, allowing for the simultaneous analysis of multiple genes.
Multicriteria Spatial Modeling: Methodological Contribution to the Analysis of Atmospheric and Surface Heat Islands in Presidente Prudente, Brazil
Authors: Teixeira Danielle Cardozo Frasca , Amorim Margarete Cristiane de Costa Trindade
Published: April 2022

Several studies demonstrate the potential of models for the representation of phenomena such as urban heat islands. This article aimed to analyze atmospheric heat islands (UHIucl) by integrating primary air temperature data with spatial information such as land use and relief from a multicriteria model based on multiple linear regression. Furthermore, we compared the measured and estimated air temperature at 11 p.m. with the surface temperature at 10:51 p.m. (local time). These temperatures were obtained through the thermal band of the Landsat 8 satellite considering extraction points of interest in Presidente Prudente city, Brazil. The multicriteria model showed reliability in UHIucl spatialization, reaching the confidence interval (p-value ≤ 0.05). The model proves that urban surface materials are the main energy sources modulating heat transfer to the atmosphere, while vegetation has a temperature-reducing effect. Precise mappings such as the one proposed here are relevant for the formulation of measures that support decision-making by public authorities. These mappings aim at urban planning that is resilient to the effects of urban climate and can be replicated in other realities.
Strategy to Avoid Skin Sensitization: Application to Botanical Cosmetic Ingredients
Authors: Puginier Mickaël , Roso Alicia , Groux Hervé , Gerbeix Cédric , Cottrez Françoise
Published: April 2022

Assessment of skin sensitization potential is mandatory for ingredients dedicated to topical applications. A battery of in vitro tests covering the key steps of the Adverse Outcome Pathway (AOP) for skin sensitization has been recommended to replace animal testing. However, despite international guidelines on in vitro methods, there is no universal approach defining their combination. The purpose of this work was to assess skin sensitization of botanical ingredients relying on a previously developed in vitro testing strategy. This tool focused on complex and poorly water-soluble substances, which were not already covered. Sixteen botanical extracts were tested in a sequential approach, starting with Sens-Is, supplemented by Organization for Economic Cooperation and Development (OECD) in vitro methods when necessary. The results on the selected well-known botanical sensitizers complemented the relevance of the strategy. Testing on experimental botanicals could detect skin sensitizers. In addition, phytochemistry was a determining support to identify and remove the components at the origin of the effect. Altogether, these results enlarged the scope of the methodology to various ingredient categories and chemical natures, contributing to place on the market new ingredients, safe for workers and end-users.
Study of P-Phenylenediamine (PPD) Concentrations after Hair Dye Mixing: A Call for Safety Reassessment
Authors: Al-Enezi Majda H. , Aldawsari Fahad S.
Published: April 2022

Para-phenylenediamine (PPD) is a chemical that is widely used in hair dyes. Multiple safety and regulatory agencies have categorized PPD as a potent sensitizer. In addition, PPD has carcinogenicity and genotoxicity attributes and, consequently, it is regulated at a maximal concentration of 2.0%. The aim of this study was to test whether the limit for PPD is surplus, and hence whether the consumer may be exposed to unnecessarily PPD levels. Experimentally, the analysis of PPD was performed using HPLC, where method validation and an inter-laboratory comparison test (ILC) were conducted to evaluate method performance. Thirty-three commercial products were analyzed, and five products were chosen to study the unconsumed PPD. Successfully, the implemented method confirmed its suitability and validity for the determination of PPD. For ILC results, PPD levels were 0.97 ± 0.04% and 0.92 ± 0.02%, quantified by our laboratory and an accredited laboratory, respectively. For all products, the initial concentration (T0) of PPD was lower than the regulatory limit. After 45 min, the content of PPD significantly reduced compared to T0. One product showed unconsumed PPD to be as high as 96% following the recommended dyeing time. In conclusion, the existence of high levels of unreacted PPD increases the likelihood of allergic events and elevates the risk of PPD-related chemicals. Collaborative efforts between industries, regulatory bodies, and health-related decision makers are deemed necessary to establish safe concentrations for PPD.
Strategic Synthesis to Disperse Zeolite NaY in Lead Tree Wood
Authors: Krukkratoke Panot , Keawkumay Chalermpan , Tayraukham Pimwipa , Prompiputtanapon Kewalee , Khemthong Pongtanawat , Prayoonpokarach Sanchai , Wittayakun Jatuporn
Published: April 2022

The goal of this work is to synthesize zeolite NaY inside Lead tree wood. The wood is mixed with zeolite seed gel before mixing with feed gel and subsequent hydrothermal treatment. In the first trial, the dried and untreated Lead tree wood is mixed with the gel of zeolite NaY before the hydrothermal process. Only zeolite NaP is produced. Then, sonication is applied to the wood and zeolite gel mixture before the hydrothermal process. The product is mixed with the phase of NaP and NaY. In the next attempt, the wood is treated with acid reflux before mixing with the zeolite seed gel. NaY is successfully produced inside the wood. When sonication is also applied, the amount of NaY is increased. The presence of zeolites in the wood are confirmed by X-ray diffraction, scanning electron microscopy, nitrogen adsorption, and thermogravimetric analysis. Moreover, the composites are tested for the adsorption of nickel (II) ions from aqueous solutions. The novel Lead tree wood-zeolite NaY composite has the potential as an adsorbent which could be separated easily from the liquid media.
NeuroCOVID: Insights into Neuroinvasion and Pathophysiology
Authors: Matschke Jakob , Krasemann Susanne , Altmeppen Hermann C. , Shafiq Mohsin , Glatzel Markus
Published: April 2022

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may lead to acute and chronic neurological symptoms (NeuroCOVID-19). SARS-CoV-2 may spread from the respiratory tract to the central nervous system as the central nervous system (CNS) of certain patients dying from COVID-19 shows virus-related neuropathological changes. Moreover, a syndrome found in many patients having passed a SARS-CoV-2 infection, which is termed long COVID and characterized by lasting fatigue and other diverse clinical features, may well have some of its pathological correlates inside the CNS. Although knowledge on the routes of SARS-CoV-2 neuroinvasion and the pathophysiology of NeuroCOVID have increased, the molecular mechanisms are not yet fully understood. This includes the key question: to understand if observed CNS damage is a direct cause of viral damage or indirectly mediated by an overshooting neuroimmune response.