bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized Clinical Trial of How Long-Term Glutathione Supplementation Offers Protection from Oxidative Damage and Improves HbA1c in Elderly Type 2 Diabetic Patients
Authors: Kalamkar Saurabh , Acharya Jhankar , Kolappurath Madathil Arjun , Gajjar Vijay , Divate Uma , Karandikar-Iyer Sucheta , Goel Pranay , Ghaskadbi Saroj
Published: May 2022

Complications in type 2 diabetes (T2D) arise from hyperglycemia-induced oxidative stress. Here, we examined the effectiveness of supplementation with the endogenous antioxidant glutathione (GSH) during anti-diabetic treatment. A total of 104 non-diabetic and 250 diabetic individuals on anti-diabetic therapy, of either sex and aged between 30 and 78 years, were recruited. A total of 125 diabetic patients were additionally given 500 mg oral GSH supplementation daily for a period of six months. Fasting and PP glucose, insulin, HbA1c, GSH, oxidized glutathione (GSSG), and 8-hydroxy-2-deoxy guanosine (8-OHdG) were measured upon recruitment and after three and six months of supplementation. Statistical significance and effect size were assessed longitudinally across all arms. Blood GSH increased (Cohen’s d = 1.01) and 8-OHdG decreased (Cohen’s d = −1.07) significantly within three months (p < 0.001) in diabetic individuals. A post hoc sub-group analysis showed that HbA1c (Cohen’s d = −0.41; p < 0.05) and fasting insulin levels (Cohen’s d = 0.56; p < 0.05) changed significantly in diabetic individuals above 55 years. GSH supplementation caused a significant increase in blood GSH and helped maintain the baseline HbA1c overall. These results suggest GSH supplementation is of considerable benefit to patients above 55 years, not only supporting decreased glycated hemoglobin (HbA1c) and 8-OHdG but also increasing fasting insulin. The clinical implication of our study is that the oral administration of GSH potentially complements anti-diabetic therapy in achieving better glycemic targets, especially in the elderly population.
Anti-Inflammatory, Anti-Apoptotic, and Antioxidant Roles of Honey, Royal Jelly, and Propolis in Suppressing Nephrotoxicity Induced by Doxorubicin in Male Albino Rats
Authors: Mohamed Hanaa K. , Mobasher Maysa A. , Ebiya Rasha A. , Hassen Marwa T. , Hagag Howaida M. , El-Sayed Radwa , Abdel-Ghany Shaimaa , Said Manal M. , Awad Nabil S.
Published: May 2022

Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Honey, propolis, and royal jelly were evaluated for their ability to protect against nephrotoxicity caused by DOX. Forty-two adult albino rats were divided into control groups. The DOX group was injected i.p. with a weekly dose of 3 mg/kg of DOX for six weeks. The DOX plus honey treated group was injected with DOX and on the next day, received 500 mg/kg/day of honey orally for 21 days. The DOX plus royal jelly treated group was injected with DOX and on the following day, received 100 mg/kg/day of royal jelly orally for 21 days. The DOX plus propolis treated group received DOX and on the following day, was treated orally with 50 mg/kg/day of propolis for 21 days. The DOX plus combined treatment group received DOX and on the following day, was treated with a mix of honey, royal jelly, and propolis orally for 21 days. Results confirmed that DOX raised creatinine, urea, MDA, and TNF-α while decreasing GPX and SOD. Damages and elevated caspase-3 expression were discovered during renal tissue’s histopathological and immunohistochemical studies. Combined treatment with honey, royal jelly, and propolis improved biochemical, histological, and immunohistochemical studies in the renal tissue. qRT-PCR revealed increased expression of poly (ADP-Ribose) polymerase-1 (PARP-1) and a decline of Bcl-2 in the DOX group. However, combined treatment induced a significant decrease in the PARP-1 gene and increased Bcl-2 expression levels. In addition, the combined treatment led to significant improvement in the expression of both PARP-1 and Bcl-2 genes. In conclusion, the combined treatment effectively inhibited nephrotoxicity induced by DOX.
Ultrafine Diesel Exhaust Particles Induce Apoptosis of Oligodendrocytes by Increasing Intracellular Reactive Oxygen Species through NADPH Oxidase Activation
Authors: Kim Ji Young , Kim Jin-Hee , Kim Yong-Dae , Seo Je Hoon
Published: May 2022

Diesel exhaust particles (DEPs) are a main contributor to air pollution. Ultrafine DEPs can cause neurodegenerative diseases by increasing intracellular reactive oxygen species (ROS). Compared with other cells in the brain, oligodendrocytes responsible for myelination are more susceptible to oxidative stress. However, the mechanisms underlying ROS generation in oligodendrocytes and the susceptibility of oligodendrocytes to ROS by ultrafine DEPs remain unclear. Herein, we examined the effects of excessive ROS generated by NOX2, an isoform of the NADPH oxidase family, after exposure to ultrafine DEPs (200 μg/mL) on the survival of two types of oligodendrocytes—oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs)––isolated from the brain of neonatal rats. In addition, mice were exposed to ultrafine DEP suspension (20 μL, 0.4 mg/mL) via the nasal route for 1 week, after which the expression of NOX2 and cleaved caspase-3 was examined in the white matter of the cerebellum. Exposure to DEPs significantly increased NOX2 expression and ROS generation in OPCs and mOLs. OPCs and mOLs clearly exhibited viability reduction, and a significant change in p53, Bax, Bcl-2, and cleaved caspase-3 expression, after DEP exposure. In contrast, treatment with berberine (BBR), an NOX2 inhibitor, significantly mitigated these effects. In mice exposed to DEP, the presence of NOX2-positive and cleaved caspase-3-positive oligodendrocytes was demonstrated in the cerebellar white matter; NOX2 and cleaved caspase-3 expression in the cerebellum lysates was significantly increased. BBR treatment returned expression of these proteins to control levels. These results demonstrate that the susceptibility of OPCs and mOLs to ultrafine DEPs is, at least in part, caused by excessive ROS produced by NOX2 and the sequential changes in the expression of p53, Bax, Bcl-2, and cleaved caspase-3. Overall, NOX2 inhibitor enhances the survival of two types of oligodendrocytes.
Mitochondrial ROS, ER Stress, and Nrf2 Crosstalk in the Regulation of Mitochondrial Apoptosis Induced by Arsenite
Authors: Cantoni Orazio , Zito Ester , Guidarelli Andrea , Fiorani Mara , Ghezzi Pietro
Published: May 2022

Long-term ingestion of arsenicals, a heterogeneous group of toxic compounds, has been associated with a wide spectrum of human pathologies, which include various malignancies. Although their mechanism of toxicity remains largely unknown, it is generally believed that arsenicals mainly produce their effects via direct binding to protein thiols and ROS formation in different subcellular compartments. The generality of these mechanisms most probably accounts for the different effects mediated by different forms of the metalloid in a variety of cells and tissues. In order to learn more about the molecular mechanisms of cyto- and genotoxicity, there is a need to focus on specific arsenic compounds under tightly controlled conditions. This review focuses on the mechanisms regulating the mitochondrial formation of ROS after exposure to low concentrations of a specific arsenic compound, NaAsO2, and their crosstalk with the nuclear factor (erythroid-2 related) factor 2 antioxidant signaling and the endoplasmic reticulum stress response.
Ganoderma lucidum Modulates Glucose, Lipid Peroxidation and Hepatic Metabolism in Streptozotocin-Induced Diabetic Pregnant Rats
Authors: Viroel Fabia Judice Marques , Laurino Leticia Favara , Caetano Érika Leão Ajala , Jozala Angela Faustino , Spim Sara Rosicler Vieira , Pickler Thaisa Borim , Sercundes Michelle Klein , Gomes Marcela C. , Hataka Alessandre , Grotto Denise , Gerenutti Marli
Published: May 2022

The consumption of functional foods, such as mushrooms, apparently influences Gestational Diabetes Mellitus (GDM), and brings benefits to maternal-fetal health. Ganoderma lucidum contains a variety of bioactive compounds, such as polysaccharides, proteins and polyphenols that are able to control blood glucose and be used in anti-cancer therapy. We aimed to evaluate the effects of the consumption of Ganoderma lucidum (Gl) on maternal-fetal outcomes in streptozotocin-induced GDM (GDM-STZ). Pregnant rats were exposed to Gl (100 mg/kg/day) before and after the induction of GDM-STZ (single dose 40 mg/kg) on the eighth pregnancy day. Biochemical and oxidative stress parameters, reproductive performance and morphometry of fetuses were assessed. Gl reduced the glycemic response in the oral glucose tolerance test. Moreover, Gl decreased AST and ALT activities. GDM increased lipid peroxidation, which was reverted by Gl. Catalase and glutathione peroxidase activities were decreased in GDM and the administered Gl after the fetus implantation increased catalase activity. Measurements of the fetal head, thorax, craniocaudal and tail showed greater values in fetuses from rats exposed to Gl compared to GDM. Ganoderma lucidum has an encouraging nutritional and medicinal potential against GDM, since it modifies glucose metabolism, reduces lipid peroxidation, and has protective effects in fetuses born from GDM dams.
Hybrid Modeling of Deformable Linear Objects for Their Cooperative Transportation by Teams of Quadrotors
Authors: Estevez Julian , Lopez-Guede Jose Manuel , Garate Gorka , Graña Manuel
Published: May 2022

This paper deals with the control of a team of unmanned air vehicles (UAVs), specifically quadrotors, for which their mission is the transportation of a deformable linear object (DLO), i.e., a cable, hose or similar object in quasi-stationary state, while cruising towards destination. Such missions have strong industrial applications in the transportation of hoses or power cables to specific locations, such as the emergency power or water supply in hazard situations such as fires or earthquake damaged structures. This control must be robust to withstand strong and sudden wind disturbances and remain stable after aggressive maneuvers, i.e., sharp changes of direction or acceleration. To cope with these, we have previously developed the online adaptation of the proportional derivative (PD) controllers of the quadrotors thrusters, implemented by a fuzzy logic rule system that experienced adaptation by a stochastic gradient rule. However, sagging conditions appearing when the transporting drones are too close or too far away induce singularities in the DLO catenary models, breaking apart the control system. The paper’s main contribution is the formulation of the hybrid selective model of the DLO sections as either catenaries or parabolas, which allows us to overcome these sagging conditions. We provide the specific decision rule to shift between DLO models. Simulation results demonstrate the performance of the proposed approach under stringent conditions.
Interaction Effect of Room Size and Opening on Trombe Wall Performance in Sichuan–Tibet Alpine Valley Areas
Authors: Zhang Lili , Cheng Jingyue , Liu Fei , Li Haolin , Dong Zhuojun , Zhang Xuemei , Wang Kai , Tian Lei , Liu Haoru , Wan Jiangjun , Tian Congshan
Published: May 2022

The Trombe wall (T-wall) system is one of the most effective systems for passive solar energy utilization technology, which is of great significance for the alleviation of the energy crisis and the protection of the environment. Taking as an example Tibetan dwellings in the Sichuan–Tibet alpine valley which have installed T-walls for heating, the effects of the length of the room (Factor A), the width of the room (Factor B), the width of the opening on the north wall of the room (Factor C), and the distance from the lower edge of the opening to the floor (Factor D) on the indoor air temperature and room energy consumption are studied by orthogonal experiment and numerical simulation. Results show that the four factors all have a significant effect on the two analysis indicators. The rankings of the factors are consistent for their impact on the two analysis indicators, as, in both cases, Factor A > Factor B > Factor C > Factor D. Therefore, the influence of room configuration cannot be ignored in the optimization of T-wall design. Additionally, the optimal parameter combination for the highest indoor temperature and low energy consumption in winter is also proposed. This research can further improve the study of T-walls, and provide a reference for the thermal environment design of buildings.
Elastic Reverse Time Migration for Weakly Illuminated Structure
Authors: Song Liwei , Shi Ying , Liu Wei , Zhao Qiang
Published: May 2022

One of the most effective techniques to obtain PP and PS images is elastic reverse time migration which employs multi-component seismic data. The two types of complementary images play an important role in reducing blind spots in seismic exploration. However, the migration image of deep structures is always blurred due to the shielding effect of overburden rock on seismic waves. To overcome this issue, we develop an elastic reverse time migration approach for insufficient illumination. This approach contains two crucial elements. The first is that we derive an elastic wave equation to extract the wavefields associated with the exploration target using the staining algorithm. Secondly, we develop an inner product imaging condition with a filter to mute migrated artifacts. The filter, consisting of two vectors, determines which part of the wavefield is contributed to imaging. Synthetic examples exhibit that the proposed elastic reverse time migration method can improve the signal-to-noise ratio of PP and PS images of weakly illuminated structures.
Numerical Analysis of the Calcaneal Nail C-NAIL
Authors: Sejda František , Frydrýšek Karel , Pleva Leopold , Pompach Martin , Hlinka Josef , Sadílek Marek , Murčinková Zuzana , Krpec Pavel , Havlíček Miroslav , Madeja Roman , Pometlová Jana , Učeň Oldřich , Dostálová Kamila
Published: May 2022

The presented article investigates the biomechanics of the calcaneal nail C-NAILTM by numerical calculations and, partially, experimentally. This nail is widely used in trauma and orthopaedics. A numerical model of implants directly interacting with the bone tissue model obtained from CT scans was calculated. The material properties of the bone tissue can be described by several models; in this work, a non-homogeneous material model with isotropic elements and prescribed elastic modulus was used to provide a more accurate model of the applied force distribution on the individual parts of the implants. The critical areas of the nail and its fixtures were investigated using finite element strength calculations to verify their strength and reliability, contributing to the safety and faster and easier treatment of patients. These analyses suggest that the strength of the calcaneal nail C-NAIL, as well as the stabilization of bone fragments resulting from its use, are sufficient for clinical practice.
Bionic Design of the Vertical Bracket of Wide Angle Auroral Imager by Additive Manufacturing
Authors: Li Hang , Liu Ruiyao , He Shuai , Xin Renlong , Wang Haijun , Yu Zhenglei , Xu Zhenbang
Published: May 2022

In the aerospace field, lightweight design is a never-ending pursuit. By integrating structural bionics and structural optimization, the vertical bracket of a wide angle auroral imager is designed and manufactured by additive manufacturing technology in this work. Initially, the classical topology optimization is utilized for the vertical bracket to find the optimal material layout and primary load carrying paths. Drawing on the width-to-diameter ratio and the bone mineral density distribution of human femur, the vertical support is designed as a bionic structure with a solid middle section and thin wall in other parts. Afterwards, size optimization is maintained for the bionic design model to obtain the optimal model. The simulation results show that the three-way eigenfrequencies of bionic optimized structure are 320 Hz, 303 Hz, and 765 Hz, respectively, which are closely approximate to the original structure. However, the mass of bionic optimized structure is reduced by 23%. Benefiting from Selective laser melting, the complex optimized design can be rapidly manufactured. The three-way eigenfrequencies of the optimized structure measured by the 0.2 g sweep tests are 307 Hz, 292 Hz, and 736 Hz, respectively. The vibration test of bionic optimized structure verifies the accuracy of the simulation results. This study indicates that the combination of structural bionics and structural optimization provides a powerful tool kit to the design of similar support structure for space applications.
Fourier and Chirp-Z Transforms in the Estimation Values Process of Horizontal and Vertical Synchronization Frequencies of Graphic Displays
Authors: Kubiak Ireneusz , Przybysz Artur
Published: May 2022

The electromagnetic protection of IT devices includes a number of organizational and technical measures aimed at ensuring control over radiated and conducted revealing emissions. This is of particular importance for ensuring information security in wireless communication and the processing of data presented in graphic form. In each of these cases, the occurring electromagnetic emissions pose the risk of a lack of electromagnetic immunity to the so-called eavesdropping process based on forming revealing emissions. Included in the elements of the security chain preventing electromagnetic eavesdropping on wireless communication and the devices building such systems are activities related to the determination of the Technical Device Security Level (TDSL) or its class. The above is related to the performance of electromagnetic emissions tests and identifying which of them must be treated as revealing emissions, which are only disturbances and do not threaten the security of the processed information. It is intuitively understandable that it is particularly important to ensure the security of interfaces that process video data. The nature of the electromagnetic emission signals generated by these interfaces means that the related information can be intercepted with the use of relatively simple methods, and under favorable circumstances even with the use of a receiving device not very technologically advanced. In the case of the electromagnetic safety assessment of video devices, common practice is therefore activities aimed at reconstructing information related to the video signal. This requires the parameters of the reconstructed image appropriate for the eavesdropped device operation mode and the conditions of recording the revealing emission signals to be determined. The article presents the results of works related to the analysis of the possibility of using spectral analysis methods (Fast Fourier FFT transform and Chirp-Z transform) to automate the process of determining the above-mentioned parameters in the case of reproducing images from emission signals recorded by using the ADC analog-to-digital converter.
Intelligent Prediction of Stuck Pipe Using Combined Data-Driven and Knowledge-Driven Model
Authors: Zhu Shuo , Song Xianzhi , Zhu Zhaopeng , Yao Xuezhe , Liu Muchen
Published: May 2022

Stuck pipe phenomena can have disastrous effects on drilling performance, with outcomes that can range from time delays to loss of expensive machinery. In this work, we provide three methods for the prediction of stuck pipe. The first method targets the detection of friction coefficient which can represent the trend of stuck pipe. The second method targets the prediction of probability for stuck pipe using ANN (artificial neural network). The last model establishes a comprehensive indicator based on the first and the second method using fuzzy mathematics which can give more accurate probability for stuck pipe. The results show that the best model is the last one which can predict stuck pipe events with a F1 of 0.98 and a FAR (false alarm rate) of 1%. Preliminary experimental results on the available dataset indicate that the use of the proposed model and can help mitigate the stuck pipe issue.
Estimation of Thickness and Speed of Sound for Transverse Cortical Bone Imaging Using Phase Aberration Correction Methods: An In Silico and Ex Vivo Validation Study
Authors: Nguyen Minh Huong , Muller Marie , Raum Kay
Published: May 2022

Delay-and-sum (DAS) beamforming of backscattered echoes is used for conventional ultrasound imaging. Although DAS beamforming is well suited for imaging in soft tissues, refraction, scattering, and absorption, porous mineralized tissues cause phase aberrations of reflected echoes and subsequent image degradation. The recently developed refraction corrected multi-focus technique uses subsequent focusing of waves at variable depths, the tracking of travel times of waves reflected from outer and inner cortical bone interfaces, the estimation of the shift needed to focus from one interface to another to determine cortical thickness (Ct.Th), and the speed of sound propagating in a radial bone direction (Ct.ν11). The method was validated previously in silico and ex vivo on plate shaped samples. The aim of this study was to correct phase aberration caused by bone geometry (i.e., curvature and tilt with respect to the transducer array) and intracortical pores for the multi-focus approach. The phase aberration correction methods are based on time delay estimation via bone geometry differences to flat bone plates and via the autocorrelation and cross correlation of the reflected ultrasound waves from the endosteal bone interface. We evaluate the multi-focus approach by incorporating the phase aberration correction methods by numerical simulation and one experiment on a human tibia bone, and analyze the precision and accuracy of measuring Ct.Th and Ct.ν11. Site-matched reference values of the cortical thickness of the human tibia bone were obtained from high-resolution peripheral computed tomography. The phase aberration correction methods resulted in a more precise (coefficient of variation of 5.7%) and accurate (root mean square error of 6.3%) estimation of Ct.Th, and a more precise (9.8%) and accurate (3.4%) Ct.ν11 estimation, than without any phase aberration correction. The developed multi-focus method including phase aberration corrections provides local estimations of both cortical thickness and sound velocity and is proposed as a biomarker of cortical bone quality with high clinical potential for the prevention of osteoporotic fractures.
Heat and Flow Study of the Internally Finned Tubes with Different Fin Geometries
Authors: Bellos Evangelos , Lykas Panagiotis , Tzivanidis Christos
Published: May 2022

Heat and flow enhancement is a critical weapon for the design of highly efficient, compact, and cost-effective devices. The objective of this analysis is the detailed examination of the implementation of different fin shapes on the internal side of a tube aiming the heat and flow enhancement. The reference empty tube is examined, while the use of circular, rectangular, and triangular fins is also studied. Different simulations were conducted with a developed computational fluid dynamic model, and the results were expressed in heat and flow terms. The developed model was validated by comparing the results with the theoretical expressions for the Nusselt number, as well as for the friction factor. The obtained results were evaluated by calculating the heat convection coefficient, the pressure drop, the Nusselt number, the friction factor, the pump work, the mean wall temperature, and the Bejan number. According to the calculations, the use of rectangular fins is the best solution; the use of triangular fins is the second choice, while the less efficient improvement method is the use of circular internal fins. Regarding the heat transfer enhancement, the rectangular fins lead to 36% enhancement, circular fins to 25%, and triangular fins to 23% compared to the reference tube.
A Deep Learning Approach for the Morphological Recognition of Reactive Lymphocytes in Patients with COVID-19 Infection
Authors: Rodellar José , Barrera Kevin , Alférez Santiago , Boldú Laura , Laguna Javier , Molina Angel , Merino Anna
Published: May 2022

Laboratory medicine plays a fundamental role in the detection, diagnosis and management of COVID-19 infection. Recent observations of the morphology of cells circulating in blood found the presence of particular reactive lymphocytes (COVID-19 RL) in some of the infected patients and demonstrated that it was an indicator of a better prognosis of the disease. Visual morphological analysis is time consuming, requires smear review by expert clinical pathologists, and is prone to subjectivity. This paper presents a convolutional neural network system designed for automatic recognition of COVID-19 RL. It is based on the Xception71 structure and is trained using images of blood cells from real infected patients. An experimental study is carried out with a group of 92 individuals. The input for the system is a set of images selected by the clinical pathologist from the blood smear of a patient. The output is the prediction whether the patient belongs to the group associated with better prognosis of the disease. A threshold is obtained for the classification system to predict that the smear belongs to this group. With this threshold, the experimental test shows excellent performance metrics: 98.3% sensitivity and precision, 97.1% specificity, and 97.8% accuracy. The system does not require costly calculations and can potentially be integrated into clinical practice to assist clinical pathologists in a more objective smear review for early prognosis.
GJB2 Is a Major Cause of Non-Syndromic Hearing Impairment in Senegal
Authors: Dia Yacouba , Adadey Samuel Mawuli , Diop Jean Pascal Demba , Aboagye Elvis Twumasi , Ba Seydi Abdoul , De Kock Carmen , Ly Cheikh Ahmed Tidjane , Oluwale Oluwafemi Gabriel , Sène Andrea Regina Gnilane , Sarr Pierre Diaga , Diallo Bay Karim , Diallo Rokhaya Ndiaye , Wonkam Ambroise
Published: May 2022

This study aimed to investigate GJB2 (MIM: 121011) and GJB6 (MIM: 604418) variants associated with familial non-syndromic hearing impairment (HI) in Senegal. We investigated a total of 129 affected and 143 unaffected individuals from 44 multiplex families by segregating autosomal recessive non-syndromic HI, 9 sporadic HI cases of putative genetic origin, and 148 control individuals without personal or family history of HI. The DNA samples were screened for GJB2 coding-region variants and GJB6-D3S1830 deletions. The mean age at the medical diagnosis of the affected individuals was 2.93 ± 2.53 years [range: 1–15 years]. Consanguinity was present in 40 out of 53 families (75.47%). Variants in GJB2 explained HI in 34.1% (n = 15/44) of multiplex families. A bi-allelic pathogenic variant, GJB2: c.94C>T: p.(Arg32Cys) accounted for 25% (n = 11/44 families) of familial cases, of which 80% (n = 12/15) were consanguineous. Interestingly, the previously reported “Ghanaian” founder variant, GJB2: c.427C>T: p.(Arg143Trp), accounted for 4.5% (n = 2/44 families) of the families investigated. Among the normal controls, the allele frequency of GJB2: c.94C>T and GJB2: c.427C>T was estimated at 1% (2/148 ∗ 2) and 2% (4/148 ∗ 2), respectively. No GJB6-D3S1830 deletion was identified in any of the HI patients. This is the first report of a genetic investigation of HI in Senegal, and suggests that GJB2: c.94C>T: p.(Arg32Cys) and GJB2: c.427C>T: p.(Arg143Trp) should be tested in clinical practice for congenital HI in Senegal.
Detection of the Synthetic Cannabinoids AB-CHMINACA, ADB-CHMINACA, MDMB-CHMICA, and 5F-MDMB-PINACA in Biological Matrices: A Systematic Review
Authors: Navarro-Tapia Elisabet , Codina Jana , Villanueva-Blasco Víctor José , García-Algar Óscar , Andreu-Fernández Vicente
Published: May 2022

New synthetic cannabinoids (SCs) are emerging rapidly and continuously. Biological matrices are key for their precise detection to link toxicity and symptoms to each compound and concentration and ascertain consumption trends. The objective of this study was to determine the best human biological matrices to detect the risk-assessed compounds provided by The European Monitoring Centre for Drugs and Drug Addiction: AB-CHMINACA, ADB-CHMNACA, MDMB-CHMICA, and 5F-MDMB-PINACA. We carried out a systematic review covering 2015 up to the present date, including original articles assessing detection in antemortem human biological matrices with detailed validation information of the technique. In oral fluid and blood, SC parent compounds were found in oral fluid and blood at low concentrations and usually with other substances; thus, the correlation between SCs concentrations and severity of symptoms could rarely be established. When hair is used as the biological matrix, there are difficulties in excluding passive contamination when evaluating chronic consumption. Detection of metabolites in urine is complex because it requires prior identification studies. LC-MS/MS assays were the most widely used approaches for the selective identification of SCs, although the lack of standard references and the need for revalidation with the continuous emergence of new SCs are limiting factors of this technique. A potential solution is high-resolution mass spectrometry screening, which allows for non-targeted detection and retrospective data interrogation.
An Insight Based on Computational Analysis of the Interaction between the Receptor-Binding Domain of the Omicron Variants and Human Angiotensin-Converting Enzyme 2
Authors: Celik Ismail , Abdellattif Magda H. , Tallei Trina Ekawati
Published: May 2022

Concerns have been raised about the high number of mutations in the spike protein of the new emergence of the highly transmissible Omicron variant (B.1.1529 lineage) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This variant’s extraordinary ability to evade antibodies would significantly impair the current vaccination program. This present study aimed to computationally analyze the interaction between the receptor-binding domain (RBD) in the spike protein of Omicron variants and human angiotensin-converting enzyme 2 (hACE2). The docking results indicated that Omicron BA.2 has exceptionally strong interactions with hACE2 in comparison to Omicron BA.1, Delta, and wild-type, as indicated by various parameters such as salt bridge, hydrogen bond, and non-bonded interactions. The results of the molecular dynamics simulation study corroborate these findings, indicating that Omicron BA.2 has a strong and stable interaction with hACE2. This study provides insight into the development of an effective intervention against this variant.
Epstein–Barr Virus Association with Breast Cancer: Evidence and Perspectives
Authors: Arias-Calvachi Claudia , Blanco Rancés , Calaf Gloria M. , Aguayo Francisco
Published: May 2022

Epstein–Barr virus (EBV) is an enveloped DNA virus that belongs to the gamma Herpesviridae family. The virus establishes a latent/lytic persistent infection, though it can be involved in cancer development in some subjects. Indeed, evidence supports an etiological role of EBV in undifferentiated nasopharyngeal carcinoma (NPC), a subset of gastric carcinomas and lymphomas. Additionally, EBV has been detected in breast carcinomas (BCs) although its role has not been established. In this review, we summarize epidemiological information regarding the presence of EBV in BC and we propose mechanistic models. However, additional epidemiological and experimental evidence is warranted to confirm these models.
Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A165 No Longer Depends on the Growth Factor’s Presence
Authors: Deissler Heidrun L. , Rehak Matus , Wolf Armin
Published: May 2022

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A165 depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes—determined as a measure of permeability—was persistently reduced by exposure to the growth factor. Late after addition of VEGF-A165 protein levels of claudin-1 and CD49e were significantly lower, those of CD29 significantly higher, and the plasmalemma vesicle associated protein was no longer detected. Nuclear levels of β-catenin were only elevated on day two. Extracellular levels of VEGF-A—measured by ELISA—were very low. Similar to the binding of the growth factor by brolucizumab, inhibition of VEGFR2 by tyrosine kinase inhibitors tivozanib or nintedanib led to complete, although transient, recovery of the low cell index when added early, though was inefficient when added three or six days later. Additional inhibition of other receptor tyrosine kinases by nintedanib was similarly unsuccessful, but additional blocking of c-kit by tivozanib led to sustained recovery of the low cell index, an effect observed only when the inhibitor was added early. From these data, we conclude that several days after the addition of VEGF-A165 to iBREC, barrier dysfunction is mainly sustained by increased paracellular flow and impaired adhesion. Even more important, these changes are most likely no longer VEGF-A-controlled.
Hyperhomocysteinemia Increases Cortical Excitability and Aggravates Mechanical Hyperalgesia and Anxiety in a Nitroglycerine-Induced Migraine Model in Rats
Authors: Gerasimova Elena , Yakovleva Olga , Enikeev Daniel , Bogatova Ksenia , Hermann Anton , Giniatullin Rashid , Sitdikova Guzel
Published: May 2022

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal hyperhomocysteinemia (hHCY) in respect of the development of behavioral correlates of headache and spreading cortical depolarization (CSD) in a migraine model induced by the administration of the nitric oxide (NO) donor nitroglycerin. Animals with hHCY were characterized by migraine-related symptoms such as mechanical hyperalgesia, high-level anxiety, photophobia, as well as an enhanced level of neuronal activity in the somatosensory cortex along with a lower threshold of CSD generation. Likewise, acute or chronic intermittent administration of nitroglycerin also induced the development of mechanical allodynia, photophobia and anxiety in control groups. However, these symptoms were more pronounced in rats with hHCY. Unlike hHCY, nitroglycerin administration did not affect the threshold of CSD generation, but like hHCY, increased the background neuronal activity in layers 2/3 and 4 of the cerebral cortex. The latter was more pronounced in animals with hHCY. Thus, the migraine profile associated with hHCY can be further exaggerated in conditions with enhanced levels of migraine triggering the gaseous transmitter NO. Our data are consistent with the view that high levels of plasma homocysteine can act as a risk factor for the development of migraine.
Reduced Platelet MAO-B Activity Is Associated with Psychotic, Positive, and Depressive Symptoms in PTSD
Authors: Repovecki Senka , Nedic Erjavec Gordana , Uzun Suzana , Tudor Lucija , Nikolac Perkovic Matea , Konjevod Marcela , Kozumplik Oliver , Svob Strac Dubravka , Kovacic Petrovic Zrnka , Mimica Ninoslav , Pivac Nela
Published: May 2022

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms.
Innate Immunity: A Balance between Disease and Adaption to Stress
Authors: Faenza Irene , Blalock William L.
Published: May 2022

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation.
Generation of hiPSC-Derived Skeletal Muscle Cells: Exploiting the Potential of Skeletal Muscle-Derived hiPSCs
Authors: Metzler Eric , Escobar Helena , Sunaga-Franze Daniele Yumi , Sauer Sascha , Diecke Sebastian , Spuler Simone
Published: May 2022

Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such as cachexia or intensive care unit (ICU)-acquired weakness. We asked how the cell of origin influences efficacy and molecular properties of hiPSC-derived muscle progenitor cells. We generated hiPSCs from primary muscle stem cells and from peripheral blood mononuclear cells (PBMCs) of the same donors (n = 4) and compared their molecular profiles, myogenic differentiation potential, and ability to generate new muscle fibers in vivo. We show that reprogramming into hiPSCs from primary muscle stem cells was faster and 35 times more efficient than from blood cells. Global transcriptome comparison revealed significant differences, but differentiation into induced myogenic cells using a directed transgene-free approach could be achieved with muscle- and PBMC-derived hiPSCs, and both cell types generated new muscle fibers in vivo. Differences in myogenic differentiation efficiency were identified with hiPSCs generated from individual donors. The generation of muscle-stem-cell-derived hiPSCs is a fast and economic method to obtain unrestricted cell numbers for cell-based therapies in muscle wasting disorders, and in this aspect are superior to blood-derived hiPSCs.
Solid Magnetoliposomes as Multi-Stimuli-Responsive Systems for Controlled Release of Doxorubicin: Assessment of Lipid Formulations
Authors: Cardoso Beatriz D. , Cardoso Vanessa F. , Lanceros-Méndez Senetxu , Castanheira Elisabete M. S.
Published: May 2022

Stimuli-responsive liposomes are a class of nanocarriers whose drug release occurs, preferentially, when exposed to a specific biological environment, to an external stimulus, or both. This work is focused on the design of solid magnetoliposomes (SMLs) as lipid-based nanosystems aiming to obtain multi-stimuli-responsive vesicles for doxorubicin (DOX) controlled release in pathological areas under the action of thermal, magnetic, and pH stimuli. The effect of lipid combinations on structural, colloidal stability, and thermodynamic parameters were evaluated. The results confirmed the reproducibility for SMLs synthesis based on nine lipid formulations (combining DPPC, DSPC, CHEMS, DOPE and/or DSPE-PEG), with structural and colloidal properties suitable for biological applications. A loss of stability and thermosensitivity was observed for formulations containing dioleoylphosphatidylethanolamine (DOPE) lipid. SMLs PEGylation is an essential step to enhance both their long-term storage stability and stealth properties. DOX encapsulation (encapsulation efficiency ranging between 87% and 96%) in the bilayers lowered its pKa, which favors the displacement of DOX from the acyl chains to the surface when changing from alkaline to acidic pH. The release profiles demonstrated a preferential release at acidic pH, more pronounced under mimetic mild-hyperthermia conditions (42 °C). Release kinetics varied with the lipid formulation, generally demonstrating hyperthermia temperatures and acidic pH as determining factors in DOX release; PEGylation was shown to act as a diffusion barrier on the SMLs surface. The integrated assessment and characterization of SMLs allows tuning lipid formulations that best respond to the needs for specific controlled release profiles of stimuli-responsive nanosystems as a multi-functional approach to cancer targeting and therapy.
OncoPan®: An NGS-Based Screening Methodology to Identify Molecular Markers for Therapy and Risk Assessment in Pancreatic Ductal Adenocarcinoma
Authors: Tibiletti Maria Grazia , Carnevali Ileana , Pensotti Valeria , Chiaravalli Anna Maria , Facchi Sofia , Volorio Sara , Mariette Frederique , Mariani Paolo , Fortuzzi Stefano , Pierotti Marco Alessandro , Sessa Fausto
Published: May 2022

Pancreatic cancer has a high morbidity and mortality with the majority being PC ductal adenocarcinomas (PDAC). Whole genome sequencing provides a wide description of genomic events involved in pancreatic carcinogenesis and identifies putative biomarkers for new therapeutic approaches. However, currently, there are no approved treatments targeting driver mutations in PDAC that could produce clinical benefit for PDAC patients. A proportion of 5–10% of PDAC have a hereditary origin involving germline variants of homologous recombination genes, such as Mismatch Repair (MMR), STK11 and CDKN2A genes. Very recently, BRCA genes have been demonstrated as a useful biomarker for PARP-inhibitor (PARPi) treatments. In this study, a series of 21 FFPE PDACs were analyzed using OncoPan®, a strategic next-generation sequencing (NGS) panel of 37 genes, useful for identification of therapeutic targets and inherited cancer syndromes. Interestingly, this approach, successful also on minute pancreatic specimens, identified biomarkers for personalized therapy in five PDAC patients, including two cases with HER2 amplification and three cases with mutations in HR genes (BRCA1, BRCA2 and FANCM) and potentially eligible to PARPi therapy. Molecular analysis on normal tissue identified one PDAC patient as a carrier of a germline BRCA1 pathogenetic variant and, noteworthy, this patient was a member of a family affected by inherited breast and ovarian cancer conditions. This study demonstrates that the OncoPan® NGS-based panel constitutes an efficient methodology for the molecular profiling of PDAC, suitable for identifying molecular markers both for therapy and risk assessment. Our data demonstrate the feasibility and utility of these NGS analysis in the routine setting of PDAC molecular characterization.
Tamoxifen Ameliorates Cholestatic Liver Fibrosis in Mice: Upregulation of TGFβ and IL6 Is a Potential Protective Mechanism
Authors: Šisl Dino , Flegar Darja , Filipović Maša , Turčić Petra , Planinić Pavao , Šućur Alan , Kovačić Nataša , Grčević Danka , Kelava Tomislav
Published: May 2022

The available treatments for cholestatic liver fibrosis are limited, and the disease often progresses to liver cirrhosis. Tamoxifen is a selective modulator of estrogen receptors, commonly used in breast cancer therapy. A recent in vitro study showed that tamoxifen deactivates hepatic stellate cells, suggesting its potential as an antifibrotic therapeutic, but its effects in vivo remain poorly investigated. In the present study, we show that tamoxifen protects against the cholestatic fibrosis induced by a diet supplemented with 0.025% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Mice fed with a DDC-supplemented diet for four weeks and treated with tamoxifen developed a significantly milder degree of liver fibrosis than vehicle-treated mice, as evidenced by a lower percentage of Sirius red-stained area (60.4% decrease in stained area in male and 42% decrease in female mice, p < 0.001 and p < 0.01, respectively) and by lower hydroxyproline content. The finding was further confirmed by qPCR analysis, which showed a lower expression of genes for Col1a1, Acta2, Sox9, Pdgf, and Krt19, indicating the inhibitory effect on hepatic stellate cells, collagen production, and biliary duct proliferation. The degree of protection was similar in male and female mice. Tamoxifen per se, injected into standard-diet-fed mice, increased the expression of genes for Il6 (p < 0.01 and p < 0.001 in male and female mice, respectively) and Tgfβ (p < 0.01 for both sexes), and had no adverse effects. We showed that tamoxifen sex-independently protects against cholestatic DDC-induced liver fibrosis. The increased expression of Il6 and Tgfβ seems to be a plausible protective mechanism that should be the primary focus of further research.
A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics
Authors: Staropoli Nicoletta , Arbitrio Mariamena , Salvino Angela , Scionti Francesca , Ciliberto Domenico , Ingargiola Rossana , Labanca Caterina , Agapito Giuseppe , Iuliano Eleonora , Barbieri Vito , Cucè Maria , Zuccalà Valeria , Cannataro Mario , Tassone Pierfrancesco , Tagliaferri Pierosandro
Published: May 2022

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an “inflammatory-score” and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.